Acute Kidney Injury

General Principles

Definition

According to the KDIGO 2012 guidelines, AKI is defined and categorized by varying Cr elevations or decreases in urine output.1

  • Stage 1 AKI is defined as a Cr 1.5–1.9 times baseline (known or presumed to have occurred within the prior 7 days), an increase in Cr ≥ 0.3 mg/dL within 48 hours, or a urine output <0.5 mL/kg/h for 6–12 hours.
  • Stage 2 AKI is defined as a Cr 2–2.9 times baseline or a urine output <0.5 mL/kg/h for at least 12 hours.
  • Stage 3 AKI is defined as a Cr ≥ 3 times baseline, a Cr increase of ≥4 mg/dL, initiation of renal replacement therapy, urine output <0.3 mL/kg/h for at least 24 hours, or anuria for at least 12 hours.

Classification

Renal failure can be classified as oliguric or nonoliguric based on the amount of urine output. Cutoffs of approximately 500 mL/d or 25 mL/h for 6–12 hours are frequently used in clinical practice.

Etiology

The etiology of AKI should be determined when possible. It can be classified based on the anatomic location of the physiologic defect. Prerenal disease involves a disturbance of renal perfusion, whereas postrenal disease involves obstruction along the urinary collecting system. Intrinsic renal disease involves the tubules, glomeruli, microvasculature, or interstitium of the kidneys. Table 13-1 lists some of the common causes of AKI.

Table 13-1: Causes of Acute Renal Failure
PrerenalIntrinsicPostrenal
Hypovolemia
Hypotension (including sepsis)
Loss of autoregulation (NSAIDs, RAAS blockers)
Abdominal compartment syndrome
Renal artery stenosis
Heart failure
Hepatic cirrhosis
Tubular: Ischemic ATN, toxic ATN (contrast, pigment, uric acid)
Vascular: Glomerulonephritis, dysproteinemia, thrombotic microangiopathy (HUS, TTP), atheroembolic disease
Interstitial: Acute interstitial nephritis, pyelonephritis
Urethral obstruction
Ureteral obstruction (bilateral, or unilateral if solitary kidney)

ATN, acute tubular necrosis; HUS, hemolytic uremic syndrome; RAAS, renin–angiotensin–aldosterone system; TTP, thrombotic thrombocytopenic purpura.

Prerenal

  • The term prerenal azotemia implies that the inherent function of the kidneys is preserved, in the setting of renal hypoperfusion and reduced GFR. States of decreased effective circulating blood volume, resulting from intravascular volume depletion, low cardiac output, or disordered vasodilation (hepatic cirrhosis), may also result in prerenal azotemia.
  • When the cause is true volume depletion, presentation involves a history of excessive volume loss or reduced intake. The physical examination may reveal dry mucous membranes, poor skin turgor, and orthostatic vital signs (drop in blood pressure by at least 20/10 mm Hg or an increase in heart rate by 10 bpm after standing from a seated or lying position). The central venous pressure is typically <8 cm H2O.
  • Low cardiac output causes prerenal azotemia via a drop in the effective circulating volume despite being in a state of total body volume overload. Sympathetic and neurohormonal activation stimulates the renin–angiotensin–aldosterone system (RAAS) for sodium reclamation, as well as driving antidiuretic hormone (ADH), promoting further water retention. This can lead to an increased reabsorption of urea nitrogen in relation to creatinine, and patients present with a prerenal pattern on laboratory investigations (BUN:Cr ratio >20, urine sodium <20 mEq/L, fractional excretion of sodium <1%). In heart failure, diuresis may paradoxically improve the prerenal azotemia by unloading the ventricles and improving cardiac function and renal perfusion (see Chapter 5, Heart Failure and Cardiomyopathy). The use of ultrafiltration (UF) was evaluated and found to be inferior to pharmacologic therapies, resulting in more adverse events in the treatment of acute decompensated heart failure.2
  • Hepatic failure with splanchnic vasodilation, venous pooling, and ascites ­formation diminishes the effective circulating volume. RAAS activation along with ADH secretion will produce a prerenal pattern on laboratory investigations, despite being in a state of total body volume overload. This can progress to hepatorenal syndrome (HRS), which is characterized by a rise in serum creatinine of >1.5 mg/dL that is not reduced with administration of albumin (1 g/kg of body weight) and after a minimum of 2 days off diuretics. The diagnosis of HRS should be made in the absence of shock, nephrotoxic agents, or findings of renal parenchymal disease (e.g., active urinary sediment on urine microscopy).3 Spontaneous bacterial peritonitis, aggressive diuresis, gastrointestinal bleeding, or large-volume paracentesis can precipitate HRS in patients with liver cirrhosis. Management of the renal disease is supportive, and if definitive treatment of the liver disorder (either through recovery or via transplantation) can occur, renal recovery is common. Temporizing measures include treatment of the underlying precipitating factor (e.g., peritonitis, gastrointestinal bleeding, hypotension) and withholding diuretics or other offending agents. Dialytic support can be used as a bridge to transplantation in appropriate candidates, with anticipation of renal recovery if the period of dialysis dependence is shorter than 6 weeks.
  • Simultaneous liver kidney (SLK) transplant should be considered if the candidate meets specific criteria published in 2016 by the US Organ Procurement and Transplant Network (OPTN) and the United Network for Organ Sharing (UNOS). These include CKD with a GFR ≤35 mL/min/1.73 m2, sustained AKI with a GFR ≤25 mL/min/1.73 m2, or dialysis dependence for at least 6 weeks. Patients with the diagnosis of a metabolic disease that would place a renal allograft at risk of failing, such as primary hyperoxaluria, atypical hemolytic uremic syndrome (HUS) from mutations in factor H or factor I, familial non-neuropathic systemic amyloidosis, or methylmalonic aciduria, would also be candidates for SLK.4 Additional treatment options are discussed further in Chapter 19, Liver Diseases.
  • In the volume-depleted patient, certain medications can affect the ability of the kidney to autoregulate blood flow and maintain GFR. NSAIDs inhibit the counterbalancing vasodilatory effects of prostaglandins at the afferent arteriole and can induce AKI in volume-depleted patients. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can cause efferent arteriolar vasodilation and a drop in the GFR.
  • Abdominal compartment syndrome from intestinal ischemia, obstruction, or massive ascites can compromise flow through the renal vasculature via increased intra-abdominal pressure (IAP). An IAP >20 mm Hg, measured via a pressure transducer attached to the bladder catheter in a patient who is sedated, supports the diagnosis.

Postrenal

  • Postrenal injury occurs when the flow of urine is obstructed within the collecting system. Common causes include prostatic enlargement, bilateral kidney stones, or malignancy (e.g., extrinsic compression by a mass, retroperitoneal fibrosis). The increased intratubular hydrostatic pressure leads to the diminished GFR. Bilateral involvement (or unilateral obstruction to a solitary functioning kidney) is generally required to produce a significant change in the Cr level. When this diagnosis is suspected, a renal ultrasound should be obtained early to evaluate for hydronephrosis. Note that hydronephrosis may be less pronounced when there is concomitant volume depletion or if retroperitoneal fibrosis has encased the ureters, preventing their dilation. Therefore, if this diagnosis is still suspected, renal ultrasound should be repeated after the patient has received adequate volume repletion.
  • Treatment depends on the level of obstruction. When urethral flow is impeded (often by prostatic enlargement in men), placement of a bladder catheter can be both diagnostic and therapeutic; a postvoid residual urine volume >300 mL suggests the diagnosis. When the upper urinary tract is involved, urologic or radiologic decompression may be necessary, with stenting or placement of percutaneous nephrostomy tubes.
  • Relief of bilateral obstruction is frequently followed by a postobstructive diuresis. Serum electrolytes need to be closely monitored if polyuria ensues, and replacement of approximately half of the urinary volume with 0.45% saline is recommended.
  • Crystals may cause micro-obstructive uropathy within the tubules. IV acyclovir and the protease inhibitor indinavir can induce AKI by this mechanism. The urine may show evidence of crystals, although sometimes not until urine flow is re-established. Treatment is typically supportive after the offending agent is discontinued. As with resolution of other forms of obstructive uropathy, a polyuric phase may occur.

Intrinsic Renal

Causes of intrinsic renal failure can be divided anatomically into tubular, glomerular/vascular, and interstitial categories. Disease can be primarily renal in nature or part of a systemic process.

  • Tubular
    • Ischemic acute tubular necrosis (ATN) is the most common cause of renal failure in the hospital setting, especially in the intensive care unit, and is the end result of any process that leads to significant hypoperfusion of the kidneys, including sepsis, hemorrhage, or any prolonged prerenal insult.
      • The injury results in the sloughing of renal tubular cells, with this cellular debris congealing in a matrix of Tamm–Horsfall protein to form granular casts. The casts have a “muddy brown” appearance and are strongly suggestive of ATN in the appropriate clinical context. The fractional excretion of sodium (FENa) (>1%) and fractional excretion of urea (FEUrea) (>35%) are typically elevated as the tubules lose their ability to concentrate the urine. However, these calculations are not specific to ATN.
      • Management of ATN is supportive, with avoidance of further nephrotoxic insults. Fluid management is aimed at maintaining euvolemia. Volume deficits, if present, should be corrected. If there are signs of volume overload and oliguria, a furosemide stress test may predict the severity of AKI. A single furosemide dose of 1.0 or 1.5 mg/kg (depending on prior furosemide exposure) is administered, and the urine output in the first 2 hours is measured. A 2-hour urine output of less than 200 mL offers the best combination of sensitivity and specificity and has a good predictive capacity to identify those patients who will progress to advanced stages of AKI. Patients must be euvolemic or hypervolemic to qualify for this test and should not be on pressor support.5 Continuing diuretic therapy if a response is seen has not been shown to hasten recovery but can simplify overall management.
      • Recovery from ATN may take days to weeks to occur but can be expected in >85% of patients with previously normal renal function. Dialysis may be necessary to bridge the time to recovery.
    • Toxic ATN can result from endogenous chemicals (e.g., hemoglobin, myoglobin pigments) or medications (e.g., iodinated contrast, aminoglycosides, combination of vancomycin and piperacillin/tazobactam). These forms share many of the diagnostic features of ischemic ATN.
      • Iodinated contrast is a potent renal vasoconstrictor and is toxic to renal tubules. When renal injury occurs, the Cr typically rises 24–48 hours after exposure and peaks in 3–5 days. Risk factors for contrast nephropathy include underlying CKD, age >75 years, diabetes, volume depletion, heart failure, higher contrast volumes, and use of hyperosmolar contrast. Preventative measures include periprocedural IV volume expansion and discontinuation of diuretics within 24 hours of the procedure. Normal saline at 150 mEq/L can be given at 3 mL/kg/h for 1 hour before exposure, then at 1 mL/kg/h for 6 hours after the procedure. In a large randomized controlled trial, sodium bicarbonate was not found to be superior to normal saline, whereas acetylcysteine was equivocal to placebo and therefore is not recommended.6
      • Aminoglycoside nephrotoxicity is typically nonoliguric, occurs from direct toxicity to the proximal tubules, and results in the renal wasting of potassium and magnesium. Replacement of these electrolytes may become necessary. A similar pattern of potassium and magnesium loss is seen in cisplatin toxicity. A prolonged exposure to the aminoglycoside of at least 5 days is required. Peak and trough levels correlate poorly with the risk of developing renal injury. Risk may be minimized by avoiding volume depletion and by using the extended-interval dosing method (see Chapter 15, Antimicrobials).
      • Pigment nephropathy results from direct tubular toxicity by hemoglobin and myoglobin. Vasoconstriction may also play a role. The diagnosis may be suspected by a positive urine dipstick test for blood but an absence of RBCs on microscopic examination. In rhabdomyolysis, the creatine kinase level is elevated to at least 10 times the upper limit of normal with a disproportionate rise in the serum Cr. Potassium and phosphorus may also be elevated in the setting of muscle breakdown. Aggressive IV fluid administration with normal saline should be initiated immediately, and large volumes are required to replace the fluid lost into necrotic muscle tissue. Urinary alkalinization with intravenous sodium bicarbonate is not generally recommended as it may worsen the hypocalcemia.
      • In tumor lysis syndrome, there is rapid death of cancer cells either spontaneously or in response to treatment. In addition to the elevated Cr, there is typically hyperuricemia, hyperphosphatemia, and hypocalcemia. A ratio of urine uric acid to urine Cr that is >1 is consistent with acute uric acid nephropathy, as is the finding of uric acid crystals in the urine sediment. Prophylaxis with allopurinol 600 mg can decrease uric acid production. Rasburicase (15 mg/kg IV) is highly effective at depleting uric acid levels and can be given as prophylaxis or as treatment. Alkalinization of the urine should be avoided if hyperphosphatemia is present because this could increase the risk of calcium phosphate precipitation in the urine.
  • Glomerular/vascular
    • The finding of dysmorphic urinary RBCs, RBC casts, or proteinuria in the nephrotic range (>3.5 g/d) would strongly suggest the presence of a glomerular disease. Glomerular diseases are described individually in further detail in later sections of this chapter.
    • A subset of glomerular diseases can present with rapidly deteriorating renal function, termed rapidly progressive glomerulonephritis. This describes a type of presentation rather than a specific disease. A nephritic picture is common, with RBC casts, edema, and hypertension. Crescent formation is seen in >50% of glomeruli, suggesting inflammation and cellular proliferation. For those deemed to have salvageable renal function, management typically consists of high-dose corticosteroids and cyclophosphamide or other potent immunosuppressive agents.
    • Thrombotic microangiopathy (TMA) is a general term encompassing a broad spectrum of disease resulting in hemolytic anemia, platelet consumption, and intracapillary thrombi, with associated endothelial cell injury. Differentiating among the various causes of this entity can allow for better targeted therapy. Hemolytic uremic syndrome (HUS) results from diarrheal bacterial toxins (e.g., Shiga and Shiga-like toxin) that cause direct injury to the endothelial cells. Thrombotic thrombocytopenic purpura (TTP) can result from a reduced activity of ADAMTS13 (due to deficiency or inhibitory antibodies) leading to von Willebrand factor–rich microthrombi secondarily affecting arterioles and capillaries of a variety of organs. Atypical HUS has been described in patients with mutations or inhibitors in proteins that regulate the complement cascade, such as factor H and factor I, responsive to treatment with eculizumab, a C5 inhibitor.7 Malignant hypertension and a variety of medications (e.g., mitomycin C, clopidogrel, gemcitabine, tacrolimus) have also been associated with TMA. Classification, diagnosis, and therapy are discussed in Chapter 20, Disorders of Hemostasis and Thrombosis.
    • Atheroembolic disease can be seen in patients with diffuse atherosclerosis after undergoing an invasive aortic or other large artery manipulation, including cardiac catheterization, coronary arterial bypass grafting, aortic aneurysm repair, and placement of an intra-aortic balloon pump. Physical findings may include retinal arteriolar plaques, lower extremity livedo reticularis, and areas of digital necrosis. Peripheral eosinophilia and hypocomplementemia may be present, and WBC casts may be found in the urine sediment. However, in many cases, the only laboratory abnormality is a rising Cr that follows a stepwise progression. Renal biopsy shows cholesterol clefts in the small arteries. Anticoagulation may worsen embolic disease and should be avoided if possible. No specific treatment is available. Many patients progress to CKD and even to end-stage renal disease (ESRD).
  • Interstitial
    • Acute interstitial nephritis (AIN) involves an acute inflammation of the renal parenchyma. The causes of AIN are broad and include medications (in >70% of cases), infectious agents, and systemic diseases. β-Lactam antibiotics are the most frequently cited causative agents, but nearly all antibiotics can be implicated. Other medications, such as proton pump inhibitors, 5-aminosalicylates, and allopurinol, have been associated with AIN. NSAIDs can produce a chronic interstitial nephritis with nephrotic range proteinuria. Streptococcal infections, leptospirosis, and sarcoidosis have also been implicated in AIN. The classic triad of fever, rash, and eosinophilia is seen in less than one-third of patients, and its absence does not exclude the diagnosis. Pyuria and WBC casts on urine microscopy are also suggestive of AIN. The time course typically requires exposure for at least 5–10 days before renal impairment occurs.
    • Treatment is principally withdrawal of the offending agent. Renal recovery typically ensues, although the time course is variable, and temporary dialytic support may be necessary in severe cases. A short course of prednisone at 1 mg/kg/d may hasten recovery.8
    • Parenchymal infections with pyelonephritis or renal abscesses are uncommon causes of AKI. Bilateral involvement is usually necessary to induce a rise in Cr. Urine findings include pyuria and WBC casts, and antibiotic therapy is guided by culture results.

Diagnosis

  • Uncovering the cause of AKI requires careful attention to the events preceding the rise in Cr. In the hospitalized patient, blood pressure patterns, irregular cardiac rhythms, hydration status, medications, and iodinated contrast use must be investigated. Antibiotic dose and duration as well as PRN medications should not be overlooked.
  • Evidence of ongoing hypovolemia or hypoperfusion is suggestive of prerenal disease but may have progressed to an acute tubular injury pattern. Most causes of postrenal disease are identified on ultrasound by dilation of the collecting system or by massive urine output upon placement of a bladder catheter. However, obstruction cannot be completely ruled out even if not identified on imaging, especially in the setting of early obstruction or volume depletion. Patients may need volume resuscitation and an ultrasound repeated in several days if renal function does not improve.
  • Urinary casts point toward an intrinsic cause of AKI. Granular casts (“muddy brown”) suggest ATN, WBC casts suggest an inflammatory or infectious interstitial process, and RBC casts strongly suggest glomerular disease. Identification of crystals in the urine sediment may be supportive of kidney disease related to intoxication of ethylene glycol, uric acid excretion, tumor lysis syndrome, or medications such as acyclovir and indinavir. This underscores the importance of examining urinary sediment in the evaluation of AKI.
  • Various laboratory parameters can be used to differentiate prerenal states from ATN in oliguric patients and are summarized in Table 13-2. The basis for these tests is to evaluate tubular integrity, which is preserved in prerenal disease but lost in ATN. In states of hypoperfusion, the kidneys should avidly reabsorb sodium, resulting in a low FENa: FENa = ([UNa × PCr]/[PNa × UCr]) × 100, where U is urine and P is plasma.
  • A value <1% suggests renal hypoperfusion with intact tubular function. Loop diuretics and metabolic alkalosis can induce natriuresis, increase the FENa, and mask the presence of renal hypoperfusion. The FEUrea can instead be calculated in these settings, where a value of <35% suggests a prerenal process.
  • Contrast and pigment nephropathy can result in a low FENa because of early vasoconstriction (“prerenal” drop in glomerular perfusion), as can glomerular diseases because of intact tubular function. The FENa also has limited utility when AKI is superimposed on CKD because the underlying tubular dysfunction makes the test difficult to interpret.
  • With hypoperfusion, the urine is typically concentrated, containing an osmolality >500 mOsm/kg and a high specific gravity (>1.020). In ATN, concentrating ability is lost and the urine is usually isosmolar to the serum (isosthenuria). In the blood, the ratio of BUN to Cr is normally <20:1, and an elevation is consistent with hypovolemia.
  • The FENa should not be used alone to determine the cause of AKI, but instead interpreted in the context of the patient and clinical scenario.
Table 13-2: Laboratory Findings in Oliguric Acute Kidney Injury
DiagnosisBUN:CrFENa (%)Urine Osmolality (mOsm/kg)Urine NaUrine SGSediment
Prerenal azotemia>20:1<1>500<20>1.020Bland
Oliguric ATN<20:1>1<350>40VariableGranular casts

ATN, acute tubular necrosis; BUN, blood urea nitrogen; Cr, creatinine; FENa, fractional excretion of sodium; SG, specific gravity.

Treatment

  • Disease-specific therapies are covered in their respective sections. In general, treatment of AKI is primarily supportive in nature. Volume status should be evaluated to correct for hypovolemia or hypervolemia. Volume deficits, if present, should be corrected, after which the goal of fluid management should be to keep input equal to output. In the oliguric volume-overloaded setting, a trial of diuretics (usually high-dose loop diuretics in a bolus or as a continuous drip) may simplify management, although it has not been shown to hasten recovery.
  • Electrolyte imbalances should be corrected in the setting of AKI. Hyperkalemia, when mild (<6 mEq/L), may be treated with dietary potassium restriction and potassium-binding resins (e.g., sodium polystyrene sulfonate, sodium zirconium cyclosilicate). When further elevated or accompanied by ECG abnormalities, immediate medical therapy is indicated with calcium gluconate, insulin and glucose, inhaled β-agonists, and possibly bicarbonate (see Chapter 12, Fluid and Electrolyte Management). Severe hyperkalemia that is refractory to medical management is an indication for urgent dialysis.
  • Mild metabolic acidosis can be treated with oral sodium bicarbonate, 650–1300 mg three times daily. Severe acidosis (pH <7.2) can be temporized with IV sodium bicarbonate but requires monitoring for volume overload, rebound alkalosis, and hypocalcemia. Acidosis that is refractory to medical management is an indication for urgent dialysis.

Special Considerations

  • Patients with AKI require daily assessment to determine the need for renal replacement therapy. Severe acidosis, hyperkalemia, or volume overload refractory to medical management mandates the initiation of dialysis. Certain drug and alcohol intoxications (methanol, ethylene glycol, or salicylates) should be treated with hemodialysis. Uremic pericarditis (with a friction rub) or encephalopathy should also be treated promptly with renal replacement therapy. Patients suffering from acute oliguric renal failure who are not expected to recover promptly may benefit from earlier initiation of dialysis.
  • In the absence of one of these acute indications, the timing of initiating dialytic therapy is less certain. Two studies analyzed this subject in ICU patients in a randomized controlled fashion with somewhat contradictory results. Starting dialytic support in patients with a threefold elevation in Cr or a Cr of 4 mg/dL or greater did not show improved outcomes as compared to delaying dialysis until a traditional indication developed.9 A smaller study, however, did show a survival advantage for patients beginning dialysis with a two- to threefold increase in Cr, as compared to patients with more severe elevations.10

References

  1. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-c184.  [PMID:22890468]
  2. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012;367:2296-2304.  [PMID:23131078]
  3. Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009;361:1279-1290.  [PMID:19776409]
  4. Formica RN, Aeder M, Boyle G, et al. Simultaneous liver-kidney allocation policy: a proposal to optimize appropriate utilization of scarce resources. Am J Transplant. 2016;16(3):758-766.  [PMID:26603142]
  5. Chawla LS, Davison DL, Brasha-Mitchell E, et al. Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Crit Care. 2013;17(5):R207.  [PMID:24053972]
  6. Weisbord SD, Gallagher M, Jneid H, et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med. 2018;378:603-614.  [PMID:29130810]
  7. Noone D, Waters A, Pluthero FG, et al. Successful treatment of DEAP-HUS with eculizumab. Pediatr Nephrol. 2014;29:841-851.  [PMID:24249282]
  8. González E, Gutiérrez E, Galeano C, et al. Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int. 2008;73(8):940-946.  [PMID:18185501]
  9. Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for renal-replacement therapy in the intensive care unit. N Engl J Med. 2016;375:122-133.  [PMID:27181456]
  10. Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial. JAMA. 2016;315:2190-2199.  [PMID:27209269]

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