Until recently, a systematic definition of acute renal failure (ARF) was lacking, which led to significant confusion both clinically and in the medical literature. In 2004, the Acute Dialysis Quality Initiative (ADQI) group published the RIFLE classification of ARF, based on changes from the patient's baseline either in serum creatinine level or glomerular filtration rate (GFR), urine output (UO), or both.
The RIFLE classification of ARF is as follows:
Risk (R) - Increase in serum creatinine level X 1.5 or decrease in GFR by 25%, or UO <0.5 mL/kg/h for 6 hours
Injury (I) - Increase in serum creatinine level X 2.0 or decrease in GFR by 50%, or UO <0.5 mL/kg/h for 12 hours
Failure (F) - Increase in serum creatinine level X 3.0, decrease in GFR by 75%, or serum creatinine level > 4 mg/dL; UO <0.3 mL/kg/h for 24 hours, or anuria for 12 hours
Loss (L) - Persistent ARF, complete loss of kidney function >4 wk
End-stage kidney disease (E) - Loss of kidney function >3 months
Since baseline serum creatinine level and GFRs are not readily available, the consensus committee recommends the use of the Modification of Diet in Renal Disease (MDRD) equation (see Lab Studies) to estimate the patients GFR/1.73 mm based upon: serum creatinine level, age, gender, and race. The proportional decrease in GFR should be calculated from 70 mL/min per 1.73 mm2, the agreed upon lower limit of normal.
ARF is a common entity in the ED. Emergency physicians play a critical role in recognizing early ARF, preventing iatrogenic injury, and reversing the course of ARF.
Pathophysiology: The driving force for glomerular filtration is the pressure gradient from the glomerulus to the Bowman space. Glomerular pressure is primarily dependent on renal blood flow (RBF) and is controlled by combined resistances of renal afferent and efferent arterioles. Regardless of the cause of ARF, reductions in RBF represent a common pathologic pathway for decreasing GFR. The etiology of ARF comprises 3 main mechanisms.
Prerenal failure is defined by conditions with normal tubular and glomerular function; GFR is depressed by compromised renal perfusion.
Intrinsic renal failure includes diseases of the glomerulus or tubule, which are associated with release of renal afferent vasoconstrictors.
Postobstructive renal failure initially causes an increase in tubular pressure, decreasing the filtration driving force. This pressure gradient soon equalizes, and maintenance of a depressed GFR is then dependent upon renal afferent vasoconstriction.
Patients with chronic renal failure also may present with superimposed ARF from any of the aforementioned etiologies.
Depressed RBF eventually leads to ischemia and cell death. This initial ischemic insult triggers production of oxygen free radicals and enzymes that continue to cause cell injury even after restoration of RBF. Tubular cellular damage results in disruption of tight junctions between cells, allowing back leak of glomerular filtrate and further depressing effective GFR. In addition, dying cells slough off into the tubules, forming obstructing casts, which further decrease GFR and lead to oliguria.
During this period of depressed RBF, the kidneys are particularly vulnerable to further insults. This is when iatrogenic renal injury is most common. The following are common iatrogenic combinations:
Preexisting renal disease (elderly, diabetic patients, jaundiced patients) and radiocontrast agents, aminoglycosides, atheroembolism, or cardiovascular surgery
Angiotensin-converting enzyme (ACE) inhibitors and diuretics, small- and large-vessel renal arterial disease
Nonsteroidal anti-inflammatory drugs (NSAIDs) and congestive heart failure (CHF), hypertension (HTN), or renal artery stenosis
Hypovolemia and aminoglycosides, amphotericin, heme pigments, or radiologic contrast agents
Recovery from ARF is first dependent upon restoration of RBF. Early RBF normalization predicts better prognosis for recovery of renal function. In prerenal failure, restoration of circulating blood volume is usually sufficient. Rapid relief of urinary obstruction in postrenal failure results in a prompt decrease of vasoconstriction. With intrinsic renal failure, removal of tubular toxins and initiation of therapy for glomerular diseases decreases renal afferent vasoconstriction.
Once RBF is restored, the remaining functional nephrons increase their filtration and eventually hypertrophy. GFR recovery is dependent upon the size of this remnant nephron pool. If the number of remaining nephrons is below some critical value, continued hyperfiltration results in progressive glomerular sclerosis, eventually leading to increased nephron loss. A vicious cycle ensues; continued nephron loss causes more hyperfiltration until complete renal failure results. This has been termed the hyperfiltration theory of renal failure and explains the scenario in which progressive renal failure is frequently observed after apparent recovery from ARF.
History: Because ARF has such a long differential diagnosis, obtain a directed history along the lines of the pathophysiology of ARF (prerenal, intrinsic renal, postrenal failure).
Prerenal failure
Patients commonly present with symptoms related to hypovolemia, including thirst, decreased urine output, dizziness, and orthostatic hypotension.
Look for a history of excessive fluid loss via hemorrhage, GI losses, sweating, or renal sources.
Patients with advanced cardiac failure leading to depressed renal perfusion may present with orthopnea and paroxysmal nocturnal dyspnea.
Insensible fluid losses can result in severe hypovolemia in patients with restricted fluid access and should be suspected in the elderly and in comatose or sedated patients.
Intrinsic renal failure
Patients can be divided into those with glomerular and those with tubular etiologies of ARF.
Glomerular diseases: Nephritic syndrome of hematuria, edema, and HTN is synonymous with a glomerular etiology of ARF. Query about prior throat or skin infections. A history of an earlier episode resembling this symptom complex is often helpful in establishing a differential diagnosis.
Tubular diseases: ATN should be suspected in any patient presenting after a period of hypotension secondary to cardiac arrest, hemorrhage, sepsis, drug overdose, or surgery.
A careful search for exposure to nephrotoxins should include a detailed list of all current medications and any recent radiologic examinations (ie, exposure to radiologic contrast agents).
Pigment-induced ARF should be suspected in patients with possible rhabdomyolysis (muscle tenderness, recent coma, seizures, drug abuse, alcohol, excessive exercise, limb ischemia) or hemolysis (recent blood transfusion).
Allergic interstitial nephritis should be suspected with recent drug ingestion, fevers, rash, and arthralgias.
Postrenal failure
Postrenal failure usually occurs in older men with prostatic obstruction and symptoms of urgency, frequency, and hesitancy. Patients may present with asymptomatic high-grade urinary obstruction because of chronicity of their symptoms.
History of prior gynecologic surgery or carcinoma often can be helpful in providing clues to the level of obstruction.
Flank pain and hematuria should raise a concern about renal calculi or papillary necrosis as the source of urinary obstruction.
Use of acyclovir, methotrexate, triamterene, indinavir, or sulfonamides implies the possibility of tubular obstruction by crystals of these medications.
Physical:
Hypotension and tachycardia are obvious clues to decreased renal perfusion. Evaluation for hypovolemia should include evaluations for orthostatic hypotension, mucosal membrane moisture, and tissue turgor.
Acute fluid overload may lead to compromise of a patient's ability to oxygenate and ventilate.
Patients also may present hypovolemic, with increased risk for iatrogenic complications of their renal failure. Physical examination should include a search for the following signs:
Urine output: Changes in urine output generally are poorly correlated with changes in GFR. Approximately 50-60% of all causes of ARF are nonoliguric. However, categories of anuria, oliguria, and nonoliguria may be useful in differential diagnosis of ARF.
Nonoliguria (>400 mL/d) - Acute interstitial nephritis, acute glomerulonephritis, partial obstructive nephropathy, nephrotoxic and ischemic ATN, radiocontrast-induced ARF, and rhabdomyolysis
Urinalysis: Microscopic examination of urine is essential in establishing differential diagnosis.
Normal urinary sediment without hemoglobin, protein, cells, or casts generally consistent with prerenal and postrenal failure, HUS/thrombotic thrombocytopenic purpura (TTP), preglomerular vasculitis, or atheroembolism
BUN: The urea concentration correlates poorly with the GFR. Because urea is highly permeable to renal tubules, urea clearance varies with urine flow rate.
Urea is filtered freely, but reabsorption along the tubule is a function of urine flow rate. During antidiuresis with urine flow rates less than 30 mL/h, urea clearance is as low as an estimated 30% of GFR. Under conditions of diuresis, with urine outputs greater than 100 mL/h, urea clearance can increase to 70-100% of GFR.
This information can be used clinically to help differentiate prerenal failure from other etiologies of ARF.
In prerenal conditions, low urine flow rates favor BUN reabsorption out of proportion to decreases in GFR, resulting in a disproportionate rise of BUN relative to creatinine, creating a serum BUN-creatinine ratio >20 in prerenal failure.
BUN concentration is dependent on nitrogen balance and renal function.
BUN concentration can rise significantly with no decrement in GFR by increases in urea production with steroids, trauma, or GI bleeding.
Tetracycline increases BUN by decreasing tissue anabolic rates.
Basal BUN concentration can be depressed severely by malnutrition or advanced liver disease.
Always first estimate basal BUN concentration when attempting to correlate changes in BUN with GFR. For example, in a patient with cirrhosis and a BUN of 12 mg/dL, a GFR in the normal range may be assumed. Only with the knowledge of a baseline BUN of 4 mg/dL does the real decrease in GFR become apparent.
Creatinine: Serum creatinine provides the ED physician with the most accurate and consistent estimation of GFR. Correct interpretation of serum creatinine extends beyond just knowing normal values for the specific laboratory.
Creatinine measuring methods
Serum creatinine level varies by method of measurement, either Jaffe or iminohydrolase. Upper limit of normal creatinine can be 1.6-1.9 mg/dL or 1.2-1.4 mg/dL, respectively. This becomes important when patients present with changes in creatinine measured in different labs.
Differing methods report markedly different results when interfacing with certain chemicals.
Jaffe method of measuring creatinine reports falsely elevated serum creatinine in the presence of the following noncreatinine chromogens: glucose, fructose, uric acid, acetone, acetoacetate, protein, ascorbic acid, pyruvate, cephalosporin antibiotics. High levels of bilirubin cause reports of falsely low creatinine by the Jaffe method.
Extremely high glucose levels and the antifungal agent flucytosine interfere with the iminohydrolase method.
Serum creatinine is a reflection of creatinine clearance.
Serum creatinine is a function of its production and excretion rates.
Creatinine production is determined by muscle mass. Serum creatinine must always be interpreted with respect to patient's weight, age, and sex. The GFR can be estimated by the following formulas: The ADQI consensus committee on ARF favors the Modification of Diet in Renal Disease (MDRD) equation to estimate GFR (70 mL/min per 1.73 mm2 is considered the lower limit of normal).
Cockcroft-Gault equation: GFR mL/min = (140 - age y)(weight kg)(0.85 if female)/(72 X serum creatinine mol/L)
MDRD equation: GFR, in mL/min per 1.73 mm2 = 186.3 X ((serum creatinine) exp[-1.154]) X (Age exp[-0.203]) X (0.742 if female) X (1.21 if African American)
For example, GFR decreases by 1% per year after age 40, yet serum creatinine generally remains stable. Balance is achieved via a decrease in muscle mass with age, which matches the fall in GFR.
Men generally have a higher muscle mass per kilogram of body weight and thus a higher serum creatinine than women.
Changes in serum creatinine reflect changes in GFR. Rate of change in serum creatinine is an important variable in estimating GFR. Stable changes in serum creatinine correlate with changes in GFR by the following relationships:
Creatinine 1.0 mg/dL - Normal GFR
Creatinine 2.0 mg/dL - 50% reduction in GFR
Creatinine 4.0 mg/dL - 70–85% reduction in GFR
Creatinine 8.0 mg/dL - 90–95% reduction in GFR
As suggested by these data, knowledge of a patient's baseline creatinine becomes very important. Small changes with low baseline levels of creatinine are important clinically much more than large changes with high basal creatinine. Significant decrements in GFR can occur in the normal range of creatinine.
Certain diseases and medications can interfere with the correlation of serum creatinine with GFR. Acute glomerulonephritis causes increased tubular secretion of creatinine, falsely depressing the rise in serum creatinine when ARF occurs in acute glomerulonephritis. Trimethoprim and cimetidine cause decreased creatinine secretion and a falsely elevated creatinine with no change in GFR.
Complete blood count
Leukocytosis is common in ARF.
Leukopenia and thrombocytopenia suggest SLE or TTP.
Anemia and rouleaux formation suggest multiple myeloma.
Microangiopathic anemia suggests TTP or atheroemboli.
Eosinophilia suggests allergic interstitial nephritis, polyarteritis nodosa, or atheroemboli.
Coagulation disturbances indicate liver disease or hepatorenal syndrome.
Blood chemistry
Creatine phosphokinase (CPK) elevations are seen in rhabdomyolysis and myocardial infarction.
Elevations in liver transaminases are seen in rapidly progressive liver failure and hepatorenal syndrome.
Hypocalcemia (moderate) is common in ARF.
Hyperkalemia is a common complication of ARF.
Urine chemical indices
Differentiation of prerenal azotemia from ATN takes on a special importance in early management of these patients.
Aggressive fluid resuscitation is appropriate in prerenal ARF. However, rapid fluid infusion in a patient with ATN who is unable to excrete the extra fluid could result in life-threatening volume overload.
To help with the differentiation of prerenal azotemia, analysis of urine may provide important clues. If possible, collect urine prior to any administration of diuretics.
Urine indices that suggest prerenal ARF include the following:
Urine specific gravity >1.018
Urine osmolality (mOsm/kg H2O) >500
Urine sodium (mEq/L) <15-20
Plasma BUN/creatinine ratio >20
Urine/plasma creatinine ratio >40
Urine indices that suggest ATN include the following:
Urine specific gravity <1.012
Urine osmolality (mOsm/kg H2O) <500
Urine sodium (mEq/L) >40
Plasma BUN/creatinine ratio <10-15
Urine/plasma creatinine ratio <20
Calculation of fractional excretion of sodium (FeNa)
Measured creatinine and sodium clearances, accounting for filtration and reabsorption of sodium
FeNa increased before oliguric phase established and predictive of incipient ARF
Exceptions (intrinsic renal failure with FeNa <1%)
Urinary tract obstruction
Acute glomerulonephritis
Hepatorenal syndrome
Radiologic contrast–induced ATN
Myoglobinuric and hemoglobinuric ARF
Renal allograft rejection
Drug-related alterations in renal hemodynamics (eg, captopril, NSAIDs)
Imaging Studies:
Imaging studies in ARF are most important in the emergent workup of suspected postrenal azotemia. Please refer to Urinary Obstruction for a complete discussion of available imaging studies for this cause of ARF.
Chest radiography
Obtain chest radiographs on a routine basis to look for evidence of volume overload.
Findings of lung infiltration can lead to pulmonary/renal syndromes, such as Wegener granulomatosis and Goodpasture syndrome, or evidence of pulmonary emboli from endocarditis or atheroembolic disease.
Other Tests:
Electrocardiography: Obtain routine ECGs to look for manifestations of hyperkalemia and arrhythmias, such as atrial fibrillation, related to atheroemboli.
Procedures:
Renal biopsy
Often helpful in finding specific cause of renal failure; however, not an ED procedure
Reserved for evaluation of ARF when cause cannot be determined
Especially important when glomerular causes of ARF are suspected
Often helpful in finding specific cause of renal failure
Prehospital Care: Stabilize acute life-threatening conditions and initiate supportive therapy.
Emergency Department Care: Treatment of ARF ideally should begin before the diagnosis of ARF is firmly established. A high index of suspicion often is necessary to diagnose early ARF. Significant decreases in GFR frequently occur before indirect measures of GFR reveal a problem. All seriously ill medical patients (eg, elderly patients, diabetic patients, hypovolemic patients) should have ARF included early in their differential diagnosis.
Physicians can play a pivotal role in reversing many of the underlying causes and preventing further iatrogenic renal injury if ARF is recognized early. After providing an adequate airway and ventilation, focus on fluid management of the ARF patient.
Fluid management
Patients with ARF represent challenging fluid management problems.
Hypovolemia potentiates and exacerbates all forms of ARF.
Reversal of hypovolemia by rapid fluid infusion often is sufficient to treat many forms of ARF. However, rapid fluid infusion can result in life-threatening fluid overload in patients with ARF.
Accurate determination of a patient's volume status is essential and may require invasive hemodynamic monitoring if physical examination and laboratory results do not lead to a definite conclusion.
Urinary catheter placement
Urinary obstruction often is an easily reversible cause of ARF.
Placement of a urinary catheter early in the workup of a patient with ARF not only allows diagnosis and treatment of urethral and bladder outlet urinary obstruction, and allows for accurate measurement of urine output.
If available, bedside ultrasonography can quickly identify a large and distended bladder.
Routine use of urinary catheters should be tempered by consideration of their inherent risks of introducing infections.
