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; stricture