Manual of Nephrology. Diagnosis and Therapy 6e

Editors: Schrier, Robert W.

Title: Manual of Nephrology, 6th Edition

Copyright 2005 Lippincott Williams & Wilkins

> Table of Contents > 10 - The Patient with Acute Renal Failure

10

The Patient with Acute Renal Failure

Sarah Faubel

Charles L. Edelstein

Robert E. Cronin

• Definition and recognition of acute renal failure. Acute renal failure (ARF) is a sudden decrease in the glomerular filtration rate (GFR) occurring over a period of hours to days and resulting in the failure of the kidney to excrete nitrogenous waste products and maintain fluid and electrolyte homeostasis. Clinically, it is recognized by an increase in serum creatinine and blood urea nitrogen (BUN). ARF may occur in patients with previously normal renal function or patients with chronic kidney disease (CKD); in either case, the clinical approach to find and treat the cause remains similar.

  • Serum creatinine as a marker for ARF and GFR. Normal serum creatinine is 0.6 to 1.2 mg per dL and is the most commonly used parameter to assess renal function. Practically, and in clinical trials of ARF, an increase in creatinine of 50% above baseline or an increase of 0.5 mg per dL are commonly used definitions of ARF. Unfortunately, the correlation between serum creatinine concentration and GFR may be confounded by several factors.

    • Creatinine excretion is dependent on glomerular filtration and proximal tubular secretion. Certain medications such as trimethoprim interfere with proximal tubular creatinine secretion and may cause a rise in serum creatinine without a fall in GFR (see Table 10-1). Once filtered, creatinine cannot be reabsorbed.

      Table 10-1. Medications that Affect Serum Creatinine without Actually Affecting Renal Function
      Mechanism and medication Increased serum creatinine by the inhibition of creatinine secretion    Trimethoprim    Cimetidine    Probenecid    Triamterene    Amiloride    Spironolactone Increased serum creatinine due to interference with creatinine measurement    Ascorbic acid    Cephalosporins

    • Creatinine production is dependent on muscle mass. Muscle mass declines with age and illness. Therefore, a serum creatinine of 1.2 mg per dL in an elderly, 40-kg patient with cancer and wasted muscles may represent a severely impaired GFR, whereas a serum creatinine of 1.2 mg per dL in a 100-kg weightlifter with large muscle mass may represent a normal GFR.

    • Creatinine production and excretion must be in a steady state before creatinine may be used in any formula for the estimate of GFR. The most commonly used formulae to estimate GFR are the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), and the modified MDRD. In a steady state, the modified MDRD is as good as the MDRD for estimating renal function; both equations are superior to the Cockcroft-Gault formula. After an acute insult, it may take several days for creatinine excretion and production to reassume a steady state. For example, if a 60 kg, 30-year-old woman with a serum creatinine of 1.0 mg per dL suddenly loses all renal function, her serum creatinine may only rise to 2.0 mg per dL after one day. By the modified MDRD her GFR is 31 mL per minute; by Cockgroft-Gault it is 39 mL per minute, but it is actually zero.

      • Cockcroft-Gault formula:

      • MDRD formula:

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        Where serum Cr (creatinine) and BUN are in mg per dL; serum albumin is in g per dL

      • Modified MDRD formula:

      • Creatinine clearance (CCr) gives a better estimate of GFR than the formulae listed above in the acute setting. This requires a 24-hour urine collection. Normal ranges for CCr are 120 25 mL per minute for men and 95 20 mL per min for women.

  • BUN as a marker for ARF and GFR. Normal BUN is 8 to 18 mg per dL. An increase in BUN typically accompanies a rise in serum creatinine in the setting of ARF. Urea is filtered, but not secreted. Increased reabsorption of urea by the proximal tubule and AVP-sensitive urea transporters in the collecting duct occurs in states of volume depletion. In this setting, BUN can rise without a rise in creatinine, resulting in a BUN to serum creatinine ratio that is greater than 20 (see section IV.H.3).

    BUN levels are affected by multiple factors not related to GFR. Because BUN production is related to protein metabolism, an increase in BUN without a decline in GFR may occur with hypercatabolic states, protein loading, and steroid administration. Conversely, a low BUN may be present in the setting of reduced GFR in patients who are on a low-protein diet, are severely malnourished, or have severe liver disease.

  • Distinguishing acute from chronic renal failure. Distinguishing acute from chronic renal failure (CRF) may be challenging. Laboratory findings such as hyperphosphatemia, hypoalbuminemia, and hyperkalemia are unreliable factors to distinguish acute from chronic renal failure and may be present in either case. Symptoms such as nausea, vomiting, and malaise may also occur in acute or chronic renal failure. Potential methods to distinguish between the two include:

    • Old records. The most reliable way to distinguish acute from chronic renal failure is an evaluation of old records. Increased BUN or serum creatinine documented months earlier and/or a history of kidney disease suggest that the renal failure is chronic.

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    • Small kidneys (less than 10 cm) on renal ultrasound. Normal-sized kidneys may be present in some patients with chronic kidney disease, such as diabetic nephropathy, amyloidosis, autosomal dominant polycystic kidney disease, rapidly progressive glomerulonephritis, or malignant hypertension.

    • Anemia. Normochromic normocytic anemia is common in patients with CKD and a GFR less than 30 mL per min; in patients with a GFR of 30 to 44 mL per minute, only about 20% of patients have anemia. Therefore, with a GFR of 30 mL or below, the absence of anemia suggests that renal failure is acute. In some etiologies of CKD (e.g., autosomal dominant polycystic kidney disease), anemia may be absent.

  • Urine output in ARF. ARF is typically described as either oliguric or nonoliguric. Oliguria is defined as a urine output of less than 400 mL per day; 400 mL is the minimum amount of urine that a person in a normal metabolic state must excrete to get rid of the daily solute production. For example, a person with a daily solute production of 500 mOsm who concentrates urine to a maximum of 1,200 mOsm per L, would need to pass 400 mL of urine per day to excrete the daily solute production.

    Anuria is defined as a lack of urine obtained from a bladder catheter; it has a short list of potential causes. It is most often caused by complete bilateral urinary tract obstruction and shock. Less common causes are the hemolytic-uremic syndrome and rapidly progressive glomerulonephritis, particularly anti-GBM antibody disease; bilateral renal arterial or venous occlusion can also cause anuria.

• Classifications of ARF: definitions and causes. ARF is classified as prerenal, intrinsic renal, and postrenal.

  • Prerenal ARF (Fig. 10-1). Prerenal ARF is a fall in the GFR due to reduced renal perfusion in which no structural or cellular damage to the kidney has occurred. Urine sediment is typically bland. Essential to this diagnosis is

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    that renal function returns to normal within 24 to 72 hours of correction of the hypoperfused state. Prerenal ARF occurs in the following situations:

    Figure 10-1. Causes of Prerenal ARF. Prerenal ARF may be secondary to true intravascular volume depletion or arterial underfilling from a decrease in cardiac output or arterial vasodilatation. The extracellular fluid volume (ECF) comprises the intravascular and the interstitial body water compartments.

    • Total intravascular volume depletion. This condition can occur in a number of settings where intravascular volume is reduced and may be secondary to

      • Hemorrhage

      • Renal fluid loss

        • Excessive diuresis (e.g., diuretics)

        • Osmotic diuresis (e.g., glucosuria)

        • Primary adrenal insufficiency (i.e, hypoaldosteronism)

        • Salt-wasting nephritis

        • Diabetes insipidus

      • Gastrointestinal fluid loss

        • Vomiting

        • Diarrhea

        • Nasogastric tube drainage

      • Skin fluid loss

        • Burns

        • Excessive sweating

        • Hyperthermia

      • Third-space fluid loss

        • Peritonitis

        • Pancreatitis

        • Systemic inflammatory response syndrome (SIRS)

        • Profound hypoalbuminemia

    • Effective volume depletion from arterial underfilling. Arterial underfilling is a state in which intravascular volume is actually normal (or even increased) but circulatory factors are inadequate to maintain renal perfusion pressure. Underfilling may be due to either a decrease in cardiac output or arterial vasodilatation and may occur in a number of clinical settings:

      • Reduced cardiac output

        • Congestive heart failure

        • Cardiogenic shock (e.g., acute myocardial infarction)

        • Pericardial effusion with tamponade

        • Massive pulmonary embolism

      • Peripheral vasodilation

        • Sepsis

        • Antihypertensive medications

        • Anaphylaxis

        • Anesthesia

        • Cirrhosis and other liver diseases

    • Intrarenal hemodynamic changes

      • Glomerular afferent arteriole vasoconstriction (preglomerular effect)

        • Nonsteroidal anti-inflammatory drugs (NSAIDs) (prostaglandin inhibition)

        • Cyclo-oxygenase 2 inhibitors (Cox 2 inhibitors) (prostaglandin inhibition)

        • Cyclosporine

        • Tacrolimus

        • Radiocontrast dye

        • Hypercalcemia

      • Glomerular efferent arteriole vasodilitation (postglomerular effect)

        • Angiotensin converting enzyme (ACE) inhibitors

        • Angiotensin II receptor blockers (ARBs)

  • Postrenal ARF. Postrenal ARF is caused by the acute obstruction of the flow of urine. Urinary obstruction of both ureters, the bladder, or the urethra may cause postrenal ARF. Patients most at risk for postrenal ARF are elderly men, in whom prostatic hypertrophy or prostatic cancer may lead to

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    complete or partial obstruction of urine flow. In women, complete urinary tract obstruction is relatively uncommon in the absence of pelvic surgery, pelvic malignancy, or previous pelvic irradiation. The causes of postrenal ARF include:

    • Bilateral ureteral obstruction or unilateral obstruction in a solitary kidney (upper urinary tract obstruction)

      • Intraureteral

        • Stones

        • Blood clots

        • Pyogenic debris or sloughed papillae

        • Edema following retrograde pyelography

        • Transitional cell carcinoma

      • Extraureteral

        • Pelvic or abdominal malignancy

        • Retroperitoneal fibrosis

        • Accidental ureteral ligation or trauma during pelvic surgery

      • Bladder neck/urethral obstruction (lower urinary tract obstruction)

        • Prostatic hypertrophy

        • Prostatic and bladder carcinoma

        • Autonomic neuropathy or anticholinergic agents causing urinary retention

        • Urethral stricture

        • Bladder stones

        • Fungal infection (e.g., fungus balls)

        • Blood clots

  • Intrarenal or intrinsic ARF. In contrast to prerenal and postrenal ARF, the disorders listed here represent problems within the kidney itself. These problems may be vascular, glomerular, interstitial, or tubular. The diseases may be primary renal or part of a systemic disease. The course of ARF in these situations cannot be changed by manipulating factors outside the kidney (e.g., performing volume repletion, improving cardiac function, correcting hypotension, or removing obstruction).

    • Vascular. Vascular disorders causing ARF are classified based on the size of the vessels involved.

      • Large- and medium-sized vessels

        • Renal artery thrombosis or embolism

        • Operative arterial cross-clamping

        • Bilateral renal vein thrombosis

        • Polyarteritis nodosa

      • Small vessels

        • Atheroembolic disease

        • Thrombotic microangiopathies

          • Hemolytic-uremic syndrome (HUS)

          • Thrombotic thrombocytopenic purpura (TTP)

          • Scleroderma renal crisis

          • Malignant hypertension

        • Thrombotic microangiopathies of pregnancy

          • Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome

        • Postpartum ARF

    • Glomerular. Glomerular diseases are typically categorized based on urine findings as either nephrotic or nephritic.

      • Nephrotic glomerular disorders are characterized by large proteinuria (greater than 3 grams in 24 hours) and minimal hematuria. Nephrotic glomerular disorders are uncommonly associated with ARF, but may occur in minimal-change disease or focal segmental glomerulosclerosis (FSGS), particularly collapsing FSGS.

      • Nephritic glomerular disorders (glomerulonephritis) are characterized by hematuria and proteinuria (typically 1 to 2 grams in 24 hours).

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        Patients with known glomerulonephritis may develop ARF; alternatively, glomerulonephritis may commonly present as ARF. Rapidly progressive (crescentic) glomerulonephritis (RPGN) should be suspected in a patient with glomerulonephritis who has a doubling of serum creatinine within a 3-month period. RPGN is caused by injury to the glomerular capillary wall, which results in subsequent inflammation, fibrosis, and crescent formation. Urgency is required to make the diagnosis of RPGN, because crescent formation can rapidly destroy the glomeruli; response to therapy is directly correlated with the percent of glomeruli having crescents. Because the diagnosis is typically made by renal biopsy, the causes of glomerulonephritis and RPGN are classified according to immunofluorescence staining on renal biopsy.

        • Diseases with linear (antiglomerular basement membrane) immune complex deposition

          • Goodpasture's syndrome (renal and pulmonary complications are present)

          • Renal-limited Goodpasture's syndrome

        • Diseases with granular immune complex deposition

          • Acute postinfectious glomerulonephritis

          • Lupus nephritis

          • Infective endocarditis

          • Immunoglobulin A (IgA) glomerulonephritis

          • Henoch-Sch nlein purpura

          • Membranoproliferative glomerulonephritis

          • Cryoglobulinemia

        • Diseases with no immune deposits (pauci-immune)

          • Wegener's granulomatosis

          • Microscopic polyangiitis

          • Churg-Strauss syndrome (CSS)

          • Idiopathic crescentic glomerulonephritis

    • Interstitium. ARF from an interstitial cause is known as acute interstitial nephritis (AIN). The primary histologic lesion of AIN is marked edema of the interstitial space with a focal or diffuse infiltration of the renal interstitium with inflammatory cells. AIN (also called acute tubulointerstitial nephritis) is most commonly due to drug hypersensitivity, but may also be a consequence of infections or systemic disease [e.g., systemic lupus erythematosus (SLE)].

      • Drug-induced AIN. Over 100 drugs have been implicated in drug-induced AIN. Some of the drugs which are most commonly associated with acute interstitial nephritis are:

        • Antibiotics (e.g., methicillin, cephalosporins, rifampicin, sulfonamides, erythromycin, and ciprofloxacin)

        • Diuretics (e.g., furosemide, thiazides, chlorthalidone)

        • NSAIDs

        • Anticonvulsant drugs (e.g., phenytoin, carbamazepine)

        • Allopurinol

      • Infection-associated AIN

        • Bacterial (e.g., staphococcus, streptococcus)

        • Viral (e.g., cytomegalovirus, Epstein-Barr virus)

        • Tuberculosis

    • Tubular. Acute tubular necrosis (ATN) is characterized by an abrupt decrease in the GFR due to proximal tubular dysfunction caused by ischemia (50% of cases) and nephrotoxins (35% of cases). Although this type of renal injury has long been designated ATN, in many cases little true necrosis of tubular cells is present on histologic examination. Rather, the tubules demonstrate morphologic changes of sublethal injury (e.g., swelling, vacuolization, loss of brush border, apical blebbing, and loss of basolateral infoldings). Loss of viable tubular epithelial cells

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      into the urine also occurs. The presence of tubular dysfunction, rather than necrosis, may explain the abrupt recovery of renal function that is seen in some patients with ATN.

      Ischemic ATN is a consequence of reduced blood flow to the kidneys, which results from a decreased total blood volume or arterial underfilling with a redistribution of blood away from the kidney. Ischemic ATN is seen most commonly after septic or hemorrhagic shock. Nephrotoxic ATN is most commonly caused by aminoglycoside antibiotics and radiocontrast dye.

      Causes of ATN include:

      • Renal ischemia

        • Shock

        • Hemorrhage

        • Trauma

        • Gram-negative sepsis

        • Pancreatitis

      • Nephrotoxic drugs

        • Aminoglycoside antibiotics

        • Amphotericin B

        • Pentamidine

        • Foscarnet

        • Acyclovir

        • Indinavir

        • Antineoplastics (e.g., cisplatin)

        • Hypotension from any cause

        • Radiocontrast dye

        • Organic solvents (e.g., carbon tetrachloride)

        • Ethylene glycol (antifreeze)

        • Anesthetics (enflurane)

      • Endogenous toxins

        • Myoglobin (e.g., rhabdomyolysis)

        • Hemoglobin (e.g., incompatible blood transfusion, acute falciparum malaria)

        • Uric acid (e.g., acute uric acid nephropathy)

• Epidemiology of ARF. See Table 10-2.

  Table 10-2. Characteristics of ARF in Regard to the Location of its Development

  Community acquired acute renal failure History/symptoms Predisposing factor(s) Type of ARF Acute systemic illness (e.g., viral influenza, gastroenteritis) Volume depletion Prerenal or ATN Streptococcal pharyngitis or pyoderma (vesicular skin lesions, typically located on the extremities, which become pustular and then crust) Immune complex deposition in the glomeruli Acute poststreptococcal glomerulonephritis Trauma, crush injury, prolonged immobilization, found down Extensive muscle damage and tissue breakdown Rhabdomyolysis Urinary tract symptoms such as difficulty voiding, incontinence, dribbling Obstruction to urine flow or neurogenic bladder Postrenal Fever and/or rash in a patient recently prescribed a new medication NSAIDS, antibiotics, and diuretics are frequently prescribed on an outpatient basis Allergic interstitial nephritis Accidental or intentional overdose of a nephrotoxin (altered mental status may be a frequent accompaniment) Heavy metal compounds, solvents, ethylene glycol, salicylates, and acetaminophen ATN Acute renal failure occurring inside the hospital History/symptoms Predisposing factor(s) Type of ARF Excessive fluid loss from aggressive diuresis, nasogastric suction, surgical drains, diarrhea, etc. Volume depletion Prerenal or ATN Surgery with or without concomitant volume depletion Anesthesia causes renal vasoconstriction, which reduces renal blood flow Prerenal or ATN Radiologic (contrast CT) or other procedures (e.g., coronary angiography) Intravenous contrast dye ATN Sepsis Infection, volume depletion, hypotension, nephrotoxic antibiotics (e.g., aminoglycosides) ATN

  • Community-acquired ARF. ARF is present on admission in about 1% of hospitalized patients. Half of cases are in patients with CKD. The most common causes of community-acquired ARF include prerenal (70%) and postrenal (17%). The overall mortality of patients presenting with ARF is 15%.

  • Hospital-acquired acute renal failure. The development of ARF in hospitalized patients is common and carries with it a significant independent risk of mortality. In patients with normal renal function, the incidence of hospital-acquired ARF is approximately 5%; in patients with CKD, it is approximately 16%. Overall, approximately 40% of ARF in hospitalized patients is due to ATN; medications account for about 15%; radiocontrast dye, 10%, and AIDS-associated, 5%.

    In ARF developing outside the intensive care unit (ICU), prerenal accounts for 28% of ARF, whereas ATN accounts for 38% of ARF. If ARF develops in the ICU, prerenal accounts for 18% of ARF and ATN accounts for 76%. ATN in the ICU is typically multifactorial and is frequently part of multisystem organ failure syndrome.

  • Prevention of ARF. Numerous factors predispose hospitalized patients to the development of ARF: volume depletion, drugs which affect renal blood flow (e.g., NSAIDs and Cox-2 inhibitors), and the use of nephrotoxic medications and contrast dye.

    Although data are limited on treatments to prevent ARF, it is prudent to carefully follow volume status and maintain adequate hydration, discontinue (when possible) medications that affect renal blood flow; choose

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    alternate nonradiocontrast imaging techniques [e.g, magnetic resonance imaging (MRI) with gadolinium]; and use non-nephrotoxic antibiotics.

  • Morbidity and mortality associated with ARF. It is commonly thought that ARF from ATN is a completely reversible disorder. Recent data suggest that of patients who develop ARF in the ICU and require dialysis, up to 30% will require maintenance dialysis after discharge from the hospital.

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    Another widely held belief is that patients die with ARF, not from ARF. Numerous well-controlled studies have challenged this notion and found that after adjusting for comorbidities, the development of ARF in hospitalized patients is an independent and significant predictor of in-hospital mortality (Table 10-3).

    Table 10-3. Mortality of ARF

    Type of ARF Mortality ARF in the ICU associated with respiratory failure and the requirement of dialysis >90% ARF in the ICU 72% ARF in hospitalized patients, not in the ICU 32% ARF following i.v. contrast 34% (compared to 7% in controls) Adjusted odds ratio of death: 5.5 ARF following cardiac surgery 64% (compared to 4.3% in controls) Adjusted odds ratio of death: 7.9 ARF following administration of amphotericin B Adjusted odds ratio of death: 6.6

• Evaluation of the patient with ARF. A stepwise evaluation approach to the patient with ARF is recommended. A comprehensive history and thorough physical examination suggest the diagnosis in the majority of patients.

  Whether the patient is seen for the first time in the office, emergency room, hospital, or ICU, careful tabulation and recording of data are the first steps in determining the diagnosis. Vital signs, daily weights, records of intake and output, past and current laboratory data, and the fluid and medication list should be recorded on a flow sheet and included in the patient's chart. When the patient has been hospitalized for several days or weeks with a complicated course before developing ARF, a carefully prepared flow sheet may often be the only way to comprehend the problem and guide the selection of proper therapy.

  Urinalysis by dipstick and the evaluation of urine sediment by microscopy should always be performed in patients with ARF. Urine chemistries that may be helpful in the diagnosis of ARF include sodium, creatinine, osmolality, and protein content.

  Clinical features of the common causes of ARF are described in the following sections.

  • Prerenal ARF. Prerenal ARF may occur in patients who are clinically hypovolemic (total intravascular volume depletion) or hypervolemic (arterial underfilling).

    • History. The following history is suggestive of prerenal ARF from true volume depletion or hypovolemia: thirst, decreased fluid intake, fever, nausea, vomiting, diarrhea, burns, peritonitis, and pancreatitis. Prerenal ARF from arterial underfilling occurs most commonly in patients with congestive heart failure (CHF) or liver disease. Features of the history that are suggestive of CHF include: recent myocardial infarction, orthopnea, paroxysmal nocturnal dyspnea, or dyspnea on exertion. Features suggesting liver disease and cirrhosis include a history of alcohol abuse or hepatitis. A complete documentation of medications (prescribed and over-the-counter) is important in the evaluation of prerenal ARF. Medications that affect intrarenal hemodynamics include cyclosporine, tacrolimus, NSAIDs, Cox-2 inhibitors, ACE inhibitors, and ARBs.

    • Physical examination. Assessment of volume status and the adequacy of the extracellular fluid volume (ECF) are critical to the diagnosis of prerenal ARF.

      • Physical findings that suggest a reduction in intravascular volume include:

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        • Absence of axillary sweat

        • A recent reduction in body weight

        • Orthostatic hypotension. Defined as a fall in systolic blood pressure of more than 20 mm Hg or a rise in pulse rate of more than 10 beats per minute after standing

        • Tachycardia

        • Dry mucus membranes

        • Tenting of upper thorax skin when pinched between the fingers

        • Jugular venous pressure not visible

      • Physical examination findings generally found in arterial underfilling states with an excess of ECF include:

        • Elevated jugular venous pressure

        • Ascites

        • Lower extremity pitting edema

        • Anasarca

        • CHF in particular may be identified by:

          • Pulmonary crackles

          • S3 gallop

        • Liver failure may be identified by:

          • Jaundice

          • Decreased liver size

          • Palmar erythema

          • Spider angiomas

    • Urinary findings. Regardless of the cause of prerenal ARF (hypovolemic, arterial underfilling, or medication-induced) the urine dipstick, sediment, and chemistries will be the same. (See Table 10-4 for a comparison of urinary findings in various types of ARF.)

      Table 10-4. Urinary Findings in Various Causes of ARF

      Dipstick Prerenala Post renalb Small vessel vascular Nephrotic glomerular Nephrotic glomerular AIN ATNc Leukocyte esterase ( ) ( ) ( ) ( ) ( ) (+;) ( ) Heme ( ) ( ) (+;) ( ) or trace (+;) (+;) ( ) Protein ( ) ( ) (+;) (+;) (+;) (+;) ( ) or trace Specific gravity >1.020 1.010 variable variable variable 1.010 1.010 Microscopy   RBCs ( ) ( ) (+;) ( ) or few (+;) (+;) ( )   WBCs ( ) ( ) ( ) ( ) ( ) (+;) ( )   RBC casts ( ) ( ) (+;) ( ) (+;) ( ) ( )   WBC casts ( ) ( ) ( ) ( ) ( ) (+;) ( )   Granular casts ( ) ( ) ( ) ( ) ( ) ( ) (+;)   Renal tubular epithelial cells ( ) ( ) ( ) ( ) ( ) ( ) (+;) Tests   Osmolality (mOsm/L) >500 350 variable variable variable 350 350   Protein (g/day) ( ) ( ) 1 2 >3 1 2 1 2 1 aAlthough classically associated with a bland urinary sediment, a few granular casts may occasionally be present. bIf a superimposed infection is present due to urine stasis, the leukocyte esterase, heme, protein, RBCs, and WBCs may be positive. cIf ATN is secondary to rhabdomyolysis, heme will be positive on dipstick and RBCs will be absent on microscopy.

      • The urine dipstick should be normal with negative protein, heme, leukocyte esterase, and nitrate. The specific gravity is increased (greater than 1.020).

      • The urine sediment is bland (no cells or casts).

      • Urine chemistry and indices. Frequently it is difficult to distinguish between prerenal ARF and other forms of renal disease, particularly ATN. Laboratory tests and indices characteristic of prerenal ARF versus other causes of ARF are summarized in Table 10-5. A discussion of the pathophysiologic basis of these tests is in section IV-G.3.

        Table 10-5. Urinary Diagnostic Indices

        Index Prerenal ARF Acute tubular necrosis Urine sodium (UNa), mEq/L <20 >40 Urine osmolality, mOsm/kg H2O >500 <350 Urine creatinine (UCr) to plasma creatinine (PCr) >40 <20 Serum BUN/serum creatinine >20 10 Fractional excretion of sodium (FENa): FENa = [(Una/Pna)/(Ucr/Pcr)] 100 <1 >1 Fractional excretion of urea (FeUN): FeUn = [(Uun/Pun)/(Ucr/Pcr)] 100 <35 >50 UNa, urine sodium (mEq/L); PNa, plasma sodium (mEq/L); Ucr, urine creatinine (mg/dL); Pcr, plasma creatinine (mg/dL); Uun, urine urea (mg/dL); Pun, BUN (mg/dL).

    • Specific disorders of prerenal ARF

      • Hepatorenal syndrome (HRS) occurs in patients with severe liver failure. It is characterized by peripheral vasodilatation (low systemic vascular resistance) accompanied by intense renal vasoconstriction that causes renal insufficiency. Two forms of HRS are recognized. Type 1 HRS is the more severe form and is characterized by an abrupt (within 2 weeks) decline of renal function, defined as a doubling of serum creatinine to greater than 2.5 or a 50% reduction in creatinine clearance to less than 20 mL per minute. Without liver transplantation, the mortality of this condition is greater than 90% at 3 months. Type II HRS is characterized by slowly progressing renal insufficiency in a patient with refractory ascites; it has a much better prognosis. Patients with type II HRS may convert to type I in the setting of certain insults such as the development of infections (e.g., spontaneous bacterial peritonitis) or the use of NSAIDs. HRS is typical of other forms of prerenal azotemia, and the kidney functions normally if transplanted into a person with a normal liver. The only permanent cure for HRS is liver transplantation.

        As agreed upon by the International Ascites Club, the diagnostic criteria for HRS are divided into major and additional criteria. To diagnose HRS, each of the major criteria must be present. The additional criteria provide supporting evidence for the diagnosis, but are not required to make the diagnosis.

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        • Major criteria

          • Severe liver failure (acute or chronic)

          • Serum creatinine greater than 1.5 mg per dL or 24 hour creatinine clearance less than 40 mL per minute

          • Absence of another cause of renal failure (e.g., proteinuria less than 500 mg per dL; no obstruction on renal ultrasound)

          • Absence of ongoing infection or fluid loss

          • Absence of a sustained improvement in renal function following diuretic withdrawal and administration of 1.5 liters of isotonic saline

        • Additional criteria

          • Oliguria

          • Urine sodium less than 10 mEq per L

          • Urine osmolality greater than plasma osmolality

          • Urine RBCs less than 50 per high powered field

          • Serum sodium less than 130 mEq per L

      • Vasomotor ARF due to NSAIDs. A history of NSAID use in all patients with ARF should be aggressively sought. Under euvolemic conditions with normal kidney, liver, and cardiac function, the administration of NSAIDs does not cause an increase in serum creatinine. In the presence of clinical conditions with increased renal vasoconstrictor activity (e.g., CHF, cirrhosis, nephrotic syndrome, hypertension, sepsis, volume depletion, anesthesia), NSAIDs can cause ARF. Patients with chronic renal insufficiency (e.g., diabetic nephropathy) are also at risk of acute vasomotor decline in renal function with NSAIDs. Typical clinical features include the presence of risk factors, decreased urinary output, bland urine sediment, low (less than 1%) fractional excretion of sodium, and prompt improvement in renal function after discontinuation of NSAIDs. NSAIDs may also cause AIN and ATN.

      • Cyclosporine and tacrolimus may cause a dose-dependent, hemodynamically mediated ARF in solid-organ and bone marrow transplant patients. A large increase in renal vascular resistance occurs. The loss of renal function is reversible when the dosage of the drug is reduced. The urine sediment is bland, and ATN is not typically present.

      • ACE inhibitors and ARBs are widely used for the treatment of hypertension, CHF, and diabetic nephropathy. ARF may occur in conditions where angiotensin plays a crucial protective role in maintaining GFR by constricting the glomerular efferent arteriole, such as volume depletion, bilateral renal artery stenosis, autosomal dominant polycystic kidney disease, cardiac failure, cirrhosis, and diabetic nephropathy. Diuretic-induced sodium depletion and underlying chronic renal

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        insufficiency are other major predisposing factors. ARF is usually asymptomatic, nonoliguric, and associated with hyperkalemia. ARF is reversible in most cases after discontinuation of the ACE inhibitor or ARB. ARF can usually be managed in the outpatient setting by discontinuation of the ACE inhibitor and discontinuation of diuretics if present. An increase in BUN and serum creatinine in a patient on an ACE inhibitor or ARB should raise the possibility of renal artery stenosis.

  • Postrenal ARF

    • History. Symptoms that suggest urinary tract obstruction are anuria or intermittent anuria and polyuria, prostatic symptoms (urinary frequency and urgency, dysuria, straining upon urination), pelvic malignancy on previous radiotherapy, and recurrent renal stones. Patients may complain of pain over a distended bladder; severe pain (renal colic) may be present if obstruction is due to renal calculi. Patients with diabetes mellitus, sickle cell anemia, and analgesic nephropathy are predisposed to papillary necrosis that causes obstruction.

    • Physical examination. The physical examination is important in diagnosing postrenal ARF, especially in the unconscious patient or in the confused patient in whom otherwise unexplained agitation may be the only clue to acute urinary retention. Careful abdominal examination may uncover a distended, tender bladder or bilaterally hydronephrotic kidneys. A digital examination of the prostate should be performed routinely in any male patient with ARF, and pelvic masses should be sought in female patients through a bimanual pelvic examination. In any patient in whom lower tract obstruction is suspected as the cause of acute ARF, a sterile in-and-out diagnostic postvoid bladder catheterization should be performed as a routine part of the physical examination. The postvoid residual urine volume should be less than 50 mL. The urine volume should be recorded and the specimen saved for studies.

    • Urine findings. The typical urinalysis and sediment finding in postrenal ARF compared to other causes of ARF is presented in Table 10-4.

      • Urinalysis. The urine dipstick should be normal with negative protein, heme, leukocyte esterase, and nitrate. The specific gravity is typically isosmotic (1.010). Heme test for red blood cells (RBCs) may be positive if obstruction is due to renal calculi. A secondary infection may be present due to urine stasis; in this setting the dipstick may be positive for leukocyte esterase, nitrate, heme, and trace protein.

      • Urine sediment is typically bland without cells or casts. As noted, hematuria may be present if obstruction is due to renal calculi. Prostatitis and some cases of benign prostatic hypertrophy may also be associated with hematuria. In the setting of a secondary urinary tract infection (UTI), the sediment may contain white blood cells, red blood cells, and/or bacteria.

    • Radiologic tests. Renal ultrasound is sufficient to diagnose urinary obstruction in the majority of patients. Because of the risk of i.v. contrast dye, intravenous pyelogram (IVP) should be avoided.

      • Renal ultrasound is the radiologic test of choice to evaluate for obstruction, characterized by dilatation of the urinary tract (hydronephrosis). The absence of hydronephrosis virtually excludes important urinary tract obstruction; hydronephrosis may be absent, however, in the following settings: (a) early obstruction (before the urinary tract has been able to dilate); and (b) obstruction due to the encasement of the urinary system by retroperitoneal fibrosis or tumor.

        Hydronephrosis that is not functionally significant may occur in pregnancy and in people with anatomic variants of the collecting system. If the functional importance of hydronephrosis is in doubt, a

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        furosemide isotope renogram can evaluate the functional significance of the obstruction.

      • Isotope renography is performed by the intravenous injection of a radionucleotide and furosemide. Furosemide increases urinary flow and normally causes a rapid washout of the radionucleotide. Persistence of the isotope in the renal parenchyma suggests obstruction. Poor renal function limits the usefulness of this test because the diuretic response may be blunted, thus making interpretation of the test difficult.

      • Noncontrast computed tomography (CT) of the kidneys, ureters, and abdomen is often done following renal ultrasound to identify the cause and location of urinary obstruction.

      • Cystoscopy and retrograde pyelography. In instances of ARF with a high clinical suspicion of urinary tract obstruction (e.g., calculi, pyogenic debris, blood clots, bladder cancer), cystoscopy and retrograde or anterograde pyelography should be performed, even if ultrasonography is negative for obstruction.

  • Intrinsic renal disease large vessel disease

    • History. Renal artery thrombosis or embolism, or bilateral renal vein thrombosis may present with flank pain. Predisposing disorders such as membranous nephropathy or antiphospholipid antibody syndrome may be present.

    • Urine findings.

      • Urinalysis. The urine dipstick is positive for heme.

      • Urine sediment. Red blood cells.

    • Labs and radiology. An elevated serum LDH may be present. Doppler ultrasound may be used to assess renal blood flow and to evaluate for renal vein thrombosis. CT is useful for detecting clots in the renal vein or inferior vena cava. Angiography may be required in emergent cases (e.g., acute anuria due to acute renal embolization).

  • Intrinsic renal disease small vessel disease. Intrinsic renal disease due to small vessel disease is caused by either atheroembolic disease or thrombotic microangiopathy. The clinical and laboratory features of these disorders are as follows:

    • Atheroembolic disease is caused by the detachment of atheromatous plaques from the intimal surface of large vessels. These plaques travel distally and occlude small arteries or large arterioles of the kidney. Showers of cholesterol crystals or microemboli from the surface of ulcerated plaques may also occur, traveling distally to occlude small arterioles throughout the body (e.g., kidney, gut, or skin). The presentation and clinical findings of atheroembolic disease can be confused with those of polyarteritis nodosa, allergic vasculitis, subacute bacterial endocarditis, or left atrial myxoma.

      The usual course is progressive renal insufficiency. However, milder forms of renal failure with some recovery of function have been described. No treatment is known. Prevention of the disease involves avoiding unnecessary invasive procedures (e.g., renal arteriogram in patients with clinical evidence of widespread atherosclerosis).

      • History. A history of ARF occurring after cardiovascular surgery, angiography, or administration of i.v. thrombolytics should raise a suspicion of atheroembolic disease as the cause of ARF, particularly in a patient with known atherosclerosis. Occasionally, the disease occurs spontaneously.

      • Physical examination. Skin manifestations of cholesterol emboli include discrete peripheral necrotic areas, blue-toe syndrome, and livido reticularis. Small cholesterol emboli to the gut and pancreas may cause abdominal pain.

      • Laboratory investigation may reveal an increased erythrocyte sedimentation rate, eosinophilia, and hypocomplementemia (C3 is

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        reduced while C4 remains normal). Biopsy of the skin, muscle, or kidney reveals intravascular cholesterol crystals.

      • Urinary evaluation

        • Urinalysis. Dipstick is frequently negative although heme and protein or both may be positive. Specific gravity is variable.

        • Urine sediment. Sediment is often bland, although red blood cells, granular casts, red blood cell casts, or all may be present.

        • Urine tests. Proteinuria is typically less than 1 g in 24 hours.

    • Thrombotic microangiopathies are characterized by a microangiopathic hemolytic anemia, thrombocytopenia, and variable renal and neurologic manifestations. These disorders begin with endothelial injury followed by secondary platelet thrombi formation in renal arterioles; renal cortical necrosis may result from the arterial lesions. The primary site of injury is the glomerulus or the vascular supply of the glomerulus; the proximal tubule and interstitium are relatively uninvolved.

      • History and physical examination. HUS-TTP should be suspected in patients with anemia, ARF, thrombocytopenia, and neurologic signs such as confusion and seizures. Malignant hypertension causing a thrombotic microangiopathy is characterized by high blood pressure associated with papilledema and/or retinal hemorrhages; other organ involvement may manifest as chest pain, shortness of breath from pulmonary edema, and confusion from brain involvement. Scleroderma renal crisis should be considered in patients with scleroderma and an abrupt rise in serum creatinine associated with hypertension.

      • Laboratory findings. Peripheral blood smear demonstrates increased red blood cell fragmentation (schistocytes) and thrombocytopenia. Indices of hemolysis (e.g., LDH) are elevated.

      • Urine findings

        • On dipstick. Variable specific gravity; heme positive, protein positive, or both.

        • Urine sediment is characterized by granular casts, red blood cell casts, or both.

  • Intrinsic renal disease glomerular disease from a nephrotic cause. Nephrotic glomerular disorders are characterized by a urine protein excretion of greater than 3 g in 24 hours. Nephrotic glomerular disorders are uncommonly associated with ARF, but it may occur in patients with minimal-change disease (especially in the elderly) and FSGS (especially from collapsing FSGS).

    • History and physical examination. Clinical symptoms and signs characteristic of a nephrotic disorder include pitting peripheral edema, hypertension, periorbital edema, and anasarca.

    • Laboratory findings. Typically hypoalbuminemia and hypercholesterolemia are present.

    • Urine findings. In cases of minimal-change-induced ARF, urine dipstick and sediment may also include features of ATN.

      • Dipstick is strongly positive for protein. Heme is negative or trace.

      • Urine sediment is typically bland; possibly with few RBCs. Oval fat bodies reflecting lipiduria may be present.

      • Urine tests show proteinuria greater than 3 g in 24 hours.

  • Intrinsic renal disease glomerular disease from a nephritic cause. Nephritic glomerular disorders (glomerulonephritis) frequently cause ARF. Nephritic glomerular disorders are characterized by hematuria and proteinuria (typically 1 to 2 g in 24 hours). RPGN should be suspected in a patient with glomerulonephritis who has a doubling of serum creatinine within a 3-month period.

    • History and physical examination. Clinical symptoms and signs that suggest that the glomerulonephritis is part of a systemic disease include palpable purpura, skin rash, arthralgias, arthritis, fever, cardiac

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      murmurs, sinusitis, hemoptysis, abdominal pain, and acute neuropathy. Hemoptysis is an ominous symptom in an ARF patient and may indicate a life-threatening vasculitis, such as Goodpasture's syndrome or Wegener's granulomatosis.

    • Urine findings. Glomerulonephritis is characterized by hematuria and proteinuria. The identification of RBC casts confirms the presence of glomerular disease.

    • Laboratory findings. Antineutrophil cytoplasmic antibodies (ANCA) are helpful in determining the cause of glomerulonephritis. ANCA staining by immunofluorescence is either cytoplasmic (c-ANCA) or perinuclear (p-ANCA). Although c-ANCA and p-ANCA are sensitive screening tests, numerous conditions other than vasculitis and glomerulonephritis may result in c-ANCA or p-ANCA positivity. Therefore, all positive results must be confirmed with enzyme-linked immunosorbent assay (ELISA) tests for the more specific antigen targets proteinase 3 (PR3) and myeloperoxidase (MPO). The PR3-ANCA antibody is typically responsible for c-ANCA staining and the MPO-ANCA antibody is typically responsible for the p-ANCA staining.

      Of patients with active Wegener's disease, 90% are ANCA-positive (the majority are PR3-ANCA positive). Of patients with microscopic polyangiitis, 70% are ANCA positive (the majority are MPO-ANCA positive). Of patients with Churg-Strauss syndrome, 50% are ANCA positive (PR3- and MPO-ANCA detected with about equal frequency). More than 90% of patients with renal limited, idiopathic pauci-immune vasculitis are ANCA-positive (the majority are MPO-ANCA positive).

    • Anti-GBM antibodies are useful for the diagnosis of Goodpasture's disease, although the false negative rate may be as high as 40%.

    • Evaluation of serum complement (C3 and C4) may be helpful in the evaluation of patients with ARF and glomerulonephritis. Hypocomplementemia is common in postinfectious glomerulonephritis, lupus nephritis, membranoproliferative glomerulonephritis, and mixed cryoglobulinemia. Another cause of ARF associated with hypocomplementemia includes atherembolic renal disease. It is important to recognize that other, nonrenal conditions may lower serum complement levels (e.g., sepsis, acute pancreatitis, and advanced liver disease).

  • Intrinsic renal disease AIN. Intrinsic renal disease due to interstitial nephritis may be secondary to medications, infections, or a systemic illness such as lupus. Drug-induced AIN may be divided into three categories: AIN from methicillin; AIN from a medication other than methicillin; and NSAID-induced AIN. The clinical presentation and findings of these three major forms of drug-induced AIN are described in Table 10-6. Renal failure typically persists for a mean of 1.5 months; however, complete recovery of renal function occurs in the majority of patients.

    Table 10-6. Three Types of Drug-Induced Interstitial Nephritis
    Drug group Age Duration of therapy Fever Rash Hematuria and pyuria Eosinophilia Nephrotic syndrome Methicillin Any age 2 weeks 80% 25% 90% 80% No Non-methicillin Any age 3 weeks <50% <50% 50% <50% No NSAIDs >50 years Months 10% 10% <50% 20% 70%

    • History. In NSAID-induced AIN, symptoms and findings do not occur until several months after initiation of drug therapy (average 6 months); fenoprofen is the culprit in half of cases. AIN from other medications typically occurs within a few weeks of drug therapy. Patients may complain of fever, rash, or flank pain.

    • Physical examination. Physical findings with acute drug-induced interstitial nephritis may be lacking, although fever and a maculopapular or

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      petechial skin eruption may occur with any of the agents, particularly the penicillin derivatives and allopurinol.

    • Laboratory findings. Eosinophilia is common in methicillin-induced AIN, but is present in less than 50% of cases of AIN from NSAIDs and other drugs.

    • Urine findings. When AIN is caused by methicillin and other drugs, red and white blood cells are present in the majority of cases; also present are WBC casts, the urine is typically isotonic, and 20% of cases are oliguric. In NSAID-induced AIN, nephrotic-range proteinuria is present in 80% of cases (greater than 3 g in 24 hours); WBCs, RBCs, and eosinophils are present in less than 50% of cases.

      The evaluation for urinary eosinophils should be performed with Hansel's secretion stain (methylene blue and eosin Y in methanol), which is superior to Wright's stain, because urinary eosinophils are readily identified by their brilliant red-pink granules. Hansel's stain is not influenced by urinary pH. In a recent review of four series of drug-induced AIN, the positive predictive value for eosinophils in the urine was only 50%; however, the negative predictive value was 90%.

  • Intrinsic renal disease ATN. ATN typically occurs in hospitalized patients as a consequence of ischemia or nephrotoxins.

    • History. The evaluation of a patient with suspected ATN must focus on identifying a predisposing cause. The chart should be reviewed for a history of hypotensive episodes, fluid losses, aminoglycoside use, NSAID administration, or radiologic procedures associated with contrast administration.

    • Physical examination. Signs of sepsis or ongoing infection should be evaluated. Volume status should be determined (see IV.2a).

    • Laboratory findings and urinalysis. Distinguishing ATN from prerenal ARF is often very difficult; this is an important clinical problem because the vast majority of ARF in hospitalized patients is due to either ATN or prerenal ARF. In addition, prolonged prerenal ARF often predisposes to the development of ATN. Because the causative factors for prerenal ARF and ATN overlap, distinguishing between the two may become possible only by the outcome of therapy (e.g., if volume repletion reverses the ARF, then prerenal ARF was present).

      In general, a urine sediment with muddy brown granular casts is characteristic of ATN. However, this finding may be lacking, and other clinical clues will be necessary to make the diagnosis. To distinguish between the two, numerous diagnostic indices and formulae have been developed based on their pathophysiologic differences.

      Prerenal ARF is a hemodynamic condition in which tubular function is normal, whereas ATN is characterized by tubular dysfunction. This distinction is the basis for the following tests (Table 10-5):

      • Urine specific gravity

      • Urine osmolality

      • Urine creatinine/plasma creatinine

      • Urine sodium concentration

      • Fractional excretion of sodium (FENa)

      • Serum BUN to creatinine ratio

        Prerenal ARF is characterized by the increased reabsorption of water and sodium by the nephron. The increased reabsorption of water increases urine specific gravity and osmolality. Tubular reabsorption of urea increases, thus increasing the serum BUN to creatinine ratio; creatinine, however, is not reabsorbed, and its concentration increases in the urine and increases the urine to plasma creatinine ratio. Sodium reabsorption increases, resulting in a low urine sodium concentration and fractional excretion of sodium (FENa). In ATN, these processes cannot occur. Therefore, urine specific gravity and osmolality are isotonic, the urine creatinine to plasma creatinine ratio does not increase above a

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        20:1 ratio, the serum BUN to creatinine ratio does not increase, and urine sodium and FENa are higher than in prerenal ARF. FENa is not always increased in ATN; the causes of ATN that are associated with a low urine sodium concentration and low FENa include radiocontrast nephropathy, rhabdomyolysis, and ATN superimposed on a prerenal state (e.g., sepsis, burns, hepatic failure, heart failure).

        The use of loop diuretics in ARF is a confounding factor in the use of FENa to distinguish prerenal ARF and ATN. Distal acting diuretics (e.g., furosemide) increase urinary sodium excretion and increase FENa even if the patient is prerenal. A recent study evaluated the use of the fractional excretion of urea (FEUN) to distinguish prerenal ARF in the setting of diuretic use from ATN (both of which are typically associated with a FENa of greater than 2%). The basis of this test is that urea absorption increases in the proximal tubule in prerenal ARF and would not be affected by the use of diuretics, which act on the distal tubule. In the setting of loop diuretic use, FEUN was an excellent test to distinguish between these conditions. In prerenal ARF, the FEUN is less than 35% and in ATN it is greater than 50%. The use of FEUN in cases of ATN associated with a low FENa could not be assessed in this study because of the lack of patients with this condition. Keep in mind that FEUN cannot be used in the setting of osmotic diuretic use (e.g., mannitol), because as these agents affect proximal tubular absorption.

    • Specific causes of ATN

      • Aminoglycoside nephrotoxicity. ARF occurs in up to 20% of patients on aminoglycosides, even with careful dosing and therapeutic plasma levels. The incidence of nephrotoxicity correlates better with total cumulative dose than with plasma levels. Predisposing factors are old age, preexisting renal disease, volume depletion, and combination with other agents (e.g., diuretics, cephalosporins, vancomycin). Nephrotoxicity is usually clinically apparent after 5 to 10 days of therapy; early findings are isosthenuria caused by nephrogenic diabetes insipidus, and magnesium and potassium wasting. Later findings include azotemia, which may not develop for the first time until after the drug has been discontinued; conversely, recovery of renal function after discontinuation of the nephrotoxic aminoglycoside is often delayed and may require weeks to months to be complete. ARF from aminoglycosides is typically nonoliguric.

        Table 10-7 shows a comparison of the clinical characteristics of aminoglycoside and radiocontrast nephropathy.

        Table 10-7. A Comparison Between Aminoglycoside Nephrotoxicity and Contrast Nephropathy

        Pathophysiology Risk factors Onset of renal failure Urine output Prevention Aminoglycoside Direct tubular toxin Older age 5 to 10 days Nonoliguric Avoidance     Volume depletion     Correct drug dosing     Diuretics           Cephalosporins           Vancomycin           Older age           Diabetes     Nonionic, iso-osmotic contrast Contrast Vasoconstriction Multiple myeloma 1 to 2 days Nonoliguric NAC     ACE-inhibitors     Isotonic saline     NSAIDs

      • Radiographic contrast nephropathy. Radiocontrast agents cause ARF through a direct nephrotoxic effect and by causing renal vasoconstriction. Risk factors include old age, high contrast dose, preexisting renal disease, (especially diabetes mellitus), volume depletion, and recent exposure to other agents, such as ACE inhibitors and NSAIDs. Renal failure develops 1 to 2 days after exposure and is typically nonoliguric and associated with a high urine specific gravity, bland urine sediment, and low FENa. Serum creatinine typically peaks at 3 to 4 days and returns to baseline after about a week.

        • Prevention. Nonionic contrast agents are less nephrotoxic and should be used in high risk patients, especially patients with preexisting renal dysfunction. Drugs that affect renal hemodynamics (NSAIDs, ACE inhibitors, etc.) and diuretics should be discontinued prior to the procedure if possible.

          Although numerous agents have been studied to prevent contrast nephropathy, the only therapy that has been proven to be clearly beneficial is hydration with saline before and after the contrast load.

          N-acetylcysteine (NAC) may be beneficial in the prevention of contrast nephropathy, and its administration prior to contrast is

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          reasonable (600 mg b.i.d. the day prior and the day of the procedure). In a frequently cited prospective trial, NAC-treated patients had a significantly lower serum creatinine 48 hours after contrast administration. The benefit of NAC in the prevention of contrast nephropathy remains uncertain. However, while some studies have confirmed the benefit of NAC in the prevention of contrast nephropathy, others have not. In addition, new evidence suggests that NAC may interfere with the measurement of creatinine resulting in a lowering of serum creatinine without a true change in renal function. This new evidence may call into question the results of NAC studies which used serum creatinine as a primary endpoint.

          The clinical significance of contrast nephropathy should not be underestimated. It has been demonstrated that the development of a 0.5 mg/dL increase in serum creatinine after contrast is associated with an adjusted odds ratio of death of 5.5 (see Table 9-3, mortality associated with ARF).

          Agents tested and demonstrated to be ineffective in the prevention of contrast nephropathy include furosemide, mannitol, theophylline, dopamine, fenoldopam, and atrial naturatic peptide.

      • Rhabdomyolysis is caused by muscle injury (traumatic or atraumatic) that leads to the systemic release of muscle contents including myoglobin. Myoglobin is a heme pigment that is directly nephrotoxic; the intratubular precipitation of myoglobin causes obstruction and also contributes to the development of renal failure. Rhabdomyolysis should be considered in patients with trauma, muscle pain, and dark brown urine. However, rhabdomyolysis is frequently atraumatic, and up to 50% of patients have no muscular complaints. Table 10-8 lists predisposing factors for rhabdomyolysis.

        Table 10-8. Causes of Rhabdomyolysis

        Direct muscle damage (e.g., crush injuries, polymyositis, prolonged immobilization associated with unconsciousness) Muscle ischemia (e.g., arterial occlusion or embolism) Excess energy consumption (e.g., seizures, hyperthermia, delirium tremens) Decreased energy production (e.g., severe hypophosphatemia, hypokalemia, myxedema, genetic defect) Drugs and toxins (e.g., alcohol, heroin, cocaine, amphetamines, poisonous insect and snake bites) Severe infections (e.g., tetanus, Legionnaire's disease, influenza)

        The characteristic urine finding is a heme positive urine with absence of red blood cells. Pigmented granular casts are typically present on urine sediment. Laboratory clues to the diagnosis include a rapid rise of serum creatinine, massively increased creatine phosphokinase, hyperphosphatemia, hyperuricemia, hypocalcemia, increased anion gap, and disproportionate hyperkalemia. Serum calcium is reduced due to the sequestration of calcium into injured muscle; this calcium is released from the tissue during the recovery phase and may cause hypercalcemia. Therefore, replacement of serum calcium should be avoided unless symptoms of hypocalcemia are present.

        The only proven therapy in the treatment of rhabdomyolysis is early and vigorous infusion of intravenous isotonic saline. In crush injury, it is recommended that i.v. saline be administered even before extrication. Mannitol administration and urinary alkalinazation are often attempted in the treatment of rhabdomyolysis, although their efficacy has not been demonstrated to be superior to vigorous

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        hydration with saline alone. Theoretically, forced diuresis with mannitol may aid in the washout of obstructing myoglobin pigment. Mannitol administration may be attempted only after the correction of volume deficits; saline and mannitol should be administered together with a goal urine output of 300 cc per hour. Urinary alkalinization may inhibit myoglobin precipitation; however, urinary alkalinizaion is difficult to achieve in practice and requires the administration of a large quantity of bicarbonate. Bicarbonate administration in rhabdomyolysis carries the risk of worsening hypocalcemia due to increased calcium and phosphorus precipitation into injured muscle.

      • Acute uric acid nephropathy causes ARF due to the intratubular deposition of uric acid crystals. A very high serum uric acid concentration is present (e.g., greater than or equal to 15 mg per dL. The condition typically occurs during induction chemotherapy for malignancies with high cell turnover (e.g., leukemias and lymphoproliferative malignancies). Acute uric acid nephropathy and ARF occur in the tumor lysis syndrome, but may occur spontaneously in patients with high tumor burden. Clinical features of acute uric acid nephropathy are hyperuricemia, hyperkalemia, hyperphosphatemia, and a urine urate to creatinine ratio higher than 1. Preventive measures include allopurinol administration and vigorous hydration and forced diuresis with mannitol. Alkalinization of the urine has been traditionally recommended, but has not been proven more beneficial than saline administration alone; additionally bicarbonate therapy carries the risk of increased calcium precipitation.

• ARF in special clinical circumstances

  • Crystal-associated ARF. A number of important causes of ARF may be due to the formation of urinary crystals. Table 10-9 lists the causes of ARF associated with crystal formation.

    Table 10-9. Urinary Crystals Associated with ARF

    Type of ARF Crystal Shape/appearance ATN from ethylene glycol Calcium oxalate monohydrate or Calcium oxalate dihydrate Needle-shaped Envelope-shaped ATN from uric acid nephropathy Uric acid Diamond-shaped, yellow or brown ARF from sulfadiazine (intratubular obstruction) Sulfadiazine Needle-shaped or shocks of wheat ARF from acyclovir (intratubular obstruction) Acyclovir Needle-shaped, birefringent ARF from indinavir (intratubular obstruction) Indinavir sulfate Needle-shaped, occasionally forming rosettes

  • ARF in patients with acquired immunodeficiency syndrome (AIDS) (Table 10-10). The approach to the causes of ARF in AIDS patients is the same as that for other patients (i.e., classification into prerenal, intrinsic renal, and postrenal causes). ARF may develop in up to 20% of hospitalized patients with AIDS and is in most cases multifactorial. ATN is seen in AIDS because the patients are often acutely ill with multiple infections or malignancies. Their clinical course is often complicated by hypovolemia, multiorgan failure, compromised cardiovascular status, invasive diagnostic procedures complicated by bleeding, and the administration of multiple nephrotoxic drugs and radiocontrast agents. Although ATN is a major cause of morbidity and mortality in AIDS patients, it is also potentially reversible

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    and treatable. All supportive measures, including dialysis, should be used as warranted by the clinical situation. Importantly, ATN is avoidable in some cases when preventative measures are used (e.g., maintaining adequate hydration before use of radiocontrast agents and during use of antibiotics and antiretroviral therapy that precipitates crystalluria).

    Table 10-10. Acute Renal Failure in Acquired Immunodeficiency Syndrome (AIDS) Patients

    Prerenal   Hypovolemia (diarrhea)   Hypotension (sepsis, bleeding)   Decreased effective arterial blood volume (hypoalbuminemia, cachexia, HIV nephropathy)   Vasoconstriction (radiocontrast agents) Postrenal   Tubular obstruction due to crystalluria (intravenous acyclovir, sulfadiazine, indinavir, saquinavir, ritonavir)   Extrinsic ureteral compression (lymph nodes, tumors)   Intrinsic ureteral obstruction (fungus balls)   Bladder obstruction (tumors, fungus balls) Renal   Hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura   Postinfectious glomerulonephritis   Collapsing focal segmental glomerularsclerosis   Acute allergic interstitial nephritis (penicillins, sulfonamides)   Plasmacytic interstitial nephritis   Acute tubular necrosis (shock, sepsis, aminoglycosides, amphotericin)   Rhabdomyolysis (pentamidine, zidovudine)

  • ARF in bone marrow transplant patients. ARF is a common complication of bone marrow transplant. [This procedure is now referred to as hematopoetic cell transplant (HCT), because other cells, such as stem cells, are transplanted as well as bone marrow.] Approximately 90% of patients have a doubling of serum creatinine after allogeneic HCT. This incidence is higher in patients who receive allogeneic as opposed to autologous transplantation. ARF also occurs in nonmyeloablative HCT, also known as mini-allo transplants. The incidence of ARF is high in HCT because of the life-threatening nature of the underlying diseases and the toxicity of the cancer drugs, immunosuppressive regimens, and antibiotics. Patients with ARF after HCT who require dialysis have a greater than 90% incidence of mortality.

    Factors that predispose to ATN are vomiting and diarrhea due to radiochemotherapy or acute graft-versus-host disease; nephrotoxic drugs such as aminoglycosides and amphotericin B; and hemorrhagic and septic shock. Hepatic veno-occlusive disease, which is more common in allogeneic than autologous bone marrow transplants, is a syndrome that may resemble the hepatorenal syndrome. A sodium retention state occurs and leads to weight gain, edema, and a low FENa of less than 1%, despite the use of diuretics. Progressive hyperbilirubinemia and nonoliguric ARF occur.

    By far, the most common time for development of ARF is 7 to 21 days after the transplant. The renal syndromes unique to bone marrow transplant patients are classified according to the time of presentation:

    • Immediate (first few days)

      • Tumor lysis syndrome

      • Stored marrow toxicity

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    • Early (7 to 21 days)

      • Hepatic veno-occlusive disease

      • Sepsis

      • ATN

      • Cyclosporin or FK506 toxicity

    • Late (6 weeks to 1 year)

      • Bone marrow transplant associated hemolytic-uremic syndrome

      • Chronic cyclosporine nephrotoxicity

  • ARF in the setting of liver disease. In addition to hepatorenal syndrome, ARF in patients with liver disease may also occur in other clinical settings. Jaundice and ARF may be due to HUS, leptospirosis, mismatched blood transfusion, or falciparum malaria. Simultaneous ARF and acute liver failure suggests acetaminophen overdose, bacteremia, or carbon tetrachloride exposure. Glomerulonephritis and liver cirrhosis is associated with cryoglobulinemia, IgA nephropathy, membranous glomerulonephritis (associated with hepatitis B), and membranoproliferative glomerulonephritis (associated with hepatitis C).

  • Indications for renal biopsy. Renal biopsy is not performed in patients with prerenal ARF or the typical features of ATN. However, important indications for a renal biopsy in a patient with ARF exist.

    • ARF of unknown etiology. In most cases, a stepwise approach reveals a cause of the ARF. However, in some patients with ARF, the diagnosis is not clear.

    • Suspicion of glomerulonephritis, systemic disease (e.g., vasculitis), or AIN as the cause of ARF. A renal biopsy in such circumstances may provide the basis and justification for aggressive and life-saving therapy (e.g., high-dose steroids, cytotoxic agents, plasmapheresis, cessation of causative agent for AIN).

    • ATN not recovering after 4 to 6 weeks of dialysis with no more recurrent insults. A renal biopsy may determine that a less favorable condition, such as diffuse cortical necrosis, has developed and that chronic hemodialysis may need to be instituted.

• Management

  • Prerenal azotemia

    • True volume depletion or hypovolemia. Therapy in this setting is directed toward correcting volume deficits. If volume depletion is due to hemorrhage, then the administration of packed red blood cells is indicated; otherwise, the administration of 0.9% normal saline (NS) is appropriate. When 1 L of 0.9 NS is given, approximately 250 mL remain in the plasma compartment, while 750 mL enter the interstitial compartment.

      The amount of intravenous fluid (IVF) and the rapidity of administration depend on the clinical situation. In a young, stable patient, IVF should be given in one-time boluses (e.g., 500 to 1,000 cc over 1 hour); 0.9NS should never be written as a continuous infusion. Smaller boluses (e.g., 250 cc over 1 hour) may be prudent in elderly patients in whom cardiac status is unknown. After a bolus, the patient should be evaluated clinically for signs of hypovolemia or volume overload. Bedside evaluation includes monitoring of orthostatic changes in blood pressure and pulse and jugular venous pulsation (JVP). JVP is a gross indicator of pressure in the central venous area of the right heart. In a normovolemic patient, jugular venous pulsations are visible when the patient is supine but disappear when the patient assumes the sitting position. Jugular venous pulsations are not visible in the volume-depleted patient; thus, their reappearance following fluid administration suggests that the central venous pressure (CVP) has returned to normal. The presence of basilar crackles or a third heart sound implies too-vigorous fluid replacement, with resultant cardiopulmonary congestion. Intravenous boluses of fluid should continue until euvolemia is achieved. Electrolyte deficits (e.g., potassium) should be monitored and replaced if necessary.

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      In patients in whom vigorous resuscitation efforts are required, and cardiovascular tolerance to sudden fluid challenges is in doubt, some form of indwelling monitoring system is desirable. Hemodynamic monitoring may be achieved through the use of a central venous catheter or Swan-Ganz catheter.

      • Central venous catheter. When rapid fluid administration is required, and severe heart or lung disease (or both) is absent, a catheter positioned in the central venous area of the right heart is a satisfactory guide to the speed of fluid administration. The CVP normally ranges between 2 and 12 cm of water. In volume-depleted states, values of zero or below can be expected. Before vigorous volume repletion is begun, a fluid challenge of 200 to 300 mL of normal saline should be attempted over a 10- to 20-minute period. In an otherwise uncomplicated volume-depleted patient, this amount of saline has little effect on the CVP reading. A CVP rise of more than 5 cm of water suggests cardiac failure, and the infusion should be immediately discontinued.

      • Swan-Ganz catheter. When a volume deficit must be repaired in the presence of tricuspid stenosis, acute or chronic pulmonary disease, or an unstable cardiovascular system, the CVP does not give a reliable index of left ventricular performance. In this situation, a balloon-tipped Swan-Ganz catheter can be wedged in a pulmonary artery. This gives a measurement of pulmonary artery wedge pressure (PAWP), an indirect measurement of left ventricular end-diastolic pressure. The PAWP is a good guide to the adequacy and speed of fluid replacement. Because of the complications of infection, pulmonary infarction, and hemopneumothorax, this device should be inserted and placed only by trained professionals and should be removed as early as possible. In patients with liver encephalopathy and ARF, a clinical judgment of fluid balance may be difficult because of massive edema and ascites. The measurement of PAWP gives critical information about fluid balance: ARF in the presence of a low PAWP may respond to fluid administration.

    • Arterial underfilling with an ECF excess. Prerenal ARF in this setting is usually a secondary problem overshadowed by primary cardiac or liver disease. The management goal, therefore, is to treat the underlying cause; if the primary disease cannot be treated, then conservative management of symptoms is desirable.

      • Heart failure. Numerous medications may be employed to improve cardiac output in patients with cardiac disease. In the outpatient setting of a patient with congestive heart failure (CHF), diuretic agents in combination with digitalis therapy may increase the cardiac output and improve renal perfusion, and thus lessen the azotemia. Cardiac unloading agents such as ACE inhibitors, ARBs, nitrates, and hydralazine may also improve cardiac function. However, with advanced heart failure that is refractory or only partially responsive to these agents, the physician may be forced to accept mild to moderate prerenal azotemia as a tradeoff. Such azotemia rarely leads to symptomatic uremia.

        In hospitalized patients with CHF who are diuretic resistant, fluid may be removed with continuous venovenous hemofiltration or intermittent ultrafiltration, without dialysis.

      • Liver disease. Prerenal ARF associated with advanced hepatic cirrhosis and patients with type II HRS are often refractory to attempts to improve intravascular volume. Ordinarily, however, the management goal is to reduce symptoms and treat ascites and edema with a sodium-restricted diet (1 to 2 g of salt per day), an aldosterone antagonist (e.g., spironolactone 200 to 400 mg per day), and a loop diuretic (e.g., furosemide) while the usually mild prerenal state is ignored. Diuretic-resistant patients may be treated with intermittent

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        large volume paracentesis, transjugular intrahepatic portosystemic stent shunt (TIPS), or liver transplantation. Treatment of hospitalized patients with type I HRS may include vasopressin analogs or somatostatin in an attempt to improve renal blood flow. These therapies have yet to be proven to impact mortality, which is greater than 90% in type I HRS. In reports from Europe, the ADH analogs ornipressin and terlipressin, with albumin infusion, have shown some promise in the treatment of HRS; however, these agents may have significant ischemic side effects. It remains to be determined if the benefits of these agents will outweigh the risk of use (neither medication is currently available in the United States). TIPS may be an option for some patients; improved mortality was demonstrated in one study; however, further studies must confirm this benefit. To date, liver transplant is the only definitive cure.

  • Postrenal failure. Foley catheter drainage is usually successful for acute obstruction secondary to prostatic hypertrophy. The decision regarding further therapy must be made in consultation with a urologist. Medical therapy with finesteride or an alpha blocker, or surgical removal of the prostate may be recommended.

    With ureteral obstruction, cystoscopy and the placement of ureteral drainage catheters or stents may allow passage of obstructing stones, sludge, or pus, but if this fails, operative intervention is required.

  • Primary renal disease: vasculitis and glomerulonephritis. When renal failure develops in the course of a systemic or vascular disorder, it is usually a grave sign. A comprehensive discussion of the treatment of these systemic and vascular disorders is beyond the scope of this chapter. Obtaining a renal biopsy early after presentation is essential to make the diagnosis and to guide appropriate therapy. Theraputic options include immunosuppressive therapy with steroids and/or cyclophosphamide. A subset of patients may benefit from plasmapheresis (e.g., Goodpasture's syndrome).

  • Acute interstitial nephritis. When a therapeutic agent is identified as the cause of acute interstitial nephritis, removal of the agent is the obvious first step in therapy. Bacterial infectious etiologies should be treated with the appropriate antibiotics. When renal impairment is minor, nothing more need be done. If renal impairment has been present for weeks, or if renal involvement is severe, high-dose, short-term prednisone therapy (60 mg per day for 3 to 4 weeks) may speed recovery of renal function. Before initiating prednisone therapy, it is important to confirm the diagnosis with a renal biopsy.

  • Intrinsic renal disease, ATN. No specific therapy exists for the treatment of ARF due to ATN, although this is a widely investigated area of interest.

    • What to avoid in ATN

      • High-dose diuretics. No data support the use of high-dose diuretic therapy in established ATN. Furosemide and other loop diuretics are frequently used in oliguric ARF in an effort to convert it to nonoliguric ARF. Although the conversion of oliguric to nonoliguric renal failure may simplify fluid management, clinical trials have failed to demonstrate that the use of diuretics is associated with improved outcome in patients with ARF.

      • Renal-dose dopamine. Dopamine is a selective renal vasodilatator. It elicits profound natriuresis and increases urine output. The renal selective dose is 1 to 3 mcg per kg per minute. No evidence suggests that renal-dose dopamine is beneficial in ARF. In fact, several studies have identified deleterious effects, such as, bowel ischemia and arrhythmias. Unless dopamine is required for circulatory support, it should not be used for ARF.

      • Nephrotoxic drugs. Potentially nephrotoxic drugs and agents should be avoided in ARF, because they may perpetuate the renal injury. These agents and drugs include NSAIDs, ACE inhibitors,

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        cyclosporine, tacrolimus, aminoglycosides, radiocontrast agents, and amphotericin B.

      • Volume overload. The amount of IVF necessary for critically ill patients is unknown, and IVFs must be given judiciously in the setting of ATN, especially if the patient is oliguric. In general, IVFs should not contain potassium.

    • Supportive therapy in ATN

      • Drug dosages. Drug dosages should be adjusted based on the measured or best estimate of creatinine clearance, not merely on the serum creatinine. Certain medication doses also must be adjusted if the ARF patient is receiving dialysis (intermittent hemodialysis or continuous renal replacement therapy).

      • Nutritional support. ARF is a hypercatabolic state associated with increased protein breakdown. Nitrogen balance is extremely negative, especially in ARF associated with sepsis, post-surgery, and multiorgan dysfunction syndrome. Renal factors contributing to the negative nitrogen balance include uremia, acidosis, parathyroid hormone abnormalities, inadequate protein intake, and protein losses. In critically ill patients, supplemental nutritional support with enteral versus parenteral nutrition is associated with improved nutritional status, a reduction in infections and sepsis, and better survival. Thus, enteral feeding is the preferred method of nutritional support, although it is not always possible. The use of parenteral nutrition remains controversial, and randomized controlled clinical trials have yet to demonstrate a benefit in acutely ill patients with ARF. Opinion papers have suggested that protein intake not exceed 1.5 g of protein per kg of body weight, that early nutritional supplementation may not be beneficial, and that supplementation after 2 to 3 weeks of not eating is likely to be beneficial.

      • Dialysis therapy. In general, the indications to start dialysis in ATN and ARF are not specific and should be individualized by nephrology consultation. Although not yet proven in clinical trials, a trend in clinical practice is to initiate dialysis early to avoid the potential consequences of uremia. Uremia that results in altered mental status or pericarditis is an absolute indication for dialysis.

        The common factors that are taken into consideration when making the decision to start dialysis are listed here. It should be kept in mind that these are guidelines, not absolute indications for the initiation of dialysis. The initiation of dialysis depends on the entire clinical picture, not just the presence or absence of one of these factors.

        • Persistent oliguria (less than 400 mL per day)

        • Serum creatinine higher than 6 mg per dL

        • BUN greater than 100 mg per dL

        • Pulmonary edema unresponsive to diuretics

        • Hyperkalemia (serum potassium greater than 6.5 mEq per dL)

        • Symptomatic uremia (e.g., encephalopathy, pericarditis)

        • Severe metabolic acidosis

          The main modalities of dialysis are intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT).

          • IHD is the same form of dialysis used in patients with end stage renal disease (ESRD). IHD is typically used in otherwise stable patients who can tolerate rapid fluid removal (e.g., 1 L per hour). IHD is mandatory in ambulatory patients.

            In this form of dialysis, the patient is connected to a dialysis machine for 4 hours at a time, daily or every second day. Fluid removal and urea clearance for the day is achieved during the period of a few hours. Rapid removal of solutes and fluids may cause hemodynamic instability. The technique requires a double-lumen catheter, tubing, a hemodialysis machine (blood pump, dialysate generation

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            system, dialysate pump, and alarms and safety monitoring de vices), a dialysis membrane, and a dialysis nurse. Daily treatment for 4 hours, with a blood urea clearance of 200 mL per minute, can achieve a weekly urea clearance of 350 L.

            The frequency of IHD and delivered dose of dialysis required in ARF is a matter of debate. In chronic end stage renal patients, IHD is typically performed on alternate days (three days per week) for approximately 4 hours at a time. The dose and frequency of dialysis for ARF may need to be much higher than in the chronic setting, because ARF patients are typically hypercatabolic and most temporary catheters have a high recirculation rate. A number of recent studies demonstrate that more urea clearance achieved by daily hemodialysis (HD) or continuous venovenous hemofiltration (CVVH), with increased ultrafiltration associated with a lower mortality rate. Thus, the available evidence seems to suggest that simple, alternate-day HD may be inadequate for a subset of patients with ARF, particularly those who are severely catabolic.

          • CRRT. Currently, four main types of CRRT are used: slow continuous ultrafiltration (SCUF), CVVH, continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration. Table 10-11 summarizes the different characteristic of each. The type of CRRT is individualized. A common approach is to start with CVVH and then add dialysate (CVVHDF), if clearance rates are too low. A recent, prospective randomized study demonstrated improved mortality in patients on CVVH who had an ultrafiltrate formation of 45 mL per kg per hour or 35 mL per kg per hour, compared with 20 mL per kg per hour. In a 70-kg man, this corresponds to 3,150 mL per hour 2,450 mL per hour, and 1,400 mL per hour respectively. Achieving ultrafiltrate formation rates greater than 2 liters per hour can be technically difficult.

            Table 10-11. Comparison of Intermittent Hemodialysis (IHD) and Various Types of Continuous Renal Replacement Therapy (CRRT).

            Type of renal replacement Amount of ultrafiltrate formed/houra Use of replacement fluidb Use of dialysate Urea clearance (L/day) Intermittent hemodialysis (IHD) 500 to 1,000 cc No Yes 40 60 Slow continuous ultrafiltration (SCUF) 50 to 100 cc No No 2 5 Continuous venovenous hemofiltration (CVVH) 1,000 to 2,000 cc Yes No 20 50 Continuous venovenous hemodialysis (CVVHD) 50 to 100 cc No Yes 20 55 Continuous venovenous hemodiafiltration (CVVHDF) 1,000 to 2,000 cc Yes Yes 25 75 aThe ultrafiltrate formed has the same electrolyte composition as plasma; therefore, with high ultrafiltrate formation, increased losses of potassium, phosphorous, calcium, and magnesium may occur. These electrolytes may need to be replaced intravenously. bReplacement fluid typically contains sodium, chloride, and calcium and replaces fluid lost in the ultrafiltrate and other sources (GI, etc.) to achieve the desired hourly net fluid loss. In IHD, net fluid loss is typically 500 to 1,000 cc per hour whereas in CRRT, net fluid loss is typically 50 to 100 cc per hour.

            In CRRT, the goal is for the patient to undergo continuous dialysis for 24 hours a day. In practice, interruptions in dialysis

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            for patient procedures, radiologic testing, and dialysis membrane clotting are frequent and reduce the amount of time the patient is actually receiving dialysis. CRRT is the mandatory form of dialysis for hemodynamically unstable patients. Because the removal of solutes and fluid is slow and continuous, hemodynamic instability and hypotensive episodes are reduced. Minimization of hypotension theoretically avoids the perpetuation of renal injury. CRRT requires a double-lumen catheter (the same catheter that is used for IHD), tubing, a simple blood pump with safety devices, sterile replacement fluid, volumetric pumps to control replacement and ultrafiltration rate, continuous anticoagulation, and a high-flux dialysis membrane. ICU nurses typically monitor therapy.

          • Intermittent versus continuous dialysis. Many nonrandomized studies have compared IHD and CRRT. Prospective randomized studies are difficult to carry out, because hemodynamically unstable patients who cannot tolerate IHD are almost always started on CRRT. Alternatively, confining a mobile patient to bed to receive CRRT may be unethical. Thus, randomization may be biased. CRRT is believed to be the modality of choice in very ill patients, and IHD is used in less ill patients. At present, IHD and CRRT are regarded as equivalent methods for the treatment of ARF. The choice of IHD or CRRT should be made in consultation with a nephrologist and tailored for the individual patient. The decision may also depend on facility-specific issues, such as experience, nursing resources, and technical proficiency. The cost of CRRT is greater than IHD. At present, indications for CRRT in ARF include hemodynamic instability, cerebral edema, hypercatabolism, and severe fluid overload. Table 10-12 lists a comparison of IHD and CRRT. CRRT is similar in solute clearance to a GFR of 15 to 20 mL per minute. A day of CRRT is roughly equivalent to one HD treatment. Thus, drug-dosing adjustments must be made in CRRT.

            Table 10-12. Analysis of Continuous Renal Replacement Therapy Versus Intermittent Hemodialysis

            Advantages    Hemodynamic stability (may relate in part to decreased body temperature)    Unlimited alimentation    Avoidance of rapid fluid and electrolyte shifts    Aggressive correction of acid-base status    Massive fluid removal    Potential elimination of mediators (e.g., cytokines) by membrane absorbance Disadvantages    Immobilization    Lactate loada    Continuous anticoagulationb aLactate should be avoided in patients with severe liver disease who cannot metabolize lactate. The lactate load may be avoided by making a custom dialysate that contains bicarbonate instead. bCRRT may be performed without anticoagulation; however, frequent clotting of the membrane may occur.

          • Type of dialysis membrane. Some studies have demonstrated that the dialysis of ARF patients with biocompatible membranes is associated with improved mortality; therefore, biocompatible membranes are used for dialysis in ARF. Biocompatible membranes are made of synthetic polymers and include polyamides, polycarbonate, and polysulfone. The adverse effects of bioincompatible

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            cellulosic membranes (e.g., cellulose, cuprophane, hemophane, cellulose acetate) include activation of complement, increased production of cytokines, and hypotension.

          • Temporary vascular access. The primary vascular sites used for insertion of temporary dialysis catheters are the internal jugular and femoral. The internal jugular access is required in patients who are mobile. Femoral access is indicated when the cardiopulmonary condition of the patient limits attempts at thoracic catheterization; it is useful in bedridden patients. The subclavian vein may be used if other access sites are unavailable; however, use of subclavian catheters entails a major risk of stenosis or thrombosis of the subclavian vein or its branches.

          • Peritoneal dialysis is uncommonly used as a mode of dialysis therapy in ARF in developed countries despite the fact that it is not technically difficult and can be used with minimally trained staff. It may be an option in locations where IHD or CRRT is not available. It is indicated in patients with minimally increased catabolism without an immediate or life-threatening indication for dialysis. It is ideal for hemodynamically unstable patients. For short-term dialysis, a rigid dialysis catheter is inserted into the peritoneum, through the anterior abdominal wall, 5 to 10 cm below the umbilicus. Exchanges of 1.5 to 2.0 L of standard peritoneal dialysis solutions are infused into the peritoneum. The major risks are bowel perforation during insertion of the catheter and peritonitis. Acute peritoneal dialysis offers the same potential advantages to the pediatric patient that CRRT offers to the adult with ARF.

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