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Harrison's Principles of Internal Medicine, 18e >

Sushrut S. Waikar; Joseph V. Bonventre

Acute kidney injury (AKI), previously known as acute renal failure, is characterized by the sudden impairment of
kidney function resulting in the retention of nitrogenous and other waste products normally cleared by the kidneys.
AKI is not a single disease but, rather, a designation for a heterogeneous group of conditions that share common
diagnostic features: specifically, an increase in the blood urea nitrogen (BUN) concentration and/or an increase in the
plasma or serum creatinine (SCr) concentration, often associated with a reduction in urine volume. AKI can range in
severity from asymptomatic and transient changes in laboratory parameters of glomerular filtration rate (GFR), to
overwhelming and rapidly fatal derangements in effective circulating volume regulation and electrolyte and acid-base
composition of the plasma.
Changing the name of a syndrome as well known as "acute renal failure" does not occur frequently. We will
summarize some of the reasons why the name was changed to "acute kidney injury." The term
reflects only
part of the spectrum of damage to the kidney that occurs clinically. In most cases of damage, the reduction in kidney
function is modest. Nevertheless, this modest change has been documented to be associated with negative effects
on outcome, albeit not nearly as ominous as seen with large decreases in kidney function associated with frank
kidney failure that often requires acute dialysis therapies. Furthermore, the term
is not well understood in the
general population and this makes communication with patients and family more challenging; hence "kidney" has
replaced "renal."

AKI complicates 5–7% of acute care hospital admissions and up to 30% of admissions to the intensive care unit. AKI
is also a major medical complication in the developing world, particularly in the setting of diarrheal illnesses,
infectious diseases like malaria and leptospirosis, and natural disasters such as earthquakes. The incidence of AKI
has grown by more than fourfold in the United States since 1988 and is estimated to have a yearly incidence of 500
per 100,000 population, higher than the yearly incidence of stroke. AKI is associated with a markedly increased risk
of death in hospitalized individuals, particularly in those admitted to the ICU where in-hospital mortality rates may
exceed 50%.

AKI in the Developing World
The epidemiology of AKI differs tremendously between developed and developing countries, owing to differences in
demographics, economics, geography, and comorbid disease burden. While certain features of AKI are common to
both—particularly since urban centers of some developing countries increasingly resemble those in the developed
world—many etiologies for AKI are region-specific such as envenomations from snakes, spiders, caterpillars, and
bees; infectious causes such as malaria and leptospirosis; and crush injuries and resultant rhabdomyolysis from

The causes of AKI have traditionally been divided into three broad categories: prerenal azotemia, intrinsic renal
parenchymal disease, and postrenal obstruction (Fig. 279-1).
FIGURE 279-1

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Classification of the major causes of acute kidney injury. ACE-1, angiotensin-converting enzyme 1; ARB,
angiotensin receptor blocker; NSAIDs, nonsteroidal anti-inflammatory drugs; TTP-HUS, thrombotic thrombocytopenic
purpura-hemolytic uremic syndrome.

Prerenal Azotemia
Prerenal azotemia (from "azo," meaning nitrogen, and "-emia") is the most common form of AKI. It is the designation
for a rise in SCr or BUN concentration due to inadequate renal plasma flow and intraglomerular hydrostatic pressure
to support normal glomerular filtration. The most common clinical conditions associated with prerenal azotemia are
hypovolemia, decreased cardiac output, and medications that interfere with renal autoregulatory responses such as
nonsteroidal anti-inflammatory drugs (NSAIDs) and inhibitors of angiotensin II (Fig. 279-2). Prerenal azotemia may
coexist with other forms of intrinsic AKI. Prolonged periods of prerenal azotemia may lead to ischemic injury, often
termed acute tubular necrosis, or ATN. By definition, prerenal azotemia involves no parenchymal damage to the
kidney and is rapidly reversible once intraglomerular hemodynamics are restored.
FIGURE 279-2

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lb:2048/content.. 4/15/2015 7:55 PM of 29 http://accessmedicine..mhmedical.

Panel C shows reduced perfusion pressure with a nonsteroidal anti-inflammatory drug (NSAID).mhmedical. Panel B shows reduced perfusion pressure within the autoregulatory range.4 of 29 Normal glomerular capillary pressure is maintained by afferent vasodilatation and efferent Panel D shows 4/15/2015 7:55 PM .lau.. Intrarenal Mechanisms for Autoregulation of the Glomerular Filtration Rate (GFR) under Decreased Perfusion Pressure and Reduction of the GFR by Drugs. this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease. Loss of vasodilatory prostaglandins increases afferent Panel A shows normal conditions and a normal GFR..

resulting ultimately in activation of vasoconstrictor responses similar to those seen in hypovolemia. A particularly poor prognosis is seen in the case of type 1 hepatorenal syndrome. In chronic kidney disease. in which decreases in solute delivery to the macula densa (specialized cells within the proximal tubule) elicit dilation of the juxtaposed afferent arteriole in order to maintain glomerular perfusion. and possibly nitric oxide (NO) also increase in response to low renal perfusion pressure. norepinephrine. processes such as inflammation.ezproxy. Systemic vascular resistance is markedly reduced due to primary arterial vasodilation in the splanchnic circulation. renal autoregulation usually fails once the systolic blood pressure falls below 80 mmHg. in general. Mild degrees of hypovolemia and reductions in cardiac output elicit compensatory renal physiologic changes. the risk of prerenal azotemia. Drugs can affect the compensatory changes evoked to maintain GFR. prostaglandin E2). by NO. Mediators of this response include angiotensin II. Many individuals with advanced cirrhosis exhibit a unique hemodynamic profile that resembles prerenal azotemia despite total body volume overload. and older age can lead to hyalinosis and myointimal hyperplasia. renal vasoconstriction and salt and water reabsorption occur as a homeostatic response to decreased effective circulating volume or cardiac output in order to maintain blood pressure and increase intravascular volume to sustain perfusion to the cerebral and coronary vessels. apoptosis. renal afferent vasodilation may be operating at maximal capacity in order to maximize GFR in response to reduced functional renal mass. ischemia. Type 2 hepatorenal syndrome is a less severe form characterized mainly by refractory ascites. to the ability of these counterregulatory mechanisms to maintain GFR in the face of systemic hypotension. Intrarenal biosynthesis of vasodilator prostaglandins (prostacyclin.. There is a limit. Glomerular filtration can be maintained despite reduced renal blood flow by angiotensin II–mediated renal efferent vasoconstriction.. Loss of angiotensin II action reduces efferent resistance. Intrinsic AKI The most common causes of intrinsic AKI are sepsis. and altered regional perfusion may be more relevant pathophysiologically. reduced perfusion pressure with an angiotensin-converting enzyme (ACE-I) inhibitor or an angiotensin receptor blocker (ARB). Atherosclerosis. nephrotoxic drugs) persists despite volume administration and withholding of diuretics.5 of 29 http://accessmedicine. which determine the glomerular plasma flow and the transcapillary hydraulic pressure gradient that drive glomerular AKI is a common complication in this setting. indeed. Autoregulation is also accomplished by tubuloglomerular feedback. this effect is particularly pronounced in patients with bilateral renal artery stenosis or unilateral renal artery stenosis (in the case of a solitary functioning kidney) because renal efferent vasoconstriction is needed to maintain GFR due to low renal perfusion.mhmedical. In many cases. and vessels. A number of factors determine the robustness of the autoregulatory response and. and vasopressin (also termed antidiuretic hormone).g.. The combined use of nonsteroidal anti-inflammatory agents with ACE inhibitors or ARBs poses a particularly high risk for developing prerenal azotemia. kallikrein and kinins. Even in healthy adults. prerenal azotemia advances to tubular injury. both endogenous and exogenous (Fig. In addition. in part. shock. thereby. ACE inhibitors and angiotensin receptor blockers (ARBs) limit renal efferent vasoconstriction." human biopsy confirmation of tubular necrosis is. and nephrotoxins. and it can be triggered by volume depletion and spontaneous bacterial peritonitis. long-standing hypertension. a mechanism mediated. in which AKI without an alternate cause (e. limiting renal afferent vasodilation. FIGURE 279-3 4/15/2015 7:55 PM . a myogenic reflex within the afferent arteriole leads to dilation in the setting of low perfusion pressure. Because renal blood flow accounts for 20% of the cardiac output. this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease. thereby maintaining glomerular perfusion.lau. Although classically termed "acute tubular necrosis. infection. lacking in cases of sepsis and ischemia. 279-3).edu. Other causes of intrinsic AKI are less common and can be conceptualized anatomically according to the major site of renal parenchymal damage: glomeruli. however. ) Normal GFR is maintained in part by the relative resistances of the afferent and efferent renal arterioles. NSAIDs inhibit renal prostaglandin production. causing structural narrowing of the intrarenal arterioles and impaired capacity for renal afferent vasodilation. which maintains glomerular capillary hydrostatic pressure closer to normal and thereby prevents marked reductions in GFR if renal blood flow reduction is not excessive. which results in microvascular thrombosis. vasopressin. Decreases in GFR with sepsis can occur even in the absence of overt hypotension. PCN.000 cases of sepsis occur each year. Sepsis may lead to endothelial damage. the renin-angiotensin-aldosterone system. postmortem examinations of kidneys from individuals with severe sepsis suggest that other factors. While there is clearly tubular injury associated with AKI in sepsis as manifest by the presence of tubular debris and casts in the urine. more than 700. methotrexate. The operative mechanisms may be excessive efferent arteriole vasodilation.. HTN. and endothelin. and greatly increases the risk of death. The hemodynamic effects of sepsis—arising from generalized arterial vasodilation..ezproxy. tubulointerstitial nephritis-uveitis. TTP/ DIC.6 of 29 http://accessmedicine. Sepsis is also a very important cause of AKI in the developing world. TINU. or renal vasoconstriction from activation of the sympathetic nervous system. must be considered in the pathophysiology of sepsis-induced AKI. AKI complicates more than 50% of cases of severe sepsis. 4/15/2015 7:55 PM . Sepsis-Associated AKI In the United States. Major causes of intrinsic acute kidney injury. particularly early in the course of sepsis.mhmedical. ATN. thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. although most cases of severe AKI typically occur in the setting of hemodynamic collapse requiring vasopressor support. disseminated intravascular coagulation. penicillin. hypertensive nephropathy. acute tubular necrosis. perhaps related to inflammation and interstitial edema. mediated in part by cytokines that upregulate the expression of inducible NO synthase in the vasculature—can lead to a reduction in GFR.

especially after major operations involving significant blood loss and intraoperative hypotension. as evidenced by the relatively low risk of severe AKI even after total interruption of renal blood flow during suprarenal aortic clamping or cardiac arrest. The outer medulla is particularly vulnerable to ischemic damage because of the architecture of the blood vessels that supply oxygen and nutrients to the tubules. Persistent preglomerular vasoconstriction may be a common underlying cause of the reduction in GFR seen in AKI. despite constituting only 0. all of which may injure renal tubular cells. Ischemia-Associated AKI Healthy kidneys receive 20% of the cardiac output and account for 10% of resting oxygen consumption. which depends on oxidative metabolism for survival. PGE2.7 of 29 increased basal vascular tone and reactivity to vasoconstrictive chronic kidney disease or older age) or coexisting insults such as sepsis. vasoactive or nephrotoxic drugs. Prerenal azotemia and ischemia-associated AKI represent a continuum of the manifestations of renal hypoperfusion. Clinically. prostaglandin E2.mhmedical. The kidneys are also the site of one of the most hypoxic regions in the body. and leukocyte adhesion and migration.. AKI more commonly develops when ischemia occurs in the context of limited renal reserve (e. Enhanced leukocyte-endothelial interactions in the small vessels lead to inflammation and reduced local blood flow to the metabolically very active S3 segment of the proximal tubule.. the renal medulla. Other contributors to low GFR include backleak of filtrate across ischemic and denuded tubular epithelium and mechanical obstruction of tubules from necrotic debris (Fig. rhabdomyolysis.5% of the human body mass. and the systemic inflammatory states associated with burns and pancreatitis. and decreased vasodilator responsiveness.lau. 279-4). Postoperative AKI Ischemia-associated AKI is a serious complication in the postoperative period. FIGURE 279-4 Interacting microvascular and tubular events contributing to the pathophysiology of ischemic acute kidney injury. activation of reactive oxygen species. Ischemia alone in a normal kidney is usually not sufficient to cause severe implicated factors for vasoconstriction include activation of tubuloglomerular feedback from enhanced delivery of solute to the macula densa following proximal tubule injury. The procedures most commonly associated with AKI 4/15/2015 7:55 PM .

Individuals undergoing massive fluid resuscitation for trauma. interstitium. The risk of AKI.lau. Nephrotoxic injury occurs in response to a number of pharmacologic compounds with diverse structures. Cardiopulmonary bypass is a unique hemodynamic state characterized by nonpulsatile flow and exposure of the circulation to extracorporeal circuits." is negligible in those with normal renal function but increases markedly in the setting of chronic kidney disease. As with other forms of AKI. and aortic injury with resultant atheroemboli. Major AKI risk factors are common in the population undergoing cardiac surgery.8 of 29 http://accessmedicine. The use of nephrotoxic agents including iodinated contrast for cardiac imaging prior to surgery may increase the risk of AKI. Large vessel diseases associated with AKI include renal artery dissection. dialysis-requiring AKI is uncommon except in the setting of significant preexisting chronic kidney disease. a foreign body reaction can result in intimal proliferation. thromboembolism. usually higher than 20 mmHg. and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP-HUS)]. lead to renal vein compression and reduced GFR. Longer duration of cardiopulmonary bypass is a risk factor for AKI. The pathophysiology of AKI following cardiac surgery is multifactorial. vascular procedures with aortic cross clamping. Nephrotoxin-Associated AKI The kidney has very high susceptibility to nephrotoxicity due to extremely high blood perfusion and concentration of circulating substances along the nephron where water is reabsorbed and in the medullary interstitium. malignant nephrosclerosis. More severe.. or spontaneously. Burns and Acute Pancreatitis Extensive fluid losses into the extravascular compartments of the body frequently accompany severe burns and acute pancreatitis. endogenous substances. and atheroembolic disease. risk factors for nephrotoxicity include older age. scleroderma. peaking within 3–5 days. vasculature. thrombosis. Severe AKI requiring dialysis occurs in approximately 1% of cardiac and vascular surgery procedures. diabetes mellitus. where markedly elevated intraabdominal pressures. All structures of the kidney are vulnerable to toxic injury. burns and acute pancreatitis both lead to dysregulated inflammation and an increased risk of sepsis and acute lung injury. Contrast Agents Iodinated contrast agents used for cardiovascular and CT imaging are a leading cause of AKI. all of which may facilitate the development and progression of AKI. which can also occur following percutaneous catheterization of the aorta. In addition to ischemic injury from sustained hypoperfusion. but appears to be of comparable magnitude. older age. including the tubules. In addition to severe hypovolemia resulting in decreased cardiac output and increased neurohormonal activation. accounting for the generally subacute (over a period of weeks rather than days) decline in renal function. Low fractional 4/15/2015 7:55 PM . is due to cholesterol crystal embolization resulting in partial or total occlusion of multiple small arteries within the kidney. burns. Common risk factors for postoperative AKI include underlying chronic kidney disease. and environmental exposures. affecting 25% of individuals with more than 10% total body surface area involvement. AKI from atheroembolic disease.. and renal vein compression or thrombosis. are cardiac surgery with cardiopulmonary bypass (particularly for combined valve and bypass procedures). Hypoalbuminemia may increase the risk of some forms of nephrotoxin-associated AKI due to increased free circulating drug concentrations. Patients with multiple myeloma and renal disease are particularly susceptible. radiation nephritis. interstitial. and resolving within 1 week. chronic kidney disease (CKD).lb:2048/content. and intraperitoneal often in association with congestive heart failure or other coexisting causes for ischemiaassociated AKI. cardiopulmonary bypass may cause AKI through a number of mechanisms including extracorporeal circuit activation of leukocytes and inflammatory processes. Diseases of the Microvasculature Leading to Ischemia Microvascular causes of AKI include the thrombotic microangiopathies [antiphospholipid antibody syndrome. and acute pancreatitis can also develop the abdominal compartment syndrome. The most common clinical course of contrast nephropathy is characterized by a rise in SCr beginning 24–48 hours following exposure. congestive heart failure. giant cell formation. particularly diabetic nephropathy. and emergency procedures. and endothelial cells. and further narrowing of the vascular lumen.ezproxy. and prerenal azotemia. hemolysis with resultant pigment nephropathy (see below). this results in high-concentration exposure of toxins to tubular. or "contrast nephropathy. The risk of severe AKI has been less well studied for major intra peritoneal procedures. AKI is an ominous complication of burns. Over and collecting system.

The metabolite 2-hydroxyethoxyacetic acid (HEAA) is thought to be responsible for tubular injury.9 of 29 hypocalcemia. without a significant reduction in urine volume) accompanies 10–30% of courses of aminoglycoside antibiotics. but a causal relationship with AKI has not been definitively established. Myoglobin can be released by injured muscle cells. The list of environmental toxins is likely to grow and contribute to a better understanding of previously catalogued "idiopathic" chronic tubular interstitial disease. prolonged seizure activity. heat stroke or malignant hyperthermia. Intensive hydration regimens have reduced the incidence of cisplatin nephrotoxicity. and . Antiangiogenesis agents such as . Chemotherapeutic Agents and are accumulated by proximal tubular cells and cause necrosis and apoptosis. can cause proteinuria and hypertension via injury to the glomerular microvasculature (thrombotic microangiopathy). including . present in automobile antifreeze. AKI secondary to acute interstitial nephritis can occur as a consequence of a number of antibiotics. . manifested as Type II renal tubular acidosis (Fanconi's syndrome). Nephrotoxicity from amphotericin B is dose and duration dependent. both cause tubular necrosis. Aristolochic acid was found to be the cause of "Chinese herb nephropathy" and "Balkan nephropathy" due to contamination of medicinal herbs or farming. may be associated with AKI. 4/15/2015 7:55 PM . Hypomagnesemia is a common finding. Antibiotics Several antimicrobial agents are commonly associated with AKI. . compression during coma or immobilization. Contrast nephropathy is thought to occur from a combination of factors.e. especially since the concentration of the agent within the tubule is markedly increased. Toxic Ingestions Ethylene glycol.. glycolaldehyde. (2) cytotoxic damage to the tubules directly or via the generation of oxygen free radicals. AKI typically manifests after 5–7 days of therapy and can present even after the drug has been discontinued. Clinical features of amphotericin B nephrotoxicity include polyuria.mhmedical.g. can precipitate in tubules and cause AKI by tubular obstruction.. . Rhabdomyolysis may result from traumatic crush injuries. . where concentrations can greatly exceed those of the plasma. Diethylene glycol is an industrial agent that has been the cause of outbreaks of severe AKI around the world due to adulteration of pharmaceutical preparations. excretion of sodium and relatively benign urinary sediment without features of tubular necrosis (see below) are common findings. including (1) hypoxia in the renal outer medulla due to perturbations in renal microcirculation and occlusion of small vessels. either through intratubular obstruction or possibly direct tubular toxicity..lau.ezproxy.. Nonoliguric AKI (i. and a modest decline in GFR. and (less commonly prescribed antimicrobials) are also frequently associated with AKI due to tubular toxicity. This drug binds to tubular membrane cholesterol and introduces pores. even when plasma levels are in the therapeutic range. and nongap metabolic acidosis. Amphotericin B causes renal vasoconstriction from an increase in tubuloglomerular feedback as well as direct tubular toxicity mediated by reactive oxygen species. hemoglobin. Aminoglycosides are freely filtered across the glomerulus and then accumulate within the renal cortex. and . hypomagnesemia. and (3) transient tubule obstruction with precipitated contrast material. particularly when trough levels are high. is metabolized to oxalic acid. a common diagnosis in both the developed and developing world. including myoglobin. excessive exercise. metabolic disorders (e. hypokalemia. infections. Melamine contamination of foodstuffs has led to nephrolithiasis and AKI. Other diagnostic agents implicated as a cause of AKI are high-dose gadolinium used for MRI and oral sodium phosphate solutions used as bowel purgatives. may cause hemorrhagic cystitis and tubular toxicity. Other antineoplastic agents such as mitomycin C and gemcitabine may cause thrombotic microangiopathy with resultant AKI. which may cause AKI through direct tubular injury. particularly when given as an intravenous bolus at high doses (500 mg/m2) or in the setting of hypovolemia. and hemoglobin can be released during massive hemolysis leading to pigment nephropathy. muscle ischemia during vascular or orthopedic surgery. and myeloma light chains. uric acid. Endogenous Toxins AKI may be caused by a number of endogenous compounds. but it remains a dose-limiting toxicity.

289) Postrenal AKI occurs when the normally unidirectional flow of urine is acutely blocked either partially or totally. possibly. 276).mhmedical. Other causes of lower tract obstruction are blood clots. Myeloma light chains can also cause AKI by direct tubular toxicity and by binding to Tamm-Horsfall protein to form obstructing intratubular casts. massive release of uric acid (with serum levels often exceeding 15 mg/dL) leads to precipitation of uric acid in the renal tubules and AKI (Chap. or inadvertent surgical damage). For AKI to occur in healthy individuals. metabolic. Bladder neck obstruction is a common cause of postrenal AKI and can be due to prostate disease (benign prostatic hypertrophy or prostate cancer).lb:2048/content. the most common protein in urine and produced in the thick ascending limb of the loop of Henle). calculi.g. neoplasia)..lau. thromboxane A2. Obstructed Foley catheters can cause postrenal AKI if not recognized and relieved. many drugs are also associated with the development of an allergic response characterized by an inflammatory infiltrate and often peripheral and urinary eosinophilia. neoplasia. AKI may be caused by severe infections and infiltrative diseases. or external compression (e. severe hypothyroidism). and urethral strictures. 279-5) and a reduction in NO production. or therapy with anticholinergic drugs. Pathogenic factors for AKI include intrarenal vasoconstriction. Diseases of the glomeruli or vasculature can lead to AKI by compromising blood flow within the renal circulation. and mechanical obstruction of the distal nephron lumen when myoglobin or hemoglobin precipitates with Tamm-Horsfall protein (uromodulin. infiltration of the ureteric wall (e. The tumor lysis syndrome can also occasionally occur spontaneously or with treatment for solid tumors or multiple myeloma... or inflammatory). Hypercalcemia. may cause AKI by intense renal vasoconstriction and volume depletion. blood calculi. Unilateral obstruction may cause AKI in the setting of significant underlying CKD or in rare cases from reflex vasospasm of the contralateral kidney. neurogenic bladder. in which case unilateral obstruction can cause AKI. hypophosphatemia. Postrenal Acute Kidney Injury (See also Chap. Allergic Acute Tubulointerstitial Disease and Other Causes of Intrinsic AKI While many of the ischemic and toxic causes of AKI previously described result in tubulointerstitial disease. a process favored by acidic urine. Tumor lysis syndrome may follow initiation of cytotoxic therapy in patients with high-grade lymphomas and acute lymphoblastic leukemia. Other features of tumor lysis syndrome include hyperkalemia and hyperphosphatemia. leading to increased retrograde hydrostatic pressure and interference with glomerular filtration... retroperitoneal fibrosis.ezproxy. Glomerulonephritis or vasculitis are relatively uncommon but potentially severe causes of AKI that may necessitate timely treatment with immunosuppressive agents or therapeutic plasma exchange. FIGURE 279-5 4/15/2015 7:55 PM .g. sloughed renal papillae).10 of 29 http://accessmedicine. and vasopressin. Ureteric obstruction can occur from intraluminal obstruction (e. The pathophysiology of postrenal AKI involves hemodynamic alterations triggered by an abrupt increase in intratubular pressures. abscess. which can also be seen in multiple myeloma. changes in the glomerular ultrafiltration coefficient. Obstruction to urinary flow may be caused by functional or structural derangements anywhere from the renal pelvis to the tip of the urethra (Fig. An initial period of hyperemia from afferent arteriolar dilation is followed by intrarenal vasoconstriction from the generation of angiotensin II. and myopathies (drug-induced. Reduced GFR is due to underperfusion of glomeruli and. obstruction must affect both kidneys unless only one kidney is functional. Normal urinary flow rate does not rule out the presence of partial obstruction. since the GFR is normally two orders of magnitude higher than the urinary flow rate. direct proximal tubular toxicity.

Table 279-1 Major Causes. and Diagnostic Studies for Acute Kidney Injury Etiology Clinical Features Laboratory Features Comments Prerenal azotemia History of poor fluid BUN/creatinine ratio Low FeNa. consistent with The presence of AKI is usually inferred by an elevation in the SCr of 29 http://accessmedicine..mhmedical. however. No set of tests. small.5 mL/kg per hour for longer than 6 hours. In such cases.lau. Serial blood tests showing continued substantial rise of SCr is clear evidence of AKI.. Clinical Features. The distinction between AKI and chronic kidney disease is important for proper diagnosis and treatment. but more difficult in the many instances in which the baseline is unknown. 4/15/2015 7:55 PM . See (Table 279-1) clues suggestive of chronic kidney disease can come from radiologic studies (e. can rule out AKI superimposed on CKD since AKI is a frequent complication in patients with CKD. It is important to recognize that given this definition. further complicating the distinction. some patients with AKI will not have tubular or glomerular damage (e.ezproxy. shrunken kidneys with cortical thinning on renal ultrasound.g. prerenal azotemia).3 mg/dL or 50% higher than baseline within a 24–48-hours period or a reduction in urine output to 0. Anatomic sites and causes of obstruction leading to postrenal acute kidney injury. its cause needs to be determined. Once the diagnosis of AKI is established. The distinction is straightforward when a recent baseline SCr concentration is available.. AKI is currently defined by a rise of at least 0. or evidence of renal osteodystrophy) or laboratory tests such as normocytic anemia or secondary hyperparathyroidism with hyperphosphatemia and hypocalcemia.

sepsis syndrome. or septic shock..018. CKD Urine sediment often contains granular casts. often superimposed upon sepsis and/or reasons for limited renal reserve such as older age. heart failure. absolute or postural diarrhea. Overt hypotension not always seen in mild to moderate AKI Positive culture from normally sterile body fluid. sequestration into extravascular space). BUN elevation out of proportion to creatinine may alternatively indicate upper GI bleed or increased catabolism. urinalysis heme positive with few red blood cells FeNa may be low (<1%) Anemia. Sepsis-associated AKI Sepsis. Etiology Clinical Features Laboratory Features Comments intake or fluid loss (hemorrhage. particularly early in the course. renal tubular epithelial cell casts FeNa may be low (<1%). seizures. diuretic use. NSAID/ACE-I/ARB. renal tubular epithelial cell casts. Nephrotoxin-Associated AKI: Endogenous Rhabdomyolysis Traumatic crush injuries. low jugular venous vomiting. urine sediment often contains granular casts. heart failure) above 20.ezproxy. Response to restoration of hemodynamics is most diagnostic.mhmedical. urine osmolality >500 mOsm/kg high specific gravity and osmolality may not be seen in the setting of CKD.lau. evidence of volume depletion (tachycardia. FeNa <1%. elevated LDH.12 of 29 http://accessmedicine. FeNa typically >1%. urine specific gravity > decreased effective circulatory volume (cirrhosis. hyaline casts in urine sediment. immobilization Hemolysis Recent blood transfusion with transfusion reaction Elevated myoglobin. creatine kinase. but is usually >1% and osmolality <500 mOsm/kg Ischemia-associated AKI Systemic hypotension. evaluation for transfusion 4/15/2015 7:55 PM . low haptoglobin FeNa may be low (<1%). dry mucous membranes).

often nonoliguric Urine eosinophils have limited diagnostic accuracy. cisplatin. renal tubular epithelial cell casts. 283) features include skin rash. ASO titer (abnormalities of these tests depending on etiology) Kidney biopsy may be necessary Other Causes of Intrinsic AKI Glomerulonephritis/vasculitis 4/15/2015 7:55 PM . arthralgias. lupus). decreased complement levels. AGBM recovery within 7 d FeNa may be low (<1%) Tubular injury Aminoglycoside antibiotics. kidney biopsy may be helpful Variable (Chap. FeNa typically >1%. cryoglobulins. blood culture. hepatitis serologies. low anion gap Bone marrow or renal biopsy can be diagnostic Contrast nephropathy Exposure to iodinated contrast Characteristic course is rise in SCr within 1–2 d. peak within 3–5 d.mhmedical. recent skin infection or pharyngitis (poststreptococcal) ANA. ANCA.. Etiology Clinical Features Laboratory Features Comments reaction Tumor lysis Recent chemotherapy Hyperphosphatemia.ezproxy. systemic signs of drug reaction often absent. constitutional symptoms. zoledronate Urine sediment often contains granular casts. rash arthralgias Eosinophilia. lung hemorrhage (AGBM. bone pain Monoclonal spike in urine or serum electrophoresis. sinusitis (AGBM disease).. hyperuricemia Multiple myeloma Age >60 years. tenofovir. can have fever.lau. sterile pyuria.13 of 29 http://accessmedicine. Nephrotoxin-Associated AKI: Exogenous Interstitial nephritis Recent medication exposure.

edu. anemia. elevated LDH. may have pyuria or hematuria Imaging with computed tomography or ultrasound ACE-1. palpable purpura. may occur spontaneously or after anticoagulation. retinal plaques. kidney biopsy may be necessary TTP/HUS Recent GI infection or use of calcineurin inhibitors Schistocytes on peripheral blood smear..14 of 29 http://accessmedicine. prostate disease.mhmedical.ezproxy. angiotensin receptor blocker. eosinophiluria (variable). antinuclear antibody. obstructed bladder catheter. angiotensin-converting enzyme-1. GI. TTP/HUS. often nonoliguric Urine eosinophils have limited diagnostic accuracy. infection Eosinophilia. antineutrophilic cytoplasmic antibody. sterile pyuria. NSAID. AGBM. variable amounts of proteinuria Skin or kidney biopsy can be diagnostic Postrenal AKI History of kidney stones. 4/15/2015 7:55 PM . thrombotic thrombocytopenic purpura/hemolytic uremic syndrome.lau. blood urea nitrogen. thrombocytopenia Kidney biopsy may be necessary Atheroembolic disease Recent manipulation of the aorta or other large vessels. nonsteroidal anti-inflammatory antistreptolysin O. ARB. ANA. retroperitoneal or pelvic neoplasm No specific findings other than AKI. LDH. chronic kidney disease. ANCA. fractional excretion of sodium. acute kidney injury. AKI. ASO. livedo reticularis. antiglomerular basement membrane. Etiology Clinical Features Laboratory Features Comments Interstitial nephritis Nondrug-related causes include tubulointerstitial nephritis-uveitis (TINU) syndrome. lactate dehydrogenase. GI bleed Hypocomplementemia.. CKD. gastrointestinal. BUN.

overwhelming septic shock. Red or brown urine may be seen with or without gross hematuria. Extremely heavy proteinuria ("nephrotic range. or nephrotoxicity from cisplatin or aminoglycosides. but they require clinical correlation because of generally limited sensitivity and specificity (Fig.15 of 29 http://accessmedicine. and several medications including diuretics. diarrhea. Colicky flank pain radiating to the groin suggests acute ureteric obstruction. AKI can also complicate cases of minimal change disease. if the color persists in the supernatant after centrifugation. 277). or severe proliferative glomerulonephritis or vasculitis. Preserved urine output can be seen in nephrogenic diabetes insipidus characteristic of longstanding urinary tract obstruction. and ARBs. Definitive diagnosis of obstruction requires radiologic investigations. and physical examination often narrow the differential diagnosis for the cause of AKI. NSAIDs. decreased skin turgor. History and Physical Examination The clinical context. Nocturia and urinary frequency or hesitancy can be seen in prostatic disease. tubulointerstitial disease. lower GFR) than when urine output is preserved. severe ischemia (often with cortical necrosis). a cause of the nephrotic syndrome (Chap. however. renal artery occlusion. Not only are medications frequently a cause of AKI but doses of administered medications must be adjusted for estimated GFR. nephrolithiasis. Physical signs of orthostatic hypotension. Atheroembolic disease can be associated with livedo reticularis and other signs of emboli to the legs. tachycardia. AKI from ischemia or nephrotoxins leads to mild proteinuria (<1 g/d). the latter are not detected with conventional urine dipsticks (which detect albumin) and require the sulfosalicylic acid test or immunoelectrophoresis.lau. Urine Findings Complete anuria early in the course of AKI is uncommon except in the following situations: complete urinary tract obstruction. Prerenal azotemia should be suspected in the setting of vomiting.5 g/d) can occasionally be seen in glomerulonephritis. Whether or not symptoms are present early during obstruction of the urinary tract depends on the location of obstruction. AKI accompanied by palpable purpura. In the absence of preexisting proteinuria from CKD. A reduction in urine output (oliguria. Idiosyncratic reactions to a wide variety of medications can lead to allergic interstitial nephritis. and a pruritic erythematous rash. A history of prostatic disease. 279-6) (Chap. FIGURE 279-6 4/15/2015 7:55 PM .lb:2048/content. reduced jugular venous pressure. Oliguria is associated with worse clinical outcomes. or interstitial nephritis (particularly from NSAIDs). pulmonary hemorrhage. does not exclude the diagnosis of interstitial nephritis. The urinalysis and urine sediment examination are invaluable tools. A careful review of all medications is imperative in the evaluation of an individual with AKI. Abdominal fullness and suprapubic pain can accompany massive bladder enlargement.. glycosuria causing careful history taking. then pigment nephropathy from rhabdomyolysis or hemolysis should be suspected.. among other causes. Atheroemboli can cause a variable degree of proteinuria. then rhabdomyolysis or hemolysis should be suspected.ezproxy. and dry mucous membranes are often present in prerenal azotemia.mhmedical.e. defined as <400 mL/24 h) usually denotes more significant AKI (i. ACE inhibitors. which requires measurement of bladder pressure. arthralgias. Signs of limb ischemia may be clues to the diagnosis of rhabdomyolysis. or pelvic or paraaortic malignancy would suggest the possibility of postrenal AKI. Greater proteinuria in AKI suggests damage to the glomerular ultrafiltration barrier or excretion of myeloma light chains. e14)." >3. If the dipstick is positive for hemoglobin but few red blood cells are evident in the urine sediment. A tense abdomen should prompt consideration of acute abdominal compartment syndrome. which may be accompanied by fever. or sinusitis raises the possibility of systemic vasculitis with glomerulonephritis. The absence of systemic features of hypersensitivity..

RTE. cystitis. although severe AKI with rapid increases in SCr can occur in this setting. 4th] Prerenal azotemia may present with hyaline casts or an unremarkable urine sediment exam. It is not related to an effect of AKI solely on production of red blood cells since this effect in isolation takes longer to manifest. or thrombotic microangiopathy (e. pyelonephritis. however... and hypocalcemia. Postrenal AKI may also lead to an unremarkable sediment. the rise in SCr is characteristically delayed for 4–5 days to 2 weeks after initial exposure. renal tubular epithelial. Creatinine 4/15/2015 7:55 PM . Interpretation of urinary sediment findings in acute kidney however. Philadelphia. Glomerulonephritis may lead to dysmorphic red blood cells or red blood cell casts.lau. Contrast nephropathy leads to a rise in SCr within 24–48 hours. GN. These findings may be absent in more than 20% of cases. HUS or TTP). but hematuria and pyuria may be seen depending on the cause of obstruction. AKI often leads to hyperkalemia. and resolution within 5–7 A complete blood count may provide diagnostic clues. atheroembolic disease. and low haptoglobin content.ezproxy. and a diagnosis is not always possible on the basis of the urine sediment alone. or certain nephrotoxins has characteristic urine sediment findings: pigmented "muddy brown" granular casts and tubular epithelial cell casts. 2010. Crystalluria may be important diagnostically. In comparison. hyperphosphatemia. suggests rhabdomyolysis or the tumor lysis syndrome. peak within 3–5 days. sepsis. [Adapted from L Yang.16 of 29 http://accessmedicine. Urine eosinophils have a limited role in differential diagnosis. they can be seen in interstitial nephritis. In Comprehensive Nephrology. The urine sediment findings overlap somewhat in glomerulonephritis and interstitial nephritis. and Churg-Strauss vasculitis. JV Bonventre: Diagnosis and clinical evaluation of acute kidney injury.mhmedical. J Floege et al (eds). or glomerulonephritis. Prerenal azotemia typically leads to modest rises in SCr that return to baseline with improvement in hemodynamic status. Elsevier. The finding of oxalate crystals in AKI should prompt an evaluation for ethylene glycol toxicity. Anemia is common in AKI and is usually multifactorial in origin. atheroembolic disease usually manifests with more subacute rises in SCr. glomerulonephritis. Severe anemia in the absence of bleeding may reflect hemolysis.. schistocytes on peripheral blood smear. Peripheral eosinophilia can accompany interstitial nephritis. multiple myeloma. Interstitial nephritis may lead to white blood cell casts.g. AKI from ATN due to ischemic injury. Marked hyperphosphatemia with accompanying hypocalcemia. Abundant uric acid crystals may be seen in the tumor lysis syndrome. Blood Laboratory Findings Certain forms of AKI are associated with characteristic patterns in the rise and fall of SCr. atheroembolic disease. Other laboratory findings of thrombotic microangiopathy include thrombocytopenia. polyarteritis nodosa. elevated lactate dehydrogenase level. With many of the epithelial cell toxins such as aminoglycoside antibiotics and cisplatin.

. GFR. and. hippurate. The fractional excretion of sodium (FeNa) is the fraction of the filtered sodium load that is reabsorbed by the tubules and is a measure of both the kidney's ability to reabsorb sodium as well as endogenously and exogenously administered factors that affect tubular reabsorption. In the patient not taking diuretics and with good baseline kidney function. As such. Imaging may also provide additional helpful information about kidney size and echogenicity to assist in the distinction between acute versus CKD. Several causes of ischemia-associated and nephrotoxin-associated AKI can present with FeNa below 1%. the FeNa may be below 1%. effective intravascular volume. hyperalimentation.lau. With prerenal and cryoglobulins. Simple bladder catheterization can rule out urethral obstruction. HIV-associated nephropathy. If a high clinical index of suspicion for obstruction persists despite normal imaging. Other causes of disproportionate BUN elevation need to be kept in mind. Findings of obstruction include dilation of the collecting system and hydroureteronephrosis. Low FeNa is therefore suggestive but not synonymous with effective intravascular volume depletion. a rare but serious complication seen most commonly in patients with end-stage renal disease. and should not be used as the sole guide for volume management. and also early in the course of obstruction. however. Imaging of the urinary tract with renal ultrasound or CT should be undertaken to investigate obstruction in individuals with AKI unless an alternate diagnosis is apparent. rhabdomyolysis.mhmedical. baseline concentrating defects may exist. and glucocorticoid use. Vascular imaging may be useful if venous or arterial obstruction is suspected. resulting in urine osmolality below 350 mOsm/kg. The response of urine output to crystalloid or colloid fluid administration may be both diagnostic and therapeutic in prerenal azotemia.. should not be taken as prima facie evidence of prerenal azotemia. Renal Failure Indices Several indices have been used to help differentiate prerenal azotemia from intrinsic AKI when the tubules are malfunctioning. Obstruction can be present without radiologic abnormalities in the setting of volume depletion. The co-occurrence of an increased anion gap and an osmolal gap may suggest ethylene glycol poisoning. but the finding is not specific. however. Large kidneys observed in these studies suggest the possibility of diabetic nephropathy. the FeNa is frequently above 1% because of tubular injury and resultant inability to reabsorb sodium. Laboratory blood tests helpful for the diagnosis of glomerulonephritis and vasculitis include depressed complement levels and high titers of antinuclear antibodies (ANAs).edu. The FeNa may also be above 1% despite hypovolemia due to treatment with diuretics.ezproxy. retroperitoneal fibrosis. hence. The anion gap may be increased with any cause of uremia due to retention of anions such as phosphate. Radiologic Evaluation Postrenal AKI should always be considered in the differential diagnosis of AKI because treatment is usually successful if instituted early. suggesting avid tubular sodium reabsorption. or occasionally acute interstitial nephritis. and intact tubular reabsorptive mechanisms. sulfate. infiltrative diseases. MRI with gadolinium-based contrast agents should be avoided if possible in severe AKI due to the possibility of inducing nephrogenic system fibrosis. urine osmolality may be above 500 mOsm/kg in prerenal including upper gastrointestinal bleeding. In ischemic AKI. Low anion gap may provide a clue to the diagnosis of multiple myeloma due to the presence of unmeasured cationic proteins. In patients with CKD. 4/15/2015 7:55 PM . consistent with an intact medullary gradient and elevated serum vasopressin levels causing water reabsorption resulting in concentrated urine. antiglomerular basement membrane (AGBM) antibodies. and contrast nephropathy. antegrade or retrograde pyelography should be performed. The ability of the kidneys to produce a concentrated urine is dependent upon many factors and reliant on good tubular function in multiple regions of the kidney. however. increased tissue catabolism. Loss of concentrating ability is common in septic or ischemic AKI. The low tubular flow rate and increased recycling of urea seen in prerenal azotemia may cause a disproportionate elevation of the BUN compared to creatinine. but the risks of contrast administration should be kept in mind. making urinary osmolality unreliable in many instances. while tumor lysis syndrome shows normal or marginally elevated creatine kinase and markedly elevated serum uric acid. encasement with tumor. including sepsis (often early in the course). In elderly patients and those with CKD. a FeNa significantly above 1% can still be present despite a prerenal state. antineutrophilic cytoplasmic antibodies (ANCAs). which may also cause oxalate crystalluria. and urate. it depends on sodium intake. Low FeNa is often seen in glomerulonephritis (and other disorders).17 of 29 http://accessmedicine. phosphokinase levels and serum uric acid are elevated in rhabdomyolysis.

Kidney biopsy is associated with a risk of bleeding. human ELISA Mouse. NGAL is highly upregulated after inflammation and kidney injury and can be detected in the plasma and urine within 2 hours of cardiopulmonary bypass–associated AKI. Proximal tubule brush border enzyme Detection Species Colorimetry Rat. Levels may not correlate with extent of functional injury 3. and other possible diagnoses are being considered such as glomerulonephritis. Table 279-2 Biomarkers of Acute Kidney Injury Biomarker Alanine aminopeptidase (AAP) Alkaline phosphatase (AP) Comments 1. BUN and creatinine are also relatively slow to rise after kidney Several novel kidney injury biomarkers have been investigated and show great promise for the early and accurate diagnosis of AKI. human Colorimetry Rat. therefore. human 2. is a type 1 transmembrane protein that is abundantly expressed in proximal tubular cells injured by ischemia or nephrotoxins such as cisplatin. HUS and TTP. and allograft dysfunction. postrenal AKI.lau.. NGAL can bind to iron siderophore complexes and may have tissue-protective effects in the proximal tubule. myeloma kidney. The results of kidney biopsy can provide definitive diagnostic and prognostic information about acute and CKDs. Kidney Biopsy If the cause of AKI is not apparent based on the clinical context. human tissue nonspecific alkaline phosphatase is specific for S1 and S2 segments The procedure is most often used in AKI when prerenal azotemia.mhmedical. which can be severe and organ or life threatening in patients with thrombocytopenia or coagulopathy. Proximal tubule brush border enzyme. Requires stabilization buffer for specimen storage and processing 4/15/2015 7:55 PM . KIM-1 is not expressed in appreciable quantities in the absence of tubular injury or in extrarenal tissues. enabling them to clear debris from the tubular lumen after kidney injury. dog. may be suboptimal for the diagnosis of actual parenchymal kidney damage.18 of 29 http://accessmedicine. therefore. Proximal tubule cytosolic enzyme 2. also known as lipocalin-2 or siderocalin) is another leading novel biomarker of vasculitis.. physical examination. kidney biopsy should be considered. interstitial nephritis. KIM-1 can be detected shortly after ischemic or nephrotoxic injury in the urine and. ( . may be an easily tested biomarker in the clinical setting. and laboratory studies. KIM-1's functional role may be to confer phagocytic properties to tubular cells. Instability may limit clinical utility α-Glutathione-transferase (α-GST) 1.ezproxy. rat. Novel Biomarkers BUN and creatinine are functional biomarkers of glomerular filtration rather than tissue injury biomarkers and. NGAL was first discovered as a protein in granules of human neutrophils. Other injury markers that are being studied in an attempt to increase the early recognition of injury and predict the outcome in AKI are listed in Table 279-2. Instability may limit clinical utility 1. and ischemic or nephrotoxic AKI have been deemed unlikely. Human intestinal alkaline phosphatase is specific for proximal tubular S3 segment.

Extensive preclinical and clinical data in a variety of conditions (nephrotoxicant exposure.19 of 29 http://accessmedicine.) 4. Instability requires samples to be analyzed quickly after collection. Early marker of tubular dysfunction. human 4/15/2015 7:55 PM . human 4. Synthesized by liver.. More stable than other urinary enzymes -Acetyl-β-(D) glucosaminidase (NAG) 3. Synthesized by the liver 2. Instability in acidic urine limits clinical utility human Colorimetry Mouse. rat. Upregulated in AKI and renal cell carcinoma γ-Glutamyl transpeptidase (γGT) 1.. Endogenous urea may inhibit activity 1.ezproxy. human 4. Monomeric form is filtered by the glomerulus and reabsorbed by the proximal tubule cells 3. etc. human 3. Early marker of tubular dysfunction in a variety of conditions ELISA Nephelometry Mouse. high levels may predict poorer outcome ELISA Nephelometry Mouse. limiting clinical utility 1. involved in vitamin A transport ELISA Mouse.mhmedical. delayed renal allograft function. Filtered by the glomerulus and reabsorbed by proximal tubule cells α1-Microglobulin 3. Light chain of the MHC I molecule expressed on the cell surface of all nucleated cells β2-Microglobulin 2. Proximal tubule lysosomal enzyme Stable across physiologic urinary pH Retinol-binding protein 1. Proximal tubule brush border enzyme 2. rat. Biomarker Comments Detection Species Colorimetry Rat. cardiopulmonary bypass. rat. rat.

20 of 29 http://accessmedicine. Elevated urinary levels may be indicative of proximal tubular damage ELISA Immunoturbidimetry Mouse. human Mouse. Filtered by the glomerulus and reabsorbed by proximal tubule cells human 3. Lack of specificity for AKI may limit its utility 1. Upregulated in various rodent 4/15/2015 7:55 PM . Biomarker Comments Detection Species 2. Increased stability in acidic urine when compared to β2-microglobulin 1. fibrosis. renal cell carcinoma. and polycystic kidney disease 1. rat. dog. Expressed on dedifferentiated proximal tubular epithelial cells Clusterin 2. Luminex®-based assay Zebrafish. Elevated urinary levels are highly sensitive and specific for AKI ELISA. Early marker of tubular dysfunction Nephelometry rat. Established marker for monitoring progression of chronic kidney disease Microalbumin 2. Important extracellular inhibitor of cysteineproteases Cystatin C 2. Elevated kidney and urinary levels are very sensitive for AKI in preclinical models ELISA Mouse.lau. rat. rat.. human 4. Type-1 cell membrane glycoprotein upregulated in dedifferentiated proximal tubule epithelial cells Kidney injury molecule-1 (KIM-1) 2. Filtered by glomerulus and reabsorbed by proximal tubule cells 3.. Elevated urinary levels reflect tubular dysfunction. monkey. dog.ezproxy. Ectodomain is shed and can be quantitated in urine following AKI in preclinical and clinical studies 3. high levels may predict poorer outcome ELISA Nephelometry 1.mhmedical. monkey. Upregulated following various models of preclinical and clinical AKI. mouse. monkey. human 3.

rat. but also may be induced in epithelial cells in the setting of inflammation or malignancy Neutrophil gelatinase associated lipocalin (NGAL) Urinary levels decrease rapidly in spite of progression of injury indicating stability issue Western blot Mouse. Induced in proximal straight tubules of kidney and secreted in the urine within 3–6 h following ischemic kidney injury Cysteine-rich protein (CYR-61) 2. Constitutively expressed in distal tubules. and polycystic kidney disease 4.ezproxy.lau. particularly in setting of ischemic injury Interleukin-18 (IL-18) 2. Biomarker Comments Detection Species models of AKI. rat. No clinical study demonstrating its use 4..mhmedical. Expression upregulated in kidney proximal tubule cells and urine following ischemic or cisplatin induced renal injury ELISA Luminex®-based assay Mouse..21 of 29 http://accessmedicine. human 3. No quantitative method 4/15/2015 7:55 PM . No clinical study demonstrating its use 1. human 3. rat. Specificity for AKI in setting of sepsis and pyuria need to be further established renal cell carcinoma. Found to be an early indicator of AKI following cardiopulmonary bypass 4. Initially identified bound to gelatinase in specific granules of the neutrophils. strong immunoreactivity in proximal tubules with transplant rejection ELISA Luminex®-based assay Mouse. human 3. Elevated urinary levels found to be early marker of AKI and independent predictor of mortality in critically ill patients 1. fibrosis. Cytokine with broad immunomodulatory properties.

ezproxy. Additional studies necessary to determine utility in setting of preclinical and clinical AKI 4/15/2015 7:55 PM . Samples require considerable processing. Current evidence suggests clinical utility as a biomarker in CKD and diabetic nephropathy Urinary levels found to discriminate between prerenal azotemia and AKI in ICU patients 3. Expressed in proximal tubule epithelial cells Liver fatty acid–binding protein (L-FABP) 2. Additional studies necessary to determine utility in setting of preclinical and clinical AKI 1. human Immunoblotting Rat. rat.. human ELISA Mouse. limiting assay throughput 1. Acute phase protein synthesized in the liver and secreted into the circulation 2. rat. Upregulated in various rodent models of AKI Osteopontin 2. limiting assay throughput 5.lau. Levels in proximal tubule cell cytoplasm correspond to degree of injury Exosomal fetuin-A 3. No clinical study demonstrating its use 1. The induction correlates with inflammation and tubulointerstitial fibrosis 3. Samples require considerable processing.22 of 29 http://accessmedicine. Most abundant sodium transporter in the renal tubule Sodium/hydrogen exchanger isoform (NHE3) rat. Urinary levels found to be much higher in ICU patients with AKI compared to ICU patients without AKI and healthy volunteers 4. human established 1. human Immunoblotting Mouse.mhmedical. Biomarker Comments Detection Species ELISA Mouse.

com. and pulmonary edema. due to impaired salt and water excretion. Recovery from AKI can sometimes be accompanied by increased jugular venous pressure. The more serious complication of hyperkalemia is due to effects on cardiac conduction.ezproxy. and depend on the severity of AKI and other associated conditions. renal cell carcinoma. acute kidney injury. and can further complicate acid-base and potassium balance in individuals with other causes of acidosis. particularly early in the course. manifested as an elevated BUN concentration. and acid-base balance. Marked hyperkalemia is particularly common in rhabdomyolysis. Mild to moderate AKI may be entirely asymptomatic. intensive care unit. leading to potentially fatal arrhythmias. which. if untreated. Acidosis Metabolic acidosis. if severe. Frequently the most concerning complication of AKI is hyperkalemia. ELISA.lau. which. Few of the many possible uremic toxins have been definitively identified. is common in AKI. Hyperphosphatemia and Hypocalcemia AKI can lead to hyperphosphatemia. The polyuric phase of recovery may be due to an osmotic diuresis from retained urea and other waste products as well as delayed recovery of tubular reabsorptive functions. usually accompanied by an elevation in the anion gap. Other toxins normally cleared by the kidney may be responsible for the symptom complex known as uremia. the latter can be life threatening. RCC. and tumor lysis syndrome due to release of intracellular potassium from damaged cells. or respiratory acidosis. and for excretion of nitrogenous and other waste products. dependent edema. AKI. mental status changes and bleeding complications can arise. Hyponatremia Administration of excessive hypotonic crystalloid or isotonic dextrose solutions can result in hypoosmolality and hyponatremia. ICU. At higher concentrations. including seizures. particularly in highly catabolic patients or those with AKI from rhabdomyolysis. plasma electrolyte composition. can cause neurologic abnormalities. AKI may also induce or exacerbate acute lung injury characterized by increased vascular permeability and inflammatory cell infiltration in lung parenchyma. 4/15/2015 7:55 PM . Uremia Buildup of nitrogenous waste products. Potassium affects the cellular membrane potential of cardiac and neuromuscular tissues. BUN itself poses little direct toxicity at levels below 100 mg/dL. Hypervolemia and Hypovolemia Expansion of extracellular fluid volume is a major complication of oliguric and anuric AKI. is a hallmark of AKI. protean. due in part to differences in urea and creatinine generation rates across individuals. Muscle weakness may be a symptom of hyperkalemia. diabetic ketoacidosis. Pulmonary edema can also occur from volume overload and hemorrhage in pulmonary renal syndromes. Complications associated with AKI are..mhmedical.23 of 29 including sepsis. therefore. The correlation of BUN and SCr concentrations with uremic symptoms is extremely variable. can lead to significant volume depletion.. The kidney plays a central role in homeostatic control of volume status. blood pressure. hemolysis. enzyme-linked immunosorbent assay. Hyperkalemia Abnormalities in plasma electrolyte composition can be mild or life threatening. The result can be weight gain.

Cardiac Complications The major cardiac complications of AKI are arrhythmias. Direct hematologic effects from AKI-related uremia include decreased erythropoiesis and platelet dysfunction. Table 279-3 Management of Ischemia. therefore. Metastatic deposition of calcium phosphate can lead to hypocalcemia. Infections Infections are a common precipitant of AKI and also a dreaded complication of Common causes of AKI such as sepsis and ischemic ATN.and Nephrotoxin-Associated AKI General Issues 1. Bleeding Hematologic complications of AKI include anemia and bleeding. and prolongation of the QT interval on electrocardiography..lau. carpopedal spasms. ACE inhibitors. Initiation of renal replacement therapy when indicated Specific Issues 1. some patients with AKI do not recover fully and may remain dialysis Tumor lysis syndrome: allopurinol or rasburicase 2. discontinuation of nephrotoxic medications. and pericardial effusion. both of which are exacerbated by coexisting disease processes such as sepsis. or ionized calcium levels should be followed. seizures. muscle cramps. and tumor lysis syndrome. aminoglycosides) if possible 3. liver disease. Elimination of nephrotoxic agents (e. Treatment: Acute Kidney Injury Prevention and Treatment The management of individuals with and at risk for AKI varies according to the underlying cause (Table 279-3). Impaired host immunity has been described in end-stage renal disease and may be operative in severe AKI. malnutrition is a major complication. asymptomatic hypocalcemia does not require treatment. Volume overload 4/15/2015 7:55 PM .ezproxy. do not yet have specific therapies once injury is established. Hypocalcemia is often asymptomatic but can lead to perioral paresthesias. Common to all are several principles. Calcium levels should be corrected for the degree of hypoalbuminemia. The kidney possesses remarkable capacity to repair itself after even severe. However. Malnutrition AKI is often a severely hypercatabolic state.. AKI-associated hypocalcemia may also arise from derangements in the vitamin D–parathyroid axis. and dose adjustment of administered medications are all Nephrotoxin-specific     a. NSAIDs. but meticulous clinical attention is needed to support the patient until (if) AKI resolves. and.24 of 29 http://accessmedicine. Mild.mhmedical. Optimization of systemic and renal hemodynamics through volume resuscitation and judicious use of vasopressors 2. pericarditis. and disseminated intravascular coagulation. Optimization of hemodynamics.. correction of fluid and electrolyte imbalances. hemolysis. if present. Rhabdomyolysis: consider forced alkaline diuresis     b.g. dialysis-requiring AKI. ARBs.

adjustment for degree of renal failure ACE. Hypermagnesemia     a.g.mhmedical. ACE inhibitors. Restriction of enteral free water intake. Phosphate binding agents (calcium acetate. Salt and water restriction     b.lau.ezproxy. Renal replacement therapy 6. Hyperuricemia     a. Discontinue Mg2+ containing antacids Ultrafiltration Hypocalcemia     a. angiotensin-converting enzyme.     a. NSAIDs     c.2 to keep serum bicarbonate >15 mmol/L)     b. minimization of hypotonic intravenous solutions including those containing dextrose 4. Acute treatment is usually not required except in the setting of tumor lysis syndrome (see above) 10. Sodium bicarbonate (if pH <7. Insulin (10 units regular) and glucose (50 mL of 50% dextrose) to promote entry of potassium intracellularly     f.. Discontinuation of potassium-sparing diuretics. Diuretics     c. Hyperphosphatemia     a. Metabolic acidosis     a. Restriction of dietary potassium intake     b. Hyperkalemia     a. THAM     c.. Calcium carbonate or calcium gluconate if symptomatic 8. Loop diuretics to promote urinary potassium loss     d. Nutrition     a. sevelamer hydrochloride.. Calcium gluconate or calcium chloride (1 g) to stabilize the myocardium 5. Careful attention to dosages and frequency of administration of drugs. Sufficient protein and calorie intake to avoid negative nitrogen balance 11. Drug dosing     a. Restriction of dietary phosphate intake of 29 http://accessmedicine. Hyponatremia     a. ARBs. Potassium binding ion-exchange resin (sodium polystyrene sulfonate)     e. Inhaled beta-agonist therapy to promote entry of potassium intracellularly     g. aluminum hydroxide—taken with meals) 7. Administration of other bases e. ARBs. angiotensin 4/15/2015 7:55 PM .

There is no specific therapy for established AKI in rhabdomyolysis. 277). Isotonic crystalloid and/or colloid should be used for less severe acute hemorrhage or plasma loss in the case of burns and pancreatitis. calcium channel blockers. ascites. Administration of intravenous fluids as a volume challenge may be required diagnostically as well as therapeutically. AKI due to acute glomerulonephritis or vasculitis may respond to immunosuppressive agents and/or plasmapheresis (Chap.. renal hypoperfusion from poor cardiac output) may require use of inotropic agents. combination therapy with octreotide (a somatostatin analog) and midodrine (an α1-adrenergic agonist). AKI due to scleroderma (scleroderma renal crisis) should be treated with ACE inhibitors. Most studies have enrolled patients with severe and well-established AKI. however. but not tested in randomized trials. loop diuretics.9% saline may lead to hyperchloremic metabolic acidosis. 75 mmol sodium bicarbonate added to 0. and mechanical aids such as an intraaortic balloon pump.g. preload.. in cases where AKI persists or worsens despite discontinuation of the suspected medication. Diuretics may be used if fluid repletion is adequate but unsuccessful in achieving urinary flow rates of 200–300 mL/h. Allergic interstitial nephritis due to medications requires discontinuation of the offending agent. endothelin low-dose dopamine. and norepinephrine.26 of 29 http://accessmedicine.. Isotonic crystalloid (e. other than dialysis in severe cases or general supportive care to maintain fluid and electrolyte balance and tissue Crystalloid solutions are less expensive and probably equally efficacious as colloid solutions. Postrenal AKI 4/15/2015 7:55 PM . Albumin may prevent AKI in those treated with antibiotics for spontaneous bacterial peritonitis. NSAIDs. Early and aggressive volume repletion is mandatory in patients with rhabdomyolysis. antioxidants. Severe acute blood loss should be treated with packed red blood cells. receptor blocker. 0. TRAM.45% saline) suffice for less severe hypovolemia. but carry the risk of worsening hypocalcemia. tris (hydroxymethyl) aminomethane. dextrose water with 150 mEq sodium bicarbonate) should be used if metabolic acidosis is a concern.9% saline) or colloid should be used for volume resuscitation in severe hypovolemia. Bridge therapies that have shown promise include terlipressin (a vasopressin analog). Peritonitis should be ruled out by culture of ascitic fluid. and insulin-like growth factor and many others. Prerenal Azotemia Prevention and treatment of prerenal azotemia requires optimization of renal perfusion.g. maximum 100 g/d). Novel kidney injury biomarkers may provide an opportunity to test agents earlier in the course of AKI.mhmedical. Careful attention must be focused on calcium and phosphate status because of precipitation in damaged tissue and released when the tissue heals. Optimization of cardiac function in the cardiorenal syndrome (i. antiarrhythmic drugs. Cirrhosis and Hepatorenal Syndrome Fluid management in individuals with cirrhosis.lau. prostaglandin analogs. Crystalloid has been reported to be preferable to albumin in the setting of traumatic brain injury. who may require 10 L of fluid per day.g. These include atrial natriuretic peptide. Excessive chloride administration from 0.45% saline) may be beneficial in preventing tubular injury and cast formation. antibodies against leukocyte adhesion molecules.. Intrinsic AKI Several agents have been tested and have failed to show benefit in the treatment of ischemic acute tubular injury.. and treatment may have been initiated too late. Alkaline fluids (e.and afterload-reducing agents. nonsteroidal anti-inflammatory drug. The composition of replacement fluids should be targeted to the type of fluid lost. whereas hypotonic crystalloids (e. Use of bicarbonate-containing solutions (e.. all in combination with intravenous albumin (25–50 mg per day. α-adrenergic receptor blockers. Glucocorticoids have been used. 0. result in worsening ascites and pulmonary compromise in the setting of hepatorenal syndrome or AKI due to superimposed spontaneous bacterial peritonitis.. Invasive hemodynamic monitoring to guide therapy may be necessary. The definitive treatment of the hepatorenal syndrome is orthotopic liver transplantation.ezproxy. Excessive volume administration may. and AKI is challenging because of the frequent difficulty in ascertaining intravascular volume status.g.

lb:2048/content. Acidosis can be treated with oral or intravenous sodium bicarbonate (Chap. hyperkalemia. Because of the risk of arrhythmias and potential bowel ischemia. with the attendant risks of infection.27 of 29 http://accessmedicine. The site of obstruction defines the treatment approach. Ureteric obstruction may be treated by percutaneous nephrostomy tube placement or ureteral stent placement. encephalopathy. The initiation of dialysis should not await the development of a life-threatening complication of renal failure. On the other hand. procedural 45. and metabolic complications of AKI. uremic bleeding). and volume overload. severe polyuria persists due to tubular dysfunction and may require continued administration of intravenous fluids and electrolytes for a period of time. Diuretic therapy should be stopped if there is no response. furosemide may be given as a bolus (200 mg) followed by an intravenous drip (10–40 mg/h). The timing of dialysis is still a matter of debate. Prompt recognition and relief of urinary tract obstruction can forestall the development of permanent structural damage induced by urinary stasis. 47). hypocalcemia.. Total parenteral nutrition requires large volumes of fluid administration and may complicate efforts at volume control.Metabolic acidosis is not treated unless severe (pH <7.20 and serum bicarbonate <15 mmol/L). Relief of obstruction is usually followed by an appropriate diuresis for several days. Excessive nutrition may increase the generation of nitrogenous waste and lead to worsening azotemia. Hypocalcemia does not usually require therapy unless symptoms are present. There is no evidence that increasing urine output itself improves the natural history of AKI. but may require dialysis in the case of longstanding or severe uremia.mhmedical. calcium acetate. Gastrointestinal prophylaxis with proton pump inhibitors or histamine (H2) receptor blockers is required. Dopamine in low doses may transiently increase salt and water excretion by the kidney in prerenal states. Uremic bleeding may respond to desmopressin or estrogens. particularly in the setting of multisystem organ failure. with or without a thiazide diuretic. ELECTROLYTE AND ACID-BASE ABNORMALITIES The treatment of dysnatremias and hyperkalemia is described in Chap.lau. ANEMIA The anemia seen in AKI is usually multifactorial and is not improved by erythropoiesis stimulating agents. hypokalemia. acidosis. Late initiation of dialysis carries the risk of avoidable volume. pericardial rub or effusion. Venous thromboembolism prophylaxis is important and should be tailored to the clinical setting. Many nephrologists initiate 4/15/2015 7:55 PM . and when there are severe complications of uremia (asterixis. Fluid and sodium should be restricted.ezproxy. bleeding. in some toxic ingestions. initiating dialysis too early may unnecessarily expose individuals to intravenous lines and invasive procedures. MALNUTRITION Protein energy wasting is common in AKI. In rare cases. Supportive Measures Volume Management Hypervolemia in oliguric or anuric AKI may be life threatening due to acute pulmonary edema. Transurethral or suprapubic bladder catheterization may be all that is needed initially for urethral strictures or functional bladder impairment. and AKI likely increases pulmonary vascular permeability. low-molecular-weight heparins and factor Xa inhibitors have unpredictable pharmacokinetics in severe AKI and should be avoided. and hypotension. or aluminum hydroxide). sevelamer. and diuretics may be used to increase the urinary flow rate. but diuretics may help to avoid the need for dialysis in some cases.. Dialysis Indications and Modalities (See also Chap. Inadequate nutrition may lead to starvation ketoacidosis and protein catabolism. it has been argued that the risks of dopamine may outweigh the benefits in the treatment or prevention of AKI. 281) Dialysis is indicated when medical management fails to control volume but clinical trials have failed to show any benefit in patients with intrinsic AKI. but overcorrection should be avoided because of the possibility of metabolic alkalosis. especially since many patients have coexisting pulmonary disease. due to their delayed onset of action and the presence of bone marrow resistance in critically ill patients. In severe cases of volume overload. Hyperphosphatemia is common in AKI and can usually be treated by limiting intestinal absorption of phosphate using phosphate binders (calcium carbonate. electrolyte.

osmolarity. Hemodialysis can be employed intermittently or continuously. One of the major complications of hemodialysis is hypotension. three to four times per week. the plasma water is then replaced by a physiologic crystalloid solution. If available. The kidneys may recover even after severe. or subclavian veins. diffusive clearance. and is the most common form of renal replacement therapy for AKI.. a newer form of therapy has been introduced. Survivors of an episode of AKI requiring temporary dialysis.ezproxy. Studies have failed to show that continuous therapies are superior to intermittent therapies. Patients with AKI are more likely to die prematurely after they leave the hospital even if their kidney function has recovered. a technology similar to hemodialysis except at lower blood flow and dialysate flow rates. Vascular access is through the femoral. typically due to high concentrations of dextrose in the dialysate. internal jugular. Peritoneal dialysis is performed through a temporary intraperitoneal catheter. It is rarely used in the United States for AKI in adults but has enjoyed widespread use internationally. with the exception of the cardiorenal and hepatorenal syndromes. The development of AKI is associated with a significantly increased risk of in-hospital and long-term mortality. Postdischarge care under the supervision of a nephrologist for aggressive secondary prevention of kidney disease is prudent. particularly in the critically Hemodialysis is performed 3–4 h per d. Contrib Nephrol 165:9. CRRT is often preferred in patients with severe hemodynamic instability. or significant volume Small solutes are removed across a semipermeable membrane down their concentration gradient ("diffusive" clearance) and/or along with the movement of plasma water ("convective" clearance). cerebral edema. The optimal dose of dialysis for AKI is not clear. hemofiltration. Bonventre JV: Pathophysiology of AKI: Injury and normal and abnormal repair. ultrafiltration of water is achieved by the presence of an osmotic gradient across the peritoneal membrane. and increased costs. it is often better tolerated than intermittent procedures like hemodialysis in hypotensive patients. blood flow and dialysate flow are higher than in CVVHD. are at extremely high risk for progressive CKD. The available modes for renal replacement therapy in AKI require either access to the peritoneal cavity (for peritoneal dialysis) or the large blood vessels (for hemodialysis. but the treatment time is reduced to 12 h.lau. CRRT can also be performed by diffusive clearance [continuous venovenous hemodialysis (CVVHD)]. Continuous renal replacement therapy (CRRT) can be performed by convective clearance [continuous venovenous hemofiltration (CVVH)]. particularly when hemodialysis technology is not available. Hemodialysis is an intermittent procedure that removes solutes through diffusive and convective clearance. Being a continuous procedure. Prerenal azotemia.mhmedical. A hybrid therapy combines both diffusive and convective clearance [continuous venovenous hemodiafiltration (CVVHDF)]. but care should be taken to avoid undertreatment. and other hybrid procedures).. The choice of modality is often dictated by the immediate availability of technology and the expertise of medical staff. and up to 10% may develop end-stage renal disease.28 of 29 http://accessmedicine. Continuous intravascular procedures were developed in the early 1980s to treat hemodynamically unstable patients without inducing the rapid shifts of volume. Dialysate solution is instilled into and removed from the peritoneal cavity at regular intervals in order to achieve diffusive and convective clearance of solutes across the peritoneal membrane. In this therapy. termed slow low-efficiency dialysis (SLED) or extended daily dialysis (EDD). Daily intermittent hemodialysis and high-dose CRRT do not confer a demonstrable survival or renal recovery advantage. dialysis-requiring AKI. Peritoneal dialysis may not be sufficient for hypercatabolic patients due to inherent limitations in dialysis efficacy. 2010 4/15/2015 7:55 PM . To achieve some of the advantages of CRRT without the need for 24-h staffing of the procedure. longer length of stay. and can be done through convective clearance. or a combination of the two. however. and postrenal azotemia carry a better prognosis than most cases of intrinsic AKI. in which large volumes of plasma water (and accompanying solutes) are forced across the semipermeable membrane by means of hydrostatic pressure. dialysis for AKI empirically when the BUN exceeds 100 mg/dL in patients without clinical signs of recovery of kidney function. and electrolytes characteristic of intermittent hemodialysis.

angiotensin-converting enzyme 1. 2010 Chertow GM et al: Acute kidney J Am Soc Nephrol 16:3365. length of stay. Intrarenal Mechanisms for Autoregulation of the Glomerular Filtration Rate (GFR) under Decreased Perfusion Pressure and Reduction of the GFR by Drugs. Panel D shows reduced perfusion pressure with an angiotensin-converting enzyme (ACE-I) inhibitor or an angiotensin receptor blocker (ARB). disseminated intravascular coagulation. tubulointerstitial nephritis-uveitis. J Floege et al (eds). angiotensin receptor blocker. Nat Biotechnol 28:436. Bonventre JV: Creatinine kinetics and the definition of acute kidney of 29 http://accessmedicine. Kidney Int 73:1008. RTE. LLC. J Am Soc Nephrol 17:1503. acute tubular necrosis. J Am Soc Nephrol 2009. Your IP address is 185.128. Normal glomerular capillary pressure is maintained by afferent vasodilatation and efferent vasoconstriction. Panel C shows reduced perfusion pressure with a nonsteroidal anti-inflammatory drug (NSAID). TINU. DIC. hypertensive nephropathy. GN. ACE-1. ) Major causes of intrinsic acute kidney injury. 2006 [PubMed: 16707563] Waikar SS. [Adapted from L Yang. MTX. JAMA 302:1532. TTP/HUS. Loss of vasodilatory prostaglandins increases afferent resistance. Anatomic sites and causes of obstruction leading to postrenal acute kidney injury. this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease. ARB.. penicillin.52 Classification of the major causes of acute kidney injury.lau.mhmedical. 4th ed. mortality. Copyright © McGraw-Hill Global Education Holdings. this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease. ATN.. Panel B shows reduced perfusion pressure within the autoregulatory range. All rights reserved. renal tubular epithelial.] 4/15/2015 7:55 PM . Elsevier. Interpretation of urinary sediment findings in acute kidney injury. Interacting microvascular and tubular events contributing to the pathophysiology of ischemic acute kidney injury. PGE2. Panel A shows normal conditions and a normal GFR. thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. glomerulonephritis. thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. 2008 [PubMed: 18094679] Devarajan P: Update on mechanisms of ischemic acute kidney injury. Loss of angiotensin II action reduces efferent resistance. and costs in hospitalized patients. [PubMed: 20427950] ——— et al: Next-generation biomarkers for detecting kidney toxicity. methotrexate. 2010. NSAIDs. TTP-HUS. 2005 [PubMed: 16177006] Coca SG et al: Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. In Comprehensive Nephrology.ezproxy. HTN. 2009 [PubMed: 19244578] Wald R: Chronic dialysis and death among survivors of acute kidney injury requiring dialysis. Philadelphia. PCN. nonsteroidal anti-inflammatory drugs. prostaglandin E2. JV Bonventre: Diagnosis and clinical evaluation of acute kidney injury.