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.⁴

• 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 dependence for at least 6 weeks.

• 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. Angiotensin­converting 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.

• 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.

/NTRINSiC 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

î 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 (FE_Na) (>1%) and fractional excretion of urea (FE_urea) (>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.⁸ 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. î 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.

■ 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 inj ury. 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.

■ 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

î 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.

î 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.

î 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.

î 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

î 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.

î 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.¹¹

î 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 FE_Na: FE_Na = ([U_Na ? P_Cr]/[P_Na ? U_Cr]) ? 100, where U is urine and P is plasma.

TABLE 13-2

LABORATORY FINDINGS IN OLIGURIC ACUTE KIDNEY INJURY

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

• A value The FE_urea can instead be calculated in these settings, where a value of 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 followed by long-term oral anticoagulation.

• Anticoagulation is absolutely indicated in the setting of deep venous thrombosis or pulmonary embolism. Prophylactic anticoagulation should be considered in severely nephrotic patients with a serum albumin 3500 cells∕μL. Rituximab, a monoclonal antibody directed against CD20, has shown promise in a variety of immune-mediated disorders, including severe lupus nephritis, MN, and ANCA-associated vasculitis.¹⁵ Other immunosuppressive agents include calcineurin inhibitors (e.g., tacrolimus, cyclosporine) and mycophenolate mofetil. Therapeutic plasma exchange has a role in only specific circumstances as described in more detail below.