Acute renal failure (ARF) is defined as an abrupt or rapid decline in renal function. A rise in serum blood urea nitrogen (BUN) or serum creatinine concentrations, with or without a decrement in urine output, is usually evidence of ARF. The condition is often transient and completely reversible, however, it can progress when treatment is delayed to a more chronic state, or it can result in death.
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ARF may occur in 3 clinical settings, including (1) as an adaptive response to severe dehydration (volume depletion) and hypotension, with structurally and functionally intact nephrons (kidney cells); (2) in response to cytotoxic or ischemic insults to the kidney, with structural and functional damage; and (3) with obstruction to the passage of urine. Therefore, ARF may be classified as prerenal, intrinsic, and postrenal. While these classifications are useful in establishing a differential diagnosis, many pathophysiologic features are shared among the different categories.
The intrinsic form of the syndrome may be accompanied by a well-defined sequence of events. The first is an initiation phase, characterized by daily increases in serum creatinine and reduced urinary volume; the second is a maintenance phase, during which the glomerular filtration rate (GFR) is relatively stable and urine volume may be increased; and the third is a recovery phase, in which serum creatinine levels fall and kidney tubular function is restored. This sequence of events is not always apparent, and oliguria (reduced urine output) may not be present.
The reason for this lack of a uniform clinical presentation is a reflection of the variable nature of the injury. A physiologic hallmark of intrinsic ARF is a failure to maximally concentrate urine. Classifying ARF as oliguric or nonoliguric based on daily urine excretion may be useful. Oliguria is defined as a daily urine volume of less than 500 mL/d. Anuria is defined as a urine output of less than 50 mL/d and, if abrupt in onset, is suggestive of obstruction. Stratification of renal failure along these lines helps in decision-making (eg, timing of dialysis) and seems to be an important criterion for patient response to therapy.
Intrarenal vasoconstriction is the dominant mechanism for the reduced GFR in patients with ARF. The mediators of this vasoconstriction are unknown, but injury to tubules seems to be an important finding. While obstruction of urine outflow into the collecting system is an obvious cause of reduced net ultrafiltration, the intratubular obstruction that results from sloughed cells and cellular debris that evolves in the course of renal failure is a less obvious cause. The importance of this mechanism is highlighted by the improvement in renal function that follows relief of such intratubular obstruction.
The stressed renal microvasculature is more sensitive to potentially vasoconstrictive drugs and otherwise-tolerated changes in systemic blood pressure. Prolonged vasoconstriction may evolve into intrinsic ARF, especially when concomitant large vessel arterial disease occurs. Renal failure caused by prolonged vasoconstriction (especially with concomitant large vessel arterial disease) often is induced by the use of angiotensin-converting enzyme (ACE) inhibitors and/or diuretics.
Approximately 1% of patients admitted to hospitals have ARF at the time of admission, and the estimated incidence rate of ARF is 2-5% during hospitalization. Approximately 95% of consultations with nephrologists are related to ARF. The mortality rate estimates vary from 25-90%. The in-hospital mortality rate is 40-50%, and the mortality rate is 70-80% in intensive care settings.
A detailed and accurate history is essential to determine the type of ARF and in determining its subsequent treatment. A detailed history and physical exam in combination with laboratory tests will help in securing an accurate diagnosis.
Distinguishing ARF from chronic renal failure is very important, yet making the distinction can be very difficult. A history of chronic symptoms of fatigue, weight loss, anorexia, nocturia, and pruritus all suggest chronic renal failure. The following history should be obtained: a history of congestive heart failure, hypertension, nephrotoxic drug ingestion, kidney trauma, severe exertion and exercise, blood loss or transfusions, connective tissue disorders, exposure to ethylene glycol, mercury vapors, lead, cadmium, or other heavy metals (welders and miners), accompanying co-morbid conditions which place the patient at higher risk for developing ARF including, hypertension, congestive heart failure, diabetes, myeloma, chronic infection, myeloproliferative disorders, and finally, a determination of whether the decrease in urine output is rapid or gradual. Abrupt urine output suggests an acute obstruction, acute glomerulonephritis, or an embolic event due to renal artery occlusion.
Obtaining a careful thorough physical examination is extremely important when collecting evidence about the etiology of ARF.
Skin: Petechiae, purpura and ecchymosis suggests inflammatory and vascular causes including infections, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and embolic phenomena.
Eyes: Evidence of uveitis may indicate interstitial nephritis and necrotizing vasculitis. Ocular palsy may indicate ethylene glycol poisoning or necrotizing vasculitis. Findings suggestive of severe hypertension, atheroembolic disease, and endocarditis may be observed after a careful examination of the eyes.
Cardiovascular System: The most important part of the physical examination is the assessment of cardiovascular and volume status. The physical examination must include pulse rate and blood pressure recordings measured in both supine and standing positions; close inspection of the jugular venous pulse; careful examination of the heart, lungs, and skin turgor mucous membranes; and assessment for the presence of peripheral edema. Accurate daily records of fluid intake and urine output and daily measurements of patient weight are important. Blood pressure recordings can be important diagnostic tools. Hypovolemia leads to hypotension; however, hypotension may not necessarily indicate hypovolemia. Severe congestive cardiac failure (CHF) may also cause hypotension. Although patients with CHF may have low blood pressure, volume expansion is present and effective renal perfusion is poor, which can result in ARF. Severe hypertension with renal failure suggests renovascular disease, glomerulonephritis, vasculitis, or atheroembolic disease.
Abdomen: Abdominal examination findings can be very useful to help detect obstruction at the bladder outlet as the cause of renal failure, which may be due to cancer or an enlarged prostate. The presence of an epigastric bruit suggests renal vascular hypertension.
The causes of ARF traditionally are divided into 3 main categories: prerenal, intrarenal, and postrenal. In prerenal ARF, perfusion of the kidneys is compromised by the following: Hypotension, CHF, and hypovolemia (from either renal loss due to Addison disease or diabetic ketoacidosis for example, or extrarenal loss due to vomiting, diarrhea, pancreatitis, burns, or sweating).
Causes of intrarenal ARF can be grouped into vascular, interstitial, and glomerular factors, as follows: Vascular causes include vasculitis involving the small vessels, scleroderma, atheroembolic renal disease, malignant hypertension, and thrombotic angiopathy. Although many of these causes can also be grouped under prerenal ARF, more frequently they cause ischemic tubular necrosis. Interstitial nephritis usually results from a reaction to a specific drug or a group of drugs. Interstitial nephritis is observed more commonly in hospitalized patients. The list of drugs causing allergic interstitial nephritis is long. The drugs commonly implicated include penicillins and other antibiotics, NSAIDs, diuretics, cimetidine, and allopurinol. Chinese herb nephropathy also may cause acute interstitial nephritis. Glomerular factors may suggest glomerulonephritis. ARF secondary to glomerulonephritis is observed in severe forms of crescentic glomerulonephritis, postinfective glomerulonephritis, lupus nephritis, hepatitis (especially cryoglobulinemia-associated hepatitis C viral infection), and several other vasculitis-associated glomerulonephritides. Early diagnosis is of utmost importance because this condition is potentially reversible if diagnosed and treated rapidly.
Postrenal causes are as follows: The most common cause of postrenal failure is secondary to bladder outlet obstruction due to prostatic hypertrophy. The obstruction must be distal to the bladder or bilateral to cause ARF unless only a single kidney is functioning properly. Urine output findings can be misleading. Renal ultrasound is a quick and noninvasive study that can help detect obstruction.
Several laboratory tests are useful for assessing the etiology of ARF, and the findings can aid in proper management. These tests include complete blood cell count, serum biochemistries, urine analysis with microscopy, and urine electrolytes. Just a word about a few of these. Increased levels of BUN and creatinine are the hallmarks of renal failure. The ratio of BUN to creatinine is an important finding because the ratio can exceed 20:1 in conditions that produce volume depletion like upper gastrointestinal bleeding. Other conditions causing a BUN-to-creatinine ratio of greater than 20:1 are increased enteral or parenteral protein load, corticosteroid therapy, and a hypercatabolic state. Complete blood cell count and peripheral smear may show schistocytes in conditions such as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura. A finding of increased rouleau formation suggests multiple myeloma, and the workup should be directed toward protein electrophoresis of serum and urine.
Urinalysis remains the most important test in the initial evaluation of ARF. Findings of granular muddy-brown casts are suggestive of tubular necrosis. The presence of tubular cells or tubular cell casts also supports the diagnosis of acute tubular necrosis (ATN). Reddish brown or cola-colored urine is present in patients with acute glomerular nephritis or in the presence of myoglobin or hemoglobin. Dipstick assay findings may show the presence of significant proteinuria such as occurs in intrinsic renal diseases, including glomerulonephritis, acute interstitial nephritis, tubular necrosis, and vascular diseases. When RBCs are present in the urine, they can aid in establishing a diagnosis. RBC casts are pathognomonic for glomerular disease. Dysmorphic RBCs also support a glomerular cause such as lupus nephritis. The presence of WBCs or WBC casts may denote pyelonephritis or acute interstitial nephritis. The presence of uric acid crystals may represent ATN associated with uric acid nephropathy, while calcium oxalate crystals may be present in ARF due to ethylene glycol poisoning. Also, urine and serum uric acid values may be a useful indicator for tumor lysis syndrome, an important cause of ARF.
In some cases, renal imaging is very useful, especially if the cause of renal failure is secondary to obstruction. Renal ultrasonography is useful for evaluating existing renal disease and obstruction of the urinary collecting system. Doppler scans are useful for detecting the presence and nature of renal blood flow. They can be quite useful in the diagnosis of thromboembolic or renovascular disease. Nuclear scans such as radionuclide imaging with a technetium Tc 99m diethylenetriamine pentaacetic acid (DTPA) or 99m Tc-DTPA iodine I 131–hippuran can be used to assess renal blood flow and tubular functions. Aortorenal angiography can be very helpful in the diagnosis of renal vascular diseases, including renal artery stenosis, renal atheroembolic disease, atherosclerosis with aortorenal occlusion, and in certain cases of necrotizing vasculitis (e.g.: polyarteritis nodosa).
A renal biopsy can be very useful in the diagnosis of intrarenal causes of ARF. Performing a renal biopsy is comparatively easy, and the findings establish the diagnosis in most cases. In as many as 40% of cases, renal biopsy results reveal an unexpected diagnosis. A renal biopsy is especially useful in rapidly progressive glomerulonephritis due to crescentic glomerulonephritis when clinical differentiation between acute glomerulonephritis and interstitial nephritis becomes difficult. Acute cellular rejection in a renal transplant can be definitively diagnosed only by performing a renal biopsy.
Aggressive treatment should begin at the earliest indication of renal dysfunction. A large proportion of the renal mass is damaged before any biochemical evidence of renal dysfunction is appreciated because the relationship between the GFR and the serum creatinine level is exponential, not linear. The rise of serum creatinine may not be evident before 50% of the GFR is lost. At this point, recognizing the presence of ARF and promptly initiating therapy aimed at minimizing the damage to the remaining functional renal mass are important considerations. This may also aid in reversing the renal damage that has already occurred. Reversing renal damage can be accomplished only by identifying the underlying cause and directing the appropriate therapy.
Maintenance of volume homeostasis and correcting biochemical abnormalities remain the primary goals of treatment. At this stage, the kidneys remain vulnerable to the toxic effects of various chemicals. All nephrotoxic agents (e.g.: radiocontrast agents, antibiotics with nephrotoxic potential, heavy metal preparations, cancer chemotherapeutic agents, NSAIDs) are either avoided or used with extreme caution. Similarly, all medications cleared by renal excretion should be avoided or their doses should be adjusted appropriately.
Correcting acidosis with bicarbonate administration is important. It cannot be overstated that the current treatment of ARF is mainly supportive in nature and no therapeutic modalities to date have shown efficacy in treating the condition. Although therapeutic agents such as dopamine, Lasix, fenoldopam, and mannitol are still being used, the efficacy of this treatment remains controversial.
Hyperkalemia, which can be life-threatening, should be treated by decreasing the intake of potassium, delaying the absorption of potassium, exchanging potassium across the gut lumen using potassium-binding resins, controlling intracellular shifts, and instituting dialysis. Correcting hematologic abnormalities (e.g.: anemia, platelet dysfunction) warrants appropriate measures, including transfusions and administration of desmopressin or estrogens.
Dietary modification is a very important facet of the treatment of ARF. Diet and fluid restriction becomes crucial in the management of oliguric renal failure, wherein the kidneys do not excrete either toxins or fluid adequately. Because potassium and phosphorous are not excreted optimally in patients with ARF, blood levels of these electrolytes tend to be high. Frequent measurements are mandatory to achieve acceptable blood levels by modification of the diet or by intravenous supplementation.
Pharmacologic treatment of ARF has been attempted on an empiric basis, with varying success rates. Several promising experimental therapies in animal models are awaiting human trials. Experimental therapies include growth factors, vasoactive peptides, adhesion molecules, endothelin inhibitors, and bioartificial kidneys. Aminophylline has also been used experimentally for prophylaxis against renal failure.
A prophylactic strategy shown to decrease the incidence of contrast nephropathy is the IV administration of isotonic NaHCO3 solution before and after the procedure. Another prophylactic agent used with varying success is N- acetylcysteine. This is administered to high-risk patients the day before a contrast study is performed and is continued the day of the procedure. Diuretics should be withheld near the time of the procedure.
The prognosis of patients with ARF is directly related to the cause of renal failure and, to a great extent, to the duration of renal failure prior to therapeutic intervention. If ARF is defined by a sudden increment of serum creatinine of 0.5-1 mg/dL and is associated with a mild-to-moderate rise in creatinine, the prognosis tends to be worse. However, even if renal failure is mild, the mortality rate is 30-60%. If these patients need dialytic therapy, the mortality rate is 50-90%. Using Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, the survival rate is nearly 0% among patients with ARF who have a score higher than 40 and is 40% in patients with APACHE II scores of 10-19.
Other prognostic factors include the following: Older age, multiorgan failure (i.e.: the more organs that fail, the worse the prognosis), oliguria, hypotension, vasopressor support, number of transfusions, and surgery. Prerenal azotemia due to volume contraction is treated with volume expansion; however, if left untreated for a prolonged duration, tubular necrosis may result and may not be reversible. Postrenal ARF (i.e.: urinary obstruction related renal failure) causes renal damage due to increased pressure proximal to the obstruction, which results in a thinning of the renal cortex. If left untreated for a long time, it may result in irreversible renal damage. Simple procedures such as catheter placement, lithotripsy, prostatectomy, stent placement, or percutaneous nephrostomy can help prevent permanent renal damage.
Timely identification of pyelonephritis, proper treatment, and further prevention using prophylactic antibiotics may improve the prognosis, especially in females. Early diagnosis of crescentic glomerulonephritis via renal biopsy and other appropriate tests may enhance early renal recovery because appropriate therapy can be initiated promptly and aggressively. The number of crescents, the type of crescents (i.e.: cellular vs fibrous), and the serum creatinine level at the time of presentation may dictate prognosis for renal recovery in this subgroup of patients.
Controversy exists regarding the timing of dialysis. Dialysis, especially hemodialysis, may delay the recovery of patients with ARF. Most authorities prefer using biocompatible membrane dialyzers for hemodialysis. Continuous renal replacement therapy may have a role in patients who are hemodynamically unstable and who have had prolonged renal failure after a stroke or liver failure. Such patients may not tolerate the rapid shift of fluid and electrolytes caused during conventional hemodialysis. Peritoneal dialysis can also be used in acute cases and probably is tolerated better hemodynamically than conventional hemodialysis.
Indications for dialysis in patients with ARF are as follows: Volume expansion that cannot be managed with diuretics, hyperkalemia, correction of severe acid-base disturbances, severe azotemia (BUN >100), symptoms of uremic pericarditis, gastritis, seizures, or encephalopathy.
Skimming over the history and physical, or failing to order the relevant lab studies often results in a delay in diagnosis the cause of ARF. This is important because the offending cause will not be identified in a timely manner, and the condition could progress to chronic renal failure, or the patient can even die.
Although ARF potentially is a reversible condition, it can occur in patients with chronic renal failure. Every effort should be made to identify reversibility, even if improvement in renal function is marginal. The best way to identify reversibility is by tracking the rate of deterioration of renal function. If the rate of worsening renal function accelerates, the cause should be sought and treated.
Renal recovery is usually observed within the first 2 weeks, and many nephrologists tend to diagnose patients with end- stage (i.e.: irreversible) renal failure 6-8 weeks after onset of ARF. It is always better to check these patients periodically because some patients may regain renal function much later.
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