Definition

Acute renal failure (ARF) or acute kidney injury (AKI), defined as a measurable increase in the serum creatinine (Cr) concentration (usually relative increase of 50% or absolute increase by 44-88 µmol/L [0.5-1.0 mg/dL]), occurs in ∼5-7% of hospitalized pts. It is associated with a substantial increase in in-hospital mortality and morbidity. AKI can be anticipated in some clinical circumstances (e.g., after radiocontrast exposure or major surgery), and there are no specific pharmacologic therapies proven helpful at preventing or reversing the condition. It is important to recognize that AKI is a clinical diagnosis and not a structural one. A pt may have AKI with or without injury to the kidney parenchyma. AKI can range in severity from asymptomatic and transient changes in laboratory parameters of glomerular filtration rate (GFR), to overwhelming and rapidly fatal derangements in effective circulating volume regulation and electrolyte and acid-base composition of the plasma. Maintaining optimal renal perfusion and intravascular volume is critical in most clinical circumstances; important cofactors in AKI include hypovolemia and drugs that interfere with renal perfusion and/or glomerular filtration (nonsteroidal anti-inflammatory drugs [NSAIDs], angiotensin-converting enzyme [ACE] inhibitors, and angiotensin receptor blockers).

Differential Diagnosis

The separation into three broad categories (prerenal, intrinsic renal, and postrenal failure) is of considerable clinical utility (Table 141-1 Common Causes of Acute Kidney Injury). Prerenal failure is most common among hospitalized pts. It may result from true volume depletion (e.g., diarrhea, vomiting, GI or other hemorrhage) or “arterial underfilling,” i.e., reduced renal perfusion in the setting of adequate or excess blood volume. Reduced renal perfusion may be seen in congestive heart failure (CHF) (due to reduced cardiac output and/or potent vasodilator therapy), hepatic cirrhosis (due mostly to peripheral vasodilation and arteriovenous shunting), nephrotic syndrome and other states of severe hypoproteinemia (total serum protein <54 g/L [<5.4 g/dL]), and renovascular disease (because of fixed stenosis at the level of the main renal artery or large branch vessels). Several drugs can reduce renal perfusion, most notably NSAIDs. ACE inhibitors and angiotensin II receptor antagonists may reduce GFR but do not tend to reduce renal perfusion.

Causes of intrinsic renal failure depend on the clinical setting. Among hospitalized pts, especially on surgical services or in intensive care units, acute tubular necrosis (ATN) is the most common diagnosis. A well-defined ischemic event or toxic exposure (e.g., aminoglycoside therapy) may lead to in-hospital ATN. Alternatively, pts may be admitted to the hospital with ATN associated with rhabdomyolysis; common predisposing factors in rhabdomyolysis include alcoholism, hypokalemia, and various drugs (e.g., statins). Allergic interstitial nephritis, usually due to antibiotics (e.g., penicillins, cephalosporins, sulfa drugs, quinolones, and rifampin), or NSAIDs, may also be responsible. More recently, the use of immune checkpoint inhibitors in cancer therapy has been linked to the development of interstitial nephritis. Radiographic contrast dyes may cause AKI in pts with preexisting kidney disease; the risk is substantially higher in diabetics with chronic kidney disease. Coronary angiography, other vascular procedures, thrombolysis, or anticoagulation may lead to atheroemboli, which cause AKI due to both hemodynamic and inflammatory effects; livedo reticularis, embolic phenomena with preserved peripheral pulses, and eosinophilia are important clues to this diagnosis. Acute glomerulonephritis (GN) (Chap. 145 Glomerular Diseases) and thrombotic microangiopathies may also cause AKI. Thrombotic microangiopathies can be clinically subdivided into renal-limited forms (e.g., Escherichia coli-associated hemolytic uremic syndrome [HUS]) and systemic forms (e.g., thrombotic thrombocytopenic purpura [TTP]). “Atypical HUS,” occurring in the absence of HUS-associated bacterial toxins, is associated with hereditary mutations in complement proteins or complement regulatory proteins, leading to exaggerated endothelial sensitivity to complement-mediated cytolysis. A variety of drugs can cause thrombotic microangiopathies, including calcineurin inhibitors (cyclosporine and tacrolimus), quinine, antiplatelet agents (e.g., ticlopidine), inhibitors of the action of vascular endothelial growth factor (VEGF), and chemotherapeutics (e.g., and gemcitabine). Important associated disorders in TTP include HIV infection, bone marrow transplantation, systemic lupus erythematosus (SLE), and antiphospholipid syndrome.

Postrenal failure is due to urinary tract obstruction, which is also more common among ambulatory rather than hospitalized pts. More common in men than women, it is most often caused by ureteral or urethral blockade. Occasionally, stones, sloughed renal papillae, or malignancy (primary or metastatic) may cause more proximal obstruction.

Characteristic Findings and Diagnostic Workup

All pts with AKI manifest some degree of azotemia (increased blood urea nitrogen [BUN] and Cr). Other clinical features depend on the etiology of renal disease. Pts with prerenal azotemia due to volume depletion usually demonstrate orthostatic hypotension, tachycardia, low jugular venous pressure, and dry mucous membranes. Pts with prerenal azotemia and CHF (“cardiorenal syndrome”) may show jugular venous distention, an S₃ gallop, and peripheral and pulmonary edema. Therefore, the physical examination is critical in the workup of pts with prerenal AKI. In general, the BUN/Cr ratio tends to be high (>20:1), more so with volume depletion and CHF than with cirrhosis. The uric acid may also be disproportionately elevated in noncirrhotic prerenal states (due to increased proximal tubular absorption). Urine chemistries tend to show low urine [Na⁺ ] (<10-20 mmol/L, <10 with hepatorenal syndrome) and a fractional excretion of sodium (FE_Na) of <1% (Table 141-2 Urine Diagnostic Indices in Differentiation of Prerenal versus Intrinsic Renal Azotemia). The urinalysis (UA) typically shows hyaline and a few granular casts, without cells or cellular casts. Renal ultrasonography is usually normal.

Pts with intrinsic renal disease present with varying complaints. GN is often accompanied by hypertension and mild to moderate edema (associated with Na retention and proteinuria, and sometimes with gross hematuria). An antecedent prodromal illness and/or prominent extrarenal symptoms and signs may occur if GN occurs in the context of a systemic illness, e.g., vasculitis or SLE; these may include hemoptysis or pulmonary hemorrhage (vasculitis and Goodpasture's syndrome), arthralgias/arthritis (vasculitis or SLE), serositis (SLE), and unexplained sinusitis (vasculitis). The urine chemistries may be indistinguishable from those in pts with prerenal failure; in fact, some pts with GN have renal hypoperfusion (due to glomerular inflammation and ischemia) with resultant hyperreninemia leading to acute volume expansion and hypertension. The urine sediment can be very helpful in these cases. Red blood cell (RBC), white blood cell (WBC), and cellular casts are characteristic of GN; RBC casts are rarely seen in other conditions (i.e., they are highly specific). In the setting of inflammatory nephritis (GN or interstitial nephritis, see next), there may be increased renal echogenicity on ultrasonography. Unlike pts with GN, pts with interstitial diseases are less likely to have hypertension or proteinuria; a notable exception is NSAID-associated acute interstitial nephritis, which can be accompanied by proteinuria due to an associated minimal-change glomerular lesion. Hematuria and pyuria may present on UA. The classic sediment finding in allergic interstitial nephritis is a predominance (>10%) of urinary eosinophils with Wright's or Hansel's stain; however, urinary eosinophils can be increased in several other causes of AKI, such that measurement of urine eosinophils has no diagnostic utility in renal disease. WBC casts may also be seen, particularly in cases of pyelonephritis.

The urinary sediment of pts with ischemic or toxic ATN will characteristically contain pigmented “muddy-brown” granular casts and casts containing tubular epithelial cells; free tubular epithelial cells can also be seen. The FE_Na is typically >1% in ATN, but may be <1% in pts with milder, nonoliguric ATN (e.g., from rhabdomyolysis) and in pts with severe underlying “prerenal” disorders, such as CHF or cirrhosis.

Pts with postrenal AKI due to urinary tract obstruction are usually less severely ill than pts with prerenal or intrinsic renal disease, and their presentation may be delayed until azotemia is markedly advanced (BUN >54 µmol/L [150 mg/dL], Cr >1060-1325 µmol/L [12-15 mg/dL]). An associated impairment of urinary concentrating ability often “protects” the pt from complications of volume overload. Urinary electrolytes typically show an FE_Na >1%, and microscopic examination of the urinary sediment is usually bland. Ultrasonography is the key initial diagnostic tool. More than 90% of pts with postrenal AKI show obstruction of the urinary collection system on ultrasound (e.g., dilated ureter, calyces); false negatives include hyperacute obstruction and encasement of the ureter and/or kidney by tumor or of the ureter by retroperitoneal fibrosis, functionally obstructing urinary outflow without structural dilation. Other imaging techniques, such as a furosemide renogram (MAG3 nuclear medicine study), may be required to define better the presence or absence of obstructive uropathy.