disorders of sodium balance

Disorders of Sodium BalanceItzchak N. Slotki and Karl L. Skorecki

Chapter

14

Physiology, 464Sodium Balance, 465Effective Arterial Blood Volume, 465Regulation of Effective Arterial Blood Volume, 466

Sodium Balance Disorders, 491Hypovolemia, 491Hypervolemia, 495

Specific Treatments Based on the Pathophysiology of Congestive Heart Failure, 521Inhibition of Renin-Angiotensin-Aldosterone System, 521β-Blockade, 521Nitric Oxide Donor and Reactive Oxygen

Species/Peroxynitrite Scavengers, 521

Endothelin Antagonists, 521Natriuretic Peptides, 522Neutral Endopeptidase Inhibitors and Vasopeptidase

Inhibitors, 522Vasopressin Receptor Antagonists, 522

Specific Treatments Based on the Pathophysiology of Sodium Retention in Cirrhosis, 523Pharmacologic Treatment, 523Transjugular Intrahepatic

Portosystemic Shunt, 525Renal Replacement Therapy, 525Liver Transplantation, 526

464

Sodium (Na+) and water balance and their distribution among the various body compartments are essential for the mainte-nance of fluid homeostasis, particularly intravascular volume. Disturbances of either or both of these components have serious medical consequences, are relatively frequent, and are among the most common conditions encountered in hospital clinical practice. In fact, abnormalities of Na+ and water bal-ance are responsible for, or associated with, a wide spectrum of medical and surgical admissions or complications. The principal disorders of Na+ balance are manifested clinically as either hypovolemia or hypervolemia, whereas disruption in water balance can be diagnosed only in the laboratory as either hyponatremia or hypernatremia. Although disorders of Na+ and water balance are often interrelated, the latter are con-sidered in a separate chapter. In this chapter the physiologic and pathophysiologic features of Na+ balance are discussed. Because Na+ is restricted predominantly to the extracellular compartment, this chapter also addresses perturbations of extracellular fluid (ECF) volume homeostasis.

Physiology

Approximately 60% of adult body mass is composed of sol-ute-containing fluids that can be divided into extracellular and intracellular compartments. Because water flows freely across

cell membranes in accordance with the prevailing osmotic forces on either side of the membrane, the solute/water ratios in the intracellular fluid (ICF) and ECF are almost equal. How-ever, the solute compositions of the ICF and ECF are quite different, as shown in Figure 14-1. The principal ECF cation is sodium; minor cations are potassium (K+), calcium, and mag-nesium. In contrast, potassium is the major ICF cation. The accompanying anions in the ECF are chloride, bicarbonate, and plasma proteins (mainly albumin), whereas electroneutrality of the ICF is maintained by phosphate and the negative charges on organic molecules. The difference in cationic composition of the two compartments is maintained by a pump-leak mecha-nism consisting of sodium-potassium adenosine triphosphatase (Na+-K+-ATPase), which operates in concert with sodium and potassium conductance pathways in the cell membrane.

The free movement of water across the membrane ensures that the ECF and ICF osmolalities are the same. However, the intracellular volume is greater because the amount of potassium salts inside the cell is larger than that of sodium salts outside the cell. The movement of water is determined by the “effective osmolality,” or tonicity, of each compart-ment, so that if tonicity of the ECF rises—for example, as a result of excess Na+—water will move from the ICF to ECF to restore tonicity. On the other hand, addition of solute-free water leads to a proportionate decrease in both osmolality and tonicity of all body fluid compartments (see Chapter 15 for

Chapter 14 Disorders of Sodium Balance 465

Intravascular

Interstitial

ECFVvs.

capacitance

Lymphatic return

Na+ intake

Normaosmoregulation

Net Na+ balance

Renal Na+

excretion

Extrarenallosses

Filtered load vtubular reabsorption

Effectormechanisms

Sensingmechanisms

−−

+

+FIGURE 14-1 Overall scheme for body sodium balance and partitioning of extracellular fluid volume (ECFV). In the setting of normal osmoregulation, extracellular Na+ content is the primary determinant of ECFV. Overall Na+ homeostasis depends on the balance between losses (extrarenal and renal) and intake. Renal Na+ excretion is determined by the balance between filtered load and tubule reabsorption. This latter balance is modulated under the influence of effector mechanisms, which, in turn, are respon-sive to sensing mechanisms that monitor the relation between ECFV and capacitance. In rats, a high-salt diet leads to intersti-tial hypertonic Na+ accumulation in skin, resulting in increased density and hyperplasia of the lymphatic capillary network.

detailed discussion). The restriction of Na+ to the ECF com-partment by the pump-leak mechanism, in combination with maintenance of the osmotic equilibrium between ECF and ICF, ensures that ECF volume is determined mainly by total body Na+ content.

The same mechanisms also govern the partitioning of fluid between the two compartments and are crucial for preserva-tion of near constancy of ECF and ICF volume in the pres-ence of variations in dietary intake and extrarenal losses of Na+ and water. In order to maintain constancy of the ECF and ICF and thereby safeguard hemodynamic stability, cell volume, and solute composition, even minute changes in these parameters can be detected by a number of sensing mecha-nisms. These sensory signals lead to activation of neural and hormonal factors, which, in turn, cause appropriate adjust-ments in urinary Na+ and water excretion and, hence, resto-ration of fluid balance. Constancy of ECF volume ensures a high degree of circulatory stability, whereas constancy of ICF volume protects against significant brain cell swelling or shrinkage.

Sodium Balance

Na+ balance is the difference between intake (diet or sup-plementary fluids) and output (renal, gastrointestinal, per-spiratory, and respiratory). In healthy humans in steady state, dietary intake is closely matched by urinary output of Na+. Thus, a person consuming a chronically low-Na+ diet (20 mmol/day, or approximately 1.2 g/day) excretes, in the steady state, a similar quantity of Na+ in the urine (minus extra-renal losses). Conversely, on a high-Na+ diet (200 mmol/day, or 12 g/day), approximately 200 mmol of Na+ is excreted in the urine. Any perturbation of this balance leads to activation of the sensory and effector mechanisms outlined in the follow-ing discussions. In practice, any deviation in ECF volume in relation to its capacitance is sensed and translated, under the influence of neural and hormonal factors, into the appropriate

change in Na+ excretion, principally through the kidneys but also, to a much lesser degree, through stool and sweat.

For normal functioning of the afferent sensing and efferent effector mechanisms that regulate ECF volume, the integrity of the intravascular and extravascular subcompartments of the ECF1 is crucial (see Figure 14-1). Although the composition and concentration of small, noncolloid electrolyte solutes in these two subcompartments are approximately equal (slight differences are due to the Gibbs-Donnan effect), the concen-tration of colloid osmotic particles (mainly albumin and glob-ulin) is higher in the intravascular compartment. The balance between transcapillary hydraulic and colloid osmotic (oncotic) gradients (Starling forces) favors the net transudation of fluid from the intravascular to interstitial compartment. However, this is countered by movement of lymphatic fluid from the interstitial to the intravascular compartment via the thoracic duct. The net effect is to restore and maintain the intravascu-lar subcompartment at 25% of the total ECF volume (corre-sponding to 3.5 L of plasma); the remaining 75% is contained in the interstitial space (equivalent to 10.5 L in a 70-kg man). The constancy of ECF volume and the appropriate parti-tioning of the fluid between intravascular and interstitial subcompartments are crucial for maintaining hemodynamic stability. In particular, intravascular volume in relation to overall vascular capacitance is a major determinant of left ventricular filling volume and, hence, cardiac output and mean arterial pressure.

Effective Arterial Blood Volume

In order to understand the mechanisms regulating ECF vol-ume, it is important to appreciate that what is sensed is the effective arterial blood volume (EABV). This can be defined as the part of the ECF in the arterial blood system that effec-tively perfuses the tissues. More specifically, in physiologic terms, what is sensed is the pressure induced by the EABV that perfuses the arterial baroceptors in the carotid sinus and

466 Section II Disorders of Body Fluid Volume and Com

glomerular afferent arterioles. Any change in perfusion pres-sure (or stretch) at these sites evokes appropriate compensa-tory responses. EABV is often, although not always, correlated with actual ECF volume and is proportional to total body Na+. This means that the regulation of Na+ balance and the maintenance of EABV are closely related functions. Na+ load-ing generally leads to EABV expansion, whereas loss leads to depletion. However, in several situations, EABV and actual blood volume are not well correlated (see Table 14-5 later in the chapter). For example, in congestive heart failure (CHF), a primary decrease in cardiac output leads to lowered pressure in the perfusion of the baroceptors; that is, reduced EABV is sensed. This leads to renal Na+ retention and ECF volume expansion. The net result is a state of increased plasma and total ECF volume, in association with reduced EABV.

The increase in plasma volume is partially appropriate in that intraventricular filling pressure rises and, by increasing myocardial stretching, leads to improved ventricular con-tractility, thereby raising cardiac output and restoring sys-temic blood pressure and baroceptor perfusion. However, this response is also maladaptive in that the elevated intraarterial pressure promotes fluid movement out of the intravascular space and into the tissues, which leads to both peripheral and pulmonary edema. In CHF, EABV is dependent on cardiac output; in other disease settings, however, these two param-eters may be dissociated. Dissociation occurs in the presence of an arteriovenous fistula, when cardiac output rises in pro-portion to the blood flow through the fistula. However, the flow through the fistula shunts blood away from the capillaries perfusing the tissues, and therefore the EABV does not rise in conjunction with the rise in cardiac output. Similarly, a fall in systemic vascular resistance—which, together with cardiac output, is a determinant of blood pressure—leads to reduc-tions in blood pressure and EABV.

Another situation in which cardiac output and EABV change in opposite directions is advanced cirrhosis with asci-tes. ECF volume expands because of the ascites, and plasma volume is increased as a result of fluid accumulation in the splanchnic venous circulation, in which the vessels are dilated but flow is sluggish. Although cardiac output may increase modestly as a result of arteriovenous shunting, marked periph-eral vasodilation leads to a fall in systemic vascular resistance, with reductions in EABV and blood pressure. In the pres-ence of reduced EABV, renal perfusion is impaired; under the influence of hormones, such as renin, norepinephrine, and antidiuretic hormone (or arginine vasopressin [AVP])—released in response to the perceived hypovolemia—further Na+ and water retention ensue (see “Efferent Limb: Effector Mechanisms for Maintaining Effective Arterial Blood Vol-ume” section).

To summarize, EABV is an unmeasured index of tissue perfusion that usually, but not always, reflects actual arterial blood volume. Therefore, EABV can be viewed as a functional parameter of organ perfusion. The diagnostic hallmark of reduced EABV is evidence of renal sodium retention, mani-fested as urinary sodium (UNa) less than 15 to 20 mmol/L. This relationship holds true with the following exceptions: If renal Na+ wasting occurs because of either diuretic therapy or intrinsic tubular disease or injury, then UNa is relatively high, despite low EABV. Conversely, the presence of selective renal or glomerular ischemia (e.g., as a result of bilateral renal artery stenosis or acute glomerular injury) will be misinterpreted as

position

indicative of poor renal perfusion and is associated with renal Na+ retention (low UNa).

Regulation of Effective Arterial Blood Volume

Regulation of EABV can be divided into two stages: affer-ent sensing and efferent effector mechanisms. A number of mechanisms for sensing low EABV exist, all of them primed to stimulate renal Na+ retention.

Afferent Limb: Sensing of Effective Arterial Blood Volume

Volume sensors are strategically situated at critical points in the circulation (Table 14-1). Each sensor reflects a specific char-acteristic of overall circulatory function so that atrial and ven-tricular sensors sense cardiac filling; arterial sensors respond to cardiac output; and renal, central nervous system (CNS), and gastrointestinal tract sensors monitor perfusion of the kidneys, brain, and gut, respectively. The common mechanism whereby volume is monitored is by physical alterations in the vessel wall such as stretch or tension. How exactly this occurs is still not fully elucidated, but the process of mechanosensing probably is dependent on both afferent sensory nerve endings in the ves-sel wall and activation of endothelial cells. Signal transduction mechanisms in endothelial cells include stretch-activated ion channels, cytoskeleton-associated protein kinases, integrin-cytoskeletal interactions, cytoskeletal-nuclear interactions, and generation of reactive oxygen species.2,3 In addition, mechanical stretch and tension of blood vessel walls, as well as the frictional forces of the circulation or shear stress, can lead to alterations in gene expression that are mediated by specific recognition sites in the upstream promoter elements of responsive genes.4,5 These signals induce efferent effector mechanisms that lead to modifi-cations in renal Na+ excretion, appropriate to the volume status.

SenSorS of CardiaC fillingAtrial Sensors. The pioneering experiments of Henry and associates6 and Goetz and colleagues7 in conscious dogs pro-vided a clear demonstration that increased atrial wall ten-sion leads to diuresis and natriuresis. The role of the atria in

TABLE 14-1 Mechanisms for Sensing Regional Changes in Effective Arterial Blood Volume

Sensors of Cardiac Filling

AtrialNeural pathwaysHumoral pathways

VentricularPulmonary

Sensors of Cardiac Output

Carotid and aortic baroceptors

Sensors of Organ Perfusion

Renal sensorsCNS sensorsGI tract sensors

Hepatic receptorsGuanylin peptides

CNS, Central nervous system; GI, gastrointestinal.

volume regulation in humans has been elucidated in experi-ments involving head-out water immersion (HWI) and expo-sure to head-down tilt or nonhypotensive lower body negative pressure (LBNP). During HWI, the increased hydrostatic pressure of the water on the lower limbs leads to redistribu-tion of the intravascular fluid from the peripheral to central circulation. The resulting increase in central blood volume causes a rise in cardiac output, which in turn produces a brisk increase in Na+ and water excretion, in an attempt to restore euvolemia.8 In contrast, LBNP results in a redistribution of blood to the lower limbs, thereby reducing central venous and cardiac filling pressures without affecting arterial pres-sure, heart rate, or atrial diameter. The resulting retention of Na+ and water occurs without any change in renal plasma flow rate (RPF).9

Central hypervolemia may not be the only mechanism of HWI-induced Na+ and water diuresis. The external hydro-static pressure of the water also reduces the hydrostatic pres-sure gradient across the capillary wall in the legs, leading to a net transfer of fluid from the interstitial to intravascular com-partment. The resulting hemodilution causes a fall in the col-loid osmotic pressure. The hemodilution effect may actually predominate, inasmuch as its abolition by placement of a tight inflated cuff (80 mm Hg) during HWI abrogates the natri-uresis.10,11 Regardless of which effect is dominant, a combina-tion of hemodilution and central hypervolemia, through atrial stretch, induces neural and humoral changes that bring about the subsequent diuresis and natriuresis.Neural Pathways. Two types of neural receptors in the atrium have been described: type A and type B. They are thought to be branching ends of small medullated fibers running in the vagus nerve. Only type B receptor activity is increased by atrial filling and stretch; type A receptors are not affected.12 The signal is then thought to travel along cranial nerves IX and X to the hypothalamic and medullary centers, where a series of responses is initiated: inhibition of AVP release (left atrial signal)13; a selective decrease in renal but not lumbar sympa-thetic nerve discharge14,15; and decreased tone in peripheral precapillary and postcapillary resistance vessels. Conversely, reduction in central venous pressure and atrial volume, as illustrated by LBNP, stimulates renal nerve activity, as assessed by renal norepinephrine spillover and plasma norepinephrine concentration.16,17

The effects just described occur in response to acute atrial stretch, whereas chronic atrial stretch leads to adaptation and downregulation of the neural responses. This phenomenon has been described in rhesus monkeys exposed to 10-degree head-down tilt. In this model, natriuresis after saline infusion occurs at lower central venous and, hence, lower cardiac filling pressures.17 Cardiac nerves appear to be essential only for res-toration of Na+ balance in states of repletion, but not for the renal response to acute volume depletion.18 For example, after human cardiac transplantation, a natural model of cardiac denervation, the expected suppression of the renin-angioten-sin-aldosterone (RAAS) system in response to chronic vol-ume expansion is not observed.19

Humoral Pathways. Cardiac denervation does not abolish the natriuresis and diuresis during atrial distension. This implies that additional factors other than cardiac nerves are involved in the response to volume repletion. The discovery of a fac-tor in atrial extracts with strong natriuretic and vasodilatory activity led to the isolation and characterization of natriuretic


peptides of cardiac origin.20,21 The natriuretic peptide family comprises atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), Den-droaspis natriuretic peptide (DNP), and urodilatin. Although their structures are quite similar, each is encoded by different genes and has distinct, albeit overlapping, functions.22-25 The actions of natriuretic peptides and their interaction with other hormone systems are discussed in detail later in the “Efferent Limb: Effector Mechanisms for Maintaining Effective Arte-rial Blood Volume” section, as well as in Chapter 12. This sec-tion is confined to a discussion of the afferent mechanisms of natriuretic peptide stimulation.

From studies in both animals and humans, it has become abundantly clear that any acute increment in atrial stretch or pressure causes a brisk release in ANP. Every 1–mm Hg rise in atrial pressure results in an approximate rise in ANP of 10 to 15 pmol/L. The process involves the cleavage of the prohormone, located in preformed stores in atrial granules, to the mature 28–amino acid C-terminus peptide in a sequence-specific manner by corin, a transmembrane serine protease.26 Release of the hormone appears to occur in two steps: the first a Ca2+-sensitive K+ channel–dependent release of ANP from myocytes into the intercellular space, and then a Ca2+-inde-pendent translocation of the hormone into the atrial lumen.27 The afferent mechanism for ANP release is activated by intra-vascular volume expansion, as well as by supine posture, HWI, saline administration, exercise, angiotensin II, tachycardia, and ventricular dysfunction.28,29 Conversely, volume deple-tion induced by Na+ restriction, furosemide administration, or LNBP-mediated reduction in central venous pressure causes a fall in plasma ANP concentration.

In contrast to the effects of acute changes in atrial pres-sure on ANP release, the role of this peptide in the long-term regulation of plasma volume appears to be modest, at best. For example, although incremental oral salt-loading was associ-ated with correspondingly higher baseline plasma ANP levels, only intravenous (not oral) salt loading led to increased ANP levels.30 Moreover, in humans subjected to either intravenous or oral salt loading, no correlation could be found between changes in ANP levels and the degree of natriuresis.31-33 The contrasting relationships among acute and chronic Na+ load-ing, plasma ANP levels, and natriuresis have been elegantly demonstrated in ANP gene–knockout mice. These mice display a reduced natriuretic response to acute ECF volume expansion in comparison with their wild-type counterparts. However, no differences in cumulative Na+ and water excre-tion were observed between the knockout and wild-type mice after a high- or low-Na+ diet for 1 week. The only difference between the two types of mice was a significant increase in mean arterial pressure. Further experiments utilizing disrup-tions of either the genes for ANP or its receptor, guanylate cyclase A (GC-A), showed the importance of this system in the maintenance of normal blood pressure and in modulating cardiac hypertrophy.34

In contrast to ANP, the other members of the natriuretic peptide family appear not to be involved in the physiologic regulation of Na+ excretion. Thus, results of gene-disrup-tion studies involving BNP, CNP, or the guanylyl cyclase B (GC-B) receptor35 indicated that these proteins exert local paracrine/autocrine cyclic guanosine monophosphate (cGMP)– mediated effects on cellular proliferation and differ-entiation in various tissues.22,24,36 In summary, of the various

mposition
468 Section II Disorders of Body Fluid Volume and Co
natriuretic peptides, only ANP appears to have a direct role in sensing volume in the atria.Ventricular and Pulmonary Sensors. Volume sensors have been found in the ventricles, coronary arteries, main pulmo-nary artery and bifurcation,37 and juxtapulmonary capillaries in the interstitium of the lungs38 but not in the intrapulmo-nary circulation.39 These sensors have generally been consid-ered as mediating reflex changes in heart rate and systemic vascular resistance, through modulation of the sympathetic nervous system (SNS) and of ANP. This also appears to be true for the coronary baroceptor reflex described in anesthe-tized dogs, by which changes in coronary artery pressure lead to alterations in lumbar and renal sympathetic discharge40 and a coronary artery response much slower than that of the carotid and aortic baroceptors.40 However, some evidence, also in dogs, suggests that ventricular and pulmonary sensors may also detect changes in blood volume through increased left ventricular pressure that causes a reflex inhibition of plasma renin activity.41,42

SenSorS of CardiaC outputThe receptors described so far are situated in low-pressure sites where they sense the fullness of the circulation and are probably more important for defending against excessive vol-ume expansion and the consequent congestive manifestations of cardiac failure. The arterial (high-pressure) sensors, on the other hand, are geared more toward detecting low car-diac output or systemic vascular resistance, which manifest as underfilling of the vascular tree (i.e., EABV depletion) and as signaling the kidneys to retain Na+. These high-pressure sen-sors are found in the aortic arch, in the carotid sinus, and in the renal vessels.Carotid and Aortic Baroceptors. Histologic and molecu-lar analysis of the carotid baroreceptor has revealed a large content of elastic tissue in the tunica media, which makes the vessel wall highly distensible in response to changes in intraluminal pressure, thereby facilitating transmission of the stimulus intensity to sensory nerve terminals. A change in the mean arterial pressure induces depolarization of these sensory endings, which results in action potentials. Afferent signals from the baroreceptors are integrated in the nucleus tractus solitarius of the medulla oblongata,43 which leads to reflex changes in both systemic and renal sympathetic nerve activity (RSNA) and, to a lesser degree, release of AVP. A role for endocannabinoids has been postulated in barocep-tor reflex modulation. In this regard, a significant increase in the endocannabinoid anandamide in the nucleus tractus solitarius was observed after an increase in blood pressure. Also, anandamide microinjections into the nucleus tractus solitarius induced prolonged baroreflex inhibition of RSNA. These results, along with other studies, support the hypoth-esis that endogenous anandamide can modulate the barore-flex through cannabinoid CB1 receptor activation within the nucleus tractus solitarius.44 An important additional function of the carotid baroreceptors is to maintain adequate cerebral perfusion. The aortic baroreceptor appears to behave in a way similar to that of the carotid baroreceptor.

SenSorS of organ perfuSionRenal Sensors. The kidney not only is the major effec-tor target responding to signals that indicate the need for adjustments in Na+ excretion but also has a central role in

the afferent sensing of volume homeostasis, by virtue of the local sympathetic innervation. However, despite consider-able knowledge concerning the mechanisms of renal sensing of EABV, the molecular identity and exact cellular location of the renal sensor or sensors remain elusive.45 The integral relationship between both afferent and efferent renal sym-pathetic activities and the central arterial baroceptors was highlighted by Kopp and colleagues.46 They showed that a high-Na+ diet increases afferent RSNA, which then decreases efferent RSNA and leads to natriuresis. Using dorsal rhizot-omy to induce afferent renal denervation in rats maintained on a high-Na+ diet, they demonstrated increased mean arterial pressure that was dependent on impaired arterial baroreflex suppression of efferent RSNA activity. Animals fed a normal-Na+ diet displayed no changes in arterial baroceptor function. Kopp and colleagues concluded that arterial baroreflex func-tion contributes to increased efferent RSNA, which, in the absence of intact afferent RSNA, would eventually lead to Na+ retention and hypertension. The role of RSNA in Na+ regula-tion is further discussed in the “Mechanisms: Renal Nerves and Sympathetic Nervous System” section.

An additional level of renal sensing depends on the close anatomic proximity of the sensor and effector limbs to one another: Volume changes may be sensed through alterations in both glomerular hemodynamics and renal interstitial pres-sure. These alterations result simultaneously in adjustments in physical forces governing tubular Na+ handling (further discussed in the “Efferent Limb: Effector Mechanisms for Maintaining Effective Arterial Blood Volume” section).

The kidneys, along with other organs, have the ability to maintain constant blood flow and constant glomerular filtra-tion rate (GFR) at varying arterial pressures. This phenom-enon, known as autoregulation, operates over a wide range of renal perfusion pressures (RPP). Autoregulation of renal blood flow (RBF) occurs through three mechanisms: the myogenic response, tubuloglomerular feedback, and a third mechanism. In the myogenic response, changes in RPP are sensed by smooth muscle elements that serve as baroreceptors in the afferent glomerular arteriole and dynamically respond by adjusting transmural pressure and tension across the arteriolar wall.47

The second mechanism, tubuloglomerular feedback, is operated by the juxtaglomerular apparatus, which comprises the afferent arteriole and, to a lesser extent, the cells of the macula densa in the early distal tubule.47-49 The juxtaglo-merular apparatus is also important because of its involve-ment in the synthesis and release of renin.48 The physiologic release of renin from the cells of the juxtaglomerular appara-tus is controlled by three pathways, all of which are driven by EABV status. First, renin release is inversely related to RPP and directly related to intrarenal tissue pressure. When RPP falls below the autoregulatory range, renin release is further enhanced. Second, renin secretion is influenced by solute delivery to the macula densa. Increased NaCl delivery past the macula densa leads to inhibition of renin release, whereas a decrease has the opposite effect. Sensing at the macula densa is mediated by NaCl entry through the Na+-K+-2Cl− cotrans-porter (NKCC2),50,51 which leads to alterations in intracel-lular Ca2+, together with production of prostaglandin E2 (PGE2),52,53 adenosine,54 and, subsequently, renin release. Third, changes in renal nerve activity influence renin release. Renal nerve stimulation increases renin release through direct


activation of β-adrenergic receptors on juxtaglomerular cells. This effect is independent of major changes in renal hemo-dynamics.55,56 Sympathetic stimulation also affects intrarenal baroreceptor input, the composition of the fluid delivered to the macula densa, and the renal actions of angiotensin II, so that renal nerves may serve primarily to potentiate other regu-latory signals.55-57

The nature of the third mechanism of RBF autoregulation is still unclear, but Seeliger and associates,58 using a normo-tensive angiotensin II clamp in anesthetized rats, were able to abolish the resetting of autoregulation during incremental shaped RPP changes. Under control conditions, the initial tubuloglomerular feedback response was dilatory after total occlusions but constrictive after partial occlusions. The ini-tial third mechanism response was a mirror image of tubulo-glomerular feedback: it was constrictive after total occlusions but dilatory after partial occlusions. The angiotensin clamp suppressed the tubuloglomerular feedback and turned the initial third mechanism response after total occlusions into dilation. Seeliger and associates concluded that (1) pressure-dependent renin-angiotensin system (RAS) stimulation was a major factor behind hypotensive resetting of autoregulation; (2) tubuloglomerular feedback sensitivity depended strongly on pressure-dependent changes in RAS activity; (3) the third mechanism was modulated, but not mediated, by the RAS; and (4) the third mechanism acted as a counterbalance to tubuloglomerular feedback.58 They proposed that their find-ings might be related to the connecting tubule glomerular feedback.59-61 Tubuloglomerular feedback is discussed further in the “Integration of Changes in Glomerular Filtration Rate and Tubular Reabsorption” section.Central Nervous System Sensors. Certain areas in the CNS appear to act as sensors to detect alterations in body salt bal-ance. This was suggested originally by results of experiments in rats, in which intracerebral injection of hypertonic saline led to reduced renal nerve activity and natriuresis.62,63 Sub-sequently, DiBona64 showed that administration of angioten-sin II into the cerebral ventricles and changes in dietary Na+ modulate baroreflex regulation of RSNA. Similarly, stimula-tion of neurons located in the paraventricular nucleus and in a region extending to the anteroventral third ventricle led to ANP release, inducing angiotensin II blockade and inhibi-tion of salt and water intake. Conversely, disruption of these neurons, as well as of the median eminence or neural lobe, led to decreased ANP release and impaired response to vol-ume expansion.65 Overall, despite the substantial evidence for CNS sensing of ECF volume status, the exact nature, mode of operation, and relative importance of this aspect of sensing remains unclear.Gastrointestinal Tract Sensors. Under normal physiologic conditions, Na+ and water reach the ECF by absorption in the gastrointestinal tract. Therefore, it is not surprising that sens-ing and regulatory mechanisms of ECF volume have been found in the GI tract itself. The evidence for this phenom-enon comes from experiments that showed more rapid natri-uresis after an oral salt load than after a similar intravenous load. Moreover, infusions of hypertonic saline into the portal vein led to greater natriuresis than similar infusions into the femoral vein. These findings were consistent with the pres-ence of Na+-sensing mechanisms in the splanchnic or por-tal circulation, or both.66 In fact, these mechanisms appear to be located primarily in the portal system and are probably

important in the pathogenesis of the hepatorenal syndrome, discussed later.Hepatoportal Receptors. The two main neural reflexes, referred to as the hepatorenal and hepatointestinal reflexes, originate from receptors in the hepatoportal region. They transduce portal plasma Na+ concentration into hepatic affer-ent nerve activity; before a measurable increase in systemic Na+ concentration occurs, the hepatointestinal reflex attenu-ates intestinal Na+ absorption via the vagus nerve, and the hepatorenal reflex augments Na+ excretion.67-69 These reflexes have been observed both in rats and in rabbits, as well as in humans, and have been shown to be impaired in the chronic bile duct ligation model of cirrhosis and portal hypertension.70 In addition, the hepatic artery shows significant autoregula-tory capacity, dilating when perfusion pressure falls and con-stricting when pressure rises, thereby maintaining hepatic arterial blood flow over a wide range of perfusion pressures. Moreover, there is extensive crosstalk between the portal and systemic circulations. For example, when portal blood flow decreases, the hepatic artery dilates, which is indicative of the presence of a sensor in the hepatic artery, which responds to changes in the contribution of the portal vein to total hepatic blood flow (see review by Oliver and Verna71). Clues to the mechanism of hepatic autoregulation come from models of reduced portal venous blood flow and acute hepatic injury, in which reduced Na+ excretion was abolished by administration of an adenosine A1 receptor antagonist; thus, these receptors probably have a role in the hepatorenal reflex.72,73

The observation that intraportal infusion of bumetanide or furosemide suppresses the response of hepatic affer-ent nerve activity to intraportal hypertonic saline suggests that the NKCC2 may be involved in sensing portal Na+ concentration.74 In addition to hepatoportal Na+-sensing chemoreceptors, the liver also contains mechanoreceptors (baroreceptors). Increased intrahepatic hydrostatic pressure has been shown to be associated with enhanced RSNA and renal Na+ retention in various experimental models.75,76 For example, when increased intrahepatic pressure was induced by thoracic caval constriction in dogs, raising venous pressure led to positive Na+ balance that was inhibited by liver dener-vation.75 A clinical model for increased intrahepatic pressure is the Budd-Chiari syndrome,77 and it is in situations such as this that hepatic volume-sensing mechanisms probably play a role in renal Na+ retention (see “Specific Treatments Based on the Pathophysiology of Sodium Retention in Cirrhosis” section).Intestinal Natriuretic Hormones: Guanylin Peptides. As described previously, the natriuretic response of the kidneys to a Na+ load is more rapid when the load is delivered orally than when the same load is administered intravenously.55 The different responses are observed without accompanying differences in plasma aldosterone.78 This observation led to the idea that the gut produced a substance that signaled the kidneys to excrete excess Na+. The discovery of the guanylin family of cGMP-regulating peptides, or “intestinal natriuretic hormones,” has shed light on this phenomenon.79,80 Of the four currently known guanylin peptides, guanylin and uro-guanylin are the ones best studied. They are small (15 to 16 amino acids), heat-stable peptides with intramolecular disul-fide bridges that share similarity with the bacterial heat-stable enterotoxins that cause traveler’s diarrhea and are found in mammals, birds, and fish.79

470 Section II Disorders of Body Fluid Volume and Composition

Both guanylin and uroguanylin are synthesized as prepro-peptides, primarily in the intestine. The former, produced mainly by the ileum through proximal colon, circulates as pro-guanylin; the latter, which is expressed principally in the jeju-num, circulates in its active form (see Sindic and Schlatter80 and references therein). A physiologically important differ-ence between guanylin and uroguanylin lies in their sensitivity to proteases. Because of a tyrosine residue at the ninth amino acid, guanylin is sensitive to protease digestion in the kidneys, which leads to its inactivation, whereas uroguanylin can be locally activated by the same proteases.79 After an oral salt load, guanylin and uroguanylin released in the intestine lead to increased intestinal secretion of Cl−, HCO3

−, and water and to inhibition of Na+ absorption.

In the kidneys, Na+, K+, and water excretion is increased, without any change in RBF or GFR and independently of RAAS, AVP, or ANPs.79 The signaling pathway of guanylin peptides in the intestine involves binding to and activation of the receptor guanylyl cyclase C (GC-C), one of the eight guanylyl cyclases.80 GC-C is a transmembrane protein, 1050 to 1053 amino acids in length, that is present in the intestinal brush border. Propagation of the signal occurs through the second messenger cGMP, which inhibits Na+/H+ exchange and activates protein kinase G II and protein kinase A, which in turn activate the cystic fibrosis transmembrane conduc-tance regulator (CFTR), leading to Cl− secretion; CFTR then activates the Cl−/HCO3

− exchanger, which leads to HCO3

− secretion.The best evidence for a link between the gut and the kidneys

comes from mice lacking the uroguanylin gene, which display an impaired natriuretic response to oral salt loading but not to intravenous NaCl infusion.81 However, because plasma pro-uroguanylin levels do not rise but urinary uroguanylin levels do increase after a high-salt meal, locally released peptide by the kidneys could still play a role in uroguanylin-associated natriuresis.82,83 In the kidneys, both GC-C–dependent and –independent signaling pathways for guanylin peptides exist, inasmuch as knockout of GC-C in mice does not affect the high-salt diet–induced increase in uroguanylin.79 From exper-iments on cell lines and isolated tubules, it appears that uro-guanylin acts on the proximal tubule and principal cells of the cortical collecting duct.

In proximal cell lines, guanylin peptides increase cGMP and decrease cyclic adenosine monophosphate (cAMP), which leads to inhibition of Na+/H+ exchange and Na+-K+-ATPase; such events are consistent with decreased Na+ reabsorption in this segment (see Sindic and Schlatter79 and references therein). Crosstalk between guanylin peptides and ANPs may also occur in the proximal tubule.84 In the principal cell, uro-guanylin activation of a G protein–coupled receptor results in phospholipase A2–dependent inhibition of the renal outer medullary potassium (ROMK) channel, which leads to depo-larization and a reduced driving force for Na+ reabsorption.79 There is also evidence that guanylin may cause cell shrink-age in the inner medullary collecting duct (IMCD), which is suggestive of water secretion from this segment and a role in water diuresis.79 Together, these data are highly suggestive of a role at least for uroguanylin, as a natriuretic hormone, in adjusting UNa excretion to balance the levels of NaCl absorbed via the gastrointestinal tract.79,80 The importance of this sys-tem in the control of renal Na+ excretion in humans awaits further clarification.

A final point is that although multiple receptors are clearly involved in regulation of EABV, their functions appear to be considerably redundant. For example, cardiac or renal denervation in nonhuman primates and chronic aldosterone administration do not significantly affect the maintenance of Na+ balance.85,86

Efferent Limb: Effector Mechanisms for Maintaining Effective Arterial Blood Volume

The maintenance of Na+ homeostasis is achieved by adjust-ment of renal Na+ excretion according to the body’s needs. Like the mechanisms sensing changes in EABV, the pathways that enable the required adjustments in renal Na+ excretion are multiple. The adjustments are made by integrated changes in both GFR and tubular reabsorption, so that changes in one component lead to appropriate changes in the other in order to maintain Na+ homeostasis. In addition, tubular reabsorp-tion is regulated by local peritubular and luminal factors, as well as by neural and humoral mechanisms (Table 14-2).

Integration of Changes in Glomerular Filtration Rate and Tubular Reabsorption

In humans, normal GFR leads to the delivery of approxi-mately 24,000 mmol of Na+ per day for downstream process-ing by the tubules. More than 99% of the filtrate is reabsorbed; only a tiny amount escapes into the final urine. Therefore, it is clear that even minute changes in the relationship between filtered load and fraction of Na+ absorbed can exert a pro-found cumulative influence on net Na+ balance. However, even marked perturbations in GFR are not necessarily asso-ciated with drastic alterations in UNa excretion; thus, overall Na+ balance is usually preserved. Such preservation results from appropriate adjustments in two important protective mechanisms: tubuloglomerular feedback, in which changes in tubular fluid Na+ inversely affect GFR, and glomerulotubular balance, whereby changes in tubular flow rate, resulting from changes in GFR, directly affect tubular reabsorption.48,49,87

TABLE 14-2 Major Renal Effector Mechanisms for Regulating Effective Arterial Blood Volume

Glomerular Filtration Rate and Tubular Reabsorption

Tubuloglomerular feedbackGlomerulotubular balance

Peritubular capillary Starling forcesLuminal compositionPhysical factors beyond proximal tubuleMedullary hemodynamics (pressure natriuresis)

Neural Mechanisms

Sympathetic nervous systemRenal nerves

Humoral Mechanisms

Renin-angiotensin-aldosterone systemVasopressinProstaglandinsNatriuretic peptidesEndothelium-derived factors

EndothelinsNitric oxide

Others (see text)


tubuloglomerular feedbaCkA remarkable feature of nephron architecture is that, after emerging from Bowman’s capsule and descending deep into the medulla, each tubule returns to its parent glomerulus. Guyton and associates88 envisioned a functional relationship between the tubule and glomerulus; this idea led to a wealth of experimental evidence supporting the existence of tubulo-glomerular feedback (reviewed by Schnermann and Briggs89). Tubuloglomerular feedback operates by changes in tubular fluid Na+ at the macula densa (the point of contact between the specialized tubular cells of the cortical thick ascending limb of Henle adjacent to the extraglomerular mesangium), which elicit adjustments in glomerular arteriolar resistance. The system is constructed as a negative feedback loop in which an increase in NaCl concentration leads to increases in afferent arteriolar resistance and a consequent fall in GFR. This, in turn, leads to an increase in proximal reabsorption and a reduction in distal delivery of solute. In that manner, NaCl delivery to the distal nephron is maintained within nar-row limits.89

The complexities of tubuloglomerular feedback have been unraveled slowly, initially by elaborate micropuncture stud-ies that clearly established the tubular-glomerular link and, subsequently, by imaging and electrophysiologic techniques in isolated perfused tubule/glomerulus preparations. With these techniques, investigators elucidated the detailed mecha-nisms of changes in epithelial function in response to lumi-nal NaCl composition. However, the signaling mechanisms linking changes in tubular composition with altered glomeru-lar arteriolar tone only much later became evident through experiments in gene-manipulated mice.89 The primary detec-tion mechanism of tubuloglomerular feedback appears to be uptake of salt by means of the NKCC2, located in the api-cal membrane of macula densa cells. The evidence comes from tubuloglomerular feedback inhibition by inhibitors of the cotransporter, furosemide and bumetanide (reviewed by Castrop90), and by deletions in mice of the A or B isoform of NKCC2, both of which are expressed in macula densa cells.50,89 In fact, complete inactivation of the NKCC2 gene leads to the severe salt-losing phenotype of antenatal Bartter’s syndrome.91 Similarly, inhibition or deletion of the ROMK channel in mice abolishes tubuloglomerular feedback (see Schnermann and Briggs89).

The next step in the juxtaglomerular cascade is less clear. One possibility is direct coupling of NKCC2-dependent NaCl uptake to the mediation step. Results of studies in the isolated perfused rabbit juxtaglomerular apparatus have indi-cated depolarization, alkalinization, and various ionic compo-sitional changes occur after increased NaCl uptake; thus, one or more of these changes could trigger the signal.92 A sec-ond possibility is that signal propagation is the consequence of transcellular NaCl transport and Na+-K+-ATPase–depen-dent basolateral extrusion. Early studies of this mechanism, in which pharmacologic inhibition with ouabain was used, yielded inconsistent evidence; however, this was probably a result of ouabain resistance of the α1-subunit, the main iso-form in the kidneys. Only the much less abundant α2-subunit is sensitive to cardiac glycosides, whereas there is no specific inhibitor of the α1-subunit. This stumbling block appears to have been overcome by the use of double-knockout mice, in which the α1-subunit was made sensitive and the α2-subunit resistant to ouabain. Results of these studies have clearly

indicated an important role for Na+-K+-ATPase in supporting tubuloglomerular feedback and that adenosine triphosphate (ATP) consumption is required for tubuloglomerular feed-back (see Schnermann and Briggs89).

There is strong evidence that ATP release and degrada-tion, rather than use, may be the link in the chain connecting NaCl changes in the macula densa with alteration of glomeru-lar arteriolar tone. According to the current working model, after NaCl uptake and transcellular transport, ATP is released from macula densa cells and undergoes stepwise hydrolysis and dephosphorylation by ecto-ATPases and nucleotidases, to adenosine diphosphate, adenosine monophosphate, and then adenosine, which, in a paracrine manner, causes A1 adenosine receptor–dependent afferent arteriolar constriction. Although the evidence for ATP breakdown is as yet incomplete, that for the effects of adenosine as a mediator of tubuloglomerular feedback is very strong. For example, isolated perfused mouse afferent arterioles exposed to adenosine display vigorous vaso-constriction, an effect not seen in A1 adenosine receptor–deficient mice.93,94 This effect is mediated by Gi-dependent activation of phospholipase C, release of Ca2+ from intracellu-lar stores, and subsequent entry of Ca2+ through L-type Ca2+ channels.93,95 Of particular interest is the fact that vasodilatory A2 adenosine receptor is more abundant than the A1 adenos-ine receptor in the renal vasculature, and continuous exog-enous application of adenosine to mouse kidneys is indeed vasodilatory.96 However, the generation of adenosine in the confines of the juxtaglomerular interstitium and its exclusive delivery to the afferent arteriole, where A1 adenosine receptor expression predominates, ensures the appropriate response for tubuloglomerular feedback.

Other factors appear to be involved in tubuloglomerular feedback, both co-constrictors and modulators. Angioten-sin II has been shown to act as an important cofactor in the vasoconstrictive action of adenosine. In this regard, dele-tions of the angiotensin II receptor or angiotensin converting enzyme (ACE) in mice abolished tubuloglomerular feedback. The effect may result from nonresponsiveness to adenosine in the absence of an intact RAS (reviewed by Schnermann and Briggs89). The high levels of neuronal nitric oxide syn-thase (nNOS, or NOS1) expression in macula densa cells are indicative of a role for nitric oxide in tubuloglomerular feed-back.97 Nitric oxide is thought to counterbalance angiotensin II–induced efferent arteriolar vasoconstriction and to modu-late renin secretion by the juxtaglomerular apparatus.98,99 Consistent with this idea is the finding that chronic absence of functional nNOS in macula densa cells is associated with enhanced vasoconstriction in the subnormal flow range, prob-ably as a result of proportional increases in preglomerular and postglomerular tone. In addition, increased delivery of fluid to the macula densa induces nitric oxide release from these cells (see Patzak and Persson98 and references therein).

Inhibition of the nitric oxide system by nonselective block-ers of nitric oxide synthase (NOS) results in an exaggerated tubuloglomerular feedback response that leads to even further renal vasoconstriction, Na+ and water retention, and arterial hypertension.99 Also, tubuloglomerular feedback responses are absent in mice with concurrent deficiencies in nNOS and A1 adenosine receptor, which implies that nNOS deficiency does not overcome deficient A1 adenosine receptor signal-ing. Moreover, nitric oxide modulation of tubuloglomerular feedback can be mediated by ecto 5′-nucleotidase, the enzyme


responsible for adenine formation.100 Together, these data suggest that A1 adenosine receptor signaling is primary and that nNOS plays a modulatory role in tubuloglomerular feedback.89

Afferent arteriolar A1 adenosine receptor may not be the sole mediator of tubuloglomerular feedback. Activation by adenosine of A2 adenosine receptor has been shown to dilate mouse cortical efferent receptors. The effect appeared to be mediated by the low-affinity A2b adenosine receptor.96 It is remarkable that this highly specific effect occurred despite the presence of A1 adenosine receptor in the efferent arte-riole. Apparently, therefore, the relative abundance of the various adenosine receptor subtypes in afferent and efferent arterioles ultimately allows fine-tuning of tubuloglomerular feedback by concerted changes in glomerular vascular tone.101 Connexin 40, which plays a predominant role in the forma-tion of gap junctions in the vasculature, also participates in the autoregulation of RBF and, therefore in tubuloglomerular feedback. Connexin-40–knockout mice displayed impaired steady-state autoregulation to a sudden-step increase in RPP. A marked reduction in tubuloglomerular feedback in con-nexin 40–knockout mice was thought to be responsible. The authors of this work showed that connexin 40 mediated RBF autoregulation occurred by transducing tubuloglomerular feedback–mediated signals to the afferent arteriole, indepen-dently of nitric oxide.102

A final point in the complexity of tubuloglomerular feed-back is that there is evidence for three sites in addition to the macula densa that are in contact with the efferent arteriole: the terminal cortical thick ascending limb of Henle, the early distal tubule, and the connecting tubule. In particular, peri-macular cells and oscillatory cells of the early distal tubule may be involved in the intracellular Ca2+ signaling required for ade-nosine-induced afferent vasoconstriction. On the other hand, the effect of the connecting tubule on the afferent arteriolar tone appears to be modulatory in that elevations in luminal NaCl, and cellular Na+ entry via the epithelial sodium channel (ENaC), lead to afferent arteriolar dilation through the release of prostaglandins and epoxyeicosatrienoic acids.59,103

glomerulotubular balanCeSeveral factors are involved in the phenomenon of glomeru-lotubular balance, which describes the ability of proximal tubular reabsorption to adapt proportionally to the changes in filtered load.Peritubular Capillary Starling Forces. Researchers have studied the natriuretic response to ECF volume expansion by examining the effects of acute infusions of saline or albumin in experimental animals and in humans. Therefore, their rel-evance to chronic regulation of ECF sodium balance is ques-tionable. Nevertheless, the findings from these studies led to the notion that alterations in hydraulic and oncotic pressures (Starling forces) in the peritubular capillary play an important role in the regulation of Na+ and water transport, especially in the proximal nephron. The peritubular capillary network is anatomically connected in series with the glomerular capillary bed of cortical glomeruli through the efferent arteriole; thus, changes in the physical determinants of GFR critically influ-ence Starling forces in the peritubular capillaries.

Of importance is that about 10% of glomeruli, mainly those at the corticomedullary junction, are connected in series to the vasa recta of the medulla. In the proximal tubule—whose

peritubular capillaries receive 90% of blood flow from glomer-uli—the relation of hydraulic and oncotic driving forces to the transcapillary fluid flux is given by the Starling relationship

Rateabs = Kr[(πc − πi) − (Pc − Pi)]

in which Rateabs is the absolute rate of reabsorption of proximal tubule absorbate by the peritubular capillary; Kr is the capillary reabsorption coefficient (the product of capil-lary hydraulic conductivity and absorptive surface area); πc and Pc are the local capillary colloid osmotic (oncotic) and hydraulic pressures, respectively; and πi and Pi are the cor-responding interstitial pressures. Whereas πi and Pc oppose fluid absorption, πc and Pi tend to favor uptake of reabsorbate. By simultaneously determining these driving forces, investiga-tors can analyze the net pressure favoring fluid absorption or filtration. As a consequence of the anatomic relationship of the postglomerular efferent arteriole to the peritubular capil-lary, the hydraulic pressure is significantly lower in the peritu-bular capillary than in the glomerular capillary. The function of the efferent arteriole as a resistance vessel contributes to a decrease in hydraulic pressure between the glomerulus and the peritubular capillary.

Also, because the peritubular capillary receives blood from the glomerulus, the plasma oncotic pressure is high at the out-set as a result of prior filtration of protein-free fluid. It follows that the greater the GFR is in relation to plasma flow rate, the greater the protein concentration in the efferent arteriolar plasma is and the lower the hydraulic pressure in the proxi-mal peritubule capillary is; as a consequence, proximal fluid reabsorption is enhanced (Figure 14-2). Therefore, in con-tradistinction to the glomerular and peripheral capillary, the peritubular capillary is characterized by high values of πc − πi that greatly exceed Pc − Pi, which results in net reabsorption of fluid.

The ratio of GFR to RBF defines the filtration fraction. The relationship of proximal reabsorption to filtration frac-tion may contribute to Na+-retaining and edema-forming states, such as heart failure (see Figure 14-2). A series of in vivo micropuncture and microperfusion studies104-107 yielded compelling experimental evidence for the relationship between proximal peritubular Starling forces and proximal fluid reabsorption. As a result of these studies, as well as stud-ies in which the isolated perfused tubule model was used,108 the role of peritubular forces in the setting of increased ECF volume can be summarized as follows: 1. Acute saline expansion results in dilution of plasma pro-

teins and reduction in efferent arteriolar oncotic pressure. Single-nephron glomerular filtration rate (SNGFR) and peritubular Pc may be increased as well, but the decrease in peritubular πc by itself results in a decreased net peri-tubular capillary reabsorptive force and decreased Rateabs. Glomerulotubular balance is disrupted because Rateabs falls despite the tendency for SNGFR to rise, and this devel-opment allows the excess Na+ to be excreted and plasma volume to be restored.

2. Iso-oncotic plasma infusions tend to raise SNGFR and peritubular Pc but lead to relative constancy of efferent arteriolar oncotic pressure. Rateabs may therefore decrease slightly, resulting in less disruption of glomerulotubu-lar balance and natriuresis of lesser magnitude than that observed with saline expansion.


3. Hyperoncotic expansion usually increases both SNGFR (because of volume expansion) and efferent arteriolar oncotic pressure; as a result, Rateabs is enhanced. Glomer-ulotubular balance therefore tends to be better preserved than with iso-oncotic plasma or saline expansion.

4. Changes in πi can directly alter proximal tubular reabsorp-tion, independently of the peritubular capillary bed.The alterations in proximal peritubular Starling forces that

modulate fluid and electrolyte movements across the peritu-bular basement membrane into the surrounding capillary bed appear to be accompanied by corresponding changes in the structure of the peritubular interstitial compartment. Ultra-structural data from rats suggest that the peritubular capillary wall is in tight apposition to the tubule basement membrane for about 60% of the tubule basolateral surface. However, irregularly shaped wide portions of peritubular interstitium also exist over about 40% of the tubule basolateral surface;

GlomerularCapillary

Arb

itrar

y P

ress

ure

Uni

ts

PeritubularCapillary

DIMENSIONLESS DISTANCES ALONG CAPILLARY SEGMENTS

0 1 10GlomerularCapillary

PeritubularCapillary

0 1 10

Normal

�P

�P

�P�P

��

��

��

CHF

FIGURE 14-2 The glomerular and peritubular microcirculations. Left, Approximate transcapillary pressure profiles for the glomerular and peri-tubular capillaries in normal humans. Vessel lengths are given in normal-ized, nondimensional terms, with 0 being the most proximal portion of the capillary bed and 1 the most distal portion. Thus, for the glomerulus, 0 corresponds to the afferent arteriolar end of the capillary bed, and 1 corre-sponds to the efferent arteriolar end. The transcapillary hydraulic pressure difference (ΔP) is relatively constant with distance along the glomerular capillary, and the net driving force for ultrafiltration (ΔP − Δπ) dimin-ishes primarily as a consequence of the increase in the opposing colloid osmotic pressure difference (Δπ), the latter resulting from the formation of an essentially protein-free ultrafiltrate. As a result of the drop in pres-sure along the efferent arteriole, the net driving pressure in the peritubular capillaries (ΔP − Δπ, in which Δπ is the change in transcapillary oncotic pressure) becomes negative, favoring reabsorption. Right, Hemodynamic alterations in the renal microcirculation in congestive heart failure (HF). The fall in renal plasma flow rate (RPF) in heart failure is associated with a compensatory increase in ΔP for the glomerular capillary, which is con-ducive to a greater-than-normal rise in the plasma protein concentration and, hence, in Δπ along the glomerular capillary. This increase in Δπ by the distal end of the glomerular capillary also translates to an increase in Δπ in the peritubular capillaries, resulting in increased net driving pressure for enhanced proximal tubule fluid absorption, believed to take place in heart failure. The increased peritubular capillary absorptive force in heart failure also probably results from the decline in ΔP, a presumed consequence of the rise in renal vascular resistance. (From Humes HD, Gottlieb M, Brenner BM: The kidney in congestive heart failure: contemporary issues in nephrology, vol 1, New York, 1978, Churchill Livingstone, pp 51-72.)

thus, a major portion of reabsorbed fluid has to cross a true interstitial space before entering the peritubular capillaries. Alterations in the physical properties of the interstitial com-partment could conceivably modulate either passive or active components of net fluid transport in the proximal tubule. Starling forces in the peritubular capillary are thought to regu-late the rate of volume entry from the peritubular interstitium into the capillary. Any change in this rate of flux could lead to changes in interstitial pressure that secondarily modify proxi-mal tubule solute transport. This formulation could explain why experimental maneuvers known to raise Pi (e.g., infusion of renal vasodilators, renal venous constriction, renal lymph ligation) were associated with a natriuretic response, whereas the opposite effect was obtained with renal decapsulation, which lowers Pi (see also the “Medullary Hemodynamics and Interstitial Pressure in the Control of Na+ Excretion: Pressure Natriuresis” section).

Because of the relatively high permeability of the proximal tubule, changes in interstitial Starling forces are likely to be transduced mainly through alterations in passive bidirectional paracellular flux through the tight junctions.109 The claudin family of adhesion molecules has clearly proved that the tight junction is a dynamic, multifunctional complex that may be amenable to physiologic regulation by cellular second mes-sengers or in pathologic states.110-112 Among the 24 known mammalian claudin family members, at least three—clau-din-2, claudin-10, and claudin-11—are located in the proxi-mal nephron of the mouse, and others are located at more distal nephron sites.111,113 Claudin-2 is selectively expressed in the proximal nephron.114 However, the exact role of the claudin family members in the influence of Starling forces on fluid reabsorption remains to be elucidated.Luminal Composition. In addition to peritubular capil-lary and interstitial Starling forces, luminal factors may also play a role in the regulation of proximal tubule transport. For example, Romano and colleagues115 showed that glomerulo-tubular balance could be fully expressed even when the native peritubular environment was kept constant while the rate of perfusion of proximal tubular segments with native tubular fluid was changed. Moreover, studies in isolated perfused rab-bit proximal tubules indicated that the presence of a trans-tubular anion gradient, normally present in the late portion of the proximal nephron, was necessary for the flow depen-dence to occur.116 A potential mechanism for modulation of proximal Na+ reabsorption in response to changes in filtered load depends on the close coupling of Na+ transport with the cotransport of glucose, amino acids, and other organic solutes. The increased delivery of organic solutes that accompanies increases in GFR, together with the preferential reabsorption of Na+ with bicarbonate in the early proximal tubule, would lead to increased delivery of both Cl− and organic solutes to the late proximal tubule. The resulting transtubular anion gra-dient would then facilitate the “passive” reabsorption of both the organic solutes and NaCl in this segment, but, overall, net reabsorption would be reduced.

In summary, regardless of the exact mechanism, ECF volume expansion impairs the integrity of glomerulotubular balance, thus allowing increased delivery of salt and fluid to more distal parts of the nephron. The major factors acting on the proximal nephron during a decrease in ECF and effec-tive arterial circulating volume are outlined schematically in Figure 14-3.


EFFECTIVE ARTERIAL VOLUME

Aortic BP

FiltrationFraction

Efferent ArteriolarVasoconstriction

Aortic OncoticPressure

Peritubular CapillaryHydrostatic Pressure

Peritubular CapillaryOncotic Pressure

Interstitial HydrostaticPressure

Interstitial OncoticPressure

Tight JunctionPermeability

Active NaClAbsorption

Net Organic SoluteAbsorption

Volume Absorption &Convective NaClAbsorption

Net NaHCO3Absorption

Net NaClAbsorption

FIGURE 14-3 Effects of hemodynamic changes on proximal tubule solute transport. (From Seldin DW, Preisig PA, Alpern RJ: Regulation of proximal reabsorp-tion by effective arterial blood volume, Semin Nephrol 11:212-219, 1991.)

Physical Factors Beyond the Proximal Tubule. Because the final urinary excretion of Na+, in response to volume expansion or depletion, can be dissociated from the amount delivered out of the superficial proximal nephron, more distal or deeper segments of the nephron contribute to the modulation of Na+ and water excretion. Several sites along the nephron, such as the loop of Henle, distal nephron, and cortical and papillary collecting ducts, were found (by micropuncture and microcatheterization tech-niques) to increase or decrease the rate of Na+ reabsorption in response to enhanced delivery from early segments of the neph-ron. However, direct evidence that these transport processes are mediated by changes in Starling forces per se is lacking. Jamison and associates117 provided a detailed review of these experiments.

In summary, the intrarenal control of Na+ excretion can be generalized as follows: If ECF volume is held relatively con-stant, an increase in GFR leads to little or no increase in salt excretion because of a close coupling between the GFR and the intrarenal physical forces acting at the peritubular capillary to control Rateabs. In addition, changes in the filtered load of small organic solutes, and perhaps other as-yet-uncharacter-ized glomerulus-borne substances in tubule fluid, may influ-ence Rateabs. To the extent that changes, if any, in the load of Na+ delivered to more distal segments also occur, parallel changes in distal reabsorptive rates also occur, to ensure a high degree of glomerulotubular balance for the kidneys as a whole. Conversely, ECF volume expansion leads to large increases in Na+ excretion even in the presence of reduced GFR. Changes in Na+ reabsorption in the proximal tubule alone cannot account for this natriuresis of volume expansion, and a num-ber of mechanisms for suppressing renal Na+ reabsorption at more distal sites have been invoked.Medullary Hemodynamics and Interstitial Pressure in the Control of Sodium Excretion: Pressure Natriuresis. The idea that changes in renal medullary hemodynamics may be involved in the natriuresis evoked by volume expansion was

initially proposed in the 1960s by Earley and Friedler.118,119 According to their theory, ECF volume expansion results in an increase in RPP that is transmitted as an increase in medul-lary plasma flow and leads to a subsequent loss of medullary hypertonicity, elimination of the medullary osmotic gradient (“medullary washout”), and, thereby, decreased water reab-sorption in the thin descending loop of Henle. The decrease in water reabsorption in the thin descending limb lowers the Na+ concentration in the fluid entering the ascending loop of Henle, thus decreasing the transepithelial driving force for salt transport in this nephron segment. At the same time, a simi-lar mechanism was proposed to explain the natriuresis after elevations in systemic blood pressure, a phenomenon termed pressure natriuresis.

The concept that alterations in the solute composition of the renal medulla and papilla play a key role in regulation of Na+ transport gained significant support in the 1970s and 1980s, when results of micropuncture studies suggested that volume expansion, renal vasodilation, and increased RPP pro-duced a greater inhibition of salt reabsorption in the loops of Henle within juxtamedullary nephrons than in those within superficial nephrons. Measurement of medullary plasma flow with laser Doppler flowmetry and videomicroscopy in experi-mental animals provided strong evidence for the redistribu-tion of intrarenal blood flow toward the medulla after volume expansion and renal vasodilation. These studies were of par-ticular interest with regard to the role of medullary hemo-dynamics in the control of Na+ excretion, especially in the context of pressure natriuresis.120-124

The importance of pressure natriuresis in the long-term control of arterial blood pressure and ECF volume regulation was first recognized by Hall and associates.123,124 According to this view, the kidneys alter Na+ excretion in response to changes in arterial blood pressure. For instance, an increase in RPP results in a concomitant increase in Na+ excretion,

thereby decreasing circulating blood volume and restoring arterial pressure. The coupling between arterial pressure and Na+ excretion was found to occur in the setting of preserved cortical autoregulation (i.e., in the absence of changes in total RBF, GFR, or filtered load of Na+). This led to the sugges-tion that the pressure natriuresis mechanism was triggered by changes in medullary circulation.118,121,125-127 Laser Doppler flowmetry and servo-null measurements of capillary pressure in volume-expanded rats revealed that papillary blood flow was directly related to RPP over a wide range of pressures studied.

As mentioned earlier, increase in medullary plasma flow might lead to medullary “washout” with a consequent reduc-tion in the driving force for Na+ reabsorption in the ascending loop of Henle, particularly in the deep nephrons. In addition, the increase in medullary perfusion may be associated with a rise in Pi. In fact, increasing Pi by ECF volume expansion, by infusion of renal vasodilatory agents, by long-term min-eralocorticoid escape, or by hilar lymph ligation resulted in a significant increase in Na+ excretion.128,129 Moreover, pre-vention of the increase in Pi by removal of the renal capsule significantly attenuated, but did not completely block, the natriuretic response to elevations in RPP. Thus, as depicted in Figure 14-4, elevation in RPP is associated with an increase in medullary plasma flow and increased vasa recta capil-lary pressure, which results in an increase in medullary Pi. This increase of Pi is thought to be transmitted to the renal cortex in the encapsulated kidneys and to provide a signal that inhibits Na+ reabsorption along the nephron. In that regard, the renal medulla may be viewed as a sensor that can detect changes in RPP and initiate the pressure natriuresis mechanism.

In order to explain how changes in systemic blood pressure are transmitted to the medulla in the presence of efficient RBF and GFR autoregulation, it has been suggested that shunt pathways connect preglomerular vessels of juxtamedullary

RPP

Pressure and flowvasa recta

Renal interstitialpressure

Washout of medullarysolute gradient

Deep NephronsSodium reabsorption in– proximal tubule– thin descending limb– thick ascending limb

Superficial NephronsSodium reabsorption in– proximal tubule– thick ascending limb

FIGURE 14-4 Role of the renal medulla in modulating tubular reabsorp-tion of sodium in response to changes in renal perfusion pressure (RPP). (Adapted from Cowley AW Jr: Role of the renal medulla in volume and arterial pressure regulation, Am J Physiol 273:R1-R15, 1997.)


nephrons directly to the postglomerular capillaries of the vasa recta.118 Alternatively, autoregulation of RBF might lead to increased shear stress in the preglomerular vasculature, trig-gering the release of nitric oxide and perhaps cytochrome P450 products of arachidonic acid metabolism (see later dis-cussion), thereby driving the cascade of events that inhibit Na+ reabsorption.130,131 The mechanisms by which changes in Pi and UNa excretion decrease tubular Na+ reabsorption, as well as the nephron sites responding to the alterations in Pi, have not been fully clarified.128 As pointed out earlier, it was postu-lated that elevations in Pi may increase passive backleak or the paracellular pathway hydraulic conductivity, with a resultant increase in back flux of Na+ through the paracellular path-ways.129 However, the absolute changes in Pi, in the range of 3 to 8 mm Hg in response to increments of about 50 to 90 mm Hg in RPP, are probably not sufficient to account for the decrease in tubular Na+ reabsorption even in the proximal tubule, the nephron segment with the highest transepithelial hydraulic conductivity.120 Nevertheless, considerable evidence from micropuncture studies indicates that pressure natriuresis is associated with significant changes in proximal fluid reab-sorption particularly in deep nephrons, with enhanced deliv-ery to the loop of Henle, alterations in the pars recta and thin descending limb.129

Pressure-induced changes in tubular reabsorption may also occur in more distal parts of the nephron, such as the ascend-ing loop of Henle, distal nephron, and collecting duct.132 Therefore, elevations in RPP can affect tubular Na+ reabsorp-tion by both proximal and distal mechanisms. The finding that small changes in Pi are associated with significant altera-tions in tubular Na+ reabsorption led to the hypothesis that the changes in Pi may be amplified by various hemodynamic, hormonal, and paracrine factors.115,118,121,125,129 Specifically, the phenomenon of pressure natriuresis is demonstrable par-ticularly in states of volume expansion and renal vasodilation and is significantly attenuated in states of volume deple-tion.129 Among a variety of hormonal and paracrine systems that have been documented to play a role in modulating pres-sure natriuresis, changes in the activity of the RAAS and local production of prostaglandins within the kidneys have received considerable attention.129 Removal of the influence of angiotensin II, by either ACE inhibitors or angiotensin II type 1 (AT1) receptor antagonists, potentiates the pressure natriuretic response, and inhibitors of cyclooxygenase attenu-ate it.129,133 Of importance, however, is that pharmacologic blockade of these systems only attenuates but does not com-pletely eliminate the pressure natriuresis response, which indi-cates that they act as modulators and not as mediators of the phenomenon.

The importance of endothelium-derived factors in the reg-ulation of renal circulatory and excretory function has been recognized. Evidence suggests that endothelium-derived nitric oxide and P-450 eicosanoids play a role in the mecha-nism of pressure natriuresis.120,125,130,131,134-136 Nitric oxide, generated in large amounts in the renal medulla, appears to play a critical role in the regulation of medullary blood flow and Na+ excretion.126,127 Several studies showed that inhi-bition of intrarenal nitric oxide production can reduce Na+ excretion and markedly suppress the pressure natriuretic response, whereas administration of a nitric oxide precursor improves transmission of perfusion pressure into the renal interstitium and normalizes the defect in pressure natriuresis


response in Dahl salt-sensitive rats.120,132,137,138 Likewise, a positive correlation between urinary excretion of nitrites and nitrates (metabolites of nitric oxide) and changes in renal arte-rial pressure or UNa excretion were observed both in dogs139 and in rats.134 Hydrogen peroxide (H2O2) has also been invoked in the mediation of RPP-induced changes in outer medullary blood flow and natriuresis. The response appears to be localized to the medullary thick ascending limb of Henle, in contrast to the nitric oxide effect, which occurs in the vasa recta.134 Other factors involved in the regulation of medul-lary blood flow include superoxide and heme oxygenase, both of which are released in the renal medulla in response to increased RPP.135,140

The cytochrome P450 eicosanoids, particularly 20-hydroxyeicosatetraenoic acid (20-HETE), are additional endothelium-derived factors that may participate in the mechanism of pressure natriuresis.130,131,141 These agents play an important role in the regulation of renal Na+ transport and of renal and systemic hemodynamics.142 These observations support the hypothesis that alterations in the production of renal nitric oxide, reactive oxygen species, and eicosanoids may be involved in mediation of the pressure-induced natri-uretic response.

It is tempting to speculate that acute elevations in RPP in the autoregulatory range result in increased blood flow velocity and shear stress, leading to increased endothelial release of nitric oxide and reactive oxygen species. Enhanced renal production of these molecules may increase UNa excre-tion either by acting directly on tubular Na+ reabsorption or through its vasodilatory effect on renal vasculature. ATP is another paracrine factor that is involved in pressure natri-uresis. ATP is an important regulator of renal salt and water homeostasis. ATP release appears to be mediated by connexin 30, inasmuch as release in response to increased tubular flow or hypotonicity was abolished in connexin 30–deficient mice. Moreover, increased arterial pressure, induced by ligation of the distal aorta, led to diuresis and natriuresis in normal mice, but the response was attenuated in connexin 30–knockout mice. These data imply that mechanosensitive connexin 30 hemichannels play an integral role in pressure natriuresis by releasing ATP into the tubular fluid, thereby inhibiting salt and water reabsorption.143 Finally, Magyar and colleagues144 reported that, in response to an increase in RPP, the apical Na+/H+ exchanger in the proximal tubules may be redistrib-uted out of the brush border into intracellular compartments. Concomitantly, basolateral Na+-K+-ATPase activity decreased significantly. The mechanisms of these cellular events have not been fully elucidated, but they may be related directly to changes in Pi or to changes in the intrarenal paracrine agents described previously.

A major assumption of the pressure natriuresis theory is that changes in systemic and RPP mediate the natriuretic response by the kidneys. As pointed out in comprehensive reviews, acute regulatory changes in renal salt excretion may occur without measurable elevation in arterial blood pres-sure.33,145-147 Of interest is that in many of these studies, the natriuresis was accompanied by a decrease in the activity of the RAAS without changes in plasma ANP levels.33,58,145-147 Thus, whereas increases in arterial blood pressure can drive renal Na+ excretion, other “pressure-independent” con-trol mechanisms must also operate to mediate the “volume natriuresis.”33

neural meChaniSmS: renal nerveS and SympathetiC nervouS SyStemExtensive autonomic innervation of the kidneys makes an important contribution to the physiologic regulation of all aspects of renal function.55,148 Sympathetic nerves, predomi-nantly adrenergic, have been observed at all segments of the renal vasculature and tubule.149 Adrenergic nerve endings reach vascular smooth muscle cells and mesangial cells, cells of the juxtaglomerular apparatus, and all segments of the tubule: proximal, loop of Henle, and distal. Only the basolat-eral membrane separates the nerve endings from the tubular cells. Initial studies determined that the greatest innerva-tion was found in the renal vasculature, mostly at the level of the afferent arterioles, followed by the efferent arterioles and outer medullary descending vasa recta.150 However, high-density tubular innervation was found in the ascending limb of the loop of Henle, and the lowest density was observed in the collecting duct, inner medullary vascular elements, and papilla.57,151 The magnitude of the tubular response to renal nerve activation may thus be proportional to the differential density of innervation. In accordance with these anatomic observations, stimulation of the renal nerve results in vasocon-striction of afferent and efferent arterioles148,151 that is medi-ated by the activation of postjunctional α1-adrenoreceptors.152

The presence of high-affinity adrenergic receptors in the nephron is also indicative of a significant role of the renal nerves in tubular function. The α1-adrenergic receptors and most of the α2-adrenergic receptors are localized in the basolateral membranes of the proximal tubule.153 In the rat, β-adrenoreceptors have been found in the cortical thick ascend-ing limb of Henle and are subtyped as β1-adrenoceptors.154 The predominant neurotransmitters in renal sympathetic nerves are noradrenaline and, to a lesser extent, dopamine and acetylcholine.151 There is abundant evidence that changes in the activity of the renal sympathetic nerve play an important role in controlling body fluid homeostasis and blood pres-sure.55,148,149 Renal sympathetic nerve activity can influence renal function and Na+ excretion through several mechanisms: (1) changes in renal and glomerular hemodynamics, (2) effect on renin release from juxtaglomerular cells with increased for-mation of angiotensin II, and (3) direct effect on renal tubular fluid and electrolyte reabsorption.55 Graded direct electrical stimulation of renal nerves produces frequency-dependent changes in RBF and GFR, reabsorption of renal tubular Na+ and water, and secretion of renin.55,149 The lowest frequency (0.5 to 1.0 Hz) stimulates renin secretion, and frequencies of 1.0 to 2.5 Hz increase renal tubule Na+ and water reabsorp-tion. Increasing the frequency of stimulation to 2.5 Hz and higher results in decreases in RBF and GFR.55,148

The decrease in SNGFR in response to enhanced renal nerve activity has been attributed to a combination of increases in both afferent and efferent glomerular resistance, the change in glomerular capillary hydrostatic pressure (ΔP)—in this case, a decrease—and a decrease in the glomerular ultrafiltration coefficient (Kf).148,149 In Munich-Wistar rats, micropuncture experiments before and after renal nerve stimulation at different frequencies revealed that the effector loci for vasomotor control by renal nerves were in the afferent and efferent arteriole. In addition, although urine flow and Na+ excretion declined with renal nerve stimulation, there was no change in absolute proxi-mal fluid reabsorption rate, which suggests that reabsorption is increased in the more distal segments of the nephron.


Results of studies of the response of the kidneys to reflex activation of renal nerves also indicate that the SNS has a role in regulating renal hemodynamic function and Na+ excretion. In rats receiving diets with different Na+ levels, DiBona and Kopp148 measured renal nerve activity in response to isotonic saline volume expansion and furosemide-induced volume contraction. A low-Na+ diet resulted in a reduction in right atrial pressure and an increase in renal nerve activity. The magnitude of the increase in renal nerve activity was approx-imately 20% for each 1–mm Hg fall in atrial pressure. The high-Na+ diet resulted in quantitatively similar changes in the opposite direction: that is, an increase in right atrial pressure and a reduction in renal nerve activity. Other studies in con-scious animals in which researchers used maneuvers such as HWI and left atrial balloon inflation (reviewed by DiBona55) yielded evidence of the importance of reflex regulation of renal nerve activity.

Collectively, these studies demonstrated the reciprocal relationship between ECF volume and renal nerve activity, which is consistent with the role of central cardiopulmonary mechanoreceptors governing renal nerve activity. Moreover, the contribution of efferent renal nerve activity is of greater significance during conditions of dietary Na+ restriction, when the need for renal Na+ conservation is maximal. When this linkage between the renal SNS and the excretory renal func-tion is defective, abnormalities in the regulation of ECF vol-ume and blood pressure may develop.151,155 Several studies in which the response of denervated kidneys to various physio-logic maneuvers was examined also yielded evidence that renal nerves played a role in regulating renal hemodynamic function and Na+ excretion.

Early studies showed that acute denervation of the kid-neys is associated with increased urine flow and Na+ excre-tion.148 Micropuncture techniques showed that in euvolemic animals, elimination of renal innervation does not alter any of the determinants of SNGFR, which indicates that renal nerves contribute little to the vasomotor tone of normal ani-mals under baseline physiologic conditions. However, abso-lute proximal reabsorption was significantly reduced, in the absence of changes in peritubular capillary oncotic pressure, hydraulic pressure, and renal interstitial pressure.148 The decrease in tubular electrolyte and water reabsorption after renal denervation was also observed in the loop of Henle and segments of the distal nephron.148

In another micropuncture study in control rats and in rats with experimentally induced heart failure or acute volume depletion, measurements obtained before and after denerva-tion demonstrated that denervation resulted in diuresis and natriuresis in normal rats but failed to alter any of the param-eters of renal cortical microcirculation (reviewed by DiBona and Kopp148). In rats with heart failure, in contrast, dener-vation caused both an amelioration of renal vasoconstriction by decreasing afferent and efferent arteriolar resistance and, again, natriuresis. This study indicates that in situations in which efferent neural tone is heightened above baseline level, renal nerve activity may profoundly influence renal circulatory dynamics. However, although the basal level of renal nerve activity in normal rats or conscious animals is apparently insufficient to influence renal hemodynamics, it is sufficient to exert a tonic stimulation on renal tubular epithelial Na+ reabsorption and renin release.148 Classical studies, in which guanethidine was given to achieve autonomic blockade or in

patients with idiopathic autonomic insufficiency, revealed that intact adrenergic innervation is required for the normal renal adaptive response to dietary Na+ restriction.156

More direct examination of efferent RSNA in humans has been made possible by the measurement of renal norepi-nephrine spillover to elucidate the kinetics of norepinephrine release. Friberg and associates157 determined that in normal subjects, a low-Na+ diet resulted in a fall in UNa excretion and an increase in norepinephrine spillover, with no change in cardiac norepinephrine uptake; these findings support the concept of a true increase of efferent renal nerve activ-ity secondary to Na+ restriction. Similarly, low-dose infusion of norepinephrine to normal salt-replete volunteers resulted in a physiologic plasma increment of this neurotransmitter in association with antinatriuresis.158 This reduction in Na+ excretion occurred without any change in GFR but was asso-ciated with a significant decline in Li+ clearance, an indication of enhanced proximal tubule reabsorption.

The cellular mechanisms mediating the tubular actions of norepinephrine appear to include stimulation of Na+-K+-ATPase activity and Na+/H+ exchange in proximal tubular epithelial cells.148 It is assumed that α1-adrenoreceptor stim-ulation, mediated by phospholipase C, causes an increase in intracellular Ca2+ that activates the Ca2+ calmodulin–depen-dent calcineurin phosphatase. Calcineurin converts Na+-K+-ATPase from its inactive phosphorylated form to its active dephosphorylated form.159 The stimulatory effect of renal nerves on Na+/H+ exchange is mediated through stimulation of the α2-adrenoreceptor.148

In addition to the direct action of Na+ on epithelial cell transport and renal hemodynamics, interactions of renal nerve input with other effector mechanisms may contribute to the regulation of renal handling of Na+. Efferent sympathetic nerve activity influences the rate of renin secretion in the kidneys by a variety of mechanisms, either directly or by interacting with the macula densa and vascular baroreceptor mecha-nisms for renin secretion.148 The increase in renin secretion is mediated primarily by direct stimulation of β1-adrenergic receptors located on juxtaglomerular granular cells.148 Sym-pathetic activation of renin release is augmented during RPP reduction.148 Results of studies in the isolated perfused rat kidney suggest that intrarenal generation of angiotensin II has an important prejunctional action on renal sympathetic nerve terminals to facilitate norepinephrine release during renal nerve stimulation.148 However, the physiologic signifi-cance of this facilitatory interaction on tubular Na+ reabsorp-tion remains controversial. Thus, administration of an ACE inhibitor or an angiotensin receptor blocker (ARB) attenuated the antinatriuretic response to electrical renal nerve stimula-tion in anesthetized rats.148 In contrast, when nonhypotensive hemorrhage was used to produce reflex increase in RSNA in conscious dogs, the associated antinatriuresis was unaffected by ACE inhibition or angiotensin II receptor blockade.160

Sympathetic activity is also a stimulus for the produc-tion and release of renal prostaglandins, coupled in series to the adrenergic-mediated renal vasoconstriction.148 Evidence indicates that renal vasodilatory prostaglandins attenuate the renal hemodynamic vasoconstrictive response to activation of the renal adrenergic system in vivo and on isolated renal arterioles.148 In Munich-Wistar rats, results of micropunc-ture experiments indicated that the primary factor respon-sible for the reduction in the glomerular Kf during renal nerve


stimulation may be angiotensin II rather than norepinephrine and that endogenously produced prostaglandins neutralize the vasoconstrictive effects of renal nerve stimulation at an intra-glomerular locus rather than at the arteriolar level.

Another interaction examined is that between the renal SNS and AVP. Studies in conscious animals showed that AVP exerted a dose-related effect on the arterial baroreflex: Low doses of AVP might have sensitized the central baroreflex neurons to afferent input, whereas higher doses caused direct excitations of these neurons, which resulted in a reduction in sympathetic outflow.148 In addition, AVP suppresses renal sympathetic outflow, and this response depends on the num-ber of afferent inputs from baroreceptors.161 Conversely, renal nerve stimulation resulted in elevations of plasma AVP levels and arterial pressure in conscious, baroreceptor-intact Wistar rats.162 Many studies demonstrated, in both normal and pathologic situations, that increased RNSA can antagonize the natriuretic/diuretic response to ANP and that removal of the influence of sympathetic activity enhances the natriuretic action of the peptide (see DiBona and Kopp148 and refer-ences therein). Conversely, renal denervation in Wistar rats increased ANP receptors and cGMP generation in glomeruli, which resulted in an increase in Kf after ANP infusion.163

In summary, renal sympathetic nerves can regulate UNa and water excretion by changing renal vascular resistance, by influ-encing renin release from the juxtaglomerular granular cells, and through a direct effect on tubular epithelial cells (Figure 14-5). These effects may be modulated through interactions with various other hormonal systems, including ANP, prosta-glandins, and AVP.

humoral meChaniSmSRenin-Angiotensin-Aldosterone System. The RAAS plays a central role in the regulation of ECF volume, Na+ homeo-stasis, and cardiac function.164 The system is activated in situations that compromise hemodynamic stability, such as blood loss, reduced EABV, low Na+ intake, hypotension, and increase in sympathetic nerve activity. The RAAS comprises a coordinated hormonal cascade whose synthesis is initiated by the release of renin from the juxtaglomerular apparatus in

−

↑ SNS activity

↑ Catecholamines

↑ RAAS

α2

α1

↑ Proximal and loopNa transport

β1

↑ Na reabsoprtion

↓ Peritubularblood flow

↓ RBF

↓ EABV

FIGURE 14-5 Sympathetic nervous system (SNS)–mediated effects of decreased effective arterial blood volume (EABV) on the kidneys. α1, α2, and β1 refer to α1-, α2-, and β1-adrenergic receptors, respectively. −, inhibitory effect; RAAS, renin-angiotensin-aldosterone system; RBF, renal blood flow.

response to reduced renal perfusion or decrease in arterial pres-sure.165 Messenger RNA for renin exists in juxtaglomerular cells and in renal tubule cells.166 Renin acts on its circulating substrate, angiotensinogen, which is produced and secreted mainly by the liver but also by the kidneys.164 Angiotensin converting enzyme 1 (ACE1), which cleaves angiotensin I to angiotensin II, exists in large amounts in the microvasculature of the lungs but also on endothelial cells of other vasculature beds and cell membrane of the brush border of the proximal nephron, heart, and brain.164 Angiotensin II is the princi-pal effector of the RAAS, although other smaller metabolic products of angiotensin II also have biologic activities.167,168 Nonrenin (cathepsin G, plasminogen-activating factor, tonin) and non-ACE pathways (chymase, cathepsin G) also exist in these tissues and may contribute to tissue angiotensin II synthesis.164

In addition to its important function as a circulating hor-mone, angiotensin II produced locally acts as a paracrine agent in an organ-specific mode (reviewed by Paul et al169). In that regard, the properties of angiotensin II as a growth-promoting agent in the cardiovascular system and the kidneys have been increasingly appreciated.164,169 For instance, local generation of angiotensin II in the kidneys results in higher intrarenal levels of this peptide in proximal tubular fluid, interstitial fluid, and renal medulla than in the circulation. The epithelial cells of the proximal nephron may be an important source for the in situ generation of angiotensin II, because these cells show abundant expression of the messenger RNA for angioten-sinogen.170 Furthermore, angiotensin II is apparently secreted from tubular epithelial cells into the lumen of the proximal nephron.171 This may account for the fact that concentrations of angiotensin II are approximately 1000 times higher in the proximal tubular fluid than in the plasma.171,172 Moreover, the mechanisms regulating intrarenal levels of angiotensin II may be dissociated from those controlling the systemic concentra-tions of the peptide.170

The biologic actions of angiotensin II are mediated through activation of at least two receptor subtypes, AT1 and AT2, encoded by different genes residing on different chromosomes.173,174 Both receptors are G protein–coupled, seven-transmembrane polypeptides containing approximately 360 amino acids.164,174 In the adult organism, the AT1 recep-tor mediates most of the biologic activities of angiotensin II, whereas the AT2 receptor appears to have a vasodilatory and antiproliferative effect.167,175 AT1 is expressed in the vascular poles of glomeruli, juxtaglomerular apparatus, and mesangial cells, whereas the quantitatively lower expression of AT2 is confined to renal arteries and tubular structures.173 Besides their functional distinction, the two receptor types employ different downstream pathways. Stimulation of the AT1 receptor activates phospholipases A2, C, and D, which results in increased cytosolic Ca2+ and inositol triphosphate and inhi-bition of adenylate cyclase. In contrast, activation of the AT2 receptor results in increases in nitric oxide and bradykinin lev-els, which lead to elevation in cGMP concentrations and to vasodilation.176

Besides being an important source of several components of the RAAS, the kidney acts as a major target organ for the principal hormonal mediators of this cascade, angiotensin II and aldosterone. In the past, it was believed that the major contribution of angiotensin II to Na+ homeostasis was the result of its action as a circulating vasoconstrictor hormone and


through stimulation of aldosterone release from the adrenal cortex with subsequent tubular action of aldosterone. How-ever, it is now abundantly clear that angiotensin II, through AT1 receptors, exerts multiple direct intrarenal influences, including renal vasoconstriction, stimulation of tubular epi-thelial Na+ reabsorption, augmentation of tubuloglomerular feedback sensitivity, modulation of pressure natriuresis, and stimulation of mitogenic pathways.164 Moreover, exogenous infusion of angiotensin II that results in relatively low circulat-ing levels of angiotensin II (picomolar range) is highly effec-tive in modulating renal hemodynamic and tubular function, in comparison with the 10- to 100-fold higher concentrations required for its extrarenal effects. Thus, the kidneys appear to be uniquely sensitive to the actions of angiotensin II.

Furthermore, the synergistic interactions that exist between the renal vascular and tubular actions of angiotensin II signifi-cantly amplify the influence of angiotensin II on Na+ excre-tion.170 Among the direct renal actions of angiotensin II, its effect on renal hemodynamics appears to be of critical impor-tance. Angiotensin II elicits a dose-dependent decrease in RBF but slightly augments GFR, as a result of its preferential vasoconstrictive effect on the efferent arteriole, and therefore increases filtration fraction. In turn, the increased filtration fraction may further modulate peritubular Starling forces, possibly by decreasing hydraulic pressure and increasing col-loid osmotic pressure in the interstitium. These peritubular changes eventually lead to enhanced reabsorption of proxi-mal Na+ and fluid. Of importance, however, is that changes in preglomerular resistance have also been described during angiotensin II infusion or blockade.177 These may be second-ary either to changes in systemic arterial pressure (myogenic reflex) or to increased sensitivity of tubuloglomerular feed-back, because angiotensin II does not alter preglomerular resistance when RPP is clamped or adjustments in tubuloglo-merular feedback are prevented.177

In addition, angiotensin II may affect GFR by reducing Kf, thereby altering the filtered load of Na+.178 This effect is believed to reflect the action of the hormone on mesangial cell contractility and increasing permeability to macromol-ecules.177 Finally, angiotensin II may also influence Na+ excre-tion through its action on the medullary circulation. Because angiotensin II receptors are highly abundant in the renal medulla, this peptide may contribute significantly to the regu-lation of medullary blood flow.177,179 In fact, use of fiberoptic probes revealed that angiotensin II usually reduces cortical blood flow and medullary blood flow and decreases Na+ and water excretion.177,179 As pointed out earlier, changes in med-ullary blood flow may affect medullary tonicity, which deter-mines the magnitude of passive salt reabsorption in the loop of Henle, and may also modulate pressure natriuresis through alterations in renal interstitial pressure.180

The other well-characterized renal effect of angiotensin II is a direct action on proximal tubular epithelial transport. Infusions of angiotensin II to achieve systemic concentra-tions of 10−12 to 10−11 mol markedly stimulated Na+ and water transport, independently of changes in renal or systemic hemodynamics.164,181 Angiotensin II exerts a dose-dependent biphasic effect on proximal Na+ reabsorption. Peritubular cap-illary infusion with solutions containing low concentrations of angiotensin II (10−12 to 10−10 mol) stimulated, whereas perfu-sion at higher concentrations of angiotensin II (>10−7 mol) inhibited proximal Na+ reabsorption rate. Addition of either

the AT1 receptor antagonist losartan or the ACE inhibitor enalaprilat directly into the luminal fluid of the proximal nephron resulted in a significant decrease in proximal fluid reabsorption, which is indicative of tonic regulation of proxi-mal tubule transport by endogenous angiotensin II.182

The specific mechanisms by which angiotensin II influ-ences proximal tubule transport include increases in reabsorp-tion of Na+ and HCO3

− by stimulation of the apical Na+-H+ antiporter, Na+/H+ exchanger isoform 3 (NHE3), basolateral Na+-3HCO3

− symporter, and Na+-K+-ATPase.183,184 Thus, angiotensin II can affect NaCl absorption by two mecha-nisms: (1) Activation of NHE3 can directly increase NaCl absorption. (2) Conditions that increase the rate of NaHCO3 absorption can stimulate passive NaCl absorption by increas-ing the concentration gradient for passive Cl− diffusion.185 Na+ reabsorption is further promoted by the action of angio-tensin II on NHE3 and Na+-K+-ATPase in the medullary thick ascending limb of Henle.164

In both the early and late portions of the distal tubule, as well as the connecting tubule, angiotensin II regulates Na+ and HCO3

− reabsorption by stimulating NHE3 and the amiloride-sensitive Na+ channel.186-188 Two additional mech-anisms may amplify the antinatriuretic effects of angiotensin II that are mediated by the direct actions of the peptide on renal hemodynamics and tubular transport. The first concerns the increased sensitivity of the tubuloglomerular feedback mecha-nism in the presence of angiotensin II, and the second con-cerns the effect of angiotensin II on pressure natriuresis. The decrease in distal delivery produced by the action of angioten-sin II on renal hemodynamics and proximal fluid reabsorption could elicit afferent arteriolar vasodilation by means of the tubuloglomerular feedback mechanism, which, in turn, could antagonize the angiotensin II–mediated increase in proxi-mal reabsorption. This effect, however, is minimized because angiotensin II increases the responsiveness of the tubuloglo-merular feedback mechanism, thus maintaining GFR at a lower delivery rate to the macula densa.61 The second mecha-nism by which the antinatriuretic effects of angiotensin II may be amplified is blunting of the pressure natriuresis mechanism so that higher pressures are needed to induce a given amount of Na+ excretion.130,164 This “shift to the right” in the pressure natriuresis curve may be viewed as an important Na+-conserv-ing mechanism in situations of elevated arterial pressure.

The use of ACE inhibitors and highly specific ARBs pro-vided additional insight into the mechanisms of action of angiotensin II in the kidneys, and the findings suggested that most of the known intrarenal actions of angiotensin II, partic-ularly regulation of renal hemodynamics and proximal tubule reabsorption of Na+ and HCO3

−, are mediated by the AT1 receptor.173 However, functional studies showed that some of the actions of angiotensin II at the renal level are medi-ated by AT2 receptors.173 The AT2 receptor subtype plays a counterregulatory protective role against the AT1 receptor–mediated antinatriuretic and pressor actions of angiotensin II. The accepted concept that angiotensin I was converted solely to angiotensin II was revised through the demonstration that angiotensin I is also a substrate for the formation of angio-tensin-(1-7).168 Moreover, a recently discovered homolog of ACE, angiotensin converting enzyme 2 (ACE2), is responsi-ble for the formation of angiotensin-(1-7) from angiotensin II and for the conversion of angiotensin I to angiotensin-(1-9), which may be converted to angiotensin-(1-7) by ACE.167,168


Angiotensin-(1-7), through its G protein–coupled receptor, Mas, may play an important role as a regulator of cardiovascu-lar and renal function by opposing the effects of angiotensin II; it does this through vasodilation, diuresis, and an antihy-pertrophic action (see Santos et al167 and references therein). Thus, the RAAS can currently be envisioned as a dual-function system in which the vasoconstrictor/proliferative or vasodila-tor/antiproliferative actions are driven primarily by the ACE/ACE2 balance. According to this model, an increased ACE/ACE2 activity ratio leads to increased generation of angioten-sin II and increased catabolism of angiotensin-(1-7), which is conducive to vasoconstriction; conversely, a decreased ACE/ACE2 ratio reduces angiotensin II and increases angioten-sin-(1-7) levels, facilitating vasodilation. The additional effect of angiotensin-(1-7)/Mas to directly antagonize the actions of angiotensin II adds a further level of counterregulation.167

The final component of the RAAS, aldosterone, also plays an important physiologic role in the maintenance of ECF and Na+ homeostasis.189 The primary sites of aldosterone action are the principal cells of the cortical collecting tubule and convoluted distal tubule, in which the hormone promotes the reabsorption of Na+ and the secretion of K+ and protons.189 Aldosterone may also enhance electrogenic Na+ transport, but not K+ secretion, in the IMCD.190 Aldosterone exerts its effects on ionic transport by increasing the number of open Na+ and K+ channels in the luminal membrane and the activ-ity of Na+-K+-ATPase in the basolateral membrane.191 The effect of aldosterone on Na+ permeability appears to be the primary event because blockade of the ENaC with amiloride prevents the initial increase in Na+ permeability and Na+-K+-ATPase activity.191 This effect on Na+ permeability is medi-ated by changes in intracellular Ca2+(levels, intracellular pH, and methylation of channel proteins, thus increasing mean open probability of ENaC.192 However, the long-term effect of aldosterone on Na+-K+-ATPase activity involves de novo protein synthesis, which is regulated at the transcriptional level by serum and glucocorticoid-induced kinase-1.192

It has become clear that aldosterone specifically regulates the α-subunit of ENaC and that changes in expression of a variety of genes are important intermediates in this process. Using microarray analysis in a mouse IMCD line, Gumz and associates193 examined the acute transcriptional effects of aldosterone. They found that the most prominent tran-script was period homolog 1 (Per1), an important component of the circadian clock. Gumz and associates194 also showed that disruption of the Per1 gene leads to attenuated expres-sion of messenger RNA encoded by the α-subunit of ENaC and increased UNa excretion. They also noted that messenger RNA encoded by the α-subunit of ENaC was expressed in an apparent circadian pattern that was dramatically altered in mice lacking functional Per1 genes. These results imply that the circadian clock has a previously unknown role in the con-trol of Na+ balance. Perhaps of more importance is that they provide molecular insight into how the circadian cycle directly affects Na+ homeostasis.

The Na+-retaining effect of aldosterone in the collecting tubule induces an increase in the transepithelial potential difference, which is conducive to K+ excretion. In terms of overall body fluid homeostasis, the actions of aldosterone in the defense of ECF result from the net loss of an osmotically active particle confined primarily to the intracellular compart-ment (K+) and its replacement with a corresponding particle

confined primarily to the ECF (Na+). The effect of a given cir-culating level of aldosterone on overall Na+ excretion depends on the volume of filtrate reaching the collecting duct and the composition of luminal and intracellular fluids. As noted earlier, this delivery of filtrate is in turn determined by other effector mechanisms (angiotensin II, sympathetic nerve activ-ity, and peritubular physical forces) acting at more proximal nephron sites.

It is not surprising that Na+ balance can be regulated over a wide range of intake, even in subjects without adrenal glands and despite fixed low or high supplemental doses of mineralocorticoids. Under these circumstances, other effector mechanisms predominate in controlling urinary Na+ excre-tion, although often in a setting of altered ECF volume or K+ concentration. In this regard, how renal Na+ reabsorption and K+ excretion are coordinately regulated by aldosterone has long been a puzzle. In states of EABV depletion, aldosterone release stimulated by angiotensin II induces maximal Na+ reabsorption without significantly affecting plasma K+ lev-els. Conversely, hyperkalemia-induced aldosterone secretion stimulates maximum K+ excretion without major effects on renal Na+ handling.

Elegant studies on the intracellular signaling pathways involved in renal Na+ and K+ transport have shed light on this puzzle. The key elements in this transport regulation are the Ste20/SPS1-related proline/alanine-rich kinase (SPAK), the with-no-lysine kinases (WNKs) and their effectors, the thia-zide-sensitive NaCl cotransporter, and the K+ secretory chan-nel ROMK. According to the proposed model, when EABV is reduced or dietary salt intake is low, angiotensin II, medi-ated by the AT1 receptor, leads to phosphorylation of WNK4, which stimulates phosphorylation of SPAK. In turn, SPAK phosphorylates the NaCl cotransporter, inducing Na+ trans-port and conservation. Simultaneous phosphorylation of the full-length isoform of WNK1, WNK1-L, causes endocyto-sis of the ROMK channel, thereby enabling K+ conservation, despite high aldosterone levels. In contrast, in the presence of hyperkalemia or low dietary salt, angiotensin II levels are low so that WNK4 cannot be activated, SPAK and NaCl cotransporter are not phosphorylated, and NaCl cotransporter trafficking to the apical membrane is inhibited. At the same time, K+-induced kidney-specific WNK1 leads to suppression of WNK1-L, which allows ROMK trafficking to the apical membrane and maximal K+ secretion. For further details, the reader is referred to an excellent recent review.195

In terms of blood pressure maintenance, systemic vasocon-striction—another major extrarenal action of angiotensin II—may be considered the appropriate response to perceived ECF volume contraction. As mentioned previously, higher concen-trations of angiotensin II are needed to elicit this response than those that govern the renal antinatriuretic actions of angioten-sin II, a situation analogous to the discrepancy between antid-iuretic and pressor actions of vasopressin. Transition from an antinatriuretic to a natriuretic action of angiotensin II at high infusion rates can be attributed almost entirely to a con-comitant rise in blood pressure.196 There is now clear evidence that, besides the adrenal glomerulosa, aldosterone may also be produced by the heart and vasculature. It exerts powerful effects on blood vessels,197 independently of actions that can be attributed to the blood pressure rise through regulation of salt and water balance. As observed with angiotensin II, aldo-sterone also possesses significant mitogenic and fibrogenic


properties. It directly increases the expression and production of transforming growth factor-β and thus is involved in the development of glomerulosclerosis, hypertension, and cardiac injury/hypertrophy.164,189,197

In summary, angiotensin II, the principal effector of the RAAS, regulates extracellular volume and renal Na+ excretion through intrarenal and extrarenal mechanisms. The intrarenal hemodynamic and tubular actions of the peptide and its main extrarenal actions (systemic vasoconstriction and aldosterone release) act in concert to adjust UNa excretion under a variety of circumstances associated with alterations in ECF volume. Many of these mechanisms are synergistic and tend to amplify the overall influence of the RAAS. However, additional coun-terregulatory mechanisms, induced directly or indirectly by angiotensin II, provide a buffer against the unopposed actions of the primary components of the RAAS.Vasopressin. AVP is a nonapeptide (nine–amino acid) hor-mone, synthesized in the brain, that is secreted from the pos-terior pituitary gland into the circulation in response to an increase in plasma osmolality (through osmoreceptor stimu-lation) or a decrease in EABV and blood pressure (through baroreceptor stimulation).198 Thus, AVP plays a major role in the regulation of water balance and the support of blood pres-sure and EABV. AVP exerts its biologic actions through at least three different G protein–coupled receptors. Two of these receptors, V1A and V2, are abundantly expressed in the cardio-vascular system and the kidneys; V1B receptors are expressed on the surfaces of corticotrophic cells of the anterior pituitary gland, in the pancreas, and in the adrenal medulla. V1A and V2 receptors mediate the two main biologic actions of the hor-mone: vasoconstriction and increased water reabsorption by the kidneys, respectively. (V2 receptor–mediated effects on hemo-stasis are discussed in Chapter 56). The V1A and V1B recep-tors operate through the phosphoinositide signaling pathway, causing release of intracellular Ca2+. Found in vascular smooth muscle cells, hepatocytes, and platelets, the V1A receptor medi-ates vasoconstriction, glycogenolysis, and platelet aggregation, respectively. The V2 receptor, found mainly in the renal col-lecting duct epithelial cells, is linked to the adenylate cyclase pathway, and cAMP is used as its second messenger.

Under physiologic conditions, AVP functions primarily to regulate water content in the body by adjusting water reab-sorption in the collecting duct according to plasma tonicity. A change in plasma tonicity by as little as 1% causes a par-allel change in AVP release. This change, in turn, alters the water permeability of the collecting duct. The antidiuretic action of AVP results from complex effects of this hormone on principal cells of the collecting duct. First, AVP provokes the insertion of aquaporin-2 (AQP2)199 water channels into the luminal membrane (short-term response) and increases synthesis of AQP2 messenger RNA and protein200; both responses increase water permeability along the collecting duct. This is considered in detail in Chapter 9. In brief, activa-tion of V2 receptors localized to the basolateral membrane of the principal cells increases cytosolic cAMP, which stimulates the activity of protein kinase A. The latter triggers a series of phosphorylation events that promotes the translocation of AQP2 from intracellular stores to the apical membrane,201 which allows the reabsorption of water from the lumen to the cells. Then the water exits the cell to the hypertonic intersti-tium via aquaporin-3 and aquaporin-4, localized at the baso-lateral membrane.202

The second complex effect of AVP on the collecting duct is to increase the permeability of the IMCD to urea, through activation of the urea transporter UT-A1, which enables the accumulation of urea in the interstitium; there, it contributes, along with Na+, to the hypertonicity of the medullary inter-stitium, which is a prerequisite for maximum urine concentra-tion and water reabsorption.203 AVP exerts several effects on Na+ handling at different segments of the nephron, in which it increases Na+ reabsorption through activation of ENaC, mainly in the cortical and outer medullary collecting duct.204

In addition, AVP may influence renal hemodynamics and reduce RBF, especially to the inner medulla.205 The latter effect is mediated by the V1A receptor and may be modulated by the local release of nitric oxide and prostaglandins. At higher concentrations,206 AVP may also decrease total RBF and GFR, as part of the generalized vasoconstriction induced by the peptide.200,207

The role of the V1A receptor in the kidneys has been further elaborated. In V1A receptor–deficient (V1AR−/−) mice, plasma volume and blood pressure were decreased.207 Also, urine vol-ume of V1AR−/− mice was greater than that of wild-type mice, particularly after a water load; however, GFR, UNa excretion, AVP-dependent cAMP generation, levels of V2 receptor, and AQP2 expression in the kidneys were lower, which indicates that the diminishment of GFR and the V2 receptor–AQP2 system led to impaired urinary concentration in V1AR−/− mice. This result is interesting because classic models implicate the V2 receptors in water handling by the nephron. Moreover, plasma renin and angiotensin II levels were decreased, as was renin expression in granule cells. In addition, the expression of renin stimulators such as nNOS and cyclooxygenase-2 (COX-2) in macula densa cells, where V1AR is specifically expressed, was decreased in V1AR−/− mice. Aoyagi and colleagues207 con-cluded that AVP regulates body fluid homeostasis and GFR through the V1AR in macula densa cells by activating the RAAS and subsequently the V2 receptor–AQP2 system.

A third receptor for AVP, V3,208 is found predominantly in the anterior pituitary gland and is involved in the regulation of adrenocorticotropic hormone (ACTH) release. In addi-tion to its renal effects, AVP also regulates extrarenal vascular tone through the V1A receptor. Stimulation of this receptor by AVP results in a potent arteriolar vasoconstriction in various vascular beds with a significant increase in systemic vascular resistance.209 However, physiologic increases in AVP do not usually cause a significant increase in blood pressure, because AVP also potentiates the sinoaortic baroreflexes that subse-quently reduce heart rate and cardiac output.209 Nevertheless, at supraphysiologic concentrations of AVP, such as those that occur when EABV is severely compromised (e.g., in shock or heart failure), AVP plays an important role in supporting arterial pressure and maintaining adequate perfusion to vital organs such as the brain and myocardium. AVP also has a direct, V1 receptor–mediated, inotropic effect in the isolated heart.210 In vivo, however, AVP has been reported to decrease myocardial function211; this effect is attributed to either car-dioinhibitory reflexes or coronary vasoconstriction induced by the peptide. Of more importance is that AVP has been shown to stimulate cardiomyocyte hypertrophy and protein synthe-sis in neonatal rat cardiomyocytes and in intact myocardium through a V1-dependent mechanism.212 These effects are very similar to those obtained with exposure of cardiomyocytes to angiotensin II or catecholamines, although not necessarily


through the same cellular mechanisms. By this growth-pro-moting property, AVP may contribute to the induction of car-diac hypertrophy and remodeling.213

Controversy exists regarding the effect of AVP on natri-uresis; some authors have found a natriuretic response with infusions, and others have found Na+ retention.214,215 These variations may result from differences between species or from acute changes in volume status.216 Regardless of the effects of AVP on Na+ excretion, in terms of overall volume homeo-stasis, the predominant influence of the hormone is indirectly through water accumulation or vasoconstriction. In fact, the vasoconstrictive V1 receptor effect of AVP overrides the osmotically driven effect (see Chapter 15) in the presence of an ECF volume deficit of 20% or more. Nevertheless, in this regard, potential hypertensive effects of AVP are buffered by a concomitant increase in baroreflex-mediated sympathoinhibi-tion or by an increase in PGE2, which results in a blunting of vasoconstriction, and by a direct vasodepressor action of V2 receptor activation.217

Prostaglandins. Prostaglandins, or cyclooxygenase-derived prostanoids, possess complex and diverse regulatory functions in the kidneys, including hemodynamics, renin secretion, growth response, tubular transport processes, and immune response in both health and disease (Table 14-3).218,219 Cur-rently, two known principal isoforms of cyclooxygenase (COX-1 and COX-2) catalyze the synthesis of prostaglandin H2 (PGH2) from arachidonic acid, released from membrane phospholipids. PGH2 is then metabolized to the five major prostanoids—PGE2; prostaglandins I2, D2, and F2α (PGI2, PGD2, and PGF2α); and thromboxane A2 (TXA2)—through specific synthases219 (see also Chapter 11). An additional splice variant of the COX-1 gene, COX-3, has been identi-fied, but its function in humans is yet to be fully elucidated.220

Prostanoids are rapidly degraded so that their effect is local-ized strictly to their site of synthesis, which accounts for the predominance of their autocrine and paracrine mode of action. Each prostanoid has a specific cell surface G protein–coupled receptor, distinct for a given location, that determines the spe-cific function of the prostaglandin in the given cell type.219 COX-1 is constitutively expressed and serves in a housekeep-ing role in many cell types; it is expressed abundantly and is highly immunoreactive in the kidneys, especially in the col-lecting duct but also in medullary interstitial, mesangial, and arteriolar endothelial cells of most species.219 In contrast, the expression of COX-2 is inducible and cell-type specific, and

its renal expression is prominent in medullary interstitial cells, cortical cells of the thick ascending limb of Henle, and cells of the macula densa, in which expression is regulated in response to varying amounts of salt intake (see Hao and Breyer219 and references therein). Furthermore, the profile of sensitivity to pharmacologic inhibitors differs between the two isoforms.221 The principal prostanoid in the kidneys is PGE2; others pres-ent are PGI2, PGF2, and TXA2.219 PGI2 and PGE2 are the main products in the cortex of normal kidneys, and PGE2 predominates in the medulla.219 Metabolism of arachidonic acid by other pathways (lipoxygenase, epoxygenase) leads to products that are involved in crosstalk with cyclooxygenase (see Nasrallah et al218). The major sites for prostaglandin production (and hence for local actions) are the renal arteries and arterioles and glomeruli in the cortex and interstitial cells in the medulla, with additional contributions from epithelial cells of the cortical and medullary collecting tubules.222,223

The two major roles for prostaglandins in volume homeo-stasis are (1) their effect on RBF and GFR and (2) their effect on tubular handling of salt and water, on the other. Table 14-3 lists target structures, mode of action, and major biologic effects of the active renal prostanoids. PGI2 and PGE2 have predominantly vasodilating and natriuretic activities; they also modulate the action of AVP and tend to stimulate renin secretion. TXA2 has been shown to cause vasoconstriction, although the importance of the physiologic effects of TXA2 on the kidneys is still controversial. The end results of the stimulation of renal prostaglandin secretion in the kidneys are vasodilation, increased renal perfusion, natriuresis, and facili-tation of water excretion.

The role of prostaglandins as vasodilators in the glomerular microcirculation is now well established. The cellular targets for vasoactive hormones in the glomerular microcirculation are vascular smooth muscle cells of the afferent and efferent arterioles and mesangial cells within the glomeruli. Action at these sites governs renal vascular resistance, glomerular func-tion, and downstream microcirculatory function in peritu-bular capillaries and vasa recta. In vivo studies showed that intrarenal infusions of PGE2 and PGI2 cause vasodilation and increased RBF.222 In agreement with these findings, in vitro experiments with isolated renal microvessels showed that both PGE2 and prostaglandin E1 (PGE1) attenuate angioten-sin II–induced afferent arteriolar vasoconstriction, and PGI2 antagonizes angiotensin II–induced efferent arteriolar vaso-constriction.224 Similarly, PGE2 has been shown to counteract

TABLE 14-3 Major Renal Biologic Effects of Prostaglandins and Thromboxane

AGENT TARGET STRUCTURE MODE OF ACTION DIRECT CONSEQUENCES

PGE2, PGI2 Intrarenal arterioles Vasodilation Increased renal perfusion (more pronounced in inner cortical and medullary regions)

PGI2 Glomeruli Vasodilation Increased filtration rate

PGE2, PGI2 Efferent arterioles Vasodilation Increased Na+ excretion through increased postglomerular perfusion

PGE2, PGI2, PGF2α Distal tubules Decreased transport Increased Na+ excretion, decreased maximum medullary hypertonicity

PGE2, PGI2, PGF2α Distal tubules Inhibition of cAMP synthesis Interference with AVP action

PGE2, PGI2 Juxtaglomerular apparatus cAMP stimulation (?) Increased renin release

TXA2 Intrarenal arterioles Vasoconstriction Decreased renal perfusionAVP, Arginine vasopressin; cAMP, cyclic adenosine monophosphate; PGE2, prostaglandin E2; PGF2α, prostaglandin F2α; PGI2, prostaglandin I2; TXA2, thromboxane A2.


angiotensin II–induced contraction of isolated glomeruli and glomerular mesangial cells in culture, and conversely, cyclo-oxygenase inhibition augments these contractile responses. An inhibitory counterregulatory role of prostaglandins with regard to renal nerve stimulation has also been demonstrated from micropuncture studies.148 Furthermore, in volume-contracted states, COX-2 expression and PGE2 release in the macula densa and cortical thick ascending limb of Henle dramatically increase in response to decreased luminal Cl− delivery. In addition to its direct vasodilator effect on affer-ent arterioles, PGE2 leads to increased renin release from the macula densa (see Hao and Breyer219). The resulting rise in angiotensin II and consequent efferent arteriolar constriction also ensure maintenance of GFR.

In the clinical situation, in volume-replete states, the renal vasoconstrictive influences of angiotensin II and norepi-nephrine are mitigated by their simultaneous stimulation of vasodilatory renal prostaglandins so that RBF and GFR are maintained.225 However, in the setting of heightened vaso-constrictor input from the RAAS, SNS, and AVP, as occurs during states of EABV depletion, the vasorelaxant action of PGE2 and PGI2 is overwhelmed, with the concomitant risk for the development of acute kidney injury.219 Similarly, when this prostaglandin-mediated counterregulatory mechanism is suppressed by nonselective or COX-2–selective inhibitors, the unopposed actions of angiotensin II and norepinephrine can also lead to a rapid deterioration in renal function.226 More-over, COX-2–derived prostanoids also promote natriuresis and stimulate renin secretion.219 Therefore, during states of volume depletion, low Na+ intake, or the use of loop diuret-ics, COX-2 inhibitors (such as celecoxib or rofecoxib), as well as the nonselective cyclooxygenase inhibitors diclofenac and naproxen, can cause Na+ and K+ retention, edema formation, heart failure, and hypertension.223

Whereas the role of prostaglandins in modulating glomer-ular vasoreactivity in states of varying salt balance is firmly established, the effects of prostaglandins on salt excretion per se are still being unraveled. Certainly, the aforementioned vas-cular effects of prostaglandins can be expected to have second-ary effects on tubular function through the various physical factors described previously in this chapter. One particular consequence of prostaglandin-induced renal vasodilation may be medullary interstitial solute washout. Such a change in medullary interstitial composition could potentially account for the observed increase in UNa excretion with intrarenal infusion of PGE2.222 The natriuretic response to PGE2 may also be attenuated by preventing an increase in renal inter-stitial hydraulic pressure, even in the presence of a persistent increase in RBF.227 In addition, in rats, the natriuresis usually accompanying direct expansion of renal interstitial volume can be significantly attenuated by inhibition of prostaglandin synthesis.227 These findings are consistent with the proposal that changes in prostaglandins have a significant effect on renal Na+ excretion.

Results of a number of micropuncture and microcatheter-ization studies in vivo suggested that prostaglandins affected UNa excretion independently of hemodynamic changes.222 Subsequently, direct effects of PGE2 on epithelial transport processes were demonstrated and were found to vary consid-erably in different nephron segments. In the medullary thick ascending limb of Henle and collecting tubule, PGE2 caused a decrease in the reabsorption of water, Na+, and Cl− that was

correlated with reduced Na+-K+-ATPase activity. In contrast, in the distal convoluted tubule, PGE2 caused increased Na+-K+-ATPase activity.228 The net effect of locally produced prostaglandins on tubular Na+ handling is probably inhibi-tory because complete blockade of prostaglandin synthesis by indomethacin in rats receiving a normal or salt-loaded diet increased fractional Na+ reabsorption and enhanced the activ-ity of the renal medullary Na+-K+-ATPase.229 In addition, PGE2 inhibits AVP-stimulated NaCl reabsorption in the medullary thick ascending limb of Henle and AVP-stimulated water reabsorption in the collecting duct.224,224,230 Both these effects tend to antagonize the overall hydroosmotic response to AVP. However, because no such effect is seen in the cortical thick ascending limb of Henle, which is capable of augment-ing NaCl reabsorption in response to an increased delivered load, and because the effects of prostaglandins on solute trans-port in the collecting tubule remain controversial, no conclu-sions can be reached from these studies with regard to the contribution of direct epithelial effects of prostaglandins to overall Na+ excretion.224

In whole animal and clinical balance studies, researchers have examined the effect of prostaglandin infusion or prostaglandin synthesis inhibition on urinary Na+ excretion, or they have attempted to correlate changes in urinary pros-taglandin excretion with changes in salt balance; these studies have also yielded conflicting and inconclusive results. Never-theless, as elaborated earlier, prostaglandins have an important role in states of Na+ imbalance (real or perceived Na+ deple-tion) wherein they are involved to preserve GFR by counter-vailing renal vasoconstrictive influences.

The influence of changes in Na+ intake on renal COX-1 and COX-2 expression has been studied extensively. The expression of COX-2 in the macula densa and thick ascend-ing limb of Henle is increased by a low-salt diet, inhibition of RAAS, and renal hypoperfusion. In contrast, a high-salt diet has been reported to decrease COX-2 expression in the renal cortex.218,219 None of these changes on Na+ intake affected the expression of COX-1 in the cortex. In the medulla, whereas a low-salt diet downregulated both COX-1 and COX-2, a high-salt diet enhanced the expression of these cyclooxygen-ase isoforms.218,219 In vitro studies showed that high osmo-larity of the medium of cultured IMCD cells induces the expression of COX-2.223 Infusion of nimesulide (a selective COX-2 inhibitor) into anesthetized dogs on normal Na+ diet reduced UNa excretion and urine flow rate, despite the lack of effect on renal hemodynamics or systemic blood pressure.223

Collectively, the differential regulation of COX-2 in the renal cortex and medulla can be integrated into a physiologi-cally relevant model, in which upregulation of COX-2 in the cortical thick ascending limb of Henle and macula densa is induced in volume-contracted or vasoconstrictory states. In the cortical thick ascending limb of Henle, the effect is by direct inhibition of Na+ excretion, whereas in the macula densa, COX-2 stimulates renin release, which leads to angio-tensin II–mediated Na+ retention. In contrast, medullary COX-2 is induced by a high-salt diet, which leads to net Na+ excretion.219

Finally, in addition to the hemodynamically mediated and potential direct epithelial effects of prostaglandins, these agents may mediate the physiologic responses to other hor-monal agents. The intermediacy of prostaglandins in renin release responses has already been cited. As another example,


some, but not all, of the known physiologic effects of bradyki-nin and other products of the kallikrein-kinin system are medi-ated through bradykinin-stimulated prostaglandin production (e.g., inhibition of AVP-stimulated osmotic water permeabil-ity in the cortical collecting tubule).224 In addition, the renal and systemic actions of angiotensin II appear to be differen-tially regulated by prostaglandin production that is catalyzed by COX-1 and COX-2. For instance, COX-2 deficiency in mice, induced by COX-2 inhibitors or knockout, dramati-cally augmented the systemic pressor effect of angiotensin II, whereas COX-1 deficiency abolished this pressor effect. Sim-ilarly, angiotensin II infusion reduced medullary blood flow in COX-2–deficient animals, but not in COX-1–deficient animals, which suggests that COX-2–dependent vasodilators are synthesized in the renal medulla. Moreover, the diuretic and natriuretic effects of angiotensin II were absent in COX-2–deficient animals, but they remained in COX-1–deficient animals. Thus, COX-1 and COX-2 exert opposite effects on systemic blood pressure and renal function.231

Natriuretic Peptides. The physiologic and pathophysiologic roles of the natriuretic peptide family in the regulation of Na+ and water balance have become better understood since the discovery of ANP by de Bold and colleagues.20 ANP is an endogenous 28–amino acid peptide secreted mainly by the right atrium. Besides ANP, two other natriuretic peptides have renal effects: BNP and CNP.22 Although encoded by different genes, these peptides are highly similar in chemical structure, gene regulation, and degradation pathways, consti-tuting a hormonal system that exerts various biologic actions on the renal, cardiac, and blood vessel tissues.232 ANP plays an important role in blood pressure and volume homeosta-sis through its ability to induce natriuretic/diuretic and vaso-dilatory responses.233,234 BNP has an amino acid sequence similar to that of ANP, with an extended NH2-terminus. In humans, BNP is produced from pro–brain natriuretic peptide (proBNP), which contains 108 amino acids and, in accor-dance with a proteolytic process, releases a mature 32–amino acid molecule and N-terminal fragment into the circulation. Although BNP was originally cloned from the brain, it is now considered a circulating hormone produced mainly in the car-diac ventricles.235 CNP, which is produced mostly by endo-thelial cells, shares the ring structure common to all natriuretic peptide members; however, it lacks the C-terminal tail.

The biologic effects of the natriuretic peptides are medi-ated by binding the peptide to specific membrane receptors localized to numerous tissues, including vasculature, renal arteries, glomerular mesangial and epithelial cells, collecting ducts, adrenal zona glomerulosa, and the CNS.22 At least three different subtypes of natriuretic peptide receptors have been identified: NP-A, NP-B, and NP-C.232 NP-A and NP-B, single-transmembrane proteins with molecular weights of approximately 120 to 140 kDa, mediate most of the biologic effects of natriuretic peptides. Both are coupled to guanyl-ate cyclase in their intracellular portions.232 After binding to their receptors, all three natriuretic peptide isoforms mark-edly increase cGMP in target tissues and in plasma. There-fore, analogs of cGMP or inhibitors of degradation of this second messenger mimic the vasorelaxant and renal effects of natriuretic peptides. The third class of natriuretic peptide–binding receptors, NP-C (molecular weight of 60 to 70 kDa), is believed to serve as a clearance receptor because it is not coupled to any known second-messenger system.236 ANP-C

is the most abundant type of natriuretic peptide receptor in many key target organs of these peptides.236

Additional routes for the removal of natriuretic peptides includes enzymatic degradation by neutral endopeptidase (NEP) 24.11, a metalloproteinase located mainly in the lungs and the kidneys.236

Atrial Natriuretic Peptide. Both in vivo and in vitro studies, in humans as well as in experimental animals, established the role of ANP in the regulation of ECF volume and the control of blood pressure by acting on all organs and tissues involved in the homeostasis of Na+ and blood pressure (Table 14-4).233 There-fore, it is not surprising that ANP and NH2-terminal ANP lev-els are increased in (1) conditions associated with enhanced atrial pressure, (2) systolic or diastolic cardiac dysfunction, (3) cardiac hypertrophy/remodeling, and (4) severe myocardial infarction.22 In the kidneys, ANP exerts hemodynamic/glomerular effects that increase Na+ and water delivery to the tubule, in combina-tion with inhibitory effects on tubular Na+ and water reabsorp-tion, which lead to remarkable diuresis and natriuresis.233

In addition to its powerful diuretic and natriuretic activi-ties, ANP also relaxes vascular smooth muscle and leads to vasodilation, by antagonizing the concomitant vasocon-strictive influences of angiotensin II, endothelin, AVP, and α1-adrenergic input.233 This vasodilation reduces preload, which results in a fall in cardiac output.233 In addition, ANP reduces cardiac output by shifting fluid from the intravascu-lar to the extravascular compartment, an effect mediated by increased capillary hydraulic conductivity for water.237 Studies in endothelial-restricted GC-A–knockout mice have yielded evidence that ANP, through GC-A, enhances microvascular endothelial macromolecule permeability in vivo. Because such mice exhibit chronic hypervolemic hypertension, the authors hypothesized that modulation of transcapillary protein and

TABLE 14-4 Physiologic Actions of the Natriuretic Peptides

TARGET ORGAN BIOLOGIC EFFECTS

Kidneys Increased GFRAfferent arteriolar vasodilationEfferent arteriolar vasoconstriction

NatriuresisInhibition of Na+/H+ exchanger (proximal tubule)Inhibition of Na+-Cl− cotransporter (distal tubule)Inhibition of Na+ channels (collecting duct)

Diuresis Inhibition of AVP-induced aquaporin-2 incorporation into collecting duct apical membrane

Cardiac Reduction in preload, leading to reduced cardiac outputInhibition of cardiac remodeling

Hemodynamic VasorelaxationElevating capillary hydraulic conductivityDecreased cardiac preload and afterload

Endocrine Suppression of RAASSuppression of sympathetic outflowSuppression of AVPSuppression of endothelin

Mitogenesis Inhibition of mitogenesis in vascular smooth muscle cellsInhibition of growth factor–mediated hypertrophy of cardiac fibroblasts

AVP, Arginine vasopressin; GFR, glomerular filtration rate; RAAS, renin- angiotensin-aldosterone system.


fluid transport might represent one of the most important hypovolemic actions of ANP.238

ANP has also been shown to exert antiproliferative, growth-regulatory properties in cultured glomerular mesangial cells, vascular smooth muscle cells, and endothelial cells.233 Within the kidneys, ANP causes afferent vasodilation, efferent vaso-constriction, and mesangial relaxation, which lead to increases in glomerular capillary pressure, GFR, and filtration fraction (see Houben et al235). In combination with increased medul-lary blood flow, these hemodynamic effects enhance diuresis and natriuresis. However, the overall natriuretic effect of ANP infusion does not require these changes in glomerular func-tion (except in response to larger doses of the peptide). At the tubular level, ANP inhibits the stimulatory effect of angio-tensin II on the luminal Na+/H+ exchanger of the proximal tubule (see Houben et al235 and references therein). Likewise, ANP, acting through cGMP, inhibits the thiazide-sensitive NaCl cotransporter in the distal tubule and ENaC in the col-lecting duct, along with inhibition of AVP-induced AQP2 incorporation into the apical membrane of these segments of the nephron (see Houben et al235 and references therein; see Table 14-4).Brain Natriuretic Peptide. The physiologic function of BNP, in contrast to that of ANP, remains unclear. Findings since 2005 suggest that BNP is produced by activated satellite cells in ischemic skeletal muscle or by cardiomyocytes in response to pressure load, thereby regulating the regeneration of neigh-boring endothelia through GC-A. Kuhn and associates239 proposed that the BNP-mediated paracrine communication may be critically involved in coordinating muscle regeneration or hypertrophy and angiogenesis. However, administration of BNP to human subjects induces natriuretic, endocrine, and hemodynamic responses similar to those induced by ANP (see Houben et al235 and references therein).

BNP is produced and secreted mainly by the ventricles, but also, in small amounts, by the atrium (see Houben et al235 and references therein). Increased volume or pressure overload states such as CHF and hypertension enhance the secretion of BNP from the ventricles. Despite the comparable elevation in plasma levels of ANP and BNP in patients with CHF and other chronic volume-expanded conditions, acute intravenous saline loading or infusion of pressor doses of angiotensin II yields different patterns of ANP and BNP secretion.240,241 Whereas plasma levels of ANP increase rapidly, the changes in plasma BNP of atrial origin are negligible, as expected in view of the minimal atrial content of BNP, in contrast to the abundance of ANP.235 Moreover, plasma levels of BNP rise with age, from 26 ± 2 pg/mL in subjects aged 55 to 64 years to 31 ± 2 pg/mL in patients aged 65 to 74 years and to 64 ± 6 pg/mL in patients aged 75 years or older.242

Studies in animals and humans have demonstrated the natriuretic effects of pharmacologic doses of BNP. When administered to normal volunteers and hypertensive subjects at low doses, BNP induces a significant increase in UNa excre-tion and, to a lesser extent, in urinary flow. Significant natri-uresis and diuresis were observed after the infusion of either ANP or BNP to normal subjects. The combination of ANP and BNP did not produce a synergistic renal effect, which sug-gests that these peptides share similar mechanisms of action (see Houben et al235 and references therein). Moreover, like ANP, BNP exerts a hypotensive effect in both animals and humans. For instance, transgenic mice that overexpress the

BNP gene exhibit significant and lifelong hypotension to the same extent as do transgenic mice that overexpress the ANP gene (see Hall243 and references therein). Therefore, it is clear that BNP induces its biologic actions through mechanisms similar to those of ANP.235

This notion is supported by several findings: (1) Both ANP and BNP act through the same receptors, and both induce similar renal, cardiovascular, and endocrine actions in associa-tion with an increase in cGMP production (see Table 14-4); and (2) BNP suppresses ACTH-induced aldosterone genera-tion both in cell culture and when BNP is infused in vivo. The latter action may be attributed to BNP inhibition of renin secretion, at least in dogs, although apparently not in humans (see Hall243 and references therein). Like the hemodynamic effects of ANP, those of BNP vary according to the dose and species. When injected as a bolus at high doses, BNP caused a profound fall in systolic blood pressure in humans; however, when infused at low doses, this peptide failed to change blood pressure or heart rate (see Houben et al235 and references therein). The effects of BNP have been used in the clinical setting both in the diagnosis and treatment of the volume overload state of CHF. This aspect is discussed in the “Spe-cific Treatments Based on the Pathophysiology of Congestive Heart Failure” section.C-Type Natriuretic Peptide. Although CNP is considered a neurotransmitter in the CNS, considerable amounts of this natriuretic peptide are produced by endothelial cells, where it plays a role in the local regulation of vascular tone.236 Smaller amounts of CNP are produced in the kidneys, heart ventricles, and intestines.236 In addition, CNP, which could be of endo-thelial or cardiac origin, has been found in human plasma. The physiologic stimuli for CNP production have not been identified, although enhanced expression of CNP messenger RNA has been reported after volume overload.236 Intravenous infusion of CNP decreases blood pressure, cardiac output, uri-nary volume, and Na+ excretion. Furthermore, the hypoten-sive effects of CNP are less pronounced compared to those of ANP and BNP, but CNP strongly stimulates cGMP produc-tion and inhibits vascular smooth muscle cells proliferation.236

Although all three natriuretic peptide forms inhibit the RAAS, CNP failed to induce significant changes in cardiac output, blood pressure, and plasma volume in sheep.236 This finding supports the widely accepted concept that ANP and BNP are the major circulating natriuretic peptides, whereas CNP is a local regulator of vascular structure and tone. Although all forms of natriuretic peptides exist in the brain, the role and significance of their CNS expression in the regu-lation of salt and water balance are not understood. Together, the various biologic actions of natriuretic peptides lead to reduction of EABV, an expected response to perceived over-filling of the central intrathoracic circulation. Furthermore, all natriuretic peptides counteract the adverse effects of RAAS, which suggests that the two systems are acting in opposite directions in the regulation of body fluid and cardiovascular homeostasis.Endothelium-Derived Factors. The endothelium is a major source of active substances that regulate vascular tone in healthy states and disease.244 The best known representatives are endothelin, nitric oxide, and PGI2. These vasoconstrict-ing and vasodilating factors regulate the perfusion pressure of multiple organ systems that are strongly involved in water and Na+ balance, such as the kidneys, heart, and vasculature.


This section summarizes some of the concepts regarding actions of endothelin and nitric oxide that are relevant to vol-ume homeostasis.Endothelin. The endothelin system consists of three vasoac-tive peptides: endothelin 1 (ET-1), endothelin 2 (ET-2), and endothelin 3 (ET-3). These peptides are synthesized and released mainly by endothelial cells and act in a paracrine and autocrine manner.245-248 ET-1, the major representative of the endothelin family, is still the most potent vasoconstric-tor known249 (however, see also the “Urotensin” section). All endothelins are synthesized by proteolytic cleavage from specific prepro-endothelins that are further cleaved to form 37– to 39–amino acid precursors, called big endothelin. Big endothelin is then converted into the biologically active, 21–amino acid peptide by a highly specific endothelin converting enzyme (ECE), a phosphoramidon-sensitive membrane-bound metalloprotease. To date, two isoforms of ECE have been identified: ECE-1 and ECE-2.250 ECE-2 is localized mainly to vascular smooth muscle cells and is probably an intracellular enzyme. In ECE-1–knockout mice, tissue lev-els of ET-1 are reduced by about one third, which suggests that ECE-independent pathways are involved in the synthesis of this peptide (see Barton and Yanagisawa250 and references therein). In this regard, both chymase251 and carboxypeptidase A252 have been shown to be involved in mature endothelin production.

The endothelins bind to two distinct receptors, designated endothelin types A and B (ET-A and ET-B).246-248 The ET-A receptor shows a higher affinity for ET-1 than for ET-2 or ET-3. The ET-B receptor shows equal affinity for each of the three endothelins. ET-A receptors are found mainly on vas-cular smooth muscle cells, on which their activation leads to vasoconstriction through an increase in cytosolic Ca2+. ET-B receptors are also found on vascular smooth muscle cells, on which they can mediate vasoconstriction, but they are found predominantly on vascular endothelium, in which their acti-vation results in vasodilation through prostacyclin and nitric oxide.248 Endothelin is detectable in the plasma of human subjects and many experimental animals and therefore may also act as a circulating vasoactive hormone.249

Selective ET-A receptor antagonism is associated with vasodilation and a reduction in blood pressure, whereas selec-tive ET-B antagonism is accompanied by vasoconstriction and a rise in blood pressure.248 These data suggest complementary roles for the endothelin receptor subtypes in the maintenance of vascular tone. In addition to its vasoconstrictive action, endothelin has a variety of effects on the kidneys.246-248,253 The kidney (mainly the inner medulla) is both a source and an important target organ of endothelin. ET-1 is synthesized by the endothelial cells of the renal vessels, whereas ET-1 and ET-3 are produced by various cell types of the nephron. ET-2 and ET-3 are produced at a rate of one to two orders of mag-nitude lower than ET-1, which appears to be the principal subtype involved in renal functional regulation.246

In relation to volume homeostasis, three major aspects of renal function are affected by ET-1 in a paracrine or auto-crine manner: (1) renal and intrarenal blood flow, (2) glo-merular hemodynamics, and (3) renal tubular transport of salt and water. Both ET-A and ET-B receptors are present in the glomerulus, renal vessels, and tubular epithelial cells, but most ET-B receptors are found in the medulla.254 The renal vasculature, in comparison with other vascular beds, appears

mposition

to be most sensitive to the vasoconstrictor action of ET-1. Infusion of ET-1 into the renal artery of anesthetized rabbits decreases RBF, GFR, natriuresis, and urine volume.255 Micro-puncture studies demonstrated that ET-1 increases afferent and efferent arteriolar resistance (afferent more than efferent), which results in a reduction in glomerular plasma flow rate. In addition, Kf is reduced because of mesangial cell contraction, resulting in a diminished SNGFR.

The profound reduction of RBF and concomitant lesser reduction in GFR should result in a rise in filtration fraction, but the effect of ET-1 on the filtration fraction appears to be variable: Some groups, using low doses in a canine model, reported a rise,256 and others reported no significant effect.257 Infusion of ET-1 for 8 days into conscious dogs increased plasma levels of endothelin by twofold to threefold and resulted in increased renal vascular resistance and decreased GFR and RBF.206 Interestingly, the effect of endothelin on regional intrarenal blood flow is not homogeneous. Using laser Doppler flowmetry, Gurbanov and colleagues258 found that administration of ET-1 in control rats produced a sus-tained cortical vasoconstriction and a transient medullary vasodilatory response. These results are in line with the med-ullary predominance of ET-B receptors, and the high density of ET-A–binding sites in the cortex.246

The effect of endothelin on Na+ and water excretion var-ies and depends on the dose and source of endothelin. Sys-temic infusion of endothelin in high doses results in profound antinatriuresis and antidiuresis, apparently secondary to the decrease in GFR and RBF. However, in low doses or when produced locally in tubular epithelial cells, endothelin has been claimed to decrease the reabsorption of salt and water, which suggests that ET-1 target sites are present on renal tubules.259 Also, administration of the endothelin precursor, big endothelin, has been shown to cause natriuresis, which supports the notion of a direct inhibitory autocrine action of endothelin on tubular salt reabsorption.

The natriuretic and diuretic actions of big ET-1 can be significantly reduced by ET-B–specific blockade.260 Similar results were reported when the same ET-B antagonist was given chronically by osmotic minipump (reviewed by Pol-lock and Pollock245). Furthermore, ET-B–knockout rats have salt-sensitive hypertension that is reversed by luminal ENaC blockade with amiloride, which suggests that, in vivo, ET-B in the collecting duct tonically inhibits ENaC activity, the final regulator of Na+ balance.261 Similarly, mice with collecting duct–specific knockout of the ET-1 gene have impaired Na+ excretion in response to Na+ load and develop hypertension with high salt intake.246 These mice also have heightened sen-sitivity to AVP and reduced ability to excrete an acute water load. These findings are in line with in vitro observations that ET-B mediates the inhibitory effects of ET-1 on Na+ and water transport in the collecting duct and thick ascending limb of Henle.246

Thus, if vascular and mesangial endothelin exerts a greater physiologic effect than does tubule-derived endothelin, then RBF is diminished and net fluid retention occurs, whereas if the tubule-derived endothelin effect predominates, salt and water excretion is increased. The ability of ET-1 to revers-ibly inhibit AVP-stimulated water permeability was first shown in the isolated perfused IMCD262 Moreover, ET-1 reduces AVP-stimulated cAMP accumulation and water per-meability in the IMCD.246 In addition, ET-1 mitigates the


hydroosmotic effect of AVP in the cortical collecting duct and the outer medullary collecting duct. Furthermore, stud-ies in rabbit cortical collecting duct have demonstrated that ET-1 may inhibit the luminal amiloride-sensitive ENaC by a Ca2+-dependent effect. Moreover, collecting duct–specific ET-1–knockout mice were shown to have an impaired ability to excrete both Na+ and water loads in comparison with their wild-type counterparts. Taking into account the facts that the medulla contains ET-B receptors and the highest endothelin concentrations in the body, and that endothelins also inhibit Na+-K+-ATPase in IMCD,246 these effects may contribute to the diuretic and natriuretic actions of locally produced ET-1. This may also explain the natriuretic effect of ET-1 reported by some investigators, despite the reduction in RBF and GFR.263

Endothelin production in the kidneys is regulated dif-ferently than that in the vasculature. Whereas vascular (and mesangial) endothelin generation is controlled by thrombin, angiotensin II, and transforming growth factor–β, tubular endothelin production seems to depend on entirely different mechanisms, of which medullary tonicity may be particularly important. Volume expansion in humans increased urinary endothelin excretion, which was suggestive of an inhibitory action of renal endothelin on water reabsorption, particu-larly in the collecting duct.254 Also, a high-salt diet, by rais-ing medullary tonicity, stimulates ET-1 release, which in turn leads to increased endothelial NOS (eNOS, or NOS3) expres-sion and natriuresis.264 (The NOS-dependent ET-1 effects are discussed further in the following “Nitric Oxide” section). Therefore, both salt and water balance appear to regulate renal endothelin production and collecting duct fluid reabsorption by altering medullary tonicity. The signaling mechanisms for these phenomena, as well other renal actions of ET-1, con-tinue be a subject of intensive research, and the interested reader is referred to a review that summarizes the current state of knowledge.254

Nitric Oxide. Nitric oxide is a diffusible gaseous molecule produced from its precursor L-arginine by the enzyme NOS, which exists in three distinct isoforms: nNOS, inducible NOS (iNOS, or NOS2), and eNOS.245 NOS is expressed in endo-thelial cells of the renal vasculature (mainly eNOS), tubu-lar epithelial and mesangial cells, and macula densa (mainly nNOS). There is controversy regarding the renal expression of iNOS in normal kidneys, but upregulation of this isoform is clearly seen in pathologic conditions such as ischemia- reperfusion injury (reviewed by Mount and Power265).

The availability of selective NOS inhibitors and NOS–knockout mice has improved the ability to investigate the individual role of the NOS isoforms in the regulation of renal function.99 However, the role of a specific nitric oxide isoform in a given cell type is not yet fully understood. Therefore, this discussion refers to the renal effects of nitric oxide regardless of its enzymatic isoform source, unless the source has been determined.

The action of nitric oxide is mediated by activation of a soluble guanylyl cyclase, thereby increasing intracellular levels of its second messenger, cGMP.266 In the kidneys, the physi-ologic roles of nitric oxide include the regulation of glomeru-lar hemodynamics, attenuation of tubuloglomerular feedback, mediation of pressure natriuresis, maintenance of medullary perfusion, inhibition of tubular Na+ reabsorption, and modu-lation of RSNA.245 Renal NOS activity is regulated by several

humoral factors, such as angiotensin II (see “Tubuloglomeru-lar Feedback” section) and salt intake.98

The role of nitric oxide in the regulation of renal hemo-dynamics and excretory function is best illustrated by the fact that inhibition of intrarenal nitric oxide production results in increased blood pressure and impaired renal function.267 Infusion of the NOS inhibitor, Ng monomethyl-L-arginine (L-NMMA), into one kidney in anesthetized dogs resulted in a dose-dependent decrease in urinary cGMP levels, decreases in RBF and GFR, Na+ and water retention, and a decline in fractional Na+ excretion in the ipsilateral kidney, in compari-son with the contralateral kidney.267 In addition, acute nitric oxide blockade amplified the renal vasoconstrictive action of angiotensin II in isolated micoperfused rabbit afferent arte-rioles and in conscious rats, which suggests that nitric oxide and angiotensin II interact in the control of renal vascula-ture (see Lai et al,94 Patzak and Persson,98 and Mount and Power265 and references therein). This notion is supported by the findings that L-NMMA–induced vasoconstriction led to decreased RBF and Kf and was prevented by RAAS blockade; thus, some of the major effects of nitric oxide are to counter-balance the vasoconstrictive action of angiotensin II.

Nitric oxide has also been shown to exert a vasodilatory action on afferent arterioles and to mediate the renal vasore-laxant actions of acetylcholine and bradykinin (reviewed by Mount and Power265). The counterbalancing effect of nitric oxide on angiotensin II–induced efferent arteriolar vasocon-striction and its role in regulating tubuloglomerular feedback and in modulating renin secretion by the juxtaglomerular apparatus are discussed in the “Tubuloglomerular Feedback” section.98,99

The involvement of nitric oxide in the regulation of Na+ balance is well characterized. In conscious dogs on a nor-mal Na+ diet, nitric oxide inhibition induced a significant decrease in natriuresis and diuresis without a change in arte-rial pressure. In dogs receiving a high-Na+ diet and treatment with the nitric oxide inhibitor, L-nitroarginine methyl ester (L-NAME), both arterial pressure and cumulative Na+ bal-ance were higher than in dogs receiving a comparable diet but no treatment with nitric oxide inhibitors.268 Exposure of rats to high-salt intake (1% NaCl drinking water) for 2 weeks induced increased serum concentration and urinary excretion of the nitric oxide metabolites, NO2 + NO3. Urinary NO2 + NO3 and Na+ excretion were significantly correlated. The increase in urinary nitric oxide metabolites is attributed to the enhanced expression of all three NOS isoforms in the renal medulla by high-salt intake.99 These findings suggest that nitric oxide may have a role in promoting diuresis and natriuresis in both normal and increased salt intake/volume-expanded states.245

As just mentioned, L-NAME infused directly into the renal medullary interstitium of anesthetized rats reduced pap-illary blood flow, in association with decreased Na+ and water excretion, which indicates that nitric oxide exerts a vasodila-tory effect on the renal medullary circulation and promotes Na+ excretion.126 Consistent with these data are the findings of high levels of eNOS in the renal medulla and the inhibi-tory effect of nitric oxide on Na+-K+-ATPase in the collecting duct.269 Additional evidence of the involvement of the nitric oxide system in Na+ homeostasis is derived from studies in which researchers examined the mechanism of salt-sensitive hypertension. According to these studies, activity of NOS,


mainly nNOS, is significantly lower in salt-sensitive rats than in salt-resistant rats maintained on a high-salt diet.270,271 In another study, the impaired activity of NOS in salt-sensitive rats was evidenced by decreased NO2 + NO3 excretion272 Intravenous L-arginine increased nitric oxide production and prevented the development of salt-induced hypertension in Dahl salt-sensitive rats.272 These findings suggest that nNOS plays an important role in Na+ handling and that decreases in nNOS activity may in part be involved in the mechanism of salt-sensitive hypertension.

The involvement of nitric oxide in the abnormal Na+ han-dling in hypertension could result from an inadequate direct effect on tubular Na+ reabsorption in proximal and distal seg-ments. However, attenuated inhibitory actions of nitric oxide on renin secretion and tubuloglomerular feedback may also contribute to salt retention and subsequent hypertension. In this context, investigators concluded that nitric oxide origi-nating from the macula densa blunted the tubuloglomeru-lar feedback–mediated vasoconstriction during high-salt intake in salt-resistant rats, whereas in salt-sensitive rats, this response was lost.273 As already mentioned, there is strong evidence that both the medullary and other effects of nitric oxide occur in response to local endothelin production.245 For example, the inhibition of NOS by L-NAME or the highly selective ET-B antagonist A-192621 abolished the diuretic and natriuretic effects of big ET-1 in the kidneys of anes-thetized rats.260 In addition, ET-1 acutely activated eNOS in the isolated medullary thick ascending limb of Henle and nNOS in isolated IMCD cells, via ET-B activation. Studies in ET-B receptor–deficient rats have shown that this activa-tion of nNOS and eNOS is accompanied by an increase in nNOS protein but no change in messenger RNA expression (see Pollock and Pollock245 and references therein). These data suggest that nNOS and eNOS activation occur by post-transcriptional pathways.

Activation of eNOS in the IMCD is also associated with inhibition of Na+ reabsorption in the medullary thick ascend-ing limb of Henle through phosphatidylinositol 3-kinase (PI3K)–stimulated Akt activity, leading to eNOS phosphor-ylation at Ser1177.274 Thus, ET-1 has a paracrine effect on eNOS expression in the IMCD. However, the functional corollary of nNOS activation in the IMCD remains to be determined. A further action of nitric oxide is the inhibition of AVP-enhanced Na+ reabsorption and hydroosmotic water permeability of the cortical collecting duct.275 The signaling mechanisms involved in the nitric oxide effects on AVP have not been studied in detail. The role of nitric oxide in pressure natriuresis and RSNA is discussed in the relevant sections.Kinins. The kallikrein-kinin system is a complex cascade responsible for the generation and release of vasoactive kinins. The active peptides bradykinin and kallidin are formed from precursors (kininogens) that are cleaved by tissue and circula-tory kinin-forming enzymes.276 Kinins are produced by many cell types and can be detected in urine, saliva, sweat, interstitial fluid, and, in rare cases, venous blood. The levels of bradyki-nin in the circulation are almost undetectable because of rapid metabolism by kininases, particularly kininase II/ACE1. The renal kallikrein-kinin system can produce local concentrations of bradykinin much higher than those present in blood. In the kidneys, bradykinin is metabolized by NEP.277

Kinins play an important role in hemodynamic and excre-tory processes through their G protein–coupled receptors,

BK-B1 and BK-B2. The BK-B2 receptors mediate most of the actions of kinins277 and are located mainly in the kidneys, although they are also detectable in the heart, lungs, brain, uterus, and testes. Activation of BK-B2 receptors results in vasodilation, probably through a nitric oxide– or arachidonic acid metabolite–dependent mechanism.276,278 Bradykinin is known for its multiple effects on the cardiovascular system, particularly vasodilation and plasma extravasation.276

Besides the vasculature, the kidney is an important target organ of kinins, in which they induce diuresis and natriure-sis through activation of BK-B2 receptors. These effects are attributed to an increase in RBF and to inhibition of Na+ and water reabsorption in the distal nephron.279,280 The latter effect is secondary to the observed action of kinins in reduc-ing vascular resistance. Unlike many vasodilators, bradykinin increases RBF without significantly affecting GFR or Na+ reabsorption at the proximal tubule level, but this increase is accompanied by a marked decrease in the water and salt reab-sorption in the distal nephron, thus contributing to increased urine volume and Na+ excretion.

Studies with transgenic animals have enriched the under-standing of the physiologic role of the kinins and the interac-tion between the kallikrein-kinin system and the RAAS.279 For instance, in the kidneys, angiotensin II acting through the AT2 receptor stimulates a vasodilator cascade of brady-kinin, nitric oxide, and cGMP during conditions of increased angiotensin II, such as Na+ depletion.267 In the absence of the AT2 receptor, pressor and antinatriuretic hypersensitivity to angiotensin II is associated with bradykinin and nitric oxide deficiency.267 Furthermore, involvement of the renal kinins in pressure natriuresis has been documented.128 Bradykinin also mediates the biologic actions of angiotensin-(1-7), as shown in rats transgenic for the kallikrein gene, which display sig-nificantly augmented angiotensin-(1-7) mediated diuresis and natriuresis.279 Because ACE is involved in the degradation of kinins, ACE inhibitors not only attenuate the formation of angiotensin II but also may lead to the accumulation of kinins. The latter are believed to be responsible in part for the benefi-cial effects of ACE inhibitors in patients with CHF, but also for their troublesome side effect of cough.281 On the basis of the results of these studies, as well as those in which BKB2 specific antagonists were used, the kallikrein-kinin system is believed to play a pivotal role in the regulation of fluid and electrolyte balance, mainly by acting as a counterregulatory modulator of vasoconstrictor and Na+-retaining mechanisms.Adrenomedullin. Human adrenomedullin is a 52–amino acid peptide that was discovered in 1993 by Kitamura and associates282 in extracts of human pheochromocytoma cells. Adrenomedullin is approximately 30% homologous in struc-ture with calcitonin gene–related peptide and amylin.282,283 Adrenomedullin is produced from a 185–amino acid prepro-hormone that also contains a unique 20–amino acid sequence in the NH2-terminus, termed proadrenomedulin NH2-terminal 20 peptide. This sequence exists in vivo and has biologic activ-ity similar to that of adrenomedullin.

Adrenomedullin messenger RNA is expressed in several tissues, including those of the atria, ventricles, vascular tissue, lungs, kidneys, pancreas, smooth muscle cells, small intestine, and brain. The synthesis and secretion of adrenomedullin are stimulated by chemical factors and physical stress. Among these stimulants are cytokines, corticosteroids, thyroid hor-mones, angiotensin II, norepinephrine, endothelin, bradykinin,


and shear stress.284 Adrenomedullin immunoreactivity has been localized in high concentrations in pheochromocytoma cells, the adrenal medulla, the atria, the pituitary gland, and, at lower levels, in cardiac ventricles, vascular smooth muscle cells, endothelial cells, glomeruli, distal and medullary collect-ing tubules, and the digestive, respiratory, reproductive, and endocrine systems.284,285

Adrenomedullin acts through a 395–amino acid membrane receptor that structurally resembles a G protein– coupled receptor and contains seven transmembrane domains. Adre-nomedullin receptors constitute the calcitonin receptor–like receptor and a family of receptor-activity–modifying pro-teins.286 Activation of these receptors increases intracellular cAMP, which probably serves as a second messenger for the peptide.283,287 The most impressive biologic effect of adre-nomedullin is long-lasting and dose-dependent vasodilation of the vascular system, including coronary arteries.283,287,288 Injection of adrenomedullin into anesthetized rats, cats, or conscious sheep induced a potent and long-lasting hypoten-sive response associated with reduction in vascular resistance in the kidneys, brain, lungs, hind limbs, and mesentery.284 The hypotensive action of adrenomedullin is accompanied by increases in heart rate and cardiac output caused by positive inotropic effects.284 The vasodilating effect of adrenomedul-lin can be blocked by inhibiting NOS, which suggests that nitric oxide partly mediates the decrease in systemic vascular resistance.283

Besides its hypotensive action, adrenomedullin increases RBF through preglomerular and postglomerular arteriolar vasodilation.287,289 The adrenomedullin-induced hyperperfu-sion is associated with dose-dependent diuresis and natriure-sis.284,287 These effects result from a decrease in tubular Na+ reabsorption despite the adrenomedullin-induced hyperfiltra-tion289 and may be mediated partially by the locally released nitric oxide290,291 and prostaglandins.292 In addition, NEP inhibition potentiates exogenous adrenomedullin-induced natriuresis without affecting GFR.293 Like natriuretic pep-tides, adrenomedullin suppresses aldosterone secretion in response to angiotensin II and high potassium levels.283 Fur-thermore, in cultured vascular smooth muscle cells, adreno-medullin inhibits endothelin production induced by various stimuli.284 Adrenomedullin acts in the CNS to inhibit both water and salt intake.294 In the hypothalamus, adrenomedullin inhibits the secretion of AVP, an effect that may also contrib-ute to its diuretic and natriuretic actions.294

Together, these findings show that adrenomedullin is a vasoactive peptide that may be involved in the physiologic control of renal, adrenal, vascular, and cardiac function. Fur-thermore, the existence of adrenomedullin-like immuno-reactivity in the glomerulus and in the collecting tubule, in association with detectable amounts of adrenomedullin mes-senger RNA in the kidneys, suggests that adrenomedullin plays a renal paracrine role.295

In 2008, a new member of the adrenomedullin family, adrenomedullin-2 or intermedin, was identified. Adreno-medullin-2 is about 30% homologous with adrenomedullin. Because its renal and cardiovascular effects are similar to those of adrenomedullin-1, they are not discussed further here. The interested reader is referred to a comprehensive review.296

Urotensin. Urotensin II is a highly conserved peptide which binds to the human orphan G protein–coupled receptor GPR14, now named the urotensin II receptor. The parent

peptide, prepro–urotensin II, is widely expressed in human tissues, including those of the CNS and peripheral nervous system, the GI tract, the vascular system, and the kidneys.297 In the kidneys, immunoreactive staining for urotensin II was detected in the epithelial cells of the tubules, mostly in the distal tubule, with moderate staining in endothelial cells of the renal capillaries.298 The C-terminus of the prohormone is cleaved to produce urotensin II, an 11–amino acid residue peptide. The human form of urotensin II includes a cyclic hexapeptide sequence that is fundamental for the action of this compound. The metabolic pathway leading to the pro-duction of urotensin II still remains incompletely character-ized. Substantial urotensin II arteriovenous gradients (36% to 44%) have been demonstrated in the heart, liver, and kidneys, which is indicative of local urotensin II production.299

In vivo in humans, systemic infusion of urotensin II range led to local vasoconstriction in the forearm, no effect, or cuta-neous vasodilation (reviewed by Richards and Charles300). These dissimilarities are probably attributable to many fac-tors, including species variation, site and modality of injection, dose, vascular bed, and functional conditions of the experi-mental model.300 Because urotensin II has been described as the most potent vasoconstrictor (see “Endothelin” section), it is reasonable to postulate that the vasoconstrictive action is direct, whereas the vasodilatory response may be mediated by other factors such as cyclooxygenase products and nitric oxide.

The involvement of the urotensin II system in the regula-tion of renal function in mammals has not been thoroughly investigated, and the data reported to date are as contradictory as those for vascular tone. In normal rats, intravenous boluses in the 1-nmol range caused minor reductions in GFR and no effect on Na+ excretion.301 However, in another study in which the same model was used, continuous infusion of urotensin II at doses in the 1-nmol/kg range elicited clear increases in GFR and nitric oxide–dependent diuresis and natriuresis.302 In contrast, bolus injections in the 1-nmol range produced a dose-dependent decrease in GFR associated with reduced urine flow and Na+ excretion.303 Studies in rats with an aorto-caval fistula (a model of chronic volume overload) showed that urotensin II boluses in the 1-nmol range exerted favorable, nitric oxide–dependent, renal hemodynamic effects.301 Thus, the effect of urotensin II on renal function seems dependent on the modality of administration (bolus vs. continuous infu-sion) and on the experimental condition being investigated (normal rats vs. those with heart failure).

The variability in renal and vascular responses to urotensin II administration may also depend on the fact that the action of this peptide is regulated at the receptor level. The bind-ing density of urotensin II is correlated with vasoconstrictor response in rats, and small changes in receptor density may result in pathophysiologic effects. Under normal conditions, most urotensin II receptors are already occupied by uroten-sin II. Changes in unoccupied receptor reserve—perhaps in response to alterations in urotensin II levels generated in experimental models or observed in disease states—might explain, at least in part, the observed variability in studies of renal and vascular function.304

Selective urotensin II receptor antagonists have been developed, the most potent of which is currently urantide. In normal rats, continuous administration of this compound increases GFR, as well as urine flow and Na+ excretion.303 On the basis of experimental results indicating that urotensin


II increases epithelial Na+ transport in fish, it appears likely that urotensin II exerts a direct tubular effect, inasmuch as its receptor is expressed in the distal tubule.303 Overall, urotensin II seems to have a tonic influence on renal function. To date, no data in humans are available.Digitalis-Like Factors. In the early 1960s, Hugh de War-dener hypothesized the existence of endogenous digitalis-like factors, and an endogenous ouabain-like compound in human and other mammalian plasma was initially reported in the late 1970s.304a,304b Since 2000, interest in such factors—also known as endogenous cardiotonic steroids—has expanded considerably. In particular, two specific cardiotonic steroids in humans have been characterized extensively: endog-enous cardenolide (or ouabain) and bufadienolide (marino-bufagenin). An alternative mechanism by which cardiotonic steroids can signal through the Na+-K+-ATPase has also been described.305 The main site of synthesis of these com-pounds is the adrenal cortex,10 and the main consequences of Na+ pump inhibition are attenuation of renal Na+ trans-port and increased cytosolic Ca2+ in vascular smooth muscle cells, which lead to increased vascular resistance.306 The lat-ter mechanism has been implicated in the pathogenesis of hypertension. More recent work has also implicated these hormones in the regulation of cell growth, differentiation, apoptosis, and fibrosis; in the modulation of immunity and of carbohydrate metabolism; and in the control of various central nervous functions, including behavior.305,307

Neuropeptide Y. Neuropeptide Y, a 36-residue peptide, is a sympathetic cotransmitter stored and released together with noradrenaline by adrenergic nerve terminals of the SNS. Structurally, neuropeptide Y is highly homologous to two other members of the pancreatic polypeptide family, peptide YY and pancreatic polypeptide. These two closely related peptides are produced and released by the intestinal endo-crine and pancreatic islet cells, respectively, and act as hor-mones.308,309 Although neuropeptide Y was originally isolated from the brain and is highly expressed in the CNS, the peptide exhibits a wide spectrum of biologic activities in the cardio-vascular system, GI tract, and kidneys310-312 through multiple Gi/o protein–coupled receptors: Y1, Y2, Y4, and Y5.313

In numerous studies, both in vivo and in vitro techniques demonstrated the capacity of the neuropeptide Y to reduce RBF and increase renal vascular resistance in various spe-cies, including rats, rabbits, pigs, and humans.310 Despite the potent vasoconstrictor effect of the peptide on renal vascu-lature, this effect does not appear to be associated with any significant change in GFR. In view of the potent renal vaso-constrictor action of neuropeptide Y, a decrease in electrolyte and water excretion could be expected after its administra-tion. However, the available data suggest that neuropeptide Y may exert either a natriuretic314 or an antinatriuretic315 action, depending on the experimental conditions and the species studied. In the absence of any new data since the publication of the previous edition of this book, the role of neuropeptide Y in the physiologic regulation of renal hemodynamics and electrolyte excretion remains enigmatic.Apelin. Apelin is the endogenous ligand of the angiotensin-like receptor 1, a G protein–coupled receptor found to be involved in various physiologic events, such as water homeo-stasis, regulation of cardiovascular tone, and cardiac contrac-tility (see Principe et al316 and references therein). Apelin and its receptor are widely expressed in the CNS and in peripheral

tissues, especially in endothelial cells. Apelin is also expressed in endothelial and vascular smooth muscle cells of glomer-ular arterioles and, to a lesser extent, in other parts of the nephron.317

Angiotensin-like receptor 1 activation leads to inhibition of cAMP production and activation of the Na+/H+ exchanger type 1. Through the former pathway, apelin enhances vascular dilation after the induction of eNOS, whereas the burst of Na+/H+ exchanger type 1 activity in cardiomyocytes leads to a dose-dependent increase in myocardial contractility (see Prin-cipe et al316 and references therein). With regard to the renal effects of apelin, direct injection into the hypothalamus of lac-tating rats inhibited AVP release and reduced circulating AVP. Conversely, water deprivation led to increased systemic AVP and decreased apelin levels (see Principe et al316 and references therein). These findings suggest that AVP and apelin have a reciprocal relationship in controlling water diuresis.

Apelin appears to also counter-regulate several effects of angiotensin II. For example, intravenous injection of apelin caused a nitric oxide–dependent fall in arterial pres-sure. Moreover, apelin receptor–knockout mice displayed an enhanced vasopressor response to systemic angiotensin II.318 In addition, apelin modulated the abnormal aortic vascular tone in response to angiotensin II through eNOS phosphory-lation in diabetic mice; this finding provided further evidence of a role for apelin in vascular function.319 Intravenous injec-tion of apelin also induced a significant diuresis and caused vasorelaxation of angiotensin II–preconstricted efferent and afferent arterioles. Activation of endothelial apelin receptors caused release of nitric oxide, which inhibited the angioten-sin II–induced rise in intracellular Ca2+ levels. Furthermore, apelin had a direct receptor-mediated vasoconstrictive effect on vascular smooth muscle.318 These results show that apelin has complex effects on the preglomerular and postglomeru-lar microvasculature regulating renal hemodynamics. A direct role in tubular function remains to be determined but is sug-gested by collecting duct expression in close proximity to the vasopressin V2 receptor.317

extrarenal meChaniSmS of volume regulation: interStitial hypertoniC Sodium aCCumulation in the SkinThe traditional two-compartment model of volume regulation, according to which the intravascular and interstitial spaces are in equilibrium, has been challenged. Results of initial studies indicated that Na+ can be bound to and stored on proteogly-cans in interstitial sites, where it becomes osmotically inactive; accordingly, a novel mechanism of volume regulation has been elucidated.320-327 In rats fed a high-salt diet, this uniquely bound Na+ was found to induce a state of subcutaneous inter-stitial hypertonicity and systemic hypertension.322 Machnik and colleagues320 offered compelling experimental evidence that this hypertonicity is sensed by macrophages, which then produce vascular endothelial growth factor C (VEGF-C), an angiogenic protein. In turn, VEGF-C stimulates increased numbers and density of lymphatic capillaries. Using cultured macrophage cell lines, subjected to osmotic stress, Go and associates328 demonstrated activation of a transcription fac-tor, tonicity-responsive enhancer–binding protein (TonEBP). This factor is known to activate osmoprotective genes in other hypertonic environments, such as the renal medulla.328 Moreover, analysis of the VEGF-C promoter revealed two TonEBP binding sites and, in subsequent experiments,


parallel upregulation of TonEBP and VEGF-C was observed. The effect of TonEBP on VEGF-C was shown to be spe-cific, inasmuch as small interfering RNA for TonEBP, but not nonspecific small interfering RNA, inhibited the VEGF-C upregulation. Furthermore, macrophage depletion or inhibi-tion of VEGF-C signaling led to exacerbation of high-salt diet–induced hypertension, clearly demonstrating the impor-tance of this pathway in blood pressure regulation.320 Finally, in humans with relatively resistant hypertension, elevated levels of VEGF-C were found,320 which is consistent with a potential role of this growth factor in the redistribution of excess volume to the intravascular space and exacerbation of hypertension.329

Sodium Balance Disorders

Hypovolemia

Definition

Hypovolemia is the condition in which the volume of the ECF compartment is reduced in relation to its capacitance. As already discussed, the reduction may be absolute or rela-tive. In states of absolute hypovolemia, the Na+ balance is truly negative, reflecting past or ongoing losses. Hypovolemia is described as relative when there is no Na+ deficit but the capacitance of the ECF compartment is increased. In this situation of reduced EABV, the ECF intravascular and extra-vascular (interstitial) compartments may vary in the same or opposite directions. ICF volume, reflected by measurements of plasma Na+ or osmolality, may or may not be concomitantly disturbed; thus, hypovolemia may be classified as normona-tremic, hyponatremic, or hypernatremic (see also Chapter 15, “Disorders of Water Balance”).

Etiology

The causes of hypovolemia are summarized in Table 14-5. Both absolute and relative hypovolemia, in turn, can have either extrarenal or renal causes. Absolute hypovolemia results either from massive blood loss or from fluid loss from the skin, the gastrointestinal or respiratory system, or the kidneys. Relative hypovolemia results from states of vasodilation, gener-alized edema, or third-space loss. In both absolute and relative hypovolemia, the perceived reduction in intravascular volume prompts the compensatory hemodynamic changes and renal responses described in the “Physiology” section; the familiar clinical manifestations include tachycardia, hypotension, and renal retention of Na+ and water.

Pathophysiology

abSolute hypovolemiaExtrarenal. Massive bleeding, either gastrointestinal or a result of trauma, is the most frequent cause of absolute hypo-volemia. The reduction in ECF volume is isotonic inasmuch as there is a proportionate loss of erythrocytes and plasma. The consequent fall in systemic blood pressure leads to com-pensatory tachycardia and vasoconstriction, and the ensuing altered transcapillary Starling hydraulic forces enable a shift of fluid from the interstitial to intravascular compartment.

In addition, the neural and hormonal responses to hypovole-mia, described in the “Physiology” section, result in renal Na+ and water retention, with the aim of restoring intravascular volume and hemodynamic stability.

Similar compensatory mechanisms become activated after fluid losses from the skin, the gastrointestinal system, and the respiratory system. Because of the large surface area of the skin, large amounts of fluid can be lost from this tissue. This can result from burns or excessive perspiration. Severe burns allow the loss of large volumes of plasma and interstitial fluid and can lead rapidly to profound hypovolemia. In the absence of medical intervention, hemoconcentration and hypoalbu-minemia supervene. As after massive bleeding, the fluid loss is isotonic, and so plasma Na+ concentration and osmolality remain normal. In contrast, excessive sweating, induced by exertion in hot environments, leads to hypotonic fluid loss as a result of the relatively low Na+ concentration in this fluid (20 to 50 mmol/L). The resulting hypovolemia may, therefore, be accompanied by hypernatremia and hyperosmolality, and the type of fluid replacement must be tailored accordingly (see also Chapter 15).

Besides oral intake, the gastrointestinal tract is character-ized by the entry of approximately 7 L of isotonic fluid, the overwhelming majority of which is reabsorbed in the large intestine. Hence, in normal conditions, fecal fluid loss is mini-mal. However, in the presence of pathologic conditions, such as vomiting, diarrhea, colostomy, and ileostomy secretions, especially those caused by infection, considerable or even massive fluid loss may occur. The ionic composition, osmo-lality, and pH of secretions vary according to the part of the gastrointestinal tract; therefore, the resulting hypovolemia is

TABLE 14-5 Causes of Absolute and Relative Hypovolemia

Absolute

Extrarenal

BleedingGastrointestinal fluid lossSkin fluid lossRespiratory fluid lossExtracorporeal ultrafiltration

Renal

DiureticsNa+ wasting tubulopathies

GeneticAcquired tubulointerstitial disease

Obstructive uropathy/postobstructive diuresisHormone deficiency

HypoaldosteronismAdrenal insufficiency

Relative

Extrarenal

Edematous statesHeart failureCirrhosis

Generalized vasodilationDrugsSepsisPregnancy

Third-space loss

Renal

Severe nephrotic syndrome


associated with a large spectrum of electrolyte and acid-base abnormalities (see appropriate chapters for further discussion).

In contrast to the massive losses that can occur from the skin and gastrointestinal system, fluid loss from the respira-tory tract—as occurs in febrile states and patients who receive mechanical ventilation with inadequate humidification—is usually modest, and hypovolemia ensues only in the presence of accompanying causes. Finally, a special situation in which hypovolemia can occur is after excessive ultrafiltration in dial-ysis patients (see Chapter 64)Renal. As described earlier, when the GFR and plasma Na+ concentration are normal, approximately 24,000 mmol of Na+ is filtered per day. Even when GFR is markedly impaired, the amount of filtered Na+ far exceeds the dietary intake. In order to maintain Na+ balance, all but 1% of the filtered load is reabsorbed. However, if the integrity of one or more of the tubular reabsorptive mechanisms is impaired, serious Na+ def-icit and absolute volume depletion can occur. The causes of absolute renal Na+ losses include pharmacologic agents, renal structural disorders, endocrine disorders, and systemic disor-ders (see Table 14-5). All the diuretics widely used to treat hypervolemic states may induce hypovolemia if administered in excess or inappropriately. In particular, the powerful loop diuretics furosemide, bumetanide, torsemide, and ethacrynic acid are often given in combination with diuretics acting on other tubular segments (thiazides, aldosterone antagonists, distal ENaC blockers, and carbonic anhydrase inhibitors). Patients receiving these combinations need to be carefully monitored and fluid balance scrupulously adjusted in order to prevent hypovolemia. Patients commonly at risk are those with CHF or underlying hypertension who develop intercur-rent infections.

Na+ reabsorption may also be disrupted in inherited and acquired tubular disorders. Inherited disorders of both the proximal tubules (e.g., Fanconi’s syndrome) and the distal tubules (e.g., Bartter’s and Gitelman’s syndromes) may lead to salt-wasting states in association with other electrolyte or acid-base disturbances. Acquired disorders of Na+ reabsorp-tion may be acute, as in nonoliguric acute kidney injury, the time immediately after renal transplantation, the polyuric recovery phase of acute kidney injury, and postobstructive diuresis (see relevant chapters for further details), or they may be chronic as a result of tubulointerstitial diseases with a propensity for salt wasting. In fact, chronic kidney disease of any cause is associated with heightened vulnerability to Na+ losses because the ability to match tubular reabsorp-tion with the sum of filtered load minus dietary intake is impaired.

In patients with hypertension, the frequent administration of diuretics for treatment further increases the risk of volume depletion. Osmotic diuretics, endogenous or exogenous, may also reduce tubular Na+ reabsorption. Endogenous agents include urea—the principle molecule involved in the poly-uric recovery phase of acute kidney injury and postobstruc-tive diuresis—and glucose in hyperglycemia. In patients with raised intracranial pressure, exogenous agents, such as man-nitol or glycerol, may be used to induce translocation of fluid from the ICF compartment to the ECF compartment and decrease brain swelling. The resulting polyuria may be associ-ated with electrolyte and acid-base disturbances, the nature of which depends on the complex interplay between fluid intake and intercompartmental fluid shifts.

In addition to intrinsic tubular disorders, endocrine and other systemic disturbances may lead to impaired Na+ reab-sorption. The principal endocrine causes are mineralocorti-coid deficiency and resistance states. A controversial cause is the systemic disturbance known as cerebral salt wasting. In this condition, salt wasting is thought to occur in response to an as-yet-unidentified factor released in the setting of acute head injury or intracranial hemorrhage.330,331 The condition is usually diagnosed because of concomitant hyponatremia, and some experts doubt its independent existence, regarding cerebral salt wasting as essentially indistinguishable from the syndrome of inappropriate AVP.332

An underappreciated but not uncommon clinical setting for renal Na+ loss is after the administration of large volumes of intravenous saline to patients over several days after surgery or after trauma. In this situation, tubular reabsorption of Na+ is downregulated. If intravenous fluids are stopped before full reabsorptive capacity is restored, volume depletion may ensue. The phenomenon can be minimized by graded reduction in the infusion rate, which allows Na+ reabsorptive pathways to be restored gradually.

In the context of volume depletion, mention should be made of diabetes insipidus. However, because this results from a deficiency of or tubular resistance to AVP, water loss is the main consequence, and the impact on ECF volume is only minor. AVP-related disorders are considered in Chapter 15.

relative hypovolemiaExtrarenal. As outlined previously, the principal causes of relative hypovolemia are edematous states, vasodilation, and third-space loss (see Table 14-5). Vasodilation may be physi-ologic, as in normal pregnancy, or induced by drugs (hypo-tensive agents, such as hydralazine or minoxidil, that cause arteriolar vasodilation), or it may occur in sepsis during the phases of peripheral vasodilation and consequent low systemic vascular resistance.333

Edematous states in which the EABV and, hence, tissue perfusion are reduced include heart failure, decompensated cirrhosis with ascites, and nephrotic syndrome. In severe heart failure, low cardiac output and resulting low systemic blood pressure lead to a fall in RPP. As in absolute hypovolemia, the kidneys respond by retaining Na+. Because the increased venous return cannot raise the cardiac output, a vicious cycle is created in which edema is further exacerbated and the per-sistently reduced cardiac output leads to further Na+ retention. In decompensated cirrhosis, splanchnic venous pooling leads to decreased venous return, a consequent fall in cardiac output, and compensatory renal Na+ retention. The pathophysiologic features of edematous states are discussed in more detail in the “Hypervolemia” section. Third-space loss occurs when fluid is sequestered into compartments not normally perfused with fluids, as in states of gastrointestinal obstruction, after trauma, with burns, in pancreatitis, in peritonitis, or in malignant asci-tes. The end result is that even though total body Na+ is mark-edly increased, the EABV is severely reduced.Renal. Approximately 10% of patients with the nephrotic syndrome—especially children with minimal change disease, but also any patient with serum albumin levels lower than 2 g/dL—manifest the clinical signs of hypovolemia. The low plasma oncotic pressure is conducive to movement of fluid from the ECF compartment to the interstitial space, thereby leading to reduced EABV.334,335


Clinical Manifestations

The clinical manifestations of hypovolemia depend on the magnitude and rate of volume loss, solute composition of the net fluid loss (i.e., the difference between input and output), and vascular and renal responses. The clinical features can be considered as being related to the underlying pathophysiologic process, the hemodynamic consequences, and the electrolyte and acid-base disturbances that attend the renal response to hypovolemia. A detailed history often reveals the cause of vol-ume depletion (bleeding, vomiting, diarrhea, polyuria, diapho-resis, medications).

The symptoms and physical signs of hypovolemia appear only when intravascular volume is decreased by 5% to 15% and are often related to tissue hypoperfusion. Symptoms include generalized weakness, muscle cramps, and postural lightheadedness. Thirst is prominent if concomitant hyper-tonicity is present (hypertonic hypovolemia). Physical signs are related to the hemodynamic consequences of hypovolemia and include tachycardia; hypotension, which may be postural, absolute, or relative to the usual blood pressure; and low cen-tral venous pressure or jugular venous pressure. Elevation of jugular venous pressure, however, does not rule out hypovole-mia, because of the possible confounding effects of underlying heart failure or lung disease. When volume depletion exceeds 10% to 20%, circulatory collapse is liable to occur, with severe supine hypotension, peripheral cyanosis, cold extremities, and impaired consciousness, extending even to coma. This is especially possible if fluid loss is rapid or occurs against a background of comorbid conditions. When the source of volume loss is extrarenal, oliguria also occurs. The traditional signs—reduced skin turgor, sunken eyes, and dry mucous membranes—are inconstant findings, and their absence is not considered useful for ruling out hypovolemia.

Diagnosis

The diagnosis of hypovolemia is based essentially on the clinical findings. Nevertheless, when the clinical findings are equivocal, various laboratory parameters may be helpful for confirming the diagnosis or for elucidating other changes that may be associated with volume depletion.

laboratory findingSHemoglobin may decrease if significant bleeding has occurred or is ongoing, but this change, which is caused by hemodilu-tion that results from translocation of fluid from the intersti-tial to intravascular compartment, may take up to 24 hours. Therefore, stable hemoglobin does not rule out significant bleeding. Moreover, the adaptive response of hemodilution may moderate the severity of hemodynamic compromise and the resulting physical signs. In hypovolemic situations that do not arise from bleeding, hemoconcentration is often seen, although this too is not universal, inasmuch as underlying chronic diseases that cause anemia may mask the differential loss of plasma.

Hemoconcentration may also be manifested as a rise in plasma albumin concentration, if albumin-free fluid is lost from the skin, gastrointestinal tract, or kidneys. On the other hand, when albumin is lost, either in parallel with other extra-cellular fluids (as in proteinuria, hepatic disease, protein-los-ing enteropathy, or catabolic states) or in protein-rich fluid

(third-space sequestration, burns), significant hypoalbumin-emia is observed.

Plasma Na+ concentration may be low, normal, or high, depending on the solute composition of the fluid lost and the replacement solution administered by either the patient or the treating physician. For example, the hypovolemic stimu-lus for AVP release may lead to preferential water retention and hyponatremia, especially if hypotonic replacement fluid is used. In contrast, the fluid content of diarrhea may be hypo-tonic or hypertonic, resulting, respectively, in hypernatremia or hyponatremia. Plasma Na+ concentration reflects tonicity of plasma and provides no direct information about volume status, which is a clinical diagnosis.

Plasma K+ and acid-base parameters can also change in hypovolemic conditions. After vomiting and also some forms of diarrhea, loss of K+ and Cl- may lead to hypokalemic alkalo-sis. More often, the principal anion lost in diarrhea is bicarbon-ate, which leads to hyperchloremic (non–anion gap) acidosis. When diuretics or Bartter’s and Gitelman’s syndromes (the inherited tubulopathies; Chapter 44) are the cause of hypo-volemia, hypokalemic alkalosis is again typically seen. On the other hand, UNa loss that occurs in adrenal insufficiency or is caused by aldosterone hyporesponsiveness is accompanied by a tendency for hyperkalemia and metabolic acidosis. Finally, when hypovolemia is sufficiently severe to impair tissue perfu-sion, high anion gap acidosis caused by lactic acid accumula-tion may be observed.

Blood urea and creatinine levels frequently rise in hypovole-mic states, and this elevation reflects impaired renal perfusion. If tubular integrity is preserved, then the rise in urea level is typically disproportionate to that of creatinine (see Chapter 30). This results mainly because AVP enhances reabsorption of urea in the medullary collecting duct and as an effect of increased filtration fraction on proximal tubule handling of urea (reviewed by Blantz336). In the presence of severe hypo-volemia, acute kidney injury may ensue, leading to loss of the differential rise in urea level. Proportional rises in urea and creatinine are also observed when hypovolemia occurs against a background of underlying renal functional impairment, as in chronic kidney disease stages 3 to 5 (Chapter 51).

Urine biochemical parameters can be extremely useful in establishing the diagnosis of hypovolemia caused by extrarenal fluid losses if there is no intrinsic renal injury and the patient is oliguric. The expected renal response of Na+ and water con-servation, by enhanced renal tubular reabsorption, results in oliguria, urine specific gravity exceeding 1.020, Na+ concen-tration higher than 10 mmol/L, and osmolality higher than 400 mOsm/kg. When Na+ concentration is 20 to 40 mmol/L, the finding of a fractional excretion of Na+ (Na+ clearance × 100/creatinine clearance) of less than 1% in the presence of a reduced GFR may be helpful. In a patient who previously received diuretic therapy, especially with loop diuretics, these indices may merely reflect the UNa losses. In that case, frac-tional excretion of urea from less than 30% to 35% may help in the diagnosis of hypovolemia, although the specificity of this test is rather low.337-339

When hypovolemia occurs in the presence of arterial vaso-dilation, as observed in sepsis, some, but not all, of the clinical manifestations of hypovolemia are observed. Thus, tachycar-dia and hypotension are usually present, but the extremities are warm, which suggests that perfusion is maintained. This finding is misleading because vital organs, particularly the


brain and kidneys, are underperfused as a result of the hypo-tension. The presence of lactic acidosis helps establish the correct diagnosis. Reduction in the EABV, as manifested by relative hypotension, may be observed in generalized edema-tous states, even though there is an overall excess of Na+ and water; however, this excess is maldistributed between the extracellular and interstitial spaces.

Treatment

abSolute hypovolemiaGeneral Principles. The goals of treatment of hypovolemia are to restore normal hemodynamic status and tissue per-fusion. These goals are achieved by reversal of the clinical symptoms and signs, described previously. Treatment can be divided into three stages: (1) initial replacement of the imme-diate fluid deficit; (2) maintenance of the restored ECF vol-ume in the presence of ongoing losses; and (3) treatment of the underlying cause whenever possible. The main strategies to be addressed by the clinician are the route, volume, rate of administration, and composition of the replacement and maintenance fluids. These are liable to change according to the patient’s response.

In general, when hypovolemia is associated with signifi-cant hemodynamic disturbance, intravenous rehydration is required. (The use of oral electrolyte solutions in the manage-ment of infant diarrhea is discussed in Chapters 73 through 77.) The volume of fluid and rate of administration should be determined on the basis of the urgency of the threat to circulatory integrity, adequacy of the clinical response, and underlying cardiac function. Elderly patients are especially vulnerable to aggressive fluid challenge, and careful monitor-ing is required, particularly to prevent acute left ventricular failure and pulmonary edema that result from overzealous correction.

Sometimes the clinical signs do not point unequivocally to the diagnosis of hypovolemia, even though the history is strongly suggestive. Because invasive monitoring of central venous and pulmonary venous pressures has not been shown to improve outcomes in this situation,340,341 a “diagnostic fluid challenge” can be performed. If the patient improves clinically, blood pressure and urine output increase, and no overt signs of heart failure appear over the succeeding 6 to 12 hours, then the diagnosis is substantiated and fluid therapy can be cau-tiously continued. Conversely, if overt signs of fluid overload appear, the fluid challenge can be stopped and diuretic therapy reinstituted.

The initial calculations for replacing the fluid deficit are based on hemodynamic status. It is notoriously difficult to calculate volume deficits; therefore, good clinical judg-ment is necessary for successful management. Patients with life-threatening circulatory collapse and hypovolemic shock require rapid intravenous replacement through the cannula with the widest bore possible. This replacement should con-tinue until blood pressure is corrected and tissue perfusion is restored. In the second stage of fluid replacement, the rate of administration should be reduced to maintain blood pres-sure and tissue perfusion. In elderly patients and those with underlying cardiac dysfunction, the risk of overrapid correc-tion and precipitating pulmonary edema is heightened; there-fore, slower treatment is preferable, to allow gradual filling of the ECF volume rather than causing pulmonary edema and

the threat of mechanical ventilation that are associated with adverse outcomes.342

Composition of Replacement Fluids. The composition of replacement fluid is less critical than the rate of infusion. The two main categories of replacement solution are crystalloid and colloid solutions. Crystalloid solutions are based largely on either NaCl of varying tonicity or dextrose. Isotonic (0.9%) saline, containing 154 mmol of Na+ per liter, is the mainstay of volume replacement therapy inasmuch as it is confined to the ECF compartment in the absence of deviations in Na+ concentration. One liter of isotonic saline increases plasma volume by approximately 300 mL; the rest is distributed to the interstitial compartment. In contrast, 1 L of 5% dextrose in water (D5W), which is also isosmotic (277 mOsm/L), is even-tually distributed throughout all the body fluid compartments, so that only 10% to 15% (100 to 150 mL) remains in the ECF. Therefore, D5W should not be used for volume replacement.

Administration of 1 L of 0.45% saline (77 mmol of Na+ per liter) in D5W is equivalent to giving 500 mL of isotonic saline and the same volume of solute-free water. The distribution of the solute-free compartment throughout all the fluid com-partments would result in plasma dilution and reduction in the plasma Na+. Therefore, this solution should be reserved for the management of hypernatremic hypovolemia. Even in that situation, it must be remembered that volume replacement is less efficient than with isotonic saline and, early on during the treatment course, may cause plasma tonicity to fall too rapidly.

When hypovolemia is accompanied by severe metabolic acidosis (pH <7.10, plasma HCO3

− <10 mmol/L), bicarbon-ate supplementation may be indicated. (For detailed discus-sion of the indications for bicarbonate administration, see Chapter 16). Because this anion is manufactured as 8.4% sodium bicarbonate (1000 mmol/L) for use in cardiac resus-citation, appropriate dilution is required for the treatment of acidosis associated with hypovolemia. Nephrologists are fre-quently called upon for consultation in these situations, and they should be ready to provide detailed protocols for the preparation of isotonic NaHCO3. Two convenient methods are suggested: Either 75 mL (75 mmol) of 8.4% NaHCO3 can be added to 1 L of 0.45% saline or 150 mL of concentrated bicarbonate can be added to 1 L of D5W. Although the latter is hypertonic in the short term, it is unlikely to be harmful.

In the presence of accompanying hypokalemia, especially if metabolic alkalosis is also present, volume replacement solu-tions must be supplemented with K+. Commercially avail-able 1-L solutions of isotonic saline supplemented with 10 or 20 mmol of KCl make this option safe and convenient. (For details, see Chapters 16 and 17). On the other hand, other commercially available crystalloid solutions containing lactate (converted by the liver to bicarbonate) and low concentrations of KCl offer no advantage and less flexibility than isotonic saline.

Colloid solutions include plasma itself, albumin, or high-molecular-weight carbohydrate molecules, such as hydroxy-ethyl starch and dextrans, at concentrations that exert colloid osmotic pressures equal to or greater than that of plasma. Because the transcapillary barrier is impermeable to these large molecules, in theory they expand the intravascular com-partment more rapidly and efficiently than do crystalloid solutions. Colloid solutions may be useful in the management of burns and severe trauma, when plasma protein losses are substantial and rapid plasma expansion with relatively small


volumes is efficacious. However, when capillary permeability is increased, as in states of multiorgan failure or the systemic inflammatory response syndrome, colloid administration is ineffective. Moreover, randomized controlled studies in which crystalloid solutions were compared with colloid solu-tions have shown no survival benefit with colloid solutions,343 except in certain very specialized clinical situations, such as cirrhosis with spontaneous bacterial peritonitis.344 Therefore, the much cheaper and more readily available isotonic saline should remain the mainstay of therapy.

relative hypovolemiaTreatment of relative hypovolemia is more difficult than that of absolute hypovolemia because there is no real fluid deficit. If the relative hypovolemia is caused by peripheral vasodilation, as in a septic patient, it may be necessary to cautiously admin-ister a crystalloid solution, such as isotonic saline, to maintain ECF volume until the systemic vascular resistance and venous capacitance return to normal. The excess volume administered can then be excreted by the kidneys. When vasodilation is more severe, vasoconstrictor agents may be needed to main-tain systemic blood pressure. In the edematous states of severe CHF, advanced cirrhosis with portal hypertension, and severe nephrotic syndrome, when EABV is low but there is an overall excess of Na+ and water, treatment may be extremely problem-atic. Administration of crystalloid solution will, in all likeli-hood, lead to worsening interstitial edema without significantly affecting the EABV. In these situations, prognosis is deter-mined by whether the underlying condition can be reversed.

HypervolemiaDefinition

Hypervolemia is the condition in which the volume of the ECF compartment is expanded in relation to its capacitance. In most people, increments in Na+ intake are matched by cor-responding changes in Na+ excretion as a result of the actions of the compensatory mechanisms detailed in the “Physiology” section. In these cases, no clinically detectable changes are observed. However, in the approximately 20% of the popula-tion who are “salt sensitive,” the upward shift in ECF vol-ume induced by high salt intake leads to a persistent rise in systemic arterial pressure, albeit without other overt signs of fluid retention (see Chapter 46 for a detailed discussion). In the following sections, the discussion is confined to the strict definition of hypervolemia in which Na+ retention is ongoing and inappropriate for the prevailing ECF volume, with the appearance of clinical signs of volume overload.

Etiology

The causes of hypervolemia can be conveniently divided into two major categories: primary renal Na+ retention and secondary retention resulting from compensatory mecha-nisms activated as a result of disease in other major organs (Table 14-6). Primary renal Na+ retention can be further sub-classified as caused by either intrinsic kidney disease or pri-mary mineralocorticoid excess. Of the primary renal diseases causing Na+ retention, oliguric renal failure limits the ability to excrete Na+ and water, and affected patients are at risk for rapidly developing ECF volume overload (see Chapter 30).

In contrast, in chronic kidney disease, renal tubular adaptation to salt intake is usually efficient until late stage 4 and stage 5. However, in some primary glomerular diseases, especially in the presence of nephrotic range proteinuria, significant Na+ retention may occur even when GFR is close to normal (see the following “Pathophysiology” section and Chapter 31). Primary mineralocorticoid excess or enhanced activity, in their early phases, lead to transient Na+ retention. However, because of the phenomenon of “mineralocorticoid escape,” the dominant clinical expression of these diseases is hypertension. Mineralocorticoid excess as a cause of secondary hypertension is discussed in Chapter 46.

Secondary renal Na+ retention occurs in both low- and high-output cardiac failure, as well as in systolic and diastolic dysfunction. Hepatic cirrhosis with portal hypertension and nephrotic syndrome are also accompanied by renal Na+ reten-tion. In this chapter, only CHF and cirrhosis are considered. Nephrotic syndrome is discussed in detail in Chapter 31.

Pathophysiology

The cause of primary renal Na+ retention is clearly disrup-tion of normal renal function. In contrast, secondary renal Na+ retention occurs either because of reduced EABV in the presence of total ECF volume expansion or in response to fac-tors, as yet only partially defined, that are secreted by either the heart or liver that signal the kidneys to retain Na+. In all conditions associated with secondary Na+ retention, the renal effector mechanisms that normally operate to conserve Na+ and protect against a Na+ deficit are exaggerated, and their actions continue despite subtle or overt expansion of ECF volume. The pathophysiologic process of hypervolemia com-prises local mechanisms of edema formation and systemic fac-tors stimulating renal Na+ retention; systemic factors can be further subclassified as abnormalities of the afferent sensing limb or of the efferent effector limb.

loCal meChaniSmS of edema formationPeripheral interstitial fluid accumulation, which is common to all conditions that cause ECF volume expansion, results from disruption of the normal balance of transcapillary Starling forces. Transcapillary fluid and solute transport can be viewed as con-sisting of two types of flow: convective and diffusive. Bulk water movement occurs via convective transport induced by hydraulic and osmotic pressure gradients.345 Capillary hydraulic pressure is under the influence of a number of factors, including systemic arterial and venous blood pressures, local blood flow, and the resis-tances imposed by the precapillary and postcapillary sphincters.

TABLE 14-6 Causes of Renal Sodium Retention

Primary

Oliguric acute kidney injuryChronic kidney diseaseGlomerular diseaseSevere bilateral renal artery stenosisSalt-retaining tubulopathies (genetic)Mineralocorticoid excess

Secondary

Heart failureCirrhosisIdiopathic edema


Systemic arterial blood pressure, in turn, is determined by cardiac output, intravascular volume, and systemic vascular resistance; systemic venous pressure is determined by right atrial pres-sure, intravascular volume, and venous capacitance. Na+ balance is a key determinant of these latter hemodynamic parameters. Also, massive accumulation of fluid in the peripheral interstitial compartment (anasarca) can itself diminish venous compliance and, hence, alter overall cardiovascular performance.346

The balance of Starling forces prevailing at the arteriolar end of the capillary (ΔP > Δπ, in which Δπ is the change in transcapillary oncotic pressure) is favorable for the net filtra-tion of fluid into the interstitium. Net outward movement of fluid along the length of the capillary is associated with an axial decrease in Pc and an increase in the πc. Nevertheless, the local ΔP continues to exceed the opposing Δπ throughout the length of the capillary bed in several tissues; thus, filtration occurs along its entire length.347 In such capillary beds, a sub-stantial volume of filtered fluid must, therefore, return to the circulation via lymphatic vessels. In view of the importance of lymphatic drainage, the lymphatic vessels must be able to expand and proliferate, and the lymphatic flow must be able to increase in response to increased interstitial fluid formation; these mechanisms help minimize edema formation.

Several other mechanisms for minimizing edema forma-tion have been identified. First, precapillary vasoconstriction tends to lower Pc and to diminish the filtering surface area in a given capillary bed. In fact, in the absence of appropriate regu-lation of microcirculatory myogenic reflex, excessive precapil-lary vasodilation appears to account for interstitial edema in the lower extremities that is associated with some Ca2+ entry blocker vasodilators.348 Second, increased net filtration itself is associated with dissipation of Pc, dilution of interstitial fluid protein concentration, and a corresponding rise in intracapil-lary plasma protein concentration. The resulting change in the profile of Starling forces in association with increased filtration therefore tends to mitigate further interstitial fluid accumula-tion.1,349 Finally, Pi is normally subatmospheric; however, even small increases in interstitial fluid volume tend to augment Pi, again opposing further transudation of fluid into the interstitial space.350 The appearance of generalized edema therefore implies that one or more disturbances in microcirculatory hemodynam-ics is present in association with expansion of the ECF volume: increased venous pressure transmitted to the capillary, unfavor-able adjustments in precapillary and postcapillary resistances, or inadequacy of lymphatic flow for draining the interstitial compartment and replenishing the intravascular compartment.

Insofar as the continued net accumulation of interstitial fluid without renal Na+ retention might result in prohibitive intravascular volume contraction and cessation of interstitial fluid formation, generalized edema therefore is indicative of substantial renal Na+ retention. In fact, the volume of accu-mulated interstitial fluid required for clinical detection of generalized edema (>2 to 3 L) necessitates that all states of generalized edema are associated with expansion of ECF vol-ume and, hence, body exchangeable Na+ content. In summary, all states of generalized edema reflect past or ongoing renal Na+ retention.

renal Sodium retentionReduced Effective Arterial Blood Volume. Renal Na+ (and water retention) in edematous disorders occurs despite an increase in total blood and ECF volumes. In stark contrast,

healthy individuals with the same degree of Na+ retention readily increase Na+ and water excretion. Moreover, intrinsic renal function, in the absence of underlying renal disease, is normal in edematous states. This fact is dramatically illus-trated by the observation that, after heart transplantation in patients with CHF351 or liver transplantation in patients with hepatic cirrhosis,352 Na+ excretion is restored to normal. Simi-larly, when kidneys from patients with end-stage liver disease are transplanted into patients with normal liver function, Na+ retention no longer occurs.

The paradox of Na+ retention in the presence of expanded total and ECF volume is explained by the concept of EABV, described earlier. In brief, because 85% of blood circulates in the venous compartment and only 15% in the arterial compart-ment, expansion of the venous compartment leads to overall ECF volume excess that could occur concurrently with arterial underfilling. Arterial underfilling could result from either low cardiac output or peripheral arterial vasodilation, or a combi-nation of the two. In turn, low cardiac output could result from true ECF volume depletion (see earlier discussion), cardiac fail-ure, or decreased πc with or without increased capillary perme-ability. All these stimuli would cause activation of ventricular and arterial sensors. Similarly, conditions such as high-output cardiac failure, sepsis, cirrhosis, and, in fact, normal pregnancy lead to peripheral arterial vasodilation and activation of arterial baroceptors. Activation of these afferent mechanisms would then induce the neurohumoral mechanisms that result in renal Na+ and water retention (Figure 14-6).353,354

Although the mechanisms leading to Na+ retention in CHF and cirrhosis are quite similar, specific differences between the two conditions have been observed, and these findings are dis-cussed separately in the following sections.Renal Sodium Retention in Heart FailureAbnormalities of Sensing Mechanisms in Congestive Heart Failure. There is strong evidence that both the cardiopulmo-nary and baroceptor reflexes are blunted in CHF, so that they cannot exert an adequate tonic inhibitory effect on sympathetic outflow.355,356 The resulting activated SNS triggers renal Na+ retention by the mechanisms already described. With regard to cardiopulmonary receptor reflexes, several researchers, using a variety of models of CHF, have shown marked attenu-ation of atrial receptor firing in CHF in response to volume expansion.357,358 In addition, loss of nerve ending arboriza-tion has been observed directly. Similarly, researchers using maneuvers that selectively alter central cardiac filling pressures (head-up tilt, LBNP) showed that patients with CHF, in con-trast to normal subjects, usually do not demonstrate signifi-cant alterations in limb blood flow, circulating catecholamines, AVP, or renin activity in response to postural stimuli.359,360 This diminished reflex responsiveness may be most impaired in patients with the greatest ventricular dysfunction.

Arterial baroceptor reflex impairment in CHF has been observed both in humans and in experimental models of CHF. High baseline values of muscle sympathetic activity were found in patients with CHF who failed to respond to activa-tion and deactivation of arterial baroreceptors by infusion of phenylephrine and Na+ nitroprusside, respectively.361 Func-tion of carotid and aortic baroreceptors was also depressed in experimental models of cardiac failure.355,356 These changes were associated with upward resetting of receptor threshold and a reduced range of pressures over which the receptors functioned.


Low output cardiac failure,pericardial tamponade,constrictive pericarditis

↓ Extracellularfluid volume

↓ Oncotic pressureand/or

↑ Capillary permeability

↓ CARDIAC OUTPUT

Activation of ventricularand arterial receptors

Stimulation of sympatheticnervous system

↑ SYSTEMIC AND RENAL ARTERIALVASCULAR RESISTANCE

MAINTENANCE OF ARTERIALCIRCULATORY INTEGRITY

RENAL SODIUMRETENTION

RENAL WATERRETENTION

Non-osmoticvasopressionstimulation

Activation of therenin-angiolensin-

aldosterone system

SYSTEMIC ARTERIAL VASODILATION

High-outputcardiac failure Sepsis Cirrhosis

Arteriovenousfistula Pregnancy

Arterialvasodilators

Activation of arterialbaroreceptors

Non-osmoticAVP stimulation

SNSstimulation

Activation ofRAAS

↑ CARDIACOUTPUT

WATERRETENTION

↑ SYSTEMIC ARTERIALVASCULAR AND

RENAL RESISTANCE

SODIUMRETENTION

MAINTENANCE OF ARTERIALCIRCULATORY INTEGRITYB

A

FIGURE 14-6 Sensing mechanisms that initiate and maintain renal sodium and water retention in various clinical conditions in which arterial underfilling, with resultant neurohumoral acti-vation and renal sodium and water retention, is caused by a decrease in cardiac output (A) and by systemic arterial vasodilation (B). In addition to activating the neurohumoral axis, adrenergic stimulation causes renal vasoconstriction and enhances sodium and fluid transport by the proximal tubule epithelium. (From Schrier RW: Decreased effective blood volume in edematous disorders: what does this mean? J Am Soc Nephrol 18:2028-2031, 2007.)

Multiple abnormalities have been described in cardiopul-monary and arterial baroreceptor control of RSNA in CHF. Thus, rats with coronary ligation displayed an increased basal level of efferent RSNA that failed to decrease normally during volume expansion (see DiBona55 and DiBona and Kopp148 and references therein). Similarly, in sinoaortic denervated dogs with pacing-induced CHF, the cardiopulmonary barore-flex control of efferent RSNA became markedly attenuated in response to cardiopulmonary receptor stimulation by volume expansion. Left atrial baroreceptor stimulation produced by

inflation of small balloons at the junction of the left atrial-pulmonary vein produced the same effect (see Zucker et al362 and references therein). The abnormal regulation of efferent RSNA was caused by impaired function of both aortic and cardiopulmonary baroreflexes; the defect in cardiopulmonary baroreceptors was functionally more important.55,148

Several mechanisms have been implicated in the patho-genesis of the abnormal cardiopulmonary and arterial baro-reflexes in CHF. Zucker and colleagues362 suggested that loss of compliance in the dilated hearts, as well as gross changes


in the structure of the receptors themselves, were the mecha-nisms underlying the depressed atrial receptor discharge in dogs with aortocaval fistula (see Zucker et al and references therein). In dogs with pacing-induced CHF, the decrease in carotid sinus baroreceptor sensitivity was related to aug-mented Na+-K+-ATPase activity in the baroreceptor mem-branes (see Zucker et al362 and references therein). Increased activity of angiotensin II through the AT1 receptor has also been invoked to explain depressed baroreflex sensitivity in CHF. Specifically, intracerebral or systemic administration of AT1 receptor antagonists to rats or rabbits with CHF signifi-cantly improved arterial baroreflex control of RSNA or heart rate, respectively (see Zucker et al362 and references therein). Moreover, angiotensin II injected into the vertebral artery of normal rabbits significantly attenuated arterial baroreflex function. This effect of angiotensin II could be blocked by the central α1-adrenoreceptor prazosin.363 In addition, ACE inhibition augmented arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with CHF.364

Newer data indicate that angiotensin II in the paraven-tricular nucleus potentiates—and AT1 receptor antisense messenger RNA normalizes—enhanced the cardiac sympa-thetic afferent reflex in rats with chronic heart failure.65,365 AT1 receptors in the nucleus tractus solitarii are thought to mediate the interaction between the baroreflex and the car-diac sympathetic afferent reflex.366 AT2 receptor in the rostral ventrolateral medulla exhibited an inhibitory effect on sym-pathetic outflow, which was mediated at least partially by an arachidonic acid metabolic pathway. These data implied that a downregulation in the AT2 receptor was a contributory factor in the sympathetic neural excitation in CHF.367

Together, these data provide evidence of the role of high endogenous levels of angiotensin II, acting through the AT1 receptor in concert with downregulation of the AT2 recep-tor, in the impaired baroreflex sensitivity observed in CHF, both in the afferent limb of the reflex arch and at more central sites. The central effect may be mediated through a central α1-adrenoreceptor. The blunted cardiopulmonary and arterial baroreceptor sensitivity in CHF may also lead to an increase in AVP release and renin secretion. However, data on this link are scarce.

Another hypothesis, for which there is scant support, is that the secretory capacity of ANP in response to atrial stretch in CHF is reduced because of limited reserve of the hormone as a result of a tonically increased stimulus for release of the hormone. First, circulating levels of ANP are not depressed but instead elevated in CHF in proportion to the severity of cardiac dysfunction (reviewed by Krupicka et al368). Second, the ventricles become a major source of ANP secretion in CHF369-371; expression is normally limited to the atria. Third, the Na+ retention of CHF is not reversed when plasma ANP levels are further increased by exogenous administration of the peptide.372-374 Thus, the main abnormality of ANP in CHF is the development of “resistance” rather than impaired secretion of the peptide.

The disturbances in the sensing mechanisms that initiate and maintain renal Na+ retention in CHF are summarized in Figure 14-6. As indicated, a decrease in cardiac output or a diversion of systemic blood flow49 diminishes the blood flow to the critical sites of the arterial circuit with pressure- and flow-sensing capabilities. The responses to diminished blood flow culminate in renal Na+ retention, mediated by the

position

effector mechanisms to be described. An increase in systemic venous pressure promotes the transudation of fluid from the intravascular to the interstitial compartment by increasing the peripheral transcapillary ΔP. These processes augment the perceived loss of volume and flow in the arterial circuit. In addition, distortion of the pressure-volume relationships as a result of chronic dilation in the cardiac atria attenuates the normal natriuretic response to central venous congestion. This attenuation is manifested predominantly as diminished neural suppressive response to atrial stretch, which results in increased sympathetic nerve activity and augmented release of renin and AVP.Abnormalities of Effector Mechanisms in Heart Failure. CHF is also characterized by a series of adaptive changes in the efferent limb of the volume-control system, many of which are similar to those that govern renal function in states of true Na+ depletion. These include adjustments in glomerular hemo-dynamics and tubular transport, which, in turn, are brought about by alterations in neural, humoral, and paracrine systems. However, in contrast to true volume depletion, CHF is also associated with activation of vasodilatory natriuretic agents, which tend to oppose the effects of the vasoconstrictor/anti-natriuretic systems. The final effect on urinary Na+ excretion is determined by the balance between these antagonistic effec-tor systems, which, in turn, may shift during the evolution of heart failure toward a dominance of Na+-retaining systems. The abnormal regulation of the efferent limb of the volume-control system reflects not only the exaggerated activity of the antinatriuretic systems but also the failure of vasodilatory/natriuretic systems that are activated in the course of the dete-rioration in cardiac function.Alterations in Glomerular Hemodynamics. CHF in patients and experimental models is characterized by an increase in renal vascular resistance and a reduction in GFR, but also an even more marked reduction of RPF, so that the filtration frac-tion is increased.375,376 In rats with CHF induced by coronary ligation or aortocaval fistula, SNGFR was lower than in con-trol rats, but glomerular plasma flow was disproportionately reduced in such a way that single-nephron filtration fraction was markedly elevated. Kf was diminished, and both afferent and efferent arteriolar resistances were elevated, accounting for the diminished single-nephron glomerular plasma flow.377,378 The rise in single-nephron filtration fraction was caused by a disproportionate increase in efferent arteriolar resistance.

In Figure 14-7, a comparison of the glomerular capillary hemodynamic profile in the normal state versus the CHF state is illustrated on the left graph of each panel. First, ΔP declines along the length of the glomerular capillary in both the normal and CHF states, but much more so in CHF, because of the increased efferent arteriolar resistance. Second, Δπ increases over the length of the glomerular capillary in both states as fluid is filtered into Bowman’s space, but again to a greater extent in CHF because of the increased filtration fraction. As outlined the “Renin-Aldosterone System” section of this chapter, this preferential increase in efferent arteriolar resistance is mediated principally by angiotensin II and is critical for the preserva-tion of GFR in the presence of reduced RPF.379-381 Because of the intense efferent arteriolar vasoconstriction, further com-pensation is not possible if RPP falls as a result of systemic hypotension, causing in a sharp decline in GFR. A dramatic clinical correlate of this phenomenon is the marked decline in GFR seen in patients with CHF whose angiotensin II drive


Glomerulus

FF

Activetransport

Passivebackleak

Reabsorbate

Lateralintercellularspace

Proximaltubule

cell

∆P

∆π

Normal

600 450

Glomerulus

FF

Activetransport

Passivebackleak

Reabsorbate

Lateralintercellularspace

Proximaltubule

cell

∆P

∆π

Heart failure

400 280

150 120

FIGURE 14-7 Peritubular control of proximal tubule fluid reabsorption. Fluid reabsorption in the normal state (left) and in patients with heart failure (right) is shown. Increased postglomerular arteriolar resistance in heart failure is depicted as narrowing. Numbers and red block arrows depict blood flow in preglomerular and postglomerular capillaries. ΔP and Δπ are the transcapillary hydraulic and oncotic pressure differences across the peritubular capillary, respectively; yellow block arrows indicate transtubular transport; pink block arrows represent the effect of peritubular capillary Starling forces on uptake of proximal reabsorbate; the thickness and font size of block arrows depict relative magnitude of effect. The increase in filtration fraction in heart failure causes Δπ to rise. The increase in renal vascular resistance in heart failure is believed to reduce ΔP. Both the increase in Δπ and the fall in ΔP enhance peritubular capillary uptake of proximal reabsorbate and thus increase absolute Na+ reabsorption by the proximal tubule. (Adapted from Humes HD, Gottlieb M, Brenner BM: The kidney in congestive heart failure: contemporary issues in nephrology, vol 1, New York, 1978, Churchill Livingstone, pp 51-72.)

is removed by ACE inhibitors. In this situation, blood pres-sure may fall below the level necessary to maintain renal perfu-sion,382 particularly in patients with preexisting renal failure, massive diuretic treatment, and limited cardiac reserve.379

Enhanced Tubular Reabsorption of Sodium. Enhanced tubular reabsorption of Na+ in CHF is both secondary to the altered glomerular function described above and a direct result of neurohumeral mechanisms. A direct consequence of the glo-merular hemodynamic alterations, and of augmented single-nephron filtration fraction, is an increase in the fractional reabsorption of filtered Na+ at the level of the proximal tubule, as shown in several classical experimental and clinical stud-ies.377,383,384 In Figure 14-2, the peritubular capillary hemo-dynamic profile of the normal state is compared with that of CHF in each panel. In CHF, in comparison with the normal state, the average value of Δπ along the peritubular capillary is increased and that of ΔP is decreased. These values are favor-able for fluid movement into the capillary and may also help reduce backleak of fluid into the tubule via paracellular path-ways, promoting overall net reabsorption.

The peritubular control of proximal fluid reabsorption in nor-mal and CHF states is illustrated schematically in Figure 14-7. A critical mediator of the enhanced tubular reabsorption of Na+ is angiotensin II, which acts by modulating physical factors through its effect on efferent resistance, as well as by augment-ing proximal epithelial transport directly, thereby amplifying the overall increase in proximal Na+ reabsorption. This is clearly illustrated by experiments with ACE inhibitors, in which the increased single-nephron filtration fraction observed in heart failure was improved, which led to normalization of proximal peritubular capillary Starling forces and Na+ reabsorption.377

Distal nephron sites also participate in the enhanced tubule Na+ reabsorption in experimental models of CHF. In dogs and in rats with arteriovenous fistulas385,386 and in dogs with

pericardial constriction387 or chronic partial thoracic vena caval obstruction,388 micropuncture studies demonstrated enhanced distal nephron Na+ reabsorption. Levy389 showed that the inability of dogs with chronic vena caval obstruction to excrete a Na+ load is a consequence of enhanced reabsorption of Na+ at the loop of Henle. Because renal vasodilation and elevation of RPP by saline loading prevented the enhanced reabsorption by the loop of Henle, altered renal hemodynamics appear to determine this response, much as in the proximal tubule.390

Neurohumoral Mediators. The primary neurohumoral media-tors of Na+ and water retention in CHF include the RAAS, SNS, AVP, and endothelins, which are vasoconstrictor/antin-atriuretic (and antidiuretic) systems. In addition, several vasodi-lator/natriuretic substances, such as nitric oxide, prostaglandins, and adrenomedullin, are also activated. Upregulation of uroten-sin II and neuropeptide Y also appears to have a vasodilator/natriuretic effect, in contrast to the physiologic tonic effects of these peptides. In the final analysis, salt and water homeostasis is determined by the fine balance between these opposing sys-tems, and the development of positive Na+ balance and edema formation in CHF represents a turning point at which the balance is in favor of the vasoconstrictor/antinatriuretic forces (Figure 14-8). The dominant activity of Na+-retaining systems in CHF is clinically important because impaired renal function is a strong predictor of mortality391 and reversal of the neuro-humoral impairment is associated with improved outcomes.392

Vasoconstrictor/Antinatriuretic (Antidiuretic) Systems

renin-angiotenSin-aldoSterone SyStemThe activity of the RAAS is enhanced in most patients with CHF in correlation with the severity of cardiac dys-function393; therefore, the activity of this system provides


ANP

Natriuretic peptidesNitric oxide

ProstaglandinsAdrenomedullin and kinins

Vasodilators/natriuretics

Increasedsodium and water

excretion

Decreasedsodium and water

excretion

Vasoconstrictors/antinatriuretics

Renin-angiotensinSympathetic nerve activity

VasopressinEndothelin

Increased extracellular volume

FIGURE 14-8 Efferent limb of extracellular fluid (ECF) volume control in heart failure. Volume homeostasis in heart failure is determined by the balance between natriuretic and antinatriuretic forces. In decompensated heart failure, enhanced activities of the Na+-retaining systems overwhelm the effects of the vasodilatory/natriuretic sys-tems, which leads to a net reduction in Na+ excre-tion and an increase in ECF volume. (Adapted from Winaver J, Hoffman A, Abassi Z, et al: Does the heart’s hormone, ANP, help in congestive heart failure? News Physiol Sci 10:247-253, 1995.)

a prognostic index for CHF patients. It is now abundantly clear that, despite providing initial benefits in hemodynamic support, continued activation of RAAS contributes to the pro-gression and worsening of the primary cardiac component of the CHF syndrome as well, through maladaptive myocardial remodeling.394,395 RAAS activation induces direct systemic vasoconstriction and activates other neurohormonal systems such as AVP, which contribute to maintaining adequate intra-vascular volume.396 However, numerous studies in patients and in experimental models of CHF have established the del-eterious role of the RAAS in the progression of cardiovascular and renal dysfunction in CHF (see Bekheirnia and Schrier41 and Schrier353,354 and references therein).

The kidneys in particular are highly sensitive to the action of vasoconstrictor agents, especially angiotensin II, and a decrease in RPF is one of the most common pathophysiologic alterations in clinical and experimental CHF. Micropuncture techniques demonstrated that rats with chronic stable CHF display depressed glomerular plasma flow rates and depressed SNGFR, as well as elevations in efferent arteriolar resistance and in filtration fraction. Direct renal administration of an ACE inhibitor did not affect renal function in sham-operated control rats, but it did normalize it in rats with experimental CHF. Using the aortocaval fistula model of CHF, Winaver and associates397 showed that only some animals developed Na+ retention, whereas the rest maintained Na+ balance. The former subgroup was characterized by a marked increase in plasma renin activity and plasma aldosterone levels. In con-trast, plasma renin activity and aldosterone levels in compen-sated animals were not different from those in sham-operated controls. Treatment with the ACE inhibitor enalapril resulted in a dramatic natriuretic response in rats with Na+ retention. Similarly, most patients with CHF maintain normal Na+ bal-ance when placed on a low-salt diet, but about 50% develop

positive Na+ balance when fed a normal-salt diet.398 A com-mon feature of both animals and patients with Na+ retention was the activation of the RAAS. In dogs with experimental high-output CHF, the initial period of Na+ retention was associated with a profound activation of the RAAS, and the return to normal Na+ balance was accompanied by a progres-sive fall in plasma renin activity.397

In summary, these findings clearly demonstrate that acti-vation of the RAAS contributes to the pathogenesis of Na+ and water retention in CHF. The deleterious effects of the RAAS on renal function are not surprising in view of the previously mentioned actions of angiotensin II and aldoste-rone on renal hemodynamics and excretory function. Activa-tion of angiotensin II in response to the decreased pumping capacity of the failing myocardium promotes systemic vaso-constriction in association with the preferential vasocon-striction of efferent and afferent arterioles and mesangial cells.164,394 In addition, angiotensin II both exerts a negative influence on renal cortical circulation in rats with CHF and increases tubular Na+ reabsorption directly and indirectly by augmenting aldosterone release.394 In combination, these hemodynamic and tubular actions lead to avid Na+ and water retention, thus promoting circulatory congestion and edema formation.

Not all studies revealed a consistent relationship between RAAS and positive Na+ balance. For instance, in dogs with pulmonary artery or thoracic inferior vena caval constriction, the RAAS was activated to a striking degree during the early phase of constriction and was necessary for the support of systemic blood pressure. Administration of the ACE inhibi-tor captopril resulted in systemic hypotension. Over subse-quent days, Na+ retention and ECF volume expansion were pronounced, and ACE inhibition was no longer accompanied by significant hypotension. However, animals with severe


impairment of cardiac output remained sensitive to the hypo-tensive effects of ACE inhibition. Similarly, among patients with CHF, plasma renin activity and levels of vasoconstrictor hormones were most elevated in patients with acute, severe, and poorly compensated CHF. Levels declined when CHF became stable in the chronic stage.399

The foregoing experimental and clinical data thus indicate that the influence of the RAAS in maintaining circulatory homeostasis may depend on the stage of CHF, being most pronounced in acute and decompensated CHF and least pro-nounced in chronic stable CHF. However, even though the circulating RAAS is not activated in chronic stable CHF, alterations in renal function can still be corrected by ACE inhibition.400 These and other supporting data are consistent with the activation of local RAAS in various tissues, includ-ing the heart, vasculature, kidneys, and brain, in the absence of alterations in the circulating hormone.399 Moreover, results of several studies suggested that activation of the local RAAS in these tissues may play a crucial role in the pathogenesis of CHF.399,401

In addition to the mechanical stress exerted on the myo-cardium due to angiotensin II–mediated increased afterload, pressure overload activates the production of local angiotensin II, as a result of upregulation of angiotensinogen and tissue ACE.394 Local angiotensin II acts through AT1 in a paracrine/autocrine manner, leading to cardiac hypertrophy (because of its growth properties), remodeling and fibrosis (mediated by transforming growth factor-β), and reduced coronary flow, hallmarks of severe CHF.402,403 In support of these observa-tions are the improved cardiac function, prolonged survival, prevention of end-organ damage, and prevention or regres-sion of cardiac hypertrophy in humans and animals with CHF treated with ACE inhibitors and ARBs.165,394 In addition, ACE inhibitors and ARBs may improve endothelial dysfunc-tion, vascular remodeling, and potentiation of the vasodilatory effects of the kinins.164,404-406

Like angiotensin II, aldosterone also acts directly on the myocardium, inducing structural remodeling of the inter-stitial collagen matrix (reviewed by Cowley and Skelton10). Moreover, cardiac aldosterone production is increased in patients with CHF, especially when caused by systolic dys-function. Convincing evidence for the local production of aldosterone was provided by the finding that CYP11B2 mes-senger RNA (aldosterone synthase) is expressed in cultured neonatal rat cardiac myocytes. The adverse contribution of aldosterone to the functional and structural alterations of the failing heart was elegantly proved by the use of eplerenone, a specific aldosterone antagonist, which prevented progressive left ventricular systolic and diastolic dysfunction in associa-tion with reduced interstitial fibrosis, cardiomyocyte hyper-trophy, and left ventricular chamber sphericity in dogs with CHF. Similarly, eplerenone attenuated the development of ventricular remodeling and reactive (but not reparative) fibro-sis after myocardial infarction in rats.407,408 These findings are in agreement with the results of clinical trials (see “Spe-cific Treatments Based on the Pathophysiology of Congestive Heart Failure” section).409,410

As noted previously, in addition to its renal and cardio-vascular hemodynamic effects, the RAAS is involved directly in the exaggerated Na+ reabsorption by the tubule in CHF. Angiotensin II has a dose-dependent direct effect on the proximal tubular epithelium that is favorable for active Na+

reabsorption.411-413 The predominant effect of the RAAS on distal nephron function is mediated by the action of aldoste-rone, which acts on cortical and medullary portions of the collecting duct to enhance Na+ reabsorption, as outlined pre-viously. Numerous researchers reported elevations in plasma aldosterone concentration, in urinary aldosterone secretion, or in natriuretic effects of aldosterone antagonists in animal models and human subjects with CHF, despite further activa-tion of other antinatriuretic systems; these findings provide evidence of the pivotal role of this hormone in the mediation of Na+ retention in CHF.393

As with angiotensin II, the relative importance of miner-alocorticoid action in the Na+ retention of CHF varies with stage and severity of disease. Further evidence for the involve-ment of the RAAS in the development of positive Na+ balance comes from studies showing that the renal and hemodynamic response to ANP is impaired in CHF and that administra-tion of either angiotensin receptor blockade or ACE inhibi-tion restores the blunted response to ANP (for further details, see the “Natriuretic Peptides” section).397 Although patients with CHF have low plasma osmolarity, they display increased thirst, probably because of the high concentrations of angio-tensin II, which stimulates thirst center cells in the hypothala-mus.393 This behavior may contribute to the positive water balance and hyponatremia in these patients (see also the “Arginine Vasopressin” section).

SympathetiC nervouS SyStemPatients with CHF experience progressive activation of the SNS with progressive decline of cardiac function.414,415 Plasma norepinephrine levels are frequently elevated in CHF, and a strong consensus exists as to the adverse influence of sympathetic overactivity on the progression and outcome of patients with CHF.414,416 Thus, sympathetic neural activ-ity is significantly correlated with intracardiac pressures, cardiac hypertrophy, and left ventricular ejection fraction (LVEF).415 Direct intraneural recordings in patients with CHF also showed increased neural traffic, which correlated with the increased plasma norepinephrine levels (reviewed by Kaye and Esler416). Activation of the SNS not only precedes the appearance of congestive symptoms but also is preferen-tially directed toward the heart and kidneys. Clinical inves-tigations revealed that patients with mild CHF have higher plasma norepinephrine in the coronary sinus than in the renal veins.417 At the early stages of CHF, increased activity of the SNS ameliorates the hemodynamic abnormalities—includ-ing hyoperfusion, diminished plasma volume, and impaired cardiac function—by producing vasoconstriction and avid Na+ reabsorption.402,415 However, chronic exposure to this system induces several long-term adverse myocardial effects, includ-ing induction of apoptosis and hypertrophy, with an overall reduction in cardiac function, which reduces contractility. Some of these effects may be mediated, in turn, by activation of the RAAS.393,402

Measurements made with catecholamine spillover tech-niques revealed that the basal sympathetic outflow to the kidneys is significantly increased in patients with CHF.416 The activation of the SNS and increased efferent RSNA may be involved in the alterations in renal function in CHF. For example, exaggerated RSNA contributes to the increased renal vasoconstriction, avid Na+ and water retention, renin secretion, and attenuation of the renal actions of ANP.418 Experimental


studies demonstrated that in rats with experimental CHF caused by coronary artery ligation, renal denervation resulted in an increase in RPF and SNGFR and a decrease in affer-ent and efferent arteriolar resistance.419 Similarly, in dogs with low cardiac output induced by vena caval constriction, admin-istration of a ganglionic blocker resulted in a marked increase in Na+ excretion.416 In rats with CHF induced by coronary ligation, the decrease in RSNA in response to an acute saline load was less than that of control rats.148 Bilateral renal dener-vation restored the natriuretic response to volume expansion; this finding implicates increased RSNA in the Na+ avidity characteristic of CHF.416

Studies in dogs with high-output CHF induced by aorto-caval fistula demonstrated that total postprandial urinary Na+ excretion was approximately twofold higher in dogs with renal denervation than in control dogs with intact nerves.420,421 In line with these observations, clinical investigation showed that administration of the α-adrenoreceptor blocker dibenamine to patients with CHF caused an increase in fractional Na+ excretion, without a change in RPF or GFR. Treatment with ibopamine, an oral dopamine analog, resulted in vasodilation and positive inotropic and diuretic effects in patients with CHF.421 Moreover, for a given degree of cardiac dysfunction, the concentration of norepinephrine is significantly higher in patients with concomitant abnormal renal function than in patients with preserved renal function.422,423 These find-ings suggest that the association between renal function and prognosis in patients with CHF is linked by neurohormonal activation, including that in the CNS.

An additional mechanism by which RSNA may affect renal hemodynamics and Na+ excretion in CHF is through its antagonistic interaction with ANP. On the one hand, ANP has sympathoinhibitory effects424-427; on the other, the SNS-induced salt and water retention in CHF may play a role in reducing renal responsiveness to ANP. For example, the blunted diuretic/natriuretic response to ANP in rats with CHF could be restored by prior renal denervation420 or by administration of clonidine,428 a centrally acting α2-adrenoreceptor agonist, which decreases RSNA in CHF. These experimental and clin-ical data indicate that the SNS may play a role in the regula-tion of Na+ excretion and glomerular hemodynamics in CHF, either by a direct renal action or by attenuating the action of ANP. However, studies in conscious dogs failed to show an ameliorative effect of renal denervation on renal hemodynam-ics and Na+ excretion in CHF.429 The discrepancies in these results probably arose because of species differences, the pres-ence or absence of anesthesia, and the method of inducing CHF. It is also possible that high circulating catecholamines could interfere with the effects of renal denervation.

In summary, the perturbation of SNS activity in the efferent limb of volume homeostasis in CHF is a result of a complex interplay between the SNS itself and other neurohormonal mechanisms that act on the glomeruli and the renal tubules.

vaSopreSSinSince the early 1980s, numerous studies have demonstrated that plasma levels of AVP are elevated in patients with CHF, mostly in those with advanced CHF with hyponatremia, but also in asymptomatic patients with left ventricular dysfunction (see Finley et al430 and references therein). The high plasma levels of AVP are not suppressed after administration of an oral water load, despite the induction of marked hypo-osmolality.431

The mechanisms underlying the enhanced secretion of AVP in CHF are related to nonosmotic factors such as attenuated compliance of the left atrium, hypotension, and activation of the RAAS.353,393 Impairment of the baroreflex control mecha-nism for AVP release was shown not to be involved.432 Data on angiotensin II–stimulated release of AVP are conflicting. Early evidence of this mechanism433 was later refuted.434 Treatment with either an ACE inhibitor (captopril) or an α-blocker (pra-zosin) resulted in suppression of AVP and improved water excretion in response to water loading in patients with CHF, with only a small decline in blood pressure.435 Therefore, improved cardiac function in response to afterload reduction (e.g., pulse pressure, stroke volume) was probably responsible for removal of the nonosmotic stimulus to AVP release.

The high circulating levels of AVP in CHF adversely affect both the kidneys and the cardiovascular system. In fact, raised levels of the C-terminal portion of the AVP prohormone (copeptin) at the time of diagnosis of acute decompensated heart failure are highly predictive of 1-year mortality.436 The prognostic power of raised copeptin in CHF is similar to that of BNP levels (see the later “Brain Natriuretic Peptide” sec-tion). The most recognized renal effect of AVP in CHF is the development of hyponatremia, which usually occurs in advanced stages of the disease and may occur at AVP con-centrations much lower than those required to produce vaso-constriction.437 Hyponatremia most probably results from impaired solute-free water excretion in the presence of sus-tained release of AVP, irrespective of plasma osmolality. In accordance with this notion, studies in animal models of CHF demonstrated increased collecting duct expression of AQP2.438,439 In addition, administration of specific V2 recep-tor antagonists has been consistently associated with improve-ment in plasma Na+ levels in both animals and patients with hyponatremia.430,440 The improvement is associated with cor-rection of the impaired urinary dilution in response to acute water load,441 increased plasma osmolarity, and downregula-tion of renal AQP2 expression.439 Treatment of CHF with selective V2 receptor antagonists is discussed further in the “Specific Treatments Based on the Pathophysiology of Con-gestive Heart Failure” section.

Apart from hyponatremia, CHF is characterized by other alterations in renal function, including a decrease in RBF, especially to the cortex, a decrease in GFR, and Na+ retention. The potential role of enhanced levels of AVP in these renal manifestations remains largely unknown.

The adverse effects of AVP on cardiac function (see Finley et al430 and references therein) occur through its V1A receptor on systemic vascular resistance (increased cardiac afterload), as well as by V2-receptor–mediated water retention, which leads to systemic and pulmonary congestion (increased preload). In addition, AVP, through its V1A receptor, acts directly on car-diomyocytes, causing a rise in intracellular Ca2+ and activa-tion of mitogen-activated kinases and protein kinase C. These signaling mechanisms appear to mediate the observed cardiac remodeling, dilation, and hypertrophy. The remodeling might be further exacerbated by the aforementioned abnormalities in preload and afterload.

In summary, the data suggest (1) that AVP is involved in the pathogenesis of water retention and hyponatremia that characterize CHF and (2) that AVP receptor antago-nists result in remarkable diuresis in both experimental and clinical CHF.


endothelinThere is considerable evidence that ET-1 is involved in the development and progression of CHF. Furthermore, this pep-tide is probably involved in the reduced renal function that characterizes CHF, by inducing renal remodeling, interstitial fibrosis, glomerulosclerosis, hypoperfusion/hypofiltration, and positive salt and water balance.442 The pathophysiologic role of ET-1 in CHF is supported by two major lines of evi-dence: (1) The endothelin system is activated in CHF, and (2) ET-1 receptor antagonists modify this pathophysiologic process.443,444 The first line of evidence is based on the dem-onstration that plasma ET-1 and big ET-1 concentrations in both clinical CHF and experimental models of CHF are elevated and are correlated with hemodynamic severity and symptoms (see Ertl and Bauersachs443 and references therein). Also, a negative correlation between plasma ET-1 concentra-tion and LVEF has been reported (see Ertl and Bauersachs443 and references therein). In another study, the degree of pulmo-nary hypertension was the strongest predictor of plasma ET-1 level in patients with CHF.445 Moreover, plasma levels of big endothelin and ET-1 were independent markers of mortality and morbidity in the Valsartan Heart Failure Trial.446 These prognostic reports are in line with the observation that plasma ET-1 is elevated only in patients with moderate and severe CHF, but not in patients with asymptomatic CHF.447

The increase in plasma levels of ET-1 may be caused by enhanced synthesis of the peptide in the lungs, heart, and circulation by several stimuli such as angiotensin II and thrombin, or it may be caused by decreased clearance by the pulmonary system.443 In parallel to ET-1 levels, ET-A recep-tors are upregulated, whereas ET-B receptors are downregu-lated in the failing human heart.448 The pathophysiologic significance of ET-1 activation in CHF remains speculative. In normal animals, increasing plasma ET-1 levels to concen-trations found in CHF is associated with significant reduction in RBF and increased vascular resistance,206 which is exactly what occurs in CHF.449

A cause-and-effect relationship between these hemody-namic abnormalities and ET-1 in CHF was demonstrated with the development of selective and highly specific endothe-lin receptor antagonists.443 In this regard, acute administra-tion of the mixed ET-A/ET-B receptor antagonists, bosentan and tezosentan, significantly improved renal cortical perfu-sion, reversed the profoundly increased renal vascular resis-tance and increased RBF and Na+ excretion in rats with severe decompensated CHF.450,451 In addition, chronic blockade of ET-A by selective or dual ET-A/ET-B receptor antagonists attenuated the magnitude of Na+ retention and prevented the decline in GFR in experimental CHF443,452 These effects are in line with observations that infusion of ET-1 in normal rats produced a sustained cortical vasoconstrictor and a tran-sient medullary vasodilatory response.258,431 In contrast, rats with decompensated CHF displayed severely blunted corti-cal vasoconstriction but significantly prolonged and preserved medullary vasodilation.269 The significance of these attenu-ated renovascular effects of ET-1 and big endothelin in CHF experimental animals is uncertain, but the effect could result from activation of vasodilatory systems such as prostaglan-dins and nitric oxide. In fact, the medullary tissue of rats with decompensated CHF contains higher eNOS immunoreactive levels was comparable with that in sham-treated controls.269 These findings indicate that endothelin may be involved in

the altered renal hemodynamics and the pathogenesis of corti-cal vasoconstriction in CHF.

Vasodilatory/Natriuretic Systems

natriuretiC peptideSIn decompensated heart failure, renal Na+ and water retention occurs despite expansion of the ECF volume and when the natriuretic peptide system is activated. Results of many clini-cal and experimental studies have implicated both ANP and BNP in the pathophysiologic process of the deranged cardio-renal axis in CHF.Atrial Natriuretic Peptide. Plasma levels of ANP and NH2-terminal ANP are frequently elevated in patients with CHF and are correlated positively with the severity of cardiac failure, as well as with the elevated atrial pressure and other parameters of left ventricular dysfunction.372,436,453-455 In this context, the concentration of circulating ANP was proposed as a diagnostic tool in the determination of cardiac dysfunc-tion and as a prognostic marker in the prediction of survival of patients with CHF.28 Although this proposal was clearly demonstrated, ANP has since been superseded by BNP as a diagnostic and prognostic tool (see later “Brain Natriuretic Peptide” section).

The high levels of plasma ANP are attributed to increased production rather than to decreased clearance. Although volume-induced atrial stretch is the main source for the ele-vated circulating ANP levels in CHF, enhanced synthesis and release of the hormone by the ventricular tissue in response to angiotensin II and endothelin also contribute to this phe-nomenon.456,457 Despite the high levels of this potent natri-uretic and diuretic agent, patients and experimental animals with CHF retain salt and water because renal responsiveness to natriuretic peptides is attenuated.372,458,459 However, infu-sion of ANP to patients with CHF does lead to hemodynamic improvement and inhibition of activated neurohumoral sys-tems. These data are in line with findings in both patients and animals that ANP is a weak counterregulatory hor-mone, insufficient to overcome the substantial vasoconstric-tion mediated by the SNS, RAAS, and AVP.460,461 However, despite the blunted renal response to ANP in CHF, elimi-nation of ANP production by atrial appendectomy in dogs with CHF aggravated the activation of these vasoconstrictive hormones and resulted in marked Na+ and water retention.462 These data suggest that ANP plays a critical role as a suppres-sor of Na+-retaining systems and as an important adaptive or compensatory mechanism aimed at reducing pulmonary vas-cular resistance and hypervolemia.

Actually, the maintenance of Na+ balance in the initial compensated phase of CHF has been attributed in part to the elevated levels of ANP and BNP.234 This notion is supported by the findings that inhibition of natriuretic peptide recep-tors in experimental CHF induces Na+ retention.463 In addi-tion, natriuretic peptides inhibit the angiotensin II–induced systemic vasoconstriction,464 proximal tubule Na+ reabsorp-tion,465 and the secretion of aldosterone464 and endothelin.466 Furthermore, in an experimental model of CHF, inhibition of the natriuretic peptides by specific antibodies to their recep-tors caused further impairment in renal function, as indicated by increased renal vascular resistance and decreased GFR, RBF, urine flow, Na+ excretion, and activation of the RAAS.466,467


In view of the remarkable activation of the natriuretic pep-tide system and the ability of natriuretic peptides to counter the effects of the vasoconstrictor/antinatriuretic neurohor-monal systems, why, then, do salt and water retention occur in overt CHF? Several mechanisms have been suggested to explain this apparent discrepancy: 1. Appearance of abnormal circulating peptides such as β-

ANP and inadequate secretory reserves in comparison with the degree of CHF. However, the fact that circulating levels of native biologically active natriuretic peptides are clearly elevated in CHF indicates that these putative factors can-not account for the exaggerated salt and water retention.

2. Decreased availability of natriuretic peptides by upregu-lation of NEP and clearance receptors.467 So far, no con-vincing evidence suggests that upregulation of clearance receptors exists in the renal tissue of CHF animals or patients, although increased abundance of clearance recep-tors for natriuretic peptides in platelets of patients with advanced CHF has been reported.468 In contrast, several studies have demonstrated enhanced expression and activ-ity of NEP in experimental CHF.469,470 Moreover, numer-ous reports have shown that NEP inhibitors improve the vascular and renal response to natriuretic peptides in CHF (see the “Specific Treatments Based on the Pathophysiol-ogy of Congestive Heart Failure” section).

3. Activation of vasoconstrictor/antinatriuretic factors and development of renal hyporesponsiveness to ANP. Renal resistance to ANP may be present even in the early pre-symptomatic stage of the disease, but it progresses pro-portionately as CHF worsens.471 In advanced CHF, when RPF is markedly impaired, the ability of natriuretic peptides to antagonize the renal effects of angiotensin II may be limited.472 This point was clearly demonstrated in an animal model of CHF, in which chronic blockade by enalapril of the profoundly activated RAAS partially, but significantly, improved the natriuretic response to endog-enous and exogenous ANP.473 The favorable effects of ACE inhibition were especially evident in decompensated heart failure. These findings are in line with the fact that activation of RAAS in CHF largely contributes to Na+ and water retention by antagonizing the renal actions of ANP. The mechanisms underlying the attenuated renal effects of ANP in CHF are not completely understood, but they are known to include angiotensin II–induced afferent and efferent vasoconstriction, mesangial cell contraction, activa-tion of cGMP phosphodiesterases that attenuate the accu-mulation of the second messenger of natriuretic peptides in target organs, and stimulation of Na+,H+-exchanger and Na+ channels in the proximal tubule and collecting duct.473

Activation of the SNS also can overwhelm the renal effects of ANP. As described earlier, overactivity of the SNS leads to vasoconstriction of the peripheral circulation and of the affer-ent and efferent arterioles, which causees reduction of RPF and GFR. These actions, together with the direct stimulatory effects of SNS on Na+ reabsorption in the proximal tubule and loop of Henle, contribute to the attenuated renal respon-siveness to ANP in CHF. Moreover, the SNS-induced renal hypoperfusion/hypofiltration stimulates renin secretion, thus aggravating the positive Na+ and water balance. In rat models of CHF, the diuretic and natriuretic response to ANP was increased after sympathetic inhibition by low-dose cloni-dine428 or bilateral renal denervation.474 The beneficial effects

of renal denervation could be attributed to upregulation of natriuretic peptide receptors and cGMP production, as was demonstrated in normal rats.163

In summary, the development of renal hyporesponsiveness to natriuretic peptides is paralleled closely by overreactivity of both the RAAS and SNS and represents a critical point in the development of positive salt balance and edema formation in advanced CHF.Brain Natriuretic Peptide. As noted previously, BNP is structurally similar to ANP but is produced mainly by the ventricles in response to stretch and pressure overload (reviewed by Richards232). As with ANP, plasma levels of BNP and N-terminal (NT)–proBNP are elevated in patients with CHF in proportion to the severity of myocardial systolic and diastolic dysfunction and New York Heart Association classification.233,368 Plasma levels of BNP are elevated only in severe CHF, whereas circulating concentrations of ANP are high in both mild and severe cases.475,476 The extreme eleva-tion of plasma BNP in severe CHF probably stems from the increased synthesis of BNP, predominantly by the hypertro-phied ventricular tissue, although the contribution of the atria is significant.477

Although echocardiography remains the “gold standard” for the evaluation of left ventricular dysfunction, numer-ous studies have shown that plasma levels of BNP and NT-proBNP are reliable markers and, in fact, superior to ANP and NT-proANP for the diagnosis and prognosis of CHF.23,232,368,436,478-480 The diagnostic capability of NT-proBNP is impressive, with high sensitivity, specificity, and negative predictive value, in patients with an ejection fraction of less than 35%. Similar high predictive values are found in patients with concomitant left ventricular hypertrophy, either in the absence of or after myocardial infarction (reviewed by several authors232,368,436,481). Moreover, the added presence of renal dysfunction appears to enhance these predictive val-ues.482 In addition, elevated plasma BNP (or NT-proBNP) and LVEF lower than 40% are complementary independent predictors of death, CHF, and new myocardial infarction at 3 years after an initial myocardial infarction. Risk stratification with the combination of LVEF lower than 40% and high lev-els of NT-proBNP is substantially better than that provided by either alone.483 The plasma level of BNP is also a power-ful marker for prognosis and risk stratification in the setting of CHF,368,481 with graded increases in mortality throughout each quartile of BNP levels both in the Valsartan in Heart Failure Trial446 and the Carvedilol Prospective Randomized, Cumulative Survival (COPERNICUS) NT-proBNP study (reviewed by Krupicka et al368).

As many as 40% to 50% of patients with CHF have normal systolic function. In these patients, even those who have no symptoms, elevated BNP levels are correlated with diastolic abnormalities on Doppler studies. Conversely, a reduction in BNP levels with treatment are associated with a reduction in left ventricular filling pressures, a lower readmission rate, and a better prognosis; thus, monitoring of BNP levels may provide valuable information regarding treatment efficacy and expected patient outcomes.484,485

Another diagnostic role for BNP is in the clear distinc-tion of dyspnea caused by CHF from that caused by non-cardiac entities.486-491 This point was dramatically illustrated by the N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study, in which the

median NT-proBNP level among 209 patients who had acute CHF was 4054 pg/mL, in contrast to 131 pg/mL among 390 patients (65%) who did not have acute CHF. At cutpoints of more than 450 pg/mL for patients younger than 50 years and more than 900 pg/mL for patients at least 50 years of age, NT-proBNP levels were highly sensitive and specific for the diagnosis of acute CHF. An NT-proBNP level lower than 300 pg/mL was optimal for ruling out acute CHF, with a nega-tive predictive value of 99%. Increased level of NT-proBNP was the strongest independent predictor of a final diagnosis of acute CHF. NT-proBNP testing alone was superior to clini-cal judgment alone for diagnosing acute CHF; NT-proBNP plus clinical judgment was superior to NT-proBNP or clini-cal judgment alone.488 Thus, the predictive accuracy of cir-culating BNP for distinguishing dyspnea caused by CHF from dyspnea with noncardiac causes equals and even exceeds the accuracy of classic examinations such as radiography and physical examination. Moreover, NT-proBNP levels perform better than both the National Health and Nutrition Exami-nation score and Framingham clinical parameters (the most established criteria in use for the diagnosis of CHF).

In addition, the median time to discharge and cost of treat-ment were significantly lower in patients assessed by BNP levels than in those assessed in a conventional manner.492,493 Circulating BNP and NT-proBNP levels have also been used as a guide in determining the therapeutic efficacy of drugs typ-ically prescribed for CHF patients, including ACE inhibitors, ARBs, diuretics, digitalis, and β-blockers.494-497 For example, in the Carvedilol Or Metoprolol European Trial, patients monitored for up to 5 years who achieved an NT-proBNP lower than 400 pg/mL after treatment with either β-blocker had a more favorable prognosis than did nonresponders.498 Similarly, both BNP (intact or NT-proBNP) and ANP lev-els accurately reflected the improvement in ejection fraction of CHF patients treated with conventional therapy including ACE inhibitors. Addition of an ARB to the regimen led to further reductions in peptide levels and ejection fraction.499,500 Conversely, the first cardiovascular event after 6 months of therapy was less frequent in CHF patients whose plasma BNP levels decreased in response to medical treatment.496

Together, these findings suggest that a simple and rapid determination of plasma levels of BNP or NT-proBNP in patients with CHF can be used to assess cardiac dysfunc-tion, serve as a diagnostic and prognostic marker, and assist in titrating relevant therapy. However, it should be empha-sized that plasma levels of both ANP and BNP are affected by several factors, including age, salt intake, gender, obesity, hemodynamic status, and renal function, and there is consid-erable overlap among different diagnostic groups (reviewed by Krupicka et al368). Therefore, a combination of conventional parameters such as clinical and echocardiographic measures assessed together with plasma levels of BNP yield better clini-cal guidelines in patients with CHF than each tool alone.501

C-Type Natriuretic Peptide. As mentioned earlier (“Physiol-ogy” section), CNP is synthesized mainly by endothelial cells, but small amounts are also produced by cardiac tissue.502 In contrast to other natriuretic peptides, CNP is predominantly a vasodilator and has little effect on or may even reduce uri-nary flow and Na+ excretion.503,504 However, the production of CNP by the endothelium in proximity to its receptors in vascular smooth muscle cells suggests that this peptide may play a role in the control of vascular tone and growth.505


Like those of ANP and BNP, plasma CNP levels were found to be increased in CHF, although early studies showed no difference in plasma CNP levels between healthy individu-als and patients with CHF.505,506 CNP levels were directly correlated with New York Heart Association classification; with levels of BNP, ET-1, and adrenomedullin; and with pulmonary capillary wedge pressure, ejection fraction, and left ventricular end-diastolic diameter.506-509 Higher levels of CNP have been found in the coronary sinuses than in the adjacent aorta, which is indicative of CNP release from the myocardium.509,510 The demonstration of a CNP-induced inhibitory effect on cultured cardiac myocyte hypertrophy suggests that overexpression of CNP in the myocardium dur-ing CHF may be involved in counteracting cardiac remod-eling.502 In contrast to the diminished physiologic responses to ANP and BNP in animals with CHF in comparison with control animals, CNP elicited twice as much guanylyl cyclase activity as did ANP, which was shown to result from dra-matic reductions in natriuretic peptide receptor A (NPR-A) activity without any change in natriuretic peptide receptor B (NPR-B) activity.511 These novel findings imply a significant role for NPR-B–mediated natriuretic peptide activity in the failing heart and may explain the modest effects of nesiritide (BNP) treatment in CHF, inasmuch as the latter is NPR-A selective.511

Higher CNP levels in the renal vein than in the adjacent aorta have been reported in normal humans, but this differ-ence was blunted in patients with CHF.512 The physiologic significance of these data currently remains unexplained. Overall, the evidence available points to a possible peripheral vascular compensatory response to CHF by overexpression of CNP. Alternately, CNP may be involved in mitigating the cardiac remodeling so characteristic of CHF. Elaboration of the exact role of CNP in CHF is crucial for the design of potentially effective natriuretic peptide analogs for the man-agement of CHF.

nitriC oxideAfter the discovery that nitric oxide is the prototypic endo-thelium-derived relaxing factor, this signaling molecule was implicated in the increased vascular resistance and impaired endothelium-dependent vascular responses characteristic of CHF.513-518 Thus, the response to acetylcholine, an endo-thelium-dependent vasodilator that acts by releasing nitric oxide, was found to be markedly attenuated in CHF, both in human patients519 and in experimental animals,520 as well as in isolated resistance arteries from patients with CHF.521 The mechanisms mediating the impaired activity of the nitric oxide system in CHF remain enigmatic. Possibilities include a reduction in shear stress associated with the decreased cardiac output,522 downregulation of NOS,523 decreased availability of the nitric oxide precursor L-arginine,518 increased levels of the endogenous NOS inhibitor asymmetric dimethyl argi-nine (ADMA)524 and overriding activity of counterregulatory vasoconstrictor systems such as the RAAS.518,520

In view of the role of nitric oxide in regulating RBF, altered activity of the nitric oxide system may be involved in the pathogenesis of the renal hypoperfusion in CHF. In line with this idea, rats with CHF induced by aortocaval fis-tula had attenuated nitric oxide–mediated renal vasodilation, which was reversed by pretreatment with an AT1 receptor antagonist. This suggests that angiotensin II may be involved


in mediating the impaired nitric oxide–dependent renal vaso-dilation.520 The resulting imbalance between nitric oxide and excessive activation of the RAAS and endothelin systems could explain some of the beneficial effects of ACE inhibitors, ARBs, and aldosterone antagonists.517

The fact that patients with CHF have higher plasma lev-els of NO2 + NO3 and exhibit augmented responsiveness to NOS inhibitors suggests that the nitric oxide system in CHF is an ineffective counterregulatory mechanism in the presence of overwhelming vasoconstrictor forces.518,525 Support for this concept came from a model of experimental CHF in rats, which overexpress eNOS in the renal medulla and, to a lesser extent, in the renal cortex.269 It was speculated that this eNOS might play a role in the preservation of intact medullary per-fusion and could attenuate the severe cortical vasoconstriction. Another explanation for the impaired renal hemodynamics in CHF is the accumulation of ADMA. In this context, plasma ADMA concentrations in patients with normotensive CHF were significantly higher than in controls, and in multiple regression analysis, ADMA levels were independently predic-tive of reduced effective RBF.524

An additional issue is that the myocardium contains all three NOS isoforms, and the locally generated nitric oxide is believed to play a modulatory role on cardiac function.393,526 Thus, alterations in the cardiac nitric oxide system in CHF might contribute to the pathogenesis of cardiac dysfunction and, thereby, indirectly, to the impaired renal function.527 Alteration in expression of cardiac NOS isoforms in CHF is complex, and the functional consequences of these changes depend on a balance among various factors, including disrup-tion of the unique subcellular localization of each isoform and nitroso-redox imbalance.528 Detailed discussion of this topic is beyond the scope of this review; the interested reader is referred to the cardiology literature (e.g., Espiner et al28 and Bauersachs and Widder513).

In summary, endothelium-dependent vasodilation is atten-uated in various vascular beds in CHF. This attenuation may occur in the presence of increased nitric oxide production, which suggests that the vascular nitric oxide may be another example of a failed vasodilator system in CHF.

proStaglandinSAlthough the contribution of prostaglandins to renal func-tion in euvolemic states is minimal, they play an important role in maintaining renal function in the setting of impaired RBF, as occurs in CHF. Renal hypoperfusion, either directly or by activation of the RAAS, stimulates the release of pros-taglandins that exert a vasodilatory effect, predominantly at the level of the afferent arteriole, and promote Na+ excretion by inhibiting Na+ transport in the thick ascending limb of Henle and the medullary collecting duct.529,530 Evidence of the compensatory role of prostaglandins in both experimen-tal and clinical CHF comes from two sources. First, plasma levels of PGE2, PGE2 metabolites, and 6-keto-PGF1 were higher in CHF patients than in normal subjects.531 More-over, studies in experimental and human CHF demonstrated a direct linear relationship between plasma renin activity and angiotensin II concentrations and levels of circulating and urinary PGE2 and PGI2 metabolites.532 This correla-tion probably reflects both angiotensin II–induced stimula-tion of prostaglandin synthesis and prostaglandin-mediated increased renin release.

A similar counterregulatory role of prostaglandins with regard to the other vasoconstrictors (catecholamines and AVP) may also be inferred. An inverse correlation between plasma Na+ concentrations and plasma levels of PGE2 metabolites has also been demonstrated. The second approach that estab-lished the protective role of renal and vascular prostaglandins in CHF was derived from studies of nonsteroidal antiinflam-matory drugs (NSAIDs), which inhibit the synthesis of pros-taglandins. In various experimental models of CHF, inhibition of prostaglandin synthesis by indomethacin was associated with an elevation in urinary excretion of PGE2, a significant increase in body weight, a profound increase in renal vascu-lar resistance. and a resultant decrease in RBF, related mainly to afferent arteriolar constriction.531,533 Serum creatinine and urea levels rose, and urine flow rate declined significantly.533 In accordance with these observations, patients with CHF and hyponatremia, in whom extreme activation of the SNS and the RAAS occurred, were most susceptible to the adverse glomerular hemodynamic consequences of indomethacin treatment.531 Such patients developed significant decreases in RBF and GFR accompanied by reduced urinary Na+ excre-tion.534 These effects were prevented by intravenous infusion of PGE2. Moreover, pretreatment with indomethacin before captopril administration attenuated the captopril-induced increase in RBF. These results suggest that prostaglandins have a significant role in the regulation of renal function in patients with CHF and that captopril-induced improvement in renal hemodynamics is mediated in part by increased pros-taglandin synthesis.

Renal prostaglandins may also play an important role in mediating the natriuretic effects of ANP. For example, in dogs with experimental CHF,535 indomethacin reduced ANP-induced Na+ excretion and creatinine clearance by 75% and 35%, respectively. Collectively, the results of both human and animal studies indicate that CHF is a “prostaglandin-dependent” state, in which elevated angiotensin II level and enhanced RSNA stimulate renal synthesis of PGE2 and PGI2, which would counteract the vasoconstrictor effects of these stimuli to maintain GFR and RBF. Therefore, administration of NSAIDs to patients or animals with CHF would leave these vasoconstrictor systems unopposed, leading to hypoperfusion, hypofiltration, and subsequent Na+ and water retention.530

Clinical data amply bear out the close relationship between the consumption of NSAIDs, both nonselective cyclooxygen-ase inhibitors and selective COX-2 inhibitors, and a signifi-cant worsening of chronic CHF, especially in elderly patients taking diuretics.536-540 The deleterious effects of selective COX-2 inhibitors on cardiac and renal functions are con-sistent with the relative abundance of COX-2 in renal tissue and, to a lesser extent, in the myocardium in patients with CHF.541,542 Moreover, the significant increase in the risk of myocardial infarction and death with the COX-2 inhibitor rofecoxib raised serious safety problems in the use of these drugs and led to the withdrawal of rofecoxib from the mar-ket and a “black box” warning from the U.S. Food and Drug Administration about celecoxib.543,544 The adverse cardiovas-cular effects are thought to be related to an imbalance between platelet COX-1–derived prothrombotic TXA2 and endothe-lial COX-2–derived antithrombotic PGI2, although maladap-tive renal effects cannot be ruled out.545 This would explain why not only selective COX-2 inhibitors but also nonselective cyclooxygenase inhibitors increase cardiovascular morbidity

and mortality.545 However, epidemiologic studies carried out since the withdrawal of rofecoxib indicate a decrease in the relative risk for hospitalization in CHF patients receiving NSAIDs, which suggests that physicians are prescribing these drugs more judiciously than in the past.546 In addition, there is some evidence that celecoxib is safer than either rofecoxib or nonselective cyclooxygenase inhibitors in elderly patients with CHF.537-540 The adverse effects of celecoxib may also be dose dependent.547

In summary, patients with preexisting CHF are dependent on adequate local prostaglandin levels in order to maintain RPF, GFR, and Na+ excretion. Consequently, they are at high risk of volume overload, edema, and deterioration of cardiac function after the use of either COX-2 or nonselective cyclo-oxygenase inhibitors.

adrenomedullinEvidence suggests that adrenomedullin plays a role in the pathophysiology of CHF. In comparison with healthy sub-jects, patients with CHF have plasma levels of the mature form of adrenomedullin, as well as of the glycine-extended form, that are elevated up to fivefold and in proportion to the severity of cardiac and hemodynamic impairment.284,548 High levels of midregional pro-adrenomedullin are also strong pre-dictors of mortality in CHF.549 In accordance with the corre-lation between plasma adrenomedullin levels and the severity of CHF, plasma adrenomedullin levels are also correlated with pulmonary arterial pressure, pulmonary capillary wedge pres-sure, norepinephrine level, ANP level, BNP level, and plasma renin activity in these patients. Plasma levels of the peptide fell with effective anti-CHF treatment, such as carvedilol.288

The origin of the increased amount of circulating adreno-medullin appears to be the failing myocardium itself, includ-ing both the ventricles and, to a lesser extent, the atria.288 Similar findings have been reported for adrenomedullin-2.550 Not only cardiac but also renal adrenomedullin level was sig-nificantly increased, in some but not all experimental models of CHF, in comparison with normal animals.551,552 Although the significance of this renal upregulation of adrenomedullin in CHF is unclear, there is accumulating evidence that adre-nomedullin has favorable effects on salt and water balance, as well as on hemodynamic abnormalities characterizing CHF. Both experimental and clinical studies showed that infusion of adrenomedullin produced beneficial renal effects in CHF-related volume overload. For example, in sheep with CHF caused by rapid pacing, brief administration (90 minutes) of adrenomedullin produced a threefold increase in Na+ excre-tion with maintenance of urine output and a rise in creati-nine clearance, in comparison with baseline levels in normal sheep.288 Prolonged (for 4 days) administration of adreno-medullin in sheep with CHF produced a significant and sus-tained increase in cardiac output in association with enhanced urine volume.288

In contrast to the results in experimental CHF, acute administration of adrenomedullin to patients with CHF increased forearm blood flow but to a lesser extent than in normal subjects, which suggests that the vascular effects of adrenomedullin are significantly attenuated in CHF (see Rademaker et al288). In addition, adrenomedullin had no sig-nificant effect on urine volume and Na+ excretion in patients with CHF, but it did reduce plasma aldosterone levels.288 Also, adrenomedullin infusion led to increased stroke index,


dilation of resistance arteries, and urinary Na+ excretion.288 The improvement in cardiac function after adrenomedullin infusion is not surprising in view of its beneficial effects on preload and afterload and cardiac contractility.284 Collectively, the vasodilatory and natriuretic activities of adrenomedullin, and its origin from the failing heart, suggest that adreno-medullin acts as a compensatory agent to balance the eleva-tion in systemic vascular resistance and volume expansion in this disease state.

Because the favorable effects of adrenomedullin alone are rather modest, recent attempts at combination therapy with other vasodilatory/natriuretic substances have been made. In this regard, adrenomedullin in combination with other therapies such as BNP, ACE inhibitors, and NEP inhibitors resulted in hemodynamic and renal benefits greater than those achieved by each agent administered separately.288 A small pilot trial of combined long-term human ANP and adreno-medullin in patients with acute decompensated heart failure demonstrated significant reductions in mean arterial pressure, pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance without changing heart rate; cardiac output was also increased in comparison with baseline. In addition, the combination of adrenomedullin and human ANP reduced amounts of aldosterone, BNP, and free-radical metabolites, as well as increasing urine volume and Na+ excre-tion over baseline values.553

These promising results should pave the way for larger controlled trials of adrenomedullin in combination with other vasodilator/natriuretic agents. However, in view of the known phenomenon of compensatory rises in vasoconstrictor/anti-natriuretic mechanisms such as the RAAS, SNS, and endo-thelin, caution is needed with the use of adrenomedullin with ANP after natriuretic peptide therapy for CHF.

urotenSinA role for urotensin II and its receptor, GPR14, in the patho-genesis of CHF has been suggested on the basis of the fol-lowing findings: First, some but not all studies revealed that plasma levels of urotensin II are elevated in patients with CHF, in correlation with levels of other markers, such as NT-proBNP and ET-1.554-556 Second, strong expression of uroten-sin II was demonstrated in the myocardium of patients with end-stage CHF, in correlation with the impairment of cardiac function.557 This suggests that upregulation of the urotensin II/GPR14 system could play a part in the cardiac dysfunction associated with CHF. The upregulated urotensin II/GPR14 system in CHF may also have a role in the regulation of renal function in CHF. In rat models of CHF, urotensin II was shown to act primarily as a renal vasodilator, apparently by a nitric oxide–dependent mechanism.301,302 Moreover, human urotensin II increased GFR in rats with CHF but did not alter urinary Na+ excretion in either control or CHF rats. How-ever, in contrast to the negligible renal vasodilatory effect in control rats, the peptide produced a prominent and prolonged decrease in renal vascular resistance in association with a sig-nificant increase in RPF and GFR in CHF rats. Thus, under conditions of increased baseline renal vascular tone found in CHF, human urotensin II has the capacity to act as a potent vasodilator in the kidneys. The clinical application of these data remains to be elucidated and is likely to be complicated, because this peptide might also be the most powerful known vasoconstrictor (see the “Physiology” section).


neuropeptide yIn contrast to the enigma surrounding its function in normal physiology, there is abundant evidence that neuropeptide Y has a significant role in the pathophysiologic process of CHF. Because neuropeptide Y co-localizes and is released with the adrenergic neurotransmitters, it is not surprising that the acti-vated peripheral SNS, with high circulating norepinephrine levels in CHF, is also accompanied by excessive co-release of neuropeptide Y.558 In fact, numerous studies demonstrated elevated plasma levels of neuropeptide Y of patients with CHF, regardless of the cause of the disease.559,560 This increase is correlated with the severity the disease, which suggests that neuropeptide Y might serve as an independent prognostic fac-tor for severity and outcome of CHF.561

Although circulating levels of neuropeptide Y are elevated in patients with CHF, local concentrations of neuropeptide Y, like those of norepinephrine, in the myocardium appear to be lower than normal.562 Using an aortocaval fistula model of CHF in rats, Callanan and colleagues313 demonstrated that the lower levels of myocardial neuropeptide Y are associated with decreased Y1 and increased Y2 receptor expression. More-over, cardiac Y1 receptor expression decreased in proportion to the severity of cardiac hypertrophy and decompensation. Because Y1 receptor activation is associated with cardio-myocyte hypertrophy563-566 and Y2 receptor activation with angiogenesis,566 the data in this model suggest that neuropep-tide Y may simultaneously attenuate the maladaptive cardiac remodeling observed in CHF and stimulate angiogenesis in the ischemic heart.566 Similar patterns of receptor expression change were observed in the kidneys that were proportional to the degree of renal failure and Na+ retention.313 In contrast, administration of neuropeptide Y was shown in experimental models of CHF to exert diuretic and natriuretic properties,567 probably by increasing the release of ANP and inhibiting the RAAS (Table 14-7),568 thereby facilitating water and electro-lyte clearance and reducing congestion. Therefore, in CHF, the higher circulating levels, together with the reduced tissue levels of neuropeptide Y, could be a counterregulatory mecha-nism to modulate the vasoconstrictive and Na+ retaining, as well as the cardiac remodeling, effects of the RAAS and the SNS.

TABLE 14-7 Renal Effects of RAAS Inhibition in Heart Failure

Factors Favoring Improvement in Renal Function

Maintenance of Na+ balanceReduction in diuretic dosageIncrease in Na+ intakeMean arterial pressure >80 mm Hg

Minimal neurohumoral activationIntact counterregulatory mechanisms

Factors Favoring Deterioration in Renal Function

Evidence of Na+ depletion or poor renal perfusionLarge doses of diureticsIncreased urea/creatinine ratioMean arterial pressure <80 mm Hg

Evidence of maximal neurohumoral activationAVP-induced hyponatremia

Interruption of counterregulatory mechanismsCoadministration of prostaglandin inhibitorsAdrenergic dysfunction (e.g., as in diabetes mellitus)

AVP, Arginine vasopressin; RAAS, renin-angiotensin-aldosterone system.

position

In addition, the downregulation of Y1 receptors, by reduc-ing vascular constriction, could contribute to reductions in vascular resistance, in both the coronary and renal circulations. However, once the stage of decompensated heart failure is reached, the likelihood is that RAAS and SNS effects domi-nate, thereby overwhelming any favorable effects of neuropep-tide Y. The precise role of neuropeptide Y in the pathogenesis of CHF progression, cardiac remodeling, and renal Na+ and water retention, via Y1, Y2 and, possibly also, Y5 receptors, requires further clarification.

pharmaCologiC agentS: peroxiSome proliferator-aCtivated reCeptor γ agoniStS and CongeStive heart failurePeroxisome proliferator-activated receptors (PPARs) are nutrient-sensing nuclear transcription factors, of which PPARγ is of special interest in the context of Na+ and water retention because of its ligands, the thiazolidinediones. Thi-azolidinediones, by virtue of their ability to increase insulin sensitivity, are clinically used for the management of type 2 diabetes mellitus. In addition, thiazolidinediones decrease amounts of circulating free fatty acids and triglycerides, lower blood pressure, reduce levels of inflammatory mark-ers, and reduce atherosclerosis in insulin-resistant patients and animal models. Moreover, they have been shown to be beneficial for cardiac remodeling in models of myocar-dial ischemia.569 However, one of the troubling side effects of thiazolidinediones is fluid retention; therefore, CHF is one of the major contraindications to the clinical use of thiazolidinediones.

The site of PPARγ-induced fluid retention appears to involve the collecting duct, inasmuch as mice with collect-ing duct knockout of PPARγ were able to excrete salt loads more easily than were wild-type controls. Because PPARγ knockout also blocked the effect of thiazolidinediones on messenger RNA expression of the γ-subunit of the ENaC, the Na+-retaining effect of thiazolidinediones appear to result from PPARγ stimulation of ENaC-mediated renal salt reabsorption.570,571 In clinical terms, the Na+-retaining effect of thiazolidinediones translates into increased inci-dence of heart failure in patients receiving these drugs, in comparison with controls.572 Because of the Na+- and fluid-retaining effects, as well as other concerns related to increased cardiovascular events,572 the exact role of thia-zolidinediones in the management of diabetes is currently undetermined.

In summary, the alterations in the efferent limb of volume regulation in CHF include enhanced activities of vasocon-strictor/Na+-retaining systems and activation of counterregu-latory vasodilatory/natriuretic systems. The magnitude of Na+ excretion by the kidneys and, therefore, the disturbance in volume homeostasis in CHF are largely determined by the balance between these antagonistic systems. In the early stages of CHF, the balancing effect of the vasodilatory/natriuretic systems is of importance in the maintenance of circulatory and renal function. However, with the progression of CHF, this balance shifts toward dysfunction of the vasodilatory/natri-uretic systems and marked activation of the vasoconstrictor/antinatriuretic systems. These disturbances are translated at the renal circulatory and tubular level to alterations that result in avid retention of salt and water, thereby leading to edema formation.

Renal Sodium Retention in Cirrhosis with Portal Hypertension

Abnormalities in renal Na+ and water excretion commonly occur with cirrhosis, in humans as well as in experimental animal models.573,574 Avid Na+ and water retention may lead eventually to ascites, a common complication of cirrhosis and a major cause of morbidity and mortality, with the occurrence of spontaneous bacterial peritonitis, variceal bleeding, and development of the hepatorenal syndrome.344,574 As in CHF, the pathogenesis of renal Na+ and water retention in cirrhosis is related not to an intrinsic abnormality of the kidneys but to extrarenal mechanisms that regulate renal Na+ and water handling.

abnormalitieS of volume-SenSing meChaniSmS in CirrhoSiSSeveral formulations have been forwarded to explain the mechanisms of Na+ and water retention in cirrhosis, of which the two major ones are the “overflow” and “underfilling” hypotheses. According to the “overflow” hypothesis, an extra-renal signal, possibly from the abnormal liver, induces primary renal Na+ and water retention and plasma volume expansion, even before the appearance of clinical signs such as ascites. Conversely, the classic “underfilling” theory posits that ascites formation causes hypovolemia, which further initiates second-ary renal Na+ and water retention.

In 1988, Schrier and associates575 proposed the “peripheral arterial vasodilation” hypothesis as the basis for relative hypo-volemia.576 The concept of peripheral arterial vasodilation was promoted in the 1990s as a unifying hypothesis to explain the mechanism of renal Na+ and water retention in such diverse states of edema formation as cirrhosis and pregnancy.41,353,354 At the same time, the importance of nitric oxide in the induc-tion of peripheral arterial vasodilation and the hemodynamic abnormalities that mediate salt and water retention in cir-rhosis became increasingly evident.577,578 The contribution of nitric oxide, as well as other vasodilatory mechanisms, to the generation of the “hyperdynamic” circulation in cirrhosis was further demonstrated by numerous other investigators (see Iwakiri and Groszmann579). In the following sections, these competing theories of the disturbance in volume sensing in cirrhosis are briefly presented and followed by a description of the efferent limb of the volume-control system.Overflow Hypothesis. On the basis of findings in patients with cirrhosis, Lieberman and colleagues580 postulated non–volume-dependent renal Na+ retention as the primary distur-bance in Na+ homeostasis in cirrhosis. In turn, this type of renal Na+ retention leads to total plasma volume expansion, and the resulting increased hydrostatic pressure in the por-tosplanchnic bed promotes “overflow” ascites. Strong support for the overflow theory came from extensive and carefully designed studies in dogs with experimental cirrhosis (see Levy581 and references therein). Results of these studies indi-cated that renal Na+ retention and volume expansion could precede ascites formation by 10 days. The Na+ retention occurred independently of measurable changes in cardiac out-put, mean arterial pressure, splanchnic blood volume, hepatic arterial blood flow, GFR, RPF, aldosterone level, and increased RSNA.582 Also, elimination of ascites with the peritoneojugu-lar LeVeen shunt did not prevent Na+ retention during liberal salt intake. In additional studies in dogs with cirrhosis induced


by common bile duct ligation, Na+ retention and ascites for-mation occurred only in dogs with partially or fully occluded portocaval fistulas, but not in animals with patent portocaval anastomosis and normal intrahepatic pressure. These results suggested that intrahepatic hypertension secondary to hepatic venous outflow obstruction was the primary stimulus for renal salt retention.581

In addition to the well-characterized increase in intrahe-patic vascular resistance and sinusoidal pressure in cirrhosis, portal venous blood flow is decreased, and hepatic arterial blood flow is either increased or normal. Moreover, the lower the portal venous flow, the higher the hepatic arterial flow (Figure 14-9A). Of note, a similar response in portal venous and hepatic arterial flow is observed during hemorrhage-induced hypotension (reviewed by Oliver and Verna71). There-fore, it is abundantly clear that the liver is integrally involved in volume sensing. However, the exact anatomic interactions among hepatic arterioles, presinusoidal portal vein branches, and hepatic sinusoids in both the normal liver and cirrhotic liver remain to be elucidated.Afferent Sensing of Intrahepatic Hypertension. The path-way by which intrahepatic hypertension could stimulate renal Na+ retention, without the intermediary of underfilling, would probably involve the hepatic volume-sensing mecha-nisms mentioned earlier. These sensing mechanisms would respond specifically to elevated hepatic venous pressure with increased hepatic afferent nerve activity. The relays for these impulses consist of two autonomic nerve plexuses: one sur-rounding the hepatic artery and the other surrounding the portal vein.583 These neural networks connect hepatic venous congestion to enhanced renal and cardiopulmonary sympa-thetic activity.

Occlusion of the inferior vena cava at the diaphragm was associated with rises in hepatic, portal, and renal venous pressures and resulted in markedly increased hepatic affer-ent nerve traffic and renal and cardiopulmonary sympathetic efferent nerve activity. Section of the anterior hepatic nerves eliminated the reflex increase in renal efferent nerve activ-ity.583 Similarly, denervation of the liver in dogs with vena caval constriction increased urinary Na+ excretion.75 More recently, intrahepatic administration of an adenosine receptor antagonist, 8-phenyltheophylline, to cirrhotic rats produced an effect similar to that of hepatic denervation.584 Subse-quently, the adenosine effect was shown to be mediated by the A1 receptor, inasmuch as a selective antagonist of the A1 receptor, but not of the A2 receptor, inhibited Na+ retention. Of importance is that the adenosine-dependent effects were abolished by hepatic denervation.72

Apart from the adenosine-mediated hepatorenal reflex, other, currently undefined humoral pathways could provide an anatomic or physiologic basis for the primary effects of altera-tions in intrahepatic hemodynamics on renal function. Only a rapid rise in sinusoidal pressure triggers the hepatorenal reflex and ascites formation (e.g., as in Budd-Chiari syndrome). However, chronically increased sinusoidal pressure, to levels even higher than those induced acutely, is usually not associ-ated with ascites formation.585 Despite the wealth of informa-tion on hepatic volume sensing, the molecular identity of the sensor, the cellular location of the sensor, and what is sensed remain elusive. Therefore, much work remains to completely unravel the role of overflow in the pathogenesis of Na+ reten-tion in cirrhosis.


Normal liver Sinusoid Cirrhotic liver

HVHV

PV

PV

HA

HA

↑Pressure

↑Pressure ↑Pressure

HAflow

PVflow

HepaticarteriolePortal

venule

1/3 bloodsupply

2/3 bloodsupplyI

AII III

IB

II III

Cirrhosis orHV constriction

Cirrhosis andside-to-side shunt

Cirrhosis andside-to-side shunt

Constriction

Normal pressure

Na+ retentionNa+ retention Na+ balance

↑

↑

IVC

FIGURE 14-9 Characteristics of hepatic blood flow. A, Hepatic circulation. i, The normal liver receives two thirds of its blood flow from the portal vein (PV) and the remaining third from the hepatic artery (HA). ii, Both the portal venules and hepatic arterioles drain into hepatic sinusoids, but the exact arrange-ment that allows forward flow of the mixed venous and arterial bloods remains unclear. iii, Cirrhosis increases intrahepatic vascular resistance and sinu-soidal pressure. In addition, PV flow is markedly decreased, and HA flow is either unchanged or increased. B, Hepatic vascular hemodynamics and sodium balance. i, Cirrhosis or restriction of HV flow increases intrahepatic vascular resistance and sinusoidal pressure, markedly decreasing PV flow and increasing HA flow. Changes in the physical forces or in the composition of the hepatic blood trigger Na+ retention and edema formation. ii, Insertion of a side-to-side portocaval shunt decreases sinusoidal pressure and maintains mixing of PV and HA blood, irrigating the liver. Under these conditions and despite cirrhosis, there is no Na+ retention. iii, Insertion of an end-to-side portocaval shunt only partially decreases the elevated sinusoidal pressure and prevents mixing of PV and HA blood supplies, inasmuch as the PV blood is diverted to the inferior vena cava. Under these conditions and, despite normalization of PV pressure, Na+ retention continues unabated. (Adapted from Oliver JA, Verna EC: Afferent mechanisms of sodium retention in cirrhosis and hepatorenal syndrome, Kidney Int 77:669-680, 2010.)

Underfilling Hypothesis. In contrast to the “overflow” con-cept, classic “underfilling” theory holds that during the devel-opment of cirrhosis, transudation of fluid and its accumulation in the peritoneal cavity as ascites result in true intravascular hypovolemia. The reduced EABV, in turn, is sensed by the various components of the afferent volume-control system described earlier. Subsequent activation of the efferent limb of the volume-control system, including the RAAS, SNS, and the nonosmotic release of AVP, results in enhanced renal Na+ and water retention, failure to escape from the Na+-retaining effect of aldosterone, and impaired excretion of solute-free water. The ultimate consequence of this mechanism is the development of positive Na+ balance and exacerbation of asci-tes formation.578

Several mechanisms have been invoked to account for the development of the hypovolemia. One such mechanism arose as a consequence of the disruption in normal Starling relationships that govern fluid movement in the hepatic sinu-soids. These, unlike capillaries elsewhere in the body, are highly permeable for plasma proteins. As a result, partition-ing of ECF between the intravascular (intrasinusoidal) and interstitial (space of Disse and lymphatic) compartments of the liver is determined predominantly by the ΔP along the length of the hepatic sinusoids. Obstruction of hepatic venous

outflow promotes enhanced efflux of a protein-rich filtrate into the space of Disse and results in augmented hepatic lymph formation. Such augmented hepatic lymph flow, the main mechanism of ascites formation, has been observed in human subjects with cirrhosis and in experimental models of liver disease.586,587

Vastly increased hepatic lymph formation is accompanied by increased flow through the thoracic duct.588 When the rate of enhanced hepatic lymph formation exceeds the capacity for return to the intravascular compartment via the thoracic duct, hepatic lymph accumulates as ascites, and the intravas-cular compartment is further compromised. As liver disease progresses, a fibrotic process surrounds the Kupffer cells lin-ing the sinusoids, rendering the sinusoids less permeable for serum proteins. Under such circumstances, termed capillariza-tion of sinusoids, a decrease in oncotic pressure also promotes transudation of ECF within the hepatic lymph space, much as it does in other vascular beds.586

Additional consequences of intrahepatic hypertension have also been postulated to contribute to perceived volume contraction. Among these, transmission of elevated intra-sinusoidal pressures to the portal vein leads to expansion of the splanchnic venous system, collateral vein formation, and portosystemic shunting. This results in increased vascular

capacitance and diversion of blood flow from the arterial cir-cuit.589 Vasodilation seems to occur not only in the splanchnic circulation but also in the systemic circulation and has been attributed to refractoriness to the pressor effects of vasocon-strictor hormones, such as angiotensin II and catecholamines, although the mechanism remains unknown.590 Along with diminished hepatic reticuloendothelial cell function, porto-systemic shunting allows various products of intestinal metab-olism and absorption to bypass the liver and escape hepatic elimination. Among these products, endotoxins are thought to contribute to perturbations in renal function in cirrhosis, possibly secondary to the hemodynamic consequences of endotoxemia or through direct renal effects.591

Levels of conjugated bilirubin and bile acids may become elevated as a result of intrahepatic cholestasis or extrahepatic biliary obstruction. In experimental studies of bile duct liga-tion, it is difficult to distinguish the effects on renal function of jaundice itself from the effects of cirrhosis that ensue after the bile duct ligation. However, bile acids actually decrease proximal tubular reabsorption of Na+, a direct renal action that would tend to promote natriuresis.592 Nevertheless, the diuretic-like effect of bile salts may also contribute to the underfilling state in cirrhotic patients.592,593

Hypoalbuminemia could also contribute to the develop-ment of hypovolemia, by diminishing colloid osmotic forces in the systemic capillaries and hepatic sinusoids.594 Hypoal-buminemia was believed to occur as a result of both decreased synthesis of albumin by the liver and dilution caused by ECF volume expansion. The development of hypoalbuminemia is a relatively late event in the course of chronic liver disease. Likewise, a relative impairment of cardiac function could con-tribute to diminished arterial blood pressure in some cirrhotic patients.593,595 In these patients, tense ascites might reduce venous return (preload) to the heart.

Other factors that may also adversely affect cardiac per-formance include diminished β-adrenergic receptor signal transduction, cardiomyocyte cellular plasma membrane dys-function, and increased activity or levels of cardiodepressant substances, such as cytokines, endocannabinoids, and nitric oxide. Although the cardiac dysfunction, termed cirrhotic car-diomyopathy, usually is clinically mild or silent, overt heart failure can be precipitated by stresses such as liver transplanta-tion or transjugular intrahepatic portosystemic shunt (TIPS) insertion.595 Finally, volume depletion in cirrhotic patients may be aggravated by vomiting, occult variceal bleeding, and excessive use of diuretics. Therefore, patients with cirrhosis tolerate hemorrhage or fluid loss very poorly, and they are prone to suffer cardiovascular collapse in the setting of hemo-dynamic disturbances.

Table 14-8 summarizes the various etiologic factors con-tributing to underfilling of the circulation in patients with advanced liver disease. Two major arguments have been pro-vided in support of the underfilling theory. First, the progres-sion of cirrhosis is characterized by increased neurohumoral activity with stimulation of the RAAS, increased sympathetic activity, and elevated plasma AVP levels. These classic markers of hypovolemia cannot be explained by the overflow hypoth-esis. Second, a salutary improvement in volume homeostasis was observed after volume replenishment in cirrhotic patients. For example, volume expansion could suppress the RAAS, increase the GFR, and cause natriuresis and negative salt bal-ance in such patients. In fact, several maneuvers of volume


expansion, such as reinfusion of ascitic fluid, placement of LeVeen shunt, and HWI, were found to cause a brisk diuretic/natriuretic response in patients with cirrhosis. Conversely, the main argument against the underfilling theory was that mea-sured plasma volume in most patients with compensated cir-rhosis was increased, and this increase frequently antedated ascites formation.596 In addition, although volume repletion by diverse measures, as described previously, could result in a dramatic improvement and natriuresis, such an improvement was, at best, temporary and occurred only in 30% to 50% of affected patients. Some of the variability could be a result of inadequate volume replenishment. Nevertheless, it appears that underfilling cannot be the entire explanation for the renal Na+ and water retention that characterizes cirrhotic patients. However, underfilling appears to contribute to Na+ retention in cirrhosis at specific stages of the disease.Peripheral Arterial Vasodilation. Irrespective of the initial trigger, the hallmark of fluid retention in cirrhosis is peripheral arterial vasodilation, in association with renal vasoconstriction. Initially, vasodilation occurs in the splanchnic vascular bed and later in the systemic and pulmonary circulations, leading to “relative arterial underfilling.”575,579 This “relative” underfill-ing unloads the arterial high-pressure baroreceptors and other volume receptors, which, in turn, stimulate a compensatory neurohumoral response. This response includes activation of the RAAS and the SNS, as well as the nonosmotic release of AVP.354,575 Thus, increased hepatic resistance to portal flow causes the gradual development of portal hypertension, col-lateral vein formation, and shunting of blood to the systemic circulation.

As portal hypertension develops, local production of vasodilators—mainly nitric oxide but also carbon monoxide, glucagon, prostacyclin, adrenomedullin, and endogenous opi-ates—increases, leading to splanchnic vasodilation.574,577 In the early stages of cirrhosis, arterial pressure is maintained through increases in plasma volume and cardiac output, in the form of a “hyperdynamic” circulation. However, as the disease progresses, vasodilation in the splanchnic and, presumably, other vascular beds is so pronounced that EABV decreases markedly, leading to sustained neurohumoral activation, renal (as well as brachial, femoral, and cerebral) vasoconstriction, and further Na+ and fluid retention.574,575 This hypothesis could, therefore, potentially explain the increased cardiac out-put and the enhanced neurohumoral changes over the entire spectrum of cirrhosis.596

Thus, decreases in systemic vascular resistance associated with low arterial blood pressure and high cardiac output are clinical manifestations of the hyperdynamic circulation that are commonly seen in patients with cirrhosis. In fact, the com-bination of warm extremities, cutaneous vascular spiders, wide

TABLE 14-8 Factors Causing Underfilling of the Circulation in Cirrhosis

Peripheral vasodilation and blunted vasoconstrictor response to reflex, chemical, and hormonal influencesArteriovenous shunts, particularly in portal circulationIncreased vascular capacity of portal and systemic circulationHypoalbuminemiaImpaired left ventricular function, cirrhotic cardiomyopathyDiminished venous return secondary to advanced tense ascitesOccult gastrointestinal bleeding from ulcers, gastritis, or varicesVolume losses resulting from vomiting and excessive use of diuretics


pulse pressure, and capillary pulsations in the nail bed has been known in cirrhotic patients since the early 1950s.578,579 Pul-monary vasodilation, associated with the hepatopulmonary syndrome, one of the most severe complications of chronic liver disease, may also be considered an example of the hyper-dynamic circulation caused by increased production of nitric oxide (and possibly also carbon monoxide in the lungs.579,597

The hepatorenal syndrome may also develop when the heart is not able to compensate any longer for the progressive decrease in systemic vascular resistance.598 Thus, the hyperdy-namic syndrome of chronic liver disease should be considered as a “progressive vasodilatory syndrome” that finally leads to multiorgan involvement.579 As pointed out earlier, increased production of nitric oxide in the splanchnic vasculature plays a cardinal role in initiating this process.Nitric Oxide. Considerable evidence indicates that aber-rations in the endothelial vasodilator nitric oxide system are involved in the pathogenesis of the hyperdynamic circula-tion and Na+ and water retention in cirrhosis, as well as in hepatic encephalopathy, hepatopulmonary syndrome, and cir-rhotic cardiomyopathy.579,599,600 Nitric oxide is produced in excess by the vasculature of different animal models of portal hypertension, as well as in cirrhotic patients (see Wiest and Groszmann599 and references therein). In animal models, the increased production of nitric oxide can be detected at the onset of Na+ retention and before the appearance of ascites,601 and nitric oxide has been implicated in the impaired vascular responsiveness to vasoconstrictors. Moreover, removal of the vascular endothelial layer has been demonstrated to abolish the difference in vascular reactivity between cirrhotic and con-trol vessels (see Iwakiri and Groszmann579).

Inhibition of NOS has beneficial effects both in experi-mental models of cirrhosis and in humans with the disease. Thus, low dose L-NAME treatment for 7 days602 reversed the high nitric oxide production to control levels and corrected the hyperdynamic circulation in cirrhotic rats with ascites. The normalization of nitric oxide production was accompanied by a marked increase in urinary Na+ and water excretion, a concomitant decrease of ascites, and decreases in plasma renin activity and in the concentrations of aldosterone and vaso-pressin.603 In patients with cirrhosis, the vascular hyporespon-siveness of the forearm circulation to norepinephrine could be reversed by the NOS inhibitor L-NMMA.604 Inhibition of nitric oxide production also corrected the hypotension and hyperdynamic circulation, led to improved renal function and Na+ excretion, and led to a decrease in plasma norepinephrine levels, in these patients.605

The main enzymatic source of the increased systemic vascular nitric oxide generation in cirrhosis has been dem-onstrated to be eNOS in the arterial and splanchnic circu-lations.577 The upregulation of eNOS appears to be, at least in part, caused by increased shear stress as a result of portal venous hypertension with increased flow in the splanchnic circulation.577,579,599 However, in rats with portal vein liga-tion, eNOS upregulation and increased nitric oxide release in the superior mesenteric arteries were found to precede the development of the hyperdynamic splanchnic circula-tion (see Wiest and Groszmann599 and references therein). In marked contrast to the increased nitric oxide generation in the splanchnic and systemic circulation, there is evidence for impaired nitric oxide production and endothelial dysfunction in the intrahepatic microcirculation in cirrhotic rats (see Wiest

position

and Groszmann599 and references therein). The mechanism of this paradoxical behavior of the intrahepatic vascular bed is unknown. However, it has been speculated that this intrahe-patic endothelial dysfunction and nitric oxide deficiency may play a significant role in the pathogenesis of the increased hepatic vascular resistance, as well as in the increased intrahe-patic thrombosis and collagen synthesis in cirrhosis (reviewed by Wiest and Groszmann599). In fact, it is currently believed that the increase in intrahepatic vascular resistance does not result merely from mechanical distortion of the vasculature by fibrosis; rather, a dynamic process, contraction of myofibro-blasts and stellate cells, is believed to determine the degree of intrahepatic vascular resistance.586,599

The decrease in nitric oxide production that results from endothelial dysfunction may shift the balance in favor of vaso-costrictors (e.g., endothelin, leukotrienes, TXA2, angiotensin II), thus causing an increase in intrahepatic vascular resis-tance.599 In accordance with this idea, upregulation of either eNOS or nNOS expression in livers of rats with experimental cirrhosis was associated with a decrease in portal hyperten-sion.606,607 It has been clearly shown that eNOS protein is increased in animal models of portal hypertension and that this increase is already detectable in cirrhotic rats without ascites.599 However, mice with targeted deletion of eNOS alone, or with combined deletions of eNOS and iNOS, may develop a hyperdynamic circulation in association with portal hypertension608 This suggests that other vasodilatory agents may be activated in these mice. In fact, some evidence indi-cates that PGI2,609 endothelium-derived hyperpolarizing factor,610 carbon monoxide,611 adrenomedullin,612 and other vasodilators may participate in the pathogenesis of the hyper-dynamic circulation in experimental cirrhosis (see Iwakiri and Groszmann579).

Evidence that other isoforms of NOS may be involved in the generation of the hyperdynamic circulation and fluid retention in experimental cirrhosis is inconclusive.613 Increased expression of nNOS has been thought to par-tially compensate for the endothelial isoform deficiency in the eNOS–knockout mouse.614 In contrast, the role of iNOS remains controversial; some researchers have shown increased iNOS in arteries of animals with experimental bili-ary cirrhosis615 but not in other forms of experimental cir-rhosis.577,616 Although nonspecific inhibition of NOS may correct the hyperdynamic circulation, preferential iNOS inhibition was shown to be generally ineffective (see Iwakiri and Groszmann579). Overall, the available data point to a predominant role for eNOS.

In experimental cirrhosis, several cellular mechanisms have been implicated in the upregulation of splanchnic eNOS activ-ity and in the downregulation of intrahepatic eNOS activity. Elevation in shear stress as a result of the hyperdynamic cir-culation and portal hypertension has already been mentioned and is consistent with this well-documented mechanism for upregulating eNOS gene transcription in general. However, additional factors related to the hepatic dysfunction could fur-ther stimulate this upregulation. For example, eNOS activity is posttranscriptionally regulated by tetrahydrobiopterin617 and by direct phosphorylation of eNOS protein.618 For example, in rats with experimental cirrhosis, circulating endo-toxins may increase the enzymatic production of tetrahydro-biopterin, thereby enhancing eNOS activity in the mesenteric vascular bed.619


Conversely, potential contributors to intrahepatic eNOS downregulation include interactions with other proteins such as caveolin, calmodulin, heat shock protein 90 (see Wiest and Groszmann599 and Langer and Shah600 and references therein) and eNOS trafficking inducer.620 In addition, disorders of guanylyl cyclase activity have been described.620 Increased levels of ADMA have been reported, and these levels corre-late with the severity of portal hypertension during hepatic inflammation. Moreover, higher ADMA levels have been found in patients with decompensated cirrhosis than in those with compensated disease.620 The raised ADMA levels have been linked to reduced activity of dimethylarginine dimeth-ylhydrolases (DDAHs) that normally metabolize ADMA to citrulline. In this regard, targeted disruption of the DDAH-1 gene in mice or chemical inhibition of DDAH-1 in a model of endotoxin shock was associated with increased plasma and tissue levels of ADMA and decreased nitric oxide–dependent vasodilation.621 Similarly, patients with alcoholic cirrhosis and superimposed inflammatory alcoholic hepatitis had higher plasma and tissue levels of ADMA, higher portal venous pressures, and decreased DDAH expression.622 The therapeu-tic potential for increasing DDAH activity has been shown in an animal model of traumatic vascular injury. Transgenic overexpression of DDAH in this model led to reduced plasma ADMA levels, enhanced endothelial cell regeneration, and reduced neointima formation.623 These data raise the possi-bility of translating the favorable effects of DDAH into the management of decompensated portal hypertension.620 In the final analysis, the relative importance of the various mecha-nisms involved in the reduced intrahepatic and increased splanchnic and systemic NOS activity in cirrhosis remains to be determined.Endocannabinoids. Endogenous cannabinoids are lipid-signaling molecules mimicking the activity of Δ9-tetrahydrocannabinol, the main psychotropic constituent of marijuana. They influence neuroprotection, pain and motor function, energy balance and food intake, cardiovascular function, immune and inflammatory responses, and cell pro-liferation. N-arachidonoylethanolamide, or anandamide, and 2-arachidonoylglycerol are the two most widely studied endocannabinoids that bind the two specific receptors CB1 and CB2. CB1 is expressed mainly in the brain, whereas the CB2 receptor is found mostly in cells of the immune system; both receptors are also expressed in many peripheral tissues under physiologic and pathologic conditions. Anandamide is also able to interact with the vanilloid receptor.624 Although both hepatocytes and nonparenchymal liver cells are capable of producing endocannabinoids, the physiologic expression of CB1 and CB2 receptors in the adult liver is very low or even absent.

A compelling series of experimental and clinical studies has shown that the hepatic expression of CB1 and CB2 receptors and endocannabinoid production are greatly upregulated in chronic and acute liver damage (see Caraceni et al625 and ref-erences therein). Of relevance to this discussion is that endo-cannabinoids have been implicated in portal hypertension and the hyperdynamic circulatory syndrome. In this regard, anandamide caused a dose-dependent increase in intrahepatic vascular resistance in the isolated perfused rat liver. This effect was magnified in cirrhotic livers and appeared to be medi-ated by enhanced production of cyclooxygenase-derived vaso-constrictive eicosanoids. In addition, chronic antagonism of

the CB1 receptor reversed the upregulation of several vaso-constrictive eicosanoids in rat bile duct ligation–induced cir-rhosis. With regard to the splanchnic vasodilation observed in cirrhosis, administration of the CB1 receptor antagonist rimonabant to cirrhotic rats reversed arterial hypotension and increased vascular resistance; with a concomitant decrease in mesenteric arterial blood flow and portal venous pressure. The reduction in splanchnic blood flow was enhanced by the vanil-loid receptor capsazepine. These findings indicate that the transient receptor potential vanilloid type 1 protein and the CB1 receptor have a dual role in the splanchnic vasodilation characteristic of cirrhosis (see Caraceni et al625 and references therein).

A role for endotoxin in the endocannabinoid effects was suggested by the demonstration that infusion of monocytes isolated from cirrhotic rats but not from control rats induced marked hypotension in normal animals (see Caraceni et al625 and references therein). Also, the amount of anandamide was significantly higher in monocytes isolated from patients or rats with cirrhosis than in those from healthy subjects or animals. Because endotoxin represents a major stimulus for endocannabinoid generation in monocytes and platelets, it has been hypothesized that these cells are stimulated to produce large amounts of endocannabinoids by the elevated circulating endotoxin levels frequently found in patients with advanced cirrhosis. This production could then trigger splanchnic and peripheral vasodilation and arterial hypotension, together with intrahepatic vasoconstriction, through activation of the CB1 receptors located in the vascular wall and in the peri-vascular nerves (see Caraceni et al625 and references therein). The role for endocannabinoid antagonism in the treatment of human hepatorenal syndrome remains to be explored.

In summary, afferent sensing of volume in cirrhosis is char-acterized by increased intrahepatic vascular resistance and sinusoidal pressure, decreased portal venous blood flow, and increased hepatic arterial flow. Either because of changes in intrahepatic physical forces or in composition of the “mixed” intrahepatic blood, abnormal Na+ retention is initiated, and edema develops (see Figure 14-9A). Cirrhosis alone is not suf-ficient to induce edema, inasmuch as a side-to-side portoca-val shunt prevents (if inserted before induction of cirrhosis) or corrects (if inserted after induction of cirrhosis) renal Na+ retention. This outcome could result from decreases in sinu-soidal pressure or maintenance of the mixing of portal venous and hepatic arterial blood perfusing the liver. In contrast, end-to-side portocaval shunting only partially decreases elevated sinusoidal pressure and prevents mixing of portal venous and arterial hepatic blood supplies, inasmuch as the portal venous blood is diverted to the inferior vena cava. Under these con-ditions, and despite normalization of portal venous pressure, Na+ retention continues unabated (see Figure 14-9B).

Available data are most consistent with the view that the putative EABV volume sensor in the hepatic circulation is pathologically activated in cirrhosis, failing to respond to the expanded ECF volume. Therefore, as the disease advances, edema worsens (see review by Oliver and Verna71).

abnormalitieS of effeCtor meChaniSmS in CirrhoSiSThe efferent limb of volume regulation in cirrhosis is simi-lar to that in CHF, consisting of adjustments in glomerular hemodynamics and tubule transport that are mediated by vasoconstrictor/antinatriuretic forces (RAAS, SNS, AVP, and


endothelin) and counterbalanced by vasodilator/natriuretic systems (natriuretic peptides and prostaglandins). Therefore, as in CHF, tilting the balance in favor of Na+ retaining forces leads to renal Na+ and water retention.344,573,574

Vasoconstrictors/AntinatriureticsRenin-Angiotensin-Aldosterone System. As in other states of secondary Na+ retention, the RAAS plays a central role in mediating renal Na+ retention in cirrhosis, as demonstrated both in patients and animal models. Elevated plasma renin activity and aldosterone levels were noted in parallel with the progressive severity of cirrhosis and the increase in Na+ reten-tion. Activation of the RAAS is more prominent in patients with ascites than in pre-ascitic patients, which suggests that activation of the RAAS occurs at a relatively advanced stage of the disease. Results of studies in animal models of cirrho-sis, in general, support this notion.626 Nevertheless, positive Na+ balance may already be evident in the pre-ascitic phase of the disease,627 although plasma renin activity and aldosterone levels either remain within the normal range or may even be depressed.

As mentioned earlier, these observations were long believed to be evidence of the role of the overflow theory in the mecha-nism of ascites formation. However, Bernardi and associ-ates628 found elevated aldosterone levels that were inversely correlated with renal Na+ excretion in pre-ascitic cirrhotic patients, particularly in the upright position. This finding suggested that posture-induced activation of the RAAS could already exist in the pre-ascitic phase. In accordance with this notion, renal Na+ retention induced by LBNP was associated with a prominent increase in renal renin and angiotensin II excretion.629 Moreover, treatment with the ARB losartan, at a dosage that did not affect systemic and renal hemodynam-ics or glomerular filtration, was associated with a significant natriuretic response.630 The losartan-induced natriuresis in the presence of normal plasma renin activity was attributed to inhibition of the local intrarenal RAAS.628,630 In fact, it has been demonstrated in rats with chronic bile duct ligation that activation of the intrarenal RAAS may precede activa-tion of the circulating system.631 In addition, losartan has been shown to cause a decrease in portal venous pressure in cirrhotic patients with portal hypertension.632 The postural-induced activation of the RAAS, as well as the beneficial effects of low-dose losartan treatment, in patients with pre-ascitic cirrhosis may be explained by compartmentalization of the expanded blood volume within the splanchnic venous bed during standing and translocation toward the central and arte-rial circulatory beds during recumbence.628

In contrast, in Na+-retaining cirrhotic patients with ascites, angiotensin II inhibition has deleterious effects. For example, administration of captopril, even in low doses, to such patients resulted in a decrease in both GFR and urinary Na+ excre-tion.633 At this stage of the disease, activation of the RAAS serves to support arterial pressure and maintain adequate cir-culation. Therefore, blockade of the RAAS by ACE inhibi-tion or angiotensin receptor blockade may lead to a profound decrease in RPP. This scenario might be important in the pathogenesis of the hepatorenal syndrome, which is regularly preceded by a state of Na+ retention and may be precipitated by a hypovolemic insult. Abnormalities of the renal circula-tion characteristic of this syndrome include marked diminu-tion of RPF with renal cortical ischemia and increased renal vascular resistance, abnormalities consistent with the known

actions of angiotensin II on the renal microcirculation. In this regard, several groups correlated activation of the RAAS with worsening hepatic hemodynamics and decreased rates of sur-vival in patients with cirrhosis (reviewed by Wadei et al573). For this reason, ACE inhibitors and ARBs should be avoided in patients with cirrhosis and ascites.Sympathetic Nervous System. Activation of the SNS is a common feature in patients with cirrhosis and ascites.634 Cir-culating norepinephrine levels, as well as urinary excretion of catecholamines and their metabolites, are elevated in patients with cirrhosis and usually are correlated with the severity of the disease. Moreover, high levels of plasma norepinephrine in patients with decompensated cirrhosis are predictive of increased rate of mortality.634 The source of the increase in norepinephrine levels is enhanced SNS activity, rather than reduced disposal, with nerve terminal spillover from the liver, heart, kidneys, muscle, and cutaneous innervation.634,635 Elevated plasma norepinephrine levels were shown to be correlated closely with Na+ and water retention in cirrhotic patients.636 In addition, increased efferent renal sympathetic tone,637 perhaps as a result of defective arterial and cardio-pulmonary baroreflex control, was observed by direct record-ings in experimental cirrhosis.638 This scenario could explain why volume expansion fails to suppress the enhanced RSNA in cirrhosis.

Concomitantly with the increase in norepinephrine release, cardiovascular responsiveness to reflex autonomic stimulation may be impaired in patients with cirrhosis.639 This impair-ment includes impeded vasoconstrictor responses to a variety of stimuli, such as mental arithmetic, LBNP, and the Valsalva maneuver. Such interference in the peripheral and central autonomic nervous system in cirrhosis could be explained par-tially by increased occupancy of endogenous catecholamine receptors, by downregulation of adrenergic receptors, or by a defect at the level of postreceptor signaling.634 It is also pos-sible that the excessive nitric oxide–dependent vasodilation found in cirrhosis could account for the vascular hyporespon-siveness. This assumption is supported by the finding that the hyporesponsiveness to pressor agents is not limited to norepi-nephrine but may also be observed in response to angiotensin II in patients and experimental animals.590,640

Metabolic derangements due to hepatic dysfunction, such as hypoglycemia and hyperinsulinemia, could also elicit sympathetic overactivity in cirrhosis.634 Although hyperin-sulinemia in cirrhotic models has been shown to stimulate Na+ retention,641 overt hypoglycemia is seldom observed in patients with compensated cirrhosis. Hypoxia may stimulate the SNS in patients with cirrhosis, as indicated by a nega-tive correlation between circulating norepinephrine levels and arterial oxygen tension. Moreover, inhalation of oxygen sig-nificantly reduced circulating levels of norepinephrine, which suggests that a causal relationship exists between hypoxia and increased SNS activity in these patients.634

The increase in renal sympathetic tone and plasma norepi-nephrine levels could contribute to the antinatriuresis of cir-rhosis by decreasing total RBF, or its intrarenal distribution, or by acting directly at the tubular epithelial level to enhance Na+ reabsorption. In fact, patients with compensated cirrhosis may have decreased RBF even in the early stages, and as the dis-ease progresses, RBF tends to decline further, concomitantly with the increase in sympathetic activity.634 In this regard, activation of the SNS in cirrhotic patients was shown to be


associated with a rightward and downward shift of the RBF/RPP autoregulatory curve in such a way that RBF became critically dependent on RPP. Moreover, this phenomenon was found to contribute to the development of the hepatorenal syndrome. Furthermore, insertion of a TIPS to reduce portal venous pressure in patients with hepatorenal syndrome leads to a fall in plasma norepinephrine levels and to an upward shift in the RBF/RPP curve.642

The centrality of SNS overactivity in cirrhosis was illus-trated by the finding that in patients with cirrhosis and increased SNS activity, addition of clonidine to diuretic treatment induced an earlier diuretic response, with fewer diuretic requirements and complications.643 In parallel with the increase in sympathetic activity, patients with progres-sive cirrhosis also showed an increase in the activities of the RAAS and AVP.353,596 The marked neurohumoral activation that occurs at relatively advanced stages of cirrhosis probably represents a shift toward decompensation, characterized by a severe decrease in EABV and, perhaps, true volume deple-tion. A correlation also exists between plasma norepinephrine and AVP levels; thus, the increased activity of the SNS may stimulate the release of AVP.596,636 In addition, a direct rela-tionship exists between plasma norepinephrine and activity of the RAAS.

Together, the evidence suggests that the three pressor sys-tems might be activated by the same mechanisms and operate in concert to counteract the low arterial blood pressure and decrease in EABV.596,634

Arginine Vasopressin. Patients and experimental animals with advanced hepatic cirrhosis frequently exhibit impaired renal water excretion as a result of nonosmotic release of AVP and, consequently, develop water retention with hyponatre-mia.353,354,575,596 For example, cirrhotic patients who were unable to normally excrete a water load had high immuno-reactive levels of AVP in comparison with cirrhotic patients who exhibited a normal response.644 Affected patients also had higher plasma renin and aldosterone levels and lower uri-nary Na+ excretion, which suggests that the inability to sup-press vasopressin was secondary to a decrease in EABV.644 In rats with experimental cirrhosis, plasma levels of AVP were elevated in association with overexpression of hypotha-lamic AVP messenger RNA, together with a diminished pitu-itary AVP content.645 In addition, the expression of AQP2, the AVP-regulated water channel in the collecting duct, was sig-nificantly increased in rats with carbon tetrachloride (CCl4)–induced cirrhosis. This finding was explained by increased AVP secretion, inasmuch as an AVP receptor antagonist sig-nificantly diminished AQP2 expression. It is, therefore, pos-sible that upregulation of AQP2 plays an important role in water retention associated with hepatic cirrhosis, as well as in other pathologic states.199

As noted earlier in this chapter, AVP supports arterial blood pressure through its action on the V1 receptors found on vascular smooth muscle cells, whereas the V2 receptor is responsible for water transport in the collecting duct.209 The availability of selective blockers of these receptors provided clear evidence for the dual roles of AVP in pathogenesis of cirrhosis.208,646,647 Thus, the administration of a V2 receptor antagonist to cirrhotic patients, as well as to rats with experi-mental cirrhosis, increased urine volume, decreased urine osmolality, and corrected hyponatremia.430,647-650 Clinical applications of V2 receptor antagonists are discussed in the

“Specific Treatments Based on the Pathophysiology of Con-gestive Heart Failure” section.

The V1 receptor is important for the maintenance of arte-rial pressure and circulatory integrity, as shown in a rat model of cirrhosis and ascites.651 After the actions of angiotensin II were blocked with saralasin, a selective V1 receptor antagonist produced a pronounced fall in arterial blood pressure. These data serve to illustrate the effectiveness of selective V2 receptor antagonists in the management of fluid retention in cirrhosis.

AVP also increases the synthesis of the vasodilatory PGE2 and PGI2 in several vascular beds, including the kidneys. This increase, in turn, may offset the vasoconstrictor action, as well as the hydroosmotic effect of AVP. In fact, urinary PGE2 was found to be markedly increased in cirrhotic patients with posi-tive free water clearance, despite an impaired ability to directly suppress AVP.652,653 These data suggest that urinary diluting capacity is enhanced after a water load by increased synthesis of PGE2 in the collecting duct.652,653

Endothelin. Plasma levels of immunoreactive endothelin are markedly elevated in patients with cirrhosis who have ascites and in the hepatorenal syndrome (see Angus654 and references therein). However, the role of endothelin in the pathogenesis of the hemodynamic disturbances, fluid retention, and Na+ retention in cirrhosis is still under debate. Although endothe-lins function as autocrine or paracrine agents by interacting with specific receptors at or near the site of synthesis, a frac-tion may spill over into the general circulation, in which it can have systemic effects. In fact, a number of studies have shown that there is a net hepatosplanchnic release of endo-thelins in cirrhosis that is correlated positively with portal venous pressure and cardiac output and inversely with central blood volume.654,655 Increased local intrahepatic production of endothelin is also believed to contribute to the development of portal hypertension, probably through contraction of the stellate cells and a concomitant decrease in sinusoidal blood flow.655

In an attempt to provide further insight into the patho-genic significance of ET-1 in cirrhosis, Martinet and asso-ciates656 measured ET-1 and its precursor, big ET-1, in the systemic circulation and in the splanchnic and renal venous beds of patients with cirrhosis and refractory ascites before and after TIPS insertion. They found that the blood levels of both peptides were higher in the vena cava, hepatic vein, portal vein, and renal vein of cirrhotic patients than in those of normal controls. One to 2 months after TIPS insertion, cre-atinine clearance and urinary Na+ excretion increased, whereas ET-1 and big ET-1 levels were significantly reduced in portal and renal veins. The authors suggested that the hemodynamic changes occurring in patients with cirrhosis and refractory ascites could be related to local production of ET-1 by the splanchnic and renal vascular beds.

However, alteration in the status of other hormones (e.g., renin, aldosterone) after TIPS insertion might also contribute to these hemodynamic changes. An opposite effect—namely, an increase in plasma ET-1—was reported in response to acute temporary occlusion of TIPS by angioplasty balloon inflation, with a transient increase in portal venous pressure.657 Inter-estingly, this was associated with a marked reduction of RPF and increased generation of ET-1 by the kidneys. Because the kidneys are uniquely sensitive to the vasoconstrictor effect of ET-1, ET-1 may play an important role in the pathogenesis of the hepatorenal syndrome.655 This possibility is supported by


the findings that the high plasma ET-1 levels in patients with the hepatorenal syndrome decreased within 1 week after suc-cessful orthotopic liver transplantation and that this decrease was accompanied by an improvement in renal function.658

The importance of the intrarenal endothelin system was demonstrated in a rat model of acute liver failure induced by galactosamine, in which renal failure also developed, despite normal renal histologic findings.659 This situation reasonably mimics the hepatorenal syndrome in humans. Plasma con-centrations of ET-1 were increased twofold after the onset of liver and renal failure, and the ET-A receptor was upregulated significantly in the renal cortex. Administration of bosentan, a nonselective endothelin receptor antagonist, prevented the development of renal failure when given before or 24 hours after the onset of liver injury.659 Although it is possible that activation of the intrarenal endothelin system may play a role in the pathogenesis of the hepatorenal syndrome,660 there is, so far, scant clinical evidence to support this view.Apelin. As mentioned earlier, apelin is the endogenous ligand of the angiotensin-like receptor 1, found to be involved in Na+ and water homeostasis and in regulation of cardiovascu-lar tone and cardiac contractility, through a reciprocal rela-tionship with angiotensin II and AVP (see Principe et al316 and references therein). Because of these properties, apelin is potentially involved in the pathogenesis of advanced liver dis-ease. Evidence for this hypothesis includes raised plasma ape-lin levels in patients and experimental animals with cirrhosis. In addition, an apelin receptor antagonist led to a reduction in the raised cardiac index, reversal of the increased total periph-eral resistance, and improvement in Na+ and water excretion in rats with experimental cirrhosis.316 These data raise the possibility for a therapeutic role of apelin antagonism in the management of severe hepatorenal syndrome. However, in view of the complex effects of apelin on glomerular hemody-namics, apelin antagonists should be used cautiously.Vasodilators/NatriureticsNatriuretic PeptidesAtrial Natriuretic Peptide. Plasma levels of ANP are elevated in patients with cirrhosis, despite the reduction in effective circulating volume in late stages of the disease.661,662 In the pre-ascitic stage of cirrhosis, the increase in plasma ANP may be important for the maintenance of Na+ homeostasis, but with progression of the disease, patients develop resis-tance to the natriuretic action of the peptide.661,662 The high levels of ANP reflect mostly increased cardiac release rather than impaired clearance of the peptide.663 The stimulus for increased cardiac ANP synthesis and release in cirrhosis has not been fully clarified. Overfilling of the circulation in early cirrhosis, secondary to intrahepatic hypertension–related renal Na+ retention, could trigger the increased plasma ANP con-centrations at these early stages. In fact, increased left atrial size, in association with increased intravascular volume and plasma ANP concentration, has been reported in both ascitic and nonascitic alcoholic cirrhotic patients.664

Pre-ascitic patients also had significantly elevated circu-lating blood volumes with higher left and right pulmonary volumes, despite having normal blood pressure and normal renin, aldosterone, and norepinephrine levels.665 High Na+ intake over a 5-week period in pre-ascitic patients resulted in weight gain and positive Na+ balance for 3 weeks, followed by a return to normal Na+ balance thereafter. Interestingly, the RAAS and SNS were suppressed, whereas ANP levels were

elevated. Thus, despite continued high Na+ intake, pre-ascitic patients reach a new steady state of Na+ balance, thereby pre-venting fluid retention and the development of ascites. These findings also suggest that ANP plays an important role in preventing the transition from the pre-ascitic stage to ascites in these patients.666 The factors responsible for maintaining relatively high levels of ANP during the later stages of cirrho-sis, in association with arterial underfilling, also have not been determined. However, ANP levels do not increase further as patients proceed from early compensated to late decompen-sated stages of cirrhosis.

As pointed out earlier, with progression of the disease, many patients with cirrhosis and ascites lose the ability to respond normally to exogenous administration of ANP or to the high endogenous levels of the peptide.661,662 The poten-tial basis for this apparent resistance to ANP was extensively investigated by Skorecki and colleagues.667 For example, in a series of patients with cirrhosis, they showed that HWI led to an increase in ANP and plasma and urinary cGMP, the sec-ond messenger for ANP in all subjects. However, not all sub-jects responded with a natriuresis. No difference in the cGMP response was observed between those who developed natri-uresis (responders) and those who did not (nonresponders). In addition, nonresponders also tended to have more severe and advanced disease.668,669 These findings suggest that the inter-ference with the natriuretic action of ANP occurs at a stage of cellular signaling beyond cGMP production and that ANP receptors in the collecting duct are not defective.

A number of experimental interventions were shown to ameliorate ANP resistance in cirrhosis. These interventions included infusion of endopeptidase inhibitors, bradyki-nin, kininase II inhibitors, and mannitol; renal sympathetic denervation; peritoneovenous shunting; and orthotopic liver transplantation.670-675 The results of these and other studies suggested that antinatriuretic factors, especially the SNS and RAAS, counterbalance and overcome the natriuretic effect of ANP in later stages of cirrhosis.669 As discussed previously, excessive activation of the SNS in cirrhosis, characterized by increased circulating norepinephrine and efferent RNSA, may lead to a decrease in RPF and excessive proximal reabsorp-tion of Na+. In fact, renal denervation was found to reverse the blunted diuretic and natriuretic responses to ANP in cirrhotic rats.675

With regard to the RAAS, overactivation of the system and failure to suppress the RAAS with HWI or ANP infu-sion was clearly associated with resistance to the natriuretic effects of ANP.667 Furthermore, infusion of angiotensin II mimicked the nonresponder state by causing patients in the early stages of cirrhosis who still responded to ANP to become unresponsive676 (Figure 14-10). This effect of angio-tensin II infusion was reversible and occurred at both proximal (decreased distal delivery of Na+) and distal nephron sites to abrogate ANP-induced natriuresis. The importance of distal Na+ delivery was further confirmed in other studies, which showed that the administration of mannitol to increase dis-tal delivery (as measured by lithium clearance) resulted in an improved natriuretic response to ANP in responders but not in nonresponders.672,677

All the available evidence indicates that ANP resistance is best explained by an effect of decreased delivery of Na+ to ANP-responsive distal nephron sites (glomerulotubular imbalance caused by abnormal systemic hemodynamics and


activation of the RAAS) combined with an effective antinatri-uretic factor’s overcoming the natriuretic action of ANP at its site of action in the medullary collecting tubule.669 The latter effect could result from decreased delivery or may be an effect of permissive cofactors such as prostaglandins and kinins. An overall formulation for the role of ANP in cirrhosis and the interrelationship of the peptide with antrinatriuretic influences are summarized at the end of this section and in Figure 14-11.Brain Natriuretic Peptide and C-Type Natriuretic Pep-tide. BNP levels have also been found to be elevated in patients with cirrhosis and ascites and, like that of ANP, its natriuretic effect is also blunted in cirrhotic patients with Na+ retention and ascites.678-680 Plasma BNP levels may be correlated with cardiac dysfunction680,681 and with severity of disease and may be of prognostic value in the progression of cirrhosis.679,680,682 Plasma CNP levels in cirrhotic pre-ascitic patients, although not elevated in comparison to healthy controls, were found to be directly correlated with 24-hour natriuresis and urine vol-ume683 and inversely correlated with arterial compliance but not with systemic vascular resistance.684 These data suggested that compensatory downregulation of CNP occurs in cirrho-sis when vasodilation persists and that regulation of large and small arteries by CNP may differ.

In contrast to the pre-ascitic stage, patients with more advanced disease and impaired renal function had lower plasma and higher urinary CNP levels than did those with intact renal function. Moreover, urinary CNP was correlated inversely with urinary Na+ excretion. In patients with refrac-tory ascites or hepatorenal syndrome treated with terlipres-sin infusion or TIPS (see “Specific Treatments Based on the Pathophysiology of Sodium Retention in Cirrhosis” section), urinary CNP declined and urinary Na+ excretion increased 1 week later.685 Thus, CNP may have a significant role in renal Na+ handling in cirrhosis.

25

20

15

10

5

0

UN

aV (

mE

q/hr

)

BL ANP1

*

*

*

ANP/AII ANP2FIGURE 14-10 Effect of antiotensin II (AII) infusion in atrial natriuretic peptide (ANP)–induced natriuresis. Sodium excretion during the four experimental protocols is depicted. Response was defined by natriuresis greater than 0.83 mmol/hr (20 mmol/day). Note that urinary sodium excretion dropped to almost baseline levels with combined ANP/angioten-sin II infusion and returned to ANP levels when angiotensin II was discon-tinued. *P < 0.05 from previous phase of experiment. ANP/AII, infusion of ANP and angiotensin II combined; ANP1, ANP infusion alone; ANP2, ANP alone; BL, baseline. (Adapted from Tobe SW, Blendis LM, Morali GA, et al: Angiotensin II modulates ANP induced natriuresis in cirrhosis with ascites, Am J Kidney Dis 21:472-479, 1993.)

Finally, Dendroapsis natriuretic peptide levels were found to be increased in cirrhotic patients with ascites, but not in those without, and levels were correlated with disease severity.686 The significance of these findings remains unknown.Prostaglandins. As noted previously, prostaglandins make important contributions to the modulation of the hydro-osmotic effect of AVP and to the protection of RPF and GFR when activity of endogenous vasoconstrictor systems is increased. These properties of prostaglandins appear to be critical in patients with decompensated cirrhosis who have ascites but not renal failure. Such patients excrete greater amounts of vasodilatory prostaglandins than do healthy sub-jects, which suggests that renal production of prostaglandins is increased.225,687 Likewise, in experimental models of cirrhosis, there is evidence for increased synthesis and activity of renal and vascular prostaglandins.687,688 Conversely, it is not sur-prising that administration of agents that inhibit prostaglan-din synthesis results in a clinically important deterioration of renal function in these patients. In fact, administration of nonselective cyclooxygenase inhibitors, such as the NSAIDs indomethacin and ibuprofen, resulted in a significant decre-ment in GFR and RPF in patients with cirrhosis and ascites, in contrast to healthy subjects. The decrement in renal hemo-dynamics varied directly with the degree of Na+ retention and neurohumoral activation, so that patients with high plasma renin and norepinephrine levels were particularly sensitive to these adverse effects.687,689 However, the deleterious effects of NSAIDs on renal function were also observed in cirrhotic patients without ascites.225,690-692

As in other situations associated with decreased EABV, the COX-2 isoform was strongly upregulated in kidneys from rats with experimental cirrhosis with ascites. Nevertheless, the negative effects of prostaglandin inhibition on renal function appear to be solely COX-1 dependent, because studies in both in human and experimental cirrhosis with ascites showed that administration of selective COX-2 antagonists spared renal function, whereas nonselective cyclooxygenase inhibition led to a fall in GFR.687,691,693 In these studies, in both patients and experimental animals, administration of the selective COX-2 inhibitor was carried out on a short-term basis. Addi-tional long-term studies are required in order to establish the safety of these drugs in patients with advanced cirrhosis.

In contrast to nonazotemic patients with cirrhosis and ascites, it has been suggested that patients with hepatorenal syndrome have reduced renal synthesis of vasodilatory pros-taglandins.694 This situation would exacerbate renal vasocon-striction and Na+ and fluid retention and may be an important factor in the pathogenesis of hepatorenal syndrome.687 How-ever, an attempt to improve renal function in these patients by treatment with intravenous infusion of PGE2 or its oral analog, misoprostol, was unsuccessful.695

An Integrated View of the Pathogenesis of Sodium Retention in Cirrhosis

Two general explanations for Na+ retention that complicates cirrhosis have been offered. According to the overflow mecha-nism of ascites formation in cirrhosis, a volume-independent stimulus is responsible for renal Na+ retention. Possible medi-ators include adrenergic reflexes activated by hepatic sinusoi-dal hypertension and increased systemic concentrations of an unidentified antinatriuretic factor as a result of impaired liver


ASCITESoverflow

?

primary renalsodium retention

underfillintravascular volume

expansion

EARLY CIRRHOSIS

release of ANP

disruption of sinusoidialStarling forces

loss of volume intoperitoneal compartment

activation of antinatriureticfactors

HEPATIC VENOUS OUTFLOW BLOCK

ANP antinatriureticfactors

LATE CIRRHOSIS

ANPantinatriuretic

factors

FIGURE 14-11 Working formulation for the role of atrial natriuretic peptide (ANP) in the renal sodium retention of cirrhosis. The primary hepatic abnor-mality for renal Na+ retention is blockade of hepatic venous outflow. In early disease, this signals renal Na+ retention with consequent intravascular volume expansion and a compensatory rise in plasma ANP. The rise in ANP is sufficient to counterbalance the primary antinatriuretic influences, but the expanded intravascular volume provides the potential for overflow ascites. With progression of disease, intrasinusoidal Starling forces are disrupted, volume is lost from the vascular compartment into the peritoneal compartment. This underfilling of the circulation may attenuate further increases in ANP levels and promote the activation of antinatriuretic factors. Whether the antinatriuretic factors activated by underfilling are the same as or different from those pro-moting primary renal Na+ retention in early disease remains to be determined. At this later stage of disease, increased levels of ANP may not be sufficient to counterbalance antinatriuretic forces. (From Warner LC, Leung WM, Campbell P, et al: The role of resistance to atrial natriuretic peptide in the pathogenesis of sodium retention in hepatic cirrhosis, in Brenner BM, Laragh JH [editors]: Advances in atrial peptide research, vol 3 of American Society of Hypertension series, New York, 1989, Raven Press, pp 185-204.)

metabolism. According to the underfilling theory, in contrast, EABV depletion is responsible for renal Na+ retention. The peripheral arterial vasodilation hypothesis is that reduced sys-temic vascular resistance lowers blood pressure and activates arterial baroreceptors, initiating Na+ retention. The retained fluid extravasates from the hypertensive splanchnic circula-tion, preventing arterial repletion, and Na+ retention and asci-tes formation continue.

It is quite obvious that neither the underfilling nor the overflow theory can account exclusively for all the observed derangements in volume regulation in cirrhosis. Rather, ele-ments of the two concepts may occur simultaneously or sequen-tially in cirrhotic patients (see Figure 14-11). Thus, there is sufficient evidence that, early in cirrhosis, intrahepatic hyper-tension caused by hepatic venous outflow obstruction signals primary renal Na+ retention, with consequent intravascular volume expansion. Whether underfilling of the arterial circuit is also a consequence of vasodilation at this stage remains to be determined. Because of expansion of the intrathoracic venous compartment at this stage, plasma ANP levels rise. This rise is sufficient to counterbalance the renal Na+ retaining forces, but at the expense of an expanded intravascular volume, with the potential for overflow ascites. The propensity for the accumulation of volume in the peritoneal compartment and the splanchnic bed results from altered intrahepatic hemo-dynamics. With progression of disease, intrasinusoidal Star-ling forces are disrupted, and volume is lost from the vascular compartment into the peritoneal compartment. These events, coupled with other factors such as portosystemic shunting,

hypoalbuminemia, and vascular refractoriness to pressor hor-mones, lead to underfilling of the arterial circuit, without measurably affecting the venous compartment.

This arterial underfilling may attenuate further increases in ANP levels and promote the activation of antinatriuretic factors. Whether these antinatriuretic factors activated by underfilling are the same as, or different from, those that pro-mote primary renal Na+ retention in early disease remains to be determined. At this later stage of disease, elevated levels of ANP may not be sufficient to counterbalance antinatriuretic influences. In early cirrhosis, salt retention is isotonic, and so normonatremia is maintained. However, with advancing cirrhosis, defective water excretion supervenes, resulting in hyponatremia, which reflects combined ECF and ICF space expansion. The impaired water excretion and hyponatremia in cirrhotic patients with ascites is a marker of the severity of the hemodynamic abnormalities that initiate Na+ retention and eventuate in the hepatorenal syndrome. The pathogen-esis is related primarily to nonosmotic stimuli for release of vasopressin acting together with additional factors such as impaired distal Na+ delivery.

Clinical Manifestations of Hypervolemia

Apart from the clinical manifestations of the underlying dis-ease, the symptoms and signs of hypervolemia per se also depend on the amount and relative distribution of the fluid between the intravascular (arterial and venous) and interstitial space. Arterial volume overload is manifested as hypertension,


whereas venous overload is manifested as raised jugular venous pressure. Interstitial fluid accumulation appears as peripheral edema, effusions in the pleural or peritoneal cavity (ascites) or in the alveolar space (pulmonary edema), or com-binations of these manifestations. If cardiac and hepatic func-tions are normal and transcapillary Starling forces are intact, the excess volume is distributed proportionately throughout the ECF compartments. In this situation, the earliest sign of hypervolemia is hypertension, followed by peripheral edema and raised jugular venous pressure. Peripheral edema appears only when the interstitial volume overload exceeds 3 L and, because plasma volume itself is approximately 3 L, the pres-ence of edema indicates substantial hypervolemia with prior or ongoing renal Na+ retention.

When cardiac systolic function is impaired, as a result of myocardial, valvular, or pericardial disease, pulmonary and systemic venous hypertension predominate, and systemic blood pressure may be low as a result of disproportionate fluid accumulation in the venous rather than the arterial circulation. Disruption in transcapillary Starling forces, as found in both advanced cardiac and hepatic disease, may lead to fluid tran-sudation into the pleural and peritoneal spaces, manifested as pleural effusions and ascites, respectively.

As already mentioned, the constellation of advanced liver cirrhosis or fulminant hepatic failure, ascites and oliguric renal failure in the absence of significant renal histopathologic dis-ease is the hepatorenal syndrome. Two subtypes have been defined: type 1 is characterized by a rapid decline in renal function (doubling of serum creatinine level to >2.5 mg/dL or 50% reduction in creatinine clearance to <20 mL/min) over a 2-week period. Typically, an acute precipitating factor can be identified. Type 2 develops spontaneously and progressively over months (serum creatinine level >1.5 mg/dL or creatinine clearance <40 mL/min). Hepatorenal syndrome is discussed in detail in Chapter 30

Diagnosis

The diagnosis of hypervolemia is usually evident from the clinical history and physical examination. Any combination of peripheral edema, raised jugular venous pressure, pulmonary crepitations, and pleural effusions is likely to be diagnostic for hypervolemia. In the presence of these findings, the systemic blood pressure is crucial for distinguishing primary renal Na+ retention from secondary Na+ retention caused by reduced EABV. For example, in advanced primary renal failure, the blood pressure is high, whereas in severe congestive heart fail-ure or advanced hepatic cirrhosis, blood pressure is likely to be relatively low. In more enigmatic cases, in which dyspnea is the sole complaint and clinical findings are minimal, mea-surement of plasma BNP or proBNP may help to distinguish between cardiac and pulmonary causes of the dyspnea.478

Simple laboratory tests may aid in confirming the clinical diagnosis. Elevated cardiac troponin level is consistent with, although not diagnostic of, myocardial damage.696,697 Trans-aminase levels may be raised in hepatic disease, and hypoal-buminemia would be consistent with either hepatic cirrhosis or nephrotic-range proteinuria caused by glomerular disease. The latter, of course, would be confirmed by appropriate urine testing.

When blood pressure is low, evidence of prerenal azote-mia (increased ratio of blood urea nitrogen to creatinine) may

be found, and in advanced cardiac or hepatic failure (the so-called cardiorenal and hepatorenal syndromes), intrinsic renal failure—proportionate increases in blood urea nitrogen and creatinine—may occur (see Chapter 30 for detailed discus-sion). In the urine, low EABV in the presence of hypervol-emia is confirmed by low Na+ concentration or low fractional excretion of Na+, indicative of secondary renal Na+ retention.

Treatment

Therapy for volume overload can be divided broadly into management of the volume overload itself and prevention or minimization of its occurrence and the associated morbid-ity and mortality. Clearly, recognition and treatment of the underlying disease causing hypervolemia is the critical first step. Thus, when EABV is significantly reduced, as in cardiac and hepatic failure, as well as in severe nephrotic syndrome, hemodynamic parameters should be optimized. Otherwise, therapy to induce negative Na+ balance is associated with enhanced risk for worsening hemodynamic compromise.

Once the EABV is adjusted, three basic strategies can be used to induce negative Na+ balance: dietary Na+ restriction, diuretics, and extracorporeal ultrafiltration. The degree of hypervolemia and the clinical urgency for Na+ removal deter-mine which modality should be used. Therefore, in a patient with life-threatening pulmonary edema, immediate intrave-nous loop diuretics are indicated; if high doses of these drugs do not induce significant diuresis, then extracorporeal ultrafil-tration may be life-saving. At the other extreme, a hyperten-sive patient with mild volume overload and preserved renal function may require only dietary salt restriction and a thia-zide diuretic.

Once the acute stage of hypervolemia has been controlled, therapy must be directed toward the prevention or minimi-zation of further acute episodes and improvement in overall prognosis. In addition to maintenance diuretic treatment, sev-eral strategies, based on the pathophysiologic process of Na+ retention, are available clinically or are under experimental development.

Sodium reStriCtionEffective management of hypervolemia of any cause must include Na+ restriction. Without this intervention, the success of diuretic therapy is limited because the relative hypovolemia induced by diuretics leads to compensatory Na+ retention and the potential creation of a vicious cycle consisting of increased diuretic dosage, further reduction in EABV, and yet greater renal Na+ retention. A reasonable goal is to restrict Na+ intake to 50 to 80 mmol (approximately 3 to 5 g of salt) per day. Because of the generally poor palatability of salt-restricted diets, salt substitutes may be used; however, because these preparations usually contain high concentrations of potas-sium, they must be used with caution by patients with renal impairment or those taking potassium-retaining drugs such as ACE inhibitors, ARBs, or aldosterone antagonists.

In hospitalized patients, extra attention must be paid to amounts and types of intravenous fluids administered. A fre-quent phenomenon encountered by nephrologists called for consultation in internal medicine departments is the scenario in which a patient is receiving intravenous saline together with high-dose diuretics. The usual rationale offered for this com-bination is that the saline will expand the intravascular volume


and the diuretic will mobilize the excess interstitial volume. This logic has no sound physiologic or therapeutic basis, inasmuch as both modalities operate principally on the intra-vascular space. Furthermore, water restriction is also inappro-priate except in the presence of accompanying hyponatremia (plasma Na+ <135 mmol/L). In stark contrast to these recom-mendations, one research group has shown that intravenously infusing small volumes of hypertonic saline during diuretic dosing and liberalizing dietary salt intake while continuing to limit water consumption resulted in improved fluid removal in patients with CHF. Furthermore, less deterioration in renal function, shorter hospitalizations, reduced readmission rates, and even reductions in mortality were observed.698,699 These novel findings stimulated the design of another clini-cal trial (Concentrated Saline Infusions and Increased Dietary Sodium with Diuretics for Heart Failure with Kidney Dys-function; ClinicalTrials.gov Identifier: NCT00575484) in which the effects of this highly unconventional combination for the treatment of heart failure were examined in patients with renal dysfunction. This study was terminated in July 2010 and the results are eagerly anticipated.

diuretiCSDiuretics are classified according to their sites of action along the nephron and are discussed in detail in Chapter 50. They are described briefly here in relation to the treatment of hypervolemia.Proximal Tubule Diuretics. The prototype of a proximal tubular diuretic is acetazolamide, a carbonic anhydrase inhibi-tor that inhibits proximal reabsorption of sodium bicarbonate. Prolonged use may cause hyperchloremic metabolic acido-sis. This drug is more typically used in the management of chronic glaucoma rather than for reducing volume overload. Another proximally acting diuretic is metolazone, which, as a member of the thiazide class of diuretics, also inhibits the NaCl cotransporter in the distal tubule. The proximal action of metolazone may be associated with phosphate loss greater than that seen with traditional thiazides.700 In general, meto-lazone is used as an adjunct to loop diuretics in resistant heart failure.701 Mannitol also inhibits proximal tubular reabsorp-tion,702 but it is used mainly to reduce increased intracranial pressure.Loop Diuretics. This group comprises the most powerful diuretics and includes furosemide, bumetanide, torsemide, and ethacrynic acid. Their mode of action is to inhibit trans-port via the NKCC2 in the apical membrane of the thick ascending limb of the loop of Henle,703 which is respon-sible for the reabsorption of about 25% of filtered Na+ (see Chapter 5). They are used for the treatment of both severe hypervolemia and hypertension, especially in stages 4 and 5 of chronic kidney disease. Because of their powerful action, loop diuretics may lead to hypokalemia, intravascular volume depletion, and worsening prerenal azotemia, especially in elderly patients and in patients with reduced EABV.Distal Tubule Diuretics. Diuretics that operate in this seg-ment operate by blockade of the apical NaCl cotransporter. The group consists of hydrochlorothiazide, chlorthalidone, and metolazone (see earlier “Proximal Tubule Diuretics” sec-tion). They are typically used as first-line treatment of hyper-tension and also, particularly metolazone, as adjuncts to loop diuretics in resistant heart failure. Thiazides are also useful for reducing hypercalciuria in recurrent nephrolithiasis,704 in

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contrast to loop diuretics that are hypercalciuric.705 Inhibi-tion of Na+ reabsorption by diuretics that work in the proxi-mal tubule (except for carbonic anhydrase inhibitors), loop of Henle, and distal tubule leads to increased solute delivery to the collecting duct. Consequently, rates of potassium and pro-ton secretion are accelerated, which may lead to hypokalemia and metabolic alkalosis.703

Collecting Duct Diuretics. Collecting duct (K+-sparing) diuretics operate either by competing with aldosterone for occupation of the mineralocorticoid receptor409 or by direct inhibition of the ENaC (amiloride and triamterene). As their alternative name implies, important side effects of this group are hyperkalemia and metabolic acidosis, which result from concomitant suppression of K+ and proton secretion. Therefore, they are widely used in combination with both thiazide and loop diuretics to minimize hypokalemia. The aldosterone antagonists are especially useful in the man-agement of disorders characterized by secondary hyper-aldosteronism, such as cirrhosis with ascites. Moreover, aldosterone antagonists have been shown to have cardio-protective and renoprotective effects, through nonepithelial mineralocorticoid receptor blockade (see “Pathophysiology” and “Specific Treatments Based on the Pathophysiology of Congestive Heart Failure” sections in this chapter; also see Chapter 61).Other Diuretic Agents. Natiuretic peptides are discussed in the “Specific Treatments Based on the Pathophysiology of Congestive Heart Failure” section. Patients with cirrho-sis and ascites, who typically have little Na+ in their urine, may have a natriuretic response to HWI as a result of effec-tive volume depletion (see earlier “Underfilling Hypothesis” section), despite elevated plasma volume and cardiac out-put.667 This modality has not been used outside the research setting.Diuretic Resistance. As already mentioned, when Na+ retention is severe and resistant to conventional doses of loop diuretics, combinations of diuretics acting at different neph-ron sites may produce effective natriuresis. Another method for overcoming diuretic resistance is the administration of a bolus dose of loop diuretic to yield a high plasma level, fol-lowed by high-dose continuous infusion. Alternately, high doses given intermittently may be successful in reversing diuretic resistance.

Whichever method is used to treat diuretic resistant hyper-volemia, it is important to monitor carefully plasma Na+, K+, Mg2+, Ca2+, phosphate, blood urea nitrogen, and creatinine levels and correct any deviations appropriately. Other less common side effects of diuretics include cutaneous allergic reactions, acute interstitial nephritis (see Chapter 35), pancre-atitis and rarely, blood dyscrasias.706

extraCorporeal ultrafiltrationOn occasion, extreme resistance to diuretics occurs, often accompanied by renal functional impairment. In such cases, removal of volume excess may be achieved by ultrafiltration through the use of hemofiltration, hemodialysis, or perito-neal dialysis (see Chapters 64 to 66). Chronic ambulatory peritoneal dialysis may yield symptomatic relief from pulmo-nary edema and anasarca in patients with resistant congestive cardiac failure, who are not candidates for surgical interven-tion.707 The effect of these therapies on prognosis remains unproven.708,709

http://ClinicalTrials.gov

Specific Treatments Based on the Pathophysiology of Congestive Heart Failure

Because the clinical situation of a patient with CHF at any given time depends on the delicate balance between vasocon-strictor/antinatriuretic and vasodilator/natriuretic factors, any treatment that can tip the balance in favor of the latter should be efficacious. Thus, either increasing the activity of the natri-uretic peptides or reducing the influence of the antinatriuretic mechanisms by pharmacologic means may achieve a shift in the balance in favor of Na+ excretion in CHF. In the interplay between the RAAS and ANP in CHF, the approaches used in experimental studies and in clinical practice included reduc-ing the activity of the RAAS by means of ACE inhibitors or ARBs, increasing the activity of ANP or its second messenger, cGMP, or combinations of approaches.

Inhibition of Renin-Angiotensin-Aldosterone System

The maladaptive actions of locally produced or circulatory angiotensin II have been examined in numerous studies, which have shown unequivocally that ACE inhibition and angiotensin receptor blockade improve renal function, cardiac performance, and life expectancy of patients with CHF.710-712 In the few studies in which renal functional deterioration was observed, the blockade of angiotensin II–induced preferential efferent arteriolar constriction probably led to a sharp fall in glomerular capillary pressure and, hence, in GFR.382 Because patients with CHF cannot overcome the Na+-retaining action of aldosterone and continue to retain Na+ in response to aldo-sterone, blockade of the latter by spironolactone induces sub-stantial natriuresis in these patients.393

Overall, the effect of angiotensin II receptor blockade or ACE inhibition on renal function in CHF depends on a mul-tiplicity of interacting factors. On the one hand, RBF may improve as a result of lower efferent arteriolar resistance. Sys-temic vasodilation may be associated with a rise in cardiac output. Under such circumstances, reversal of hemodynami-cally mediated effects of angiotensin II on Na+ reabsorp-tion would promote natriuresis. Moreover, inhibition of the RAAS could theoretically facilitate the action of natriuretic peptides to improve GFR and enhance Na+ excretion. On the other hand, the aim of angiotensin II–induced elevation of the single-nephron filtration fraction is to preserve GFR in the presence of diminished RPF. In patients with precari-ous renal hemodynamics, a fall in systemic arterial pressure below the autoregulatory range combined with removal of the angiotensin II effect on glomerular hemodynamics may cause severe deterioration of renal function. The net result depends on the integrated sum of these physiologic effects, which, in turn, depends on the severity and stage of heart disease (see Table 14-5).

In addition, the other active component of the RAAS, aldosterone, plays a pivotal role in the pathogenesis of CHF by promoting Na+ retention and contributing to vascular and cardiac remodeling by inducing perivascular and interstitial fibrosis.713 In accordance with this notion, two clinical tri-als have shown that the addition of small doses of aldoste-rone inhibitors to standard therapy substantially reduces the


mortality rate and the degree of morbidity in CHF patients. The Randomized Aldactone Evaluation Study (RALES) showed that therapy with spironolactone reduced overall mor-tality among patients with advanced CHF by 30% in com-parison with placebo.410 In addition, the study of eplerenone in patients with heart failure caused by systolic dysfunction, Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS), showed that addition of eplerenone to optimal medical therapy reduced morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and CHF.409 Aldosterone inhibitors are now routinely used in the management of CHF. Caution is, of course required in the presence of renal dysfunc-tion, because of the significant risk of hperkalemia.714

β-Blockade

Insofar as β-blockade is now standard of care in the manage-ment of CHF, this review would not be complete without mention of this class of drugs. However, because their effect in CHF is not directly related to Na+ and water, this important therapy is not elaborated further in this chapter. The reader is referred to recent cardiology texts (e.g., Dickstein et al712).

Nitric Oxide Donor and Reactive Oxygen Species/Peroxynitrite Scavengers

Because nitric oxide signaling is disrupted in CHF, achieving nitric oxide balance by either nitric oxide donors or selective NOS inhibitors has emerged as an important therapeutic con-cept in addressing and correcting the pathophysiologic process of CHF.528 In this regard, the beneficial effects of combined isosorbide dinitrate (nitric oxide donor)/hydralazine (reac-tive oxygen species and peroxynitrite scavenger) therapy, par-ticularly in African-American patients, are noteworthy.715,716 However, the question still remains as to the efficacy of this combination in other ethnic groups.715

Endothelin Antagonists

Initial clinical studies showed that acute endothelin antago-nism by bosentan decreased vascular resistance and increased cardiac index and cardiac output in patients with CHF, which suggested that ET-1 played a role in the pathogenesis of CHF by increasing systemic vascular resistance.717 However, in con-trast to early studies, more recent comprehensive clinical tri-als demonstrated, at best, no benefits or, at worst, increased hepatic transaminase levels and mortality rate in patients with CHF that was treated with ET-A receptor antagonists (see Ertl and Bauersachs443 and references therein). These dis-appointing results may be explained by the observation that ET-A receptor antagonism in experimental CHF further activates the RAAS in association with sustained Na+ reten-tion.718 In summary, the increased local cardiac-pulmonary-renal production of ET-1 in CHF, together with the marked vasoconstrictor and mitogenic properties of the molecule, suggests that ET-1 contributes directly and indirectly to the enhanced Na+ retention and edema formation by aggravating renal and cardiac functions, respectively.444,719 However, the


fact that ET-1 receptor antagonists were ineffective in clinical trials and that they led to secondary activation of the RAAS in animals indicates that these drugs are unlikely to be of sig-nificant benefit in the management of CHF.

Natriuretic Peptides

As noted previously, circulating levels of natriuretic peptides are elevated in CHF in proportion to the severity of the dis-ease. However, the renal actions of these peptides are attenu-ated and even blunted in severe CHF. Nevertheless, several studies demonstrated that elimination of natriuretic peptide action through the use of blockers of NPR-A or surgical removal of the atrium disrupts renal function and cardiac per-formance in experimental CHF.462,466 Therefore, increasing circulating levels of natriuretic peptides by the administration of exogenous synthetic peptides was tested in both clinical and experimental CHF and appeared to be beneficial under certain circumstances. For example, intravenous administra-tion of ANP to patients with acute CHF improved their clini-cal status.720 Similarly, injection of BNP reduced pulmonary arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, systemic vascular resistance, and systemic blood pressure, in association with increased cardiac output and diuresis.721,722 The hemodynamic and natriuretic effects of exogenous BNP administration were significantly greater than those obtained after similar doses of ANP in patients with CHF.

Suppressed plasma levels of norepinephrine and aldoste-rone have also been observed. In view of its beneficial effects, BNP (nesiritide) was approved for the treatment of acute decompensated CHF in the United States in 2001. However, more recent controlled studies have shown that, overall, the natriuretic effects of nesiritide are minimal in comparison with placebo. Moreover, up to one third of patients do not exhibit increased Na+ excretion after BNP infusion, a phenomenon also observed with ANP.723 A further limitation of nesirit-ide treatment is dose-related hypotension,722 which would be enhanced if nesiritide were given with other vasodilators, such as ACE inhibitors.494 Also, nesiritide leads to worsening renal function in more than 20% of patients, which could increase the risk of death, as occurs in other situations complicated by renal impairment.723 Therefore, the role of BNP in the man-agement of CHF is currently unclear, and further investiga-tion is required.724,725

Neutral Endopeptidase Inhibitors and Vasopeptidase Inhibitors

Correcting the imbalance between the RAAS and the natri-uretic peptide systems could also be achieved by inhibiting the enzymatic degradation of ANP by NEP or blocking CNP. Several specific and differently structured NEP inhibitors were developed and tested in experimental models and clinical trials. Most studies revealed enhanced plasma ANP and BNP levels in association with vasodilation, natriuresis, diuresis, and, subsequently, reduced cardiac preload and afterload.726 Because NEP degrades other peptides (e.g., kinins), the latter may also be involved in the beneficial effects of NEP inhibi-tors. Candoxatril, the first NEP inhibitor released for clinical

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trials, produced favorable hemodynamic and neurohormonal effects in patients with CHF.727,728 In addition, acute NEP inhibition in mild CHF resulted in marked increases in RPF and Na+ excretion, which exceeded the increase observed either in control animals or in severe CHF; thus, NEP inhibi-tion has a potential therapeutic role in enhancing renal func-tion in mild CHF.729

In later studies of CHF, apparently the more marked acti-vation of the RAAS served to attenuate the beneficial renal and hemodynamic actions of NEP inhibitors; thus, mecha-nisms other than exaggerated NEP activity were thought to be involved in the renal resistance to natriuretic peptides. More-over, NEP inhibitors did not reduce afterload. On the basis of the foregoing findings, investigators predicted that a com-bination of RAAS and NEP inhibitors would be more effec-tive than each treatment alone. This was indeed confirmed in dogs with pacing-induced CHF, in which NEP inhibition prevented the ACE inhibitor–induced decrease in GFR.730 These findings led to the development of dual NEP and ACE inhibitors, known as vasopeptidase inhibitors.727,731,732

Of the various vasopeptidase inhibitors, omapatrilat has been the most studied. In fact, results in both experimental and clinical CHF suggested beneficial hemodynamic and renal effects mediated by the synergistic ACE and NEP inhibition offered by this drug.733-737 This was thought to be a potential advantage because renal function frequently deteriorates dur-ing the progression of chronic CHF, and renal impairment is one of the most powerful prognostic indicators in patients with CHF.391 However, as the results of definitive clinical trials emerged, it became evident that neither vasopeptidase inhibitors nor NEP inhibitors as add-on therapy to ACE inhibitors were more effective than ACE inhibitors alone in the treatment of CHF (reviewed by Iyengar and Abra-ham738). Furthermore, the combination was associated with more side effects, especially angioedema. Possible reasons for their failure include disproportionate increase in RAAS and endothelin activity over time, the development of tolerance to NEP inhibitors with chronic treatment, and downregulation of natriuretic peptide receptors in response to degradation of NEP inhibitors. A potential explanation for the angioedema that appears with the combination is an excessive accumu-lation of bradykinin that results from both ACE and NEP inhibition.738

Despite the failure of omapatrilat to live up to its initial promise, the evaluation of vasopeptidase inhibitors has greatly increased the understanding of the neurohumoral mecha-nisms involved in the pathogenesis of CHF.

Vasopressin Receptor Antagonists

The development of AVP receptor antagonists, known col-lectively as vaptans, has dramatically increased the under-standing of the contribution of AVP to the alterations in renal and cardiac function.739 and opened the way for their therapeutic use in CHF. Vaptans are small, orally active, non-peptide molecules that lack agonist effects and display high affinity for and specificity to their corresponding receptors.740 Highly selective and potent antagonists for the V1A, V2, and V1B receptor subtypes and mixed V1A/V2 receptor antago-nists are now available.208 Vaptans have been clearly shown to produce hemodynamic improvement with transient decrease

in systemic vascular resistance, increased cardiac output, and improved water diuresis in both experimental models of CHF and clinical trials (see Finley et al430 and Farmakis et al440 and references therein).

Several clinical trials have amply demonstrated the efficacy of AVP receptor antagonists in reversing hyponatremia, hemody-namic disturbances, and renal dysfunction in both compensated and decompensated CHF.430,440 In CHF with hyponatremia, three randomized controlled trials involving tolvaptan741-743 and one involving conivaptan744 demonstrated normalization and maintenance of plasma Na+ levels, decreases in body weight and edema, and increases in urine output, after treatment for up to 60 days. There was subjective improvement in dyspnea in some but not all patients. In contrast to the detrimental effects of aggressive therapy with loop diuretics on renal function, no significant changes in blood urea nitrogen and creatinine were reported after vaptan therapy (reviewed by Finley et al430). The positive effects were observed regardless of whether LVEF was less or greater than 40%. In one trial, tolvaptan, but not fluid restriction, corrected hyponatremia.742 However, in the sole trial in which all-cause mortality was the primary endpoint, no sig-nificant effects of tolvaptan given for 60 days were seen after 9 months of follow-up.743 In general, the patients participating in these trials had decompensated CHF.

Another trial (Treatment of Hyponatremia Based on Lix-ivaptan in NYHA Class III/IV Cardiac Patient Evaluation [ BALANCE]) in which lixivaptan is used for decompensated CHF was completed in June 2010; results were not yet avail-able at the time of this book going to press.745 In four trials, researchers have examined the role of vaptans in stable class II or III CHF; tolvaptan was used in three trials (one published as an abstract only)746,747 and conivaptan in one (published as an abstract only). As in decompensated CHF, decrease in body weight, increase in urine output, and a rise in plasma Na+ (within the normal range) were observed. However, there was no improvement in functional capacity, exercise tolerance, or overall quality of life.430

In contrast to furosemide, tolvaptan did not reduce RBF.430 Moreover, in the Multicenter Evaluation of Tolvaptan Effect on Remodelling (METEOR) trial, no beneficial or adverse effects of tolvaptan on cardiac remodeling or LVEF were observed after 1 year of treatment in patients receiving opti-mal evidence-based background therapies for CHF (ACE inhibitors, ARBs, and β-blockers).747 These results are reas-suring because tolvaptan is highly selective for the V2 recep-tor, which raises the theoretical possibility that unopposed V1 receptor–mediated effects under the influence of raised AVP levels may result from tolvaptan treatment.

With regard to hemodynamic effects of vaptans, two stud-ies have been published on patients with advanced CHF and systolic dysfunction who received a single intravenous dose of either conivaptan or placebo.748,749 The active drug modestly reduced pulmonary capillary wedge pressure and significantly reduced right atrial pressure in comparison with placebo, without affecting cardiac index, pulmonary arterial pressure, systemic or pulmonary vascular resistance, systemic arterial pressure, or heart rate. Urine output rose and osmolarity fell significantly.

In view of the impressive diuretic effect of vaptans, there is considerable interest in the potential loop diuretic–sparing effect mentioned previously. This idea was evaluated in one preliminary study.430 In patients with chronic CHF who had


signs of congestion, background diuretic therapy was with-drawn, salt restriction was instituted, and the patients were then randomly assigned to receive a 7-day regimen of tolvap-tan, 30 mg/day; furosemide, 80 mg/day; or a combination of the two. Tolvaptan, but not furosemide, led to a significant decline in body weight, with no effect on plasma K+. This favorable effect of tolvaptan may result from its 24-hour action, in contrast to furosemide, the effect of which lasts only approximately 6 hours, thus allowing 18 hours of compen-satory salt and water retention. Further studies are needed to explore the potential for vaptans as loop diuretic–sparing agents.

Adverse effects of vaptans appear to be relatively few and, on the whole, minor. Thirst and dry mouth are not unex-pected; hypokalemia occurs in fewer than 10% of recipients, which is favorably comparable with loop diuretics. In the largest study to date, Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST), involving more than 4000 patients, there was a small but sig-nificant increase in reported strokes; however, there was also a small but significant reduction in myocardial infarction rate (see Finley et al430).

In summary, AVP receptor antagonists appear to be prom-ising in the treatment of advanced heart failure. Many unan-swered questions remain regarding the exact role of AVP receptor antagonists in the management of CHF. These include the potential for long-term efficacy, the use in vol-ume overload in the setting of preserved ejection fraction with a nondilated ventricle, the role in possible loop diuretic dose sparing, the duration of treatment, and dosing over the shorter and longer term.430 Finally, and perhaps most important, is the question of whether AVP receptor antagonists improve longer term prognosis and reduce the high rate of mortality among patients with CHF who are already receiving optimal doses of ACE inhibitors, ARBs, and β-blockers.

Specific Treatments Based on the Pathophysiology of Sodium Retention in Cirrhosis

The prognosis of type 1 hepatorenal syndrome is dismal; the mortality rate is as high as 80% in the first 2 weeks, and only 10% of patients survive longer than 3 months.573,587 There-fore, specific aggressive therapy in these patients is usually indicated in preparation for liver transplantation.344,573,574 Patients with type 2 hepatorenal syndrome have a better prognosis; the median length of survival is approximately 6 months.750 Aggressive management may be considered for such patients, regardless of transplantation candidacy. There are four major therapeutic interventions for hepatorenal syn-drome: pharmacologic therapy, TIPS insertion, renal replace-ment therapies (RRTs), and liver transplantation.

Pharmacologic Treatment

The goals of pharmacologic therapy are to reverse the func-tional renal failure and prolong survival until suitable candi-dates can undergo liver transplantation. On the basis of the pathophysiologic features of renal vasoconstriction against a background of systemic and, specifically, splanchnic arterial

position
vasodilation, specific treatments consist broadly of renal vaso-dilators and systemic vasoconstrictors. The former group includes direct renal vasodilators (dopamine, fenoldopam, and prostaglandins) and antagonists of endogenous renal vasocon-strictors (ACE inhibitors, ARBs, aldosterone antagonists, and endothelin antagonists). Systemic vasoconstrictors comprise vasopressin analogs (ornipressin, terlipressin), the somatosta-tin analog octreotide, and the α-adrenergic agonists.751 In addition, the nonosmotically stimulated rise in plasma AVP levels and resulting impaired water excretion and hyponatre-mia can be potentially reversed by V2 receptor antagonists.

Renal Vasodilators and Renal Vasoconstrictor Antagonists

Although these agents are theoretically attractive for the man-agement of Na+ retention in cirrhosis, none of the studies of renal vasodilators showed improvement in renal perfusion or GFR (see Wadei et al573 and references therein). Low-dose dopamine infused for up to 24 hours improved cortical blood flow and the angiographic appearance of renal cortical vascu-lature without improvement in GFR or urine flow. Responses were the same both in refractory ascites and in hepatorenal syndrome. Dopamine in combination with vasoconstrictors proved more successful, but this could be attributed to vaso-constrictor therapy alone. Similarly, neither the oral PGE1 analog misoprostol nor intravenous prostaglandin infusion induced significant changes in GFR or Na+ excretion. The ET-A antagonist BQ-123 produced dose-dependent renal improvement in one study on three patients, but subsequent studies showed a paradoxical vasodilating effect of endothe-lin in patients with cirrhosis (see Wadei et al573 and refer-ences therein). Therefore, the role of endothelin blockers in hepatorenal syndrome remains controversial. With regard to RAAS blockade, a single study revealed that 1-week treat-ment with the ARB losartan led to increased Na+ excretion and an improvement in renal function in cirrhotic patients with and without ascites (see Wadei et al573 and references therein). Further confirmatory studies are awaited.

In general, because of adverse effects and lack of benefit, the use of renal vasodilators in hepatorenal syndrome has largely been abandoned.

Systemic Vasoconstrictors

Systemic vasoconstrictors are the most promising pharmaco-logic agents in the management of hepatorenal syndrome, by virtue of their predominant action on the vasodilated splanch-nic circulation without affecting the renal circulation. Three groups of vasoconstrictors have been studied: vasopressin V1 receptor analogs (ornipressin and terlipressin), the somatosta-tin analog (octreotide), and the α-adrenergic agonists.751

vaSopreSSin v1 reCeptor analogSThese agents cause marked vasoconstriction through their action on the V1 receptors present in the smooth muscle of the arterial wall. They are used extensively for the management of acute variceal bleeding in patients with cirrhosis and portal hypertension. Ornipressin infusion in combination with vol-ume expansion or low-dose dopamine was associated with a remarkable improvement in renal function and an increase in RPF, GFR, and Na+ excretion in almost half of the treated

patients (see Wadei et al573 and references therein). Unfor-tunately, ornipressin had to be abandoned because of signifi-cant ischemic adverse effects that occurred in almost 30% of treated patients.750

Terlipressin, on the other hand, has favorable effects simi-lar to those of ornipressin without the accompanying adverse ischemic reactions. The administration of terlipressin and albumin in type 1 hepatorenal syndrome was associated with significant improvement in GFR, increase in arterial pres-sure, near-normalization of neurohumoral levels, and reduc-tion of serum creatinine level in 42% to 77% of cases.573,574 The length of survival was also improved over that of historic cases, but it remained dismal: the median length was only 25 to 40 days. In nonresponders, who tended to have more severe cirrhosis (Child-Pugh score >13), length of survival was notably reduced.752 The rates of response to terlipressin in type 2 hepatorenal syndrome were better than those in type 1, with 100% survival at 3 months.753,754 Despite hepatorenal syndrome relapses in 50% of cases, reintroduction of therapy produced a further response.

From the results of two randomized controlled trials, it is now clear that both terlipressin alone and the combination of terlipressin and albumin are superior to albumin alone in improving renal function and reversing hepatorenal syndrome type 1.755,756 However, these relatively small studies were unable to show a survival benefit for terlipressin. Attempts to prevent relapse of type 2 hepatorenal syndrome with mido-drine after terlipressin-induced improvement were also unsuc-cessful.757 The optimum duration of terlipressin therapy is not clear. In all studies, terlipressin was given until serum creati-nine levels decreased to less than 1.5 mg/dL or for a maximum of 15 days. Whether extending the therapy beyond 15 days will add any benefit is not known. Moreover, the apparent sur-vival advantage of terlipressin, seen in the cohort studies, was poor; 80% of patients who did not receive a transplant died of their liver disease within 3 months of therapy. Therefore, terlipressin and albumin infusion may be appropriate only for patients awaiting liver transplantation.

The importance of V1 receptor analogs is underscored by the observation that pretransplantation normalization of renal function in patients with hepatorenal syndrome by this ther-apy confers similar posttransplantation outcomes on patients with normal renal function who received transplants.758 Despite the favorable effects of terlipressin, a major drawback is its unavailability in many countries, including the United States and Canada. In these countries, vasopressin itself may be a reasonable alternative.759

SomatoStatin analogS and α-adrenergiC agoniStSOctreotide, an inhibitor of glucagon and other vasodilator peptide release, is currently the only available somatostatin analog. In small cohort studies, octreotide with albumin infu-sion or midodrine alone had no effect on renal function in hepatorenal syndrome.576,760 However, both agents in combi-nation with albumin infusion led to a significant improvement in renal function and survival in both types 1 and 2 hepa-torenal syndrome, in comparison to historical controls.761 A literature review concluded that the exact role of combined octreotide/midodrine therapy in hepatorenal syndrome man-agement remains to be determined.762

Whether vasopressin analogs or combined therapy with octreotide and midodrine are more efficacious in reversing


hepatorenal syndrome remains an open question. Patients treated with vasopressin had a significantly higher recovery rate from type 1 hepatorenal syndrome, had improved length of survival, and were more likely to receive a liver transplant.759 Finally, the administration of intravenous norepinephrine in association with albumin and furosemide resulted in reversal of hepatorenal syndrome in 10 (83%) of 12 patients with type 1 hepatorenal syndrome, and ischemic episodes were observed in only two.763 It is interesting that in two of the responders to norepinephrine, terlipressin therapy had previously failed. Regression of renal failure was associated with improvement in patient survival, and four of the responders did not require liver transplantation 6 to 18 months after recovery of renal function. Although norepinephrine use seems to be counter-intuitive because of already elevated levels in patients with hepatorenal syndrome, a recently published pilot randomized controlled trial showed that norepinephrine was a safe and effective as terlipressin.763a

Vasopressin V2 Receptor Antagonists

As already mentioned hyponatremia is often seen in advanced cirrhosis with ascites and hepatorenal syndrome and is a marker of poor prognosis.764 Therefore, attaining a water diuresis and reversing hyponateremia through the use of V2 receptor antagonists are potentially important therapeutic goals. To date, the few cohort studies performed in animals and patients with cirrhosis have yielded promising results (reviewed by several authors765-767). Moreover, in the only randomized controlled trial so far reported, the V2 receptor antagonist satavaptan given for 15 days improved the control of ascites and increased serum Na+ in patients with cirrhosis, ascites, and hyponatremia who were already receiving spirono-lactone (100 mg/day). The only notable adverse effect, thirst, was significantly more common in the satavaptan than in the placebo group.646 Further studies of vaptans in cirrhosis with ascites and hyponatremia are under way, and the results are eagerly awaited.

Transjugular Intrahepatic Portosystemic Shunt

The efficacy of TIPS in the reduction of portal venous pres-sure in patients with cirrhosis and refractory ascites with either type 1 or type 2 hepatorenal syndrome has been demonstrated in several small cohort studies.768,769 Signifi-cant improvement in renal hemodynamics, GFR, and vaso-constrictive neurohumoral factors were observed in most patients770,771 (reviewed by Wadei et al573). The rates of survival at 3, 6, 12, and 18 months were 81%, 71%, 48%, and 35%, respectively, a marked improvement in comparison with historical controls.771 Of importance was that among patients who had type 1 hepatorenal syndrome and were treated with TIPS, the rate of 10-week survival was 53%, a significant improvement over that in historical cases and bet-ter than that reported after terlipressin and albumin infu-sion.753 A novel finding was the ability to discontinue dialysis in four of seven dialysis- dependent patients after TIPS inser-tion. Moreover, liver transplantation was performed in two patients 7 months and 2 years, respectively, after TIPS inser-tion, when the medical condition that precluded transplanta-tion had resolved.771

The mechanism by which TIPS exerts its favorable effects appears to be the result of reduction in sinusoidal hyperten-sion, possible suppression of the putative hepatorenal reflex discussed earlier, improvement of the EABV by shunting por-tal venous blood into the systemic circulation, or amelioration of cardiac dysfunction.769 Despite the encouraging benefi-cial effects of TIPS on reversal of hepatorenal syndrome and improvement in patient survival, some unanswered questions remain. First, the clinical, biochemical and neurohumoral parameters, although improved, are not normalized after TIPS insertion; thus, other factors in the pathogenetic path-way of hepatorenal syndrome may remain active. Second, the maximum renal recovery is delayed for up to 2 to 4 weeks after TIPS insertion, and renal Na+ excretory capacity is still sub-normal. The cause of this delay and the inability to normalize salt excretion are not clear, although one possibility is related to the proportionately greater action of TIPS to reduce presi-nusoidal pressure, as opposed to postsinusoidal and intrasinu-soidal pressure. Third, patients with advanced cirrhosis are at risk for worsening liver failure, hepatic encephalopathy, or both and are not candidates for TIPS insertion. Fourth, TIPS has the potential for worsening the existing hyperdynamic cir-culation or precipitating acute heart failure in at risk patients; therefore, careful attention to cardiac status is mandatory (see Wadei et al573 and references therein). Finally, TIPS is associ-ated with a high incidence of portosystemic encephalopathy when used for the treatment of refractory ascites. Of interest is that this complication is far less frequent when TIPS is used for treating variceal hemorrhage.768

Notwithstanding these unsolved dilemmas, there is clearly a group of patients with hepatorenal syndrome for whom TIPS might prolong survival enough either to enable liver transplantation or, if they are not candidates, to remain dialy-sis independent. The possibility of combination or sequential therapies has also been examined in preliminary studies. For example, treatment with octreotide, midodrine, and albumin infusion, followed by TIPS insertion, in selected patients with preserved liver function was associated with persistent improvements in serum creatinine levels, RPF, GFR, natriure-sis, plasma renin activity, and aldosterone levels.751 Another group of 11 patients with type 2 hepatorenal syndrome showed similar improvement after sequential terlipressin and TIPS insertion. Whether combination therapy can preclude the need for liver transplantation or significantly improve sur-vival remains to be investigated.

Renal Replacement Therapy

Conventional hemodialysis and continuous RRT have been extensively assessed in patients with hepatorenal syndrome (reviewed by Wadei et al573). The benefits, if any, in terms of prolonging survival, are dubious, and the rate of morbidity resulting from these therapies is high (see Wadei et al573 and references therein). In oliguric patients awaiting liver trans-plantation who do not respond to vasoconstrictors or TIPS and who develop diuretic-resistant volume overload, hyper-kalemia, or intractable metabolic acidosis, RRT may be a rea-sonable option as a bridge to transplantation. In view of the dismal prognosis of hepatorenal syndrome, especially type 1, decisions on RRT in patients who are not transplantation can-didates should be carefully deliberated on an individual basis.


In contrast to conventional RRT, molecular adsorbent recirculating system (MARS) offers the potential advantage of removing albumin-bound water-soluble vasoactive agents, toxins, and proinflammatory cytokines. Relevant molecules include bile acids, tumor necrosis factor-α, interleukin-6, and nitric oxide that are known to be implicated in the patho-genesis of advanced cirrhosis.574 The uniqueness of MARS lies in its ability to enable partial recovery of hepatic func-tion, and results of preliminary studies are consistent with this idea.772 In one study, MARS treatment led to a decrease in renal vascular resistance and improvement in splenic resis-tance index, a parameter related to portal resistance. The authors hypothesized that the hemodynamic effects were probably mediated by clearance of vasoactive substances.773 Other researchers have shown that MARS leads to signifi-cantly reduced bilirubin levels, reduced grade of encephalopa-thy, decreased serum creatinine levels, and increased serum Na levels.774 Finally, one study demonstrated a survival benefit; the mortality rate was reduced from 100% in the control group to 62.5% in the MARS-treated patients. At 30 days, 75% of the MARS group had survived.774 However, all these studies were conducted with no more than 12 or 13 patients; thus, MARS, like the pharmacologic therapies described previously, should probably be considered currently as only a bridge to transplantation.

Liver Transplantation

Liver transplantation is the best option for treating hepatore-nal syndrome because it offers a cure for both the liver disease and the renal dysfunction. The outcomes are somewhat worse in transplant recipients with hepatorenal syndrome than in those without the syndrome (3-year survival rates of 60% vs. 70% to 80%) and may be improved by the bridging therapies described previously (see Angeli and Merkel574 and references therein). More data are needed to confirm the initial favorable reports.

With respect to renal function after transplantation in patients with hepatorenal syndrome, GFR decreases in the first month as a result of the stress of surgery, infections, immu-nosuppressive therapy, and other factors. Dialysis in the first month is required in 35% of patients with hepatorenal syn-drome, as opposed to only 5% of patients without hepatorenal syndrome. Despite the prompt correction of hemodynamic and neurohumoral parameters, GFR recovers incompletely to 30-40 mL/min at 1 to 2 months, and renal functional impair-ment often persists over the long term. Overall, the rate of posttransplantation reversal of hepatorenal syndrome has been estimated to be no greater than 58%. Predictors of renal recovery included younger recipient and donor, nonalcoholic liver disease, and low posttransplantation bilirubin level.775

Perhaps surprisingly, duration of dialysis pre-transplanta-tion did not influence renal recovery after transplantation. In this regard, the question of combined liver-kidney transplan-tation becomes critical. Data from the United Network for Organ Sharing showed better rates of 5-year survival of 62.2% after liver-kidney transplantation than after liver transplanta-tion alone among patients with pretransplantation serum cre-atinine levels higher than 2.2 mg/dL. In contrast, single center results were similar, regardless of pretransplantation renal function.776 The introduction of MELD (model of end-stage

linffat

t

R

ver disease) scores for allocation of livers has increased the umber of transplantations in patients with impaired renal unction, but more liver-kidney transplantation are also per-ormed.777 More data are needed to enable a rational decision bout who should receive liver-kidney transplants, as opposed o liver transplants alone.

For a general review of all aspects of liver transplantation, he reader is referred to several excellent recent reviews.777-779

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