refarat acute tubular necrosis
TRANSCRIPT
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 1/35
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 2/35
2
Furosemide may convert the oliguric ATN to a nonoliguric type, which is managed more
easily. In addition, ATN is frequently complicated by hyperphosphatemia and hypocalcemia,
which respond to calcium-containing oral phosphate binders.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 3/35
3
THE RENAL TUBULES
The renal tubules, commencing in the renal corpuscles, present, during their course, manychanges in shape and direction, and are contained partly in the medullary and partly in the
cortical substance. At their junction with the glomerular capsule they exhibit a somewhat
constricted portion, which is termed the neck. Beyond this the tubule becomes convoluted, and
pursues a considerable course in the cortical substance constituting the proximal convoluted
tube. After a time the convolutions disappear, and the tube approaches the medullary substance
in a more or less spiral manner; this section of the tubule has been called the spiral
tube. Throughout this portion of their course the renal tubules are contained entirely in the
cortical substance, and present a fairly uniform caliber. They now enter the medullary substance,
suddenly become much smaller, quite straight in direction, and dip down for a variable depth
into the pyramids, constituting the descending limb of Henle’s loop. Bending on themselves,
they form what is termed the loop of Henle, and reascending, they become suddenly enlarged,
forming the ascending limb of Henle’s loop, and reenter the cortical substance. This portion of
the tubule ascends for a short distance, when it again becomes dilated, irregular, and angular.
This section is termed the zigzag tubule; it ends in a convoluted tube, which resembles the
proximal convoluted tubule, and is called the distal convoluted tubule. This again terminates in a
narrow junctional tube, which enters the straight or collecting tube.(1)
The straight or collecting tubes commence in the radiate part of the cortex, where they
receive the curved ends of the distal convoluted tubules. They unite at short intervals with one
another, the resulting tubes presenting a considerable increase in caliber, so that a series of
comparatively large tubes passes from the bases of the rays into the renal pyramids. In the
medulla the tubes of each pyramid converge to join a central tube (duct of Bellini) which finally
opens on the summit of one of the papilla; the contents of the tube are therefore discharged intoone of the calyces.
(1)
The renal tubules consist of a basement membrane lined with epithelium. The epithelium
varies considerably in different sections of the tubule. In the neck the epithelium is continuous
with that lining the glomerular capsule, and like it consists of flattened cells each containing an
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 4/35
4
oval nucleus . The two convoluted tubules, the spiral and zigzag tubules and the ascending limb
of Henle’s loop, are lined by a type of epithelium which is histologically the same in all. The
cells are somewhat columnar in shape and dovetail into one another of their lateral aspect. Each
has a striated border next the lumen of the tube, its inner part is granular and its outer portion
vertically striated. The nucleus is spherical and situated about the center of the cell. In the
descending limb of Henle’s loop the epithelium resembles that found in the glomerular capsule
and the commencement of the tube, consisting of flat, clear epithelial plates, each with an oval
nucleus. The nuclei alternate on opposite surfaces of the tubule so that the lumen remains fairly
constant. In the straight tube the epithelium is clear and cubical: in its papillary portion the cells
are distinctly columnar and transparent.(1)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 5/35
5
TUBULAR FUNCTION
Water and electrolytes are freely filtered at the level of the glomerulus. Thus, the
electrolyte content of "ultrafiltrate" at the beginning of the proximal tubule is similar to that of
plasma. Carefully regulated processes of tubular reabsorption and/or tubular secretion determine
final water content and electrolyte composition of urine. As a general principle, "bulk"
movement of solute tends to occur in the proximal portions of the nephron, whereas fine
adjustments tend to occur distally. Modern advances in molecular biology have helped to
delineate the role of specific nephron segments in regulating ion and water transport and the
diseases that occur as a result of abnormalities in these processes.(2)
Sodium
Sodium is essential in maintaining extracellular fluid balance and, thus, volume status.
The kidney is capable of effecting large changes in sodium excretion in a variety of normal and
pathologic states. There are four main sites of sodium transport. Approximately 60% of sodium
is absorbed in the proximal tubule by coupled transport with glucose or amino acids, 25% in the
ascending loop of Henle (bumetanide-sensitive sodium-potassium 2 chloride transporter,
NKCC2), and 15% in the distal tubule (thiazide-sensitive sodium chloride cotransporter, NCCT)
and collecting tubule (epithelial sodium channel, ENaC). Under normal circumstances, the
urinary excretion of sodium approximates the sodium intake (80-250 mEq/24 hr for an adult who
consumes a typical American diet) minus 1-2 mEq/kg/24 hr required for normal metabolic
processes. However, in states of volume depletion (e.g., dehydration, blood loss) or decreased
effective circulating blood volume (e.g., septic shock, hypoalbuminemic states, or congestive
heart failure), there may be a dramatic decrease in urinary sodium excretion to as low as 1
mEq/L. Changes in volume status are detected by baroreceptors in the atria, afferent arteriole,
and the carotid sinus and by the macula densa, which detects changes in chloride delivery. The
major hormonal mechanisms mediating sodium balance include the renin-angiotensin-
aldosterone (RAA) axis, atrial natriuretic factor (ANF), and norepinephrine. Angiotensin II and
aldosterone increase sodium reabsorption in the proximal tubule and distal tubules, respectively.
Norepinephrine, released in response to volume depletion, does not directly act on tubular
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 6/35
6
transport mechanisms but impacts on sodium balance by decreasing renal blood flow and thus
decreasing the filtered load of sodium, as well as stimulating renin release. With more severe
volume depletion antidiuretic hormone (ADH) is also released (see Chapter 522). Sodium
excretion is promoted by atrial natriuretic factor (ANF) and suppression of renin.(2)
Potassium
Extracellular potassium homeostasis is very tightly regulated, because small changes in
plasma potassium concentrations have dramatic effects on cardiac, neural, and neuromuscular
function. Essentially all filtered potassium is fully reabsorbed in the proximal tubule. Therefore,
urinary excretion of potassium is completely dependent on tubular secretion by potassium
channels present in the principal cells of the collecting tubule. Factors that promote potassium
secretion include aldosterone, increased sodium delivery to the distal nephron, and increased
urine flow rate.(2)
Calcium
A significant portion of filtered calcium (65%) is reabsorbed in the proximal tubule.
Additional calcium is reabsorbed in the ascending loop of Henle by passive movement between
cells (paracellular absorption) in a process driven by sodium chloride reabsorption and potassium
recycling into the lumen. Calcium uptake in this nephron segment is regulated by an extracellular
calcium receptor (CaR). Factors that promote calcium reabsorption include parathyroid hormone
(PTH, released in response to hypocalcemia), thiazide diuretics, and volume depletion. Factors
that promote calcium excretion include sodium intake (either orally or by infusion of sodium-
containing intravenous fluids) and loop diuretics such as furosemide.(2)
Phosphate
The majority of filtered phosphate is reabsorbed in the proximal tubule. Reabsorption is
increased by endogenous or exogenous calcitriol (1,25-dihydroxyvitamin D) and inhibited by
PTH.(2)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 7/35
7
Magnesium
About 25% of filtered magnesium is reabsorbed in the proximal tubule. Modulation of
renal magnesium excretion occurs primarily in the ascending loop of Henle, with some
contribution of the distal convoluted tubule. Although specific magnesium transporters have
been identified, the precise mechanisms by which they are regulated remain unclear.(2)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 8/35
8
ACUTE TUBULAR NECROSIS
PATHOPHYSIOLOGY
The current understanding of the pathophysiology of acute tubular necrosis (ATN) is the
result of intensive scientific studies performed over many decades. Despite the nomenclature,
frank necrosis of tubule cells is relatively inconspicuous in ischemic ATN, whereas it can be
more extensive in heavy metal – induced nephrotoxic ATN.(9)
The typical findings in humans include the following: (7)
Patchy loss of tubular epithelial cells with resultant gaps and exposure of denuded
basement membrane.
Diffuse effacement and loss of proximal tubule cell brush border.
Patchy necrosis, most typically in the outer medulla where the straight (S3) segment of
the proximal tubule and the medullary thick ascending limb (mTAL) of Henle loop.
Tubular dilatation and intraluminal casts in the distal nephron segments.
Evidence of cellular regeneration.
Regenerating cells are often detected in biopsies together with freshly damaged cells,
suggesting the occurrence of multiple cycles of injury and repair.
The clinical course of ATN may be divided into the following 3 phases(7)
Initiation
Maintenance
Recovery
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 9/35
9
Initiation phase
The initiation phase corresponds to the period of exposure to ischemia or nephrotoxins.
Renal tubule cell damage begins to evolve (but is not yet established) during this phase. The
glomerular filtration rate (GFR) starts to fall, and urine output decreases.
(7)
Maintenance phase
During the maintenance phase, renal tubule injury is established, the GFR stabilizes at the
level well below normal, and the urine output is low or absent. Although oliguria (or anuria) is
one of the clinical landmarks of ATN, it is absent in a minority of patients with so-called
nonoliguric ATN. Acute kidney injury (AKI) due to nephrotoxins is typically nonoliguric. The
second phase of ATN usually lasts for 1-2 weeks but may extend to a few months.(7)
Recovery phase
The recovery phase of ATN is characterized by polyuria and gradual normalization of the
GFR. This phase involves the restitution of cell polarity and tight junction integrity in sublethally
injured cells, removal of dead cells by apoptosis, removal of intratubular casts by
reestablishment of tubular fluid flow, and regeneration of lost renal epithelial cells. (7)
In the absence of multiorgan failure, most patients with ATN regain most renal function.
However, when ATN occurs (as it often does) in the context of multiorgan dysfunction,
regeneration of renal tissue may be severely impaired and renal function may not return.
Morbidity and mortality in such situations remains dismally high despite significant scientific
and technological advances.(7)
Following ischemia-reperfusion, a marked up-regulation of numerous genes that play
important roles in renal tubule cell proliferation occurs, including epidermal growth factor
(EGF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor (FGF), and hepatocyte
growth factor (HGF).(7)
In animals, exogenous administration of several of these growth factors has been shown
to accelerate recovery from ischemic AKI ; however, in a single human trial, IGF-1 did not prove
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 10/35
10
to be beneficial when given to adults with AKI of various etiologies.
Additional human studies
with growth factors are currently under way.(7)
Heat shock proteins (HSPs) are a group of highly conserved proteins that are expressed
constitutively in normal cells and markedly induced in cells injured by heat, hypoxia, or toxins.They act as intracellular chaperones, allowing proper folding, targeting, and assembly of newly
synthesized and denatured proteins.(7)
At least 2 families of HSPs, namely HSP-70 and HSP-25, have been shown to be
overexpressed in renal tubule cells following ischemia - reperfusion injury in animals. HSP-70
may play a role in the restitution of cell polarity, and HSP-25 is an actin-capping protein that
may assist in the repair of actin microfilaments in sublethally injured cells. The role for HSPs in
human ATN remains to be elucidated.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 11/35
11
ETIOLOGY
The following are prevalent causes of ATN in neonates : (10)
Ischemia : Perinatal asphyxia, respiratory distress syndrome, hemorrhage (eg,
maternal, twin-twin transfusion, intraventricular), congenital cyanotic heart disease,
shock/sepsis.
Exogenous toxins : Aminoglycosides, amphotericin B, maternal ingestion of
angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory
drugs (NSAIDs).
Endogenous toxins : Hemoglobin following hemolysis, myoglobin following
seizures.
Kidney disease : Renal venous thrombosis, renal artery thrombosis, renal hypoplasia
and dysplasia, autosomal recessive polycystic kidney disease, bladder outlet
obstruction.
Causes of ATN in Older Children
The following are prevalent causes of ATN in older children : (7)
Ischemia - Severe dehydration, hemorrhage, shock/sepsis, burns, third-space losses in
major surgery, trauma, nephrotic syndrome, cold ischemia in cadaveric kidney
transplant, near drowning, severe cardiac or pulmonary disease.
Exogenous toxins - Drugs that impair autoregulation (eg, cyclosporine, tacrolimus,
ACE inhibitors, NSAIDs), direct nephrotoxins (eg, aminoglycosides, amphotericin B,
cisplatin, contrast agents, cyclosporine, tacrolimus).
Endogenous toxins - Hemoglobin release (eg, transfusion reactions, malaria, snake and
insect bites, glucose 6-phosphate dehydrogenase deficiency, extracorporeal circulation,
cardiac valvular prostheses), myoglobin release (eg, crush injuries, prolonged seizures,
malignant hyperthermia, snake and insect bites, myositis, hypokalemia,
hypophosphatemia, influenza).
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 12/35
12
EPIDEMIOLOGY
Frequency varies widely, depending on the clinical context. ATN is the most frequent
cause of hospital acquired AKI. In adults, prevalence of ATN is approximately 1% at admission,
2-5% during hospitalization, and 4-15% after cardiopulmonary bypass. ATN occurs in
approximately 5-10% of newborn patients in the ICU and 2-3% of pediatric patients in the
ICU. Prevalence in children undergoing cardiac surgery is 5-8%. ATN is more common in
neonates than in other pediatric populations because of the high frequency of comorbid
conditions.(11)
PROGNOSIS
The prognosis for children with ATN from prerenal causes or in the absence of
significant comorbid conditions is usually quite good if appropriate therapy is instituted in a
timely fashion. Most patients recover adequate renal function to lead normal lives. Some are left
with permanent renal damage. In those left with mild-to-moderate renal damage, further
deterioration in kidney function may occur later in childhood; therefore, long-term follow-up is
required in these patients.(7)
Mortality rates widely vary according to the underlying cause and associated medical
condition. The most common causes of death are sepsis, cardiovascular and pulmonary
dysfunction, and withdrawal of life support measures.(7)
For patients with community-acquired ATN without other serious comorbid conditions,
mortality is approximately 5% and has decreased over the past decades because of the
availability of efficient renal replacement therapies.[25] Mortality jumps to 80% in patients in the
ICU with multiorgan failure, although death is almost never caused by renal failure.(7)
Despite significant advances in supportive care and renal replacement therapy, the high
mortality rates with multiorgan failure have not improved in the past few decades. Patients die
not because of renal failure but because of serious involvement of other systems during the
period of ATN.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 13/35
13
HISTORY
Patients with hospital-acquired acute tubular necrosis (ATN) frequently have no specific
symptoms. The diagnosis is, at times, suspected when urine output diminishes and is usually
made by the documentation of successive elevations in blood urea nitrogen (BUN) and serum
creatinine levels. Careful evaluation of the hospital course usually reveals the cause of ATN. In
patients with community-acquired ATN, a thorough history and physical examination are
invaluable in pinpointing the etiology.(7)
In children, the most common form is ischemic ATN caused by severe hypovolemia,
shock, trauma, sepsis, burns, and major surgery. Nephrotoxic ATN is also common and is caused
by various drugs. Their deleterious effect is markedly enhanced by hypovolemia, renal ischemia,
or other renal insults.(7)
Conditions Resulting in Fluid Loss
Severe vomiting and/or diarrhea are common causes of renal hypoperfusion in children.
Significant fluid loss may also result from hemorrhage or burns. Loss of intravascular volume
into the interstitial compartment accompanies major surgery, shock syndromes, and the nephrotic
syndrome.(7)
Children with fluid losses may complain of thirst, dizziness, palpitations, and fatigue. A
history of acute weight loss and oliguria may be documented; however, ATN resulting from
nephrotoxic drugs and from perinatal events are frequently nonoliguric. Refer to the illustration
shown below.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 14/35
14
Medication use
In the presence of mild prerenal insufficiency, ingestion of seemingly innocuous
medications that impair renal autoregulation can precipitate oliguric ATN; for example,
nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the renal synthesis of vasodilator
prostaglandins and can precipitate ATN when administered to febrile children with intercurrent
dehydration.(7)
Cyclosporine, tacrolimus, and contrast agents are afferent arteriolar constrictors. Their
nephrotoxicity is potentiated by preexisting hypovolemia because they inhibit the myogenic
response of the afferent arteriole to renal hypoperfusion.(7)
Drugs that induce direct tubule cell damage include aminoglycosides, amphotericin B,
cyclosporine, tacrolimus, antineoplastic agents (eg, cisplatin, methotrexate), and contrast agents.
Acyclovir and sulfonamides can precipitate and obstruct the tubular lumens, especially in
children with diminished tubular fluid flow.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 15/35
15
Conditions associated with release of endogenous tubular toxins
Myoglobinuric ATN may be encountered in various clinical situations, including muscle
trauma, prolonged seizures, malignant hyperthermia, snake and insect bites, myositis, severe
hypokalemia and hypophosphatemia, and infections such as severe influenza.
(7)
Hemoglobinuric ATN can accompany various states of hemolysis, including transfusion
reactions, malaria, snake and insect bites, glucose 6-phosphate dehydrogenase deficiency, and
mechanical causes such as extracorporeal circulation and cardiac valvular prostheses. (7)
Hyperuricosuric ATN is primarily observed during treatment of lymphoproliferative or
myeloproliferative malignancies and presents as tumor lysis syndrome.(7)
Hypoxia
In infants, ATN frequently complicates severe perinatal asphyxia, respiratory distress
syndrome, hemorrhage, and cyanotic congenital heart disease. Older children with severe
pulmonary or cardiac disease are also prone to ATN. (7)
PHYSICAL EXAMINATION
Signs of acute kidney injury (AKI) include hypertension, edema, anemia, and signs
of heart failure, such as hepatomegaly, gallop rhythm, and pulmonary edema. Signs of
intravascular volume depletion include tachycardia, orthostatic hypotension, decreased skin
turgor, dry mucous membranes, and changes in sensorium.(7)
DIFFERENTIAL DIAGNOSIS
Although oliguria is a criterion used to diagnose and stage acute kidney injury (AKI),
AKI can be present without oliguria, especially in patients with nephrotoxic kidney injury,
interstitial nephritis, or perinatal asphyxia. Oliguria may be defined as urine output less than 1
mL/kg/h in children and less than 400 mL/d in adults.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 16/35
16
Differentials(7)
Dehydration
Oliguria
Renal Cortical Necrosis
Tumor Lysis Syndrome
LABORATORY FINDING
The following studies are indicated in patients with acute tubular necrosis (ATN):(7)
Urinalysis
Urinary indexes
Blood urea nitrogen (BUN) and serum creatinine
Serum electrolytes (sodium, potassium, phosphate, and calcium)
Arterial blood gases
Complete blood cell count
Although acute kidney injury (AKI) is usually secondary to ischemic or nephrotoxic injury, other
causes of intrinsic AKI should be kept in mind and excluded by history, physical examination,
and laboratory evaluation. Laboratory evaluation should include urine cultures and serologic
tests (including C3 and C4 in all patients) and lupus serologies and hepatitis profiles when
appropriate.(7)
Urinalysis
Careful examination of freshly voided urine is a rapid and inexpensive way of
distinguishing prerenal failure from ATN. In prerenal failure, a few hyaline and fine granular
casts may be observed with little protein, heme, or red blood cells (RBCs). Broad, brown
granular casts are typically found in ischemic or nephrotoxic ATN. Heme-positive urine in the
absence of erythrocytes in the sediment suggests ATN due to hemolysis or rhabdomyolysis.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 17/35
17
Urinary Indices
Simultaneous measurement of urinary and serum sodium, creatinine, and osmolality can
help differentiate between prerenal azotemia (in which the reabsorptive capacity and
concentrating ability of the kidney are preserved or enhanced) and ATN (in which these
functions are impaired).(7)
In prerenal failure, urine specific gravity and the ratio of urine to plasma creatinine levels
are high, and the urinary sodium concentration is low (see Table, below). In contrast, the urine in
ATN is isosthenuric with a low urine-to-plasma creatinine ratio and high urine sodium
concentration.(7)
The fractional excretion of sodium (FENa) is the percentage of filtered sodium that is
excreted. It is easily calculated by the formula FENa (%) = ([U/P]Na)/([U/P]Cr) x 100, where Na
and Cr represent concentrations of sodium and creatinine in the urine (U) and plasma (P),
respectively. The FENa is typically more than 1% in ATN and less than 1% in prerenal azotemia.
Be alert to the fact that FENa may be low in intrinsic renal failure from glomerular diseases.(7)
Interpretation of urinary indexes requires caution. Collect blood and urine specimens
before the administration of fluids, mannitol, or diuretics. Urine should be free of glucose,
contrast material, or myoglobin. Urinary indexes suggestive of prerenal failure (FENa, < 1%)
may be observed in the ATN of contrast nephropathy and rhabdomyolysis (see Table, below). (7)
Table : Urinary Indexes in Acute Tubular Necrosis vs Prerenal Failure(7)
ATN Prerenal
Urine specific gravity 1010 >1020
Urine sodium (mEq/L) >40 < 10
Urine/plasma creatinine < 20 >40
FENa (%) >2 < 1
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 18/35
18
Measurement of Blood Urea Nitrogen and Serum Creatinine Levels
The hallmark of established AKI is a daily increase in serum creatinine (by 0.5-1.5
mg/dL/d) and BUN (by 10-20 mg/dL/d) levels. In ATN, the BUN-to-creatinine ratio is usually
around 10, as opposed to a ratio of more than 20 that is commonly observed in prerenal failure
(due to enhanced proximal tubular reabsorption of urea). However, the BUN-to-creatinine ratio
may be misleading in patients whose conditions are wasting or in infants with physiologically
low muscle mass.(12)
Elevations of BUN can also result from steroid therapy, parenteral nutrition,
gastrointestinal (GI) bleeding, and catabolic states. A spurious elevation in serum creatinine may
be observed following the use of drugs that interfere with the tubular secretion of creatinine
(cimetidine, trimethoprim) or drugs that provide chromogenic substrates (cephalosporins) that
interfere with the Jaffe reaction for the determination of serum creatinine.(7)
Serum creatinine is the current criterion standard for the diagnosis of AKI. However,
important limitations have been noted, as follows:(7)
First, serum creatinine levels can widely vary with age, sex, lean muscle mass, muscle
metabolism, and hydration status.
Second, serum creatinine levels may not change until about 50% of kidney function has
been lost.
Third, at lower glomerular filtration rates (GFRs), the amount of tubular secretion of
creatinine results in overestimation of renal function.
Finally, during acute changes in glomerular filtration, serum creatinine does not
accurately depict kidney function until steady-state equilibrium has been reached, which
may require several days.
In the future, defining AKI by either a predictive biomarker of kidney damage or a sensitive
measure of decrease in kidney function may be appropriate. Fortunately, novel biomarkers are
currently undergoing evaluation and validation.(13,14)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 19/35
19
Determination of Serum Electrolyte Concentrations
Hyponatremia is a common finding in ATN and is usually dilutional secondary to fluid
retention and administration of hypotonic fluids.(7)
Hyperkalemia is a common and often serious complication of ATN. Contributing factors
include reduced GFR, reduced tubular secretion, metabolic acidosis (each 0.1 unit reduction in
arterial pH raises serum potassium by 0.3-0.4 mEq/L), and associated catabolic state.
Hyperkalemia is most pronounced in individuals with excessive endogenous potassium
production, such as in rhabdomyolysis, hemolysis, and tumor lysis syndrome. Symptoms are
nonspecific and may include malaise, nausea, and muscle weakness. Hyperkalemia represents a
life-threatening emergency that must be promptly and aggressively treated, primarily because of
its depolarizing effect on cardiac conduction pathways.(7)
Hyperphosphatemia and hypocalcemia frequently complicate ATN. The phosphate
excess is secondary to reduced renal excretion and can lead to hypocalcemia and calcium
phosphate deposition in various tissues.(7)
Hypocalcemia results predominantly from hyperphosphatemia and impaired absorption
of calcium from the GI tract because of inadequate 1,25-hydroxyvitamin D3 production by the
diseased kidneys. Severe hypocalcemia results in tetany, seizures, and cardiac arrhythmias. (7)
Determining ionized calcium concentration may be important because this unbound form
of serum calcium determines physiologic activity. Acidosis increases the fraction of serum
calcium that is in the ionized form, while correction of acidosis may decrease it; thus,
overzealous bicarbonate therapy can acutely decrease ionized calcium.(7)
Hypomagnesemia is a prominent finding in nephrotoxic ATN, particularly associated
with gentamicin, amphotericin B, cisplatinum, or pentamidine administration.(7)
Evaluation of Acid-Base Balance
The high anion gap metabolic acidosis of ATN is a consequence of impaired renal
excretion of nonvolatile acids. Decreased tubular reabsorption of bicarbonate further contributes
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 20/35
20
to the metabolic acidosis. Severe acidosis can develop in children who are hypercatabolic (shock,
sepsis) or who have inadequate respiratory compensation.(7)
Complete Blood Cell Count
A mild-to-moderate anemia is commonly observed as a result of dilution and decreased
erythropoiesis. Severe anemia should prompt a search for hemolysis from a variety of causes,
because it can result in hemoglobinuric ATN. These patients usually display elevated serum
lactate dehydrogenase levels.(7)
Microangiopathic hemolytic anemia with schistocytes and thrombocytopenia are
indicative of possible hemolytic-uremic syndrome (HUS), which is an important cause of
intrinsic ARF in children. Prolonged ATN also can result in bleeding due to dysfunctional
platelets.(7)
Tests for Rhabdomyolysis and Tumor Lysis Syndrome
A suspicion of rhabdomyolysis may be confirmed by direct determination of urinary
myoglobin and elevation of serum creatine kinase (specifically the CK3 isoenzyme). Children
with rhabdomyolysis also usually display marked increases in serum potassium and phosphate.(7)
In the tumor lysis syndrome following cancer chemotherapy, a marked elevation in serum
uric acid occurs along with hyperkalemia and hyperphosphatemia.(7)
Determination of Serum Nephrotoxin levels
Serum levels of nephrotoxins should be determined and serially followed, particularly
when using gentamicin, vancomycin, cyclosporine, or tacrolimus.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 21/35
21
Renal Ultrasonography
Ultrasonography of the kidneys and bladder with Doppler flow is essential in the workup
of ARF. Exceptions to this rule may include children with unmistakable prerenal failure from
well-documented dehydration who respond promptly to fluid therapy or children with renal
insufficiency secondary to obvious glomerular disease, hypoxia-ischemia, or exposure to
nephrotoxins.(7)
Ultrasonography provides important information regarding kidney size, contour,
echogenicity, corticomedullary differentiation, and blood flow. In ischemic or nephrotoxic ATN,
the kidneys are of normal size or slightly enlarged, with increased echogenicity. With prolonged
ATN, renal cortical necrosis may result in decreased kidney size. Bilateral small scarred kidneys
are indicative of chronic renal disease.(7)
Congenital disorders, such as polycystic kidney disease and multicystic dysplasia, are
easily detected, and calculi and tumors are also evident. Hydronephrosis is suggestive of urinary
tract obstruction, and accompanying hydroureter and a thickened bladder wall are consistent with
bladder outlet obstruction. A Doppler study is important in the evaluation of vascular
obstruction.(7)
Radionuclide Scanning
Radionuclide scans ( functional scans with mercaptotriglycylglycine [MAG-3] or
diethylenetriamine penta-acetic acid [DTPA] ) are useful in the assessment of obstruction and
may provide additional information regarding GFR, renal blood flow, and tubule function. Their
major clinical use in children with ATN is in the immediate post transplant period, when scans
can help differentiate between ATN and transplant rejection. (15)
Electrocardiography
Perform electrocardiography (ECG) if hyperkalemia is suspected or detected by laboratory
tests. The following are sequential ECG changes in hyperkalemia:(7)
Tall peaked T waves
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 22/35
22
Prolongation of PR interval
Widening of QRS complex
ST segment changes
Ventricular tachycardia
Terminal ventricular fibrillation
Renal Biopsy
In general, a kidney biopsy is not necessary in the initial evaluation; however, if prerenal
and postrenal causes of ARF have been ruled out and an intrinsic renal disease other thanischemic ATN, nephrotoxic ATN, HUS, or postinfectious glomerulonephritis is a possibility,
renal biopsy findings may be valuable in establishing the diagnosis, guiding therapy, and
assessing prognosis. Renal biopsy findings may be also useful in the immediate post transplant
period for differentiating between ATN and acute rejection.(7)
Histologic Findings
Typical histologic findings in ATN include the following: (7)
Patchy loss of tubular epithelial cells with resultant gaps and exposure of denuded
basement membrane
Diffuse effacement and loss of proximal tubule cell brush border
Patchy necrosis, most typically in the outer medulla where the straight (S3) segment of
the proximal tubule and the medullary thick ascending limb (mTAL) of the loop of Henle
are located
Tubular dilatation and intraluminal casts in the distal nephron segments
Evidence of cellular regeneration
Regenerating cells are often detected in biopsies together with freshly damaged cells, suggesting
the occurrence of multiple cycles of injury and repair.
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 23/35
23
TREATMENT
Recognition of the circumstances that place children at risk for acute tubular necrosis
(ATN) and institution of corrective measures may prevent the development of this disorder.
Treatment of pediatric patients with ATN requires correction of imbalances in fluid volume,electrolytes, and acid-base balance. Children with ATN who are hemodynamically unstable or
require acute dialysis should be transferred to an intensive care unit (ICU).(7)
Fluid Management
The major goal of fluid management is to restore and maintain intravascular volume.
ATN may manifest itself with hypovolemia, euvolemia, or volume overload, and an estimation
of fluid status is a prerequisite for initial and ongoing therapy. This is accomplished by
measuring input and output, serial body weights, vital signs, skin turgor, capillary refill, serum
sodium, and fractional excretion of sodium (FENa).(7)
Children with intravascular volume depletion require prompt and vigorous fluid
resuscitation. Initial therapy includes normal saline or lactated Ringer solution at 20 mL/kg over
30 minutes. It can be repeated twice if necessary, after careful monitoring to avoid possible fluid
overload. Potassium administration is contraindicated until urine output is established. If anuria
persists after 3 fluid boluses (confirmed by bladder catheterization), central venous monitoring
may be required to guide further management.(7)
Oliguria in the presence of volume overload requires fluid restriction and possibly
intravenous administration of furosemide. Children with established ATN may not respond to
furosemide; in such cases, consider fluid removal by dialysis or hemofiltration, especially if signs
of pulmonary edema are evident.(7)
Input and output records, daily weights, physical examination, and serum sodium
concentration guide ongoing therapy. A bedside indicator of appropriate fluid therapy is a body
weight decrease of approximately 0.5% per day as a result of caloric deprivation; serum sodium
concentration should remain stable. A more rapid weight loss and increasing serum sodium
indicate inadequate fluid replacement. An absence of weight loss with decreasing serum sodium
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 24/35
24
suggests excess free water replacement. During the recovery phase, children develop significant
polyuria and natriuresis and may become dehydrated if appropriate adjustments in fluid
requirements are not made.(7)
Correction of Electrolyte Abnormalities and Acid-Base Imbalance
ATN may lead to hyperkalemia, hyponatremia, hyperphosphatemia, hypocalcemia, and
metabolic acidosis.(7)
Hyperkalemia
If serum potassium levels exceed 5.5-6.5 mEq/L, eliminate all sources of potassium from
the diet or intravenous fluids and administer a cation exchange resin such as sodium polystyrenesulfonate (Kayexalate). Kayexalate requires several hours of contact with the colonic mucosa to
be effective; the rectal route of administration is preferred. Complications of this therapy include
hypernatremia and constipation. An attempt can be made to lower serum potassium
concentration by increasing the dose of diuretics in those patients responding to them.(7)
When serum potassium exceeds 6.5 mEq/L or tall peaked T waves are evident on the
ECG, emergency treatment of hyperkalemia is indicated. In addition to Kayexalate, administer
intravenous sodium bicarbonate, which causes a rapid shift of potassium into cells. Themagnitude of the potassium intracellular shift is variable, and thus, bicarbonate is not reliable in
lowering the potassium level. Such therapy should be used with caution because it can
precipitate hypocalcemia and sodium overload.(7)
Sodium bicarbonate uptake of potassium by cells can also be stimulated by infusion of
glucose and insulin or by beta agonists (albuterol by nebulizer). The efficacy and convenience of
nebulized albuterol has been well described in chronic hemodialysis patients with hyperkalemia;
however, it can cause tachycardia, and the overall pediatric experience is limited.(7)
The presence of electrocardiographic (ECG) changes requires the immediate
administration of calcium gluconate (with continuous ECG monitoring) to counteract the effects
of hyperkalemia on the myocardium. This therapy may precipitate bradycardia and other cardiac
arrhythmias.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 25/35
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 26/35
26
severity of the abnormality to be corrected. Common indications for dialysis in ATN are as
follows:(16)
Fluid overload that is unresponsive to diuretics
Fluid overload that hinders adequate nutritional support
Hyperkalemia with oliguria
Symptomatic acid-base imbalances
Refractory hypertension
Symptomatic uremia ( pleuritis, pericarditis, CNS symptoms )
The choice between hemodialysis and peritoneal dialysis depends on the overall clinical
condition, availability of technique, etiology of the ATN, institutional preferences, and specificindications or contraindications. In general, peritoneal dialysis is a gentler and preferred method
in infants and younger children. Specific contraindications include abdominal wall defects,
bowel distention, perforation or adhesions, and communications between the abdominal and
chest cavities.(16)
Hemodialysis has the distinct advantage of rapid correction of fluid, electrolyte, and acid-
base imbalances, and it may be the treatment of choice in hemodynamically stable patients,
especially older children. Disadvantages include the requirement for vascular access, largeextracorporeal blood volume, heparinization, and skilled personnel.
(16)
An important advance has been the use of biocompatible synthetic dialysis membranes,
such as polysulfone. These membranes should minimize complement activation and neutrophil
infiltration into the kidney. Their use is generally recommended in children with AKI, although
not all studies have documented beneficial effects.(16)
Continuous venovenous hemofiltration (CVVH) has emerged as an alternative therapy
primarily for children with ATN who require fluid removal and are unstable or critically ill . The
major advantage of this technique lies in the ability to remove fluid in a hypotensive child in
whom hemodialysis may be relatively contraindicated and peritoneal dialysis inefficient. The
patient requires the continuous presence of trained personnel and specialized equipment that are
currently available only at select tertiary care centers. CVVH also can be modified easily to
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 27/35
27
allow for significant solute removal, and as experience accumulates, this continuous but gentle
modality may emerge as the dialytic therapy of choice for patients with ATN in the ICU.(16)
Some concern remains that dialysis may actually be detrimental to recovery of renal
function in ATN. Institution of dialysis may decrease any residual urine output (whichexacerbates intratubular obstruction), may induce episodes of hypotension (which further
compromises renal perfusion), and may activate complement (which increases neutrophil
infiltration into the kidney). Complement activation may be minimized by the use of
biocompatible membranes, and CVVH may allow for dialysis with better hemodynamic
control.(16)
Adjustment of Medications
Avoid nephrotoxic agents, as they may worsen the renal injury and delay recovery of
function. Such agents include contrast media, aminoglycosides, and nonsteroidal anti-
inflammatory drugs (NSAIDs).(7)
Prescribing medication in ATN requires knowledge of the route of elimination, and
modifications in dose or frequency should be made based on residual renal function. When
making these adjustments, patients in the early phase of ATN with a rising serum creatinine level
should be assumed to have a glomerular filtration rate (GFR) of less than 10 mL/min,
irrespective of the serum creatinine value.(7)
Administration of Calcium Channel Blockers
Calcium channel blockers (CCBs) have been shown to ameliorate ischemic renal injury
in various animal studies, although the mechanisms that confer the protection are unclear. They
may include an improvement in renal hemodynamics, a membrane stabilizing effect on tubule
epithelial cells, and a calmodulin antagonizing effect, in addition to the prevention of calcium
overloading of cells.(7)
CCBs have also yielded encouraging results in human ATN. Administration of CCBs to
both donors and recipients has been shown to reduce the prevalence of AKI following cadaveric
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 28/35
28
kidney transplants; however, the beneficial effect of CCBs in this setting may be because of their
ability to blunt the nephrotoxicity of the concomitantly administered cyclosporine.(7)
In addition, CCB administration prior to radio contrast materials confers protection
against nephrotoxicity. Therefore, the prophylactic use of CCBs prior to a potential renal insult,such as cold ischemia in cadaveric transplants or administration of contrast material, appears to
be beneficial; however, CCBs are unlikely to be effective in established ATN.(7)
Surgical Care
Patients with ATN secondary to obstruction frequently require urologic care. The site of
obstruction determines the therapy. In neonates, obstruction of the bladder neck caused byposterior urethral valves must be immediately relieved by gentle insertion of a fine urethral
catheter. The subsequent management of choice is endoscopic ablation of the valves. A
temporary cutaneous vesicostomy may be required in a small infant.(7)
Dietary Measures
Children with ATN are frequently in a highly catabolic state. Aggressive nutritional
support is important. Adequate calories to account for maintenance requirements and
supplements to combat excessive catabolism must be provided. Oral feeding is the preferred
route of administration. Children who are nauseous or anorexic may benefit from parenteral
feedings or intravenous hyperalimentation.(7)
Infants should receive a low-phosphorus diet (Similac PM 60/40), and older children
should be placed on a low-potassium, low-phosphorus diet. Additional calories may be supplied
by fortifying foods with Polycose and medium-chain triglyceride (MCT) oils. If adequate
nutrition cannot be achieved because of fluid restriction, consider early institution of
ultrafiltration or dialysis.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 29/35
29
Restriction of Activity
Children with ATN are usually hospitalized, and activity is restricted; however, strict bed
rest does not accelerate recovery.(7)
Consultations
Children with ATN are best treated in a tertiary care institution with pediatric nephrology
consultants.(7)
PREVENTION OF ACUTE TUBULAR NECROSIS
In clinical situations in which renal hypoperfusion or toxic injury is anticipated,
administration of fluids, diuretics, mannitol, and low-dose dopamine have been used to prevent
or reverse renal injury. Vigorous prophylactic fluid administration has been used successfully to
prevent ATN following cardiac surgery, cadaveric kidney transplantation, major trauma, burns,
hemoglobinuria, myoglobinuria, tumor lysis syndrome, radio contrast administration,
amphotericin B therapy, and cisplatin infusion.(17)
Ensuring adequate hydration prior to any of the above procedures is now an established
standard of care. However, the role of diuretics, mannitol, and low-dose dopamine is more
controversial. In one well-designed study using either low-dose dopamine or furosemide prior to
cardiac surgery in adults, no renoprotective effect could be documented. The prophylactic use of
diuretics or dopamine prior to the above procedures is not recommended at this time. (17)
Several studies, albeit uncontrolled, suggest that diuretics may be beneficial when
administered during the early phase of ATN. Although they do not appear to alter the course of
the acute kidney injury (AKI), they may convert an oliguric to a nonoliguric AKI, which is more
easily managed because it eliminates the need for fluid restriction and allows for maximal
nutritional support.(17)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 30/35
30
The current recommendation is that a trial of intravenous furosemide should be attempted
in children with oliguria of less than 48 hours duration who have not responded to adequate
hydration. The dose of furosemide should be in the high range (2-5 mg/kg). Some evidence
suggests that in the prevention of crush syndrome, early administration of mannitol, before
muscle toxins and breakdown products are released into the circulation, may protect from the
development of ATN.(17)
MEDICATION
Diuretic treatment may convert oliguric acute tubular necrosis (ATN) to nonoliguric
ATN, although diuretics do not appear to alter the course of acute kidney injury (AKI).(7)
Hyperkalemia in ATN is a medical emergency that may be managed by shifting
potassium into cells with sodium bicarbonate, glucose/insulin infusion, or beta agonists; by
increasing potassium excretion with exchange resins (sodium polystyrene) or loop diuretics
(furosemide); or by dialysis. Protecting the myocardium from hyperkalemia is managed with
intravenous (IV) calcium.(7)
Hyperphosphatemia may be initially managed with oral calcium to bind dietary
phosphate. Oral citrate salts may be used to manage mild metabolic acidosis, whereas IV sodium
bicarbonate is needed for severe metabolic acidosis.(7)
Loop diuretics
In children with recent-onset oliguria from prerenal or toxic injury who are unresponsive
to hydration, a trial of furosemide may convert the oliguric ATN to a nonoliguric type, which ismanaged more easily. These agents have a direct vasodilatory action and additionally may
prevent tubular obstruction by increasing intratubular fluid flow.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 31/35
31
Furosemide (Lasix)
Furosemide increases excretion of water by interfering with the chloride-binding
cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending
loop of Henle and distal renal tubule. It is used for ATN prevention in children with oliguriaduration less than 48 hours who have not responded to adequate hydration. It may also be
considered for oliguria in the presence of volume overload. Furosemide is also used for
hyperkalemia to increase potassium excretion in the urine.(7)
Alkalizing agents
Intravenous sodium bicarbonate and oral sodium citrate are used as buffers that break
down to water and carbon dioxide after picking up free hydrogen ions, thus counteracting
acidosis by raising blood pH. IV sodium bicarbonate is also used to manage hyperkalemia.(7)
Sodium bicarbonate
Sodium bicarbonate is used to treat hyperkalemia. It causes a rapid shift of potassium into
cells. The magnitude of the potassium intracellular shift varies; thus, bicarbonate is not reliable
in lowering the potassium level by itself. It is also used emergently to manage severe metabolic
acidosis.(7)
Sodium citrate (Bicitra, Oracit)
Sodium citrate manages mild metabolic acidosis and is used as an alkalinizing agent
when long-term maintenance of an alkaline urine is desirable.(7)
Myocardium stabilizers
Intravenous calcium is primarily used to protect the myocardium from the deleterious
effects of hyperkalemia (ie, arrhythmias) by antagonizing the potassium actions on the
myocardial cell membrane. It does not lower serum potassium levels.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 32/35
32
Calcium gluconate (Kalcinate)
Calcium gluconate is given intravenously to provide myocardial protection from
hyperkalemia. It is indicated if hyperkalemia is accompanied by ominous electrocardiographic
(ECG) changes beyond peaked T waves or if ECG changes persist after bicarbonate therapy.
(7)
Intracellular transporters
Insulin and glucose (dextrose) cause a transcellular shift of potassium into muscle cells,
thereby lowering (temporarily) potassium serum levels.(7)
Dextrose and insulin infusion
Dextrose and insulin infusion is used as an adjunct to bicarbonate therapy to promote
intracellular shift of potassium.(7)
Exchange resins
Sodium polystyrene sulfonate is an exchange resin that can be used to treat mild-to-
moderate hyperkalemia. Each 1 mEq of potassium is exchanged for 1 mEq of sodium.(7)
Sodium polystyrene sulfonate (Kayexalate)
Sodium polystyrene sulfonate is indicated in all cases of hyperkalemia because it is the
only modality (other than diuretics and dialysis) that actually removes excessive potassium from
the body. It exchanges sodium for potassium and binds it in the gut, primarily in the large
intestine, and decreases total body potassium. Its onset of action after oral administration ranges
from 2-12 hours and is longer when rectally administered. (7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 33/35
33
Phosphate binders
ATN is frequently complicated by hyperphosphatemia and hypocalcemia, which respond
to calcium-containing oral phosphate binders.(7)
Calcium carbonate (Oystercal, Caltrate)
Calcium carbonate combines with dietary phosphate to form insoluble calcium
phosphate, which is excreted in feces.(7)
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 34/35
34
REFERENCES
1. Gray H. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918; Bartleby.com,
2000. www.bartleby.com/107/.
2. Kliegman R, Nelson W. Nelson Textbook of Pediatric. 19th
ed. Philadelphia : Elsevier &
Saunders; 2011:1757-58..
3. American Society of Nephrology. American Society of Nephrology Renal Research
Report. J Am Soc Nephrol. Jul 2005;16(7):1886-903.
4. Andreoli SP. Management of acute renal failure. In: Barratt TM, Avner ED, Harmon W,
eds. Pediatric Nephrology. 4th
ed. Baltimore, MD: Lippincott Williams & Wilkins;
1999:1119-34.
5. Devarajan P, Goldstein SL. Acute renal failure. In: Kher KK, Schnaper HW, Makker
SP. Clinical Pediatric Nephrology. 2nd
ed. Oxon, UK: Informa Healthcare; 2007:363-
376.
6. Warnock DG. Towards a definition and classification of acute kidney injury. J Am Soc
Nephrol. Nov 2005;16(11):3149-50.
7. Devarajan P, Langman C. Pediatric Acute Tubular necrosis. 2010. Cited from :
http://emedicine.medscape.com/article/980830
8. Mehta RL, Chertow GM. Acute renal failure definitions and classification: time for
change?. J Am Soc Nephrol. Aug 2003;14(8):2178-87.
9. Devarajan P. Update on Mechanisms of Ischemic Acute Kidney Injury. J Am Soc
Nephrol. Jun 2006;17(6):1503-1520.
10. Devarajan P. Cellular and molecular derangements in acute tubular necrosis. Curr Opin
Pediatr . Apr 2005;17(2):193-9.
11. Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay,
and costs in hospitalized patients. J Am Soc Nephrol. Nov 2005;16(11):3365-70.
8/4/2019 Refarat Acute Tubular Necrosis
http://slidepdf.com/reader/full/refarat-acute-tubular-necrosis 35/35
12. Rabb H, Colvin RB. Case records of the Massachusetts General Hospital. Case 31-2007.
A 41-year-old man with abdominal pain and elevated serum creatinine. N Engl J Med .
Oct 11 2007;357(15):1531-41.
13. Devarajan P. The future of pediatric acute kidney injury management-biomarkers. Semin
Nephrol. Sep 2008;28(5):493-8.
14. Parikh CR, Devarajan P. New biomarkers of acute kidney injury. Crit Care Med . Apr
2008;36(4 Suppl):S159-65.
15. Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney
transplantation. Lancet . Nov 13-19 2004;364(9447):1814-27.
16. Himmelfarb J, Tolkoff Rubin N, Chandran P, et al. A multicenter comparison of dialysis
membranes in the treatment of acute renal failure requiring dialysis. J Am Soc Nephrol.
Feb 1998;9(2):257-66.
17. Lameire NH, De Vriese AS, Vanholder R. Prevention and nondialytic treatment of acute
renal failure. Curr Opin Crit Care. Dec 2003;9(6):481-90.