ACUTE RENAL FAILURE

Introduction
Background

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) or urine output (UO).

The RIFLE classification of ARF is as follows:1

* 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 with acute increase of >0.5 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 weeks
* End-stage kidney disease (E) - Loss of kidney function >3 months

Since baseline serum creatinine level and GFRs may not be 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 75 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 acute renal failure (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 kidney itself, predominantly affecting the glomerulus or tubule, which are associated with release of renal afferent vasoconstrictors. Ischemic renal injury is the most common cause of intrinsic renal failure.
* 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 efferent vasoconstriction.

Patients with chronic renal failure may also present with superimposed ARF from any of the aforementioned etiologies.

Depressed RBF eventually leads to ischemia and cell death. This may happen before frank systemic hypotension is present and is referred to as normotensive ischemic ARF. The initial ischemic insult triggers a cascade of events that includes production of oxygen free radicals, cytokines and enzymes, endothelial activation and leukocyte adhesion, activation of coagulation, and initiation of apoptosis. These events 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) with radiocontrast agents, aminoglycosides, atheroembolism, or cardiovascular surgery
* Angiotensin-converting enzyme (ACE) inhibitors with diuretics, small- or large-vessel renal arterial disease
* Nonsteroidal anti-inflammatory drugs (NSAIDs) with congestive heart failure (CHF), hypertension (HTN), or renal artery stenosis
* Hypovolemia with 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.

For related information, see Medscape's Nephrology specialty page and Chronic Kidney Disease Resource Center and End-Stage Renal Disease Resource Center.
Frequency
United States

The distinction between community- and hospital-acquired acute renal failure (ARF) is important for the differential diagnoses, treatment, and eventual outcome of patients with ARF. The annual incidence of community-acquired ARF is approximately 100 cases per 1 million population, and it is diagnosed in only 1% of hospital admissions at presentation. Using the RIFLE classification, hospital-acquired ARF of Risk, Injury and Failure category has been found in 9%, 5%, and 4% of hospital admissions,2 respectively, and in approximately 17%, 12%, and 7% of critical care admissions.3,4 This high incidence of hospital-acquired ARF is multifactorial; it is related to an aging population with increased risks of ARF, the high prevalence of nephrotoxic exposures possible in a hospital setting, and increasing severity of illness.

Mortality/Morbidity

Because most cases of community-acquired ARF are secondary to volume depletion, as many as 90% of cases are estimated to have a potentially reversible cause. Hospital-acquired ARF often occurs in an ICU setting and is commonly part of multiorgan failure. This dichotomy in the etiology of ARF explains the increased mortality rate, dialysis requirements, and rates of progression to end-stage renal failure seen in hospital-acquired ARF compared with community-acquired ARF.

Mortality rates for ARF have changed little since the advent of dialysis at 50%. This curious statistic simply reflects the changing demographics of ARF from community- to hospital-acquired settings. Currently, the mortality rate for hospital-acquired ARF is reported to be as high as 70% and is directly correlated to the severity of the patient's other disease processes. The mortality rate among patients presenting to the ED with prerenal ARF may be as low as 7%. With the advent of dialysis, the most common causes of death associated with ARF are sepsis, cardiac failure, and pulmonary failure. Interestingly, patients who are older than 80 years with ARF have mortality rates similar to younger adult patients. Pediatric patients with ARF represent a different set of etiologies and have mortality rates averaging 25%.

* ARF is not a benign disease. In a recent study, a 31% mortality rate was noted in patients with ARF not requiring dialysis, compared with a mortality rate of only 8% in matched patients without ARF. Even after adjusting for comorbidity, the odds ratio for dying of ARF was 4.9 compared to patients without ARF.
* There seems to be a stepwise relationship between the RIFLE category of renal injury and mortality. Compared with non-AKI, the relative risk (RR) of death for Risk is 2.40; for Injury, it is 4.15; and for Failure, it is 6.4.5
* Mortality rates are generally lower for nonoliguric ARF (>400 mL/d) than for oliguric (<400 mL/d) ARF, reflecting the fact that nonoliguric ARF is usually caused by drug-induced nephrotoxicity and interstitial nephritis, which have few other systemic complications. Sex Males and females are affected equally. Age The patient's age has significant implications for the differential diagnosis of acute renal failure (ARF). * Newborns and infants o The most common cause of ARF is prerenal etiologies. o Prerenal ARF + Perinatal hemorrhage - Twin-twin transfusion, complications of amniocentesis, abruptio placenta, birth trauma + Neonatal hemorrhage - Severe intraventricular hemorrhage, adrenal hemorrhage + Perinatal asphyxia and hyaline membrane disease (newborn respiratory distress syndrome) both may result in preferential blood shunting away from the kidneys (ie, prerenal) to central circulation. o Intrinsic ARF + Acute tubular necrosis (ATN) can occur in the setting of perinatal asphyxia. ATN also has been observed secondary to medications (eg, aminoglycosides, NSAIDs) given to the mother perinatally. + ACE inhibitors can traverse placenta, resulting in a hemodynamically mediated form of ARF. + Acute glomerulonephritis is rare and most commonly the result of maternal-fetal transfer of antibodies against the neonate's glomeruli or transfer of chronic infections (syphilis, cytomegalovirus) associated with acute glomerulonephritis. o Postrenal ARF: Congenital malformations of urinary collecting systems should be suspected. * Children o The most common cause of ARF is prerenal etiologies. o Prerenal ARF + The most common cause of hypovolemia in children is gastroenteritis. + Congenital and acquired heart diseases are also important causes of decreased renal perfusion in this age group. o Intrinsic ARF + Hemolytic uremic syndrome (HUS) often is cited as the most common cause of ARF in children. The most common form of the disease is associated with a diarrheal prodrome caused by Escherichia coli O157:H7. These children usually present with microangiopathic anemia, thrombocytopenia, colitis, mental status changes, and renal failure. + Acute poststreptococcal glomerulonephritis should be considered in any child who presents with HTN, edema, hematuria, and renal failure. * Adults o Please refer to History for a general discussion of ARF. o Please remember that postobstructive ARF in elderly patients should never be overlooked in the ED. Clinical History Acute renal failure (ARF) has a long differential diagnosis. History can help classify the pathophysiology of ARF as prerenal, intrinsic renal, or postrenal failure, and it may suggest some specific etiologies. * Prerenal failure o Patients commonly present with symptoms related to hypovolemia, including thirst, decreased urine output, dizziness, and orthostatic hypotension. o Elders with vague mental status change are commonly found to have prerenal or normotensive ischemic ARF. o Ask about volume loss from vomiting, diarrhea, sweating, polyuria, or hemorrhage. o Patients with advanced cardiac failure leading to depressed renal perfusion may present with orthopnea and paroxysmal nocturnal dyspnea. o Insensible fluid losses can result in severe hypovolemia in patients with restricted fluid access and should be suspected in elderly patients and in comatose or sedated patients. * Intrinsic renal failure o Patients can be divided into those with glomerular etiologies and those with tubular etiologies of ARF. + Glomerular diseases: Nephritic syndrome of hematuria, edema, and HTN indicates a glomerular etiology of ARF. Query about prior throat or skin infections. + 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. o 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). o Pigment-induced ARF should be suspected in patients with possible rhabdomyolysis (muscular pain, recent coma, seizure, intoxication, excessive exercise, limb ischemia) or hemolysis (recent blood transfusion). o Allergic interstitial nephritis should be suspected with fevers, rash, arthralgias, and exposure to certain medications including NSAIDs and antibiotics. * Postrenal failure o 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. o History of prior gynecologic surgery or abdominopelvic malignancy often can be helpful in providing clues to the level of obstruction. o Flank pain and hematuria should raise a concern about renal calculi or papillary necrosis as the source of urinary obstruction. o 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: * Skin o Livido reticularis, digital ischemia, butterfly rash, palpable purpura - Systemic vasculitis o Maculopapular rash - Allergic interstitial nephritis o Track marks (ie, intravenous drug abuse) - Endocarditis * Eyes o Keratitis, iritis, uveitis, dry conjunctivae - Autoimmune vasculitis o Jaundice - Liver diseases o Band keratopathy (ie, hypercalcemia) - Multiple myeloma o Signs of diabetes mellitus o Signs of hypertension o Atheroemboli (retinopathy) * Ears o Hearing loss - Alport disease and aminoglycoside toxicity o Mucosal or cartilage ulcerations - Wegener granulomatosis * Cardiac o Irregular rhythms (ie, atrial fibrillation) - Thromboemboli o Murmurs - Endocarditis o Increased jugulovenous distention, rales, S3 - Congestive heart failure (CHF) * Pulmonary o Rales - Goodpasture syndrome, Wegener granulomatosis o Hemoptysis - Wegener granulomatosis * Abdomen o Pulsatile mass or bruit - Atheroemboli o Costovertebral angle tenderness - Nephrolithiasis, papillary necrosis o Pelvic, rectal masses; prostatic hypertrophy; distended bladder – Urinary obstruction o Limb ischemia, edema - Rhabdomyolysis * 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. o Anuria (<100 mL/d) - Urinary tract obstruction, renal artery obstruction, rapidly progressive glomerulonephritis, bilateral diffuse renal cortical necrosis o Oliguria (100-400 mL/d) - Prerenal failure, hepatorenal syndrome o Nonoliguria (>400 mL/d) - Acute interstitial nephritis, acute glomerulonephritis, partial obstructive nephropathy, nephrotoxic and ischemic ATN, radiocontrast-induced ARF, and rhabdomyolysis

Causes

* Prerenal failure - Diseases that compromise renal perfusion
o Decreased effective arterial blood volume - Hypovolemia, CHF, liver failure, sepsis
o Renal arterial disease - Renal arterial stenosis (atherosclerotic, fibromuscular dysplasia), embolic disease (septic, cholesterol)
* Intrinsic renal failure - Diseases of the renal parenchyma, specifically involving the renal tubules, glomeruli, interstitium
o ATN, ischemia, toxins (eg, aminoglycosides, radiocontrast, heme pigments, cisplatin, myeloma light chains, ethylene glycol)
o Interstitial diseases - Acute interstitial nephritis, drug reactions, autoimmune diseases (eg, systemic lupus erythematosus [SLE]), infiltrative disease (sarcoidosis, lymphoma), infectious agents (Legionnaire disease, hantavirus)
o Acute glomerulonephritis
o Vascular diseases - Hypertensive crisis, polyarteritis nodosa, vasculitis
* Postrenal failure - Diseases causing urinary obstruction from the level of the renal tubules to the urethra
o Tubular obstruction from crystals (eg, uric acid, calcium oxalate, acyclovir, sulfonamide, methotrexate, myeloma light chains)
o Ureteral obstruction - Retroperitoneal tumor, retroperitoneal fibrosis (methysergide, propranolol, hydralazine), urolithiasis, papillary necrosis
o Urethral obstruction - Benign prostatic hypertrophy; prostate, cervical, bladder, colorectal carcinoma; bladder hematoma; bladder stone; obstructed Foley catheter; neurogenic bladder; strictureDifferential Diagnoses
Alcoholic Ketoacidosis
Metabolic Acidosis
Anemia, Sickle Cell
Pediatrics, Dehydration
Aneurysm, Abdominal
Pediatrics, Diabetic Ketoacidosis
Congestive Heart Failure and Pulmonary Edema
Pediatrics, Inborn Errors of Metabolism
Diabetic Ketoacidosis
Pediatrics, Sickle Cell Disease
Glomerulonephritis, Acute
Pediatrics, Urinary Tract Infections and Pyelonephritis
Hemolytic Uremic Syndrome
Renal Calculi
Henoch-Schonlein Purpura
Renal Failure, Chronic and Dialysis Complications
Hyperkalemia
Toxicity, Alcohols
Hypermagnesemia
Urinary Obstruction
Hypernatremia
Urinary Tract Infection, Female
Hypertensive Emergencies
Urinary Tract Infection, Male
Workup
Laboratory Studies

* Urinalysis: Microscopic examination of urine is essential in establishing differential diagnosis for acute renal failure (ARF).
o 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
o Granular casts - ATN, glomerulonephritis, interstitial nephritis
o RBC casts - Glomerulonephritis, malignant HTN
o WBC casts - Pyelonephritis
o Eosinophiluria - Acute allergic interstitial nephritis, atheroembolism
o Crystalluria - Acyclovir, sulfonamides, methotrexate, ethylene glycol toxicity, radiocontrast agents (Mild crystalluria can be a normal finding.)
* BUN: The urea concentration correlates poorly with the GFR. Because urea is highly permeable to renal tubules, urea clearance varies with urine flow rate.
o 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.
o 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 measurement provides the ED physician with an accurate and consistent estimation of GFR. Correct interpretation of serum creatinine measurement extends beyond just knowing normal values for the specific laboratory.
o Creatinine measuring methods
+ Serum creatinine level varies by method of measurement, either Jaffe or iminohydrolase. Upper limit of normal creatinine level 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 laboratories.
+ 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.
o Serum creatinine level is a reflection of creatinine clearance.
+ Serum creatinine level is a function of its production and excretion rates.
+ Creatinine production is determined by muscle mass. Serum creatinine level 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.
+ 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 years, yet serum creatinine level generally remains stable. Balance is achieved via a decrease in muscle mass with age, which matches the fall in GF
+ Men generally have a higher muscle mass per kilogram of body weight and thus a higher serum creatinine level than women.
o An important consideration and limitation is that significant decrements in GFR can occur while creatinine levels remain in the normal range.
o Changes in serum creatinine level reflect changes in GFR. Rate of change in serum creatinine level is an important variable in estimating GFR. Stable changes in serum creatinine level correlate with changes in GFR by the following relationships:
+ If creatinine 1 mg/dL is baseline for a given patient with normal GFR
+ Creatinine 2 mg/dL - 50% reduction in GFR
+ Creatinine 4 mg/dL - 70–85% reduction in GFR
+ Creatinine 8 mg/dL - 90–95% reduction in GFR
+ As suggested by these data, knowledge of a patient's baseline creatinine level becomes very important. Small changes with low baseline levels of creatinine may be much more important clinically than large changes with high basal 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 level when ARF occurs in acute glomerulonephritis. Trimethoprim and cimetidine cause decreased creatinine secretion and a falsely elevated creatinine with no change in GFR.
* Cystatin C is emerging as a superior biomarker for early kidney injury.
o It is generated at a constant rate by all nucleated cells and is not secreted by the tubules or eliminated by other routes than renal excretion.
o It does not appear to be affected by body habitus, nutritional state, or comorbid illness.
o One of its principal advantages is that it identifies kidney injury while creatinine levels remain in the normal range.
* Complete blood cell count
o Leukocytosis is common in ARF.
o Leukopenia and thrombocytopenia suggest SLE or TTP.
o Anemia and rouleaux formation suggest multiple myeloma.
o Microangiopathic anemia suggests DIC, TTP, or atheroemboli.
o Eosinophilia suggests allergic interstitial nephritis, polyarteritis nodosa, or atheroemboli.
o Coagulation disturbances indicate liver disease, DIC, TTP, or hepatorenal syndrome.
* Blood chemistry
o Creatine phosphokinase (CPK) elevations are seen in rhabdomyolysis and myocardial infarction.
o Elevations in liver transaminase levels are seen in rapidly progressive liver failure and hepatorenal syndrome.
o Hypocalcemia (moderate) is common in ARF; marked hypocalcemia is more typical of chronic renal failure.
o Hyperkalemia is a common and important complication of ARF.
* Urine chemical indices
o 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, overly aggressive volume resuscitation in a patient with ATN who is unable to excrete the extra fluid can result in volume overload and respiratory embarrassment.
o To help with the differentiation of prerenal azotemia, analysis of urine may provide important clues. Diuretics interfere with some of these indices, so collect urine prior to any considered administration of diuretics.
o Urine indices that suggest prerenal ARF include the following:
+ Urine specific gravity >1.018
+ Urine osmolality (mOsm/kg H2 O) >500
+ Urine sodium (mEq/L) <15-20 + Plasma BUN-creatinine ratio >20
+ Urine-plasma creatinine ratio >40
o Urine indices that suggest ATN include the following:
+ Urine specific gravity <1.012 + Urine osmolality (mOsm/kg H2 O) <500 + Urine sodium (mEq/L) >40
+ Plasma BUN/creatinine ratio <10-15 + Urine-plasma creatinine ratio <20 * Calculation of fractional excretion of sodium (FeNa) o FeNa = (urine Na/plasma Na)/(urine creatinine/plasma creatinine) o FeNa <1% suggests prerenal ARF o FeNa >1% suggests ATN
* Advantages of FeNa compared to other indices
o Physiologic measure of sodium reabsorption
o Measured creatinine and sodium clearances, accounting for filtration and reabsorption of sodium
o FeNa increased before oliguric phase established and predictive of incipient ARF
* Exceptions (intrinsic renal failure with FeNa <1%) o Acute glomerulonephritis o Hepatorenal syndrome o Radiologic contrast–induced ATN o Myoglobinuric and hemoglobinuric ARF o Renal allograft rejection o Drug-related alterations in renal hemodynamics (eg, captopril, NSAIDs) Imaging Studies Imaging studies in acute renal failure (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. * Renal ultrasonography o Renal ultrasonography is the test of choice for urologic imaging in the setting of acute renal failure.6 It has excellent sensitivity and specificity for detecting hydronephrosis due to obstruction, and it can also give valuable information other than ruling obstruction in or out. o Bipolar renal length is easy to assess, and kidneys smaller than 9 cm suggest chronic renal failure. o Renal parenchyma should be isoechogenic or hypoechogenic when compared with that of the liver and spleen; hyperechogenicity indicates diffuse parenchymal disease. o Color Doppler allows assessment of renal perfusion and can allow diagnosis of large-vessel etiologies of ARF. o In critically ill patients, bedside sonography warrants special consideration as it can quickly diagnose treatable etiologies of the patient’s condition and give guidance for fluid resuscitation. * Chest radiography o Obtain chest radiographs on a routine basis to look for evidence of volume overload. o 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, ischemia, and infarction. Procedures * Renal biopsy o Renal biopsy is often helpful in finding specific cause of intrinsic renal failure; however, it is not an ED procedure. o This is reserved for evaluation of ARF when the cause cannot be determined. o Renal biopsy is especially important when glomerular causes of ARF are suspected. o It is often helpful in finding a specific cause of renal failure.Treatment Prehospital Care Stabilize acute life-threatening conditions and initiate supportive therapy. Watch for electrocardiographic evidence of hyperkalemia. Emergency Department Care Treatment of acute renal failure (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 patient with ARF. * Fluid management o Patients with ARF represent challenging fluid management problems. o Hypovolemia potentiates and exacerbates all forms of ARF. o 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. o 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. o Bedside sonographic evaluation including IVC measurement may give additional useful information. * Urinary catheter placement o Urinary obstruction often is an easily reversible cause of ARF. o 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 but also allows for accurate measurement of urine output. o If available, bedside ultrasonography can quickly identify a large and distended bladder. o Routine use of urinary catheters should be tempered by consideration of their inherent risks of introducing infections. * Renal replacement therapy o The principal methods of renal replacement therapy (RRT) are intermittent hemodialysis (IHD), continuous venovenous hemodiafiltration (CVVHD), and peritoneal dialysis (PD). Each has advantages and limitations. o IHD is widely available, has only moderate technical difficulty, and is the most efficient way of removing a volume or solute from the vascular compartment quickly. Unfortunately, dialysis-associated hypotension may adversely affect remaining renal function, particularly in patients who are hemodynamically unstable. This is one reason CVVHD is widely recommended in this setting. o Continuous RRT techniques are more expensive, associated with increased bleeding risk and not universally available; however, in addition to avoiding hypotension, they are believed to achieve better control of uremia and clearance of solute from the extravascular compartment. CVVHD may also preserve cerebral perfusion pressure more effectively. Although several studies have sought to directly compare CVVHD to IHD, no study has shown a convincing advantage for one therapy over the other. o Peritoneal dialysis is inexpensive, widely available, and does not result in hypotension. However, it is not capable of removing large volumes of fluid or solute. Its use may be most common in children and in developing countries. o Indications for and timing of initiation of RRT are also important and somewhat controversial subjects. Widely accepted indications for initiation of RRT include the following: + Volume overload + Hyperkalemia (K+ >6.5 or rising)
+ Acid-base imbalance
+ Symptomatic uremia (pericarditis, encephalopathy, bleeding dyscrasia, nausea, vomiting, pruritus)
+ Uremia (BUN >100)
+ Dialyzable intoxications
o Severe dysnatremia (<115 or >165), and dysthermia may also be appropriate indications for RRT.
o Significant intoxications with a dialyzable agent (eg, methanol, ethylene glycol, theophylline, aspirin, lithium) may be the strongest single indication for emergent dialysis because other effective therapeutic interventions are available for most of other complications of ARF. Volume overload can be treated with nitrates and phlebotomy; hyperkalemia can be treated with calcium, insulin, glucose, bicarbonate, binding resins, and beta-agonists. Note, in light of little evidence of effectiveness, the possible adverse effects of the ion-exchange resin, sodium polystyrene sulfonate, in sorbitol should be considered. There is emerging concern about use of this time-honored but scientifically unproven management of hyperkalemia.7
o The timing of initiation of RRT in the absence of these indications is controversial, although the consensus that RRT itself contributes to the resolution of ARF may be growing.
o Intensity of RRT is another area of active controversy and research; some studies suggest that more is better. In a study of CVVH intensity in which patients with ARF were randomly given standard or supernormal levels of ultrafiltration, the patients with more intense RRT had significantly lower mortality rates. A second randomized trial compared daily IHD with traditional every-other-day IHD in patients with ARF and found that the mortality rate (28% vs 46%) and speed of renal recovery (9 d vs 16 d) were significantly improved. However, before these studies, no significant evidence indicated that increased dialysis dosage improved outcomes.

Consultations

Consider consultation with a nephrologist or critical care specialist in patients with newly diagnosed ARF.
Medication

Diuretics and vasodilators are used commonly to treat acute renal failure (ARF). Unfortunately, in large randomized studies, these agents have failed to prove effective.

Atrial natriuretic factor also has been tested in a randomized double-blind study in ARF but failed to improve the course of ARF.

Calcium channel blockers have been shown in animal models to be protective in ARF if given before renal insult. Their only benefit in humans is preventing ARF in renal transplant patients receiving cyclosporine.

Infusion of mannitol is reported to be protective of myoglobinuric ARF if given within 6 hours of rhabdomyolysis. In addition, mannitol infusion has been shown to decrease the rate of ARF if given before cardiothoracic surgery and radiocontrast agents. No controlled studies have shown any benefit to mannitol infusion in patients with established ARF. In fact, mannitol given in high doses has been associated with ARF. Significant risks of prescribing large doses of mannitol to patients with ARF include fluid overload and hyperkalemia.
Renal Vasodilator

Fenoldopam is a potent dopamine A-1 receptor agonist that increases blood flow to the renal cortex and outer medulla and evidence to date suggests that it reduces mortality and provides renal protection in critically ill patients with or at risk of renal failure. Because it is titratable and it reliably controls severe hypertension, fenoldopam may be ideal for treating hypertensive emergencies where the affected end organ is the kidneys.

Fenoldopam (Corlopam)

Selective postsynaptic dopamine agonist (1-receptors), which exerts hypotensive effects by decreasing peripheral vasculature resistance with increased renal blood flow, diuresis, and natriuresis.
In patients with renal insufficiency, fenoldopam provides an alternative to nitroprusside without the threat of cyanide and thiocyanate toxicity. Permits precise titration to the desired blood pressure level. Studies demonstrate safety of administration without invasive monitoring; however, clinician may choose invasive monitoring because fenoldopam causes rapid blood pressure changes.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

0.03-0.2 mcg/kg/min IV
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Acetaminophen may increase levels up to 70%; beta-blockers increase risk of hypotension

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

May cause headache, nausea, vomiting, and hypotension; monitor blood pressure and heart rate q15min; caution in cirrhosis, portal hypertension, unstable angina, and glaucoma
Diuretics

Patients with nonoliguric (rather than oliguric) ARF have better mortality and renal recovery rates, prompting many to recommend diuretics in oliguric ARF. Unfortunately, randomized double-blind controlled trials fail to show benefit. Studies conclude that diuretics are useful only in management of fluid-overloaded patients and venodilators and dialysis are more effective interventions for this indication.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Also is potent vasodilator of medullary vessels, serving to wash out concentration gradient of countercurrent system, resulting in marked diuresis.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

20-80 mg PO/IV once; ordinarily, prompt diuresis ensues; repeat 6-8 h later prn, or dose may be increased; increase dose by 20-40 mg no sooner than 6-8 h after previous dose until desired effect
Pediatric

2 mg/kg PO/IV, once; may increase by 1-2 mg/kg no sooner than 6-8 h after previous dose; not to exceed 6 mg/kg

* Dosing
* Interactions
* Contraindications
* Precautions

Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; concurrent aminoglycosides cause auditory toxicity—hearing loss of varying degrees may occur; may increase anticoagulant activity of warfarin; increased plasma lithium levels and toxicity are possible

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; hepatic coma; anuria; severe electrolyte depletion

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Measure serum electrolytes, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN frequently during first few months of therapy and periodically thereafter; excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in elderly patients
Vasodilators

Renal vascular vasodilators in ARF make a great deal of sense from theoretical and experimental viewpoints. However, effective blood-volume restoration is the best physiologic vasodilator.

Low-dose dopamine is a potent vasodilator, increasing RBF in ARF. Unfortunately, most clinical studies fail to show that it improves recovery or mortality rates. In the majority of ARF studies, dopamine was associated only with an increase in urine output. Current recommendations for dopamine favor its use in patients with ARF and concomitant hypodynamic heart failure. Balance benefits of diuretic action with proarrhythmic side effects.

Dopamine (Intropin)

Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect depends on dose; lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation; cardiac stimulation and renal vasodilation produced by higher doses.
After initiating therapy, dose may be increased by 1-4 mcg/kg/min q10-30min until satisfactory response attained; maintenance doses <20 mcg/kg/min usually satisfactory for 50% of patients treated.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Low renal dose: 1-5 mcg/kg/min IV
Pediatric

Administer as in adultsFollow-up
Further Inpatient Care

* Patients with acute renal failure (ARF) should generally be admitted to an inpatient setting; intensive care will be appropriate for many of them.

Transfer

* Transfer patients with significant ARF to a facility with capability for hemodialysis on a 24-hour basis.

Deterrence/Prevention

* It is important to recognize renal failure early as well as risk factors for renal injury and to avoid interventions that may iatrogenically induce renal failure.

Complications

* A vast array of fluid and electrolyte abnormalities can be seen with acute renal failure (ARF). Refer to the appropriate articles for a more complete discussion of these disorders (see Hypercalcemia and Hyperkalemia).
* Cardiovascular complications (eg, CHF, myocardial infarction, arrhythmias, cardiac arrest) have been observed in as many as 35% of patients with ARF. Fluid overload secondary to oliguric ARF is a particular risk for elderly patients with little cardiac reserve.
o Pericarditis is a relatively rare complication of ARF. When pericarditis complicates ARF, consider additional diagnoses, such as SLE and hepatorenal syndrome.
o ARF also can be a complication of cardiac diseases, such as endocarditis, worsening CHF, or atrial fibrillation with emboli.
o Cardiac arrest in a patient with ARF always should arouse suspicion of hyperkalemia. Many authors recommend a trial of intravenous calcium chloride (or gluconate) in all patients with ARF who experience cardiac arrest.
* Pulmonary complications have been reported in approximately 54% of patients with ARF. Pulmonary complications are the single most significant risk factor for death in patients with ARF.
o Several diseases exist that commonly present with simultaneous pulmonary and renal involvement, including pulmonary/renal syndromes (eg, Goodpasture syndrome, Wegener granulomatosis, polyarteritis nodosa, cryoglobulinemia, sarcoidosis).
o Hypoxia commonly occurs during hemodialysis and can be particularly significant in the patient with pulmonary disease. This dialysis-related hypoxia is thought to occur secondary to WBC lung sequestration and alveolar hypoventilation.
* GI symptoms of nausea, vomiting, and anorexia are frequent complications of ARF and represent one of the cardinal signs of uremia.
o GI bleeding occurs in approximately one third of patients with ARF. Most episodes are mild, but GI bleeding accounts for 3-8% of deaths in patients with ARF.
o Mild hyperamylasemia (2-3 times controls) commonly is seen in ARF. Elevation of baseline amylase can complicate diagnosis of pancreatitis in patients with ARF.
o Lipase, which commonly is not elevated in ARF, often is necessary to make the diagnosis of pancreatitis. Pancreatitis has been reported as a concurrent illness with ARF in patients with atheroemboli, vasculitis, and sepsis from ascending cholangitis.
o Jaundice has been reported to complicate ARF in approximately 43% of cases. Etiologies of jaundice with ARF include hepatic congestion, blood transfusions, and sepsis.
o Hepatitis occurring concurrently with ARF should prompt the differential diagnosis of common bile duct obstruction, fulminant hepatitis B, leptospirosis, acetaminophen toxicity, and Amanita phalloides toxin.
* Infections commonly complicate the course of ARF and have been reported to occur in as many as 33% of patients with ARF. Most common sites are pulmonary and urinary tracts. Infections are the leading cause of morbidity and death in patients with ARF. Various studies have reported mortality rates of 11-72% in infections complicating ARF.
* Neurologic signs of uremia are a common complication of ARF and have been reported in approximately 38% of patients with ARF.
o Neurologic sequelae include lethargy, somnolence, reversal of the sleep-wake cycle, and cognitive or memory deficits.
o Focal neurologic deficits rarely are due solely to uremia and should remain a diagnosis of exclusion in patients with ARF.
o Pathophysiology of neurologic symptoms is still unknown but they do not correlate well to levels of BUN or creatinine. A number of diseases express themselves with concurrent neurologic and renal manifestations (eg, SLE, TTP, HUS, endocarditis, malignant hypertension).

Prognosis

* Mortality rates from ARF remain 50%, despite the institution of effective renal replacement therapies.
o Deaths from ARF are related directly to the patient's underlying disease process (eg, sepsis, CHF).
o Mortality rates in patients older than 80 years are approximately 40%, very similar to those in younger patients. Age should not be a determining factor in instituting renal replacement therapy.
* Approximately 20–60% of patients experiencing ARF require dialysis during their hospital stay. The majority of these patients recover, with only 25% requiring long-term renal replacement therapy.

Patient Education

* Stress to patients that progressive renal failure is a silent disease. Symptoms of uremia occur only with advanced, generally irreversible renal failure. The only way for patients to reliably follow the course of their disease is by regular checkups with their physicians.
* For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article, Acute Kidney Failure.

Miscellaneous
Medicolegal Pitfalls

* Failing to consider ARF: Normal-range BUN and creatinine levels do not reliably rule out the diagnosis of ARF. Patients with low muscle mass and/or vegetarians may have significant decreases in GFR and still remain in normal ranges for BUN and creatinine. Comparison with baseline values and trends are more important than absolute numerical values.
* Most cases of ARF in inpatients are secondary to iatrogenic causes. Be especially careful in prescribing potential nephrotoxins (eg, radiocontrast agents, aminoglycosides, NSAIDs) to patients predisposed to ARF (eg, dehydration, CHF, diabetes mellitus, chronic renal failure, elderly patients).