Acute renal failure (ARF) is characterized by a rapid decline in glomerular filtration rate (GFR) over hours to days. Depending on the exact definition used, ARF complicates approximately 5–7% of hospital admissions and up to 30% of admissions to intensive care units. Retention of nitrogenous waste products, oliguria (urine output <400 mL/d contributing to extracellular fluid overload), and electrolyte and acid-base abnormalities are frequent clinical features. ARF is usually asymptomatic and diagnosed when biochemical monitoring of hospitalized patients reveals a new increase in blood urea and serum creatinine concentrations. For purposes of diagnosis and management, causes of ARF are generally divided into three major categories: (1) diseases that cause renal hypoperfusion, resulting in decreased function without frank parenchymal damage (prerenal ARF, or azotemia) (~55%); (2) diseases that directly involve the renal parenchyma (intrinsic ARF) (~40%); and (3) diseases associated with urinary tract obstruction (postrenal ARF) (~5%). ARF is often considered to be reversible, although a return to baseline serum creatinine concentrations postinjury might not be sufficiently sensitive to detect clinically significant irreversible damage that may ultimately contribute to chronic kidney disease. ARF is associated with significant in-hospital morbidity and mortality, the latter in the range of 30–60%, depending on the clinical setting and presence or absence of nonrenal organ system failure.
Etiology and Pathophysiology
Prerenal ARF (Prerenal Azotemia)
The most common form of ARF is prerenal ARF, which occurs in the setting of renal hypoperfusion. Prerenal ARF is generally reversible when renal perfusion pressure is restored. By definition, renal parenchymal tissue is not damaged. More severe or prolonged hypoperfusion may lead to ischemic injury, often termed acute tubular necrosis, or ATN. Thus, prerenal ARF and ischemic ATN fall along a spectrum of manifestations of renal hypoperfusion. As shown in Table 273-1, prerenal ARF can complicate any disease that induces hypovolemia, low cardiac output, systemic vasodilatation, or selective intrarenal vasoconstriction.
Table 273-1 Classification and Major Causes of Acute Renal Failure
A. Increased extracellular fluid losses: hemorrhage
B. Gastrointestinal fluid loss: vomiting, diarrhea, enterocutaneous fistula
D. Extravascular sequestration: burns, pancreatitis, severe hypoalbuminemia (hypoproteinemia)
E. Decreased intake: dehydration, altered mental status
II. Altered renal hemodynamics resulting in hypoperfusion
A. Low cardiac output state: diseases of the myocardium, valves, and pericardium (including tamponade); pulmonary hypertension or massive pulmonary embolism leading to right and left heart failure; impaired venous return (e.g., abdominal compartment syndrome or positive pressure ventilation)
B. Systemic vasodilation: sepsis, antihypertensives, afterload reducers, anaphylaxis
C. Renal vasoconstriction: hypercalcemia, catecholamines, calcineurin inhibitors, amphotericin B
D. Impairment of renal autoregulatory responses: cyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory drugs), angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers
E. Hepatorenal syndrome
I. Renovascular obstruction (bilateral, or unilateral in the setting of one kidney)
A. Renal artery obstruction: atherosclerotic plaque, thrombosis, embolism, dissection aneurysm, large vessel vasculitis
B. Renal vein obstruction: thrombosis or compression
B. Exogenous: acyclovir, gancyclovir, methotrexate, indinavir
Postrenal ARF (Obstruction)
I. Ureteric (bilateral, or unilateral in the case of one kidney): calculi, blood clots, sloughed papillae, cancer, external compression (e.g., retroperitoneal fibrosis)
II. Bladder neck: neurogenic bladder, prostatic hypertrophy, calculi, blood clots, cancer
III. Urethra: stricture or congenital valves
Hypovolemia leads to a fall in mean systemic arterial pressure, which is detected as reduced stretch by arterial (e.g., carotid sinus) and cardiac baroreceptors. In turn, this triggers a coordinated series of neurohormonal responses that aim to restore blood volume and arterial pressure. These include activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, as well as release of arginine vasopressin. Relatively "nonessential" vascular beds (such as the musculocutaneous and splanchnic circulations) undergo vasoconstriction in an attempt to preserve cardiac and cerebral perfusion pressure. In addition, salt loss through sweat glands is inhibited, and thirst and salt appetite are stimulated. Renal salt and water retention also occur.
In states of mild hypoperfusion, glomerular perfusion and the filtration fraction are preserved through several compensatory mechanisms. In response to the reduction in perfusion pressure, stretch receptors in afferent arterioles trigger afferent arteriolar vasodilatation through a local myogenic reflex (autoregulation). Angiotensin II increases biosynthesis of vasodilator prostaglandins (e.g., prostaglandin E2 and prostacyclin), also resulting in afferent arteriolar vasodilation. In addition, angiotensin II induces preferential constriction of efferent arterioles. As a result, the fraction of plasma flowing through glomerular capillaries that is filtered is increased (filtration fraction), intraglomerular pressure is maintained, and GFR is preserved. With more severe hypoperfusion, these compensatory responses are overwhelmed and GFR falls, leading to prerenal ARF.
Autoregulatory dilatation of afferent arterioles allows for maintenance of GFR despite systemic hypotension; however, when hypotension is severe or prolonged, these autoregulatory mechanisms fail, resulting in a precipitous decline in GFR. Lesser degrees of hypotension may provoke prerenal ARF in those at risk: the elderly and patients with diseases that affect the integrity of afferent arterioles (e.g., hypertensive nephrosclerosis, diabetic vasculopathy and other forms of occlusive (including atherosclerotic) renovascular disease). In addition, drugs that interfere with adaptive responses to hypoperfusion may convert compensated renal hypoperfusion into overt prerenal ARF or ATN. Pharmacologic inhibitors of renal prostaglandin biosynthesis [nonsteroidal anti-inflammatory drugs (NSAIDs)] or angiotensin-converting enzyme (ACE) activity (ACE inhibitors) and angiotensin II receptor blockers (ARBs) are major culprits. While NSAIDs do not compromise GFR in healthy individuals, these medications may precipitate prerenal ARF in patients with volume depletion or in those with chronic kidney disease (in whom GFR is maintained, in part, through prostaglandin-mediated hyperfiltration by the remaining functional nephrons). ACE inhibitors should be used with special care in patients with bilateral renal artery stenosis or unilateral stenosis in a solitary functioning kidney. In these settings, glomerular perfusion and filtration may be exquisitely dependent on the actions of angiotensin II. Angiotensin II preserves GFR in these circumstances by raising systemic arterial pressure and by triggering selective constriction of efferent arterioles. ACE inhibitors and ARBs blunt these responses and can precipitate ARF.
Hepatorenal syndrome (HRS) is a unique form of prerenal ARF that frequently complicates advanced cirrhosis as well as acute liver failure. In HRS the kidneys are structurally normal but fail due to splanchnic vasodilation and arteriovenous shunting, resulting in profound renal vasoconstriction. Correction of the underlying liver disease (e.g., by liver transplantation) results in resolution of the acute renal failure. There are two forms of HRS, type I and type II, that differ in their clinical course. In type I HRS, the more aggressive form of the disease, ARF progresses even after optimization of systemic hemodynamics and carries a mortality rate of >90%. The diagnosis and management of this condition are discussed in Chap. 302.
Intrinsic causes of ARF can be conceptually divided based on the predominant compartment of the kidney that is affected: (1) ischemic or nephrotoxic tubular injury, (2) tubulointerstitial diseases, (3) diseases of the renal microcirculation and glomeruli, and (4) diseases of larger renal vessels (Table 273-1). Ischemia and nephrotoxins classically induce acute tubular injury. Although many patients with ischemic or nephrotoxic ARF do not have morphologic evidence of cellular necrosis, this disease is often referred to as acute tubular necrosis , or ATN. More recently, because of the important role of sublethal injury to tubular epithelial and other renal cells (e.g., endothelial cells) in the pathogenesis of this syndrome, the term acute kidney injury (AKI) has been proposed.
Etiology and Pathophysiology of Ischemic ATN
Prerenal ARF and ischemic ATN are part of a spectrum of manifestations of renal hypoperfusion. In its most extreme form, ischemia leads to bilateral renal cortical necrosis and irreversible renal failure. ATN differs from prerenal ARF in that the renal tubular epithelial cells are injured in the latter. ATN occurs most frequently in patients undergoing major cardiovascular surgery or suffering severe trauma, hemorrhage, sepsis, and/or volume depletion (Table 273-1). Patients with other risk factors for ARF (e.g., exposure to nephrotoxins or preexisting chronic kidney disease) are at increased risk for ATN. Recovery typically takes 1–2 weeks after normalization of renal perfusion, as it requires repair and regeneration of renal cells.
The course of ischemic ATN is typically characterized by four phases: initiation, extension, maintenance, and recovery (Fig. 273-1). These phases are often preceded by a period of prerenal azotemia. During the initiation phase (lasting hours to days), GFR declines because (1) glomerular ultrafiltration pressure is reduced as renal blood flow falls, (2) the flow of filtrate within tubules is obstructed by casts comprised of shed epithelial cells and necrotic debris, and (3) there is backleak of glomerular filtrate through injured tubular epithelium. Ischemic injury is most prominent in the S3 segment of the proximal tubule and the medullary portion of the thick ascending limb of the loop of Henle. These segments of the tubule are particularly sensitive to ischemia because of high rates of active (ATP-dependent) solute transport and location in the outer medulla, where the partial pressure of oxygen is low, even under basal conditions. Cellular ischemia results in ATP depletion, inhibition of active sodium transport, cytoskeletal disruption, loss of cell polarity, cell-cell and cell-matrix attachment, and oxygen free-radical formation. Renal injury may be limited by restoration of renal blood flow during this period. If severe, cell injury results in apoptosis or necrosis.
Four phases of acute tubular necrosis.
The extension phase follows the initiation phase and is characterized by continued ischemic injury and inflammation. It has been proposed that endothelial damage (resulting in vascular congestion) contributes to both of these processes. During the maintenance phase (typically 1–2 weeks), GFR stabilizes at its nadir (typically 5–10 mL/min), urine output is lowest, and uremic complications may arise (see below). It is not clear why the GFR remains low during this phase, despite correction of systemic hemodynamics. Proposed mechanisms include persistent intrarenal vasoconstriction and medullary ischemia triggered by dysregulated release of vasoactive mediators from injured endothelial cells, congestion of medullary blood vessels, and reperfusion injury induced by reactive oxygen species and inflammatory mediators released by leukocytes or renal parenchymal cells. In addition, epithelial cell injury may contribute to persistent intrarenal vasoconstriction through tubuloglomerular feedback. Specialized epithelial cells in the macula densa region of distal tubules detect increases in distal salt delivery that occur as a consequence of impaired reabsorption by more proximal nephron segments. Macula densa cells, in turn, stimulate constriction of adjacent afferent arterioles by a poorly defined mechanism and further compromise glomerular perfusion and filtration, thereby contributing to a vicious circle.
The recovery phase is characterized by tubular epithelial cell repair and regeneration as well as a gradual return of GFR toward premorbid levels. The recovery phase may be complicated by a marked diuretic phase due to delayed recovery of epithelial cell function (solute and water reabsorption) relative to glomerular filtration (see below).
Etiology and Pathophysiology of Nephrotoxic ARF
Nephrotoxic ATN may complicate exposure to many structurally diverse pharmacologic agents (Table 273-1). With most nephrotoxins, the incidence of ARF is increased in the elderly and in patients with preexisting chronic kidney disease, true or "effective" hypovolemia, or concomitant exposure to other toxins.
Radiocontrast agents, cyclosporine, and tacrolimus (FK506) cause kidney injury through intrarenal vasoconstriction. Consequently, ATN in association with these medications is characterized by an acute fall in renal blood flow and GFR, a relatively benign urine sediment, and a low fractional excretion of sodium (see below). Severe cases may show clinical or pathologic evidence of tubular cell necrosis. Contrast nephropathy is also thought to result from the generation of reactive oxygen species that are directly toxic to renal tubular epithelial cells. Contrast nephropathy classically presents as an acute (onset within 24–48 h) but reversible (peak 3–5 days, resolution within 1 week) rise in blood urea nitrogen and serum creatinine. Contrast nephropathy is most common in individuals with preexisting chronic kidney disease, diabetes mellitus, congestive heart failure, hypovolemia, or multiple myeloma. The type (low vs. isoosmolar contrast) and dose of contrast also influence the likelihood of injury associated with its administration.
Antibiotics and anticancer drugs typically cause ATN through direct toxicity to the tubular epithelial cells and/or intratubular obstruction. ARF complicates 10–30% of courses of aminoglycoside antibiotics. Aminoglycosides accumulate in renal tubular epithelial cells, where they cause oxidative stress and cell injury; thus, ARF usually occurs after several days of aminoglycoside therapy. Damage may occur in both the proximal and distal tubule; defects in the distal tubule may result in decreased concentrating ability. Amphotericin B causes dose-related ARF through intrarenal vasoconstriction and direct toxicity to proximal tubule epithelium. Newer (liposomal) formulations of amphotericin B may be associated with less nephrotoxicity. Acyclovir may precipitate in the renal tubules and cause acute renal failure. Foscarnet and pentamidine are less commonly prescribed antimicrobials also frequently associated with acute renal failure. Cisplatin and carboplatin, like the aminoglycosides, are accumulated by proximal tubule cells and typically provoke ARF after 7–10 days of exposure, typically in association with potassium and magnesium wasting. Ifosphamide administration may lead to hemorrhagic cystitis, manifested by hematuria, as well as acute and chronic renal failure. Type II renal tubular acidosis (Fanconi syndrome) often accompanies ifosphamide-associated ARF.
Endogenous nephrotoxins include calcium, myoglobin, hemoglobin, urate, oxalate, and myeloma light chains. Hypercalcemia can compromise GFR, predominantly by inducing intrarenal vasoconstriction as well as volume depletion from obligate water loss. Both rhabdomyolysis and hemolysis can induce ARF. Common causes of rhabdomyolysis include traumatic crush injury, acute muscle ischemia, prolonged seizure activity, excessive exercise, heat stroke or malignant hyperthermia, and infectious or metabolic disorders (e.g., hypophosphatemia, severe hypothyroidism). ARF due to hemolysis is relatively rare and is observed following blood transfusion reactions. It has been postulated that myoglobin and hemoglobin promote intrarenal oxidative stress, resulting in injury to tubular epithelial cells and inducing intratubular cast formation. In addition, cell-free hemoglobin and myoglobin are potent inhibitors of nitric oxide bioactivity and may trigger intrarenal vasoconstriction and ischemia. Hypovolemia or acidosis may further promote intratubular cast formation. Intratubular casts containing filtered immunoglobulin light chains and other proteins (including Tamm-Horsfall protein produced by thick ascending limb cells) cause ARF in patients with multiple myeloma (myeloma cast nephropathy). Light chains are also directly toxic to tubule epithelial cells. Intratubular obstruction is an important cause of ARF in patients with severe hyperuricosuria or hyperoxaluria. Acute uric acid nephropathy can complicate the treatment of selected lymphoproliferative or myeloproliferative disorders (e.g., Burkitt's lymphoma, acute myelogenous leukemia), especially after the administration of chemotherapy, resulting in increased cell lysis ("tumor lysis syndrome").
Pathology of Ischemic and Nephrotoxic Atn
The classic pathologic features of ischemic ATN are patchy and focal necrosis of the tubular epithelium, with detachment of cells from the basement membrane, and occlusion of tubule lumens with casts composed of intact or degenerating epithelial cells, Tamm-Horsfall protein, and pigments. Leukocyte accumulation is frequently observed in vasa recta; however, the morphology of the glomeruli and renal vasculature is characteristically normal. Necrosis is most severe in the S3 segment of proximal tubules but may also affect the medullary thick ascending limb of the loop of Henle.
With exposure to nephrotoxins, morphologic changes tend to be most prominent in both the convoluted and straight portions of proximal tubules. Cellular necrosis is less pronounced than in ischemic ATN.
Other Causes of Intrinsic ARF
Virtually any pharmacologic agent may trigger allergic interstitial nephritis, which is characterized by infiltration of the tubulointerstitium by granulocytes (typically but not invariably eosinophils), macrophages, and/or lymphocytes and by interstitial edema. The most common offenders are antibiotics (e.g., penicillins, cephalosporins, quinolones, sulfonamides, rifampin) and NSAIDs (Table 273-1).
Patients with advanced atherosclerosis can develop ARF after manipulation of the aorta or renal arteries during surgery or angiography, following trauma, or, rarely, spontaneously (atheroembolic ARF). Cholesterol crystals embolize to the renal vasculature, lodge in small- and medium-sized arteries, and incite a giant cell and fibrotic reaction in the vessel wall with narrowing or obstruction of the vessel lumen. Atheroembolic ARF is often associated with hypocomplementemia and eosinophiluria, and it is frequently irreversible. The acute glomerulonephritides are immune-mediated diseases characterized by proliferative or crescentic glomerular inflammation (glomerulonephritis). These diseases are discussed in detail in Chap. 277.
(See also Chap. 283) Urinary tract obstruction accounts for fewer than 5% of cases of hospital-acquired ARF. Because one kidney has sufficient reserve to handle generated nitrogenous waste products, ARF from obstruction requires obstruction to urine flow between the external urethral meatus and bladder neck, bilateral ureteric obstruction, or unilateral ureteric obstruction in a patient with one functioning kidney or with significant preexisting chronic kidney disease. Bladder neck obstruction is the most common cause of postrenal ARF and is usually due to prostatic disease (e.g., hypertrophy, neoplasia, or infection), neurogenic bladder, or therapy with anticholinergic drugs. Less common causes of acute lower urinary tract obstruction include blood clots, calculi, and urethritis with spasm. Ureteric obstruction may result from intraluminal obstruction (e.g., calculi, blood clots, sloughed renal papillae), infiltration of the ureteric wall (e.g., neoplasia), or external compression (e.g., retroperitoneal fibrosis, neoplasia or abscess, inadvertent surgical ligature). During the early stages of obstruction (hours to days), continued glomerular filtration leads to increased intraluminal pressure upstream to the site of obstruction. As a result, there is gradual distention of the proximal ureter, renal pelvis, and calyces and a fall in GFR.
Clinical Features and Differential Diagnosis
The first step in evaluating a patient with renal failure is to determine if the disease is acute or chronic. If review of laboratory records demonstrates that the rise in blood urea nitrogen and creatinine is recent, this suggests that the process is acute. However, previous measurements are not always available. Findings that suggest chronic kidney disease (Chap. 274) include anemia, evidence of renal osteodystrophy (radiologic or laboratory), and small scarred kidneys. However, anemia may also complicate ARF (see below), and renal size may be normal or increased in several chronic renal diseases (e.g., diabetic nephropathy, amyloidosis, polycystic kidney disease, HIV associated nephropathy). Once a diagnosis of ARF has been established, the etiology of ARF needs to be determined. Depending on the cause, specific therapies may need to be instituted. If the etiology is felt to be an exogenous nephrotoxin (often a medication), the nephrotoxin should be eliminated or discontinued. Lastly, the prevention and management of complications should be instituted.
Symptoms of prerenal ARF include thirst and orthostatic dizziness. Physical signs of orthostatic hypotension, tachycardia, reduced jugular venous pressure, decreased skin turgor and dry mucous membranes suggest prerenal ARF. Careful clinical examination may reveal stigmata of chronic liver disease and portal hypertension, advanced cardiac failure, sepsis, or other causes of reduced "effective" arterial blood volume (Table 273-1). Case records should be reviewed for documentation of a progressive fall in urine output and body weight and recent initiation of treatment with diuretics, NSAIDs, ACE inhibitors, or ARBs.
Hypovolemia, septic shock, and major surgery are important risk factors for ischemic ATN. The risk of ischemic ATN is increased further if ARF persists despite normalization of systemic hemodynamics. Diagnosis of nephrotoxic ATN requires careful review of the clinical data and records for evidence of recent exposure to nephrotoxic medications, radiocontrast agents, or endogenous toxins.
Although ischemic and nephrotoxic ATN account for >90% of cases of intrinsic ARF, other renal parenchymal diseases must be considered (Table 273-2). Fever, arthralgias, and a pruritic erythematous rash following exposure to a new drug suggest allergic interstitial nephritis, although systemic features of hypersensitivity are frequently absent. Flank pain may be a prominent symptom following occlusion of a renal artery or vein and with other parenchymal diseases distending the renal capsule (e.g., severe glomerulonephritis or pyelonephritis). Subcutaneous nodules, livedo reticularis, bright orange retinal arteriolar plaques, and digital ischemia ("purple toes"), despite palpable pedal pulses, suggest atheroembolization. ARF in association with oliguria, edema, and hypertension, with an "active" urine sediment (nephritic syndrome), suggests acute glomerulonephritis or vasculitis. Malignant hypertension may result in ARF, often in association with hypertensive injury to other organs (e.g., papilledema, neurologic dysfunction, left ventricular hypertrophy) and may mimic glomerulonephritis in its other clinical manifestations.
Table 273-2 Epidemiology, Clinical Features, and Diagnostic Studies for Major Causes of Acute Renal Failure
Most common cause of community-acquired ARF; history of poor fluid intake, treatment with NSAIDs/ACE inhibitors/ARBs, worsening heart failure
History of nephrotic syndrome or pulmonary embolism
Mild proteinuriaOccasional hematuria
Renal venogram or MR venogram are diagnostic
Diseases of small vessels and glomeruli
Associated with recent infection (postinfectious or endocarditis), systemic lupus erythematosus, liver disease (hepatitis B or C)Anti-GBM disease: Typically men in their 20s–40sANCA disease: Two peaks: 20s–30s and 50s–60s
Postrenal ARF may present with suprapubic and flank pain due to distention of the bladder and of the renal collecting system and capsule, respectively. Colicky flank pain radiating to the groin suggests acute ureteric obstruction. Prostatic disease is likely if there is a history of nocturia, frequency, and hesitancy and enlargement of the prostate on rectal examination. Neurogenic bladder should be suspected in patients receiving anticholinergic medications or with physical evidence of autonomic dysfunction. Definitive diagnosis of postrenal ARF hinges on judicious use of radiologic investigations and rapid improvement in renal function following relief of obstruction.
(See also Chap. e9) Anuria suggests complete urinary tract obstruction but may complicate severe cases of prerenal or intrinsic renal ARF. Wide fluctuations in urine output raise the possibility of intermittent obstruction, whereas patients with partial urinary tract obstruction may present with polyuria due to impairment of urine concentrating mechanisms.
In prerenal ARF, the sediment is characteristically acellular and contains transparent hyaline casts ("bland," "benign," "inactive" urine sediment). Hyaline casts are formed in concentrated urine from normal constituents of urine—principally Tamm-Horsfall protein, which is secreted by epithelial cells of the loop of Henle. Postrenal ARF may also present with an inactive sediment, although hematuria and pyuria are common in patients with intraluminal obstruction or prostatic disease. Pigmented "muddy brown" granular casts and casts containing tubule epithelial cells are characteristic of ATN and suggest an ischemic or nephrotoxic etiology. These casts are usually found in association with mild "tubular" proteinuria (<1 g/d), reflecting impaired reabsorption and processing of filtered proteins by injured proximal tubules. Casts may be absent in 20–30% of patients with ATN and are not required for diagnosis. In general, red blood cell casts indicate glomerular injury or, less often, acute tubulointerstitial nephritis. White cell casts and nonpigmented granular casts suggest interstitial nephritis, whereas broad granular casts are characteristic of chronic kidney disease and probably reflect interstitial fibrosis and dilatation of tubules. Eosinophiluria (>5% of urine leukocytes) is a common finding (~90%) in antibiotic-induced allergic interstitial nephritis and can be detected with Hansel's stain; however, lymphocytes may predominate in allergic interstitial nephritis induced by NSAIDs and some other drugs (i.e., ampicillin, rifampicin, and interferon ). Occasional uric acid crystals (pleomorphic in shape) are common in the concentrated urine of prerenal ARF but suggest acute urate nephropathy if seen in abundance. Oxalate (envelope-shaped) and hippurate (needle-shaped) crystals raise the possibility of ethylene glycol ingestion and toxicity.
Proteinuria of >1 g/d suggests injury to the glomerular ultrafiltration barrier ("glomerular proteinuria") or excretion of myeloma light chains. The latter may not be detected by conventional dipstick analysis, and other tests may be needed (e.g., sulfosalicylic acid precipitation, immunoelectrophoresis). Hemoglobinuria or myoglobinuria should be suspected if urine is strongly positive for heme by dipstick but contains few red cells, and if the supernatant of centrifuged urine is positive for free heme. Bilirubinuria may provide a clue to the presence of HRS.
Renal Failure Indices
Analysis of urine and blood biochemistry may be useful for distinguishing prerenal ARF from ischemic or nephrotoxic intrinsic renal ARF. The fractional excretion of sodium (FENa) is most useful in this regard. The FENa relates sodium clearance to creatinine clearance. Sodium is reabsorbed avidly from glomerular filtrate in patients with prerenal ARF, in an attempt to restore intravascular volume. The FENa tends to be high in ischemic ATN but is often low in patients with sepsis-induced, pigment-induced, and some forms of nephrotoxic ATN (e.g., contrast-associated). In contrast, creatinine is not reabsorbed in either setting. Consequently, patients with prerenal ARF typically have a FENa of <1.0% (frequently <0.1%). In patients with metabolic alkalosis, where there may be obligate losses of sodium in the urine to maintain electroneutrality, the fractional excretion of chloride (FECl) may be more sensitive than the FENa in detecting prerenal azotemia. The urine sodium concentration is a less-sensitive index for distinguishing prerenal ARF from ischemic and nephrotoxic ARF as values overlap between groups. Similarly, indices of urinary concentrating ability such as urine specific gravity, urine osmolality, urine-to-plasma urea ratio, and blood urea-to-creatinine ratio are of limited value in differential diagnosis.
Many caveats apply when interpreting biochemical renal failure indices. The FENa may be >1.0% in prerenal ARF if patients are receiving diuretics or with preexisting chronic kidney disease, certain salt-wasting syndromes, or adrenal insufficiency.
Serial serum creatinine measurements can provide useful insights to the cause of ARF. Prerenal ARF is typified by fluctuating serum creatinine levels that parallel changes in hemodynamic status. Creatinine rises rapidly (within 24–48 h) in patients with ARF following renal ischemia, atheroembolization, and radiocontrast exposure. Peak serum creatinine concentrations are observed after 3–5 days with contrast nephropathy and return to baseline after 5–7 days. In contrast, serum creatinine concentrations typically peak later (7–10 days) in ATN and atheroembolic disease. The initial rise in serum creatinine is characteristically delayed until the second week of therapy with many tubular epithelial cell toxins (e.g., aminoglycosides, cisplatin) and is thought to reflect the need for accumulation of these agents within tubular epithelial cells to cause injury.
Hyperkalemia, hyperphosphatemia, hypocalcemia, and elevations in serum uric acid and creatine kinase (MM isoenzyme) levels at presentation suggest a diagnosis of rhabdomyolysis. Hyperuricemia [>890 mol/L (>15 mg/dL)] in association with hyperkalemia, hyperphosphatemia, and increased circulating levels of intracellular enzymes such as lactate dehydrogenase may indicate acute urate nephropathy and tumor lysis syndrome following cancer chemotherapy. A wide anion and osmolal gap [the latter calculated as the difference between the observed (measured) serum osmolality minus the expected osmolality calculated from serum sodium, glucose, and urea concentrations] indicate the presence of an unusual anion or osmole in the circulation (e.g., ingestion of ethylene glycol or methanol). Severe anemia in the absence of hemorrhage raises the possibility of hemolysis, multiple myeloma, or thrombotic microangiopathy. Systemic eosinophilia suggests allergic interstitial nephritis but is also a feature of atheroembolic disease and polyarteritis nodosa.
Imaging of the urinary tract by ultrasonography is useful to exclude postrenal ARF. CT and MRI are alternative imaging modalities. Whereas pelvicalyceal dilatation is usual with urinary tract obstruction (98% sensitivity), dilatation may be absent immediately following obstruction or in patients with ureteric encasement (e.g., retroperitoneal fibrosis, neoplasia). Retrograde or anterograde pyelography are more definitive investigations in complex cases and provide precise localization of the site of obstruction. A plain film of the abdomen or unenhanced helical CT scan is a valuable initial screening technique in patients with suspected nephrolithiasis. Magnetic resonance angiography (MRA) is often used to assess patency of renal arteries and veins in patients with suspected vascular obstruction. Alternative methods include Doppler ultrasound (which is much more operator-dependent than MRA) and CT-based angiography. Catheter-based angiography may be required for definitive diagnosis and treatment.
Biopsy is reserved for patients in whom prerenal and postrenal ARF have been excluded and the cause of intrinsic ARF is unclear. Renal biopsy is particularly useful when clinical assessment and laboratory investigations suggest diagnoses other than ischemic or nephrotoxic injury that may respond to disease-specific therapy. Examples include glomerulonephritis, vasculitis, and allergic interstitial nephritis.
ARF impairs renal excretion of sodium, potassium, and water and perturbs divalent cation homeostasis and urinary acidification mechanisms. As a result, ARF is frequently complicated by intravascular volume overload, hyponatremia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypermagnesemia, and metabolic acidosis. In addition, patients are unable to excrete nitrogenous waste products and are prone to develop the uremic syndrome (Chap. 45). The speed of development and the severity of these complications reflect the degree of renal impairment and catabolic state of the patient.
Expansion of extracellular fluid volume is an inevitable consequence of diminished salt and water excretion in oliguric or anuric individuals. Whereas milder forms are characterized by weight gain, bibasilar lung rales, raised jugular venous pressure, and dependent edema, continued volume expansion may precipitate life-threatening pulmonary edema. Excessive administration of free water, either through ingestion and nasogastric administration or as hypotonic saline or isotonic dextrose solutions, can induce hypoosmolality and hyponatremia, which, if severe, lead to neurologic abnormalities, including seizures.
Hyperkalemia is a frequent complication of ARF. Coexistent metabolic acidosis may exacerbate hyperkalemia by promoting potassium efflux from cells. Hyperkalemia may be particularly severe, even at the time of diagnosis, in patients with rhabdomyolysis, hemolysis, and tumor lysis syndrome. Mild hyperkalemia (<6.0 mmol/L) is usually asymptomatic. Higher levels may trigger electrocardiographic abnormalities and/or arrhythmias.
ARF is typically complicated by metabolic acidosis, often with an increased anion gap (Chap. 48). Acidosis can be particularly severe when endogenous production of hydrogen ions is increased by other mechanisms (e.g., diabetic or fasting ketoacidosis; lactic acidosis complicating generalized tissue hypoperfusion, liver disease, or sepsis; metabolism of ethylene glycol or methanol).
Hyperphosphatemia is an almost invariable complication of ARF. Severe hyperphosphatemia may develop in highly catabolic patients or following rhabdomyolysis, hemolysis, or tissue ischemia. Metastatic deposition of calcium phosphate can lead to hypocalcemia, particularly with elevation of serum calcium (mg/dL) and phosphate (mg/dL) concentrations. Other factors that contribute to hypocalcemia include tissue resistance to the actions of parathyroid hormone and reduced levels of 1,25-dihydroxyvitamin D. Hypocalcemia is often asymptomatic but can cause perioral paresthesia, muscle cramps, seizures, altered mental status, prolongation of the QT interval and other nonspecific T-wave changes on electrocardiography.
Anemia develops rapidly in ARF and is usually multifactorial in origin. Contributing factors include impaired erythropoiesis, hemolysis, bleeding, hemodilution, and reduced red cell survival time. Prolongation of the bleeding time is also common. Common contributors to the bleeding diathesis include mild thrombocytopenia, platelet dysfunction, and/or clotting factor abnormalities (e.g., factor VIII dysfunction). Infection is a common and serious complication of ARF. It is unclear whether patients with ARF have a clinically significant defect in host immune responses or whether the high incidence of infection reflects repeated breaches of mucocutaneous barriers (e.g., intravenous cannulae, mechanical ventilation, bladder catheterization). Cardiopulmonary complications of ARF include arrhythmias, pericarditis and pericardial effusion, and pulmonary edema.
Protracted periods of severe ARF are invariably associated with the development of the uremic syndrome (Chap. 45).
A vigorous diuresis can occur during the recovery phase of ARF (see above), which may be inappropriate on occasion and lead to intravascular volume depletion. Hypernatremia can also complicate recovery if water losses via hypotonic urine are not replaced or if losses are inappropriately replaced by relatively hypertonic saline solutions. Hypokalemia , hypomagnesemia , hypophosphatemia, and hypocalcemia are less common metabolic complications during this period but may develop in response to injury associated with selected drugs (e.g., ifosphamide may lead to Fanconi syndrome or type II renal tubular acidosis associated with hypokalemia, acidosis, hypophosphatemia, and glycosuria).
Acute Renal Failure: Treatment
Because there are no specific therapies for ischemic or nephrotoxic ARF, prevention is of paramount importance. Many cases of ischemic ARF can be avoided by close attention to cardiovascular function and intravascular volume in high-risk patients, such as the elderly and those with preexisting chronic kidney disease. Indeed, aggressive restoration of intravascular volume has been shown to dramatically reduce the incidence of ischemic ARF after major surgery or trauma, burns, or cholera. The incidence of nephrotoxic ARF can be reduced by tailoring the administration (dose and frequency) of nephrotoxic drugs to body size and GFR. In this regard, it should be noted that serum creatinine is a relatively insensitive index of GFR and may overestimate GFR considerably in small or elderly patients. For purposes of drug dosing, it is advisable to estimate the GFR using the Cockcroft-Gault formula (which factors in age, sex, and weight) or the simplified Modification of Diet in Renal Disease (MDRD) equation (which factors in age, sex, weight, and race) (Chap. 277). Of note, these equations cannot be used to estimate GFR when creatinine is not at steady state (e.g., during evolving ARF). Adjusting drug dosage according to circulating drug levels also appears to limit renal injury in patients receiving aminoglycoside antibiotics, cyclosporine, or tacrolimus. Diuretics, NSAIDs, ACE inhibitors, ARBs, and vasodilators should be used with caution in patients with suspected true or "effective" hypovolemia or renovascular disease as they may precipitate prerenal ARF or convert the latter to ischemic ARF. Allopurinol and forced alkaline diuresis are useful prophylactic measures in patients at high risk for acute urate nephropathy (e.g., cancer chemotherapy in hematologic malignancies) to limit uric acid generation and prevent precipitation of urate crystals in renal tubules. Rasburicase, a recombinant urate-oxidase enzyme, catalyzes enzymatic oxidation of uric acid into a soluble metabolite, allantoin. Forced alkaline diuresis may also prevent or attenuate ARF in patients receiving high-dose methotrexate or suffering from rhabdomyolysis. N-acetylcysteine limits acetaminophen-induced renal injury if given within 24 h of ingestion.
A number of preventive measures have been proposed for contrast nephropathy. It is clear that hydration is an effective preventive measure. Other measures that have been proposed include loop diuretics and mannitol, dopamine, fenoldopam, N-acetylcysteine, theophylline, and sodium bicarbonate. Despite favorable experimental data, there is insufficient evidence to support the use of loop diuretics or mannitol to prevent radiocontrast nephropathy or any other cause of ARF. Likewise, despite its widespread use, dopamine has proved ineffective as a prophylactic agent. Fenoldopam, a dopamine a-1 specific agonist approved for use as a parenteral antihypertensive agent, has been tested in several clinical trials and does not appear to reduce the incidence of contrast nephropathy. Moreover, fenoldopam is associated with significant side effects, including systemic hypotension, and its use as an agent to prevent radiocontrast nephropathy should be discouraged. In contrast, several (relatively small) randomized clinical trials (RCTs) have suggested a clinical benefit to the use of N-acetylcysteine, although meta-analyses have been inconclusive. However, aside from the potential hazards associated with a delay in radiographic imaging, N-acetylcysteine appears to be safe, and its use in patients at high risk for radiocontrast nephropathy is reasonable, based on its low side effect profile. Larger RCTs will be required to show definitive benefit. Theophylline and aminophylline (adenosine antagonists) offer the potential advantage of use immediately preceding radiocontrast administration, although the benefit, if present, appears marginal in most studies. Lastly, volume expansion with bicarbonate-containing intravenous fluids has been suggested to be superior to sodium chloride (saline) administration and showed a significant benefit in a single center RCT. Unlike N-acetylcysteine, the use of sodium bicarbonate does not obligate a delay in imaging (the published protocol began IV fluids 1 h before the imaging study was begun). Whether a combination of strategies (e.g., N-acetylcysteine + sodium bicarbonate) offers additive benefit and that patients require treatment remain unclear and warrant further study.
By definition, prerenal ARF is rapidly reversible upon correction of the primary hemodynamic abnormality, and postrenal ARF resolves upon relief of obstruction. To date there are no specific therapies for established AKI. Management of these disorders should focus on elimination of the causative hemodynamic abnormality or toxin, avoidance of additional insults, and prevention and treatment of complications. Specific treatment of other causes of intrinsic renal ARF depends on the underlying pathology.
The composition of replacement fluids for treatment of prerenal ARF due to hypovolemia should be tailored according to the composition of the lost fluid. Severe hypovolemia due to hemorrhage should be corrected with packed red cells, whereas isotonic saline is usually appropriate replacement for mild to moderate hemorrhage or plasma loss (e.g., burns, pancreatitis). Urinary and gastrointestinal fluids can vary greatly in composition but are usually hypotonic. Hypotonic solutions (e.g., 0.45% saline) are usually recommended as initial replacement in patients with prerenal ARF due to increased urinary or gastrointestinal fluid losses, although isotonic saline may be more appropriate in severe cases. Subsequent therapy should be based on measurements of the volume and ionic content of excreted or drained fluids. Serum potassium and acid-base status should be monitored carefully, and potassium and bicarbonate supplemented as appropriate. Cardiac failure may require aggressive management with inotropic agents, preload and afterload reducing agents, antiarrhythmic drugs, and mechanical aids such as intraaortic balloon pumps. Invasive hemodynamic monitoring may be required in selected cases to guide therapy for complications in patients in whom clinical assessment of cardiovascular function and intravascular volume is difficult.
Fluid management may be particularly challenging in patients with cirrhosis complicated by ascites. In this setting, it is important to distinguish between full-blown HRS (Chap. 302), which carries a grave prognosis, and reversible ARF due to true or "effective" hypovolemia induced by overzealous use of diuretics or sepsis (e.g., spontaneous bacterial peritonitis). The contribution of hypovolemia to ARF can be definitively assessed only by administration of a fluid challenge. Fluids should be administered slowly and titrated to jugular venous pressure and, if necessary, central venous and pulmonary capillary wedge pressure. Patients with a reversible prerenal component typically have an increase in urine output and fall in serum creatinine with fluid challenge, whereas patients with HRS do not. Patients with HRS may suffer increased ascites formation and pulmonary compromise if not monitored closely during fluid challenge. Large volumes of ascitic fluid can usually be drained by paracentesis without deterioration in renal function if intravenous albumin is administered simultaneously. Indeed, "large-volume paracentesis" may afford an increase in GFR, likely by lowering intraabdominal pressure and improving flow in renal veins. Alternatively, for patients with refractory ascites, transjugular intrahepatic portosystemic shunting is an alternative. Older peritoneal-venous shunts (LaVeen or Denver shunt) have largely fallen out of favor. Transjugular intrahepatic portosystemic shunts may improve renal function through increased central blood volume and suppression of aldosterone and norepinephrine secretion.
Many different approaches to attenuate injury or hasten recovery have been tested in ischemic and nephrotoxic AKI. These include atrial natriuretic peptide, low-dose dopamine, endothelin antagonists, loop-blocking diuretics, calcium channel blockers, -adrenoreceptor blockers, prostaglandin analogues, antioxidants, antibodies against leukocyte adhesion molecules, and insulin-like growth factor type I. Whereas many of these are beneficial in experimental models of ischemic or nephrotoxic ATN, they have either failed to confer consistent benefit or proved ineffective in humans.
ARF due to other intrinsic renal diseases such as acute glomerulonephritis or vasculitis may respond to immunosuppressive agents (glucocorticoids, alkylating agents, and/or plasmapheresis, depending on the primary pathology). Glucocorticoids also may hasten remission in allergic interstitial nephritis, although data are limited to small-case series. Aggressive control of systemic arterial pressure is of paramount importance in limiting renal injury in malignant hypertensive nephrosclerosis. Hypertension and ARF due to scleroderma may be exquisitely sensitive to treatment with ACE inhibitors.
Management of postrenal ARF requires close collaboration between nephrologist, urologist, and radiologist. Obstruction of the urethra or bladder neck is usually managed initially by transurethral or suprapubic placement of a bladder catheter, which provides temporary relief while the obstructing lesion is identified and treated definitively. Similarly, ureteric obstruction may be treated initially by percutaneous catheterization of the dilated renal pelvis or ureter. Indeed, obstructing lesions can often be removed percutaneously (e.g., calculus, sloughed papilla) or bypassed by insertion of a ureteric stent (e.g., carcinoma). Most patients experience an appropriate diuresis for several days following relief of obstruction. Approximately 5% of patients develop a transient salt-wasting syndrome that may require administration of intravenous saline to maintain blood pressure.
(Table 273-3) Following correction of hypovolemia, salt and water intake are tailored to match losses. Hypervolemia can usually be managed by restriction of salt and water intake and diuretics. Indeed, there is, as yet, no proven rationale for administration of diuretics in ARF except to treat this complication. Despite the fact that subpressor doses of dopamine may transiently promote salt and water excretion by increasing renal blood flow and GFR and by inhibiting tubule sodium reabsorption, subpressor ("low-dose," "renal-dose") dopamine has proved ineffective in clinical trials, may trigger arrhythmias, and should not be used as a renoprotective agent in this setting. Ultrafiltration or dialysis is used to treat severe hypervolemia when conservative measures fail. Hyponatremia and hypoosmolality can usually be controlled by restriction of free water intake. Conversely, hypernatremia is treated by administration of water or intravenous hypotonic saline or isotonic dextrose-containing solutions. The management of hyperkalemia is described in Chap. 46.
Table 273-3 Management of Ischemic and Nephrotoxic Acute Renal Failurea
Reversal of Renal Insult
Restore systemic hemodynamics and renal perfusion through volume resuscitation and use of vasopressors
Eliminate nephrotoxic agents
Consider toxin-specific measures: e.g., forced alkaline diuresis for rhabdomyolysis, allopurinol/rasburicase for tumor lysis syndrome
Prevention and Treatment of Complications
Intravascular volume overload
Salt and water restriction
Restriction of enteral free water intake
Avoidance of hypotonic intravenous solutions, including dextrose-containing solutions
Restriction of dietary K+ intake
Eliminate K+ supplements and K+-sparing diuretics
Loop diuretics to promote K+ excretion
Potassium binding ion-exchange resins (e.g., sodium polystyrene sulfonate or Kayexelate)
Insulin (10 units regular) and glucose (50 mL of 50% dextrose) to promote intracellular mobilization
Inhaled -agonist therapy to promote intracellular mobilization
Calcium gluconate or calcium chloride (1 g) to stabilize the myocardium
Metabolic acidosis is not usually treated unless serum bicarbonate concentration falls below 15 mmol/L or arterial pH falls below 7.2. More severe acidosis is corrected by oral or intravenous sodium bicarbonate. Initial rates of replacement are guided by estimates of bicarbonate deficit and adjusted thereafter according to serum levels (Chap. 48). Patients should be monitored for complications of sodium bicarbonate administration such as hypervolemia, metabolic alkalosis, hypocalcemia, and hypokalemia. From a practical point of view, most patients who require supplemental sodium bicarbonate administration will need emergency dialysis within days. Hyperphosphatemia is usually controlled by restriction of dietary phosphate and by oral phosphate binders (calcium carbonate, calcium acetate, sevalamer, and aluminum hydroxide) to reduce gastrointestinal absorption of phosphate. Hypocalcemia does not usually require treatment unless severe, as may occur with rhabdomyolysis or pancreatitis or following administration of bicarbonate. Hyperuricemia is typically mild [<890 mol/L (<15 mg/dL)] and does not require intervention.
The objective of nutritional management during the maintenance phase of ARF is to provide sufficient calories and protein to minimize catabolism. Nutritional requirements will vary based on the underlying disease process; for example, those with sepsis-associated AKI are likely to be hypercatabolic. The presence of oliguria complicates nutritional management, and if the patient is not on dialysis, minimizing production of nitrogenous waste is a consideration. Often, the institution of dialysis facilitates the provision of adequate nutritional support. There is no clear benefit of parenteral nutrition compared with enteral nutrition; indeed, those supported with parenteral nutrition are at increased risk of complications, including infection.
Anemia may necessitate blood transfusion if severe. Recombinant human erythropoietin is rarely used in ARF because bone marrow resistance to erythropoietin is common, and more immediate treatment of anemia (if any) is required. Uremic bleeding may respond to administration of desmopressin or estrogens. Often dialysis is instituted to control bleeding that appears to be related to uremia. Gastrointestinal prophylaxis with histamine receptor (H2) antagonists or proton pump inhibitors should be prescribed, especially in the setting of critical illness. Meticulous care of intravenous and bladder catheters, and other invasive devices is mandatory to avoid infections.
Indications and Modalities of Dialysis
(See also Chap. 275) During ARF, dialysis is often used to support renal function until renal repair/recovery occur. Absolute indications for dialysis include symptoms or signs of the uremic syndrome and management of refractory hypervolemia, hyperkalemia, or acidosis. Many nephrologists also initiate dialysis empirically for blood urea levels of >100 mg/dL; however, this approach has yet to be validated in controlled clinical trials. Although direct clinical comparisons are limited, hemodialysis appears to be somewhat more effective than peritoneal dialysis for management of ARF. Peritoneal dialysis may be useful when hemodialysis is unavailable or if it is impossible to obtain vascular access. However, peritoneal dialysis is associated with increased protein losses and is contraindicated in those patients who have undergone recent abdominal surgery or those with ongoing infection. Peritoneal dialysis access requires insertion of a cuffed catheter into the peritoneal cavity.
Vascular access for hemodialysis requires insertion of a temporary double-lumen hemodialysis catheter into the internal jugular or femoral vein. Insertion into the subclavian vein is generally avoided owing to the risk of subclavian stenosis. Hemodialysis may be provided in the form of intermittent hemodialysis (typically performed for 3–4 hours per day, 3–4 times per week), slow low-efficiency dialysis (performed for 6–12 hours per day, 3–6 times per week), or continuous renal replacement therapy (CRRT). CCRTs are particular valuable techniques in patients in whom intermittent therapy fails to control hypervolemia, uremia, or acidosis or in those who do not tolerate intermittent hemodialysis due to hemodynamic instability. In those patients where hemodynamic instability is a primary consideration, slow low-efficiency hemodialysis (SLED), a relatively new hybrid mode of dialysis, is an excellent alternative to CRRT.
Continuous arteriovenous modalities [continuous arteriovenous hemofiltration, hemodialysis, and hemodiafiltration (CAVH, CAVHD, and CAVHDF, respectively)] require both arterial and venous access. The patient's own blood pressure generates an ultrafiltrate of plasma across a porous biocompatible dialysis membrane. With the advent of peristaltic pumps, the arteriovenous modalities have fallen out of favor, in part because of the complications associated with cannulation of a large artery with a large bore catheter. In continuous venovenous hemodialysis (CVVHD), a blood pump generates ultrafiltration pressure across the dialysis membrane. In continuous venovenous hemofiltration (CVVH), the hemodialysis (diffusive clearance) component is eliminated, and an ultrafiltrate of plasma is removed across the dialysis membrane and replaced by a physiologic crystalloid solution (convective clearance). In continuous venovenous hemodiafiltration (CVVHDF), these two methods of clearance are combined. The bulk of evidence to date suggests that intermittent and continuous dialytic therapies are equally effective for the treatment of ARF. The choice of technique is currently tailored to the specific needs of the patient, the resources of the institution, and the expertise of the physician. Potential disadvantages of continuous techniques include the need for prolonged immobilization, systemic anticoagulation, and prolonged exposure of blood to synthetic (albeit biocompatible) dialysis membranes.
The optimal dose of dialysis for ARF remains unclear at present. Recent evidence (from a single center, nonrandomized trial) suggests that more intensive hemodialysis (e.g., daily rather than alternate-day intermittent dialysis) may be clinically superior and confers improved survival in ARF once dialysis is required. This conclusion may not be as intuitive as it first appears since dialysis itself has been postulated to prolong ARF by inducing hypotension and other adverse effects related to the blood-dialyzer contact (e.g., complement activation and inflammation). Similarly, data suggest that increased doses of continuous renal replacement therapy may be of benefit for ARF, although these results need to be confirmed in a larger, multicenter study.
Outcome and Long-Term Prognosis
The in-hospital mortality rate among patients with ARF ranges from 20 to 50% or more, depending on underlying conditions, and has declined only marginally over the past 15 years. Most patients who survive an episode of ARF recover sufficient renal function to remain dialysis-independent, although a fraction (roughly 10–20%) go on to require maintenance dialysis.
Common etiologies for acute renal failure will vary, depending on the availability of health care in a given country. In general, the most common cause of community-acquired ARF is prerenal azotemia. However, in countries with less well-developed health care systems, infective etiologies for ARF predominate. In developed countries, postoperative and ischemic/nephrotoxic causes of ARF are more common.