Adaptation of kidney to renal injury Size of kidney and total number of nephrons formed late in embryologic devt depends on deg of ureteric bud undergoing branching morphogenesis determines how well the kidney will adapt to physiologic demands of blood pressure and body size, various envt stresses or unwanted inflammation that may lead to CRF 225,000 and 900,000 nephrons in each kidney Residual nephrons in CRF hyperfunction to compensate for loss of nephrons to primary dse. Depends on: Changes by renal hypertrophy Adjustments in tubuloglomerular feedback Glomerulotubular balance Common mechanisms of progressive renal disease Sentinel event--- remaining kidney enlarges (compensatory renal hypertrophy, with little cellular prolif) and inc GFR (80% of normal for two kidneys) Done by inc size of each cell along nephron--- accommodated by elasticity or growth of interstitial spaces under renal capsule Hyperfiltration: produces no ill consequences Inc in rate of single nephron glomerular filtration in presence of significant ablation of renal mass Renal progression: Maladaptive deterioration esp with critical amt of primary nephrons loss (80%) Six mechanisms that hypothetically unify this final common pathway: (compare with Fig 278-2) Persistent glomerular injury--- local HPN in capillary tufts--- inc of single-nephron GFR--- protein leak into tubular fluid Sig glomerular proteinuria + inc in local prdxn of angiotensin II--- downstream cytokine bath--- accumulation of interstitial mononuclear cells Initial appearance of interstitial neutrophils--- replaced by Mac and T lymph--- forms nephritogenic immune response--- interstitial nephrosis Some tubular epithelia respond to inflammation by disaggregating from basement membrane and adjacent sister cells--- epithelial-mesenchymal transitions--- forms new interstitial fibroblasts Surviving fibroblasts lay down collagenous matrix--- disrupts adjacent capillaries and tubular nephrons--- acellular scar Hyperfiltration + intraglomerular filtration--- eventual appearance of glomerulosclerosis Angiotensin II: essential mediator of inc intraglomerular capillary pressure Selectively inc efferent arteriolar vasoconstriction to afferent arteriolar tone Impairs glomerular size selectivity, induces protein ultrafiltration and inc intracellular Ca in podocytes (alters podocyte fxn) Vasoconstrictor mechanisms Blockade of NO synthase Angiotensin II and thromboxane receptor activation All these can induce oxidative stress in surrounding renal tissue Aldosterone: Inc renal vascular resistance and glomerular capillary pressure Stimulates plasminogen activator inhibitor--- facilitates fibrogenesis--- complements detrimental act of angiotensin II Inflammation that begins in renal interstitium: disables tubular reclamation of filtered protein--- mild nonselective proteinuria Inflammation that initially damages glomerular capillaries: usu spreads to tubulointerstitium --- assoc with heavier proteinuria !!! inc in severe proteinuria--- downstream inflammatory cascade in tubular epith cells--- interstitial nephritis, fibrosis and tubular atrophy Albumin is an abundant polyanion--- poss binds variety of cytokines, chemokines and lipid mediators--- might initiate tubular inflammation brought on by proteinuria Glomerular injury adds activated mediators to proteinuric filtrate Or may alter balance of cytokine inhibitors and activators--- critical level of activated cytokines--- damages downstream tubular nephron Tubular epith respond by inc secretion of chemokines + relocation of NF-kappaB to nucleus--- proinflammatory release of TGF-beta, PDGF-BB, FGF-2--- inflamm cells drawn into renal interstitium--- reduces likelihood that kidney will survive Immunologic mechanisms for spreading Loss of tolerance to parenchymal self Immune deposits that share cross-reactive epitopes in either compartment or glomerular injury Drugs, infection and metabolic defects--- induce autoimmunity via TLRs Bacterial and viral ligands activate TLRs via Tamm-Horsfall protein Bacterial CpG repeats RNA released nonspecifically from injured tubular cells Nephritogenic interstitial T cells: Mix of CD4 helper, CD17 effector and CD8 cytotoxic lymphocytes !!! Epithelial/Endothelial-mesenchymal transition Long-term consequence of tubular epithelia and adjacent endothelia exposed to cytokines Initiated by persistent cytokine activity during renal inflammation and disruption of underlying BM Emergence of new fibroblasts from epithelia Tubulointerstitial scars Composed principally of fibronectin, collagen I and III, tenascin and glycoproteins such as thrombospondin, SPARC, osteopontin, proteoglycan ! tubular epithelia supposedly can secrete collagens I and III, but these disappear through transition and tubular atrophy Fibroblasts deposit fibronectin which provides scaffold for interstitial collagens--- outdistance their survival factors--- death of fibroblasts from apoptosis--- acellular scar Response to reduction in numbers of functioning nephrons Glomerular hyperfiltration: From inc vasoconstriction in postglomerular efferent arterioles relative to preglomerular afferent arterioles--- inc intraglomerular capillary pressure and filtration fraction Antiotensin II: chiefly implicated for mediation of hyperfiltration Vasoconstriction of efferent arteriole Endothelin: implicated for hyperfiltration too May be mediated also by tubuloglomerular feedback system Relies on macula densa: modulates renal blood flow and glomerular filtration Glomerulotublar balance Even with loss of functioning nephrons, this balance is still maintained by residual tubules via single nephron glomerular filtration With appropriate alterations in reabsorption or excretion of filtered water and solutes to maintain homeostasis Results from tubular hypertrophy and from regulatory adjustments in tubular oncotic pressure Tubular function in CRF Sodium Usu remains near normal until until limitations from advanced renal bdisease inadequately excreted dietary Na intake Na excretion inc predominantly by dec Na reabsorption in loop of Henle and distal nephron Inc in osmotic obligation of residual nephron --- inc tubular water and lowers Na conc in tubular fluid--- reduced Na reclamation--- inc excretion of inorganic and organic anions also obligates more Na excretion Inc ANP--- inc distal Na excretion--- impt role in maintaining Na excretion With advancing nephron loss--- ANP lose their effectiveness--- Na retention results--- intravascular volume expansion, edema and worsening HPN Urinary dilution and conc Gradual loss of capacity to dilute or conc urine--- urine osmolality fixed at 350mOsm/L Reduced number of fxning nephrons obligates inc fractional solute excretion by residual nephrons--- impairs ability to dilute fluid maximally Urinary conc ability falls as more water is neeed to hydrate inc solute load Tubulointerstitial damage--- insensitivity to antidiuretic effects of vasopression along collecting duct or loss of medullary gradient Potassium Renal excretion: major pathway for reducing excess K+ Normally: excretes 90% of dietary K (10% through sweat) 30% of ingested K may be excreted in stool of pxs with worsening renal failure, majority of which continues to be excreted by kidneys due to elevation in lvls of serum K--- inc of filtered load Aldosterone: regulates collecting duct Na reabsorption and K secretion Released in adrenal cortex not only in RAS response but also to direct response to elev lvls of serum K Acid-base regulation Normally: 1 meq/kg/day of noncarbonic H ion on normal diet is excreted Ca and PO4 Dec renal fxn + tubulointerstitial nephritis Expression of 1alpha-hdroxylase by proximal tubule is reduced--- levels of Ca2, calcitriol and gut absorption Modifiers influencing progression of renal disease HPN, DM, RAAS activation Low protein diet: dec or progressive nephron loss LBW: seen as consequence of low birth wt

Acute Kidney Injury A group of conditions that share common dx features: Inc in BUN conc Inc in plasma or serum crea Often reduction in urine volume Etiology and pathophysiology Prerenal azotemia Most common form Besides the usual causes of hypovolemia or any other perfusion decreasing conditions, NSAIDs, ACE-I/ARB and cyclosporine are implicated due to impaired renal autoregulation Involves no parenchymal damage and is rapidly reversible once intraglomerular hemodynamics are restored Normal GFR is maintained by resistances of afferent and efferent renal arterioles Glomerular filtration maintained despite reduced renal blood flow by: Angiotensin II Vasoconstriction maintains glomerular capillary hydrostic pressure closer to normal--- prevents marked reductions in GFR Norepinephrine Vasopressin Myogenic reflex of afferent arteriole--- dilation in setting of low perfusion--- maintaining glomerular perfusion Intrarenal vasodilator prostaglandins (prostacyclin, PGE2), kallikrein and kinins and NO--- inc in response to low renal perfusion pressure !!! renal autoregulation usu fails once systolic BP < 80 mmHg Impaired renal autoregulation due to drugs: NSAIDs: inhibits renal PG prdxn--- limiting renal afferent vasodilation ACEi and ARB: limits renal efferent vasoconstriction Pronounced in pxs with bilat renal artery stenosis or unilateral renal artery stenosis Px with advanced cirrhosis: Hemodynamic profile: Resembles prerenal azotemia despite total body volume overload Markedly reduced systemic vascular resistance r/t primary arterial vasodilation in splanchnic circ--- causes activation of vasoconstrictor responses similar to those seen in hypovolemia Type I hepatorenal syndrome: Poor prognosis as AKI here persists despite volume replacement Type 2 Less severe form characterized mainly by refractory ascites Intrinsic AKI/Acute Tubular Necrosis Most common causes: Sepsis, ischemia and nephrotoxins (endo and exogenous) Usu advances to tubular injury Sepsis-assoc AKI Dec in GFR with sepsis can occur even in absence of overt hypotension Hemodynamic effects of sepsis: generalized arterial vasodilationby cytokines--- leads to reduction in GFR Operative mechanisms: excessive efferent arteriole vasodilation, esp early in course of sepsis, or renal vasoconstriction from SNS, RAAS, vasopressin and endothelin Sepsis--- leads to endothelial damage--- microvascular thrombosis--- ROS activation--- leukocyte adhesion and migration--- may injure renal tubular cells Ischemia-assoc AKI Healthy kidneys receive 20% of CO, acct for 10% of resting O2 consumption Site of one of most hypoxic regions of body: renal medulla Ischemia alone usu not enough to cause severe AKI AKI more commonly develops when ischemia occurs in context of limited renal reserve or coexisting insults such as sepsis, vasoactive or nephrotoxic drugs, rhabdomyolysis and systemic inflammatory states assoc with burns and pancreatitis Postoperative AKI Usu assoc with cardiopulmonary bypass, aortic cross clamping and intraperitoneal procedures Use of nephrotoxic agents including iodinated contrast for cardiac imaging inc risk for AKI AKI from atheroembolic dse may occur as with percutaneous catheterization of aorta Burns and acute pancreatitis Severe hypovolemia, dysregulated inflammation and inc risk for sepsis and acute lung injury facilitate devt and progression of AKI If with massive resuscitation for trauma, buns and acute pancreatitis--- abdominal compartment syndrome may develop Markedly elevated intraabdominal pressures (higher than 20mmHg)--- renal vein compression and reduced GFR Diseases of microvasculature leading to ischemia Includes thrombotic microangiopathies, scleroderma, atheroembolic dse Large vessel diseases assoc with AKI Renal artery dissection, thromboembolism, thrombosis, renal vein compression or thrombosis Nephrotoxin-associated AKI High susceptibility to nephrotoxicity due to extremely high blood perfusion and conc of circulating substances along nephron All structures of the kidney are vulnerable to toxic injury Contrast agents Rise in SCr beginning 24-48 hrs ff exposure, peaks within 3-5 days and resolves within 1 week Severe AKI is uncommon except in setting of signif preexisting CKD Occurs from: Hypoxia in renal outer medulla r/t pertuberations in renal microcirc and occlusion of small vessels Cytotoxic damage to tubules Transient tubule obstruction Antibiotics Chemotherapeutic agents Endogenous toxins and allergic acute tubulointerstitial disease and other causes of intrinsic AKI Postrenal Acute Kidney Injury When normally unidirectional flow of urine is blocked partially or totally--- inc retrograde hydrostatic pressure + interference with glomerular filtration Normal urinary flow rate does not rule out presence of partial obstruction, since GFR is normally two-orders of magnitude higher than urinary flow rate Obstruction must usu affect both kidneys Unilateral may cause in setting of significant underlying CKD Bladder neck obstruction is a common cause, may be due to: Prostate dse Neurogenic bladder Anticholinergic agents Obstructed foley catheters may cause postrenal AKI Diagnostic eval (table 279-1) Usu inferred from elevation in SCr conc AKI= a rise of at least 0.3mg/dL or 50% higher than baseline within a 24-48 hr period; or reduction of UO to 0.5mL/kg/hr for longer than 6 hours Distinction bet AKI and CKD: Straightforward when recent baseline SCr is available CKD Radiologic, laboratory, (normocytic anemia, secondary hyperparathyroidism with phosphatemia and hyocaclemia Urinalysis Complete anuria early in AKI is uncommon Except in Complete UT obstruction Renal artery occlusion Overwhelming septic shock, severe anemia Severe proliferative GN or vasculitis Oliguria: assoc with worse clinical outcomes Greater proteinuria in AKI suggests damage to glomerular ultrafiltration barrier, or excretion of myeloma light chains Atheroemboli cause variable degree of proteinuria Extremely heavy proteinuria nephrotic range Seen in pxs with GN, vasculitis or interstitial nephritis Prerenal may present with hyaline casts or unremarkable urine sediment Renal failure indices Fractional excretion of sodium Fraction of filtered sodium load that is reabsorbed by tubules measure of both kidneys ability to reabsorb sodium wih prerenal azotemia FeNa may be below 1% suggesting avid tubular sodium reabsorption with CKD: may be above 1% despite hypovolemia low FeNa seen in glomerulonephritis ischemic AKI: FeNa is above 1% Radiologic eval Imaging with UTZ or CT should be undertaken early Findings of obstruction include dilation of collecting system and hydroureteronephrosis Obstruction can be present without radiologic abnormalities in setting of volume depletion, retroperitoneal fibrosis, encasement with tumor and early in course of obstruction Large kidneys: probably diabetic nephropathy, HIV assoc nephropathy, infiltrative diseases or acute interstitial nephritis Kidney biopsy Most often used in AKI when prerenal azotemia, postrenal AKI, and ischemic or nephrotoxic AKI have been deemed unlikely But when GN, vasculitis, interstitial nephritis, myeloma, kidney, HUS and TTP and allograft dysfxn Assoc with risk of bleeding which may be severe or life-threatening in pxs with thrombocytopenia or coagulopathy Complications Uremia Hallmark of AKI: Buildup of nitrogenous waste products--- elevated BUN Little direct toxicity at level below 100mg/dL Hypervolemia and hypovolemia Expansion of ECF volume--- major complication of oliguric and anuric AKI Mgmt of this could lead to polyuria--- significant volume depletion--- polyuric phase may be due to osmotic diuresis from retained urea and oter waste products Hyponatremia Admin of excessive hypotonic crystalloid or isotonic dextrose--- hypoosmolality and hyponatremia--- seizures if severe Hyperkalemia Common in rhabdomyolysis, hemolysis and tumor lysis syndrome Muscle weakness Effects on cardiac conduction Acidosis Usu accompanied by anion gap--- further complicates acid-base and K balance in individuals with other causes of acidosis (sepsis, DKA, respi acidosis) Hyperphosphatemia and hypocalcemia Usu in highly catabolic pxs or those with AKI from rhabdomyolysis, hemolysis and tumor lysis syndrome Metastatic deposition of CaPO4 can lead to hypocalcemia May also arise from derangements in vitamin D-parathyroid axis Should be corrected for deg of hypoalbuminemia if present or ionized Ca levels should be followed Bleeding Includes anemia and bleeding, both which are exacerbated by coexisting disease processes such as sepsis, liver dse and disseminated intravascular coag Direct hematologic effects include dec erythropoiesis and plt dysfxn Infxns Common precipitant of AKI Cardiac complications Arrhythmias, pericarditis, and pericardial effusion Malnutrition AKI is usu a severely hypercatabolic state Treatment Seven principles common to all courses of ttt of AKI Optimization of hemodynamics Correction of fluid and electrolyte imbalances Discontinuation of nephrotoxic medications Dose adjustment of administered medications Prerenal azotemia Requires optimization of renal perfusion Cirrhosis and hepatorenal syndrome Rule out peritonitis by culture of ascetic fluid Albumin may prevent AKI in those ttd with antibiotics Definitive ttt of hepatorenal syndrome: Orthotopic liver transplantation Bridge therapies: Terlipressin (vasopressin analog) Combo Rx with octreotide (somatostatin analog) and midodrine (alpha1-adrenergic agonist) and norepinephrine; All of which in combination with IV albumin (25-50mg/day--- max 100g/d) Intrinsic AKI Many agents fail to show benefit If due to GN or vasculitis: may respond to immunosuppressive agents and/or plasmapheresis Allergic interstitial nephritis: d/c of offending agent If AKI persists: glucocorticoids may be useful AKI due to scleroderma: Ttt with ACE inhibitors Rhabdomyolysis: Early and aggressive volume repletion 10L fluid per day Alkaline fluid may be beneficial in preventing tubular injury and cast Carries risk for hypocalcemia Diuretics may be used but unsuccessful with urinary flow rate of 200-300mL/h No specific Rx tho other than dialysis in severe cases Postrenal AKI Ureteric obstruction Percutaneous nephrostomy tube placement or ureteral stent placement Relief of obstruction usu ffd by appropriate diuresis for several days Rare: severe polyuria persists still due to tubular dysfxn--- may require continued admin of IV fluids and electrolytes for a period of time Supportive measures Volume mgmt. Fluid and sodium restriction Diuretics may be used to inc urinary flow rate No evidence that inc urine output itself improves natural hx of AKI But may help avoid need of dialysis in some cases Furosemide bolus ffd by IV drip with or without thiazide diuretic in severe cases of volume overload Stop diuretic rx if no response Dopamine in low doses transiently inc salt and water excretion But risks of dopamine may outweigh the benefits in ttt or prevention of AKI Electrolyte and acid-base abnormalities Metabolic acidosis is not ttd unless severe (pH