Section Six GENITOURINARY AND GYNECOLOGIC SYSTEMS

Transcription

1 Section Six GENITOURINARY AND GYNECOLOGIC SYSTEMS CHAPTER 97 Renal Failure Allan B.Wolfson 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. Urinalysis The standard urinalysis consists of dipstick screening for heme pigment, protein, glucose, ketones, ph, leukocyte esterase, and nitrite and microscopic examination of a spun specimen of freshly voided urine. Heme The dipstick detects both free hemoglobin from lysed red blood cells (RBCs) (or myoglobin) and the hemoglobin inside RBCs but is more sensitive to free hemoglobin. Although as few as three RBCs per high-power field can be detected, on any given sample the dipstick may fail to identify 10 to 15% of patients who are otherwise found to have microscopic hematuria, as defined by more than five RBCs per high-power field. A positive result on dipstick testing should prompt microscopic examination of the urine. If red cells are seen, the diagnosis of hematuria is confirmed. If the dipstick result is positive but findings on microscopic examination are negative, pigmenturia (myoglobin or free hemoglobin) is suspected as a potential cause. Protein The dipstick test for protein, which uses the color change of tetrabromophenol blue, can detect protein at concentrations of 10 to 15 mg/dl but does not yield reliably positive results until the concentration is greater than 30 mg/dl. Moreover, the relation between color intensity and protein concentration is only approximate. The dipstick reagent is three to five times more sensitive to albumin than to globulins and immunoglobulin light chains (e.g., Bence Jones protein) an important limitation. 1 False-positive results are caused by alkaline urine, hematuria, or prolonged immersion of the dipstick in the urine. False-negative results are seen with dilute urine. 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 1291

2 1292 PART III Medicine and Surgery / Section Six Genitourinary and Gynecologic Systems 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. Eosinophilcontaining 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 equation 3 : Creatinine clearance ( ml/min) ( 140 age) weight = ( if female) 72 serum creatinine Table 97-1 LABORATORY TEST FINDING Urinalysis Urine sodium concentration (meq/l) Fractional excretion of sodium (%) Urine-to-plasma creatinine ratio BOX 97-1 Typical Urinary Findings in Prerenal Azotemia and Acute Tubular Necrosis PRERENAL AZOTEMIA Normal or hyaline casts <20 >40 <1 >1 >40 <20 ACUTE TUBULAR NECROSIS Causes of High or Low FENa and UNa in Patients with Acute Kidney Injury UNa <20 meq/l, FENa <1% Prerenal azotemia Acute glomerulonephritis Acute obstruction Contrast-induced ATN (some cases) Rhabdomyolysis-associated ATN (some cases) Early sepsis Nonoliguric ATN (10% of cases) Brown granular casts, cellular debris UNa >40 meq/l, FENa >1% ATN (90% of cases) Chronic obstruction Diuretic drugs Osmotic diuresis Underlying chronic renal failure From Kelley WN (ed): Internal Medicine, 2nd ed. Philadelphia, JB Lippincott, ATN, acute tubular necrosis; FENa, fractional excretion of sodium; UNa, urine sodium concentration. 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). 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

3 Chapter 97 / Renal Failure 1293 Figure Computed tomography scan of bilateral hydronephrotic kidneys without intravenous contrast medium. BOX 97-2 Hematologic Causes Coagulopathy Sickle hemoglobinopathies Renal Causes Glomerular Primary glomerular disease Multisystem disease (e.g., systemic lupus erythematosus, Henoch- Schönlein purpura, hemolytic uremic syndrome, polyarteritis nodosa, Wegener s granulomatosis, Goodpasture s syndrome) Nonglomerular Renal infarction Tuberculosis Pyelonephritis Causes of Hematuria Polycystic kidney disease Medullary sponge kidney Acute interstitial nephritis Tumor Vascular malformation Trauma Papillary necrosis Postrenal Causes Stones Tumor of ureter, bladder, urethra Cystitis Benign prostatic hypertrophy Prostatitis, urethritis Foley catheter placement Exercise Tuberculosis 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. Ultrasonography. Ultrasonography allows accurate measurement of renal dimensions and is a safe and reasonably reliable method of excluding obstruction as a cause of AKI. The normal kidney shows an echo-free renal parenchyma surrounding the echogenic central urothelium of the renal pelvis and calices. The sonographic appearance of the kidney in obstruction is that of an enlarged central sonolucent area that spreads the normal central echo densities. A similar pattern may be produced by renal cysts, but without associated ureteral dilation. Dilation of the collecting system generally is apparent within 24 to 36 hours of the onset of obstruction, but obstruction may not be evident in patients who are evaluated early in the development of obstructive AKI. 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

4 1294 PART III Medicine and Surgery / Section Six Genitourinary and Gynecologic Systems 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. Clinical Features On physical examination, findings of arthritis, skin lesions, hypertension, or edema suggest underlying glomerulonephritis. Examination of the external genitalia may reveal a urethral meatal lesion that may be the source of bleeding; in adult women, a pelvic examination will reveal vulvovaginal sources of blood. Because endocarditis or atrial fibrillation may cause renal embolism, the patient should be checked for a new heart murmur or an irregular rhythm. Costovertebral angle tenderness suggests pyelonephritis or obstructive stone disease, and a palpably enlarged kidney suggests polycystic kidney disease or renal malignancy. The prostatic examination may offer clues to the presence of prostatitis, benign prostatic hypertrophy, or cancer. 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/m 2 /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

5 Chapter 97 / Renal Failure 1295 BOX 97-3 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 Causes of the Nephrotic Syndrome Primary renal disease Multisystem disease Diabetes mellitus Systemic lupus erythematosus Rheumatoid arthritis Henoch-Schönlein purpura Polyarteritis nodosa Wegener s granulomatosis Amyloidosis Cryoglobulinemia Drugs and toxins Heroin Captopril Heavy metals Nonsteroidal antiinflammatory drugs Penicillamine Others Allergens Infection Bacterial Infective endocarditis Poststreptococcal infection Syphilis Viral Hepatitis B Human immunodeficiency virus infection Cytomegalovirus infection Protozoal Malaria Toxoplasmosis Malignancy Solid tumors Multiple myeloma Lymphoma Leukemia Miscellaneous Hereditary nephritis Preeclampsia Malignant hypertension Reflux nephropathy Renal vein thrombosis Transplant rejection 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 BOX 97-4 Cardiovascular Pulmonary edema Arrhythmia Hypertension Pericarditis Pericardial effusion Myocardial infarction Pulmonary embolism Metabolic Hyponatremia Hyperkalemia Acidosis Hypocalcemia Hyperphosphatemia Hypermagnesemia Hyperuricemia Neurologic Asterixis Neuromuscular irritability Mental status changes From Brady HR, Brenner BM, Clarkson MR, Lieberthal W: Acute renal failure. In Brenner BM: Brenner and Rector s the Kidney, 6th ed. Philadelphia, Saunders, 2000, pp 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 Clinical Features of Acute Kidney Injury Somnolence Coma Seizures Gastrointestinal Nausea Vomiting Gastritis Gastroduodenal ulcer Gastrointestinal bleeding Pancreatitis Malnutrition Hematologic Anemia Hemorrhagic diathesis Infectious Pneumonia Septicemia Urinary tract infection Wound infection Decreased renal perfusion that is sufficient to cause a decrease in the GFR results in azotemia. The possible causes can be grouped

6 1296 PART III Medicine and Surgery / Section Six Genitourinary and Gynecologic Systems Azotemia History, physical exam, serum chemistries Correct prerenal azotemia Rule out obstruction Intrinsic renal disease Improves Improves BOX 97-6 Causes of Postrenal Renal Failure Intrarenal and Ureteral Causes Kidney stone Sloughed papilla Malignancy Retroperitoneal fibrosis Uric acid, oxalic acid, or phosphate crystal precipitation Sulfonamide, methotrexate, acyclovir, or indinavir precipitation Bladder Kidney stone Blood clot Prostatic hypertrophy Bladder carcinoma Neurogenic bladder Urethra Phimosis Stricture Vascular (vasculitis) Urinalysis Urine electrolytes Glomerular (glomerulonephritis) Interstitial (AIN) ATN Figure Evaluation of azotemia. AIN, acute interstitial nephritis; ATN, acute tubular necrosis. BOX 97-5 Volume Loss Gastrointestinal: vomiting, diarrhea, nasogastric drainage Renal: diuresis Blood loss Insensible losses Third-space sequestration Pancreatitis Peritonitis Trauma Burns Cardiac Causes Myocardial infarction Valvular disease Causes of Prerenal Azotemia Cardiomyopathy Decreased effective arterial volume Antihypertensive medication Nitrates Neurogenic Causes Sepsis Anaphylaxis Hypoalbuminemia Nephrotic syndrome Liver disease 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 antiinflammatory 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

7 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, BOX 97-7 Intrinsic Renal Diseases That Cause Acute Kidney Injury Vascular Diseases Large-Vessel Diseases Renal artery thrombosis or stenosis Renal vein thrombosis Atheroembolic disease Small- and Medium-Vessel Diseases Scleroderma Malignant hypertension Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura HIV-associated microangiopathy Glomerular Diseases Systemic Diseases Systemic lupus erythematosus Infective endocarditis Systemic vasculitis (e.g., periarteritis nodosa, Wegener s granulomatosis) Henoch-Schönlein purpura HIV-associated nephropathy Essential mixed cryoglobulinemia Goodpasture s syndrome Primary Renal Diseases Poststreptococcal glomerulonephritis Other postinfectious glomerulonephritis Rapidly progressive glomerulonephritis Tubulointerstitial Diseases and Conditions Drugs (many) Toxins (e.g., heavy metals, ethylene glycol) Infections Multiple myeloma Acute Tubular Necrosis Ischemia Shock Sepsis Severe prerenal azotemia Nephrotoxins Antibiotics Radiographic contrast agents Myoglobinuria Hemoglobinuria Other Diseases and Conditions Severe liver disease Allergic reactions NSAIDs HIV, human immunodeficiency virus; NSAIDs, nonsteroidal anti-inflammatory drugs. Chapter 97 / Renal Failure 1297 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

8 1298 PART III Medicine and Surgery / Section Six Genitourinary and Gynecologic Systems 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. ATN is common in postoperative patients, although not all cases can be attributed to intraoperative hypotension or hemorrhage. Concomitant sepsis, increased age, preexisting renal disease, and other comorbid conditions are associated with a worse outcome. 20,21 BOX 97-8 Causes of Pigment-Induced Acute Kidney Injury Rhabdomyolysis and myoglobinuria Vigorous exercise Arterial embolization Status epilepticus Status asthmaticus Coma-induced and pressureinduced myonecrosis Heat stress Diabetic ketoacidosis Myopathy Alcoholism Hypokalemia Hypophosphatemia Hemoglobinuria Transfusion reactions Snake envenomation Malaria Mechanical destruction of RBCs by prosthetic valves G6PD deficiency G6PD, glucose-6-phosphate dehydrogenase; RBCs, red blood cells. Nephrotoxins constitute the other major cause of ATN. Among the most prominent of these are the endogenous pigments myoglobin and hemoglobin. Rhabdomyolysis and ARF resulting from crush injuries first received widespread attention after their description in survivors of the London blitz during World War II, but many other causes of pigment nephropathy have been reported (Box 97-8). Hypotension secondary to fluid loss into damaged muscle is thought to worsen the effects of myoglobinuria on the renal tubule, as does acidemia. Hemolysis, resulting in the release of hemoglobin into the circulation and hemoglobinuria, can cause ATN but usually only in the presence of coexisting dehydration, acidosis, or other causes of decreased renal perfusion. ATN may be associated with the hemolysis of as little as 100 ml of blood. ATN associated with rhabdomyolysis is often oliguric; it is characterized by rapid increases in the serum creatinine, potassium, phosphorus, and uric acid levels. 22,23 Creatine released from muscle is metabolized to creatinine, which may result in serum creatinine increases of more than 2 mg/dl/day, in contrast to the increase of 0.5 to 1.0 mg/dl/day typically seen in other forms of AKI. The BUN/creatinine ratio often is less than 10 : 1. Intracellular potassium released from damaged muscle may raise the serum potassium by 1 to 2 meq/l in several hours. Likewise, phosphate released from muscle may cause dramatic increases in the serum phosphate level. Uric acid, produced by metabolism of purines released from damaged muscle, may accumulate to levels high enough to cause acute uric acid nephropathy. Urine dipstick testing yields a positive result for heme in only 50% of patients with rhabdomyolysis, because myoglobin is rapidly cleared from the serum and may therefore be undetectable in the urine at the time of presentation. Thus a negative result on urine dipstick testing does not rule out the diagnosis. Serum creatine kinase (CK) is cleared much more slowly, so measurement of serum CK levels is a more sensitive test. No biochemical parameter can be used to predict which patients who have rhabdomyolysis will experience AKI. In one classic study of patients in whom alcoholism, muscle compression, and seizures were the most common causes of rhabdomyolysis, AKI developed in only one third. 22 Neither the degree of serum CK elevation, the presence (or absence) of myoglobinuria, nor the degree of hyperkalemia correlates well with the development of AKI. Antibiotics and radiographic contrast agents are other nephrotoxins that commonly are implicated in the development of ATN. Aminoglycosides are the most commonly implicated antibiotics. Higher doses and longer duration of therapy are associated with higher serum drug levels, leading to greater accumulation of drug in the renal parenchyma and a greater likelihood of nephrotoxicity. Increased age, impaired renal function, dehydration, and exposure to other nephrotoxins are additional risk factors. Once-daily administration of a somewhat higher dose is associated with less nephrotoxicity but equal effectiveness. 24,25

9 Aminoglycoside-induced ATN typically has a gradual onset. Clinically significant renal dysfunction usually occurs only after several days and often after more than a week of therapy. However, renal failure can develop as late as 10 days after a drug has been discontinued, an observation that appears to be explained by the prolonged tissue half-life characteristic of these agents. Renal function returns to normal after an average of 6 weeks, but the condition occasionally progresses to permanent renal injury. Radiographic contrast agents constitute a common cause of hospital-acquired renal insufficiency. Renal failure produced by these agents has been defined as an increase in serum creatinine level of 25% over baseline with a temporal relation to contrast medium administration and in the absence of other identifiable causes. Radiocontrast agent induced ATN encompasses a spectrum ranging from asymptomatic nonoliguric renal insufficiency to severe renal failure requiring dialysis, but most cases are mild. It can occur after any procedure involving intravascular administration of contrast material. Typically, an increase in the serum creatinine level is noted within 3 days of exposure, with a return to normal within 10 to 14 days. The most important risk factors for radiocontrast agent induced ATN are preexisting renal insufficiency, diabetes mellitus, multiple myeloma, age older than 60 years, volume depletion, and higher doses of contrast material. Among these, preexisting renal insufficiency is the most important. 26 Diabetic patients with a serum creatinine level less than 1.5 mg/dl are at low risk for the development of radiocontrast agent induced ATN, whereas those whose serum creatinine is greater than 1.5 mg/dl are at significant risk. Multiple myeloma, particularly in patients who are dehydrated, is another reasonably well-documented risk factor. Advanced age also appears to make ATN more likely, possibly because of decreased renal mass and cortical blood flow. Volume depletion appears to be an independent risk factor, and aggressive volume expansion before contrast exposure has been shown to have a protective effect. 27,28 Finally, large doses and repeated doses of contrast material are associated with increased risk of ATN, particularly if a second study is performed within 72 hours of the first. N-acetylcysteine in combination with periprocedural hydration appears to decrease the incidence of contrast-associated ATN, 29 although this has not been a consistent finding in published studies. 30 Modest volumes of intravenous normal saline (3 ml/kg over 1 hour, followed by 1.5 ml/kg/hr for 4 hours after contrast exposure) appear to be effective in decreasing the likelihood of nephrotoxicity; sodium bicarbonate does not appear to offer an advantage over normal saline. 30,31 Recent reviews continue to emphasize the importance of appropriately limiting exposure to contrast agents as well as ensuring preprocedural hydration. 27 Clinical Features When the presence of azotemia or renal failure has been discovered, the first consideration in the ED evaluation should be the possibility of potentially life-threatening complications (e.g., hyperkalemia, pulmonary edema). Assuming these have been satisfactorily ruled out, the next step is to determine whether the condition represents AKI or is the result of preexisting renal disease. The clinical distinction between AKI and chronic kidney disease (CKD) often is difficult; old records and laboratory results are invaluable. The finding of small kidneys on abdominal radiography or bone changes of secondary hyperparathyroidism on hand films suggests that the renal failure is chronic. Anemia, hypocalcemia, and hyperphosphatemia, on the other hand, should not be relied on to identify patients who have CKD because these abnormalities can develop rapidly in AKI. In evaluating the patient with azotemia, the clinician uses history, physical examination, and laboratory studies to seek clues Chapter 97 / Renal Failure 1299 to the cause and to identify signs and symptoms of uremia, volume overload, or other complications of renal failure. In attempting to identify the cause of azotemia, the general strategy is to rule out both prerenal and postrenal causes before considering the many intrinsic renal causes. First, potential sources of volume loss and causes of decreased cardiac output are sought in the history, and the patient is questioned about lightheadedness, bleeding, GI fluid loss, abnormal polyuria, or symptoms of CHF. In men a history of nocturia, frequency, hesitancy, or decreased urinary stream suggests prostatic obstruction. A history of lower tract symptoms or of abdominal or pelvic tumor in either sex is determined, as is a history of kidney stones or chronic UTI. A history of acute anuria (defined as the production of less than 100 ml of urine per day) is most often the result of high-grade urinary tract obstruction, although it also may accompany severe volume depletion, severe acute glomerulonephritis, cortical necrosis, or bilateral renal vascular occlusion. Intermittent anuria, on the other hand, is characteristic of obstructive disease. Medication use and possible exposure to radiographic contrast agents or other exogenous toxins are other key components of the history. A history of hypertension, dark-colored urine, rash, fever, or arthritis suggests intrinsic renal disease or a multisystem disorder. In older patients the presence of symptoms suggestive of multiple myeloma should be elicited. The physical examination focuses on signs of volume depletion such as tachycardia and decreased skin turgor. Documented shortterm changes in body weight offer a valuable clue in assessing volume status, particularly in chronically ill patients. In addition, suspected bleeding should be specifically excluded. Similarly, volume overload is determined by assessment of jugular vein distention and attention to the presence of rales, an S 3 gallop, or edema. The area of the bladder is palpated and percussed. A distended bladder is percussible when it contains 150 ml of urine, and the dome is palpable abdominally when it contains 500 ml. Ultrasonography can be used to detect bladder distention or postvoid residual volume if there is a question of urinary retention. 32 Prostate examination in adult men and pelvic examination in adult women are necessary components of the examination. The presence of rash, purpura, pallor, or petechiae is noted, as is arthritis, musculoskeletal tenderness, or findings suggestive of infection or malignancy. Diagnostic Strategy Laboratory Findings The laboratory evaluation begins with a dipstick and microscopic urinalysis and measurement of urine output. BUN, serum creatinine, urine sodium, and FENa levels are determined to help evaluate renal function and to provide clues to the cause of AKI. A complete blood count, serum electrolyte panel (expanded to include calcium, phosphorus, and magnesium determinations), electrocardiogram (ECG), and chest radiograph help to establish the patient s baseline status and to provide information about possible complications. Other studies may be of value in the ED setting when the history or physical findings suggest that they may have a specific role in immediate diagnosis or management. Prerenal azotemia is suspected in the setting of volume loss, volume redistribution, or decreased effective renal perfusion. It typically is associated with a normal urinalysis, high BUN/ creatinine ratio, increased urine osmolality, a urine sodium concentration less than 20 meq/l, and FENa less than 1%. A rapid response to volume repletion also is characteristic. Urethral or bladder neck obstruction is documented by the finding of significant amounts of residual urine in the bladder (by catheterization or ultrasound examination) after the patient has

10 1300 PART III Medicine and Surgery / Section Six Genitourinary and Gynecologic Systems voided or attempted to void spontaneously. An important point is that the ability to void does not rule out obstruction. In fact, the urine volume in the presence of obstruction may range from zero to several liters per day. Flank pain is likewise an insensitive marker for obstruction. Urine indices and the BUN/creatinine ratio tend not to be helpful, although an increase in the latter is common in obstruction. A renal parenchymal disorder often can be diagnosed by its manifestations on microscopic urinalysis or by associated extrarenal manifestations (e.g., with multisystem disease) or the clinical setting (e.g., recent exposure to a new medication). The absence of evidence of prerenal or postrenal causes in a patient with AKI may be taken as presumptive evidence of an intrarenal parenchymal process. Among these, the possibility of an acute or ongoing vascular insult should be kept in mind, because timely intervention may be important in preserving ultimate renal function. Radiography and Ultrasonography Significant hydronephrosis usually is readily demonstrable by ultrasonography and may indicate either upper or lower tract obstruction. In questionable cases, or if bilateral ureteral obstruction is strongly suspected on the basis of clinical findings, the next step is retrograde urography performed by a urologist. 33 CT imaging is less useful in this setting; in fact, intravenous radiocontrast material may compound the injury to the kidney. Management ED management of AKI is directed at reversing decreases in GFR and urine output (if possible) while minimizing further hemodynamic and toxic insults, maintaining normal fluid and electrolyte balance, and managing other complications of AKI as required. Because renal failure alters the metabolism and action of many drugs, often in ways that are not predictable, great care should be exercised in prescribing all medications. A compendium of guidelines for drug dosage in renal failure, such as the one by Aronoff and colleagues, 34 is of great help for this purpose. After ensuring that the vital signs are adequate and that the patient is in no immediate danger from volume or metabolic derangements, the next step is to correct prerenal and postrenal factors, if any are identified. Intravascular volume is repleted in hypovolemic patients and maintained in euvolemic patients by matching input to measured and insensible output. Inadequate cardiac output is augmented when possible. Postrenal or obstructive ARF is treated by restoration of normal urine outflow. Bladder outlet obstruction may be relieved by passage of a Foley catheter, whereas upper tract obstruction may require percutaneous nephrostomy. When prerenal and postrenal factors have been ruled out, the challenge to the emergency physician is to identify the cause of intrinsic renal AKI, keeping in mind the multitude of known possible causes (see Box 97-7). The clinical setting and physical and laboratory findings often allow the scope of the differential diagnosis to be considerably narrowed. The clinical picture is often most consistent with the broad category of ATN. It has been noted repeatedly that patients who have oliguric AKI have a significantly higher mortality rate and a much greater risk of complications than those who are not oliguric. The difference in prognosis may simply reflect a more severe renal insult in patients who are oliguric, however, and it is not clear that interventions aimed at converting oliguric to nonoliguric AKI have an effect on renal function or mortality. 20 Nevertheless, because nonoliguric patients are easier to manage, an attempt to increase urine flow is warranted. Use of loop diuretics or mannitol often is effective in increasing urine flow when intravascular volume deficits have been corrected. Furosemide has not been shown to shorten the clinical course or affect mortality. Mannitol appears to be most useful when given at the time of or shortly after the renal insult; the recommended dose is 12.5 to 25 g given intravenously (IV). If urine output does not increase, further doses may cause hyperosmolality and clinically significant intravascular volume overload in patients with impaired renal function. 35 Dopamine also has been used, with and without furosemide, in an effort to increase urine output, but has not proven effective. Certain specific considerations apply to toxin-induced ATN. Pigment-induced ATN may be prevented by avoidance of hemolysis and muscle injury and by correction of the factors (e.g., dehydration, acidemia) that are known to predispose patients with pigmenturia to the development of renal failure. When hemolysis or rhabdomyolysis has occurred, treatment is directed at eliminating the cause and preventing the development of renal failure. Mannitol has been shown to prevent AKI in experimental models of myoglobinuria, presumably by inducing osmotic diuresis and decreasing intratubular deposition of pigment. Furosemide, on the other hand, has not consistently shown a beneficial effect. Other studies have suggested that myoglobin precipitates in an acid urine but not in an alkaline urine. Thus, aggressive volume repletion, alkalinization, and mannitol infusion have traditionally been recommended after crush injuries to reduce the likelihood or severity of AKI. 23 This regimen also helps control hyperkalemia. Other evidence, however, suggests that aggressive volume resuscitation alone may be equally effective. 23 When AKI has occurred, management is similar to that of other forms of AKI, but early dialysis may be required to control rapidly developing hyperkalemia, hyperphosphatemia, and hyperuricemia. Patients who have radiocontrast agent induced ATN usually require only supportive therapy but are often hospitalized and seen by a nephrologist. A more significant aspect of ED management is preventing the occurrence of contrast nephropathy, particularly by identification of risk factors in patients for whom contrast studies are being considered. BUN and serum creatinine levels should be checked before contrast exposure in patients with risk factors. Moreover, before contrast medium is administered to a high-risk patient, it should be established that there is a compelling reason to perform the contrast study and that there is no adequate alternative to use of a contrast agent. The patient should be volume repleted before the study, the administered dose of contrast agent should be kept as low as possible, and multiple studies should be avoided, as should concomitant use of other nephrotoxins. As noted previously, N-acetylcysteine given before and after contrast administration appears to decrease the incidence of contrast nephropathy. Intravenous saline given before and after contrast administration appears to be at least as important in prevention Volume and Metabolic Complications In addition to those general measures aimed at minimizing decreases in GFR and increasing urine output, an important component of the management of AKI is the prevention or control of systemic complications. Of particular significance in this regard are metabolic derangements (e.g., hyperkalemia, hypocalcemia, hyperphosphatemia, metabolic acidosis) and complications of volume overload (e.g., hypertension, CHF). Hyperkalemia, the most common metabolic cause of death in patients with AKI, results from an inability to excrete endogenous and exogenous potassium loads. In oliguric patients the serum potassium level typically increases by 0.3 to 0.5 meq/l per day, but greater increases occur in catabolic, septic, or traumatized patients and in the presence of acidosis or exogenous potassium loads from diet or medication.

11 Hyperkalemia results in serious disturbances in cardiac electrophysiology that may culminate in cardiac arrest. Although some hyperkalemic patients note muscular weakness, most generally are asymptomatic until major manifestations of cardiotoxicity appear. Accordingly, detection of hyperkalemia is a primary consideration in these patients. ECG changes correlate only roughly with the serum potassium level. Mild hyperkalemia (serum potassium less than 6.0 meq/l) may be cautiously observed without specific treatment while all exogenous sources of potassium are eliminated. If the serum potassium level is greater than 6.5 meq/l, and particularly if ECG changes are present, urgent intervention is necessary. When cardiotoxicity must be reversed immediately (e.g., when there is hemodynamic compromise), intravenous calcium (10 ml of 10% calcium gluconate or calcium chloride infused over 2 minutes and repeated after 5 minutes if necessary) is the treatment of choice. Calcium directly antagonizes the membrane effects of hyperkalemia. Intravenous insulin (given with glucose to prevent hypoglycemia) temporarily shifts potassium to the intracellular space. Bicarbonate appears to be less effective in shifting potassium into cells than once thought. 36 It should be used with caution in patients with renal failure because of its potential to cause volume overload and to provoke hypocalcemic tetany or seizures. The safety and efficacy of beta-agonists in hyperkalemic patients have been well documented; like insulin, inhaled albuterol (in a dose of mg) causes potassium to move into cells, thereby controlling hyperkalemia for 2 hours or more. 37,38 Elimination of potassium from the body can be promoted by use of a potassium-binding ion exchange resin (sodium polystyrene sulfonate [Kayexalate]) or, much more effectively, by enhancing urinary potassium excretion or by initiating dialysis. 36 Hypocalcemia is a common feature of AKI and can develop rapidly after its onset. Vitamin D dependent intestinal absorption of calcium is decreased in AKI because of decreased renal synthesis of 1,25-dihydroxyvitamin D. Another factor promoting hypocalcemia is the complexing of calcium with retained phosphate. Rhabdomyolysis-associated AKI in particular often is associated with the deposition of complexed calcium in muscle and other tissues. Asymptomatic hypocalcemia requires no immediate treatment, but subtle or frank tetany should be treated with intravenous calcium (10-20 ml of 10% calcium gluconate infused over several minutes). Hyperphosphatemia resulting from decreased renal elimination of phosphate is another common feature of AKI. The serum phosphorus level usually ranges from 6 to 8 mg/dl but may be much higher with rhabdomyolysis or in catabolic states. A calciumphosphate product greater than 70 may result in metastatic soft tissue calcification. Hyperphosphatemia often is treated with oral calcium-based antacids that bind ingested phosphate in the gut. 39 Acids produced in normal metabolic processes accumulate in AKI and are buffered in part by serum bicarbonate, resulting in a decrease in the serum bicarbonate level and a high anion-gap metabolic acidosis. Compensatory hyperventilation may be mistakenly attributed to primary cardiac failure or volume overload. The metabolic acidosis associated with AKI usually is mild, and treatment generally is not necessary if the serum bicarbonate level is greater than 10 meq/l. Overzealous correction may result in hypokalemia, hypocalcemia, or volume overload. Hypermagnesemia may complicate AKI when patients are given magnesium-containing antacids or laxatives. Thus these products, as well as magnesium itself (e.g., when given for preeclampsia or for treatment of arrhythmia or wheezing), should be avoided in the setting of AKI. Disturbances of volume regulation can be expected to occur in most patients with AKI. Some nonoliguric patients excrete enough salt and water that intravascular volume depletion can occur if adequate fluid replacement is not provided. Volume depletion prolongs recovery from AKI. Much more commonly, AKI Chapter 97 / Renal Failure 1301 is complicated by volume overload because sodium and water excretion may be inadequate to match even modest intakes. Volume overload is largely responsible for the hypertension often seen in AKI and commonly leads to CHF and pulmonary edema. Iatrogenic volume overload is particularly common and can be prevented only by careful attention to fluid intake and output with prudent estimates of insensible loss. Volume overload can be treated with diuretics or intravenous nitroglycerin while preparations are being made to initiate dialysis. Organ System Effects The clinician should be alert to the numerous other important systemic and organ-specific effects of renal failure. Only the more prominent of these are mentioned here. Uremia impairs host defenses, particularly leukocyte function, and infection is a significant cause of morbidity and mortality in AKI. Thus patients with fever require prompt investigation and aggressive treatment. Pericarditis, which has a prevalence of 10 to 20% in dialyzed patients with CKD, also may occur in patients with AKI. Chest pain that is worse in a recumbent position is the most common symptom, and most patients have a pericardial friction rub. Fever is common. The ECG may show ST-T wave elevation, low voltage, electrical alternans, or atrial fibrillation. The presence of pericardial effusion is identified most accurately by echocardiography; tamponade, with typical clinical signs, occurs in some patients. In contrast to the situation in chronic kidney failure, pericarditis or pericardial effusion in the setting of AKI generally is an indication for the urgent initiation of dialysis. Patients who have hemodynamically significant tamponade require surgical drainage of the effusion or, occasionally, emergency pericardiocentesis. Neurologic abnormalities in AKI may be precipitated by electrolyte abnormalities, medications, or uremia. Common signs and symptoms in uremic patients include lethargy, confusion, agitation, asterixis, myoclonus, and seizures. Anorexia, nausea, vomiting, gastritis, and pancreatitis also are associated with AKI. Significant GI hemorrhage is seen in about 10% of patients. Impaired erythropoiesis, shortened RBC survival, hemolysis, hemodilution, and GI blood loss all play a role in the normocytic normochromic anemia that usually accompanies AKI. Although mild thrombocytopenia may be present, it is the qualitative defect in platelet function, which is felt to be caused by the effect of circulating uremic toxins, that is more significant and that contributes to these patients bleeding tendencies. In patients with active bleeding or those in whom an invasive procedure is being contemplated, the prolonged bleeding time can be corrected pharmacologically. 40 Administration of 1-deamino-8-d-arginine vasopressin (DDAVP) shortens the bleeding time within 30 minutes. Infusion of 10 units of cryoprecipitate normalizes the bleeding time in 1 to 2 hours, with a return to baseline in 24 hours. Disposition Patients with new-onset AKI should be hospitalized. If nephrology consultation and dialysis facilities are not available, transfer to another institution is advisable, once volume and metabolic abnormalities have been adequately controlled and the patient is hemodynamically stable. Decisions regarding dialysis generally are made by the nephrology consultant and take into account many factors, including laboratory test abnormalities and the presence or absence of signs and symptoms of uremia (e.g., nausea, vomiting, change in mental status). Many nephrologists choose to initiate dialysis when the

12 1302 PART III Medicine and Surgery / Section Six Genitourinary and Gynecologic Systems BUN level exceeds 100 mg/dl or the serum creatinine level exceeds 10 mg/dl. Intractable volume overload and life-threatening hyperkalemia are the two most common indications for emergency dialysis. CHRONIC KIDNEY DISEASE In contrast to the typical patient with AKI, the patient with CKD has most commonly experienced a slowly progressive course of decreasing renal function over months or years and is likely to have either slowly progressive symptoms or acute problems brought on by superimposed illness, trauma, or other physiologic stress. The most common problems requiring emergent intervention are severe hyperkalemia and symptomatic volume overload. Barring renal transplantation, CKD is an essentially irreversible condition generally characterized by a relentless decrease in renal function. Thus, whereas preservation of renal function may be a high priority in the patient with known AKI, management need not as a rule involve efforts to reverse the process presumed to have caused CKD, nor even perhaps efforts to determine the exact cause. On occasion, however, the kidney disease may have a reversible component. In some cases the underlying pathologic process affecting the kidneys may be arrested or treated; more commonly, correctable extrarenal factors (e.g., volume depletion or urinary tract obstruction) may be identified. In the patient with CKD who has an acute problem, the focus should be the identification and treatment of an intercurrent illness that has caused clinical decompensation, with the goal of returning the patient to a stable, chronically compensated status. Principles of Disease The standard terminology for chronic renal failure has changed. 41 Chronic kidney disease denotes kidney damage or decreased renal function for 3 months or more and is characterized by irreversible nephron loss and scarring. Chronic renal insufficiency, which denotes a condition in which GFR has been moderately reduced but not to a degree sufficient to cause clear-cut clinical symptoms, has been replaced by an indication of the degree to which GFR is reduced. End-stage renal disease, now termed kidney failure, describes a condition in which renal function has diminished to a low level and in which serious, life-threatening manifestations can be expected to occur without dialysis or transplantation. At this stage the kidneys often are shrunken and diffusely scarred to such a degree that it may be impossible to make an etiologic diagnosis, even on pathologic examination. The causes of CKD are numerous; their relative frequency depends primarily on the population studied. As with AKI, they can be conveniently classified (Box 97-9) as prerenal (vascular), intrinsic renal (glomerular and tubulointerstitial), or postrenal (obstructive). Glomerular disease accounts for approximately one third to one half of the cases of CKD; in the United States, diabetic nephropathy forms the largest group of these. Hypertensive nephrosclerosis is another important cause, particularly among blacks, in whom it may be the cause of 25% or more of cases of CKD. Among children and adolescents, reflux nephropathy is the most common cause of CKD. Renal failure related to intravenous drug use or to human immunodeficiency virus disease is a major consideration in some populations. Clues to other specific causes may be gained from elements of the history, physical examination, or laboratory and imaging studies. Although determining the underlying cause of CKD can permit the underlying disease to be treated and make possible some improvement in renal function in some cases, this is the exception rather than the rule. BOX 97-9 Vascular Causes Renal arterial disease Hypertensive nephrosclerosis Glomerular Causes Primary Glomerulopathies Focal sclerosing glomerulonephritis (GN) Membranoproliferative GN Membranous GN Crescentic GN IgA nephropathy Secondary Glomerulopathies Diabetic nephropathy Collagen vascular disease Amyloidosis Postinfectious HIV nephropathy Tubulointerstitial Causes Nephrotoxins Analgesic nephropathy Uremia Progressive loss of renal function eventually results in a recognizable syndrome termed uremia. Clinical manifestations do not generally appear, however, until GFR has been reduced to approximately 15 to 20% of normal. As the patient becomes unable to excrete an ingested salt or water load promptly, external balance of sodium and water is affected; volume overload or hypernatremia or hyponatremia may result. Inability to concentrate the urine is an early manifestation of renal insufficiency and may be manifested as nocturia. Potassium homeostasis is likewise disrupted, and a relatively small potassium load may lead to dangerous hyperkalemia. Acid-base balance is affected, because the kidney fails to clear the daily metabolic acid load owing to a decreased ability to excrete ammonium and phosphate; the result is a non anion-gap acidosis in the earlier stages of CKD and a superimposed anion-gap acidosis as GFR decreases further. Calcium and phosphate metabolism is affected as well; retention of phosphate and progressive loss of the kidney s capacity to synthesize 1,25-dihydroxycholecalciferol, the active form of vitamin D, lead to hypocalcemia, secondary hyperparathyroidism, and eventually the development of renal osteodystrophy. Nitrogenous byproducts of protein catabolism retained in the blood are the presumed cause of many of the diverse abnormalities of organ function in renal failure. Most patients with CKD show decreased glucose tolerance, although it is rarely severe enough to require treatment unless the medical history includes established diabetes. In such cases, insulin or other hypoglycemic therapy may need to be continued but generally at a lower dosage than required before the onset of renal failure, because the normal kidney has a major role in insulin degradation. Alterations in lipid metabolism result in elevated low-density lipoproteins and hypertriglyceridemia in many patients with CKD. Clinical Features Major Causes of Chronic Kidney Disease Hypercalcemia or nephrocalcinosis Multiple myeloma Reflux nephropathy Sickle nephropathy Chronic pyelonephritis Tuberculosis Obstructive Causes Nephrolithiasis Ureteral tuberculosis Retroperitoneal fibrosis Retroperitoneal tumor Prostatic obstruction Congenital abnormalities Hereditary Causes Polycystic kidney disease Alport s syndrome Medullary cystic disease HIV, human immunodeficiency virus; IgA, immunoglobulin A. Uremia has specific effects on a variety of organ systems. Many of these manifestations are relieved by dialysis, but others are not. A number have been attributed in some degree to the retention of nitrogenous wastes and to the previously noted derangements in vitamin D and parathyroid hormone metabolism.

13 Chapter 97 / Renal Failure 1303 Cardiovascular System The cardiovascular system is perhaps most dramatically affected in CKD Many of the manifestations can be attributed to the effects of chronic volume overload, anemia, hyperlipidemia, alterations in calcium and phosphorus metabolism, and volume- and hormonally mediated hypertension Pericarditis, with or without pericardial fluid accumulation, also is common in CKD, particularly among patients who have not had dialysis. Pulmonary Effects Similarly, uremic pleuritis, with or without associated pleural fluid collections, may develop in some patients. So-called uremic lung, manifested radiographically by batwing perihilar infiltrates, represents pulmonary edema and is almost always caused by volume overload or myocardial dysfunction. Noninflammatory pleural effusion caused by volume overload also is fairly common. Of special importance in the ED evaluation is the fact that the radiographic appearance in pulmonary edema may at times be misleading, simulating an infectious lobar infiltrate or even assuming a nodular appearance in some cases. 48 Neurologic Features Neurologic dysfunction is common in advanced uremia and usually manifests with lethargy, somnolence, difficulty concentrating, or frank alteration in mental status. Seizures also may occur, although causes other than uremia alone must be ruled out. Uremic encephalopathy also commonly manifests with hiccups, asterixis, or myoclonic twitching. The last should not be confused with tetany caused by hypocalcemia, which also is common in untreated patients with CKD. In the peripheral nervous system, uremia often causes cramps and a distal sensorimotor neuropathy. A troublesome and characteristic complaint is restless legs syndrome, in which persistent neuropathic discomfort in the legs can be relieved only by movement. Gastrointestinal System Anorexia, nausea, and vomiting are nearly constant features of uremia. These GI manifestations are thought to be caused by accumulation of nitrogenous wastes because they often are relieved, even in the undialyzed patient, by introduction of a lowprotein diet, and seem to correlate roughly with the BUN level. Dermatologic Features The skin of patients with CKD has a characteristic yellowish tinge. Uremic frost, the result of deposition of urea from evaporated sweat on the skin, is a classic finding that, like uremic fetor, is seen only rarely now with the widespread use of dialysis (Fig. 97-3). Diffuse pruritus is often a major source of discomfort for the patient with CKD; in some cases it may be caused by calcium deposition in the skin secondary to derangements in calcium metabolism. The use of gadolinium-based contrast agents for magnetic resonance imaging (MRI) has been associated with the development of nephrogenic systemic fibrosis, a potentially fatal disorder that occurs in patients with chronic kidney failure. 49 Musculoskeletal System The bones and joints are sites of problems for many of these patients, particularly those with long-standing renal disease. The complex disturbances of calcium and phosphate metabolism in CKD result in renal osteodystrophy, a clinical entity encompassing Figure Uremic frost. Note the fine white powder on the skin of this patient with kidney failure. several overlapping varieties of bone disease that can cause bone pain or frank fractures. Patients with CKD generally are treated with long-term oral calcium and vitamin D in an effort to prevent both secondary hyperparathyroidism and uremic osteodystrophy. Occasional patients will have a poor response to therapy and require parathyroidectomy. A specific type of arthritis caused by deposition of calcium hydroxyapatite or calcium oxalate crystals in joints is seen in some patients, as are periarticular calcium deposition, spontaneous tendon rupture, myopathy, and carpal tunnel syndrome. Immunologic Considerations Uremic patients have long been noted to have an increased susceptibility to infection, even when not challenged by the invasive procedures associated with dialysis. Both humoral and cellular immunity have been shown to be affected. The relative importance of each in the pathogenesis of infection in renal failure has not been clarified, but defects in cellular immunity appear to be more significant clinically. Although patients with renal failure should be considered to be immunocompromised, most infections in patients with CKD are caused by common pathogens rather than opportunistic organisms. Hematologic Effects A pronounced normochromic normocytic anemia, with a hematocrit commonly in the range of 18 to 25%, is nearly universal in untreated CKD, except among patients with polycystic disease. It is caused primarily by the kidneys decreased production of erythropoietin, a hormone that stimulates red cell production by the bone marrow. Other contributing factors are increased red cell hemolysis, nutritional deficiencies, and increased bleeding secondary to platelet dysfunction. Although platelet number generally is normal in uremia, the bleeding time is prolonged because of defective platelet adhesiveness and activation. Numerous ecchymoses, seen in many patients with CKD, is a common manifestation. Diagnostic Strategies The patient with CKD, particularly one who is not yet receiving dialysis, is likely to be seen in the ED with one of the

14 1304 PART III Medicine and Surgery / Section Six Genitourinary and Gynecologic Systems BOX Causes of Chronic Kidney Disease with Normal or Large Kidney Size BOX Polycystic kidney disease Amyloidosis Diabetic nephropathy Malignant hypertension Multiple myeloma Glomerulonephritis (some cases) Obstructive uropathy (some cases) manifestations previously noted. In cases in which the diagnosis of renal failure has not previously been made, patients complaints most commonly are nonspecific and often of insidious onset, such as generalized weakness, poor appetite, or deterioration of mental functioning. The initial laboratory finding of a reasonably well-tolerated but rather severe anemia may be the first clue to the diagnosis, which is subsequently confirmed by elevated BUN and serum creatinine levels. A prudent next step is to check the ECG for evidence of immediately life-threatening hyperkalemia before further laboratory and radiographic investigations are undertaken. Once it has been determined that the patient is in no immediate danger, the ED evaluation can establish that renal failure is indeed chronic rather than acute. An explicit history to that effect obtained from previous medical records or from the patient or family provides the most straightforward and reliable confirmation, as does the presence of a dialysis access device on physical examination. If such a history is unavailable, the finding of bilaterally small kidneys (readily detected on plain abdominal films or by ultrasonography) constitutes equally good evidence. However, the converse is not necessarily true a finding of normal-sized or large kidneys does not rule out CKD (Box 97-10). In such cases, additional diagnostic steps are required to establish the diagnosis. A convincing history of the long-standing presence of the presenting symptoms or of symptoms such as nocturia may be helpful in suggesting chronicity, as may a history of familial kidney disease such as polycystic kidney disease or Alport s syndrome. Laboratory abnormalities such as anemia, acidosis, hyperuricemia, hypocalcemia, and hyperphosphatemia can occur in patients with acute kidney failure as early as 10 days after onset. Although urinary findings likewise tend not to be helpful, the presence of broad waxy casts on microscopic examination is suggestive of chronic disease, whereas the finding of an active sediment (e.g., red cell casts) is good evidence for an acute process. Although as a rule chronic kidney failure is irreversible and slowly progressive, an essential component of the ED evaluation is to exclude the possibility of potentially reversible factors (in effect, ruling out acute on chronic renal failure) and to ensure that treatable causes of CKD disorders that if treated might allow for some return of renal function have not been overlooked. These potentially reversible factors and treatable causes of CKD are important to keep in mind because they represent the only potential opportunity to reverse the patient s disease rather than simply to manage its results (Box 97-11). Primary among superimposed reversible factors are those that lead to decreased renal perfusion. Of these, the most common is volume depletion. Regardless of the initiating cause, the process is exacerbated by the diseased kidney s impaired ability to conserve sodium and to concentrate the urine appropriately. Decreased renal perfusion caused by cardiac dysfunction of any cause is another extremely common and potentially reversible factor. An uncommonly encountered but important vascular cause of reversible deterioration of renal function is scleroderma renal crisis, a syndrome of accelerated hypertension and severe vasoconstriction in patients with underlying scleroderma that can be reversed by timely treatment with ACE inhibitors. 18 Reversible Factors Hypovolemia Congestive heart failure Pericardial tamponade Severe hypertension Catabolic state, protein loads Nephrotoxic agents Obstructive disease Reflux disease Treatable Causes Renal artery stenosis Malignant hypertension Increased catabolism caused by infection, trauma, surgery, corticosteroids, or GI bleeding is another reversible factor that often is responsible for worsening azotemia and the development of uremic symptoms. Drugs and toxins constitute another important group of reversible factors. Not only may these agents exacerbate renal insufficiency by causing intravascular volume depletion (diuretics), decreased renal perfusion (antihypertensive agents), or increased catabolism (tetracycline); they also can cause ATN (radiographic contrast material), AIN (many drugs), or inhibition of renal prostaglandin synthesis (NSAIDs). Particularly noteworthy is the dramatic decrease in renal function produced when an ACE inhibitor is administered to a patient with renal insufficiency caused by bilateral renal artery stenosis (or renal artery stenosis in a solitary kidney). 50 Postrenal reversible factors also are important because of their frequency, particularly obstructive disease in the older male patient and reflux nephropathy in the child. Papillary necrosis should remain a consideration in the diabetic patient, the patient with sickle cell disease, and the patient with a history of long-term analgesic use. Stone disease, retroperitoneal fibrosis, and even rarer entities such as ureteral tuberculosis also should not be overlooked. Finally, treatment of the underlying disorder that has caused the CKD can occasionally result in the return of some renal function, most notably in cases of myeloma kidney, some forms of secondary glomerulonephritis, and severe hypertensive disease. Although this consideration should relate to long-term care and follow-up, it is appropriate that ED management address this issue to ensure that appropriate evaluation and disposition are arranged. Management Reversible Factors and Treatable Causes of Chronic Kidney Disease Acute interstitial nephritis Hypercalcemic nephropathy Multiple myeloma Vasculitis (e.g., systemic lupus erythematosus, Wegener s granulomatosis, polyarteritis nodosa) Obstructive nephropathy Reflux nephropathy Persons with CKD constitute a group of patients who merit special attention in the ED setting. These patients are susceptible to infection, bleeding, and the numerous other complications associated with renal failure, as well as those that may be associated with the underlying causative disorder. Moreover, these patients are more vulnerable to the effects of any intercurrent illness or trauma. Those who are maintained with chronic hemodialysis or peritoneal dialysis are subject to potential complications from the dialysis therapy itself. Patients with CKD also are uniquely susceptible to iatrogenic illness. First, they are less able to handle fluid and solute loads than are normal persons. Just as important, the presence of renal failure significantly alters the metabolism and action of many drugs, often in ways that are not predictable (Box 97-12). Thus the dose and schedule of every administered agent, even apparently innocuous ones such as antacids, laxatives, antiemetics, or multivitamin preparations, should be carefully considered. 51 For this purpose,

15 ready access to a compendium such as the one by Aronoff and colleagues or availability of a hospital pharmacist for frequent consultations is invaluable. 34 In general, consultation with the patient s nephrologist is recommended on completion of the initial ED evaluation, because management and follow-up monitoring after the patient has left the ED often are complex. In the United States, most patients with advancing CKD eventually will require dialysis, but several true emergencies may develop in the patient with CKD before chronic dialysis has been instituted. Specific diagnostic and therapeutic considerations apply to the management of these conditions regardless of whether they occur in dialyzed or undialyzed patients. Hyperkalemia Potentially the most rapidly lethal complication of CKD encountered in the ED setting is severe hyperkalemia. As a rule, this BOX Mechanisms of Drug Toxicity in Renal Failure Excessive drug level Impaired renal excretion of drug Impaired renal excretion of active metabolite Impaired hepatic metabolism Increased sensitivity to drug Changes in protein binding Changes in volume of distribution Changes in target organ sensitivity Metabolic loads administered with drug Misinterpretation of measured serum drug level (i.e., change in therapeutic range) From Wolfson AB, Singer I: Hemodialysis-related emergencies: Part I. J Emerg Med 5:533, Chapter 97 / Renal Failure 1305 condition is clinically silent until it causes potentially lifethreatening manifestations. Accordingly, hyperkalemia must be looked for in every patient with CKD. These patients can become severely hyperkalemic when required to handle even modest exogenous and endogenous potassium loads; moreover, even drugs that have only minimal effects on the serum potassium in normal persons, such as beta-blockers and ACE inhibitors, can cause hyperkalemia in these patients. There is concern that the use of succinylcholine in patients with CKD has the potential to cause rapid deterioration in patients who are already hyperkalemic, although this appears to be rare. An ECG should be obtained whenever hyperkalemia is a possibility, and if signs of hyperkalemia are noted, appropriate therapy should be started immediately, even before laboratory confirmation of a high serum potassium level. ECG changes may be completely absent even when hyperkalemia is severe, however. 52 Thus a normal ECG does not preclude the need for laboratory confirmation of a normal serum potassium level. A potassium level of 6 meq/l should be considered potentially dangerous, even though many patients with CKD chronically tolerate levels somewhat above this threshold without ECG changes. A patient with CKD who is in cardiac arrest should be assumed to be hyperkalemic and treated accordingly while the usual resuscitative measures are taken. The most rapidly effective treatment for hyperkalemia is intravenous calcium, which transiently reverses the cardiac manifestations of hyperkalemia without altering the serum potassium level or total-body potassium (Table 97-2). Calcium should be given to buy time until more definitive measures can take effect. It makes little sense to administer calcium in response to an elevated serum potassium level in the absence of manifestations of hyperkalemia on the ECG. In treating hyperkalemia, it also is important to keep in mind the CKD patient s limited ability to tolerate volume and solute Table 97-2 AGENT OR MODALITY Calcium gluconate (10%) or calcium chloride (10%) Albuterol Glucose and insulin Sodium bicarbonate Kayexalate Dialysis Intravenous diuretics (intravenous fluid if patient is hypovolemic) Treatment of Hyperkalemia DOSE AND REGIMEN 10 ml IV (may repeat 2 prn every 5-10 min) mg (nebulized) by inhalation units regular insulin per 100 g glucose 150 meq/l IV infusion (rate variable) 25 g in 25 ml 70% sorbitol PO q6h ± 50 g in 50 ml 70% sorbitol by retention enema q6h HD PD ONSET/DURATION OF ACTION MECHANISM OF ACTION COMMENTS 1-5 min/ 1 hr Antagonizes membrane effects of K 30 min/2+ hr Intracellular movement of K 30 min/while infusion continued Approximately min/1-2 hr Intracellular movement of K Possible intracellular movement of K ECG monitoring required Do not mix with HCO 3 Beware: Hypercalcemia Relatively free of significant side effects; tachycardia Beware: Hyperglycemia Hypoglycemia Infused volume may be decreased by giving D 10 W, D 20 W, or D 50 W Sodium bicarbonate Hours/while continued Exchange of K for Na Slow and modest effect Beware: Na overload Enema must be retained min Minutes/while continued Removal of K from blood HD may remove 50 meq/hr (beware: K rebound) PD may remove 15 meq/hr Minutes/while diuresis continued (depending on renal function) Urinary K excretion Only in patients with some residual renal function D 10 W, 10% dextrose in water; D 20 W, 20% dextrose in water; D 50 W, 50% dextrose in water; ECG, electrocardiogram; HD, hemodialysis; IV, intravenously; PD, peritoneal dialysis; PO, orally.

16 1306 PART III Medicine and Surgery / Section Six Genitourinary and Gynecologic Systems loads (see Table 97-2). Thus, sodium bicarbonate infusion risks causing volume overload and precipitating pulmonary edema. Intravenous glucose and insulin treatment also entails some volume administration but is much more effective in any case, and hyperkalemia can be controlled for as long as the infusion is continued. Another effective temporizing measure is the administration of inhaled albuterol to promote movement of potassium into cells while more definitive maneuvers are being instituted. 37,38 To remove potassium from the body, dialysis remains the most rapid and effective intervention. Sodium polystyrene sulfonate (Kayexalate), a resin that exchanges sodium for potassium ions, can be administered orally or rectally but is slow acting and only somewhat effective as a temporizing measure until dialysis (if necessary) can be instituted. In patients who still retain some renal function, the most effective way to treat hyperkalemia may be to administer an intravenous diuretic such as furosemide (if the patient is not hypovolemic) and to give volume if necessary. Large doses of diuretic may be necessary for a satisfactory diuresis to be induced. In light of the potential for ototoxicity with the use of loop-active diuretics, these drugs should be administered by slow infusion rather than by bolus and may be contraindicated in patients who also are receiving other potentially ototoxic agents. During the course of any of these therapeutic interventions, both the ECG and serum potassium levels must be monitored frequently. A C B D Pulmonary Edema Perhaps the most common ED problem in patients with CKD is pulmonary edema secondary to volume overload. Surprisingly, the diagnosis is not always straightforward. A history of increasing dyspnea on exertion or paroxysmal nocturnal dyspnea may be suggestive, but physical examination may not reveal the expected signs of CHF, and even chest radiography may be deceptive (Fig. 97-4). 48 Recent weight gain or a body weight considerably over dry weight (typically more than 5 pounds) is the most reliable clue, and in the absence of convincing evidence of another cause for dyspnea, volume overload should be assumed to be the cause, and the patient should be treated accordingly. Treatment of pulmonary edema in the patient with CKD is of necessity somewhat different from that in other patients (Box 97-13). 53,54 Arrangements for initiation of dialysis should be made as soon as possible because it is the most rapidly effective means to decrease intravascular volume in the absence of renal function. Other immediate measures should be instituted in the meantime. Although such measures may occasionally prove to be effective enough to avoid dialysis temporarily in patients who possess some residual renal function, it should nevertheless be anticipated that the response to even extremely aggressive medical therapy short of dialysis will be inadequate. The CKD patient with pulmonary edema is placed in the sitting position, and high-flow oxygen is administered by mask. The use of continuous or bilevel positive airway pressure (CPAP or BL-PAP) delivered by face mask has been reported to be a useful adjunct in patients with CKD, as it is in patients without renal failure. 55,56 Sublingual or topical nitroglycerin, or both, can be administered immediately and functions rapidly to reduce both preload and afterload; an intravenous infusion can be begun promptly and titrated to effect. Intravenous nitroprusside may have an advantage in producing more arteriolar dilation if the patient is hypertensive. Diuretics are not expected to be helpful unless the patient has retained a significant level of renal function. Infection Because infection is a major contributor to morbidity and mortality among patients with CKD, the possibility of serious infection Figure Pulmonary edema simulating right lower lobe pneumonia in a dialysis-dependent patient. Marked improvement with decreased infiltrate and return of heart to normal size were evident after dialysis and ultrafiltration. A, Chest x-ray film obtained immediately before dialysis shows cardiomegaly and right lower lobe infiltrate interpreted as pneumonia. B, Chest x-ray film at 5 hours after initiation of dialysis, with 2-kg weight reduction. The extent of the infiltrate has markedly decreased. C and D, Lung and heart have returned to normal size. (From Kjellstrand C, et al: In: Drukker W, Parson FM, Maher JF (eds): Replacement of Renal Function by Dialysis. Boston, Martinus Nijhoff, 1983, pp ) BOX Dialysis Hemodialysis Hemofiltration Peritoneal dialysis Treatment of Pulmonary Edema in Renal Failure Oxygen Nitroglycerin Nitroprusside Diuretics should be entertained even when the expected classic findings are not all present. 51,57-59 For example, bacteremia may manifest with fever alone, just as in other patients with impaired immunity. Patients with pneumonia may have only vague dyspnea or malaise, symptoms that may be attributed to volume overload or uremia. Thus, all diagnostic possibilities should be pursued, and empirical broad-spectrum antibiotic coverage often is advisable until infection has been ruled out in the hospital. Bacteremia resulting from vascular access infection is quite common in patients receiving hemodialysis, as is peritonitis in patients undergoing peritoneal dialysis. UTI can occur even in patients with minimal urine output or those with long-standing renal failure. Urinary stasis is undoubtedly a predisposing factor. 59 Upper UTI associated with a clinical picture typical of pyelonephritis or renal colic is seen most commonly in patients with polycystic kidney disease and requires parenteral treatment. A clinical diagnosis can be made presumptively in the ED, but invasive measures sometimes are necessary to document infection and guide therapy. For infected cysts, lipid-soluble antibiotics (e.g., clindamycin, trimethoprim-sulfamethoxazole) offer the best antibiotic penetration; surgical intervention for refractory infection sometimes becomes necessary, however. 61