Renal Failure

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Chapter 97

Renal Failure

Evaluation of Renal Function

The evaluation of renal disease in the emergency department (ED) requires the intelligent use of urinalysis, serum and urine chemical determinations, and renal imaging studies to assess the degree of renal dysfunction and to take the first steps in determining its cause.

Diagnostic Strategies

Urine Volume

Because urine flow does not diminish until the glomerular filtration rate (GFR) is sharply decreased, urine volume is a poor indicator of renal dysfunction. In fact, urine volume often increases as concentrating ability is lost with advancing renal dysfunction; patients with renal failure typically produce urine that is isosmolar with serum. Oliguria, defined as a urine volume of 100 to 400 mL/24 hr, may be seen with prerenal (blood flow dependent), intrinsic (intrarenal), or postrenal (obstructive) causes of acute kidney injury (AKI) (previously known as acute renal failure [ARF]). Although uncommon, alternating oliguria and anuria (the latter defined as less than 100 mL/24 hr), is a classic indicator of intermittent obstruction, which occurs as urine collects behind an obstructing stone or tumor and then is allowed to flow past as the obstructing material shifts position.

Microscopic Examination

After dipstick testing of the urine has been completed, 10 mL of urine is placed in a conical test tube and spun at 2000 revolutions per minute for 5 minutes (higher speeds may break up casts). The supernatant is discarded. The sediment is resuspended in the residual urine, and a drop is placed on a slide and covered with a coverslip. Observations are recorded as the number of cells per high-power field. A level of two to three RBCs per high-power field in adult men or two to four RBCs per high-power field in adult women is commonly accepted as normal; in many studies a finding of five RBCs per high-power field is considered to represent the threshold of abnormality.2

Casts are formed from urinary Tamm-Horsfall protein, a product of the tubular epithelial cells that gels at low pH and high concentration and when mixed with albumin, or from red cells, tubular cells, or cellular debris in the urine. The composition of a cast thus reflects the contents of the tubule. Casts are described and classified according to their appearance or constituents (e.g., hyaline, red cell, white cell, granular, or fatty casts). Hyaline casts, those that are devoid of contents, are seen with dehydration, after exercise, or in association with glomerular proteinuria. Red cell casts indicate glomerular hematuria, as seen in glomerulonephritis; the presence of even a few red cell casts is significant. White cell casts imply the presence of renal parenchymal inflammation. Granular casts are composed of cellular remnants and debris. Fatty casts, like oval fat bodies, generally are associated with heavy proteinuria and nephrotic syndrome.

Microscopic examination of the urinary sediment can be helpful in establishing the cause of AKI. A sediment without formed elements or with only hyaline casts is characteristic of prerenal azotemia or obstruction. Red cell casts suggest glomerulonephritis or vasculitis. Fatty casts also suggest glomerular disease. In acute tubular necrosis (ATN), the urinary sediment commonly shows granular casts and renal tubular epithelial cells. Large numbers of polymorphonuclear leukocytes are observed in interstitial nephritis, papillary necrosis, and pyelonephritis. Eosinophil-containing casts (appreciated only after staining of the sediment) are typical of allergic interstitial nephritis. Uric acid crystals suggest uric acid nephropathy but are extremely nonspecific; oxalic acid or hippuric acid crystals may be seen in ethylene glycol ingestion.

Serum and Urine Chemical Analysis

Creatinine and Blood Urea Nitrogen.: The normal range for the serum creatinine level extends from 0.5 mg/dL in thin people to 1.5 mg/dL in muscular persons. Spurious elevations (up to 2 mg/dL) can be caused by acetoacetate (which cross-reacts with creatinine in commonly used assays) as well as by certain medications that either cross-react in the assay or reversibly inhibit tubular creatinine secretion despite a normal GFR (generally less than 0.5 mg/dL). Serum creatinine concentration is a function of the amount of creatinine entering the blood from muscle, its volume of distribution, and its rate of excretion. Because the first two are usually constant, changes in serum creatinine concentration generally reflect changes in GFR. The creatinine clearance is commonly estimated by the Cockcroft-Gault equation3:

image

Under steady-state conditions, if the GFR is halved, the serum creatinine doubles. Abrupt cessation of glomerular filtration causes the serum creatinine to rise by 1 to 2 mg/dL per day. Thus a daily increment of less than 1 mg/dL suggests that at least some renal function has been preserved. Rhabdomyolysis releases creatine into the plasma and may cause the serum creatinine to increase by more than 2 mg/dL per day. The blood urea nitrogen (BUN) level also rises with renal dysfunction but is influenced by many extrarenal factors as well. Increased protein intake, gastrointestinal (GI) bleeding, and the catabolic effects of fever, trauma, infection, and drugs such as tetracycline and corticosteroids all increase protein turnover and result in increased hepatic urea production and increased BUN. Conversely, BUN tends to be decreased in patients with liver failure or protein malnutrition.

When glomerular filtrate has been formed, renal urea clearance is largely a function of flow rate. Urea clearance is thus decreased in patients with prerenal azotemia or acute obstruction, despite preservation of tubular function. In such cases the BUN/creatinine ratio usually is greater than the normal value of 10 : 1, whereas this ratio usually is not markedly increased in cases of uncomplicated intrinsic AKI.

Urine Sodium and Fractional Excretion of Sodium.: Measurement of the urine sodium concentration provides information on the integrity of tubular reabsorptive function. Normally, urine sodium concentration parallels sodium intake. Low urine sodium concentration thus indicates not only intact reabsorptive function but also the presence of a stimulus to conserve sodium. The urine sodium concentration, as well as the fractional excretion of sodium (FENa), an additional measure of tubular sodium handling, helps distinguish between the two most common causes of AKI: prerenal azotemia and ATN (Table 97-1).

Table 97-1

Typical Urinary Findings in Prerenal Azotemia and Acute Tubular Necrosis

LABORATORY TEST FINDING PRERENAL AZOTEMIA ACUTE TUBULAR NECROSIS
Urinalysis Normal or hyaline casts Brown granular casts, cellular debris
Urine sodium concentration (mEq/L) <20 >40
Fractional excretion of sodium (%) <1 >1
Urine-to-plasma creatinine ratio >40 <20

Urinary indices are most helpful in oliguric patients.4 In general, an oliguric patient with a urine sodium concentration below 20 mEq/L and an FENa below 1% should be considered to have prerenal azotemia, whereas urine sodium concentration above 40 mEq/L and FENa above 1% suggest ATN. Values in patients with prerenal azotemia overlap somewhat with those in patients with nonoliguric ATN, particularly if the renal injury is mild and some capability to retain sodium has been preserved. Thus, intermediate values for urine sodium concentration and FENa are of little help in differentiating between the two conditions. The administration of mannitol or a loop diuretic within the several hours preceding urine collection also may make interpretation of urine values difficult because the urinary sodium will tend to be higher and the urine less concentrated, causing the results in prerenal azotemia to resemble those in intrinsic renal failure (Box 97-1).

In glomerulonephritis, the urinary indices generally reflect intact tubular sodium handling, but the diagnosis is more accurately made by urine microscopy. In obstructive uropathy, the values of the urinary indices depend on the duration of obstruction and cannot be relied on to indicate either the presence or absence of obstruction.

Renal Imaging

Renal imaging is often helpful in evaluation of the patient with kidney dysfunction, particularly when obstruction is suspected. Contrast-enhanced computed tomography (CT) scanning provides an anatomic image of the urinary tract but does not provide an evaluation of renal function. The classic CT findings of obstruction are kidneys that are normal to large in size, nephrograms that become increasingly dense, and delayed opacification of dilated collecting systems. However, contrast-enhanced CT subjects the kidneys of an already azotemic patient to the risk of an additional potential insult from the contrast agent. Thus techniques such as ultrasonography and CT that do not involve contrast administration are much preferred in patients with preexisting renal insufficiency (Fig. 97-1).

Computed Tomography.: Noncontrast CT may be useful in evaluating some azotemic patients. Hydronephrosis can be recognized without the use of contrast material. Often, dilated ureters also can be seen without contrast enhancement, and the level of obstruction can be determined. Moreover, the cause of obstruction (e.g., bilateral stones, lymphoma, retroperitoneal hemorrhage, metastatic cancer, retroperitoneal fibrosis) often can be delineated as well. Occasionally, obstruction severe enough to result in renal failure may not cause detectable proximal dilation of the urinary tract. Bilateral ureteral obstruction produced by malignancy or retroperitoneal fibrosis is the most important cause of this nondilated obstructive uropathy. When noninvasive studies yield negative results, the diagnosis of obstruction can be made by retrograde pyelography or by antegrade pyelography performed via a percutaneous nephrostomy.

Hematuria and Proteinuria

Hematuria

Principles of Disease

Microscopic hematuria often is discovered incidentally on routine urinalysis, but as little as 1 mL of blood in 1 L of urine can cause grossly appreciable hematuria. Although not invariably a sign of disease, the finding of hematuria calls for an effort to rule out any treatable underlying disorder. Both gross and microscopic hematuria are caused by similar disorders, but the amount of blood in the urine does not correlate with the severity or the seriousness of the underlying condition.2

The causes of hematuria can be divided into hematologic, renal, and postrenal; renal causes may be further classified as glomerular or nonglomerular (Box 97-2). Overall, the most common causes of nontraumatic hematuria, in roughly descending order of occurrence, are kidney stones, urinary tract infection (UTI), carcinoma of the kidney or bladder, urethritis, benign prostatic hypertrophy, and glomerulonephritis. The scope of the differential diagnosis can be narrowed by taking into account the patient’s age and sex and by distinguishing between upper and lower urinary tract sources. When gross hematuria is present, cystoscopy can determine whether blood is emerging from one or both ureteral orifices, thereby defining a source in the upper tract. Red cell casts indicate a renal source, as does associated proteinuria (excretion of more than 500 mg of albumin in 24 hours). In differentiating between proteinuria from renal parenchymal disease and that simply produced by admixture of urine with extravasated blood, a useful rule of thumb is that 1 mL of whole blood contains approximately 5 billion RBCs and approximately 50 mg of albumin.

ED evaluation of the patient with gross or microscopic hematuria should begin with a complete history to define the pattern and character of the hematuria. Blood noted only on initiation of voiding suggests a urethral source, whereas blood noted only in the last few drops of urine suggests a prostatic or bladder neck source. Hematuria present throughout urination suggests a source in the bladder, ureter, or kidney. Brown or smoky-colored urine usually has a renal source. Blood clots indicate a nonglomerular renal or lower urinary tract source of bleeding. Hematuria may rarely be cyclic or associated with menses, suggesting endometriosis of the ureter or bladder. Flank pain suggests calculus, neoplasm, renal infarction, obstruction, or infection as the cause. Symptoms of frequency, dysuria, and suprapubic pain suggest cystitis or urethritis; in adult men, perineal pain, dysuria, and terminal hematuria suggest prostatitis.

Other clues to the cause are obtained by careful questioning. Because glomerulonephritis or interstitial nephritis may be caused by a variety of bacterial, viral, and parasitic infections, a history of recent infection is important. Symptoms suggestive of a multisystem disorder (e.g., systemic lupus erythematosus) also should be sought, as should a history of human immunodeficiency virus infection.5 Because drugs may cause acute interstitial nephritis (AIN), papillary necrosis, or hemorrhagic cystitis, a complete medication history is elicited. When hematuria is associated with anticoagulant use, significant underlying disease can be identified in about one third of patients.6 The family history may provide a clue to the presence of polycystic or other familial kidney disease, sickle cell disease, or renal calculi. A history of recent strenuous exercise is important to identify; 15 to 20% of normal persons exhibit hematuria after strenuous exercise. The mechanism is unclear, but the hematuria resolves spontaneously within a few days.

Laboratory Findings

Evaluation of hematuria in the ED setting includes assessment of the blood pressure and measurement of the BUN and serum creatinine levels to gauge the patient’s underlying renal function, but urinalysis can be expected to provide more specific information. Red or orange urine that is dipstick negative and free of red cells on microscopy may be caused by ingestion of beets, red berries, or food coloring; by urate crystals; or by drugs such as phenazopyridine (Pyridium) and rifampin. A finding of red cell or other casts, lipiduria, or significant proteinuria in combination with hematuria suggests intrinsic renal disease. Microscopic hematuria usually does not produce a positive dipstick test result for protein, but gross hematuria may contribute enough protein to cause a positive result; thus a finding of proteinuria should be confirmed and the amount quantified with a 24-hour urine collection. Hematuria in combination with pyuria or bacteriuria suggests UTI; the infection should be treated and hematuria reassessed after therapy has been completed. Even if white cells or organisms are not seen on urinalysis, the urine should be cultured to rule out hemorrhagic cystitis, especially when lower tract symptoms are present.

Blood studies should be ordered only as necessary to gauge renal function and to confirm causes suggested by the clinical presentation. In the ED setting, routine ordering of the full gamut of chemical and serologic studies necessary to rule out all possible causes of hematuria is rarely appropriate. In particular, a platelet count and coagulation studies are extremely unlikely to be helpful in the absence of a suggestive history or other specific clinical clues.

Radiography and Ultrasonography

The role of urinary tract imaging studies in the immediate evaluation of hematuria also is limited. Visualization of the urinary tract generally is helpful only when the history suggests renal colic or other disorders of the upper urinary tract (e.g., polycystic kidney disease, tumor, obstruction). CT without contrast is the imaging modality of choice.7 Ultrasonography can be used to determine kidney size and shape and to detect renal masses or obstruction. Further imaging studies, if indicated, should be planned after urologic consultation.

If no upper tract lesions are identified on initial imaging studies, cystoscopy usually is the next step in evaluation because it is the most effective means of visualizing the bladder and the male urethra. It is the initial study of choice for patients with active gross hematuria not caused by an obvious source (e.g., hemorrhagic cystitis); in fact, some urologists prefer to perform endoscopic procedures promptly during an acute bleeding episode to maximize the chance of localizing the source. In older patients in whom urinalysis shows only hematuria and the findings on the history and physical examination are otherwise unhelpful, urinary cytologic examination also may be undertaken.

Monitoring on an outpatient basis constitutes appropriate management in patients with hematuria who have no other abnormality revealed by urinalysis; who are otherwise asymptomatic; who are not azotemic, hypertensive, or severely anemic; and who have no evidence of intrinsic renal disease. (A possible exception may be the patient who has a known bleeding disorder or who is taking an anticoagulant.) Extensive outpatient evaluation for an isolated episode of hematuria usually is not undertaken in patients younger than 40 years unless hematuria is persistent, but it is generally recommended that most patients older than 40 undergo a thorough evaluation after even a single episode of hematuria.

The cause of hematuria can be determined on initial medical and urologic evaluation in about 70% of cases. In other cases a diagnosis of small calculi, occult bladder tumor, arteriovenous malformation, or early glomerulonephritis is made only after repeated examination or the development of further signs or symptoms. In about 20% of cases no cause can be determined.

Proteinuria

Principles of Disease

Abnormal proteinuria is defined as excretion of more than 150 mg of protein (albumin) per 24 hours in adults, or more than 140 mg/m2/24 hr in children. Patients with mild to moderate degrees of proteinuria commonly are identified incidentally on routine urinalysis; patients with more severe degrees of proteinuria often seek medical attention because of edema or other effects of hypoproteinemia.

With alteration in the glomerular capillary barrier (e.g., with the nephrotic syndrome and the many varieties of primary and secondary glomerulonephritis), albumin and globulins, which under normal circumstances are restricted from the glomerular ultrafiltrate because of their ionic charge and size, are lost into the urine. Persistent proteinuria is a marker for renal disease even in the absence of azotemia or an abnormal urine sediment.

Excretion of more than 2 g of protein in 24 hours is likely to be caused by a glomerular process. In the nephrotic syndrome, protein losses exceed the liver’s capacity to synthesize albumin, resulting in hypoalbuminemia. This leads to decreased plasma oncotic pressure and accumulation of edema fluid in the extravascular interstitial space. Increased aldosterone secretion and further retention of salt and water ensue. Thus edema is the clinical hallmark of the nephrotic syndrome and often is the initial complaint of patients who have significant proteinuria. Edema ranges in severity from mild dependent peripheral edema or periorbital swelling to frank anasarca with pleural effusions and ascites. Nephrotic-range proteinuria is defined arbitrarily as excretion of more than 3.5 g of protein per 24 hours.

Patients with the nephrotic syndrome are at increased risk for thromboembolic events, including deep vein thrombosis of the lower extremity, renal vein thrombosis, and pulmonary embolism. The reason for this propensity appears to be a hypercoagulable state that is complex and incompletely understood.8 Hyperlipidemia is another typical feature of the nephrotic syndrome; the mechanism is thought to be related indirectly to hypoalbuminemia and decreased oncotic pressure or viscosity. The major clinical significance of the nephrotic syndrome, however, is that it indicates the presence of an underlying renal process or systemic disease affecting the glomerulus (Box 97-3).

Clinical Features

Evaluation of the patient with proteinuria focuses not only on gauging the severity of proteinuria and the likelihood of complications but also on identifying any associated signs of underlying renal disease or systemic illness. Careful questioning will elicit a history of recent infections or use of medications or drugs or a past history of proteinuria, hypertension, edema, or renal disease. In young female patients, the presence of pregnancy is determined, as pregnancy can exacerbate previously inapparent renal disease; in late pregnancy, proteinuria may be the first sign of preeclampsia. Clues to the presence of systemic diseases that commonly affect the kidneys (e.g., diabetes, collagen vascular disease) should be sought as well. The physical examination includes evaluation of the blood pressure, determination of the presence or absence of edema, and assessment for signs of systemic disease or renal insufficiency.

Laboratory Findings

The laboratory evaluation in the patient with proteinuria includes urinalysis and measurement of the BUN and serum creatinine. Although the finding of isolated proteinuria may or may not be clinically important, proteinuria is almost always significant when it occurs in combination with hematuria. RBCs and red cell casts suggest glomerulonephritis; proteinuria with pyuria may be seen with AIN. The combination of proteinuria and glycosuria suggests diabetic nephropathy. A 24-hour urine collection provides an accurate measure of GFR and will quantify protein excretion.

Abnormal findings on the history, physical examination, or laboratory evaluation greatly increase the probability of the presence of significant renal disease, and early referral to an internist or nephrologist is indicated. However, in the absence of edema, azotemia, hypertension, active urine sediment, or known systemic illness affecting the kidney, patients with proteinuria may be referred to their primary care provider for follow-up. Because transient, mild proteinuria is not uncommon in healthy persons, patients with mild proteinuria as indicated by dipstick testing (particularly if the urine is concentrated) should have dipstick testing repeated at the follow-up visit before further evaluation is undertaken. Persistent proteinuria may necessitate referral to a nephrologist; in some cases, renal biopsy will be necessary to establish a diagnosis and guide management.

Acute Kidney Injury

The hallmark of AKI (formerly known as acute renal failure [ARF]) is progressive azotemia, which commonly is accompanied by a wide range of other disturbances, depending on the severity and duration of renal dysfunction. These include metabolic derangements (e.g., metabolic acidosis and hyperkalemia), disturbances of body fluid balance (particularly volume overload), and a variety of effects on almost every organ system (Box 97-4).

The causes of AKI may be divided into those that decrease renal blood flow (prerenal), produce a renal parenchymal insult (intrarenal), or obstruct urine flow (obstructive or postrenal). Identification of either a prerenal or a postrenal cause of AKI generally makes it possible to initiate specific corrective therapy; if these two broad categories of AKI can be excluded, an intrarenal cause is implicated. The renal parenchymal causes of AKI can be usefully subdivided into those primarily affecting the glomeruli, the intrarenal vasculature, or the renal interstitium. The term acute tubular necrosis denotes another broad category of intrinsic renal failure that cannot be attributed to specific glomerular, vascular, or interstitial causes (Fig. 97-2).4

Principles of Disease

Prerenal Azotemia

Decreased renal perfusion that is sufficient to cause a decrease in the GFR results in azotemia. The possible causes can be grouped into entities causing intravascular volume depletion, volume redistribution, or decreased cardiac output (Box 97-5). Patients who have preexisting renal disease are particularly sensitive to the effects of diminished renal perfusion.

Prerenal azotemia is characterized by increased urine specific gravity, BUN/creatinine ratio generally between 10 : 1 and 20 : 1, urine sodium concentration less than 20 mEq/dL, and FENa less than 1%. The condition generally can be corrected readily by expanding extracellular fluid volume, augmenting cardiac output, or discontinuing vasodilating antihypertensive drugs. However, severe prolonged prerenal azotemia can eventuate in ATN.

Patients who have congestive heart failure (CHF) or cirrhosis form an important subset of those with prerenal azotemia. These patients often are salt-overloaded and water-overloaded, yet their effective intra-arterial volume is decreased. Administration of diuretics has the potential to decrease intravascular volume further, resulting in decreased glomerular filtration and prerenal azotemia. For some patients with advanced CHF or hepatic disease, a state of chronic stable prerenal azotemia may be the best achievable compromise between symptomatic volume overload and severe renal hypoperfusion.9

Glomerular perfusion also may be decreased in patients with normal intravascular volume and normal renal blood flow who take angiotensin-converting enzyme (ACE) inhibitors or, more commonly, prostaglandin inhibitors. All nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, inhibit prostaglandin synthesis. Renal vasodilator prostaglandins are critical in maintaining glomerular perfusion in patients with conditions such as CHF, chronic renal insufficiency, and cirrhosis, in which elevated circulating levels of renin and angiotensin II decrease renal blood flow and GFR. In this setting, a decrease in the production of vasodilator prostaglandins may result in acute intrarenal hemodynamic changes and a reversible decrease in renal function.10 This phenomenon also is seen with the selective cyclooxygenase-2 inhibitor class of NSAIDs.11,12 Other risk factors include advanced age, diuretic use, renovascular disease, and diabetes. This entity is distinct from other renal complications of NSAIDs, including interstitial nephritis and papillary necrosis.

Renal insufficiency secondary to NSAIDs generally is reversible after withdrawal of the causative agent. For patients who are at increased risk but require treatment with NSAIDs, a short-acting preparation (e.g., ibuprofen) should be prescribed, and follow-up monitoring of renal function and serum potassium level should begin within days rather than weeks. If renal function is unchanged after a short course of treatment, adverse effects from continuing therapy are unlikely, although other potential mechanisms for the development of renal dysfunction (e.g., interstitial nephritis) should be kept in mind.

Postrenal (Obstructive) Acute Renal Failure

Obstruction is an eminently reversible cause of AKI and should be considered in every patient with newly discovered azotemia or worsening renal function. Obstruction may occur at any level of the urinary tract but most commonly is produced by prostatic hypertrophy or by functional bladder neck obstruction (e.g., secondary to medication side effects or neurogenic bladder) (Box 97-6). Intrarenal obstruction may result from intratubular precipitation of uric acid crystals (e.g., with tumor lysis), oxalic acid (as in ethylene glycol ingestion), phosphates, myeloma proteins, methotrexate, sulfadiazine, acyclovir, or indinavir.13 Bilateral ureteral obstruction (or obstruction of the ureter of a solitary kidney) may be caused by retroperitoneal fibrosis, tumor, surgical misadventure, stones, or blood clots. A sudden deterioration in renal function in the setting of diabetes mellitus, analgesic nephropathy, or sickle cell disease should suggest papillary necrosis.

Treatment of postrenal AKI consists of relief of the obstruction. In the absence of infection, full renal recovery is possible even after 1 to 2 weeks of total obstruction, although the serum creatinine level may not return to baseline for several weeks. Because the onset of irreversible loss of renal function with obstruction appears to be gradual, a few days’ delay in diagnosis generally is considered acceptable. Still, common sense dictates that obstructions should be detected and relieved promptly.

Intrinsic Acute Renal Failure

Of the specific intrarenal disorders that cause AKI, glomerulonephritis, interstitial nephritis, and abnormalities of the intrarenal vasculature are amenable to specific therapy and are important to consider as possible causes. These entities are responsible for only 5 to 10% of cases of AKI in adult inpatients; most are caused by ATN. In adults in whom AKI develops outside the hospital, the incidence of glomerular, interstitial, and small-vessel disease is much greater. In children, these entities account for approximately one half of the cases of AKI (Box 97-7).4

Glomerular Disease.: Acute glomerulonephritis may represent a primary renal process or may be the manifestation of any of a wide range of other disease entities (see Box 97-7). Patients may have dark urine, hypertension, edema, or CHF (secondary to volume overload) or may be completely asymptomatic, in which case the diagnosis rests on an incidental finding on urinalysis. The hematuria associated with glomerular disease may be microscopic or gross and may be persistent or intermittent. Proteinuria, although often in the range of 500 mg/day to 3 g/day, not uncommonly is in the nephrotic range. The presence of hematuria, proteinuria, or red cell casts is highly suggestive of glomerulonephritis. In fact, red cell casts are essentially diagnostic of active glomerular disease, although occasionally they are seen with other types of renal disease. Conversely, the absence of red cell casts, proteinuria, and hematuria essentially excludes glomerulonephritis as the cause of AKI.

The specific diagnosis of acute glomerulonephritis caused by primary renal disease often is ultimately made by renal biopsy. However, when glomerulonephritis is secondary to a systemic disease such as systemic lupus erythematosus, the patient’s clinical signs and symptoms, in combination with the results of laboratory assessment, aid considerably in narrowing the scope of the differential diagnosis. As a rule, extensive laboratory testing to identify the cause of acute glomerulonephritis is not indicated in the ED setting and is more appropriately performed as part of an inpatient evaluation.

Interstitial Disease.: AIN most commonly is precipitated by drug exposure or by infection.14 Drug-induced AIN is poorly understood, but the absence of a clear relationship to the dose and the recurrence of the syndrome on rechallenge with the offending agent suggests that an immunologic mechanism is responsible. The most commonly incriminated drugs are the penicillins, diuretics, and NSAIDs. AIN has been reported in association with bacterial, fungal, protozoan, and rickettsial infections.

Patients with AIN classically have rash, fever, eosinophilia, and eosinophiluria, but it is common for one or more of these cardinal signs to be absent.15 Pyuria, gross or microscopic hematuria, and mild proteinuria are observed in some cases. A definite diagnosis sometimes can be made only on renal biopsy. Treatment of AIN is directed at removing the presumed cause; infections should be treated and offending drugs discontinued. Renal function generally returns to baseline over several weeks, although chronic renal failure has been reported to occur.

Intrarenal Vascular Disease.: Vascular disease of the kidney can be classified according to the size of the vessel that is affected. Disorders such as renal arterial thrombosis or embolism, which affect large blood vessels, must be bilateral (or affect a single functioning kidney) to produce AKI. Whether to attribute such cases of AKI to prerenal or intrarenal vascular causes is a matter of semantics. The most common cause of thrombosis probably is trauma; thrombosis also may occur after angiography or may be secondary to aortic or renal arterial dissection. Renal atheroembolism is thought to occur commonly—at least on a microscopic level—after arteriography but is an uncommon cause of AKI. Similarly, patients with chronic atrial fibrillation or infective endocarditis may experience embolization of the kidney but rarely develop AKI as a result. Renal arterial embolism can cause acute renal infarction, generally manifested by sudden flank, back, chest, or upper abdominal pain. Urinary findings, including hematuria, are variable. Fever, nausea, and vomiting are not uncommon; in some cases, evidence of embolization to other vessels provides a useful clue. The diagnosis usually is made by renal flow scanning or arteriography. Surgical embolectomy has been reported to restore function when undertaken within several hours of occlusion, but significant return of function has been documented in patients operated on as long as 6 weeks after total occlusion. This outcome presumably is possible because collateral circulation has developed in association with a preexisting partial occlusion.

An interesting but relatively uncommon type of AKI occurs when an ACE inhibitor is given to a patient with underlying bilateral renal artery stenosis (or unilateral stenosis of a solitary functioning kidney). With inhibition of angiotensin synthesis, efferent arteriolar tone is not maintained and GFR decreases. The condition is reversible with cessation of therapy.

Several diseases that affect the smaller intrarenal vessels can cause AKI (see Box 97-7). Patients whose disease is severe enough to cause ARF also generally are found to have hypertension, microangiopathic hemolytic anemia, and other systemic and organ-specific manifestations. Infection with Escherichia coli O157:H7 has emerged as a major cause of hemolytic uremic syndrome, an important cause of AKI in children.16

Malignant hypertension, although much less common since the advent of more effective antihypertensive therapy, has by no means disappeared. Patients with scleroderma (systemic sclerosis) may have “scleroderma renal crisis,”17,18 characterized by malignant hypertension and rapidly progressive renal failure. Whereas vasculitis associated with glomerular capillary inflammation typically causes gross or microscopic hematuria and formation of red cell casts, vascular involvement of the medium-size vessels, such as that produced by scleroderma, often spares the preglomerular vessels and tends not to produce an active urine sediment. Extrarenal manifestations (rash, fever, arthritis, pulmonary symptoms) are usually evident.

For malignant hypertension, both as a separate entity and as a part of scleroderma renal crisis, appropriate treatment can produce a gratifying remission of AKI. Patients with malignant hypertension have been reported to recover renal function after aggressive antihypertensive therapy, with temporary maintenance with dialysis if necessary.19 In patients with scleroderma renal crisis, specific therapy with ACE inhibitors has been shown to result in improvement in renal function in a significant proportion of cases.18

Acute Tubular Necrosis

The term acute tubular necrosis refers to a generally reversible deterioration of kidney function associated with a variety of renal insults. Oliguria may or may not be a feature. The diagnosis is made after prerenal and postrenal causes of ARF and disorders of glomeruli, interstitium, and intrarenal vasculature have been excluded. These discrete categories do overlap in a few disorders. For example, AKI associated with multiple myeloma or ethylene glycol toxicity is associated with both intrarenal obstruction and interstitial disease, as well as a probable direct toxic effect on the renal tubule itself.

The most common precipitant of ATN is renal ischemia occurring during surgery or after trauma and sepsis.20 The remainder of cases occur in the setting of medical illness, most commonly as a result of the administration of nephrotoxic aminoglycoside antibiotics or radiocontrast agents or in association with rhabdomyolysis. Multiple causes can be identified in some cases; in others a definitive cause is never established.

Decreased renal perfusion results in a continuum of renal dysfunction that ranges from transient prerenal azotemia at one extreme to ATN at the other. Early during the period of renal ischemia, renal function can be restored completely by restoring renal blood flow, but at some point, continued hypoperfusion results in renal dysfunction unresponsive to volume repletion, and ATN will supervene. ATN may occur in the absence of frank hypotension; even modest renal ischemia may result in ATN in susceptible persons. Individual susceptibility to ATN may be related to the balance of prostaglandin-mediated vasopressor and vasodilatory influences on the renal vasculature.

Postischemic ATN can occur in the setting of volume loss from the GI tract (upper or lower), skin, or kidneys or can result from severe hemorrhage or major burns. Heatstroke commonly is associated with the development of ATN, which is thought to result from a combination of volume loss, hyperpyrexia, and rhabdomyolysis. Another cause of ATN is hyperglycemic hyperosmolar nonketotic coma, which can be associated with loss of as much as 25% of total body water. ATN also is seen in the setting of cardiogenic shock, sepsis, and third spacing of fluids in pancreatitis and peritonitis.

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