Acute Kidney Injury (AKI) Practice Essentials Acute kidney injury (AKI) is defined as an abrupt or rapid decline in renal

filtration function. Essential update: Assessment of acute kidney injury in pediatric posttraumatic rhabdomyolysis In a recent study of 521 pediatric trauma patients with posttraumatic rhabdomyolysis, AKI occurred in 70 (13.4%) patients. Independent risk factors for AKI were a creatine kinase level of 3,000, an Injury Severity Score of 15, a Glasgow Coma Scale score of 8, an abdomin al Abbreviated Injury Scale (AIS) score of 3, imaging studies with contrast of 3, blunt mechanism of injury, administration of nephrotoxic agents, and requirement for administration of fluids in the emergency department. Creatine kinase levels should be monitored in pediatric trauma patients.[1] Signs and symptoms

Skin

Skin examination may reveal the following in patients with AKI: Livido reticularis, digital ischemia, butterfly rash, palpable purpura: Systemic vasculitis Maculopapular rash: Allergic interstitial nephritis Track marks (ie, intravenous drug abuse): Endocarditis

Eyes

Eye examination may reveal the following: Keratitis, iritis, uveitis, dry conjunctivae: Autoimmune vasculitis Jaundice: Liver diseases Band keratopathy (ie, hypercalcemia): Multiple myeloma Signs of diabetes mellitus Signs of hypertension Atheroemboli: Retinopathy

Ears

Examination of the patients ears may reveal the following signs: Hearing loss: Alport disease and aminoglycoside toxicity Mucosal or cartilaginous ulcerations: Wegener granulomatosis

Cardiovascular system

Cardiovascular examination may reveal the following: Irregular rhythms (ie, atrial fibrillation): Thromboemboli Murmurs: Endocarditis Pericardial friction rub: Uremic pericarditis Increased jugulovenous distention, rales, S3: Heart failure

Abdomen

The following signs of AKI may be discovered during an abdominal examination: Pulsatile mass or bruit: Atheroemboli Abdominal or costovertebral angle tenderness: Nephrolithiasis, papillary necrosis, renal artery thrombosis, renal vein thrombosis Pelvic, rectal masses; prostatic hypertrophy; distended bladder: Urinary obstruction Limb ischemia, edema: Rhabdomyolysis

Rales: Goodpasture syndrome, Wegener granulomatosis Hemoptysis: Wegener granulomatosis See Clinical Presentation for more detail. Diagnosis The following tests can aid in the diagnosis and assessment of AKI: Kidney function studies: Increased levels of blood urea nitrogen (BUN) and creatinine are the hallmarks of renal failure; the ratio of BUN to creatinine can exceed 20:1 in conditions that favor the enhanced reabsorption of urea, such as volume contraction (this suggests prerenal AKI) Complete blood count Peripheral smear Serologic tests: These may show evidence of conditions associated with AKI, such as schistocytes in disorders such as hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura Fractional excretion of sodium and urea Bladder pressure: Patients with a bladder pressure above 25 mm Hg should be suspected of having AKI caused by abdominal compartment syndrome Ultrasonography: Renal ultrasonography is useful for evaluating existing renal disease and obstruction of the urinary collecting system Aortorenal angiography : Can be helpful in establishing the diagnosis of renal vascular diseases, such as renal artery stenosis, renal atheroembolic disease, atherosclerosis with aortorenal occlusion, and certain cases of necrotizing vasculitis (eg, polyarteritis nodosa) Renal biopsy: Can be useful in identifying intrarenal causes of AKI See Workup for more detail. Management Maintenance of volume homeostasis and correction of biochemical abnormalities remain the primary goals of AKI treatment and may include the following measures: Correction of fluid overload with furosemide Correction of severe acidosis with bicarbonate administration, which can be important as a bridge to dialysis Correction of hyperkalemia Correction of hematologic abnormalities (eg, anemia, uremic platelet dysfunction) with measures such as transfusions and administration of desmopressin or estrogens Dietary changes are an important facet of AKI treatment. Restriction of salt and fluid becomes crucial in the management of oliguric renal failure, wherein the kidneys do not adequately excrete either toxins or fluids. Pharmacologic treatment of AKI has been attempted on an empiric basis, with varying success rates. See Treatment and Medication for more detail.

Pulmonary system

Pulmonary examination may reveal the following:

Image library

Photomicrograph of a renal biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Patchy or diffuse denudation of the renal tubular cells with loss of brush border is observed, suggesting acute tubular necrosis as the cause of acute renal failure. Background Acute kidney injury (AKI)or acute renal failure (ARF), as it was previously termedis defined as an abrupt or rapid decline in renal filtration function. This condition is usually marked by a rise in serum creatinine concentration or by azotemia (a rise in blood urea nitrogen [BUN] concentration).[2] However, immediately after a kidney injury, BUN or creatinine levels may be normal, and the only sign of a kidney injury may be decreased urine production. (See History.) A rise in the creatinine level can result from medications (eg, cimetidine, trimethoprim) that inhibit the kidneys tubular secretion, while a rise in the BUN level can also occur without renal injury, resulting instead from such sources as gastrointestinal (GI) or mucosal bleeding, steroid use, or protein loading. Therefore, a careful inventory must be taken before concluding that a kidney injury is present. (See Etiology and History.) See Chronic Kidney Disease and Acute Tubular Necrosis for complete information on these topics. For information on pediatric cases, see Chronic Kidney Disease in Children. An example of AKI, apparently the result of acute tubular necrosis (ATN), is seen in the image below.

While this classification is useful in establishing a differential diagnosis, many pathophysiologic features are shared among the different categories. (See Etiology.) Oliguric and nonoliguric patients with AKI Patients who develop AKI can be oliguric or nonoliguric, can have a rapid or slow rise in creatinine levels, and may have qualitative differences in urine solute concentrations and cellular content. (Approximately 50-60% of all causes of AKI are nonoliguric.) This lack of a uniform clinical presentation reflects the variable nature of the injury. Classifying AKI as oliguric or nonoliguric on the basis of daily urine excretion has prognostic value. Oliguria is defined as a daily urine volume of less than 400 mL and has a worse prognosis, except in prerenal injury. Anuria is defined as a urine output of less than 100 mL/day and, if abrupt in onset, suggests bilateral obstruction or catastrophic injury to both kidneys. Stratification of renal injury along these lines helps in diagnosis and decision-making (eg, timing of dialysis) and can be an important criterion for patient response to therapy. RIFLE classification system In 2004, the Acute Dialysis Quality Initiative work group set forth a definition and classification system for acute renal failure, described by the acronym RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure or Loss of kidney function, and End-stage kidney disease).[3] Investigators have since applied the RIFLE system to the clinical evaluation of AKI, although it was not originally intended for that purpose. AKI research increasingly uses RIFLE. See Table 1, below. Table 1. RIFLE Classification System for Acute Kidney Injury (Open Table in a new window) Stage Risk GFR** Criteria Urine Output Probability Criteria

SCreat increased UO < 0.5 High sensitivity 1.5 mL/kg/h 6 (Risk >Injury h >Failure)

or

Photomicrograph of a renal biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Patchy or diffuse denudation of the renal tubular cells with loss of brush border is observed, suggesting acute tubular necrosis as the cause of acute renal failure. Categories of AKI AKI may be classified into 3 general categories, as follows: Prerenal - As an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons Intrinsic - In response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage Postrenal - From obstruction to the passage of urine

GFR >25%

decreased

Injury

SCreat increased UO < 0.5 2 mL/kg/h 12 h

or

GFR >50%

decreased

Failure SCreat increased UO < 0.3 3 mL/kg/h 24 h

or

(oliguria)

A reduction in urine output, defined as less than 0.5 mL/kg/h for more than 6 hours AKIN has proposed a staging system for AKI that is modified from RIFLE. In this system, either serum creatinine or urine output criteria can be used to determine stage. See Table 2, below. Table 2. Acute Kidney Injury Network Classification/Staging System for AKI[4] (Open Table in a new window) Stage Serum Creatinine Criteria 1 Urine Output Criteria

GFR 75%

decreased

or

or

anuria 12 h

Increase of 0.3 mg/dL (26.4 < 0.5 mL/kg/h mol/L) or 1.5- to 2-fold increase for >6 h from baseline >2-fold to 3-fold increase from < 0.5 mL/kg/h baseline for >12 h >3-fold increase from baseline, or < 0.3 mL/kg/h increase of 4.0 mg/dL (35.4 for 24 h or mol/L) with an acute increase of at anuria for 12 h least 0.5 mg/dL (44 mol/L)

2 3*

SCreat 4 mg/dL; acute rise 0.5 mg/dL

Loss

Persistent acute renal failure: High specificity complete loss of kidney function >4 wk

*Patients who receive renal replacement therapy (RRT) are considered to have met the criteria for stage 3 irrespective of the stage they are in at the time of RRT. Cardiovascular complications Cardiovascular complications (eg, heart failure, myocardial infarction, arrhythmias, cardiac arrest) have been observed in as many as 35% of patients with AKI. Fluid overload secondary to oliguric AKI is a particular risk for elderly patients with limited cardiac reserve. In cardiac patients who experience AKI either in the setting of acute decompensated heart failure or cardiac surgery, AKI is associated with worse morbidity and mortality.[5] Pericarditis is a relatively rare complication of AKI. When pericarditis complicates AKI, consider additional diagnoses, such as systemic lupus erythematosus (SLE) and hepatorenal syndrome. AKI also can be a complication of cardiac diseases, such as endocarditis, decompensated heart failure, or atrial fibrillation with emboli. Cardiac arrest in a patient with AKI always should arouse suspicion of hyperkalemia. Many authors recommend a trial of intravenous calcium chloride (or gluconate) in all patients with AKI who experience cardiac arrest. Pulmonary complications Pulmonary complications have been reported in approximately 54% of patients with AKI and are the single most significant risk factor for death in patients with AKI. In addition, diseases exist that commonly present with simultaneous pulmonary and renal involvement, including the following: Goodpasture syndrome Wegener granulomatosis Polyarteritis nodosa Cryoglobulinemia Sarcoidosis Hypoxia commonly occurs during hemodialysis and can be particularly significant in the patient with pulmonary disease. This dialysis-related hypoxia is thought to occur secondary to white blood cell (WBC) lung sequestration and alveolar hypoventilation.

ESKD* Complete loss of kidney function >3 mo *ESKDend-stage kidney disease; **GFRglomerular filtration rate; SCreatserum creatinine; UOurine output

Note: Patients can be classified by GFR criteria and/or UO criteria. The criteria that support the most severe classification should be used. The superimposition of acute on chronic failure is indicated with the designation RIFLEFC; failure is present in such cases even if the increase in SCreat is less than 3-fold, provided that the new SCreat is greater than 4.0 mg/dL (350 mol/L) and results from an acute increase of at least 0.5 mg/dL (44 mol/L).

When the failure classification is achieved by UO criteria, the designation of RIFLE-FO is used to denote oliguria. The initial stage, risk, has high sensitivity; more patients will be classified in this mild category, including some who do not actually have renal failure. Progression through the increasingly severe stages of RIFLE is marked by decreasing sensitivity and increasing specificity. Acute Kidney Injury Network classification system The Acute Kidney Injury Network (AKIN) has developed specific criteria for the diagnosis of AKI. The AKIN defines AKI as abrupt (within 48 hours) reduction of kidney function, manifested by any 1 of the following[4] : An absolute increase in serum creatinine of 0.3 mg/dL or greater (26.4 mol/L) A percentage increase in serum creatinine of 50% or greater (1.5-fold from baseline)

GI complications Nausea, vomiting, and anorexia are frequent complications of AKI and represent one of the cardinal signs of uremia. GI bleeding occurs in approximately one third of patients with AKI. Most episodes are mild, but GI bleeding accounts for 3-8% of deaths in patients with AKI.

Pancreatitis

Mild hyperamylasemia commonly is seen in AKI (2-3 times controls). Elevation of baseline amylase concentrations can complicate diagnosis of pancreatitis in patients with AKI. Measurement of lipase, which commonly is not elevated in AKI, often is necessary to make the diagnosis of pancreatitis. Pancreatitis has been reported as a concurrent illness with AKI in patients with atheroemboli, vasculitis, and sepsis from ascending cholangitis.

Jaundice

Jaundice has been reported to complicate AKI in approximately 43% of cases. Etiologies of jaundice with AKI include hepatic congestion, blood transfusions, and sepsis.

Hepatitis

Hepatitis occurring concurrently with AKI should prompt consideration of the following disorders in the differential diagnosis: Common bile duct obstruction Fulminant hepatitis B Leptospirosis Acetaminophen toxicity Amanita phalloides poisoning Infectious complications Infections commonly complicate the course of AKI and have been reported to occur in as many as 33% of patients with AKI. The most common sites of infection are the pulmonary and urinary tracts. Infections are the leading cause of morbidity and death in patients with AKI. Various studies have reported mortality rates of 11-72% in infections complicating AKI. Neurologic complications Neurologic signs of uremia are a common complication of AKI and have been reported in approximately 38% of patients with AKI. Neurologic sequelae include lethargy, somnolence, reversal of the sleep-wake cycle, and cognitive or memory deficits. Focal neurologic deficits are rarely caused solely by uremia. The pathophysiology of neurologic symptoms is still unknown, but these symptoms do not correlate well to levels of BUN or creatinine. A number of diseases express themselves with concurrent neurologic and renal manifestations, including the following: SLE Thrombotic thrombocytopenic purpura (TTP) Hemolytic uremic syndrome (HUS) Endocarditis Malignant hypertension Also see Management of Acute Complications of Acute Renal Failure. Patient education Educating patients about the nephrotoxic potential of common therapeutic agents is always helpful. Nonsteroidal anti-inflammatory drugs (NSAIDs) provide a good example; most patients are unaware of their nephrotoxicity, and their universal availability makes them a constant concern.

For patient education information, see the Diabetes Center, as well as Acute Kidney Failure. Pathophysiology The driving force for glomerular filtration is the pressure gradient from the glomerulus to the Bowman space. Glomerular pressure depends primarily on renal blood flow (RBF) and is controlled by the combined resistances of renal afferent and efferent arterioles. Regardless of the cause of AKI, reductions in RBF represent a common pathologic pathway for decreasing glomerular filtration rate (GFR). The etiology of AKI consists of 3 main mechanisms: prerenal, intrinsic, and obstructive. In prerenal failure, GFR is depressed by compromised renal perfusion. Tubular and glomerular function remain normal. Intrinsic renal failure includes diseases of the kidney itself, predominantly affecting the glomerulus or tubule, which are associated with the release of renal afferent vasoconstrictors. Ischemic renal injury is the most common cause of intrinsic renal failure. Patients with chronic kidney disease may also present with superimposed AKI from prerenal failure and obstruction, as well as intrinsic renal disease. Obstruction of the urinary tract initially causes an increase in tubular pressure, which decreases the filtration driving force. This pressure gradient soon equalizes, and maintenance of a depressed GFR then depends on renal efferent vasoconstriction. Depressed RBF Depressed RBF eventually leads to ischemia and cell death. This may happen before frank systemic hypotension is present and is referred to as normotensive ischemic AKI. The initial ischemic insult triggers a cascade of events, including production of oxygen free radicals, cytokines and enzymes; endothelial activation and leukocyte adhesion; activation of coagulation; and initiation of apoptosis. These events continue to cause cell injury even after restoration of RBF. Tubular cellular damage results in disruption of tight junctions between cells, allowing back leak of glomerular filtrate and further depressing effective GFR. In addition, dying cells slough off into the tubules, forming obstructing casts, which further decrease GFR and lead to oliguria. During this period of depressed RBF, the kidneys are particularly vulnerable to further insults; this is when iatrogenic renal injury is most common. The following are common combinations: Radiocontrast agents, aminoglycosides, or cardiovascular surgery with preexisting renal disease (eg, elderly, diabetic, jaundiced patients) Angiotensin-converting enzyme (ACE) inhibitors with diuretics, small- or large-vessel renal arterial disease NSAIDs with chronic heart failure, hypertension, or renal artery stenosis Acute tubular necrosis Frank necrosis is not prominent in most human cases of ATN and tends to be patchy. Less obvious injuries include the following (see the images below): Loss of brush borders Flattening of the epithelium Detachment of cells Formation of intratubular casts

Dilatation

of

the

lumen

Flattening of the renal tubular cells due to tubular dilation.

Intratubular cast formation. Although these changes are observed predominantly in proximal tubules, injury to the distal nephron can also be demonstrated. In addition, the distal nephron may become obstructed by desquamated cells and cellular debris. See the image below.

Intratubular obstruction due to the denuded epithelium and cellular debris. Note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules. Apoptosis In contrast to necrosis, the principal site of apoptotic cell death is the distal nephron. During the initial phase of ischemic injury, loss of integrity of the actin cytoskeleton leads to flattening of the epithelium, with loss of the brush border, loss of focal cell contacts, and subsequent disengagement of the cell from the underlying substratum. Inflammatory response Many endogenous growth factors that participate in the process of regeneration following ischemic renal injury have not been identified. However, administration of growth factors exogenously has been shown to ameliorate and hasten recovery from AKI. Depletion of neutrophils and blockage of neutrophil adhesion reduce renal injury following ischemia, indicating that the inflammatory response is responsible, in part, for some features of ATN, especially in postischemic injury after transplant. Vasoconstriction Intrarenal vasoconstriction is the dominant mechanism for reduced GFR in patients with ATN. The mediators of this vasoconstriction are unknown, but tubular injury seems to be an important concomitant finding. Urine backflow and intratubular obstruction (from sloughed cells and debris) are causes of reduced net ultrafiltration. The importance

of this mechanism is highlighted by the improvement in renal function that follows relief of such intratubular obstruction. In addition, when obstruction is prolonged, intrarenal vasoconstriction is prominent in part due to the tubuloglomerular feedback mechanism, which is thought to be mediated by adenosine and activated when there is proximal tubular damage and the macula densa is presented with increased chloride load. Apart from the increase in basal renal vascular tone, the stressed renal microvasculature is more sensitive to potentially vasoconstrictive drugs and otherwise-tolerated changes in systemic blood pressure. The vasculature of the injured kidney has an impaired vasodilatory response and loses its autoregulatory behavior. This latter phenomenon has important clinical relevance because the frequent reduction in systemic pressure during intermittent hemodialysis may provoke additional damage that can delay recovery from ATN. Often, injury results in atubular glomeruli, where the glomerular function is preserved, but the lack of tubular outflow precludes its function. Isosthenuria A physiologic hallmark of ATN is a failure to maximally dilute or concentrate urine (isosthenuria). This defect is not responsive to pharmacologic doses of vasopressin. The injured kidney fails to generate and maintain a high medullary solute gradient, because the accumulation of solute in the medulla depends on normal distal nephron function. Failure to excrete concentrated urine even in the presence of oliguria is a helpful diagnostic clue in distinguishing prerenal from intrinsic renal disease. In prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg, whereas in intrinsic renal disease, urine osmolality is less than 300 mOsm/kg. Restoration of renal blood flow and associated complications Recovery from AKI is first dependent upon restoration of RBF. Early RBF normalization predicts better prognosis for recovery of renal function. In prerenal failure, restoration of circulating blood volume is usually sufficient. Rapid relief of urinary obstruction in postrenal failure results in a prompt decrease of vasoconstriction. With intrinsic renal failure, removal of tubular toxins and initiation of therapy for glomerular diseases decreases renal afferent vasoconstriction. Once RBF is restored, the remaining functional nephrons increase their filtration and eventually undergo hypertrophy. GFR recovery depends on the size of this remnant nephron pool. If the number of remaining nephrons is below a critical threshold, continued hyperfiltration results in progressive glomerular sclerosis, eventually leading to increased nephron loss. A vicious cycle ensues; continued nephron loss causes more hyperfiltration until complete renal failure results. This has been termed the hyperfiltration theory of renal failure and explains the scenario in which progressive renal failure is frequently observed after apparent recovery from AKI.

Etiology Prerenal AKI Prerenal AKI represents the most common form of kidney injury and often leads to intrinsic AKI if it is not promptly corrected. Volume loss can provoke this syndrome; the source of the loss may be GI, renal, or cutaneous (eg, burns) or from internal or external hemorrhage. Prerenal AKI can also result from decreased renal perfusion in patients with heart failure or shock (eg, sepsis, anaphylaxis). Several classes of medications can induce prerenal AKI in volume-depleted states, including ACE inhibitors and angiotensin receptor blockers (ARBs), which are otherwise safely tolerated and beneficial in most patients with chronic kidney disease. Aminoglycosides, amphotericin B, and radiologic contrast agents may also do so. Arteriolar vasoconstriction leading to prerenal AKI can occur in hypercalcemic states, as well as with the use of radiocontrast agents, NSAIDs, amphotericin, calcineurin inhibitors, norepinephrine, and other pressor agents. The hepatorenal syndrome can also be considered a form of prerenal AKI, because functional renal failure develops from diffuse vasoconstriction in vessels supplying the kidney. To summarize, volume depletion can be caused by the following: Renal losses - Diuretics, polyuria GI losses - Vomiting, diarrhea Cutaneous losses - Burns, Stevens-Johnson syndrome Hemorrhage Pancreatitis Decreased cardiac output can be caused by the following: Heart failure Pulmonary embolus Acute myocardial infarction Severe valvular disease Abdominal compartment syndrome - Tense ascites Systemic vasodilation can be caused by the following: Sepsis Anaphylaxis Anesthetics Drug overdose Afferent arteriolar vasoconstriction can be caused by the following: Hypercalcemia Drugs - NSAIDs, amphotericin B, calcineurin inhibitors, norepinephrine, radiocontrast agents Hepatorenal syndrome Diseases that decrease effective arterial blood volume include the following: Hypovolemia Heart failure Liver failure Sepsis Renal arterial diseases that can result in AKI include renal arterial stenosis, especially in the setting of hypotension or initiation of ACE inhibitors or ARBs. Renal artery stenosis typically results from atherosclerosis or fibromuscular dysplasia, but is also a feature of the genetic syndromes type 1 neurofibromatosis, Williams syndrome, and Alagille syndrome.

Patients can also develop septic embolic disease (eg, from endocarditis) or cholesterol emboli, often as a result of instrumentation or cardiovascular surgery. Intrinsic AKI Structural injury in the kidney is the hallmark of intrinsic AKI; the most common form is ATN, either ischemic or cytotoxic. Glomerulonephritis can be a cause of AKI and usually falls into a class referred to as rapidly progressive (RP) glomerulonephritis. Glomerular crescents (glomerular injury) are found in RP glomerulonephritis on biopsy; if more than 50% of glomeruli contain crescents, this usually results in a significant decline in renal function. Although comparatively rare, acute glomerulonephritides should be part of the diagnostic consideration in cases of AKI. To summarize, vascular (large- and small-vessel) causes of intrinsic AKI include the following: Renal artery obstruction - Thrombosis, emboli, dissection, vasculitis Renal vein obstruction - Thrombosis Microangiopathy - TTP, HUS, disseminated intravascular coagulation (DIC), preeclampsia Malignant hypertension Scleroderma renal crisis Transplant rejection Atheroembolic disease Glomerular causes include the following: Anti-glomerular basement membrane (GBM) disease - As part of Goodpasture syndrome or renal limited disease Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-associated glomerulonephritis) - Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis Immune complex glomerulonephritis - Lupus, postinfectious glomerulonephritis, cryoglobulinemia, primary membranoproliferative glomerulonephritis Tubular etiologies may include ischemia or cytotoxicity. Cytotoxic etiologies include the following: Heme pigment - Rhabdomyolysis, intravascular hemolysis Crystals - Tumor lysis syndrome, seizures, ethylene glycol poisoning, megadose vitamin C, acyclovir, indinavir, methotrexate Drugs - Aminoglycosides, lithium, amphotericin B, pentamidine, cisplatin, ifosfamide, radiocontrast agents Interstitial causes include the following: Drugs - Penicillins, cephalosporins, NSAIDs, proton-pump inhibitors, allopurinol, rifampin, indinavir, mesalamine, sulfonamides Infection - Pyelonephritis, viral nephritides Systemic disease - Sjgren syndrome, sarcoid, lupus, lymphoma, leukemia, tubulonephritis, uveitis Postrenal AKI Mechanical obstruction of the urinary collecting system, including the renal pelvis, ureters, bladder, or urethra, results in obstructive uropathy or postrenal AKI. Causes of obstruction include the following: Stone disease Stricture Intraluminal, extraluminal, or intramural tumors

Thrombosis or compressive hematoma Fibrosis If the site of obstruction is unilateral, then a rise in the serum creatinine level may not be apparent, because of preserved function of the contralateral kidney. Nevertheless, even with unilateral obstruction a significant loss of GFR occurs, and patients with partial obstruction may develop progressive loss of GFR if the obstruction is not relieved. Bilateral obstruction is usually a result of prostate enlargement or tumors in men and urologic or gynecologic tumors in women. Patients who develop anuria typically have obstruction at the level of the bladder or downstream to it. To summarize, causes of postrenal AKI include the following: Ureteric obstruction - Stone disease, tumor, fibrosis, ligation during pelvic surgery Bladder neck obstruction - Benign prostatic hypertrophy (BPH), cancer of the prostate (CA prostate or prostatic CA), neurogenic bladder, tricyclic antidepressants, ganglion blockers, bladder tumor, stone disease, hemorrhage/clot Urethral obstruction - Strictures, tumor, phimosis Intra-abdominal hypertension - Tense ascites Renal vein thrombosis Diseases causing urinary obstruction from the level of the renal tubules to the urethra include the following: Tubular obstruction from crystals - Eg, uric acid, calcium oxalate, acyclovir, sulfonamide, methotrexate, myeloma light chains Ureteral obstruction - Retroperitoneal tumor, retroperitoneal fibrosis (methysergide, propranolol, hydralazine), urolithiasis, or papillary necrosis Urethral obstruction Benign prostatic hypertrophy; prostate, cervical, bladder, or colorectal carcinoma; bladder hematoma; bladder stone; obstructed Foley catheter; neurogenic bladder; stricture Etiology in newborns and infants

Postrenal AKI

ACE inhibitors - Can traverse the placenta, resulting in a hemodynamically mediated form of AKI Acute glomerulonephritis Rare; most commonly the result of maternal-fetal transfer of antibodies against the neonate's glomeruli or transfer of chronic infections (syphilis, cytomegalovirus) associated with acute glomerulonephritis

Congenital malformations of the urinary collecting systems should be suspected in cases of postrenal AKI. Etiology in children

Prerenal AKI

In children, gastroenteritis is the most common cause of hypovolemia and can result in prerenal AKI. Congenital and acquired heart diseases are also important causes of decreased renal perfusion in this age group.

Intrinsic AKI

Prerenal AKI

The patient's age has significant implications for the differential diagnosis of AKI. In newborns and infants, causes of prerenal AKI include the following: Perinatal hemorrhage - Twin-twin transfusion, complications of amniocentesis, abruptio placenta, birth trauma Neonatal hemorrhage - Severe intraventricular hemorrhage, adrenal hemorrhage Perinatal asphyxia and hyaline membrane disease (newborn respiratory distress syndrome) - Both may result in preferential blood shunting away from the kidneys (ie, prerenal) to central circulation

Intrinsic AKI

Causes of intrinsic AKI include the following: ATN - Can occur in the setting of perinatal asphyxia; ATN also has been observed secondary to medications (eg, aminoglycosides, NSAIDs) given to the mother perinatally

Intrinsic AKI may result from any of the following: Acute poststreptococcal glomerulonephritis Should be considered in any child who presents with hypertension, edema, hematuria, and renal failure HUS - Often is cited as the most common cause of AKI in children The most common form of HUS is associated with a diarrheal prodrome caused by Escherichia coli O157:H7. These children usually present with microangiopathic anemia, thrombocytopenia, colitis, mental status changes, and renal failure. Cardiopulmonary bypass and AKI Longer time on extracorporeal cardiopulmonary bypass is commonly accepted as a risk factor for AKI. However, a study by Mancini et al found that extracorporeal cardiopulmonary bypass time did not predict AKI requiring dialysis, suggesting that a risk assessment may be a more reliable marker.[6] Epidemiology In the United States, approximately 1% of patients admitted to hospitals have AKI at the time of admission. The estimated incidence rate of AKI during hospitalization is 2-5%. AKI develops within 30 days postoperatively in approximately 1% of general surgery cases[7] and arises in up to 67% of intensive care unit (ICU) patients.[8] Approximately 95% of consultations with nephrologists are related to AKI. Feest and colleagues calculated that the appropriate nephrologist referral rate is approximately 70 cases per million population.[9] Prognosis The prognosis for patients with AKI is directly related to the cause of renal failure and, to a great extent, to the presence or absence of preexisting kidney disease (estimated GFR [eGFR] < 60 mL/min), as well as to the duration of renal dysfunction prior to therapeutic intervention. In the past, AKI was thought to be completely reversible, but long-term follow-up of patients with this condition has shown otherwise. A study from Canada showed a much higher incidence of AKI than did previous reports, with a rate of 18.3% (7856 of 43,008) in hospitalized patients.[10] The incidence of AKI correlated inversely with eGFR and was associated with a higher mortality rate and a higher incidence of subsequent

end-stage renal disease (ESRD) at each level of baseline eGFR. However, the greatest impact on mortality was seen in individuals with an eGFR of greater than 60 mL/min who developed AKI. Those with stage 3 AKI (AKIN criteria; see Overview) had a mortality rate of 50%, while mortality in individuals with an eGFR of greater than 60 mL/min but who did not develop AKI was only 3%. Among individuals with an eGFR of less than 30, the mortality rate was 12.1% in those who did not develop AKI, versus 40.7% among patients with stage 3 AKI.[10] Mortality rates and associated factors If AKI is defined by a sudden increment of serum creatinine of 0.5-1 mg/dL and is associated with a mild to moderate rise in creatinine, the prognosis tends to be worse. (Increments of 0.3 mg/dL in serum creatinine, especially at lower ranges of serum creatinine, have important prognostic significance). The inhospital mortality rate for AKI is 40-50%. The mortality rate for ICU patients with AKI is higher (>50% in most studies), particularly when AKI is severe enough to require dialysis treatment.[11] ICU patients with sepsisassociated AKI have significantly higher mortality rates than do nonseptic AKI patients.[12] In addition, the pooled estimate for general ICU patients with AKI shows a stepwise increase in relative risk for death through the risk, injury, and failure classifications of the RIFLE criteria in AKI patients versus non-AKI patients.[13] This reflects the fact that the high mortality rate in patients with AKI who require dialysis may not be related to the dialysis procedure or accompanying comorbidities and that AKI is an independent indicator of mortality. The survival rate is nearly 0% among patients with AKI who have an Acute Physiology and Chronic Health Evaluation II (APACHE II) score higher than 40. In patients with APACHE II scores of 10-19, the survival rate is 40%.

Hypotension Vasopressor support Number of transfusions Noncavitary surgery Occurrence of AKI by itself[15] - Has significant negative prognostic implications Prerenal azotemia from volume contraction is treated with volume expansion; if left untreated for a prolonged period, tubular necrosis may result and may not be reversible. Postrenal AKI, if left untreated for a long time, also may result in irreversible renal damage. Procedures such as catheter placement, lithotripsy, prostatectomy, stent placement, and percutaneous nephrostomy can help to prevent permanent renal damage.

Nephritis

Timely identification of pyelonephritis, proper treatment, and further prevention using prophylactic antibiotics may improve the prognosis, especially in females. Early diagnosis of crescentic glomerulonephritis via renal biopsy and other appropriate tests may enhance early renal recovery, because appropriate therapy can be initiated promptly and aggressively. The number of crescents, the type of crescents (ie, cellular vs fibrous), and the serum creatinine level at the time of presentation may dictate prognosis for renal recovery in these patients.

Proteinuria

A large cohort study demonstrated that proteinuria coupled with low baseline GFR is associated with a higher incidence of AKI and should be considered as an identifying factor for individuals at risk.

Statins

Fluid balance and mortality

In a post hoc analysis of the Fluid and Catheter Treatment Trial (FACTT), which examined liberal versus conservative fluid management in intubated ICU patients, fluid balance and diuretic use were identified as prognostic factors for mortality in individuals with AKI. Specifically, greater cumulative fluid accumulation over an average of 6 days (10.2 L vs 3.7 L in the liberal vs conservative group, respectively) was associated with a higher mortality rate, and higher furosemide use (cumulatively, 562 mg vs 159 mg, respectively) was associated with a lower mortality rate.[14] Of note, more than half of the individuals in FACTT had stage 1 AKI (AKIN criteria), so whether these results apply to more severe stages of AKI is not clear. One interpretation of this study is that patients who can be stabilized with less volume resuscitation fare better. From a practical standpoint, one conclusion is that aggressive, prolonged volume resuscitation does not improve prognosis in AKI in the ICU setting.[14] Additional prognostic factors Other prognostic factors include the following: Older age Multiorgan failure - Ie, the more organs that fail, the worse the prognosis Oliguria

One study examining AKI after elective surgery in more than 200,000 patients older than 66 years suggested that patients taking statins had a lesser incidence and lower severity of AKI, as well as lower mortality, than did individuals not on statins. Furthermore, the incidence and severity correlated with the potency of the statin. As the study was a retrospective review, the authors were not able to recommend routine preoperative administration of statins; however, the study certainly suggests that statins should not be routinely discontinued prior to elective surgery.[16] Long-term prognosis In contrast to previous belief, it is now known that survivors of AKI do not universally have a benign course. On long-term follow-up (1-10 years), approximately 12.5% of survivors of AKI are dialysis dependent; rates range widely, from 1-64%, depending on the patient population. From 19-31% of survivors experience partial recovery of kidney function and have chronic kidney disease.[8] History A detailed and accurate history is crucial for diagnosing acute kidney injury (AKI) and determining treatment. Distinguishing AKI from chronic kidney disease is important, yet making the distinction can be difficult. A history of chronic symptomsmonths of fatigue, weight loss, anorexia, nocturia, sleep disturbance, and pruritus suggests chronic kidney disease. AKI can cause identical symptoms, but over a shorter course. It is important to elicit a history of any of the following etiologic factors:

Volume restriction (eg, low fluid intake, gastroenteritis) Nephrotoxic drug ingestion Trauma or unaccustomed exertion Blood loss or transfusions Exposure to toxic substances, such as ethyl alcohol or ethylene glycol Exposure to mercury vapors, lead, cadmium, or other heavy metals, which can be encountered in welders and miners People with the following comorbid conditions are at a higher risk for developing AKI: Hypertension Chronic heart failure Diabetes Multiple myeloma Chronic infection Myeloproliferative disorder Connective tissue disorders Autoimmune diseases Urine output history can be useful. Oliguria generally favors AKI. Abrupt anuria suggests acute urinary obstruction, acute and severe glomerulonephritis, or embolic renal artery occlusion. A gradually diminishing urine output may indicate a urethral stricture or bladder outlet obstruction due to prostate enlargement. Because of a decrease in functioning nephrons, even a trivial nephrotoxic insult may cause AKI to be superimposed on chronic renal insufficiency. Acute kidney injury (AKI) has a long differential diagnosis. History can help to classify the pathophysiology of AKI as prerenal, intrinsic renal, or postrenal failure, and it may suggest some specific etiologies. Prerenal failure Patients commonly present with symptoms related to hypovolemia, including thirst, decreased urine output, dizziness, and orthostatic hypotension. Ask about volume loss from vomiting, diarrhea, sweating, polyuria, or hemorrhage. Patients with advanced cardiac failure leading to depressed renal perfusion may present with orthopnea and paroxysmal nocturnal dyspnea. Elders with vague mental status change are commonly found to have prerenal or normotensive ischemic AKI. Insensible fluid losses can result in severe hypovolemia in patients with restricted fluid access and should be suspected in elderly patients and in comatose or sedated patients. Intrinsic renal failure Patients can be divided into those with glomerular etiologies and those with tubular etiologies of AKI. Nephritic syndrome of hematuria, edema, and hypertension indicates a glomerular etiology for AKI. Query about prior throat or skin infections. Acute tubular necrosis (ATN) should be suspected in any patient presenting after a period of hypotension secondary to cardiac arrest, hemorrhage, sepsis, drug overdose, or surgery. A careful search for exposure to nephrotoxins should include a detailed list of all current medications and any recent radiologic examinations (ie, exposure to radiologic contrast agents). Pigment-induced AKI should be suspected in patients with possible rhabdomyolysis (muscular pain, recent coma, seizure, intoxication, excessive exercise, limb ischemia) or hemolysis (recent blood transfusion). Allergic

interstitial nephritis should be suspected with fevers, rash, arthralgias, and exposure to certain medications, including NSAIDs and antibiotics. Postrenal failure Postrenal failure usually occurs in older men with prostatic obstruction and symptoms of urgency, frequency, and hesitancy. Patients may present with asymptomatic, highgrade urinary obstruction because of the chronicity of their symptoms. A history of prior gynecologic surgery or abdominopelvic malignancy often can be helpful in providing clues to the level of obstruction. Flank pain and hematuria should raise a concern about renal calculi or papillary necrosis as the source of urinary obstruction. Use of acyclovir, methotrexate, triamterene, indinavir, or sulfonamides implies the possibility that crystals of these medications have caused tubular obstruction. Physical Examination Obtaining a thorough physical examination is extremely important when collecting evidence about the etiology of AKI. Clues may be found in any of the following: Skin Eyes Ears Cardiovascular system Abdomen Pulmonary system Skin Skin examination may reveal the following: Livido reticularis, digital ischemia, butterfly rash, palpable purpura - Systemic vasculitis Maculopapular rash - Allergic interstitial nephritis Track marks (ie, intravenous drug abuse) Endocarditis Petechiae, purpura, ecchymosis, and livedo reticularis provide clues to inflammatory and vascular causes of AK. Infectious diseases, thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), and embolic phenomena can produce typical cutaneous changes. Eyes and ears Eye examination may reveal the following: Keratitis, iritis, uveitis, dry conjunctivae Autoimmune vasculitis Jaundice - Liver diseases Band keratopathy (ie, hypercalcemia) - Multiple myeloma Signs of diabetes mellitus Signs of hypertension Atheroemboli - Retinopathy Evidence of uveitis may indicate interstitial nephritis and necrotizing vasculitis. Ocular palsy may indicate ethylene glycol poisoning or necrotizing vasculitis. Findings suggestive of severe hypertension, atheroembolic disease, and endocarditis may be observed on careful examination of the eyes. Ear examination may reveal the following: Hearing loss - Alport disease and aminoglycoside toxicity Mucosal or cartilaginous ulcerations - Wegener granulomatosis

Cardiovascular system The most important part of the physical examination is the assessment of cardiovascular and volume status. The physical examination must include the following: Pulse rate and blood pressure recordings measured in the supine and the standing position Close inspection of the jugulovenous pulse Careful examination of the heart and lungs, skin turgor, and mucous membranes Assessment for peripheral edema Cardiovascular examination may reveal the following: Irregular rhythms (ie, atrial fibrillation) Thromboemboli Murmurs - Endocarditis Pericardial friction rub - Uremic pericarditis Increased jugulovenous distention, rales, S3 Heart failure In hospitalized patients, accurate daily records of fluid intake and urine output, as well as daily measurements of patient weight, are important. Hypovolemia leads to hypotension; however, hypotension may not necessarily indicate hypovolemia. Severe heart failure may also cause hypotension. Although patients with heart failure may have low blood pressure, volume expansion is present and effective renal perfusion is poor, which can result in AKI. Severe hypertension with renal failure suggests one of the following disorders: Renovascular disease Glomerulonephritis Vasculitis Atheroembolic disease Abdomen Abdominal examination may reveal the following: Pulsatile mass or bruit - Atheroemboli Abdominal or costovertebral angle tenderness Nephrolithiasis, papillary necrosis, renal artery thrombosis, renal vein thrombosis Pelvic, rectal masses; prostatic hypertrophy; distended bladder Urinary obstruction Limb ischemia, edema - Rhabdomyolysis Abdominal examination findings can be useful in helping to detect obstruction at the bladder outlet as the cause of renal failure; such obstruction may be due to cancer or to an enlarged prostate. The presence of tense ascites can indicate elevated intraabdominal pressure that can retard renal venous return and result in AKI. The presence of an epigastric bruit suggests renal vascular hypertension, which may predispose to AKI. Pulmonary system Pulmonary examination may reveal the following: Rales - Goodpasture syndrome, Wegener granulomatosis Hemoptysis - Wegener granulomatosis Diagnostic Considerations Although acute kidney injury (AKI) is a potentially reversible condition, it can occur in patients with chronic renal failure. Every effort should be made to identify reversibility, even if improvement in renal function is marginal. The best way to identify reversibility is by tracking the rate of deterioration of renal function. If there is an acceleration of the rate at which the patients

renal function is worsening, the cause should be sought and treated. Differentials to consider in AKI include the following: Abdominal aneurysm Alcohol toxicity Alcoholic ketoacidosis Chronic renal failure Dehydration Diabetic ketoacidosis Gastrointestinal (GI) bleeding Heart failure Metabolic acidosis Obstructive uropathy Protein overloading Renal calculi Sickle cell anemia Steroid use Urinary obstruction Urinary tract infection Urine output in differential diagnosis Changes in urine output generally correlate poorly with changes in the glomerular filtration rate (GFR). Approximately 50-60% of all causes of AKI are nonoliguric. However, the identification of anuria, oliguria, and nonoliguria may be useful in the differential diagnosis of AKI, as follows: Anuria (< 100 mL/day) - Urinary tract obstruction, renal artery obstruction, rapidly progressive glomerulonephritis, bilateral diffuse renal cortical necrosis Oliguria (100-400 mL/day) - Prerenal failure, hepatorenal syndrome Nonoliguria (>400 mL/day) - Acute interstitial nephritis, acute glomerulonephritis, partial obstructive nephropathy, nephrotoxic and ischemic ATN, radiocontrast-induced AKI, and rhabdomyolysis Differential Diagnoses Acute Glomerulonephritis in Emergency Medicine Acute Tubular Necrosis Azotemia Chronic Renal Failure Hemolytic Uremic Syndrome in Emergency Medicine Henoch-Schonlein Purpura in Emergency Medicine Hyperkalemia Hypermagnesemia Hypernatremia Hypertensive Emergencies Approach Considerations Several laboratory tests, including the following, are useful for assessing the etiology of acute kidney injury (AKI) and can aid in proper management of the disease: Complete blood count (CBC) Serum biochemistries Urine analysis with microscopy Urine electrolytes In some cases, renal imaging is useful, especially if renal failure is secondary to obstruction. The American College of Radiology recommends ultrasonography, preferably with Doppler methods, as the most appropriate imaging method in AKI.[17]

Kidney Function Studies Although increased levels of blood urea nitrogen (BUN) and creatinine are the hallmarks of renal failure, the rate of rise depends on the degree of renal insult and, with respect to BUN, on protein intake. BUN may be elevated in patients with gastrointestinal (GI) or mucosal bleeding, steroid treatment, or protein loading. The ratio of BUN to creatinine is an important finding. The ratio can exceed 20:1 in conditions in which enhanced reabsorption of urea is favored (eg, in volume contraction); this suggests prerenal AKI. Assuming that the patient has no renal function, the rise in BUN over 24 hours can be roughly predicted using the following formula: 24-hour protein intake in milligrams 0.16 divided by total body water in mg/dL added to the BUN value Assuming no renal function, the rise in creatinine can be predicted using the following formulas: For males: Weight in kilograms [28 - 0.2(age)] divided by total body water in mg/dL added to the creatinine value For females: Weight in kilograms [23.8 0.17(age)] divided by total body water added to the creatinine value As a general rule, if serum creatinine increases to more than 1.5 mg/dL/day, rhabdomyolysis must be ruled out. CBC, Peripheral Smear, and Serology The peripheral smear may show schistocytes in conditions such as hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP). A finding of increased rouleaux formation suggests multiple myeloma, and the workup should be directed toward immunoelectrophoresis of serum and urine. The presence of the following, along with related findings, may help to further define the etiology of AKI: Myoglobin or free hemoglobin - Eg, pigment nephropathy Increased serum uric acid level - Eg, tumor lysis syndrome Serum lactate dehydrogenase (LDH) - Eg, renal infarction Although serologic tests can be informative, the costs can be prohibitive if these tests are not ordered judiciously. Possible tests include the following: Complement levels Antinuclear antibody (ANA) Antineutrophil cytoplasmic antibody (ANCA) Anti-glomerular basement membrane (anti-GBM) antibody Hepatitis B and C virus studies Antistreptolysin (ASO) Urinalysis Findings of granular, muddy brown casts are highly suggestive of tubular necrosis (see the image below). The presence of tubular cells or tubular cell casts also supports the diagnosis of ATN. Often, oxalate crystals are observed in cases of ATN.

Sloughing of cells, which is responsible for the formation of granular casts, is a feature of acute tubular necrosis. Reddish brown or cola-colored urine suggests the presence of myoglobin or hemoglobin, especially in the setting of a positive dipstick for heme and no red blood cells (RBCs) on the microscopic examination. The dipstick assay may reveal significant proteinuria as a result of tubular injury. The presence of RBCs in the urine is always pathologic. Eumorphic RBCs suggest bleeding along the collecting system. Dysmorphic RBCs or RBC casts indicate glomerular inflammation, suggesting glomerulonephritis is present. The presence of white blood cells (WBCs) or WBC casts suggests pyelonephritis or acute interstitial nephritis. The presence of urine eosinophils is helpful in establishing a diagnosis but is not necessary for allergic interstitial nephritis to be present. The presence of eosinophils, as visualized with Wright stain or Hansel stain, suggests interstitial nephritis. However, this finding can also be seen in urinary tract infections, glomerulonephritis, and atheroembolic disease. The presence of uric acid crystals may represent ATN associated with uric acid nephropathy. Calcium oxalate crystals are usually present in cases of ethylene glycol poisoning. Fractional Excretion of Sodium and Urea Sodium Urine electrolyte findings also can serve as valuable indicators of functioning renal tubules. The fractional excretion of sodium (FENa) is the commonly used indicator. However, the interpretation of results from patients in nonoliguric states, those with glomerulonephritis, and those receiving or ingesting diuretics can lead to an erroneous diagnosis. FENa can be a valuable test for helping to detect extreme renal avidity for sodium in conditions such as hepatorenal syndrome. The formula for calculating the FENa is as follows: FENa = (UNa/PNa) / (UCr/PCr) X 100 Calculating the FENa is useful in AKI only in the presence of oliguria. In patients with prerenal azotemia, the FENa is usually less than 1%. In ATN, the FENa is greater than 1%. Exceptions to this rule are ATN caused by radiocontrast nephropathy, severe burns, acute glomerulonephritis, and rhabdomyolysis. In the presence of liver disease, FENa can be less than 1% in the presence of ATN. On the other hand, because administration of diuretics may cause the FENa to be greater than 1%, these findings cannot be used as the sole indicators in AKI. Urea In patients who are receiving diuretics, a fractional excretion of urea (FEUrea) can be obtained, since urea transport is not affected by diuretics. (FEUrea of less

than 35% is suggestive of a prerenal state.) The formula for calculating the FEUrea is as follows: FEUrea = (Uurea/Purea) / (UCr/PCr) X 100 Bladder Pressure An intra-abdominal pressure of less than 10 mm Hg is considered normal and suggests that abdominal compartment syndrome is not the cause of AKI. An intraabdominal pressure above 10 mm Hg is abnormal, but patients who have pressures of 15-25 mm Hg are at particular risk for abdominal compartment syndrome, and those with bladder pressures above 25 mm Hg should be suspected of having AKI as a result of abdominal compartment syndrome. Emerging Biomarkers Creatinine elevation is a late marker for renal dysfunction and, once elevated, reflects a severe reduction in glomerular filtration rate (GFR). Consequently, a number of biomarkers are being investigated to risk stratify and predict AKI in patients at risk for the disease. The most promising biomarker to date is urinary neutrophil gelatinase-associated lipocalin (NGAL), which has been shown to detect AKI in patients undergoing cardiopulmonary bypass surgery.[18] Breidthardt et al studied a model that combined the markers plasma B-type natriuretic peptide (BNP) and NGAL and found it to be a strong predictor of early AKI in patients with lower respiratory tract infection. The presence of a BNP level of over 267 pg/mL or an NGAL level of greater than 231 ng/mL correctly identified 15 of 16 early AKI patients, with a sensitivity of 94% and a specificity of 61%.[19] A study of adults on the first day of meeting AKI criteria found that urine protein biomarkers and microscopy findings offer a significant improvement over clinical determination of prognosis. In this study, the risk for worsened AKI stage or inhospital death was approximately 3-fold higher for upper values than it was for lower ones for NGAL, kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and microscopy score for casts and tubular cells.[20] A prospective study of serum cystatin C as a biomarker for AKI after cardiac surgery found that the cystatin C level was less sensitive than the creatinine level for detecting AKI. However, confirmation by cystatin C level appeared to identify a subset of patients with AKI with a substantially higher risk for adverse outcomes.[21] Ultrasonography Renal ultrasonography is useful for evaluating existing renal disease and obstruction of the urinary collecting system. Obtaining images of the kidneys can be technically difficult in patients who are obese, however, as well as in those with abdominal distention from ascites, gas, or retroperitoneal fluid collection. The degree of hydronephrosis found on an ultrasonogram does not necessarily correlate with the degree of obstruction. Mild hydronephrosis may be observed with complete obstruction if found early. Small kidneys suggest chronic renal failure. Doppler ultrasonography Doppler scans are useful for detecting the presence and nature of renal blood flow. Because renal blood flow is reduced in prerenal and intrarenal AKI, findings are of little use in the diagnosis of AKI. However, Doppler scans

can be quite useful in the diagnosis of thromboembolic or renovascular disease. Increased resistive indices can be observed in patients with hepatorenal syndrome. Nuclear Scanning Radionuclide imaging with technetium-99mmercaptoacetyltriglycine (99m Tc-MAG3),99m Tcdiethylenetriamine penta-acetic acid (99m Tc-DTPA), or iodine-131 (131 I)-hippurate can be used to assess renal blood flow, as well as tubular function. There is, however, a marked delay in the tubular excretion of radionuclide in prerenal and intrarenal AKI, limiting the value of nuclear scans. Aortorenal Angiography Aortorenal angiography can be helpful in establishing the diagnosis of renal vascular diseases, including the following: Renal artery stenosis Renal atheroembolic disease Atherosclerosis with aortorenal occlusion Certain cases of necrotizing vasculitis (eg, polyarteritis nodosa) Renal Biopsy A renal biopsy can be useful in identifying intrarenal causes of AKI and can be justified if the results may change management (eg, initiation of immunosuppressive medications). A renal biopsy may also be indicated when renal function does not return for a prolonged period and a prognosis is required to develop long-term management. In as many as 40% of cases, renal biopsy results reveal an unexpected diagnosis. Acute cellular or humoral rejection in a transplanted kidney can be definitively diagnosed only by performing a renal biopsy Approach Considerations Measures to correct underlying causes of acute kidney injury (AKI) should begin at the earliest indication of renal dysfunction. Serum creatinine does not rise to abnormal levels until a large proportion of the renal mass is damaged, because the relationship between the glomerular filtration rate (GFR) and the serum creatinine level is not linear, especially early in disease. Indeed, the rise of serum creatinine may not be evident before 50% of the GFR is lost. It cannot be overstated that the current treatment for AKI is mainly supportive in nature; no therapeutic modalities to date have shown efficacy in treating the condition. Therapeutic agents (eg, dopamine, nesiritide, fenoldopam, mannitol) are not indicated in the management of AKI and may be harmful for the patient. Maintenance of volume homeostasis and correction of biochemical abnormalities remain the primary goals of treatment and may include the following measures: Correction of fluid overload with furosemide Correction of severe acidosis with bicarbonate administration, which can be important as a bridge to dialysis Correction of hyperkalemia Correction of hematologic abnormalities (eg, anemia, uremic platelet dysfunction) with measures such as transfusions and administration of desmopressin or estrogens

Volume overload Furosemide can be used to correct volume overload when patients are still responsive; this often requires high intravenous (IV) doses. Furosemide plays no role in converting an oliguric AKI to a nonoliguric AKI or in increasing urine output when a patient is not hypervolemic. However, response to furosemide can be taken as a good prognostic sign. Hyperkalemia Hyperkalemia in patients with AKI can be life-threatening. Approaches to lowering serum potassium include the following: Decreasing the intake of potassium in diet or tube feeds Exchanging potassium across the gut lumen using potassium-binding resins Promoting intracellular shifts in potassium with insulin, dextrose solutions, and beta agonists Instituting dialysis Nephrotoxic agents In AKI, the kidneys are especially vulnerable to the toxic effects of various chemicals. All nephrotoxic agents (eg, radiocontrast agents, antibiotics with nephrotoxic potential, heavy metal preparations, cancer chemotherapeutic agents, nonsteroidal anti-inflammatory drugs [NSAIDs]) should be avoided or used with extreme caution. Similarly, all medications cleared by renal excretion should be avoided, or their doses should be adjusted appropriately. A 2013 study indicated that triple therapy using nonsteroidal anti-inflammatory drugs (NSAIDs) with 2 antihypertensive medicationsa diuretic along with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB)significantly increases the risk of hospitalization for AKI, particularly in the first 30 days of treatment with these drugs. The retrospective, case-controlled study involved a cohort of 487,372 users of antihypertensive drugs between 1997 and 2008. During a mean follow-up of almost 6 years, 2215 cases of acute kidney injury were identified (incidence rate of 7 per 10 000 person-years), and each was compared with up to 10 matched controls.[22, 23] Consultation Nephrology consultation should be sought early in the course of AKI. A nephrologist can help to optimize management and avoid the preventable complications of AKI. Vasodilators The rationale for vasodilator therapy in AKI is that improved renal perfusion may reduce renal damage. Strong evidence in support of this approach is lacking, however. A meta-analysis of 16 randomized studies concluded that the vasodilator fenoldopam reduces the need for renal replacement therapy and lowers the mortality rate in patients with AKI.[24] However, larger trials need to be conducted before the use of fenoldopam can be recommended. Dopamine in small doses (eg, 1-5 mcg/kg/min) causes selective dilatation of the renal vasculature, enhancing renal perfusion. Dopamine also reduces sodium absorption; this enhances urine flow, which helps to prevent tubular cast obstruction. However, most clinical studies have failed

to establish this beneficial role of low-dose dopamine infusion, and one study demonstrated that low-dose dopamine may worsen renal perfusion in patients with AKI.[24] Dietary Modification Dietary changes are an important facet of AKI treatment. Restriction of salt and fluid becomes crucial in the management of oliguric renal failure, wherein the kidneys do not adequately excrete either toxins or fluids. Because potassium and phosphorus are not excreted optimally in patients with AKI, blood levels of these electrolytes tend to be high. Restriction of these elements in the diet may be necessary, with guidance from frequent measurements. In the polyuric phase of AKI, potassium and phosphorus may be depleted, so that patients may require dietary supplementation and IV replacement. Calculation of the nitrogen balance can be challenging, especially in the presence of volume contraction, hypercatabolic states, GI bleeding, and diarrheal disease. Critically ill patients should receive at least 1 g/kg/day protein but should avoid hyperalimentation, which can lead to an elevated blood urea nitrogen (BUN) level and water loss resulting in hypernatremia. Dialysis Dialysis, especially hemodialysis, may delay the recovery of patients with AKI. Most authorities prefer using biocompatible membrane dialyzers for hemodialysis. Indications for dialysis (ie, renal replacement therapy) in patients with AKI are as follows: Volume expansion that cannot be managed with diuretics Hyperkalemia refractory to medical therapy Correction of severe acid-base disturbances that are refractory to medical therapy Severe azotemia (BUN >80-100) Uremia Timing and intensity Great controversy exists regarding the timing of dialysis. Older studies suggested decreased mortality with early, versus late, initiation of dialysis, but timing of dialysis initiation has not been assessed in large, randomized, controlled trials.[25] Approaches vary widely at present. The Acute Renal Failure Trial Network (ATN) Study found that increasing the intensity of dialysis (either intermittent or continuous) did not improve clinical outcomes (morbidity/mortality).[26] The best evidence suggests that patients with dialysis-dependent AKI should receive at least 3 hemodialysis treatments per week with a delivered Kt/V value of 1.2, or continuous hemodialysis (continuous venovenous hemodialysis or hemofiltration) of 20 mg/kg/h (prescribed). CRRT There seems to be no difference in outcome between the use of intermittent hemodialysis and continuous renal replacement therapy (CRRT), but this question is currently under investigation. CRRT may have a role in patients who are hemodynamically unstable and who have had prolonged renal failure after a stroke or liver failure. Such patients may not tolerate the rapid shift of fluid and electrolytes caused during conventional hemodialysis.

Peritoneal dialysis Peritoneal dialysis is not frequently used in patients with AKI. Nevertheless, it can technically be used in acute cases and probably is tolerated better hemodynamically than is conventional hemodialysis. Prevention of Contrast-Induced Nephropathy Saline In patients undergoing imaging studies with contrast, prophylactic administration of IV fluid has been shown to decrease the incidence of contrast nephropathy. Although controversy exists regarding the ideal fluid, normal saline and isotonic NaHCO3 have proved to be effective. A normal saline solution of 1 mL/kg/h administered 12 hours before the procedure and then 12 hours after the procedure is recommended for most patients. NaHCO3 In patients who are at high risk for volume overload in particular, those with chronic heart failure who have a left ventricular ejection fraction of less than 40%isotonic NaHCO3 solution should be administered before and after the procedure. It can be prepared by mixing 3 ampules of NaHCO3 in a liter of 5% dextrose in water (D5W) and can be given at a rate of 3 mL/kg/h for 1 hour prior to the procedure, with the rate decreased to 1 mL/kg/h during the procedure and for 6 hours afterward. N -acetylcysteine Another prophylactic agent, used with varying success, is oral N -acetylcysteine at a dosage of 1200 mg every 12 hours. This is administered to high-risk patients the day before a contrast study is performed and is continued the day of the procedure. Diuretics, nonsteroidal antiinflammatory drugs (NSAIDs), and possibly angiotensinconverting enzyme (ACE) inhibitors should be withheld near the time of the procedure.[27] Any protective effect of N -acetylcysteine would appear to be limited to patients receiving radiocontrast. A metaanalysis of patients undergoing major surgery found no evidence that N -acetylcysteine used perioperatively can alter mortality or renal outcomes when radiocontrast is not used.[28] Even among patients receiving radiocontrast, N acetylcysteine appears to provide only borderline benefit.[29] Other agents Similarly, a review of randomized, controlled trials of other measures used to protect renal function perioperatively (eg, the administration of dopamine, diuretics, calciumchannel blockers, NSAIDs, ACE inhibitors, or hydration fluids) found no reliable evidence that these interventions are effective.[30] Long-Term Monitoring Renal recovery in most cases is not complete, with the kidneys remaining vulnerable to the nephrotoxic effects of all therapeutic agents. Therefore, agents with nephrotoxic potential are best avoided. Renal recovery is usually observed within the first 2 weeks, and many nephrologists tend to diagnose patients with endstage (ie, irreversible) renal failure 6-8 weeks after the onset of AKI. It is always better to check these patients periodically, because some patients may regain renal function much later. Medication Summary

Pharmacologic treatment of acute kidney injury (AKI) has been attempted on an empiric basis with varying success rates. Several promising experimental therapies in animal models are awaiting human trials. Experimental therapies include growth factors, vasoactive peptides, adhesion molecules, endothelin inhibitors, and bioartificial kidneys. Aminophylline has also been used experimentally for prophylaxis against renal failure. There is no specific pharmacologic therapy proven to treat AKI secondary to hypoperfusion and/or sepsis. The only therapeutic or preventive intervention that has an established beneficial effect in the management of AKI is the intravenous (IV) administration of isotonic sodium chloride solution. It should be given in quantities sufficient to keep the patient euvolemic or even hypervolemic. Diuretics, Loop Class Summary Although diuretics seem to have no effect on the outcome of established AKI, they appear to be useful in fluid homeostasis and are used extensively. They have also been used to reduce the requirement for renal replacement therapy. The use of isotonic sodium chloride solution in conjunction with diuretics is debatable. View full drug information Furosemide (Lasix) Furosemide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the thick ascending loop of Henle and the distal renal tubule. It is a potent and rapid-acting agent with peak action at 60 minutes and a 6- to 8-hour duration of action. In renal failure, higher doses must be used for greater diuretic effect. Doses as high as 600 mg/day may be needed under monitored conditions. Frequently, IV doses are needed in AKI to maintain urine output. IV infusions are often helpful in intensive care settings, in which larger doses are necessary. This method promotes a sustained natriuresis with reduced ototoxicity compared with conventional intermittent bolus dosing. Inotropic Agents Class Summary Dopamine in small doses (eg, 1-5 mcg/kg/min) causes selective dilatation of the renal vasculature, enhancing renal perfusion. Dopamine also reduces sodium absorption, thereby decreasing the energy requirement of the damaged tubules. This enhances urine flow, which, in turn, helps to prevent tubular cast obstruction. The clinical benefit of low-dose dopamine remains uncertain. View full drug information Dopamine (Intropin) Dopamine stimulates adrenergic and dopaminergic receptors. Its hemodynamic effect is dose dependent. Lower doses (0.5-3.0 mcg/kg/min) predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Higher doses produce cardiac stimulation and renal vasodilation. Potential complications of dopamine use include cardiac arrhythmias, myocardial ischemia, and intestinal ischemia.

Vasodilators Class Summary Fenoldopam decreases systemic vascular resistance and increases renal blood flow to the cortex and medullary regions in the kidney. It has been noted to improve renal function in patients with severe hypertension. View full drug information Fenoldopam (Corlopam) Fenoldopam is a selective dopamine-receptor agonist that acts as a rapid-acting vasodilator. It is 6 times more potent than dopamine in producing renal vasodilation. It increases diuresis and has minimal adrenergic effects. Fenoldopam is indicated for the treatment of severe hypertension, including patients with renal compromise. Calcium Channel Blockers Class Summary These drugs are effective in animal models of AKI, but their efficacy has not been proven in humans. The effects of calcium channel blockers are believed to be mediated through vasodilation, and they are increasingly used to enhance the function of transplanted kidneys. View full drug information Nifedipine (Adalat, Procardia, Afeditab CR, Nifediac CC, Nifedical XL) Nifedipine relaxes smooth muscle and produces vasodilation, which, in turn, improves blood flow and oxygen delivery. Antidotes, Other Class Summary N -acetylcysteine is used for the prevention of contrast toxicity in susceptible individuals, such as those with diabetes mellitus. The mechanism by which it prevents contrast-induced nephropathy is presumed to be its ability to scavenge free radicals and improve endotheliumdependent vasodilation. View full drug information N-acetylcysteine (Acetadote) This drug may provide substrate for conjugation with toxic metabolites.