MKSAP - Nephrology and hypertension

AMERICAN COLLEGE OF PHYSICIANS

Nephrology and Hypertension Phillip M. Hall, Book Editor Virginia U. Collier, Associate Editor Contributors Richard A. Fatica Paul L. Kimmel Joseph V. Nally, Jr. Sharon G. Adler Michael E. Falkenhain

Paul E. Epstein, EDITOR IN CHIEF

Nephrology and Hypertension

AMERICAN COLLEGE OF PHYSICIANS

MKSAP 13 Nephrology and Hypertension Contributors

Consulting Authors 1

Phillip M. Hall, MD, Book Editor Director, Renal Function Laboratory Department of Nephrology and Hypertension The Cleveland Clinic Foundation Cleveland, Ohio Virginia U. Collier, MD, FACP, Associate Editor 1 Vice Chair and Residency Program Director Department of Medicine Christiana Care Health System Newark, Delaware Richard A. Fatica, MD 1 Associate Staff Department of Nephrology and Hypertension The Cleveland Clinic Foundation Cleveland, Ohio Paul L. Kimmel, MD, FACP 2 Professor of Medicine Division of Renal Diseases and Hypertension Department of Medicine George Washington University Medical Center Washington, DC Joseph V. Nally Jr., MD 2 Fellowship Director of Nephrology and Hypertension Department of Nephrology and Hypertension The Cleveland Clinic Foundation Cleveland, Ohio

Sharon G. Adler, MD, FACP 2 Professor of Medicine The Geffen School of Medicine at UCLA Associate Chief Division of Nephrology and Hypertension Harbor – UCLA Medical Center Torrance, California Michael E. Falkenhain, MD 1 Associate Professor of Medicine – Clinical The Ohio State University Medical Center Columbus, Ohio

Editor in Chief Paul E. Epstein, MD, FACP 1 Clinical Professor of Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania __________________________________________________________________ 1 Has no significant relationship with relevant commercial companies/ organizations. 2 Has disclosed significant financial relationship(s) with relevant organizations. 3 Has refused to disclose any significant financial relationship with relevant commercial companies/organizations.

Disclosure of Significant Relationships with Relevant Commercial Companies and Organizations Sharon G. Adler, MD, FACP Stock Options/Holdings Pfizer, Amgen Research Grants/Contracts Alexion Pharmaceuticals Paul L. Kimmel, MD, FACP Stock Options/Holdings GlaxoSmithKline Research Grants/Contracts Ortho Biotech Joseph V. Nally, Jr., MD Speakers Bureau Novartis, Merck

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Introduction Dear Colleagues: As authors of this book, we have made every attempt to include the latest information regarding new concepts of disease pathophysiology and information from treatment trials, while at the same time providing brief reviews of basic information in each section. In the hypertension section, we have emphasized current recommendations for management of hypertension, including supporting data from recent large clinical trials. New recommendations for staging patients with chronic kidney disease by renal function and levels of proteinuria are included in the renal function and chronic kidney disease sections. A concise review of the clinical features, diagnosis, and current management of glomerular and tubulointerstitial disorders is followed by a brief update regarding the growing knowledge of genetic disorders of the kidney. This section also includes information regarding a National Institutes of Health (NIH) Web site for you to get the latest genetic renal diseases information. A clinician’s guide to evaluation and treatment of common electrolyte and acid-base disorders follows. In the acute renal failure section, the results of therapy trials to prevent contrast-induced acute renal failure are included. Extensive clinical trial information regarding treatments to retard the progression of kidney disease makes up an important part of the chronic kidney disease section. You can read about the role of dietary calcium in the prevention of kidney stones in the nephrolithiasis section. The management and diagnosis of hypertension and renal failure in the peripartum woman constitutes the last section of this book.

Phillip M. Hall, MD, Book Editor

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Table of Contents

Hypertension Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Initial Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Initial Management . . . . . . . . . . . . . . . . . . . . . . . . . 3 Lifestyle Modifications . . . . . . . . . . . . . . . . . . . . 3 Initiation of Pharmacologic Therapy . . . . . . . . . . 3 Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Secondary Hypertension . . . . . . . . . . . . . . . . . . . . . . 5 Renovascular Hypertension . . . . . . . . . . . . . . . . 6 Indications for Therapy . . . . . . . . . . . . . . . . . . . . . . . 8 Diabetes Mellitus with Proteinuria . . . . . . . . . . . 9 Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 After Myocardial Infarction . . . . . . . . . . . . . . . 10

Acute Glomerulonephritis . . . . . . . . . . . . . . . . . . . . 26 IgA Nephropathy (Berger’s Disease) . . . . . . . . . 26 Poststreptococcal Glomerulonephritis and Other Bacterial Infections . . . . . . . . . . . . . . . . 27 Lupus Nephritis . . . . . . . . . . . . . . . . . . . . . . . . 28 Rapidly Progressive Glomerulonephritis . . . . . . 29 Goodpasture’s Syndrome . . . . . . . . . . . . . . . . . 30 Wegener’s Granulomatosis . . . . . . . . . . . . . . . . 31

Tubulointerstitial Diseases Causes and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 32 Nephrosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Myeloma Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Analgesic Nephropathy . . . . . . . . . . . . . . . . . . . . . . 33

Clinical Assessment of Kidney Function Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . 10 Glomerular Filtration Rate . . . . . . . . . . . . . . . . 10 Serum Creatinine and Creatinine Clearance . . . . 11 Urinalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Proteinuria . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Hematuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Leukocytes and Other Formed Elements . . . . . . 15 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Ultrasonography . . . . . . . . . . . . . . . . . . . . . . . 15 Computed Tomography . . . . . . . . . . . . . . . . . . 16 Magnetic Resonance Imaging . . . . . . . . . . . . . . 16 Radionuclide Scanning . . . . . . . . . . . . . . . . . . . 16 Kidney Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Genetic Disorders and Renal Disease Genetic Disorders That Cause Direct Renal Effects . . . 34 Genetic Disorders That Cause Systemic Abnormalities Affecting The Kidney . . . . . . . . . . . . 36 Genetic Factors in Diabetic Nephropathy . . . . . . . . 36

Fluid and Electrolytes Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Hypernatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Potassium Metabolism . . . . . . . . . . . . . . . . . . . . . . 41 Hypokalemia . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Hyperkalemia . . . . . . . . . . . . . . . . . . . . . . . . . 42 Hypophosphatemia . . . . . . . . . . . . . . . . . . . . . . . . 43 Hypomagnesemia . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Glomerular Diseases Glomerular Anatomy and Its Relation to Glomerular Disease . . . . . . . . . . . . . . . . . . . . . . 17 Clinical Syndromes of Glomerular Disease . . . . . . . . 19 The Nephrotic Syndrome . . . . . . . . . . . . . . . . . 19 Minimal Change Disease . . . . . . . . . . . . . . . . . 21 Focal and Segmental Glomerulosclerosis . . . . . . 21 Membranous Nephropathy . . . . . . . . . . . . . . . 22 Membranoproliferative Glomerulonephritis . . . . 23 Secondary Causes of Glomerular Diseases . . . . . . . . 24 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 HIV-Associated Nephropathy . . . . . . . . . . . . . . 25 Diabetic Nephropathy . . . . . . . . . . . . . . . . . . . 25

Acid–Base Disorders Approach to Acid–Base Problem Solving . . . . . . . . . 45 Delta–Delta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Metabolic Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . 47 Non–Anion Gap Metabolic Acidosis . . . . . . . . . 47 Anion Gap Metabolic Acidosis . . . . . . . . . . . . . 49 Lactic Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . 49 Ketoacidosis . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Metabolic Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . 50 Respiratory Acidosis . . . . . . . . . . . . . . . . . . . . . . . . 53 Respiratory Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . 53 Mixed Acid–Base Disorders . . . . . . . . . . . . . . . . . . . 53

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Acute Renal Failure

Nephrolithiasis

Prerenal Azotemia . . . . . . . . . . . . . . . . . . . . . . . . . 54 Postrenal Azotemia (Urinary Tract Obstruction) . . . 57 Intrinsic Acute Renal Failure . . . . . . . . . . . . . . . . . . 57 Nephrotoxicity . . . . . . . . . . . . . . . . . . . . . . . . 60 Drug-Induced Nephrotoxicity . . . . . . . . . . . . . 61 HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . 62 Acute Renal Failure in Patients with Cancer . . . . . . . 63 Other Causes of Acute Renal Failure . . . . . . . . . . . . 64

Calcium Stone Disease . . . . . . . . . . . . . . . . . . . . . . 75 Struvite (Infection) Stone Disease . . . . . . . . . . . . . . 76 Uric Acid Stone Disease . . . . . . . . . . . . . . . . . . . . . 76 Cystine Stone Disease . . . . . . . . . . . . . . . . . . . . . . . 76 Work-up and Management of Nephrolithiasis . . . . . 77

Chronic Kidney Disease Management Issues . . . . . . . . . . . . . . . . . . . . . . . . 68 Progression of Kidney Disease . . . . . . . . . . . . . 68 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . 68 Dietary Protein . . . . . . . . . . . . . . . . . . . . . . . . 69 Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Hyperparathyroidism and Renal Osteodystrophy . . . . . . . . . . . . . . . . . . . . . . . . 70 Medical Management of the Uremic State . . . . . . . . 70 Treatment of End-Stage Renal Disease . . . . . . . . . . 72 Dialysis versus Renal Transplantation . . . . . . . . 72 Dialysis Techniques . . . . . . . . . . . . . . . . . . . . . 72 Medical Problems in Patients Undergoing Dialysis . . . . . . . . . . . . . . . . . . . . 73 Kidney Transplantation . . . . . . . . . . . . . . . . . . 73

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Renal Function and Disease in Pregnancy Normal Renal Function . . . . . . . . . . . . . . . . . . . . . 77 Hypertension during Pregnancy . . . . . . . . . . . . . . . 78 Chronic Hypertension . . . . . . . . . . . . . . . . . . . 78 Gestational Hypertension . . . . . . . . . . . . . . . . . 79 Preeclampsia and Eclampsia . . . . . . . . . . . . . . . 80 Chronic Renal Insufficiency in Pregnant Patients . . . 81 Acute Renal Failure in Pregnant Patients . . . . . . . . . 82

Self-Assessment Test . . . . . . . . . . . . . . . . . . . . . 83 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

Nephrology and Hypertension

Hypertension An estimated 50 million Americans—about 20% of adults and 60% of persons older than 65 years of age—have hypertension. The risk of cardiovascular complications escalates in a continuous, graded, and predictable manner with increases in systemic blood pressure. Systolic blood pressure (and pulse pressure in patients older than 50 years of age) correlates better with cardiovascular risk than does diastolic blood pressure.

Definition Table 1 shows the definition of hypertension by the Sixth Joint National Committee (JNC-VI) on Detection, Prevention and Evaluation of High Blood Pressure. Of note, the report introduces a new stratification of normal blood pressure (<140/90 mm Hg) that includes the categories “optimal,” “normal,” and “high normal” (The Sixth Report of the Joint National Committee). In a recent analysis of Framingham Study patients, a twofold to threefold increase in risk for coronary heart disease events was documented in patients with high normal blood pressure compared with those with optimal blood pressure (Vasan et al.). For this reason, the stages of hypertension as traditionally defined were modified in JNC-VI to include three stages based on systolic blood pressure or diastolic blood pressure. This emphasizes that the important objective of identifying and treating hypertensive patients is not only to control blood pressure but also to reduce cardiovascular morbidity and mortality.

The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413-46. PMID: 9385294 Vasan RS, Larson MG, Leip EP, Evans JC, O’Donnell CJ, Kannel WB, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345:1291-1.PMID: 11794147

TA B L E 1 Classification of Blood Pressure in Adults 18 Years of Age or Older

Category

Systolic (mm Hg)

Diastolic (mm Hg)

Follow-up

Optimal Normal High normal Hypertension Stage 1 Stage 2

<120 <130 130–139

and and or

<80 <85 85–89

Recheck in 2 years Recheck in 1 year

140–159 160–179

or or

90–99 100–109

Confirm in 2 months Check in 1 month

≥180

or

≥110

Immediate follow-up

Stage 3

Adapted from: The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413-46.

The recognition, treatment, and control of hypertension have improved in the past 25 years. Age-adjusted death rates from stroke and coronary heart disease have decreased by 60% and 53%, respectively. However, the recent JNCVI report offers several sobering notes of caution. The JNC-VI proposed a more intensive effort to identify and stage hypertension on the basis of blood pressure, cardiovascular risk, and clinical target organ damage (Table 2). Emphasis is directed toward more intensive therapy for patients with higher risk, since greater benefit is expected. For example, a 1

Initial Evaluation

KEYPOINTS

• Only 53% of hypertensive patients are receiving treatment, and only 27% have adequately controlled disease. • Of patients taking active therapy, only 45% maintain a blood pressure less than 140/90 mm Hg. • Since 1993, age-adjusted rates of stroke have increased slightly and the rate of decrease in coronary heart disease appears to be leveling off. • The incidence of end-stage renal disease, for which hypertension is the second most common cause, has increased. Hypertension also contributes to the progression of renal disease in diabetic nephropathy and other glomerular diseases. • The prevalence of congestive heart failure, a condition in which most patients have had antecedent hypertension, has increased among elderly persons in the United States.

TA B L E 2 Components of Cardiovascular Risk Stratification

in Patients with Hypertension Major Risk Factors

Target Organ Damage/Clinical Cardiovascular Disease

Smoking

Heart disease

Dyslipidemia Diabetes mellitus Age older than 60 years Sex (men and postmenopausal women) Family history of cardiovascular disease

Left ventricular hypertrophy Angina/prior myocardial infarction Prior coronary revascularization Heart failure Stroke or transient ischemic attack

Women < age 65 years Men < age 55 years

Nephropathy Peripheral arterial disease Retinopathy

Adapted from: The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413-46.

recent study reexamined the effect of antihypertensive therapy on mortality rates on the basis of the presence or absence of target organ damage at the time of initiation of therapy in patients with stage 1 hypertension. Although the relative risk reduction was similar in both groups (22%), the absolute benefit of lives saved per 100 patients treated was greater among those with target organ damage.

Initial Evaluation Initial evaluation of patients with hypertension should establish the etiology and severity of the hypertension, document target organ damage, and identify other cardiovascular risk factors. Case 1 A 53-year-old black man presents for “high blood pressure.” He had a series of elevated blood pressure readings averaging 150/95 mm Hg at his local community center over 2 months. The medical history is significant for an 8-year history of type 2 diabetes mellitus without retinopathy or nephropathy. He has no history of cardiovascular or renal disease. He is a former smoker, and he does not use alcohol or recreational drugs. His family history is positive for hypertension and stroke. He takes glyburide, 5 mg/d. Examination reveals blood pressure 148/92 mm Hg while seated and standing. His body weight is 70 kg (154 lb). A detailed physical examination is normal. Laboratory studies show hemoglobin A1C,8%; blood urea nitrogen, 18 mg/dL; serum creatinine, 1.0 mg/dL; plasma glucose, 119 mg/dL; serum sodium, 138 meq/L; serum potassium, 4 meq/L; serum chloride, 100 meq/L; serum bicarbonate, 25 meq/L; serum total cholesterol, 189 mg/dL; serum low-density cholesterol, 164 mg/dL; serum high-density lipoprotein cholesterol, 38 mg/dL; serum triglycerides, 180 mg/dL. Levels of thyroid-stimulating hormone are normal, as are results of urinalysis and electrocardiography. Microalbuminuria is documented by a urine albumin-to-creatinine ratio of 118 mg/g. The clinical presentation, positive family history of hypertension, results of urinalysis, electrolyte levels, and renal function suggest that primary hypertension 2

Initial Management

is the likely diagnosis. There is little evidence for an overt secondary cause of hypertension. However, the presence of microalbuminuria suggests incipient type 2 diabetic nephropathy. The patient in case 1 has stage 1 hypertension in the setting of diabetes with microalbuminuria and no overt target organ damage. The JNC-VI equates the presence of diabetes with the presence of other target organ damage. In contrast to previous reports, the JNC-VI recommends both lifestyle modifications and drug therapy for diabetic patients. Current recommendations also suggest a similar approach to diabetic patients with high normal blood pressure given their increased cardiovascular risk. Microalbuminuria in a patient with type 2 diabetes is an indication for therapy with angiotensin receptor blockers (Parving et al.).

Initial Management Management of hypertension is designed to decrease blood pressure and reduce cardiovascular risk.

Lifestyle Modifications The most beneficial lifestyle modifications for decreasing blood pressure are weight loss, reduction of alcohol intake, a low-sodium diet, and exercise. Weight reduction in a patient whose weight is 10% above ideal body weight will lower blood pressure by an average of 5 to 7 mm Hg. Alcohol intake should be limited to two drinks daily. Reduction of dietary sodium intake has a modest effect on blood pressure, although some patients (such as African American patients and elderly persons) may respond dramatically to a low-salt diet. Recent results of the Dietary Approaches to Stop Hypertension (DASH) trial demonstrate that the DASH diet (one in which intake of total and saturated fat is reduced and fruits, vegetables, and low-fat dairy foods is increased) in conjunction with reduced sodium intake decreased blood pressure by 7/4 mm Hg in patients older than 45 years of age (Vollmer et al.). A low-salt diet may also potentiate the effect of some antihypertensive medications (especially diuretics and angiotensin-converting enzyme inhibitors). Regular aerobic physical activity increases weight loss, reduces cardiovascular risk factors, and modestly decreases blood pressure. Potassium supplements and relaxation therapies have inconsistent effects on blood pressure. Results from randomized trials have failed to establish convincing evidence that calcium, magnesium, fish oil, or garlic supplements are beneficial.

KEYPOINTS

• The Sixth Joint National Committee on Detection, Prevention and Evaluation of High Blood Pressure (JNC-VI) introduced a new stratification of blood pressures to include optimal (<120/80 mm Hg), normal (<130/85 mm Hg), and high normal (>130–139/85–89 mm Hg). • During the initial evaluation, the physician should identify and stage hypertensive patients on the basis of blood pressure measurement, cardiovascular risk factors (especially diabetes mellitus), and clinical target organ damage. Parving HH, Lehnert H, BrochnerMortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-8. PMID: 11565519

Vollmer WM, Sacks FM, Ard J, Appel LJ, Bray GA, Simons-Morton DG, et al. Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASHsodium trial. Ann Intern Med. 2001;135:1019-28. PMID: 11747380

Initiation of Pharmacologic Therapy Effective antihypertensive therapy reduces the likelihood of stroke, coronary events, heart failure, and all-cause mortality; slows progression of renal disease; and prevents progression to more severe hypertension. Several factors should be considered in selecting an initial agent; these include efficacy, side effects, convenience, cost, and the patient’s comorbid conditions and response to therapy. The current evidence supports the recommendation of the JNC-VI that β-blockers and diuretics are the preferred initial agents for patients with primary hypertension but no target organ damage or other complications. Randomized controlled trials have demonstrated the efficacy (and perhaps lower cost) in reducing cardiovascular complications in such patients. Thiazide diuretics may be effective in doses as low as 12.5 to 25 mg/d for hydrochlorothiazide. At these low dosages, the metabolic effects (such as hyperglycemia, hyperuricemia, or hypokalemia) are negligible, and maximal 3

Initial Management

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-97. PMID: 12479763 Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;285:2719–28. PMID: 11386927 Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-9. PMID: 11565518 Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-60. PMID: 11565517 Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-75. PMID: 11759645 Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003. PMID: 11937178 Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645–52. PMID: 9486993 Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:175562. PMID: 963594 Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators. N Engl J Med. 1999;340:677-84. PMID: 10053176

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antihypertensive effects can be achieved. Results of ALLHAT also showed that thiazide diuretics (chlorthalidone) are equivalent to amlodipine and lisinopril in reducing acute myocardial infarction and death from coronary disease (The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). β-Blockers are well tolerated by many older patients and do not affect cognition or mental status. β-Blockers should be avoided in diabetic patients who require insulin and those with asthma, heart block, or depression. The JNC-VI recommended angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium antagonists, α-blockers, and α-β–blockers as alternative initial monotherapy when a diuretic or β-blocker (or their combination) is contraindicated or poorly tolerated, as well as in special clinical situations. Angiotensin-converting enzyme inhibitors are especially indicated to treat hypertension in patients with diabetes mellitus, renal disease, or congestive heart failure (see below). Furthermore, the recent African American Study of Kidney Disease and Hypertension demonstrated a renoprotective effective of angiotensin-converting enzyme inhibitors in African-American patients with proteinuria and renal insufficiency (Agodoa et al.). Angiotensin-converting enzyme inhibitors may induce angioedema, hyperkalemia, and renal failure, and patients taking them should be closely monitored when therapy is first given. Angiotensin receptor blockers are a new class of agents that pharmacologically block the angiotensin effect at the receptor level. Like angiotensinconverting enzyme inhibitors, angiotensin receptor blockers may preserve renal function and can reduce proteinuria. Three recent trials demonstrated that angiotensin receptor blockers slow the development of incipient nephropathy or progression of overt nephropathy in patients with type 2 diabetes. Angiotensin receptor blockers may also provide benefit in treating patients with congestive heart failure (see below) (Brenner et al.; Lewis et al.; Cohn and Tognoni) In the recent LIFE trial, patients with primary hypertension and electrocardiographic evidence of left ventricular hypertrophy treated with the angiotensin receptor blocker losartan had a significantly reduced the rate of stroke and a trend toward less coronary heart disease compared to patients treated with β-blockers (Dahlof et al.). Earlier retrospective studies suggested that treatment of hypertension with short-acting calcium channel blockers is associated with an increased risk for myocardial infarction. These agents are known to increase sympathetic tone, which in turn may increase the risk for cardiovascular events. Although the idea is still controversial, most authorities agree that short-acting calcium channel blockers should be avoided in the treatment of hypertension. More recent observations in large prospective trials have not settled the controversy. In the Appropriate Blood Pressure Control in Diabetes trial (Estacio et al.), diabetic patients randomized to receive a long-acting dihydropyridine calcium channel blocker (amlodipine) had a greater frequency of myocardial infarctions than did patients treated with angiotensin-converting enzyme inhibitors. In contrast, in the multinational Hypertension Optimal Therapy trial (Hansson et al.), the long-acting dihydropyridine calcium channel blocker felodipine was used as step 1 therapy for nearly 19,000 patients, and fewer than predicted cardiovascular events were noted. In the Systolic Hypertension in Europe trial (Tuomilehto et al.), the long-acting dihydropyridine calcium channel blocker nitrendipine reduced the incidence of cardiovascular morbidity and mortality. For patients with type 2 diabetes, the presence of microalbuminuria affects therapeutic decision making and estimation of cardiovascular risk. From the perspective of cardiovascular risk, examination of renal variables in the Heart Outcomes and Prevention Evaluation trial demonstrated that patients with

Secondary Hypertension

microalbuminuria have increased risk for cardiovascular disease, death, and hospitalization. Similarly, patients with renal insufficiency (serum creatinine level ≥1.4 mg/dL) have increased cardiovascular and all-cause mortality compared with patients with normal renal function (Mann et al.; Gerstein et al.). Given the development of incipient diabetic nephropathy with microalbuminuria, the results of the recent Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria trial suggest that effective antihypertensive therapy with an angiotensin receptor blocker slows the development of overt nephropathy and preserves renal function.

Follow-up If after 1 to 3 months the response to initial therapy with a particular agent is inadequate, three options are available: 1) increase the dose of the first drug to maximal levels, if tolerated; 2) add a second agent from another class; or 3) substitute an agent from another class. Combining antihypertensive drugs allows use of lower dosages of each drug, which may minimize side effects. Since publication of the most recent JNC-VI report, review of such studies as the United Kingdom Prospective Diabetes Study and the Hypertension Optimal Treatment trial has led to recommendations of a lower target blood pressure of 130/80 mm Hg in patients with type 1 or type 2 diabetes. The objective of this recommendation is to reduce cardiovascular complications of hypertension. In the Hypertension Optimal Treatment trial, lower target blood pressures were associated with fewer myocardial infarctions and cardiovascular events in a cohort of 1,500 diabetic patients. In the United Kingdom Prospective Diabetes study, lower blood pressure targets were associated with a reduction in macrovascular (cerebrovascular accident and coronary heart disease) and microvascular (retinopathy and nephropathy) events (UK Prospective Diabetes Study Group).

Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001;134:629-36. PMID: 11304102 Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286:421-6. PMID: 11466120 Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703-13. PMID: 9732337

KEYPOINTS

• Lower target blood pressure values are recommended in patients with diabetes mellitus (<130/80 mm Hg) and those with renal disease (<130/85 mm Hg, or <125/75 mm Hg if proteinuria >1 g/d is present).

Secondary Hypertension Most cases of secondary hypertension fall into three categories: renal, renovascular, and endocrine (Table 3). These cases can be detected from the history, physical examination, and simple laboratory tests. Fewer than 10% of patients have secondary forms of hypertension. The following case illustrates more problematic issues in a hypertensive patient. Case 2 A 69-year-old executive is referred for severe hypertension. Before his referral, he had had a severe headache and was examined in a local emergency department, where his blood pressure was 210/120 mm Hg. He had no history of hypertension. He is a long-term smoker who had a myocardial infarction 2 years ago with subsequent therapy, including atenolol and aspirin. His medical history was negative for congestive heart failure, stroke, diabetes mellitus, or renal disease. On examination, his blood pressure is 216/118 mm Hg seated and standing, and his body weight is 70 kg (154 lb). Optic funduscopy demonstrates grade II hypertensive changes without hemorrhages, exudate, or papilledema. A left carotid bruit is auscultated. Cardiac examination shows a normal sinus rhythm without murmur or gallop. Lungs are clear. Abdominal examination reveals only a systolic epigastric bruit. Neuromuscular examination is unremarkable. Laboratory studies show plasma glucose, 96 mg/dL; blood urea nitrogen, 5

Secondary Hypertension

TA B L E 3 Classification of Hypertension

Type

Prevalence

Essential (primary) hypertension

90%–95%

Secondary hypertension Renal Renal parenchymal disease Polycystic kidney disease Urinary tract obstruction

5%–10% 2.5%–6.0%

Renin-producing tumor Liddle’s syndrome Renovascular hypertension or renal infarction Coarctation of the aorta Endocrine Oral contraceptives Adrenal Primary aldosteronism

0.2%–4.0% Rare 1%–2%

Cushing’s syndrome Pheochromocytoma Congenital adrenal hyperplasia Hyperthyroidism and hypothyroidism Hypercalcemia Hyperparathyroidism Exogenous hormones: glucocorticoids, mineralocorticoids, sympathomimetics Pregnancy-induced hypertension Neurogenic Alcohol, cocaine, and medications (cyclosporine A, erythropoietin)

TA B L E 4 Features Suggesting Secondary Hypertension

Clinical Features Age at onset < 30 or > 55 years Abrupt-onset, severe hypertension (≥ stage 3) Hypertension resistant to effective medical therapy Target organ damage Fundi with acute hemorrhages or exudates Renal dysfunction Left ventricular hypertrophy Other Features Unprovoked hypokalemia Abdominal bruit or diffuse atherosclerosis ACE inhibitor–induced renal dysfunction Labile hypertension, sweats, tremor, headache Family history of renal disease Palpable polycystic kidneys ACE = angiotensin-converting enzyme.

6

Unknown

20 mg/dL; serum creatinine, 1.4 mg/dL; serum sodium, 138 meq/L; serum potassium, 3.3 meq/L; serum chloride, 100 meq/L; serum bicarbonate, 28 meq/L; serum cholesterol, 230 mg/dL; serum low-density lipoprotein cholesterol, 150 mg/dL. Serum thyroid-stimulating hormone level and urinalysis are normal Electrocardiography shows normal sinus rhythm with inferior-wall myocardial infarction (remote). The patient in case 2 presents with stage 3 hypertension and clinical target organ damage, as evidenced by previous myocardial infarction. Presentation of abrupt-onset, severe hypertension in an older man with diffuse atherosclerosis obliterans is atypical for primary hypertension and suggests a secondary form of hypertension (Table 4). The presentation above is typical of renovascular hypertension.

Renovascular Hypertension Renovascular hypertension is caused by hemodynamically significant unilateral or bilateral renal artery stenosis, with or without occlusion. In more than two thirds of cases, the cause is atherosclerotic disease in the renal arteries. Other, less common causes are fibromuscular disease of the renal arteries, arteritis, and arterial dissection. Because renovascular hypertension is uncommon, the diagnosis should only be considered in patients with certain clinical features that indicate secondary hypertension.

Secondary Hypertension

Diagnosis Because surgery or angioplasty stenting may improve control of blood pressure and renal function, one should search for renovascular hypertension only in patients whose clinical status would permit such interventions (Plouin et al.). In trying to diagnose renovascular hypertension, it is crucial to remember that not all hypertension in the presence of anatomic renal artery stenosis is renovascular hypertension. Renography using 131I-hippuran, 99mTc-diethylenetriaminepentaacetic acid, 99mTc-mercaptoacetyltriglycine after oral captopril administration identifies or renovascular hypertension with a sensitivity and specificity of about 85%. Sensitivity is compromised by the presence of azotemia and bilateral renal artery stenosis. Duplex ultrasonography of the renal arteries has been shown in prospective studies to have a sensitivity greater than 90% for the presence and degree of renal arterial disease. The accuracy of ultrasonography is operator dependent, and the technique may not be widely available. Magnetic resonance angiography may be used as a noninvasive screening, but it is costly. Threedimensional images can be obtained by spiral computed tomography, a technique that requires administration of potentially nephrotoxic contrast material. A recent meta-analysis concluded that spiral computed tomographic angiography and gadolinium-enhanced three-dimensional magnetic resonance angiography seemed to be preferred in patients referred for evaluation of renovascular hypertension (Vasbinder et al.).

Management In many patients with renovascular hypertension, blood pressure can be well controlled with medical therapy, and renal function is sustained. Successful correction of renal artery stenosis cures or ameliorates hypertension, most often in young patients with fibrous renal artery disease and those with atherosclerotic renal artery stenosis who have had hypertension for less than 2 years, who have unilateral (rather than bilateral) renal artery stenosis, and who have had a positive captopril renogram or lateralizing renal vein renins. Successful angioplasty of fibromuscular renal artery stenosis has a 60% to 80% success rate for cure or improvement of hypertension and is the preferred method of treatment in this disease. In atherosclerotic disease, angioplasty corrects the stenosis in only 30% to 50% of patients and cures or alleviates hypertension in about 20% to 30%. Reports of renal artery stenting to treat ostial lesions demonstrated excellent initial technical success rates and secondary patency rates of 92% at 27 months of follow-up. However, long-term normalization of blood pressure was achieved in only 16% of patients, and serum creatinine concentration did not change in patients with previously impaired renal function. Surgical correction of renal artery stenosis has resulted in cure or alleviation of hypertension in 61% and 27%, respectively, of fibromuscular lesions and 38% and 41% of atherosclerotic lesions. Three randomized controlled trials from Europe compared percutaneous transluminal renal angioplasty and medical therapy with medical therapy alone in atherosclerotic renal artery stenosis. Percutaneous transluminal renal angioplasty provided only modest improvements in control of blood pressure and reduction of medication dosages and no demonstrable improvement in renal function. The rate of complications was significant. At present, the optimal management of such patients is not known (Webster et al.). In a patient like the one in case 2, magnetic resonance angiography, spiral computed tomography, duplex ultrasonography, or angiotensin-converting enzyme renography may confirm clinical suspicion of renal artery stenosis. If blood pressure can be adequately controlled with medication and renal function

Plouin PF, Chatellier G, Darne B, Raynaud A. Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group. Hypertension. 1998;31:823-9. PMID: 9495267

Vasbinder GB, Nelemans PJ, Kessels AG, Kroon AA, de Leeuw PW, van Engelshoven JM. Diagnostic tests for renal artery stenosis in patients suspected of having renovascular hypertension: a meta-analysis. Ann Intern Med. 2001;135:401-11. PMID: 11560453

Webster J, Marshall F, Abdalla M, Dominiczak A, Edwards R, Isles CG, et al. Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. Scottish and Newcastle Renal Artery Stenosis Collaborative Group. J Hum Hypertens. 1998;12:329-35. PMID: 9655655

7

Indications for Therapy

KEYPOINTS

• When secondary forms of hypertension are suspected, consider renal, renovascular, or endocrine diseases.

is preserved, further invasive interventions may not be warranted. Angiotensinconverting enzyme inhibitors or angiotensin receptor blockers should be used with caution in such a patient because renal dysfunction, or even renal failure, may occur, especially in the presence of bilateral renal artery stenosis. Serum creatinine should be monitored carefully in such cases. Calcium channel blockers, β-blockers, and diuretics may be suitable alternatives. Optimal medical care of patients with renal artery stenosis due to atherosclerosis obliterans includes more than management of hypertension alone. Modification of cardiovascular risk factors is important, because most deaths in these patients are attributable to coronary heart disease and stroke. Careful attention should be given to management of dyslipidemia in the patient in case 2, and he should be strongly counseled to discontinue smoking.

Indications for Therapy Using evidence-based medicine from a literature review of clinical trials, the JNC-VI recommended compelling indications for specific classes of antihypertensive agents in four disease states that may coexist in the hypertensive patient. Case 3 A 76-year-old white man presents for his periodic health assessment. Several of his blood pressure readings have averaged 175/80 mm Hg in the last 6 to 8 months. His medical history is negative for atherosclerotic heart disease, dyslipidemia, and diabetes mellitus. He takes no medications. He is a nonsmoker and drinks alcohol only socially. His blood pressure is 178/68 mm Hg seated and standing, and his body weight is 74 kg (163 lb). Detailed physical examination is unremarkable. Laboratory studies show blood urea nitrogen, 8 mg/dL; serum creatinine, 1.0 mg/dL; serum sodium, 140 meq/L; serum potassium, 4.2 meq/L; serum chloride, 103 meq/L; serum bicarbonate, 24 meq/L; serum cholesterol, 212 mg/dL. Urinalysis is normal. Electrocardiography reveals normal sinus rhythm with nonspecific ST-wave changes. Hypertension is present in about 60% of persons in the United States who are older than 65 years of age. Particularly in elderly persons, systolic blood pressure is a better predictor of cardiovascular events than is diastolic blood pressure. The benefit of therapy of systolic hypertension in persons older than 60 years of age has been well documented in five large, randomized trials. The case-patient’s elevated blood pressure may be classified as isolated systolic hypertension (systolic blood pressure >140 mm Hg and diastolic blood pressure <90 mm Hg) and further categorized as stage 2 hypertension. Even in stage 1 isolated systolic hypertension, elevated systolic blood pressure confers risk of coronary heart disease, congestive heart failure, cerebrovascular accident, and end-stage renal disease. The benefits of treatment have been demonstrated for patients with isolated systolic hypertension and systolic blood pressure greater than 160 mm Hg. The benefits of therapy for those with stage 1 isolated systolic hypertension have not yet been conclusively shown in controlled trials. Antihypertensive therapy in older persons should begin with lifestyle modifications, including modest sodium restriction and weight loss. If target blood pressure is not achieved, pharmacologic therapy should be started. The target blood pressure is the same as that in younger patients (<140/90 mm Hg), although an interim target systolic blood pressure less than 160 mm Hg may be 8

Indications for Therapy

necessary in patients with marked isolated systolic hypertension (Savage et al.). The JNC-VI recommends low–dose diuretics or long-acting dihydropyridine calcium channel blockers as initial therapy in isolated systolic hypertension (Table 5). In addition to isolated systolic hypertension in the elderly, compelling indications for aggressive and specific antihypertensive treatment exist for three other disease states.

Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, et al. Influence of long-term, low-dose, diureticbased, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: the Systolic Hypertension in the Elderly Program. Arch Intern Med. 1998;158:741-51. PMID: 9554680

TA B L E 5 Compelling Indications for Specific Classes of Antihypertensive

Therapy in Concomitant Diseases Indication

Drug Therapy

Diabetes mellitus with proteinuria

ACE inhibitors (especially in type 1)

ARBs (especially in type 2) Heart failure ACE inhibitors, diuretics Carvedilol, ARB Isolated systolic hypertension (older patients) Diuretics (preferred) After myocardial infarction

Long-acting dihydropyridine CCBs β-Blockers ACE inhibitors (with systolic dysfunction)

ACE = angiotensin-converting-enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker.

Diabetes Mellitus with Proteinuria In patients with type 1 diabetic nephropathy, angiotensin-converting enzyme therapy has an impressive renoprotective effect in slowing the progression of diabetic renal disease. A similar renoprotective effect has been noted in nondiabetic renal disease. In type 2 diabetic nephropathy, therapy with angiotensin receptor blockers was demonstrated to slow progression of diabetic renal disease. The section on hypertension in the discussion of chronic kidney disease section provides more details on specific antihypertensive therapy and lower target blood pressures (less than 130/85 mm Hg [or <125/75 mm Hg in patients with proteinuria >1 g/d]) in patients with proteinuric renal disease.

Heart Failure The Framingham Study demonstrated that hypertension continues to be the major risk factor for left ventricular hypertrophy, myocardial ischemia, and congestive heart failure. Evidence from clinical trials demonstrates that most antihypertensive agents, but particularly angiotensin-converting enzyme inhibitors, are effective in preventing and reversing left ventricular hypertrophy. Because angiotensin-converting enzyme inhibitors reduce morbidity and mortality due to congestive heart failure, hypertensive patients with congestive heart failure will benefit from treatment with these drugs. If these patients cannot tolerate or have contraindications to angiotensin-converting enzyme inhibitors, a combination of the vasodilators hydralazine and nitrates is also effective. In addition, the α-β–blocker carvedilol has also proven beneficial. A trial of the angiotensin receptor blocker losartan for treatment of congestive heart failure has provided encouraging data. A subsequent study of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers suggests benefit in patients with congestive heart failure. Caution may need to be exercised when using a combination of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients being treated with con-

9

Laboratory Evaluation

KEYPOINTS

• Agents that block the renin–angiotensin system are preferred to treat diabetic nephropathy. • The evidence supports angiotensinconverting enzyme inhibitors (type 1 diabetes) or angiotensin receptor blockers (type 2 diabetes) to treat diabetes mellitus with proteinuria. • Angiotensin-converting enzyme inhibitors, diuretics, carvedilol, or angiotensin receptor blockers are indicated to treat hypertension in heart failure. • Diuretics (preferred) or long-acting dihydropyridine calcium channel blockers are indicated to treat isolated systolic hypertension. • In patients with systolic dysfunction, β-blockers or angiotensin-converting enzyme inhibitors are indicated to treat hypertension after myocardial infarction.

comitant β-blockers, because congestive heart failure may be more problematic. Two dihydropyridine calcium channel blockers, amlodipine and felodipine, have been shown to be safe in treating angina in hypertensive patients with advanced left ventricular dysfunction; other calcium antagonists are not recommended in such patients because they may worsen left ventricular function and increase mortality.

After Myocardial Infarction Hypertensive patients with known coronary heart disease are at high risk for cardiovascular morbidity and mortality. The benefits and safety of antihypertensive therapy in these patients have been well documented. Care should be taken to avoid an excessively rapid decrease in systemic pressure, especially when it causes reflex tachycardia and sympathetic activation. Patients who have had myocardial infarction have compelling indications for treatment with β-blockers that do not have intrinsic sympathomimetic activity because they reduce the risk for subsequent myocardial infarction or sudden cardiac death. If β-blockers are contraindicated or not tolerated, verapamil or diltiazem may be used. Angiotensin-converting enzyme inhibitors are also useful after myocardial infarction in patients with left ventricular systolic dysfunction.

Clinical Assessment of Kidney Function Kidney disease is a growing public health concern, as the rate of chronic kidney disease increases in an aging population. Accurate assessment of kidney function through laboratory, imaging, and pathologic testing allows the clinician to address the causes and severity of kidney disease and prevent further deterioration, complications, and associated comorbid conditions.

Laboratory Evaluation

Clase CM, Garg AX, Kiberd BA. Prevalence of low glomerular filtration rate in nondiabetic Americans: Third national health and nutrition examination survey (NHANES III). J Am Soc Nephrol. 2002;13:1338-49. PMID: 11961022 Eknoyan G, Levin NW. Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease. Am J Kidney Dis. 2002;39(2 Suppl 1):S76-S110.

10

Assessment of kidney function should involve a multitiered approach, with determination of both structural and functional abnormalities. Because kidney disease is often silent in the early stages, diagnostic tests to detect subtle kidney abnormalities are important. The glomerular filtration rate is an excellent measure of the filtering ability of the kidney; however, because of wide physiologic variability, it is not a useful screening tool (Figure 1). A large proportion of middle-aged, nondiabetic Americans may have a glomerular filtration rate less than 80 mL/min (Clase et al.). Urinalysis is most often used to detect early markers of kidney disease. Imaging studies and pathologic examination of tissue assist in diagnosis, and tests of renal function are often used to measure disease progression.

Glomerular Filtration Rate In February 2002, the National Kidney Foundation published the Kidney Disease Quality Outcomes Initiative (K/DOQI), a comprehensive clinical practice guideline for evaluation and classification of patients with chronic kidney disease. In this guideline, the definition and staging of chronic kidney disease depends on assessment of kidney function by measurement of the glomerular filtration rate, proteinuria, and other markers of kidney disease (Eknoyan et al.). The glomerular filtration rate cannot be measured directly. Rather, it is measured as renal clearance of a substance from the plasma. The clearance is the amount of a substance removed from plasma divided by the average plasma concentration of the substance over that time period, such that:

serum creatinine (mg/dL)

Laboratory Evaluation

20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

Failure Severe

Moderate

Mild

Normal GFR

A D

C B

0

10

20

30

40

50

60

70

80

90

FIGURE 1. Relationship between glomerular filtration rate (GFR ) by 125I-iothalamate clearance and serum creatinine concentration and stage of chronic kidney disease. At any particular GFR, the width of the shaded area shows the range of serum creatinine that might be seen as result of differences in muscle mass. Points A and B show different level of serum creatinine in two patients with the same GFR. Points C and D show markedly different GFR in patients with the same creatinine concentration. The stages of chronic kidney disease are as follows: mild, GFR of 89 mL/min to 60 mL/min; moderate, 59 mL/min to 30 mL/min; severe, 29 mL/min to 15 mL/min; and kidney failure, <15 mL/min. A normal GFR is 120 mL/min to 90 mL/min.

100 110 120

glomerular filtration rate (mL/min)

Cx = Ux V/Px Where: Cx = clearance of substance X; Ux = urinary concentration of X; V= volume of urine, Px = plasma concentration of X. If a substance is freely filtered at the glomerulus but is then neither secreted nor absorbed by the renal tubular epithelial cells, its clearance represents the glomerular filtration rate. The fructose polysaccharide inulin has these properties and is currently the gold standard for measurement of the glomerular filtration rate. Inulin clearance is calculated as: C inulin = U inulin × V/ P inulin = glomerular filtration rate Because measurement of the inulin clearance is complex, its use is mostly confined to research settings. Urinary clearance of such markers as 125I-iothalamate and 99mTc-diethylenetriaminepentaacetic acid and plasma clearance of iohexol and 51Cr-ethylenediaminetetraacetic acid have been used to estimate the glomerular filtration rate. Although accurate, these techniques involve considerable time and expense and are not readily available. The most common laboratory marker used to estimate glomerular filtration rate is serum creatinine. Case 4 A 68-year-old woman presents for evaluation before radical nephrectomy for a unilateral renal mass suspicious for carcinoma. She has had well-controlled type 2 diabetes mellitus for 20 years. She weighs 54 kg (119 lb). The current serum creatinine concentration is 1.2 mg/dL. Urinalysis shows trace protein and 3+ heme by dipstick analysis.

Serum Creatinine and Creatinine Clearance Creatinine is produced from creatine and phosphocreatine, both of which are released from muscle. Nonrenal elimination of creatinine is negligible in healthy persons but is increased in those with kidney disease. Creatinine, which has a molecular weight of 113 Da, is freely filtered at the glomerulus but is also 11

Urinalysis

Coresh J, Astor B, McQuillen G, Kusek J, Greene T, Van Lente F, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 2002;39:920-9. PMID: 11979335

secreted from the renal tubule. Low muscle mass, as in malnutrition, aging, and chronic disease, may lead to a serum creatinine concentration within the normal reference range but reflect a markedly abnormal glomerular filtration rate. The serum creatinine may therefore underestimate the glomerular filtration rate by as much as 20% to 40%. Diurnal variation in glomerular filtration rate, ingestion of creatine through eating meat, and interlaboratory and intralaboratory variations (Coresh et al.) also account for variability in a glomerular filtration rate based on serum creatinine alone. The K/DOQI guidelines propose that serum creatinine alone not be used to estimate glomerular filtration rate. Collection of a 24-hour urine sample can provide useful information on excretion of solutes, volume, and assessment of protein intake. The 24-hour collection for measurement of creatinine clearance has been shown to be no more accurate than equations using serum creatinine to estimate glomerular filtration rate. Faulty collection techniques, day-to-day variations in excretion of creatinine, and diurnal variation in glomerular filtration rate have been proposed as potential errors. The 24-hour urine collection may be useful in the assessment of glomerular filtration rate in selected groups, such as persons with extremes of protein intake (vegetarians or those who take creatine supplements) or muscle mass (weightlifters and those with malnutrition or chronic liver disease). Most authorities now recommend using prediction equations, such as the Modification of Diet in Renal Disease (MDRD) equation or the Cockcroft–Gault equation, to estimate the glomerular filtration rate. In case 4, the estimated creatinine clearance (CCr) according to the Cockcroft–Gault equation would be: CCr = [(140 − age in years) × body weight in kg] /72 × Cr Multiplied by a correction factor of 0.85 for female sex, such that: [(140 − 68) × 54 kg] / (72 × 1.2 mg/dL) × 0.85 = 38

KEYPOINTS

• Abnormal kidney function can manifest with a low glomerular filtration rate, abnormal urinary findings, or both. • The glomerular filtration rate should be estimated by using creatinine-based equations, such as the Cockcroft–Gault or the Modified Diet in Renal Disease equation.

Thus, the estimated preoperative creatinine clearance is 38 mL/min for this patient according to the Cockcroft–Gault formula. The MDRD equation was derived from a cohort of patients who underwent 125I-iothalamate clearance measurement of glomerular filtration rate. This formula was also validated separately in more than 500 persons. The MDRD equation, which is based on plasma chemistry results and clinical characteristics, is an accurate predictor of glomerular filtration rate as high as approximately 90 mL/min/1.73 m2. This formula should be available at most clinical laboratories in the near future. Thus, the current National Kidney Foundation guidelines recommend using serum creatinine–based equations to estimate the glomerular filtration rate. Serum creatinine alone and 24-hour urine collections for creatinine clearance should not be used, except in the special circumstances outlined above.

Urinalysis Results of urinalysis will often provide the first indication of renal or urologic disease. The United States Preventive Services Task Force does not recommend using the urinalysis as screening for bacteriuria, proteinuria, or hematuria in asymptomatic, low-risk adults. It is still used in many situations, however, such as student sports physicals and insurance physicals. Therefore, the primary care provider may still be faced with an abnormal urinalysis in the otherwise asymptomatic patient. 12

Urinalysis

Proteinuria The patient in case 4 has both hematuria and proteinuria. The dipstick analysis relies on pH-induced color change on an impregnated plastic strip. The negatively charged proteins, mostly albumin, induce a color change that is then graded on a scale. Dipstick analysis may not detect positively charged proteins, such as immunoglobulin light chains. The lower limit of detection is approximately 20 mg/dL, or approximately 200 mg/d given 1 L of urine production. Trace to 1+ amounts of protein, especially in a concentrated urine sample, are rarely significant if this is the only finding. On the other hand, large amounts of protein may appear to be falsely low in very dilute urine. Precipitation of the protein with sulfosalicylic acid accurately quantifies protein. The turbidity of the precipitate is then compared with standard values. High-molecular-weight plasma proteins, such as albumin and globulin, usually cannot enter the urinary space because of their size and the charge selectivity of the glomerular basement membrane. Plasma proteins with a molecular weight less than 20,000 Da readily penetrate the glomerular capillary wall. Compared with albumin, these proteins normally have much smaller plasma concentrations and are reabsorbed by the renal tubule. Normal total protein excretion is approximately 100 mg/d, and normal albumin excretion is less than 30 mg/d. Most renal parenchymal diseases will manifest some degree of abnormal protein excretion in the urine. There are three mechanisms for abnormal appearance of protein in the urine. 1 Glomerular damage resulting in the abnormal appearance of plasma proteins in the urine. 2 Tubular damage resulting in abnormal appearance of low-molecular-weight proteins (such as β-2 microglobulin and peptides) in the urine. 3 Overproduction of the freely filtered low-molecular-weight proteins, such as immunoglobulin light chains, that exceeds the resorptive capacity of the renal tubule. In states of physiologic stress, such as exercise or fever, transient proteinuria may appear. This phenomenon, which is rarely clinically significant, is thought to be related to alterations in intrarenal hemodynamics. Benign positional, or orthostatic, proteinuria is easily diagnosed with split daytime (standing) and nighttime (supine) urine collections. A favorable renal outcome is seen in long-term follow-up of patients with orthostatic proteinuria. After confirmation on subsequent dipstick analysis, proteinuria should be quantified with either a protein-to-creatinine ratio, or a carefully done 24-hour collection. Referral to a nephrologist for further evaluation and possibly treatment should be done for patients with persistent proteinuria.

Hematuria Blood in the urine can originate anywhere along the urinary tract, and both gross and microscopic hematuria may represent serious underlying disease. Hematuria is defined as the abnormal presence of red blood cells in the urine and is commonly divided into gross and microscopic hematuria. As little as 1 mL of blood in 1 L of urine can cause gross hematuria; therefore, the color of the urine does not reflect the degree of blood loss. In addition, numerous other substances can induce a color change (Table 6). When true gross hematuria exists, a full evaluation is warranted (Grossfeld et al.). Microscopic hematuria is often found incidentally during office evaluation of symptoms of urinary tract infection or during routine health screening. Approximately 1 million erythrocytes pass into the urine daily, corresponding to 1 to 3 erythrocytes/hpf in centrifuged urine sediment examined microscopically. The American Urological Association defines microscopic hematuria as 3

Grossfeld GD, Wolf JS Jr, Litwan MS, Hricak H, Shuler CL, Agerter DC, et al. Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policy recommendations. Am Fam Physician 2001;63:1145-54. PMID: 1127755

13

Urinalysis

TA B L E 6 Substances That May

Cause Red Pigmenturia Endogenous Sources Bilirubin Myoglobin Hemoglobin Porphyrins Foods Rhubarb Blackberries Blueberries Paprika Beets Fava beans Artificial food colorings Drugs Rifampin Nitrofurantoin Sulfonamides Metronidazole Phenytoin Prochlorperazine Phenolphthalein Quinine Chloroquine Phenazopyridine Levodopa Methyldopa Doxorubicin Desferoxamine

Sokolosky MC. Hematuria. Emerg Med Clin North Am 2001;19:621-32. PMID: 11554278

14

erythrocytes/hpf on microscopic examination of the centrifuged urine specimen, in two of three freshly voided, clean-catch, midstream urine samples. Repeated testing is done because hematuria is intermittent in some diseases. The reported prevalence of asymptomatic hematuria in adults varies widely. Population-based studies have shown prevalence of less than 1% to 16%. This range is attributed to differences in patient demographic characteristics, duration of follow-up, definition of hematuria, diagnostic technique, and number of screening tests per patient. Patients at high risk for urologic disease, such as elderly men, have a higher prevalence of hematuria. The pathophysiology of hematuria depends on the site in the urinary tract from which blood loss occurs. Hematuria in which blood originates from the nephron is termed glomerular hematuria. Erythrocytes can enter the urinary space from the glomerulus or, rarely, from the renal tubule. Disruption of the filtration barrier in the glomerulus may result from inherited or acquired abnormalities in the structure and integrity of the glomerular capillary wall. These erythrocytes can be trapped in Tamm–Horsfall mucoprotein and will be manifest in the urine by erythrocyte casts. Casts in the urine indicate clinically significant disease at the glomerular level. However, in disease of the nephron, casts may be absent, and isolated red blood cells may be the only finding. The presence of proteinuria supports a glomerular source of blood loss. Hematuria without proteinuria or casts is termed isolated hematuria. Although a few glomerular diseases may produce isolated hematuria, this finding is more consistent with extraglomerular bleeding. Disruptions of the uroepithelium such as irritation, inflammation, or invasion, can result in normalappearing erythrocytes in the urine. Cancer, renal stones, trauma, infection, and medications may cause these disruptions. Nonglomerular renal causes of blood loss, such as tumors of the kidney, renal cysts, infarction, and arteriovenous malformation, can also cause blood loss into the urinary space. The dipstick urinalysis records a reaction between hydrogen peroxide and chromogen that is catalyzed by hemoglobin. This reaction results in a green color change of the chromogen that is visible on the dipstick. The sensitivity of the dipstick to detect hematuria at a concentration of more than 3 erythrocytes/hpf is more than 90% (Sokolosky). Many factors can produce false-positive and false-negative results on dipstick analysis. Vitamin C ingestion, urine pH less than 5.1, or prolonged exposure of the dipstick to air before testing can cause false-negative results. Contamination of the urine with menstrual blood, myoglobinuria, and bacterial peroxidases can produce false-positive findings. For these reasons, all positive results on dipstick analysis and all negative results with a high index of suspicion should be sent for microscopy. Samples sent for microscopy should be evaluated within 1 hour, because casts will begin to disintegrate and erythrocytes may lyse. Cellular elements may be preserved for a few more hours by refrigeration of the sample. On microscopy, dysmorphic erythrocytes (which are distorted in both shape and size) and casts are consistent with a glomerular source of bleeding. Best seen with phase-contrast microscopy by trained personnel, these findings, especially in conjunction with significant proteinuria, should prompt referral to a nephrologist for evaluation for glomerular disease and consideration of a kidney biopsy. Erythrocytes from a nonglomerular source more closely resemble peripheral blood on microscopy, with isomorphic erythrocytes and absence of casts. The current American Urological Association Best Practice Policy Recommendations for evaluation of isolated hematuria are based on presence of risk factors for significant urologic disease. Low-risk patients should undergo either urine cytology examination or cystoscopy along with upper-tract imaging

Imaging

(computed tomography or intravenous pyelography). Patients with suspicious findings on cytology should then be referred for cystoscopy. Patients with significant risk factors such as smoking history, occupational exposure to benzenes or aromatic amines, age greater than 40 years, history of urologic disorder or disease, irritative voiding symptoms, history of analgesic abuse, history of pelvic irradiation should undergo a complete evaluation including upper-tract imaging, urine cytology and cystoscopy.

Leukocytes and Other Formed Elements The finding of more than 1 leukocyte/hpf in the urine can be considered abnormal; however, fewer than 3 to 5 leukocytes/hpf is usually considered acceptable. Leukocytes may originate from any point along the urogenital tract, and, like hematuria, leukocyturia has a broad differential diagnosis. The finding of other formed elements in the urine, casts, and proteinuria implicate a glomerular or renal source. Most leukocytes in the urine are polymorphonuclear; these cells contain esterases that can be detected on chemical dipstick analysis of urine. The finding of leukocytes in the urine usually implies infection; however, glomerular or tubulointerstitial inflammation and allergic reaction can cause leukocyturia. Lipids and fat in the urine are almost always seen in association with heavy proteinuria or the nephrotic syndrome. They may appear as free lipid droplets, in round oval fat bodies, or in fatty casts. Fat is best seen under polarized light, where the cholesterol esters appear as refractile objects shaped like Maltese crosses. Casts are cylindrical aggregates of Tamm–Horsfall mucoprotein that are secreted by the distal nephron, which trap the intraluminal contents and appear in the urine. Erythrocytes, leukocytes, and debris may appear in cast form, and all implicate different pathologic mechanisms. Erythrocyte casts most often imply glomerular disease; leukocyte casts connote inflammation or infection of the renal parenchyma, and granular casts result from degenerating cellular elements and protein precipitates. Other casts, such as hyaline, waxy, and fatty casts, may also be seen.

Imaging Plain radiography of the abdomen can provide rudimentary information of the kidneys and will reveal calcifications in the pelvis, but this technique alone is not useful for assessment of kidney disease. Intravenous administration of contrast agent combined with serial radiography (intravenous urography or pyelography) can be useful in assessment of nonglomerular bleeding and nephrolithiasis but may have significant side effects, such as allergic reaction and azotemia. Diabetic patients and those with mild kidney disease may be especially prone to azotemia secondary to iodinated contrast agents. The routine use of plain radiography and intravenous urography to assess kidney disease has been replaced by such techniques as ultrasonography and computed tomography.

Ultrasonography Ultrasonography of the kidney, ureters, and bladder has become the initial test of choice in many kidney and urologic diseases because of the relative ease, availability, and safety at all levels of kidney function. Ultrasonography reliably detects hydronephrosis with a sensitivity greater than 90%. Both radiopaque and radiolucent renal stones larger than 5 mm may be seen. Echogenicity of the renal cortex is used as a surrogate marker for kidney fibrosis and, along with kidney length, can be used to monitor disease progression. Simple cysts are eas-

15

Kidney Biopsy

Radermacher J, Chavan A, Bleck J, Vitzthum A, Stoess B, Gebel MJ, et al. Use of Doppler ultrasound to predict the outcome of therapy for renal-artery stenosis. N Engl J Med 2001;344:410-7. PMID: 11172177

ily distinguished from solid renal tumors. Solid tumors smaller than 3 cm are best seen with other methods, as described below. Duplex sonography has been used in renal artery stenosis to diagnose and predict outcome after revascularization (Radermacher et al.).

Computed Tomography Computed tomography is now the test of choice for renal lithiasis and masses. Helical computed tomography is especially helpful in imaging the retroperitoneal area and can have a spatial resolution up to 0.5 mm. Nonenhanced computed tomography is used to detect kidney stones and calcification; enhanced contrast scans using iodinated contrast agents are helpful in delineating masses, abscesses, and tumors of the kidneys, renal pelvis, and adrenal glands. The need to use intravenous contrast material for most scans limits the utility of computed tomography for patients with advanced kidney disease or those at high risk for contrast-induced kidney failure.

Magnetic Resonance Imaging

Schoenberg SO, Knopp MV, Londy F, Krishnan S, Zuna I, Lang N, et al. Morphologic and functional magnetic resonance imaging of renal artery stenosis: a multireader tricenter study. J Am Soc Nephrol 2002;13:158-69. PMID: 11752033 Postma CT, Joosten FB, Rosenbusch G, Thien T. Magnetic resonance angiography has a high reliability in the detection of renal artery stenosis. Am J Hypertens 1997;10:957-63. PMID 9324099 Olin JW, Peidemonte MR, Young JR, DeAnna S, Grubb M, Childs MB. The utility of duplex ultrasound scanning of the renal arteries for diagnosing significant renal artery stenosis. Ann Intern Med. 1995;122:833-8. PMID 7741367

Magnetic resonance imaging exposes atoms in the body to a powerful external magnetic field and pulses them at a specific radiofrequency. Magnetic resonance imaging yields high-resolution images of the kidney parenchyma and perirenal tissues. Tumors smaller than 3 cm that are difficult to visualize with ultrasonography are easily seen on magnetic resonance imaging. Use of the intravenous, noniodinated contrast agent gadolinium in magnetic resonance angiography has greatly enhanced the ability of magnetic resonance imaging to analyze the vasculature of the kidney and diagnose renal artery stenosis. Threedimensional gadolinium-enhanced magnetic resonance angiography is better than digital subtraction angiography in detecting ostial lesions, but visibility of the distal renal artery and hilum is worse (Schoenberg et al.). As for duplex ultrasonography of the renal arteries, interobserver variability exists with use of magnetic resonance angiography. Use of arteriography for diagnosis of renal artery stenosis is usually reserved for cases in which the index of suspicion is higher an intervention is required.

Radionuclide Scanning Radionuclide scanning is primarily used to assess renal perfusion and is especially useful for detecting substantial differences in perfusion between the kidneys. This technique easily detects severe reduction in or absence of renal perfusion, especially when involvement is unilateral. Renography has a sensitivity of 75% for detection of hemodynamically significant renal artery stenosis. The sensitivity increases to 92%, and specificity to 95% by repeating renography after administration of oral captopril. Comparatively, using intra-arterial angiography as the standard, magnetic resonance angiography has a sensitivity and specificity of 100% and 96% respectively (Postma et al.) and duplex ultrasonography has a sensitivity and specificity of 98% and 98%, respectively (Olin et al.).

Kidney Biopsy A kidney biopsy is obtained to establish a diagnosis, aid in prognosis, or tailor therapy. Biopsy provides information on the glomeruli, tubulointerstitium, and vasculature. The level of fibrosis in the interstitium and vasculature correlates better than the glomerular histopathology with renal function. Common indications for kidney biopsy are evaluation of primary nephrotic syndrome in adults or corticosteroid-unresponsive nephrotic syndrome in children, acute or rapidly progressive glomerulonephritis, and an elevated serum 16

Glomerular Anatomy and Its Relation to Glomerular Disease

creatinine concentration in kidney transplant recipients. Kidney biopsy may also prove useful in the evaluation of common diseases that do not display typical features, such as diabetic patients with kidney disease but no evidence of other microvascular disease and in those with acute renal failure of no clear origin. Kidney biopsies are usually not performed in advanced chronic kidney disease because the risk for complications outweighs the benefit of the test. Biopsies may be performed percutaneously with local anesthesia, by an open surgical technique, or laparoscopically. The laparoscopic approach offers direct visualization of the kidney and controlled hemostasis (Gimenez et al.). This technique requires general anesthesia but may benefit high-risk patients who require a kidney biopsy, since the rate of complications is low and the procedure has a high success rate. The most common complications of percutaneous kidney biopsy are selflimited microscopic hematuria, which occurs in most patients, and benign perinephric hematomas. Gross hematuria occurs in less than 10% of patients and is also self-limited in most instances. Complications such as arteriovenous fistulas, aneurysm, requirement of blood transfusion, and infection are much more rare. Mortality following a kidney biopsy is approximately 0.12%.

Gimenez LF, Micali S, Chen RN, Moore RG, Kavoussi LR, Scheel PJ Jr. Laparoscopic renal biopsy. Kidney Int. 1998;54:525-9. PMID: 9690219

Glomerular Diseases Primary glomerular disorders occur in the absence of known systemic diseases. Secondary glomerular disorders occur as a consequence of systemic disease. Secondary glomerular disorders may complicate metabolic or immune disorders, infections, neoplasms, hereditary factors, or other processes.

Glomerular Anatomy and Its Relation to Glomerular Disease • What is the structure of the glomerulus? • How does glomerular structural integrity relate to glomerular function?

The glomerulus consists of four regions: arterioles, the glomerular capillary wall (endothelium, glomerular basement membrane, and podocyte), the mesangium, and Bowman’s space and capsule (Figure 2). Abnormalities of these structures result in failure of function, which manifests as proteinuria, hematuria, or declining glomerular filtration rate. Glomeruli are bound by afferent and efferent arterioles, thus permitting fine regulation of intraglomerular pressure by modulation of these two structures. Angiotensinconverting enzyme inhibitor therapy makes use of this unique anatomy by preferentially dilating the efferent arteriole over the afferent arteriole, thereby decreasing intraglomerular pressure. Ultrafiltration occurs across the glomerular capillary wall. Endothelial cells line the capillary lumen, create a nonthrombogenic surface, and act as a porous filter with spaces or fenestrae to permit filtration. The glomerular basement membrane has historically been viewed as the seat of glomerular permselectivity, but this role was recently challenged. Podocytes attach to the outer surface of the glomerular basement membrane predominantly by integrins, a family of proteins that act as adhesion molecules. Podocytes are connected to each other by a slit membrane that covers the glomerular basement membrane, which is composed, at least in part, of a secreted podocyte protein called nephrin. Mutations in nephrin cause massive proteinuria in newborns (the congenital Finnish nephrotic syndrome). This discovery led to the idea that the podocyte slit membrane, rather than the glomerular basement membrane, may be the 17

Glomerular Anatomy and Its Relation to Glomerular Disease

FIGURE 2. The glomerulus Schematic representation of a glomerulus indicating the urinary space, capillary lumen, the glomerular basement membrane and cells which are intrinsic to the glomerulus: mesangial cell and matrix, the fenestrated endothelial cells and epithelial cells. Immune-complex deposits are depicted in the mesangial, subendothelial, and subepithelial areas. (U.S. = urinary space; C.L. = capillary lumen; Mes. = mesangial; GBM = glomerular basement membrane.)

seat of glomerular permselectivity. Podocytes may be injured by stretch accompanying glomerular hypertrophy, such as in minimal change disease and focal sclerosis; by metabolic factors, such as hyperglycemia; by complement activation, such as in lupus nephritis or membranous nephropathy; by chemical toxins or medications; and by direct infection, such as in HIV-associated nephropathy. Injury to podocytes may thus induce proteinuria. The mesangium is composed of cells and matrix. Mesangial expansion may be due to hypercellularity, such as that seen in immune disorders (for example, systemic lupus erythematosus or IgA nephropathy), matrix expansion (diabetic nephropathy), or infiltration by abnormal proteins (amyloidosis). Mesangial hypercellularity is often associated with both hematuria and some degree of proteinuria. Mesangial matrix expansion may reduce glomerular filtration rate by occluding the capillary lumina. Bowman’s space is the glomerular region bounded by podocytes and slit membrane and the parietal epithelial cells. It is usually empty apart from these intrinsic glomerular cells and ultrafiltrate. In inflammatory glomerular disorders, this space may fill with infiltrating mononuclear cells, activated and dividing glomerular epithelial cells, and the fibrous products of these cells. This phenomenon is called a crescent. Crescentic glomerulonephritis is a nephrologic emergency because rapid collapse of the glomerular tuft induces loss of glomerular filtration, often irreversibly. Glomerular disorders are diagnosed on the basis of their clinical presentation and their histomorphologic appearance. Sometimes a diagnosis is strongly suspected by the history, physical examination, and serologic studies (including complement levels, antinuclear and anti-DNA antibodies, antinuclear cytoplasmic antibody [ANCA] levels, and HIV and hepatitis status) alone. This is usually the case for diabetic nephropathy and for the idiopathic nephrotic syndrome of childhood. Renal biopsy is rarely performed for asymptomatic urinary abnormalities, such as proteinuria less than 1 g/d, or for microscopic hematuria

18

Clinical Syndromes of Glomerular Disease

in the absence of renal insufficiency or a systemic disorder. However, renal biopsy is indicated in patients with heavy proteinuria, dysmorphic hematuria, erythrocyte casts, and proteinuria or hematuria in the presence of low glomerular filtration rate when the underlying cause is uncertain.

Clinical Syndromes of Glomerular Disease Case 5 A 30-year-old man in otherwise good health presents with weight gain of 4.5 to 6.5 kg (10 to 14 lb); periorbital and facial edema in the morning, with resolution during the day; and ankle edema toward evening, which has worsened in severity over 3 months. He reports that “his urine looks like beer.” There is no family history of proteinuria or renal disease. Physical examination is unremarkable apart from mild hypertension (blood pressure, 140/95 mm Hg) and modest ankle and pretibial pitting edema. Blood urea nitrogen, creatinine concentration, and glucose level are normal; the serum albumin level is low; and the serum cholesterol level is high. Urinalysis shows 4+ proteinuria on dipstick, and microscopic analysis is negative apart from oval fat bodies. A 24-hour urine collection shows 10 g proteinuria, and a random urinary protein-to-creatinine ratio is 7. Serologic studies that are normal or negative included hepatitis B and C and HIV serologies, urine and serum immunofixation, C3 and C4 levels, and a test for syphilis.

TA B L E 7 Causes of the Nephrotic

Syndrome Primary glomerular disease Minimal change disease Focal and segmental glomerulosclerosis Membranous nephropathy Membranoproliferative glomerulonephritis Mesangial proliferative glomerulonephritis Drugs Gold- and mercury-containing medications Captopril NSAIDs Penicillamine Lithium Secondary to systemic diseases

The Nephrotic Syndrome This patient has the nephrotic syndrome, characterized by proteinuria of 3 to 3.5 g/d or greater, hypoalbuminemia, hyperlipidemia, lipiduria, and edema. Table 7 lists many of the causes of the nephrotic syndrome. Diagnosis and follow-up of nephrotic-range proteinuria by measurement of random urinary protein-to-creatinine ratios instead of 24-hour urine protein and creatinine is now a common and validated practice. Edema is the most common presenting manifestation of the nephrotic syndrome. It is caused by a combination of low oncotic pressure and renal sodium retention, of which the latter is due to activation of the renin–angiotensin–aldosterone system or renal resistance to natriuretic peptides. Volume overload is an important consequence of the nephrotic syndrome, although total-body sodium and water overload may occur simultaneously with intravascular volume depletion. Many patients with the nephrotic syndrome, however, have normal intravascular volume. Particularly in adults, volume overload associated with nephrotic syndrome may also contribute to hypertension and edema. In children, ascites and pleural and pericardial effusions may accompany the nephrotic syndrome. In adults, extravasation of fluid from the vascular compartment into the interstitium (“third-spacing”) may also occur but is less common, and it may suggest the presence of a disorder in which serosal permeability is increased, such as systemic lupus erythematosus, tuberculosis, or neoplasm. Hyperlipidemia and increased lipoprotein are common but not universal complications of nephrotic syndrome. Before the advent of HMG-CoA reductase inhibitors, uncontrolled hyperlipidemia contributed to accelerated atherogenesis in these patients. Hypercoagulability is another complication of the nephrotic syndrome; this state may be associated with decreased plasma levels of protein S, protein C, and antithrombin III. Deep venous thromboses more

Diabetes Cancer: lymphoma, breast, lung, myeloma, colon, thyroid Infection: subacute bacterial endocarditis, post-streptococcal, hepatitis B or C, HIV, syphilis, ventriculoatrial shunts, chronic visceral abscesses Connective tissue disorder: systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, anticardiolipin syndrome Amyloidosis Heredofamilial diseases Alport’s syndrome Fabry’s disease Nail–patella syndrome Lecithin-cholesterol acyltransferase deficiency Familial focal and segmental glomerulosclerosis Uncommon secondary causes Ulcerative colitis Toxemia of pregnancy Vesicoureteral reflux Renal artery stenosis NSAIDs = nonsteroidal anti-inflammatory drugs.

19

Clinical Syndromes of Glomerular Disease

so than arterial thromboses occur frequently, and in patients with membranous nephropathy, renal vein thromboses are characteristic. Thromboses occur at greater frequency in patients with a serum albumin level less than 2 g/dL. Other significant complications of the nephrotic syndrome include loss of 25hydroxyvitamin D, which may induce secondary hyperparathyroidism; low thyroxine levels with normal thyroid-stimulating hormone levels and euthyroidism; and susceptibility to infection as a consequence of numerous factors, including urinary loss of complement, immunoglobulins, and zinc-binding proteins, abnormalities in leukocyte function, and use of immunosuppressive medications.

Treatment The treatment of patients with the nephrotic syndrome has changed greatly in recent years because of the effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in diminishing proteinuria and slowing renal disease progression. These agents have favorable side-effect profiles compared with the immunosuppressive agents usually used in patients with immune forms of glomerulonephritis. As a result, therapeutic decision making has become more complex, since neither specific randomized treatment efficacy studies nor evidenced-based studies clearly delineate whether immunosuppressive therapy or treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is superior in a manner that is generalizable to treatment of individual patients. Thus, angiotensin-converting enzyme inhibitors or angiotensin receptor blocker therapy, alone or in combination with immunosuppressive therapies, should be used as first-line treatment to diminish proteinuria. Dosing of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be increased sequentially until proteinuria fails to decline further. The total dose used to inhibit proteinuria may exceed dosing guidelines advised for hypertension. Increasing the dose may be limited by unacceptable increments in serum creatinine or potassium, which should be carefully monitored with each dose increment. Women treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should avoid pregnancy and breast-feeding due to teratogenicity and postpartum acute renal failure in neonates. Combining angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have theoretical advantages, but the two should probably not be used in concert with β-blockers in patients with congestive heart failure due to concerns regarding increased cardiovascular morbidity and mortality. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers to treat proteinuria slows the rate of loss of renal function. The hyperlipidemia of nephrotic syndrome is poorly responsive to dietary therapies alone. The HMG-CoA reductase inhibitors control nephrotic hyperlipidemia and should be used for the duration of the nephrotic syndrome. Similarly, patients experiencing a venous or arterial thrombosis should be treated with anticoagulants for the duration of the nephrotic syndrome. In Europe, it is common to anticoagulate prophylactically patients with a serum albumin less than 2 g/dL; in the United States, use of this practice varies. Children with the nephrotic syndrome are sometimes given vitamin D to prevent secondary hyperparathyroidism. For adult patients prescribed corticosteroids, consideration should be given to the use of bone-sparing therapy that includes vitamin D and calcium. Before immunosuppressive therapy is started, isoniazid therapy or vaccinations may be appropriate on an individualized basis. The patient described in case 5 has idiopathic nephrotic syndrome, probably due to idiopathic membranous glomerulopathy. Common serologic tests performed to identify secondary causes of the nephrotic syndrome before con-

20

Clinical Syndromes of Glomerular Disease

sideration of renal biopsy are listed in the case description. These tests should be used selectively to address specific diagnostic concerns on the basis of a careful history and physical examination. The following primary glomerulopathies can present as the nephrotic syndrome.

Minimal Change Disease Minimal change disease is thus named because there are scant light microscopic glomerular abnormalities and few or no immunoreactants on immunofluorescence microscopy. Ultrastructural analysis demonstrates almost universal effacement of the podocyte foot process. The pathogenesis is unclear, but a circulating permeability factor has been implicated. Rare familial cases have been reported. Secondary causes of minimal change disease include hypersensitivity induced by use of nonsteroidal anti-inflammatory drugs, usually along with acute tubulointerstitial nephritis; lithium treatment; non-Hodgkin’s lymphoma; and occasionally, leukemia. Minimal change disease may occur more frequently in atopic persons. In its idiopathic form, minimal change disease is the most common cause of the nephrotic syndrome in children, with a male-to-female predominance of 2 to 1. Occurring at a rate of 12 to 18 million persons yearly, its incidence peaks at 4 years of age. In adults, minimal change disease has no sex-based predilection and occurs at a rate of about 2 million persons yearly, with a peak in incidence at approximately 65 years of age. The predominant clinical manifestation is edema, which may be massive and occur rapidly over just a few days. Ascites and pleural and pericardial effusions are more common in children than adults. Hypertension occurs in a minority of patients but is three times more prevalent in adults than children. Hematuria is uncommon. Azotemia, if it occurs, is often related to hypovolemia and may be precipitated by overaggressive diuresis. Conversely, acute renal failure may also occur spontaneously in the setting of massive edema and may resolve with diuresis. Laboratory tests to assess secondary causes are usually negative or normal. However, the sedimentation rate may be elevated, particularly if marked hypoalbuminemia is present. The most corticosteroid-sensitive of all glomerular diseases, complete remission is achieved in at least 90% of children within 2 to 3 months of initiation of prednisone and at least 75% of adults after 4 months. Unfortunately, relapse is common. Re-treatment with steroids is often sufficient to reinduce remission, but for patients with frequent relapse and those with steroid dependence, the addition of oral alkylators, such as cyclophosphamide or chlorambucil, may reinduce and maintain remission while minimizing the total steroid dose administered. Cyclosporine has been used in small studies, but nephrotoxicity and more frequent relapse are concerns. Experience with mycophenolate mofetil is so limited that guidelines for its use are not yet available. Salt restriction and diuretics should be used as palliative therapy, but aggressive diuresis should be avoided. Renal failure is uncommon, occurring in less than 2% of patients, and may represent conversion to focal segmental glomerulosclerosis.

Focal and Segmental Glomerulosclerosis Histopathologically, focal and segmental glomerulosclerosis is defined by segments of sclerosis in only a portion (segmental) of some glomeruli (focal). Podocytes in focal and segmental glomerulosclerosis show diffuse foot process effacement, a feature that probably contributes to the nephrotic-range proteinuria characteristic of the disorder. Numerous histologic variants occur, the most important of which is the collapsing lesion. This lesion is characteristic of HIVassociated nephropathy but is also occasionally seen in the absence of HIV, and it is the least corticosteroid-sensitive glomerular disease. Focal and segmental

21

Clinical Syndromes of Glomerular Disease

glomerulosclerosis is best thought of as a common histologic picture that can result from numerous pathogenetic etiologies. In patients with idiopathic focal segmental glomerulosclerosis, a circulating permeability factor has been proposed to play a pathogenetic role. This factor may be present but not yet identified in as many as one third of patients. Diseases that promote glomerular growth or cause loss of nephrons predispose to focal segmental glomerulosclerosis, presumably by inducing intraglomerular hypertension. These include such diverse entities as morbid obesity, subtotal nephrectomy, unilateral renal dysgenesis, chronic ureterovesical reflux, sickle-cell anemia, and congenital cyanotic heart disease. Focal and segmental glomerulosclerosis may also complicate the progressive forms of almost any primary glomerulopathy. Heroin use has been associated with focal and segmental glomerulosclerosis, but this association has waned in the past decade. Familial forms of focal and segmental glomerulosclerosis have been identified, and mutations in the genes for the podocyte proteins α-actinin 4 and podocin induce autosomal dominant and recessive forms, respectively. The collapsing form of focal and segmental glomerulosclerosis is most notably associated with HIV, but infection with parvovirus has also been implicated, as has use of high-dose pamidronate. The collapsing form can also occur idiopathically. Focal and segmental glomerulosclerosis is the most frequent form of idiopathic nephrotic syndrome in African-American persons. It presents most often as the nephrotic syndrome but may also present as persistent non–nephroticrange proteinuria. Microscopic hematuria may accompany the proteinuria. Hypertension is common, and accelerated or malignant hypertension may be the presenting manifestation. Serologic tests to assess secondary causes are usually negative or normal in patients with idiopathic focal segmental glomerulosclerosis. Treatment is controversial. Some patients may be adequately managed with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers alone, particularly if proteinuria can be controlled to less than 1 g/d, although outcome comparisons of this treatment strategy with immunosuppressive regimens have not been studied. Although focal and segmental glomerulosclerosis was once thought to be steroid resistant, about 20% to 40% of adult patients respond to steroid therapy, particularly high-dose oral prednisone given for at least 3 to 6 months. In nonresponders, cyclosporine and, recently, mycophenolate mofetil have been used with some success. The rate of progression to renal failure varies, and more rapid progression is associated with heavy proteinuria that is refractory to therapy. Spontaneous remission is rare, although weight loss reportedly prompted remission in a few patients with morbid obesity. Recent reports suggest that highly active antiretroviral therapy for recentonset HIV may limit progression and reverse some of the histologic damage observed in patients with HIV-associated collapsing focal segmental glomerulosclerosis. Idiopathic focal and segmental glomerulosclerosis may recur in renal allografts within days or months of transplantation, particularly in patients with circulating permeability factor. In these patients, plasmapheresis may decrease proteinuria and improve allograft function.

Membranous Nephropathy Idiopathic membranous nephropathy is one of the most frequent causes of the nephrotic syndrome in adults, accounting for 30% to 50% of cases, depending on the subgroup studied. A broad range of systemic disorders may predispose to secondary membranous nephropathy. The nephrotic syndrome is the presenting manifestation in about 95% of patients with membranous nephropathy. Microscopic hematuria is present in 15% to 30% of patients. The incidence of deep venous thrombosis, especially renal vein thrombosis, is more common in 22

Clinical Syndromes of Glomerular Disease

membranous nephropathy than in other forms of the nephrotic syndrome. Pulmonary emboli may occur and may in rare cases be the presenting manifestation. The diagnosis is confirmed by the finding of subepithelial immune complexes along the glomerular basement membrane on renal biopsy. Certain histologic changes on renal biopsy help to distinguish idiopathic membranous nephropathy from a secondary form. Laboratory tests to assess secondary causes are usually negative or normal in idiopathic membranous nephropathy. The course of patients with idiopathic membranous nephropathy varies widely and has been summarized by the “rule of thirds”: One third of patients progress to end-stage renal disease over 10 years of follow-up, one third remain proteinuric with stable or slowly declining renal function, and one third experience spontaneous remission. Factors associated with an increased risk for progression include a high serum creatinine concentration at diagnosis, hypertension, tubulointerstitial fibrosis on renal biopsy, heavy proteinuria (>10 g/d), and male sex. The course is also affected by patient age (children rarely progress to end-stage renal disease), ethnicity (disease may be more benign in Japan, Southeast Asia, and parts of Europe than in the United States), and genetic factors (persons with certain haplotypes have a worse prognosis). Thus, the choice of therapy should be guided by estimates of risk of progressive renal disease and risks associated with the severity of the nephrotic syndrome. Treatment of membranous nephropathy remains controversial. For patients at low risk for progression, angiotensin-converting enzyme inhibitors or angiotensin receptor blocker therapy can decrease proteinuria, and in so doing, diminish the rate of progression of renal disease and ameliorate the nephrotic syndrome. The dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker should be incrementally increased until the proteinuria fails to decrease further or the patient develops an unacceptable side effect. For patients at high risk for progression or those with severe nephrotic complications, immunosuppressive therapy is advocated. Therapy with prednisone alone achieves remission in only a minority of patients and is no longer generally recommended. A meta-analysis suggested that immunosuppressive therapy with corticosteroids and either chlorambucil or cyclophosphamide is more efficacious than supportive therapy in achieving partial and complete remission (Imperiale et al.). A randomized prospective study showed that cyclosporine was also efficacious in maintaining renal function and diminishing proteinuria (Cattran et al.). However, the durability of these remissions after discontinuation of cyclosporine therapy and the long-term consequences of this therapy remain a concern. Mycophenolate mofetil has been used with some anecdote success. Membranous nephropathy occasionally recurs and can occur de novo in the transplanted kidney.

Membranoproliferative Glomerulonephritis There are two major histologic types of membranoproliferative glomerulonephritis, reflecting different pathogenetic mechanisms. Membranoproliferative glomerulonephritis type I is characterized by subendothelial and mesangial deposits and capillary-wall mesangial interposition. Most adults who present with membranoproliferative glomerulonephritis type I have underlying hepatitis C, although some cases are idiopathic (Johnson et al.). A membranoproliferative glomerulonephritis type I histologic pattern may also be seen in adults with underlying chronic infectious, neoplastic, inflammatory disorders, or, rarely, partial lipodystrophy. Membranoproliferative glomerulonephritis type II is characterized by deposition of electron-dense material in the capillary wall. Membranoproliferative

Imperiale TF, Goldfarb S, Berns JS. Are cytotoxic agents beneficial in idiopathic membranous nephropathy? A meta-analysis of the controlled trials. J Am Soc Nephrol. 1995;5:1553-8. PMID: 7756587 Cattran DC, Greenwood C, Ritchie S, Bernstein K, Churchill DN, Clark WF, et al. A controlled trial of cyclosporine in patients with progressive membranous nephropathy. Canadian Glomerulonephritis Study Group. Kidney Int. 1995;47:1130-5. PMID: 7783410 Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P, et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med. 1993;328:465-70. PMID: 7678440

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Secondary Causes of Glomerular Diseases

KEYPOINTS

• The nephrotic syndrome is characterized by proteinuria of 3 to 3.5 g/d or greater, hypoalbuminemia, hyperlipidemia, lipiduria, and edema. • Diagnosis and follow-up of nephroticrange proteinuria by measurement of random urinary protein-to-creatinine ratios is a common and validated practice. • 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors control nephrotic hyperlipidemia and should be used for the duration of the nephrotic syndrome. • Diseases that promote glomerular growth or cause loss of nephrons predispose to focal segmental glomerulosclerosis, presumably by inducing intraglomerular hypertension; these include such diverse entities as morbid obesity, subtotal nephrectomy, unilateral renal dysgenesis, chronic ureterovesical reflux, sickle-cell anemia, and congenital cyanotic heart disease. • Focal segmental glomerulosclerosis is the most frequent form of the idiopathic nephrotic syndrome in AfricanAmerican persons. • About 20% to 40% of adult patients with focal segmental glomerulosclerosis respond to corticosteroid therapy, particularly high-dose oral prednisone given for at least 3 to 6 months. In nonresponders, cyclosporine and mycophenolate mofetil have been used with some success. • Deep venous thrombosis, especially renal vein thrombosis, is more common in membranous nephropathy than in other forms of the nephrotic syndrome. • About one third of patients with idiopathic membranous nephropathy progress to end-stage renal disease over 10 years of follow-up, one third remain proteinuric with stable or slowly declining renal function, and one third experience spontaneous remission. • Interferon-α with ribavirin is recommended to treat the underlying hepatitis C in membranoproliferative glomerulonephritis but cannot be used in patients with a glomerular filtration rate less than 50%.

Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997;337:898-909. PMID: 9302305

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glomerulonephritis most commonly presents as the nephrotic syndrome with microscopic or, occasionally, gross hematuria. However, it may also be asymptomatic with microhematuria or non–nephrotic-range proteinuria, and it infrequently presents as an acute nephritic syndrome. Hepatitis C–associated membranoproliferative glomerulonephritis is characterized by frequent cryoglobulinemia, sometimes causing arteritis, low levels of C3 or C4, low levels of rheumatoid factor, and skin leukocytoclastic vasculitis. Serum levels of aminotransferases are frequently but not always elevated. A low C3 level is found in approximately 70% of patients with type I disease and 90% of patients with type II disease. Therapy is controversial. Interferon-α with ribavirin is recommended to treat the underlying hepatitis C but cannot be used in patients with a glomerular filtration rate less than 50%. In addition, interferon-α may exacerbate cryoglobulinemic vasculitis. Relapse of hepatitis C is frequent on discontinuation of therapy. Experience with pegylated interferon is limited. Corticosteroids are relatively contraindicated because they may exacerbate hepatitis C, but they may be indicated, along with plasmapheresis, in patients with cryoglobulinemic vasculitis before beginning interferon therapy. For membranoproliferative glomerulonephritis associated with other infections, neoplasms, or inflammatory disorders, treatment of the associated systemic disorder is indicated. For idiopathic membranoproliferative glomerulonephritis, steroids are often used, particularly in children; however, their efficacy is a matter of controversy. Membranoproliferative glomerulonephritis often recurs in renal allograft recipients.

Secondary Causes of Glomerular Diseases Table 7 lists secondary glomerular disorders that may present as the nephrotic syndrome.

Amyloidosis Amyloidosis is a heterogeneous group of disorders characterized by deposition of extracellular fibrillar materials of varying types (AA, AL, transthyretin, gelsolin, lysozyme, fibrinogen A-α, and β2-microglobulin) in tissues and organs. Renal involvement is frequent with AA and AL amyloidosis and less frequent or not seen at all with some of the other forms. In the United States, amyloidosis involving the kidney is associated with chronic inflammatory conditions (AA) or is due to increased secretion of a monoclonal lymphoid product (AL). In developing countries, AA amyloidosis is most commonly associated with chronic infections, such as tuberculosis. In the Middle East, AA amyloidosis is one of the more common causes of end-stage renal disease in patients with familial Mediterranean fever. The AL form, most commonly seen in patients with systemic idiopathic amyloidosis or multiple myeloma, reflects overproduction and deposition of immunoglobulin or immunoglobulin-like light chains, most commonly λ, produced by a clone of B lymphocytes (Falk et al.). Patients with amyloidosis may present with proteinuria with or without microscopic hematuria, often with orthostatic hypotension. Diagnosis is made by identification of the paraprotein in serum by protein electrophoresis or immunofixation; in glomeruli, the tubulointerstitium, and arterioles on renal biopsy; or in other tissues, including fat pad aspirates and gingival or rectal biopsy samples. With Congo red, AL amyloid stains with apple-green birefringence. Ultrastructurally, it appears as 8- to 10-nm fibrils. Progressive renal failure is common, and patients with end-stage renal disease have shortened survival. Treatment of AL amyloidosis is controversial. Melphalan and prednisone, and more recently vincristine, doxorubicin, and dexamethasone, may extend

Secondary Causes of Glomerular Diseases

survival in some patients. Colchicine has also been used, particularly in patients with familial Mediterranean fever. Treatment of AA amyloidosis should be directed toward the underlying inflammatory or infectious process when possible.

HIV-Associated Nephropathy The predominant glomerular lesion in patients with HIV is collapsing focal segmental glomerulosclerosis, usually referred to as HIV-associated nephropathy (Winston et al.). It is distinguished from idiopathic focal segmental glomerulosclerosis histologically by the presence of numerous prominent abnormalappearing podocytes crowding the urinary space, microcystic tubular changes, and tubulointerstitial nephritis, and clinically by the propensity for more rapid progression to end-stage renal disease. Although it is usually seen in patients with long-term disease, HIV-associated nephropathy has also been reported in patients with acute infection. In addition, a diverse spectrum of other histologic forms of glomerular disease have been reported in patients with HIV infection, including IgA nephropathy; non-IgA mesangial proliferative glomerulonephritis; membranous glomerulopathy; thrombotic microangiopathies; and the glomerular lesions associated with lymphomas and hepatitis B and C, which are occasionally comorbid conditions.

Diabetic Nephropathy Diabetic nephropathy is characterized by mesangial expansion, thickening of the glomerular basement membrane, effacement of the foot process, proteinuria, and resultant tubulointerstitial fibrosis. Recent work indicates that diabetic nephropathy is due in large part to structural injury induced by hyperglycemia, intraglomerular hypertension, cytokine and growth factor elaboration, and oxidant stress. The likelihood of developing diabetic nephropathy appears to be modulated by environmental and genetic factors. Patients with diabetic nephropathy are usually known to have diabetes for at least 5 to 10 years before the onset of proteinuria and have concomitant diabetic vascular complications, including retinopathy and cardiovascular, cerebrovascular, and peripheral arterial disease. Overt diabetic nephropathy is preceded by a period of microalbuminuria (albumin excretion of 30 to 300 mg/d). However, among patients with long-term type 1 diabetes (>10 years), those with microalbuminuria already have significant histologic glomerular damage. Microalbuminuria is also associated with increased risk for cardiovascular morbidity and mortality. In many patients with microalbuminuria who do not first die of cardiovascular disease, renal disease will progress to overt proteinuria (>300 mg/d albuminuria or >500 mg/d proteinuria), followed by progressive azotemia. Glycemic control delays or prevents progression from normoalbuminuria to microalbuminuria to overt nephropathy. Ideally, the hemoglobin A1C should be maintained at approximately 7%. Specific strategies to diminish microalbuminuria and proteinuria by blocking the renin–angiotensin system and decreasing blood pressure to less than 125/75 mm Hg (which usually requires treatment with three or four drugs) slow progression from one diagnostic category to the next (Diabetes Control and Complications Trial Research Group). Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers slows the rate of loss of glomerular filtration rate (Lewis et al., 2001; Lewis et al., 1993; Brenner et al.). Diabetic nephropathy may recur or occur de novo in the transplanted kidney.

Winston JA, Bruggeman LA, Ross MD, Jacobson J, Ross L, D’Agati VD, et al. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N Engl J Med. 2001;344: 1979-84. PMID: 11430327 The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-85. PMID: 8366922 Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-60. PMID: 11565517 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-convertingenzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456-62. PMID: 8413456 Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-9. PMID: 11565518

KEYPOINTS

• Melphalan and prednisone, and more recently vincristine, doxorubicin, and dexamethasone, may extend survival in some patients with renal amyloidosis. • The predominant glomerular lesion in patients with HIV is collapsing focal segmental glomerulosclerosis, usually referred to as HIV-associated nephropathy. • In diabetes mellitus, glycemic control delays or prevents progression from normoalbuminuria to microalbuminuria to overt nephropathy. • Specific strategies to diminish microalbuminuria and proteinuria by blocking the renin–angiotensin system and decreasing blood pressure to less than 125/75 mm Hg (which usually requires treatment with three or four drugs) slow progression from one diagnostic category to the next.

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Acute Glomerulonephritis

Acute Glomerulonephritis Case 6 A 25-year-old Japanese-American man presents with a sore throat and brown urine. Physical examination is unremarkable except for blood pressure of 140/95 mm Hg and pharyngeal erythema without exudate. He does not have skin rash, arthritis, or guaiac-positive stool. Throat culture demonstrates only normal flora. Serum electrolytes and complete blood count are normal. The serum creatinine concentration is elevated (1.6 mg/dL). Urinalysis reveals 1+ to 2+ protein, 4+ heme, and no leukocytes or nitrites. Microscopic analysis reveals 20 dysmorphic erythrocytes/hpf on an unspun specimen. Serologic studies that are normal or negative include complement measurement, hepatitis and HIV serologies, serum IgA levels, antinuclear antibodies, anti–double-stranded DNA, anti-streptozyme panel, serologic test for syphilis, antineutrophil cytoplasmic antibody, and anti-glomerular basement membrane antibody. Renal biopsy shows mesangial hypercellularity and mesangial immune complexes composed predominantly of IgA and C3 but also some IgG. This patient has acute glomerulonephritis, which, when fully expressed, is characterized by abrupt-onset hematuria, sometimes with erythrocyte casts, hypertension, and decreased glomerular filtration rate and often with oliguria. Proteinuria is common, but non–nephrotic-range proteinuria is characteristic. Erythrocytes in the urine because of glomerular injury can sometimes be distinguished from hematuria from a lower urinary tract source by their dysmorphic shape (many acanthocytes), which is best seen on phase contrast microscopy, and by their small volume when measured by an automatic analyzer (mean corpuscular volume <72 fL or urine-to-blood erythrocyte ratio of mean corpuscular volume <1). Acute glomerulonephritis is often reversible.

IgA Nephropathy (Berger’s Disease) The patient in case 6 most likely has IgA nephropathy, the most common cause of idiopathic glomerulonephritis. He presents with synpharyngitic hematuria, that is, hematuria precipitated or exacerbated by pharyngitis. This characteristic distinguishes IgA nephropathy from post-streptococcal glomerulonephritis, in which the hematuria is delayed by 2 to 3 weeks; during that time, an immunologic response evolves in the host. IgA nephropathy is especially prevalent in Asia and in the Mediterranean regions of Europe. In the United States, underdiagnosis is likely because definitive diagnosis is made by renal biopsy, a practice that is discouraged in patients with asymptomatic microhematuria with or without non–nephrotic-range proteinuria and normal renal function. The defining renal pathology involves IgA and C3 in mesangial deposits, often with codeposition of lesser amounts of IgG or IgM. The characteristic light microscopic finding is mesangial proliferation, although minimal proliferation to superimposed crescents can be seen. The pathogenesis and antigen are unknown, but the antibody appears to originate in the mucosal secretory system. Secondary forms exist and include associations with alcoholic cirrhosis, gluten enteropathy, and HLA-B27 arthritides. Up to 30% of cases may be familial, and putative susceptibility genes have been identified. Henoch–Schönlein purpura, a systemic vasculitis with mesangial and extrarenal vascular IgA deposits that presents with

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Acute Glomerulonephritis

nephritis, purpura, and gastrointestinal bleeding as its classical manifestations, may be pathogenetically related to IgA nephropathy (Rai et al.). The clinical presentation of IgA nephropathy ranges from asymptomatic microscopic hematuria with or without proteinuria (<15% of patients are nephrotic) to acute glomerulonephritis (5% to 10%) with episodic gross hematuria, and occasionally rapidly progressive glomerulonephritis. Serum complement levels are normal. Apart from urinary findings, hypertension may be the only clinical manifestation of IgA nephropathy. Half of patients have increased serum IgA levels, and levels do not correlate with disease activity. As in case 6, results of other serologic tests are normal or negative. Although IgA nephropathy was originally described as a benign form of renal disease, it now appears that as many as 30% to 50% of patients may reach end-stage renal disease over 20 years of follow-up. Older age at onset, heavy proteinuria, hypertension, and crescents or segmental sclerosis on biopsy are risk factors for a poor prognosis. Treatment is controversial. Most patients who have suspected IgA nephropathy but normal renal function and non–nephrotic-range proteinuria should be observed. In patients with minimal mesangial proliferation and nephrotic-range proteinuria, corticosteroid-induced remissions of proteinuria are common (Ballardie and Roberts). In patients with more classical mesangial proliferation, hematuria, and non–nephrotic-range proteinuria, studies evaluating the efficacy of combinations of steroids, cytotoxic agents, warfarin, and dipyridamole differ in their results. These agents are used much more frequently in countries in which the prevalence of IgA nephropathy is the highest. Fish oil therapy has been reported to slow progression of renal failure. Mycophenolate mofetil is reported to be useful in anecdotal case reports, and a large-scale trial is under way. In patients with Henoch–Schönlein purpura, renal involvement is often not severe and usually remits spontaneously. However, in patients with crescentic glomerulonephritis, immunosuppressive therapy may be helpful. Deposits of IgA recur in the transplanted kidney but have not been functionally significant except in a few patients with Henoch–Schönlein purpura.

Rai A, Nast C, Adler S. Henoch-Schönlein purpura nephritis. J Am Soc Nephrol. 1999;10:2637-44. PMID: 10589705

Ballardie FW, Roberts IS. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. J Am Soc Nephrol. 2002;13:142-8. PMID: 11752031

Poststreptococcal Glomerulonephritis and Other Bacterial Infections Poststreptococcal glomerulonephritis is an immune complex disorder associated with infection by nephritogenic strains of group A or, sometimes, group C streptococci. Acute glomerulonephritis may follow pharyngitis or impetigo, usually by 1 to 3 weeks. It is principally a disease of children. The classic clinical presentation of poststreptococcal glomerulonephritis is one of acute glomerulonephritis and consists of dark or smoky-colored urine and edema, often with hypertension and sometimes with oliguria. More subtle clinical manifestations, such as asymptomatic hematuria and non–nephrotic-range proteinuria, may also occur. Classic laboratory manifestations include antibodies to streptococcal antigens (antistreptolysin O, antihyaluronidase, antistreptokinase, and anti-DNase B) and hypocomplementemia. Treatment is directed at the underlying infection if it is still present at the time of diagnosis of glomerulonephritis, although it will not alter the course of glomerulonephritis. Supportive therapy for hypertension and volume overload is important to avoid congestive heart failure and encephalopathy. Immunosuppressive therapy is rarely indicated, except perhaps when the classic subepithelial hump–mesangial hypercellularity lesion is complicated by crescentic glomerulonephritis. The glomerulonephritis resolves spontaneously over weeks to months in both children and adults, but a propensity for persistent proteinuria and slowly progressive renal insufficiency may be more common in older persons.

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Acute Glomerulonephritis

Other infectious processes associated with glomerulonephritis include subacute bacterial endocarditis, ventriculoatrial shunt nephritis, chronic visceral abscesses, malaria, syphilis, hepatitis B and C infection, and HIV infection.

Lupus Nephritis

Austin HA 3rd, Klippel JH, Balow JE, le Riche NG, Steinberg AD, Plotz PH, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986;314:614-9. PMID: 3511372 Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong KongGuangzhou Nephrology Study Group. N Engl J Med. 2000;343:1156-62. PMID: 11036121

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Lupus nephritis is an immune complex–mediated complication of systemic lupus erythematosus that presents in various histologic patterns described in a World Health Organization (WHO) classification. The histologic classification is useful because it delineates lesions with different prognoses and, therefore, different treatments. Patients in classes I (normal) and II (mesangial proliferative glomerulonephritis) have good prognoses and minimal or no clinical presenting features. Patients in classes III (focal proliferative glomerulonephritis), IV (diffuse proliferative glomerulonephritis), and V (membranous lupus) present similarly, usually with nephrotic-range proteinuria and hematuria and sometimes with rapidly declining renal function. The latter occurs most commonly in patients with diffuse proliferative glomerulonephritis. The prognosis of patients with diffuse proliferative glomerulonephritis is the most serious, and most clinical trials in systemic lupus erythematosus nephritis are directed towards its treatment. Approximately 60% of patients with systemic lupus erythematosus nephritis who undergo renal biopsy have diffuse proliferative glomerulonephritis. Some biopsy results in patients with systemic lupus erythematosus are inadequately described by the WHO classification system, including those with thrombotic microangiopathic changes and those with characteristics of more than one WHO class. At least 30% of patients move from one class to another because of progression or response to therapy. Patients with systemic lupus erythematosus nephritis may present with any of the classic symptoms of the systemic disease, including arthralgias, nondeforming arthritis, malar or discoid rash, photosensitivity, oral ulcers, alopecia, myalgias, serositis, cerebritis, and myocarditis, although nephritis may sometimes be the sole initial presenting manifestation. Serum complement levels are usually low because of classic complement pathway activation. In addition, baseline superimposed congenital C4 deficiencies associated with systemic lupus erythematosus may be present. The renal presentation is generally non–nephrotic-range or nephrotic-range proteinuria, usually with hematuria, often with some pyuria and, occasionally, erythrocyte casts; the latter finding usually indicates the presence of crescents. Although not reliably distinguishable without renal biopsy, patients with diffuse proliferative glomerulonephritis tend to have more hypertension and proteinuria, a more active urine sediment, higher titers of antineutrophil antibody and anti-double-stranded DNA antibody, and more profound hypocomplementemia than do patients in other WHO classes. The most aggressive therapy is directed toward the treatment of diffuse proliferative glomerulonephritis, since rates of renal failure are still as high as 25% over 5 to 10 years of follow-up. The prognosis in patients with membranous lupus is similar to that in patients with idiopathic membranous nephropathy. In general, the more sclerosis on biopsy, the less likely the patient will benefit from drug therapy. The more proliferative the lesion, the greater the likelihood of clinical response. Treatment for diffuse proliferative glomerulonephritis usually consists of prednisone and intravenous cyclophosphamide, although azathioprine may be substituted for cyclophosphamide during pregnancy and when patients wish to maintain ovarian function (Austin et al.). Initial studies demonstrating benefit from mycophenolate mofetil are emerging, both for induction and for maintenance of remission (Chan et al.). Optimal duration of the treatment course is controversial, but therapy for 1 year after achievement

Acute Glomerulonephritis

of remission has been advised. The treatment of classes III and V are even more controversial than the treatment of diffuse proliferative glomerulonephritis, and there are fewer data to guide decision-making.

Rapidly Progressive Glomerulonephritis Case 7 A 28-year-old man who works in a chemical manufacturing plant presents with arthralgias and cough of 2 to 3 weeks’ duration, followed by hemoptysis and dark-colored urine. The patient has normal blood pressure and low-grade fever (37.2 °C [99.0 °F]). Fine crackles are heard in his lungs bilaterally. He has no cardiac murmurs, rubs, or gallops and no neck vein distention. Frank arthritis, skin rashes, and edema are absent, and abdominal and neurologic examinations are normal. Urinalysis shows 30 to 40 dysmorphic erythrocytes/hpf and occasional erythrocyte casts. He has 1+ to 2+ proteinuria. Serum creatinine concentration is elevated (2.3 mg/dL). Complete blood count is normal except for a hemoglobin level of 9.8 g/dL with microcytic indices. Results of serologic testing are normal or negative, except for the presence of anti–glomerular basement membrane antibody and a low titer of p-ANCA. Chest radiography reveals diffuse bilateral pulmonary infiltrates. Renal biopsy shows that more than 90% of the glomeruli have crescents. Immunofluorescence microscopy shows linear IgG and C3 along the glomerular basement membrane. No deposits are observed ultrastructurally. Rapidly progressive glomerulonephritis is clinically similar to acute glomerulonephritis with hematuria. Erythrocyte casts and non–nephrotic-range proteinuria, azotemia, and hypertension are often present. Unlike acute glomerulonephritis, however, rapidly progressive glomerulonephritis tends to move quickly to end-stage renal disease. The term is used interchangeably with crescentic glomerulonephritis. Crescentic glomerulonephritis is a nephrologic emergency. A frequently used classification of crescentic glomerulonephritis is based on three basic pathogenetic features: association with antineutrophil cytoplasmic antibody (ANCA), anti–glomerular basement membrane antibody, or immune complex (Table 8). Patients with ANCA-associated crescentic glomerulonephritis lack or have few glomerular immune deposits, and this disease category includes Wegener’s granulomatosis, microscopic polyangiitis, Churg–Strauss disease, and idiopathic crescentic glomerulonephritis. These disorders are characterized by circulating antibodies against neutrophil lysosomal enzymes. Cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) is directed against the lysosomal enzyme protease-3, and, when present, is almost always associated with a vasculitic condition. Perinuclear antineutrophil cytoplasmic antibody (p-ANCA) is most often directed against the lysosomal enzyme myeloperoxidase, but numerous other antigens have been implicated, and the antibody may be present without evidence of a classical vasculitic disorder. There is controversy regarding whether antineutrophil cytoplasmic antibodies are simply markers of vasculitis or whether they play a pathogenetic role in the development of vasculitis. The category of anti–glomerular basement membrane–associated crescentic glomerulonephritis consists of Goodpasture’s syndrome, with or without pulmonary hemorrhage. Immune complex–mediated crescentic glomerulonephritis consists of various diseases that occur in both noncrescentic and

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Acute Glomerulonephritis

TA B L E 8 Causes of Rapidly Progressive Glomerulonephritis

ANCA-associated Wegener’s granulomatosis Microscopic polyarteritis nodosa Churg–Strauss disease Idiopathic crescentic glomerulonephritis Anti-GBM mediated Goodpasture’s syndrome Idiopathic anti-GBM disease Immune-complex mediated Lupus nephritis Infection-associated (poststreptococcal, atrioventricular shunts, chronic visceral abscesses, subacute bacterial endocarditis) Cryoglobulinemia Henoch–Schönlein purpura ANCA = antineutrophil cytoplasmic antibody; GBM = glomerular basement membrane.

crescentic forms, including systemic lupus erythematosus, cryoglobulinemia, poststreptococcal (and other infection-related) glomerulonephritis, and Henoch–Schönlein purpura.

Goodpasture’s Syndrome

Kalluri R, Wilson CB, Weber M, Gunwar S, Chonko AM, Neilson EG, et al. Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome. J Am Soc Nephrol. 1995;6:1178-85. PMID: 8589284

KEYPOINTS

• Goodpasture’s syndrome is suggested by the clinical presentation of a pulmonary–renal syndrome consisting of hemoptysis, pulmonary infiltrates, and hematuria with red blood cell casts. • The diagnosis of Goodpasture’s syndrome is confirmed by circulating anti–glomerular basement membrane antibodies in the blood and the characteristic linear immunofluorescent pattern of deposition of antibodies (and complement) along the glomerular basement membrane on renal biopsy.

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The patient in case 7 has Goodpasture’s syndrome, as suggested by the clinical presentation of a pulmonary-renal syndrome consisting of hemoptysis, pulmonary infiltrates, and hematuria with erythrocyte casts. The diagnosis is confirmed by the presence of circulating anti–glomerular basement membrane antibodies in the blood and the characteristic linear immunofluorescent pattern of deposition of antibodies (and complement) along the glomerular basement membrane on renal biopsy. Approximately 30% of patients with Goodpasture’s syndrome also manifest p-ANCA. The pathogenesis is unknown but reflects development of antibodies to an epitope on the noncollagenous domain of the α chain of type IV collagen present in normal glomerular basement membrane and alveolar basement membrane (Kalluri et al.). Exposure to volatile hydrocarbons, cigarette smoke, or respiratory viral infections have been posited to unmask the antigen in alveoli and induce antibody in genetically susceptible persons. Goodpasture’s syndrome occurs in all age groups and has only a minimal male predominance. Pulmonary symptoms (cough, dyspnea, crackles, and hemoptysis) precede or are coincident with renal symptoms in more than 70% of patients. Substantial alveolar bleeding can occur without frank hemoptysis. Anemia (with characteristics of iron deficiency) may be out of proportion to the degree of azotemia, presumably owing to sequestration of blood in the lungs. Azotemia occurs in 50% to 70% of cases at initial presentation. Arthritis or arthralgias are common. Hypertension is uncommon (<20% of patients) until renal failure is advanced. Urinalysis shows hematuria, erythrocyte casts, and non–nephrotic-range proteinuria. Results of serologic testing are usually negative or normal except for the presence of anti–glomerular basement membrane antibody. Antibody titer does not correlate with severity of illness. In nonoliguric patients with less functional impairment, combination treatment with corticosteroids, plasmapheresis, and cyclophosphamide can successfully induce remission. Most untreated patients progress to end-stage renal disease, and oliguric patients with a serum creatinine concentration greater than 6 mg/dL are less likely to recover renal function even if treated. Smoking or exposure to volatile hydrocarbons may precipitate relapse of pulmonary hemorrhage. Recurrence in renal allografts is uncom-

Acute Glomerulonephritis

mon unless patients undergo transplantation while they still have high titers of anti–glomerular basement membrane antibody.

Wegener’s Granulomatosis Wegener’s granulomatosis is a granulomatous vasculitis of medium-sized to small arterioles and venules. Classically, the diagnosis is made by the histologic findings of necrotizing vasculitis and granulomas. Cytoplasmic antineutrophil cytoplasmic antibody is present in approximately 80% of patients with Wegener’s granulomatosis and aids in diagnosis. Some evidence suggests that c-ANCA may also be important in pathogenesis. Presenting symptoms most often involve the upper respiratory tract and include rhinorrhea, sinusitis, nasopharyngeal mucosal ulceration, cough, shortness of breath, and hemoptysis. Transient infiltrates or nodular densities may be seen on chest radiography. Renal involvement is characterized by proteinuria, dysmorphic hematuria, and occasionally erythrocytes. Approximately 10% of patients have azotemia on presentation. Serum complement levels are normal. Renal biopsy usually shows crescentic glomerulonephritis without glomerular immune deposits in patients who present with an acute or rapidly progressive nephritic picture. Tubulointerstitial granulomas may occasionally be seen. Additional symptoms include fever, weight loss, malaise, arthralgias, nondeforming arthritis, mononeuritis multiplex, skin papules, vesicles, purpura, and leukocytoclastic vasculitis. A finding of c-ANCA is specific and sensitive in establishing in the diagnosis; however, some patients have p-ANCA, and up to 10% of patients may test negative for ANCA. Antineutrophil cytoplasmic antibody titers may be useful in following response to therapy and predicting relapse. The mortality rate at 2 years is more than 80% to 90% for patients with untreated nephritis. Cyclophosphamide and prednisone induce remission in 80% to 90% of treated patients, but there is a significant incidence (5% to 6%) of bladder cancer in the decade after prolonged treatment with daily oral cyclophosphamide. Intravenous cyclophosphamide, mycophenolate mofetil, and azathioprine are occasionally used in place of oral cyclophosphamide to minimize toxicity, although it remains to be proven that the latter two agents are as effective in inducing or maintaining remission as are regimens using cyclophosphamide. Relapse is frequent, and multiple courses of treatment may be necessary. Other forms of systemic vasculitis that cause crescentic glomerulonephritis, including microscopic polyangiitis nodosa and Churg–Strauss disease, are treated with protocols similar to that of Wegener’s granulomatosis. Patients with this disease are more likely to test positive for perinuclear and cytoplasmic antineutrophil cytoplasmic antibody.

Tubulointerstitial Diseases Case 8 A 65-year-old woman presents with chronic fatigue that has worsened over the past 3 to 4 months. In the 2 previous months, she noted polydipsia and polyuria and woke up once or twice each night to urinate. On the day of presentation, she experienced severe back pain. She has no fever, sweats, or chills. Medical history is unremarkable, and she is taking no medications except for oral calcium carbonate, 1 g/d, to prevent osteoporosis. Physical examination is remarkable for normal vital signs. She appears pale. There is point tenderness over the 10th tho-

KEYPOINTS

• Berger’s disease, or IgA nephropathy, is the most common cause of idiopathic glomerulonephritis. • The clinical presentation of IgA nephropathy ranges from asymptomatic microscopic hematuria with or without proteinuria to acute glomerulonephritis with episodic gross hematuria and, occasionally, rapidly progressive glomerulonephritis. • Up to 30% to 50% of patients with IgA nephropathy may reach end-stage renal disease over 20 years of follow-up. Older age at onset, heavy proteinuria, hypertension, and crescents or segmental sclerosis on biopsy are risk factors for a poor prognosis. • Most patients who have IgA nephropathy but normal renal function and non–nephrotic-range proteinuria should be observed. • In lupus nephritis, the most aggressive therapy is directed toward the treatment of diffuse proliferative glomerulonephritis (World Health Organization class IV), since rates of renal failure are still as high as 25% over 5 to 10 years of follow-up. The prognosis in patients with membranous lupus is similar to that in patients with idiopathic membranous nephropathy. • In rapidly progressive glomerulonephritis (also known as crescentic glomerulonephritis), red blood cell casts, non–nephrotic-range proteinuria, azotemia, and hypertension are often present. • Goodpasture’s syndrome is suggested by the clinical presentation of a pulmonary–renal syndrome consisting of hemoptysis, pulmonary infiltrates, and hermaturia with red blood cell casts. • The diagnosis of Goodpasture’s syndrome is confirmed by circulating anti–glomerular basement membrane antibodies in the blood and the characteristic linear immunofluorescent pattern of deposition of antibodies (and complement) along the glomerular basement membrane on renal biopsy.

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Causes and Diagnosis

racic vertebra. Hemography shows normochromic normocytic anemia without abnormalities of platelets or leukocytes. Serum electrolytes are normal except for a calcium level of 12.8 mg/dL. Serum creatinine concentration is elevated (2.6 mg/dL), and blood urea nitrogen is 50 mg/dL. Urinalysis is unremarkable except for trace proteinuria on dipstick and 3+ precipitation with sulfosalicylic acid. Measurement of quantitative immunoglobulins shows a monoclonal increment in IgG λ light chains in serum and urine and decreases in serum IgM and IgA levels.

Causes and Diagnosis

KEYPOINTS

• Tubulointerstitial diseases of the kidney may result from direct injury to the tubulointerstitium by infections, metabolic disorders, crystal-induced injury, medications, immunologic processes, genetic disorders, neoplasms, ischemia, and obstruction. • Tubulointerstitial inflammation and fibrosis is a concomitant feature of most forms of glomerular proteinuria and correlates well with progressive renal insufficiency. • Many tubulointerstitial diseases do not have characteristic features on renal biopsy; thus, renal biopsy is not often performed for diagnostic purposes in patients with suspected tubulointerstitial disease.

KEYPOINTS

• Nephrosclerosis consists of intimal thickening and luminal narrowing of renal arteries and arterioles, which in turn causes tissue ischemia that leads to inflammation and scarring fibrosis. • Chronic hypertension is the most common systemic condition that causes nephrosclerosis.

32

Tubulointerstitial diseases of the kidney may be due to direct injury to the tubulointerstitium. Factors that cause such injury include infections; metabolic disorders; crystal-induced injury; medications; immunologic processes; genetic disorders; neoplasms; and miscellaneous processes, including ischemia and obstruction (Table 9). Chronic glomerular proteinuria may also injure the tubulointerstitium. In this setting, the injury is believed to stem from one of two causes. Some studies have shown that albuminuria is a direct cause of tubulointerstitial injury in the setting of glomerular proteinuria. Others have demonstrated that in glomerular proteinuria, injury results from activation of tubular and interstitial cells by filtered or locally stimulated growth factors and cytokines. Thus, tubulointerstitial inflammation and fibrosis is a concomitant feature of most forms of glomerular proteinuria and correlates well with progressive renal insufficiency. Unlike glomerular disease, which is classified and diagnosed on the basis of histologic characteristics, many tubulointerstitial diseases are histologically similar and do not have characteristic features on renal biopsy. History, physical examination, and laboratory and radiologic diagnostic tests are often helpful in suggesting specific forms of tubulointerstitial diseases. For these reasons, renal biopsy is not often performed for diagnostic purposes in patients with suspected tubulointerstitial disease.

Nephrosclerosis Nephrosclerosis is a disease of large and small arteries and glomerular arterioles that causes tubulointerstitial injury. The disease consists of intimal thickening and luminal narrowing of renal arteries and arterioles, which in turn causes tissue ischemia that leads to inflammation and scarring fibrosis. Chronic hypertension is the most common systemic condition causing nephrosclerosis, but older age, black ethnicity, and diabetes mellitus increase the risk for this condition in the setting of hypertension.

Myeloma Kidney The patient described in case 8 has myeloma kidney, which is characterized by anemia, hypercalcemia, a pathologic vertebral fracture, increased urinary light chains in the absence of proportional albuminuria, and a monoclonal paraprotein. The elevated serum creatinine concentration most likely represents composite processes due to prerenal azotemia from hypercalcemia-induced nephrogenic diabetes insipidus and to intratubular precipitation of the paraprotein inducing tubular obstruction, causing direct and indirect tubular injury. The latter process is known as myeloma kidney and is attributable to biochemical

Analgesic Nephropathy

characteristics of the light chain and not of the host. Paraproteins with λ light chains are most likely to induce myeloma kidney, whereas paraproteins with κ light chains are more likely to deposit in glomeruli and induce the nephrotic syndrome. Occasionally, plasma-cell infiltration may occur. Renal amyloidosis may also complicate the lesion and is associated with λ light chains. Myeloma kidney is best prevented by maintenance of hydration to inhibit supersaturation and precipitation of the paraprotein and by therapy to minimize the amount of circulating paraprotein. Chemotherapy is both preventive and therapeutic. In cases of progressive azotemia despite adequate chemotherapy, plasmapheresis has been advocated, although this practice is not universally accepted. Renal involvement in patients with multiple myeloma is associated with shortened survival.

Analgesic Nephropathy Analgesic nephropathy is a chronic tubulointerstitial disease characterized by progressive loss of renal function in a patient with a history of ingestion of at least 2 kg of analgesics over time, without any evidence for another identifiable cause of tubulointerstitial disease (De Broe and Elseviers). The disorder is diagnosed by exclusion. Analgesic nephropathy usually occurs when a mixture of analgesics has been used, such as phenacetin, acetaminophen, caffeine, and codeine, but it may also occur when a single agent is used long term. The role of nonsteroidal anti-inflammatory drugs in the development of analgesic nephropathy remains controversial, but many believe that these drugs may be contributors. Whether the newer cyclooxygenase-2 inhibitors have similar actions is not currently known. An irregular contour of the kidney on computed tomography helps to confirm clinical suspicion. The presentation of analgesic nephropathy is often nonspecific, with renal insufficiency as the presenting manifestation in a patient with a bland urinary sediment and non-nephrotic proteinuria, but patients may also present with the hematuria and colicky pain of papillary necrosis. Treatment consists predominantly of discontinuation of treatment with analgesics, which, if done early in the course, may stabilize renal function. However, discontinuation is often difficult to achieve because patients may be using the drugs to relieve the pain of chronic headache or degenerative joint disease. The long-term consequences of analgesic nephropathy include endstage renal disease and transitional-cell carcinoma of the urinary tract; the latter occurs particularly in patients who used phenacetin. Patients with persistent nondysmorphic hematuria and long-term use of analgesics should be evaluated for neoplasm. Analgesic abuse may also contribute to a worse renal outcome in patients with other independent renal diseases. A Chinese herb that contains a plant nephrotoxin called aristolochic acid, taken to relieve pain, has also been implicated as a cause of chronic interstitial nephritis. Its use produces a characteristic histopathologic profile that progresses to end-stage renal disease.

Genetic Disorders and Renal Disease Genetic disorders may cause kidney disease either directly by causing genetically mediated renal functional or morphologic abnormalities (for example, autosomal dominant polycystic kidney disease) or through genetically induced systemic disturbances in which the kidney is involved secondarily (such as Fabry’s disease or primary hyperoxaluria). About 50 mendelian, or single-gene, renal disorders are currently known (George and Neilson) (Table 10). The most

TA B L E 9 Major Causes of Acute

and Chronic Tubulointerstitial Diseases Genetic Polycystic kidney disease Medullary cystic disease Infectious Pyelonephritis Emphysematous pyelonephritis Tuberculosis Metabolic Hypercalcemia Hyperuricemia Hypokalemia Oxalosis Cystinosis Immunologic Sjögren’s syndrome Drug hypersensitivity Renal transplant rejection Toxic Analgesics Chinese herbs Lithium Amphotericin Cisplatin Cyclosporine Radiation Anatomic Obstruction Reflux Miscellaneous Atheroembolic disease

De Broe ME, Elseviers MM. Analgesic nephropathy. N Engl J Med. 1998;338:44652. PMID: 9459649 KEYPOINTS

• Analgesic nephropathy is a chronic tubulointerstitial disease characterized by progressive loss of renal function in a patient with a history of ingestion of at least 2 kg of analgesics over time, with no other identifiable cause of tubulointerstitial disease.

George A Jr, Neilson E. Genetics of kidney disease. Am J Kidney Dis. 2000;35(4 Suppl 1:S160-S169. PMID: 10766015

33

Genetic Disorders That Cause Direct Renal Effects

Sessa A, Conte F, Meroni M, Battini G. Hereditary kidney diseases. Contrib Nephrol. 1997;122:1-217. PMID: 9399028

common are polycystic kidney disease, medullary sponge kidney disease, Alport’s syndrome, and cystinuria. These disorders are transmitted in families as autosomal dominant, autosomal recessive, or X-linked traits. The genetics of even single-gene disorders is complex because several disorders that appear to be phenotypically the same (for example, autosomal dominant polycystic kidney disease, Bartter’s syndrome, Alport’s syndrome, and cystinuria) can be caused by two or three distinct genotypes. A complete and continuously updated list of these single-gene disorders, most of which are rare, can be found at http://www.ncbi.nim.nih.gov/Omim (Sessa et al.). In contrast, a wide variety of common disorders affecting the kidney result from complex interactions between genetic predisposition and environmental factors. Such genetically complex traits, also called polygenic disorders, arise from subtle variations in multiple genes that interact with diverse environmental factors. In these disorders, the clinical expression of disease varies according to the interaction between genetic predisposition and key environmental or host factors. Examples include hypertension and salt intake, or diabetic predisposition and obesity.

TA B L E 1 0 Some Renal Disorders Caused by Single-Gene Abnormalities

Disease

Mode of Inheritance

Gene Locus

Frequency

Polycystic kidney disease

Autosomal dominant (common) Autosomal recessive (rare)

Chromosome 16 and 4

1:1000 1:40,000

Alport’s syndrome

X-linked (80%) Autosomal recessive (10%)

Xq22

Benign familial hematuria Nephrogenic diabetes insipidus Bartter’s syndrome

Autosomal recessive (carrier)

2q35-37 2q and 13q

Autosomal recessive Autosomal recessive

Not known

1:2 Million

Gitelman’s syndrome Cystinosis Fabry’s disease

Autosomal recessive Autosomal recessive X-linked

Chromosome 16 Chromosome 2p X-q21,22

1:7000 1:40,000

Hyperoxaluria, type I, II, II

Autosomal recessive

2q36-37

Not known

Genetic Disorders That Cause Direct Renal Effects

Igarashi P, Somlo S. Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol. 2002;13:2384-98. PMID: 12191984

34

Polycystic kidney disease is characterized by multiple epithelial-lined renal cysts scattered throughout the cortex and medulla of both kidneys. The disease has two major forms. Autosomal dominant polycystic kidney disease is typically discovered in patients 30 to 50 years of age, whereas autosomal recessive polycystic kidney disease is usually expressed at birth and causes death during the neonatal period (Igarashi and Somlo). Autosomal recessive polycystic kidney disease is caused by a mutation on chromosome 16 and is rare (1 in 40,000 live births). Autosomal dominant polycystic kidney disease is the fourth leading cause of renal failure. It is caused by an abnormal gene on the short arm of chromosome 16 in 95% of cases. An abnormal gene on chromosome 4 accounts for most of the remainder of cases. Recent evidence implicates a third gene in some cases of this disease. Autosomal dominant polycystic kidney disease occurs at a frequency of about 1 in 1000 persons. It affects all racial and ethnic groups. Early clinical manifestations include back and flank pain, hematuria, renal

Genetic Disorders That Cause Direct Renal Effects

stones, hypertension, and urinary tract infections (Fick and Gabow). Approximately 50% of patients develop renal insufficiency before 70 years of age, and renal function declines linearly over several years. Autosomal dominant polycystic kidney disease is associated with cerebral aneurysms (especially if there is a family history of aneurysm), hepatic cysts (40% to 60% of patients), mitral and aortic valve prolapse, and colonic diverticular disease. As many as 25% of patients with autosomal dominant polycystic kidney disease do not have a family history of the disease. In some of these patients, the disease is due to a new mutation. In other patients, family members may have died of other causes, so that disease in the patient is detected only at a later age, when symptoms or signs of renal failure are first observed. Medullary sponge kidney, which does not cause renal failure, is associated with hematuria, hypercalciuria (50% of patients), nephrocalcinosis, calcium stone disease, and hemihypertrophy. Familial occurrence accounts for some, but not most, cases. The diagnosis is made by intravenous pyelography showing small cystic outpouchings of the renal papillary ducts. Alport’s syndrome is an X-linked disorder in 80% of patients and an autosomal recessive disorder in 11% of patients. Affected men develop hematuria, proteinuria, and renal failure in the second or third decade of life. The abnormal gene is on Xq22 in the X-linked disorder and on 2q in the autosomal recessive disorder. The genetic abnormality causes a disorder of type IV and V collagen and results in abnormalities of the lens and glomerular basement membrane and in deafness. Affected heterozygous women have hematuria, but renal failure is uncommon. Benign familial hematuria is a disorder of collagen synthesis that causes microscopic or gross hematuria and an abnormally thin glomerular basement membrane. Genetic studies have suggested that this disorder represents a carrier state of the autosomal recessive Alport’s syndrome. Unlike Alport’s syndrome, benign familial hematuria usually does not result in renal failure. Benign familial hematuria usually presents in childhood; a family history of hematuria is suggestive of the condition. Nephrogenic diabetes insipidus, Bartter’s syndrome, Gitelman’s syndrome, and Liddle’s syndrome are genetically mediated disorders of renal tubular function. Tubular unresponsiveness to antidiuretic hormone in nephrogenic diabetes insipidus causes urinary concentrating defects, polyuria, and thirst. Abnormal chloride transporters in the ascending loop of Henle (Bartter’s syndrome) and the distal tubule (Gitelman’s syndrome) result in hypokalemia, hypochloremic metabolic alkalosis, renal potassium wasting, and normotension. Bartter’s syndrome causes growth retardation. Nephrogenic diabetes insipidus is usually discovered in infancy or early childhood, whereas Bartter’s syndrome is usually diagnosed in childhood or the early teen years. Nephronophthisis and medullary cystic disease complex are related conditions characterized by multiple cysts located in the corticomedullary junction and medulla. The cysts arise from the distal and collecting tubules. The disease produces tubular atrophy, interstitial inflammation and scarring, and renal failure. Familial nephronophthisis is a recessive disorder that causes renal failure before 20 years of age. Medullary cystic disease, an autosomal dominant condition, produces renal failure in early adulthood. In these disorders, the initial clinical presentation consists of polyuria, polydipsia, and nocturia (due to a renal concentrating disorder) and renal salt wasting, all of which stem from the tubular injury produced by the cystic and scarring process. Azotemia and end-stage renal failure follow. Cystinuria is covered in the section on nephrolithiasis.

Fick GM, Gabow PA. Hereditary and acquired cystic disease of the kidney. Kidney Int. 1994;46:951-64. PMID: 7861721

KEYPOINTS

• Autosomal dominant polycystic kidney disease is typically found in patients 30 years of age or older who have a family history of the disorder. • Autosomal dominant polycystic kidney disease is the fourth most common cause of renal failure and is characterized by multiple cysts distributed among both kidneys. • Benign familial hematuria is characterized by unexplained microhematuria or gross hematuria and erythrocyte casts. It does not usually result in renal failure. • Benign familial hematuria usually presents in childhood; a family history of hematuria is suggestive. • Nephrogenic diabetes insipidus is usually discovered in infancy or early childhood. It is characterized by polyuria and thirst. • Bartter’s syndrome is usually diagnosed in childhood or the early teen years. The syndrome causes growth retardation and hypokalemia, but patients are normotensive.

35

Genetic Disorders That Cause Systemic Abnormalities Affecting The Kidney

Genetic Disorders That Cause Systemic Abnormalities Affecting The Kidney

KEYPOINTS

• Fabry’s disease is characterized by acroparesthesias, cutaneous angiokeratomas, proteinuria, and azotemia. • Primary hyperoxaluria causes calcium oxalate nephrolithiasis in childhood.

Fabry’s disease is due to a deficiency of α-galactosidase-A enzyme caused by a gene abnormality on the long arm of the X chromosome (q21 and q22). Men are more often affected than women. The enzyme deficiency causes an accumulation of neutral glycophospholipid in endothelial, epithelial, and smoothmuscle cells throughout the body. Marked accumulation of glycophospholipids in the glomerular and tubular cells occurs. Clinical features include proteinuria, azotemia, renal failure, cutaneous angiokeratomas, painful paresthesias of the hands, and premature coronary disease. Electron microscopy of the kidney reveals the characteristic inclusion bodies in the cytoplasm, with concentric lamellation and zebra or onion-skin appearance. The same structures are found on electron microscopic examination of spun urine sediment. Primary hyperoxaluria results from an inborn error of metabolism in which glyoxalate cannot be converted to glycine because of a deficiency of glyoxalate aminotransferase or glyoxalate reductase in the liver. There are three genetic forms. Type I and II disease have similar clinical presentations. Typically, the patient develops nephrolithiasis and nephrocalcinosis before 20 years of age, and end-stage renal failure occurs in 50% of patients by 15 years of age. Renal biopsy demonstrates marked calcium oxalate deposition, but oxalate deposition is found in many other tissues as well. Type I disorder is caused by an abnormal gene on chromosome 2q36–37 and is the most common. Type III disorder is caused by excessive intestinal reabsorption of oxalate in the absence of other gastrointestinal disease.

Genetic Factors in Diabetic Nephropathy Four lines of evidence support a genetic susceptibility for diabetic nephropathy. First, familial clustering of nephropathy is observed among Pima Indians, in whom the incidence of proteinuria in diabetic offspring is 14% if neither parent had proteinuria, 23% if one diabetic parent had proteinuria, and 46% if both parents had diabetes and proteinuria. Second, family history of hypertension and nephropathy are strongly associated. Third, renal lesions in diabetic siblings are similar. Finally, polymorphisms of angiotensin-converting enzyme gene and collagen gene are present.

Fluid and Electrolytes Figure 3 shows the normal distribution of water and electrolyte solutes and their contributions to intracellular fluid, extracellular fluid, and plasma osmolality (the concentration of solutes in the body water, expressed as mosmol/kg). The concentration of solute in the intracellular fluid is the same as that in the extracellular fluid, resulting in equivalent osmolality in both spaces. The solutes responsible for the osmolality in the intracellular fluid and extracellular fluid, however, differ substantially. In the intracellular fluid, potassium and organic phosphate esters are the predominant osmoles. In the extracellular fluid, sodium salts account for most of the osmoles. Nonsodium solutes, such as urea and glucose, have effects on the plasma osmolality equal to their molar concentrations: for example, Posm = 2 × Na + blood urea nitrogen/2.8 + glucose/18. High levels of glucose and urea have varying effects on water distribution and the serum sodium concentration. Urea readily distributes across cell mem-

36

Hyponatremia

tive extracellular fluid volume is greatly reduced. When significant volume depletion and hypo-osmolality occur simultaneously, the volume stimulus overrides the inhibitory effect of hypo-osmolality and secretion of antidiuretic hormone increases.

Hyponatremia Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342:1581-9. PMID: 10824078

Hyponatremia, defined as a plasma sodium concentration less than 136 meq/L, occurs in as many as 4% of hospitalized patients (Adrogue et al.). With the exception of the rare patient with psychogenic polydipsia, whose water intake exceeds the water-excreting capacity of kidney, hyponatremia usually results from the inability to appropriately excrete dilute urine. Hyponatremia can be associated with a high, normal, or low plasma osmolality. Hyponatremia with normal or high osmolality occurs most often in patients with hyperglycemia or those receiving mannitol infusion. In these cases, the hyponatremia occurs as water moves from the cellular to the extracellular space through the osmotic effect of glucose or mannitol. Most patients with hyponatremia have low plasma osmolality with excess body water relative to body sodium. Usually this state is due to the nonosmotic stimulation of antidiuretic hormone, and these patients excrete concentrated urine (that is, their renal water excretion is decreased). Evaluation of the extracellular fluid status is the first step in determining the cause of hypoosmolal hyponatremia (Table 11). Biochemical findings help to further confirm the diagnosis. For example, very low levels of blood urea nitrogen and uric acid in a euvolemic patient suggest the syndrome of inappro-

TA B L E 1 1 Evaluation of Hyponatremia

Cause

Extracellular Fluid Volume Status

Clinical

Volume Depletion*

Euvolemia†

Volume Excess‡

Gastrointestinal fluid loss

SIADH

Adrenal insufficiency Renal sodium loss

Hypothyroidism Cortisol deficiency or panhypopituitarism

Congestive heart failure Cirrhosis Nephrotic syndrome

Adrenal Renal salt wasting From Nonrenal Losses

From Renal Losses

Plasma osmolality

120 meq/L 250 mosmol/kg

120 meq/L 250 mosmol/kg

120 meq/L 250 mosmol/kg

120 meq/L 250 mosmol/kg

Urine sodium Urine osmolality

<10 meq/L >600–800 mosmol/kg

>20 meq/L 600–800 mosmol/kg

<10 meq/L

Plasma ADH BUN

Elevated Elevated

Elevated Elevated

Equals dietary intake Inappropriately elevated (>100 mosmol/kg) Elevated <10 mg/dL

Serum uric acid

Elevated

Elevated

<4 mg/dL

Elevated

Biochemical§ Serum sodium||

*Volume depletion is defined as orthostasis, decreased skin turgor, and hypotension. †Euvolemia

is defined as no clinically evident volume abnormalities.

‡

Volume excess is defined as edema.

§It

is assumed that diuretics are not being used.

||Serum

sodium level of 120 meq/L has been arbitrarily assumed in each category.

ADH = antidiuretic hormone; BUN = blood urea nitrogen; SIADH = syndrome of inappropriate secretion of antidiuretic hormone.

38

>300–400 mosmol/kg Elevated Elevated

Hyponatremia

priate antidiuretic hormone. An elevated blood urea nitrogen level and low urine sodium excretion suggest that true volume depletion is present or that the patient has nephrotic syndrome, cirrhosis, or congestive heart failure (conditions that cause decreased effective circulatory volume). The clinical history and findings on physical examination allow differentiation among these possibilities. Proper treatment of hyponatremia should follow from the above assessment. Volume-depleted patients should be treated with normal saline to expand the extracellular fluid volume and thus inhibit the release of antidiuretic hormone that had been triggered by hypovolemia. Patients with extracellular fluid volume expansion (such as those with heart failure) require treatment of the underlying disorder and restriction of water and salt intake. Water restriction (intake of less than 600 to 800 mL/d) needs to be imposed only when the serum sodium concentration is less than 125 meq/L. Such patients may also benefit from treatment with loop diuretics because these diuretics favor excretion of more water than sodium, thus increasing water excretion. In hyponatremic patients with euvolemia, the pathophysiologic cause is increased production or release of antidiuretic hormone on a nonosmolar and nonvolume basis. Cortisol and thyroid deficiencies may cause euvolemic hyponatremia due to increased release of antidiuretic hormone. As many as one third of hospitalized patients with hyponatremia have the syndrome of inappropriate antidiuretic hormone secretion. The causes for this syndrome include central nervous system disorders; such medications as fluoxetine and thiazide diuretics; and neoplasms, especially small-cell carcinoma (Table 12). TA B L E 1 2 Some Causes of the Syndrome of Inappropriate Antidiuretic

Hormone Secretion Increased hypothalamic production of antidiuretic hormone Neuropsychiatric disorders Central nervous system infections Central nervous system malignancies Psychosis Drugs: cyclophosphamide, vincristine, haloperidol, fluoxetine Pulmonary disease: pneumonia, acute respiratory failure Surgery Severe nausea Idiopathic cause Ectopic production of antidiuretic hormone Carcinoma: small-cell lung, bronchogenic, neuroblastoma Potentiation of antidiuretic hormone effect in the kidney Chlorpropamide, carbamazepine, intravenous cyclophosphamide, tolbutamide

When the serum sodium concentration decreases to less than 110 meq/L, coma and death may result. Severe symptomatic hyponatremia occurs particularly postoperatively in women of child-bearing age. Treatment usually requires infusions of hypertonic saline with or without furosemide. The quantity of sodium chloride required to increase the plasma sodium is calculated as follows: meq Na required = total body water × desired increase in plasma Na meq Na required = 0.6 (or 0.5 in women) × body weight in kg × desired increase in plasma Na 39

Hypernatremia

Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol. 1994;4:1522-30. PMID: 8025225 Decaux G. Difference in solute excretion during correction of hyponatremic patients with cirrhosis or syndrome of inappropriate secretion of antidiuretic hormone by oral vasopressin V2 receptor antagonist VPA-985. J Lab Clin Med. 2001;138:18-21. PMID: 11433224

KEYPOINTS

• Although ethanol, methanol, and ethylene glycol are not included in the formula for calculating the plasma osmolality, they do cause an increase in measured osmolality. • A difference of greater than 10 mosmol/kg between the measured and calculated osmolality is considered an elevated osmolal gap and suggests the presence of one of these osmoles. The most common cause of an elevated osmolol gap is ethanol intoxication. • Hyponatremia with normal or high osmolality occurs most often in patients with hyperglycemia or those receiving mannitol infusion. Most patients with hyponatremia have low plasma osmolality with excess body water relative to body sodium; usually this state is due to the nonosmotic stimulation of antidiuretic hormone. • In hyponatremic patients with euvolemia, the pathophysiologic cause is increased production or release of antidiuretic hormone on a nonosmolar and nonvolume basis. • Up to one third of hospitalized patients with hyponatremia have the syndrome of inappropriate antidiuretic hormone, which can be caused by central nervous system disorders; by medications, such as fluoxetine and thiazide diuretics; and neoplasms, especially small-cell carcinoma. • In acute symptomatic hyponatremia, the rate of correction should not exceed 8 to 12 meq/L in the first 24 hours; increasing the serum sodium concentration too rapidly can result in central pontine myelinosis. In chronic asymptomatic hyponatremia, correction is best accomplished slowly by water restriction.

Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med. 2000;342:1493-9. PMID: 10816188

40

Although the sodium circulates mainly in the extracellular fluid, the above formula uses total body water as the space of distribution for sodium because when sodium is infused, water shifts from the intracellular fluid to the extracellular fluid. The rate of correction of symptomatic hyponatremia should be guided by the rate at which the hyponatremia has developed. In acute symptomatic hyponatremia (usually defined as hyponatremia of less than 48 hours’ duration), the rate of correction should not exceed 8 to 12 meq/L in the first 24 hours. Increasing the serum sodium concentration too rapidly can result in a severe neurologic injury known as central pontine myelinosis. In one recent study, no patient experienced a severe neurologic complication if the serum sodium concentration was corrected at a rate less than 0.55 meq/h to a concentration of 120 meq/L, or by less than 12 meq during the first 12 hours or 18 meq by 48 hours (Sterns et al.). In chronic asymptomatic hyponatremia, correction is best accomplished slowly by water restriction. Recently, a vasopressin V2 receptor antagonist was used clinically to successfully treat hyponatremic patients with cirrhosis and the syndrome of inappropriate antidiuretic hormone (Decaux). This agent may prove to be an effective therapy.

Hypernatremia Hypernatremia is defined as an increase in the serum sodium concentration to greater than 145 meq/L (Adrogue et al.). It is rarely caused by excessive ingestion of sodium; rather, it is due to loss of hypotonic fluids from the body with TA B L E 1 3 Causes of Hypernatremia

Increased water loss Insensible Burns Fever/heat Mechanical ventilation/hyperventilation Gastrointestinal loss Vomiting/nasogastric tube suction Diarrhea Renal loss Central diabetes insipidus Nephrogenic diabetes insipidus Osmotic diuresis Reduced water intake Hypothalamic dysfunction Reduced thirst Essential hypernatremia Inability to drink water Comatose Infant not given adequate water Hypertonic infusions Saline/sodium bicarbonate Water shifts out of extracellular fluid compartment Seizure/extreme exercise (water shifts into muscle cells) Gastrointestinal bleeding with intraluminal protein catabolism (water shifts into lumen of intestine)

Potassium Metabolism

inadequate water replacement (Table 13). A typical patient with the latter condition is an elderly person with dementia and fever who resides in a nursing home, has increased insensible water losses, and is unable or too confused to drink adequately. Hypernatremia (hypertonicity) stimulates central nervous system receptors to produce and release antidiuretic hormone and stimulates thirst. Even if release of antidiuretic hormone or its renal action is defective, thirst-driven drinking will prevent the patient from becoming severely hypernatremic. Therefore, severe hypernatremia usually indicates a defective thirst stimulus or an inability to drink water, as well as some defect in renal concentrating function. Symptoms of hypernatremia are weakness, lethargy, seizures, and coma; the condition may cause death. Hypernatremia due to inadequate water intake is associated with concentrated urine and elevated plasma levels of antidiuretic hormone. Hypernatremia due to inadequate production or release of antidiuretic hormone (central diabetes insipidus) is associated with inadequately concentrated urine and low or undetectable plasma levels of antidiuretic hormone. Treatment requires water replacement and administration of exogenous antidiuretic hormone. Hypernatremia due to renal unresponsiveness to antidiuretic hormone is associated with normal or high plasma levels of antidiuretic hormone and inappropriately dilute urine. This disorder may be congenital or acquired. Acquired nephrogenic diabetes insipidus may be caused by drugs (such as lithium and foscarnet), hypokalemia, hypercalcemia, sickle-cell disease and trait, and amyloidosis. Treatment requires adequate water replacement. Treatment with exogenous antidiuretic hormone is of no benefit. Since hypernatremia is usually due to a deficit of body water, the water deficit should be calculated to estimate the quantity of hypotonic fluid that should be administered. Only about 50% of the calculated deficit should be replaced in the first 24 hours.

Potassium Metabolism The serum potassium concentration is tightly regulated because of its important role in transmembrane potential difference of cells. Derangements in serum potassium are manifested by disorders in muscle, cardiac, and neurologic cells. More that 98% of body potassium is intracellular (cellular K = 150 meq/L) resulting in a ratio of cellular to extracellular fluid potassium of 35:1. Small changes in the potassium concentration of extracellular fluid substantially alter this ratio and thereby affect vital functions. The average potassium intake is 50 to 100 meq/d. Potassium is eliminated mostly by renal excretion via the distal nephron. Renal excretion of potassium is regulated by aldosterone, urine flow rate, distal tubular delivery of sodium, acid–base status, and intracellular potassium stores. The intracellular potassium balance is maintained by insulin, catecholamines, acid–base status, extracellular fluid osmolality, and cell integrity.

Hypokalemia

KEYPOINTS

• Acquired nephrogenic diabetes insipidus may be caused by drugs (such as lithium and foscarnet), hypokalemia, hypercalcemia, sickle-cell disease and trait, and amyloidosis. Treatment requires adequate water replacement.

KEYPOINTS

• Hypomagnesemia should be suspected in hypokalemic patients because these intracellular ions are often lost together. • Potassium-sparing diuretics, the trimethoprim component of trimethoprim–sulfamethoxazole, and pentamidine can cause hyperkalemia because they inhibit the potassium secretory channels in the distal nephron. • Among the most common reasons for hyperkalemia is the syndrome of hyporeninemic hypoaldosteronism, characterized by decreased angiotensin II production (owing to diminished renin release) and an intra-adrenal defect, both of which contribute to decreased aldosterone secretion. Excessive dietary potassium intake is rarely a cause of hyperkalemia unless renal potassium excretion is simultaneously decreased. • In acute hyperkalemia, treatment is targeted toward antagonism of cardiac toxicity (by administration of calcium gluconate), shifting of potassium into cells (by infusion of insulin and glucose and aerosol administration of β-adrenergic agonists), and removal of potassium (by administration of cation exchange resins or hemodialysis). Chronic hyperkalemia is treated by restriction of dietary potassium, avoidance of drugs that impair potassium excretion, and use of kaliuretic diuretics, such as hydrochlorothiazide or furosemide.

Hypokalemia (serum potassium level <3.5 meq/L) can result from potassium loss or shifts but rarely from inadequate intake alone (Table 14). The most common causes of hypokalemia are gastrointestinal (vomiting and diarrhea) and renal (use of diuretics). Rare causes of hypokalemia include primary aldosteronism, Bartter’s syndrome, Gitelman’s syndrome, and periodic paralysis. Hypokalemia may cause ileus, muscle cramps, rhabdomyolysis, and cardiac arrhythmias. Electrocardiographic findings include U waves and flat or inverted T waves. Hypokalemia decreases insulin secretion, and chronic hypokalemia has been associated with formation of renal cysts. 41

Potassium Metabolism

TA B L E 1 4 Differential Diagnosis of Hypokalemia

High Urinary Potassium*

Low Urinary Potassium†

Metabolic acidosis Renal tubular acidosis Distal

Gastrointestinal loss Diarrhea Laxative abuse

Proximal Drugs Acetazolamide Metabolic alkalosis See section on Acid–Base Disorders

Internal shifts Periodic paralysis Insulin β2-Agonists Alkalosis Dietary deficiency

*Greater than 20 meq/24 h or 20 meq/L. †

Less than 20 meq/L or 20 meq/L.

Hypokalemia can often be treated by administration of oral potassium salts, but in severe hypokalemia, intravenous potassium chloride should be given. The potassium concentration of the intravenous fluid should not exceed 40 meq/L, and the infusion rate should not exceed 20 to 40 meq/h. Total potassium deficits are difficult to predict, but a serum potassium level of 3.0 meq/L is equivalent to a 200- to 400-meq potassium deficit and a level of 2.0 meq/L is equivalent to a 400- to 800-meq deficit. Hypomagnesemia should be suspected in hypokalemic patients because these intracellular ions are often lost together. Furthermore, hypokalemia is difficult to correct in the presence of hypomagnesemia because the hypomagnesemia causes renal potassium wasting through a mechanism not yet elucidated.

Hyperkalemia Excessive dietary potassium intake is rarely a cause of hyperkalemia unless renal potassium excretion is simultaneously decreased (Table 15). Potassium may TA B L E 1 5 Causes of Hyperkalemia

Increased intake Shift from intracellular to extracellular fluid compartment Ex vivo: pseudohyperkalemia Metabolic acidosis (especially hyperchloremia) β-Adrenergic blockers Insulin deficiency or resistance Hyperosmolality or hyperglycemia Rhabdomyolysis Hyperkalemic periodic paralysis Arginine hydrochloride infusion Succinylcholine Digoxin overdose Reduced renal excretion Hyporenin hypoaldosteronism Renal insufficiency or failure Hypoaldosteronism Aldosterone resistance (inherited, acquired, drug related) Type IV renal tubular acidosis

42

Hypophosphatemia

shift out of cells in rhabdomyolysis and hemolysis, hyperosmolality, insulin deficiency, β-adrenergic blockade, or metabolic acidosis and thus cause hyperkalemia. Decreased renal potassium excretion occurs in acute and chronic renal failure, in states of low urine flow, aldosterone deficiency, and tubular unresponsiveness to aldosterone. Such medications as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, heparin, and cyclosporine impair aldosterone production. Potassium-sparing diuretics, the trimethoprim component of trimethoprim–sulfamethoxazole, and pentamidine can cause hyperkalemia because they inhibit the potassium secretory channels in the distal nephron. Among the most common reasons for hyperkalemia is the syndrome of hyporeninemic hypoaldosteronism, characterized by decreased angiotensin II production (owing to diminished renin release) and an intraadrenal defect, both of which contribute to decreased aldosterone secretion. This syndrome is most commonly encountered in patients with renal insufficiency due to diabetic nephropathy or chronic interstitial nephritis. It may also be seen in renal transplant recipients taking cyclosporine, those with HIV infection, and those taking nonsteroidal anti-inflammatory drugs. The hyporeninemic hypoaldosterone syndrome is usually associated with relatively mild hyperkalemia unless renal insufficiency is also present. Severe hyperkalemia causes cardiac toxicity, as manifested by peaked T waves, flattened P waves, and widened QRS complexes on electrocardiography, and ventricular arrythmias. Hyperkalemia may cause muscle weakness or flaccid paralysis. In acute hyperkalemia, treatment is targeted toward antagonism of cardiac toxicity (by administration of calcium gluconate), shifting of potassium into cells (by infusion of insulin and glucose and aerosol administration of β-adrenergic agonists), and removal of potassium (by administration of cation exchange resins or hemodialysis). Chronic hyperkalemia is treated by restriction of dietary potassium; avoidance of drugs that impair potassium excretion, and use of kaleuretic diuretics, such as hydrochlorothiazide or furosemide.

Hypophosphatemia As many as 5% to 10% of hospitalized patients may have hypophosphatemia, defined as a serum phosphorus level less than 2.5 mg/dL. Less often, severe hypophosphatemia (serum phosphorus level less than 1 mg/dL) can lead to serious physiologic disturbance (Miller and Slovis). Hypophosphatemia can occur by three major mechanisms: redistribution of phosphate from extracellular fluid into cells, decreased gastrointestinal absorption of phosphate, and increased urinary excretion of phosphate. Phosphate redistribution into cells occurs when there is stimulation of glycolysis, a process that requires that extracellular fluid phosphate to move into cells. Glycolysis may occur during refeeding after starvation (as in patients with alcoholism or anorexia nervosa) or insulin administration to diabetics with ketotic or nonketotic hyperglycemia. Patients with hypophosphatemia often have pre-existing phosphate depletion due to deficient dietary phosphate intake (as in anorexia nervosa) or renal phosphate losses (as in diabetes with glycosuria). Acute respiratory alkalosis (as might occur in sepsis syndrome), the hungry bone syndrome (after parathyroidectomy for hyperparathyroidism), and severe burns are other states in which redistribution hypophosphatemia may occur. Intestinal absorption of phosphate may be decreased in patients taking aluminum- or magnesium-containing antacids. Use of these drugs is less common now because of the availability of H2-receptor blockers. Steatorrhea or chronic diarrhea may also cause hypophosphatemia because of decreased intestinal

Miller DW, Slovis CM. Hypophosphatemia in the emergency department therapeutics. Am J Emerg Med. 2000;18:457-61. PMID: 10919539

43

Hypomagnesemia

KEYPOINTS

• Hypophosphatemia can occur by three major mechanisms: redistribution of phosphate from extracellular fluid into cells, decreased gastrointestinal absorption of phosphate, and increased urinary excretion of phosphate.

absorption and renal phosphate loss caused by concomitant vitamin D deficiency. Renal phosphate wasting occurs with hyperparathyroidism, vitamin D deficiency, vitamin D–resistant rickets, oncogenic osteomalacia, and disorders associated with Fanconi’s syndrome. Elevated urinary excretion of phosphorus differentiates renal phosphate wasting from hypophosphatemia due to ionic shifts or intestinal malabsorption. Symptoms and signs of hypophosphatemia include muscle weakness, hematologic abnormalities (such as leukocyte dysfunction, hemolytic anemia, or platelet disorders), and metabolic encephalopathy. Treatment may be given orally with skimmed milk or phosphasoda (by enema) three to four times daily. Rarely, intravenous administration of phosphate may be required in severe hypophosphatemia. When given intravenously, the concentration of plasma calcium, phosphorus, and creatinine must be monitored to prevent hyperphosphatemia, metastatic calcification, and acute renal failure.

Hypomagnesemia

Agus ZS. Hypomagnesemia. J Am Soc Nephrol. 1999;10:1616-22. PMID: 10405219

44

Hypomagnesemia is most often diagnosed in hospitalized patients, especially those in the intensive care unit; the incidence in these settings is 12% and as many as 60%, respectively (Agus). Hypomagnesemia is caused primarily by gastrointestinal or renal losses. Shifting of magnesium from the extracellular to intracellular space is a less common cause. Continued loss of gastrointestinal secretions without replacement can also result in hypomagnesemia. More often, severe diarrhea, steatorrhea, malabsorption, and intestinal bypass can produce clinically significant hypomagnesemia. Pancreatitis can be associated with hypomagnesemia that is due in part to saponification of calcium and magnesium in necrotic fat. Renal magnesium wasting occurs when reabsorption of renal sodium is inhibited at tubular sites where magnesium is also reabsorbed. Loop diuretics and thiazide diuretics can have this effect. Of note, potassium-sparing diuretics enhance magnesium transport and decrease magnesium excretion. Extracellular fluid volume expansion in primary hyperaldosteronism causes hypomagnesemia because of reduction in passive reabsorption of magnesium. Hypercalcemia may cause hypomagnesemia because the increased filtered load of calcium reaching the loop of Henle results in increased calcium reabsorption in the loop, an event that reduces loop reabsorption of magnesium. Cisplatin, aminoglycosides, amphotericin B, and cyclosporine are examples of drugs that cause renal magnesium wasting. Renal tubular magnesium wasting is also seen in obstructive uropathy; renal transplantation; and Bartter’s syndrome, Gitelman’s syndrome, and other rare familial disorders. Hypomagnesemia due to shifts occur in the hungry bone syndrome after parathyroidectomy, osteoblastic metastases, acute respiratory alkalosis, or insulin therapy. Since hypomagnesemia is known to suppress parathyroid hormone release and inhibit its effect on its receptor, hypocalcemia often accompanies severe hypomagnesemia. Hypomagnesemia must be corrected before hypocalcemia can be successfully treated. The symptoms and signs of hypomagnesemia include lethargy, anorexia, nausea, neuromuscular disorders (Chvostek’s and Trousseau’s signs), and cardiac arrhythmias, even in the absence of hypocalcemia. The causes of hypomagnesemia are frequently apparent from the history; however, patients in the intensive care unit may have multiple factors, including poor nutrition, hypoalbuminemia, and administration of aminoglycosides or diuretics. If no cause is apparent, gastrointestinal and renal losses can be differentiated by measuring

Approach to Acid–Base Problem Solving

the 24-hour urinary magnesium excretion. In a patient with hypomagnesemia and normal renal magnesium handling, the 24-hour urinary magnesium excretion will be less than 30 mg and the fractional excretion of magnesium will be less than 2%. In those with renal magnesium wasting, the fractional excretion will exceed 4% to 8% (Elisaf et al.). Treatment of hypomagnesemia requires correction of the underlying cause whenever possible. Oral administration of slow-release magnesium oxide may be sufficient to treat mild hypomagnesemia and patients whose illnesses necessitate continued use of diuretics. In severe hypomagnesemia (plasma magnesium level <1.0 mg/dL), administration of intravenous magnesium sulfate at a rate of 50 meq every 8 to 24 hours may be required to keep the plasma magnesium level above 1.0 mg/dL. The plasma magnesium concentration controls the rate of magnesium reabsorption in the loop of Henle, the major site of magnesium reabsorption. Sudden large increases in plasma magnesium concentration (such as after administration of an intravenous bolus of magnesium) will suppress tubular reabsorption of magnesium and make attempts at correction of hypomagnesemia less effective.

Acid–Base Disorders The concentration of free hydrogen ions in the serum is maintained around 40 nmol, which corresponds to a pH of 7.4. Any acid or base added to the system is buffered, which maintains the concentration of free hydrogen concentration within narrow limits. The primary buffer system is the bicarbonate–PCO2 system. The following law of mass action describes the relationship among free hydrogen, PCO2, and bicarbonate (Rose and Post): [H+ ] = 24 × PCO2/ HCO3 This relationship demonstrates that a primary increase in arterial PCO2 (respiratory acidosis) or decrease in serum bicarbonate (metabolic acidosis) will result in an increased hydrogen ion concentration and a low pH. A primary decrease in arterial Pco2 (respiratory alkalosis) or increase in serum plasma bicarbonate (metabolic alkalosis) results in a lower hydrogen ion concentration and an elevated pH. The rate of alveolar ventilation regulates the Pco2, and the kidney regulates the bicarbonate concentration (Gennari et al.). Bicarbonate can be considered the base and PCO2 the acid. Although arterial Pco2 is not technically an acid, it acts as such in the body by combining with water to form H2CO3

Elisaf M, Panteli K, Theodorou J, Siamopoulos KC. Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia. Magnes Res. 1997;10:315-20. PMID: 9513927

KEYPOINTS

• Hypomagnesemia is caused primarily by gastrointestinal or renal losses. • Hypomagnesemia must be corrected before hypocalcemia can be successfully treated. • Treatment of hypomagnesemia requires correction of the underlying cause whenever possible. Oral administration of slow-release magnesium oxide may be sufficient to treat mild hypomagnesemia and patients whose illnesses require continued use of diuretics. In severe hypomagnesemia (plasma magnesium level <1.0 mg/dL), administration of intravenous magnesium sulfate at a rate of 50 meq every 8 to 24 hours may be required to keep the plasma magnesium level above 1.0 mg/dL. • Since hypomagnesemia is known to suppress parathyroid hormone release and inhibit the effect of the hormone on its receptor, hypocalcemia often accompanies severe hypomagnesemia.

Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. St. Louis: McGraw Hill; 2001:535-49. Gennari FG, Cohen JJ, Kassirer JP. Measurement of acid-base status. In: Cohen JJ, Kassirer JP, eds. Acid/Base. Boston: Little, Brown; 1982.

CO2 + H2O ↔ H2CO3– ↔ H+ + HCO3

Approach to Acid–Base Problem Solving A systemic approach to acid–base problem solving involves asking four questions: • • • •

What is the primary disturbance? Is compensation appropriate? What is the anion gap? Does the change in the anion gap equal the change in the serum bicarbonate concentration (a value called the delta–delta)?

Case 9 A 47-year-old man with a 3-day history of severe diarrhea presents to the emergency department because of weakness, dyspnea, and dizziness. On physical examination, his supine blood 45

Approach to Acid–Base Problem Solving

pressure is 100/70 mm Hg, and his supine pulse rate is 110/min. When the patient sits up, his systolic blood pressure decreases to 80 mm Hg and his heart rate increases to 130/min. Laboratory studies show blood urea nitrogen, 30 mg/dL; serum creatinine, 1.7 mg/dL; serum sodium, 130 meq/L; serum potassium, 3.2 meq/L; serum chloride, 100 meq/L; serum bicarbonate, 10 meq/L. Arterial blood gas studies on room air reveal pH 7.24, Pco2 23 mm Hg, Po2105 mm Hg, and bicarbonate concentration 9 meq/L. The pH indicates the primary disturbance (Table 16). A low pH, as in case 9, means that an acidosis is present. A low HCO3 concentration further narrows the diagnosis to primary metabolic acidosis; this is the disorder present in case 9. A high Pco2 indicates a primary respiratory acidosis. In contrast, a high pH indicates an alkalosis. A high bicarbonate concentration means that a metabolic alkalosis is present, whereas a low Pco2 indicates respiratory alkalosis. The compensatory response to a primary disturbance is predictable (Table 16) and brings the pH toward normal. Compensation may be appropriate even if the pH is abnormal. When assessing for appropriate compensation, the expected change in Pco2 is best used in primary metabolic problems and the expected change in bicarbonate in primary respiratory problems. Assessment of compensation can help in the detection of mixed respiratory and metabolic acid-base disturbances. In case 9, increased alveolar ventilation would be expected to decrease the Pco2 to between 19.5 and 23.5 mm Hg [Pco2 = 0.5(9) + 8 ± 2] (Table 16). Because the Pco2 is 23 mm Hg and therefore within the predicted range, respiratory compensation in this patient is appropriate. The anion gap should be calculated regardless of the primary disturbance. The sum of all anions and all cations in serum (as measured in meq/L) must be equal. On the basis of sodium, chloride, and bicarbonate measurements, healthy persons have an anion gap of 8 to 12 meq/L. The anion gap is calculated as follows: Anion gap = [Na+] − ([Cl–] + [HCO3])

TA B L E 1 6 Acid–Base Disorders and Compensatory Responses

Disorder

H+

pH

HCO3

Arterial Blood PCO2

Metabolic acidosis

↑

↓

↓↓

↓

Metabolic alkalosis

↓

↑

↑↑

↑

Acute

↑

↓

↑

↑↑

1-meq/L increase in HCO3 for every10-mm Hg increase in PCO2

Minutes to hours

Chronic

↑

↓

↑

↑↑

3.5-meq/L increase in HCO3 for every 10-mm Hg increase in PCO2

Days

Acute

↓

↑

↓

↓↓

2-meq/L reduction in HCO3 for every 10-mm Hg decrease in PCO2

Minutes to hours

Chronic

↓

↑

↓

↓↓

4-meq/L decrease in HCO3 for every10-mm Hg decrease in PCO2

Days

Adaptive Response ∆ PCO2= (1.5) HCO3 + 8 ∆ PCO2= HCO3+ 15 Pco2 increases 0.7 mm Hg for every 1.0-meq/L increase in HCO3

Time for Adaptation 12 to 24 h 24 to 36 h

Respiratory acidosis

Respiratory alkalosis

Double arrows indicate the primary disturbance.

46

Delta–Delta

Negative charges on proteins account for the missing unmeasured anions. The charges on cations not included in the calculation, such as potassium and magnesium, are balanced by the unmeasured anions, such as phosphates and sulfates. The presence of either a low level of albumin (an anion) or an unmeasured cationic light chain may result in a low anion gap. When the primary disturbance is a metabolic acidosis, the anion gap helps narrow the diagnostic possibilities to an anion gap acidosis or a non–anion gap acidosis (Ishihara and Szerlip). If the primary disturbance is a condition other than metabolic acidosis, calculation of the anion gap helps to reveal a “hidden” anion gap metabolic acidosis. In case 9, the anion gap is 20 (130 − [100 + 10] = 20), indicating an anion gap metabolic acidosis.

Ishihara, K, Szerlip HM. Anion gap acidosis. Semin Nephrol. 1998;18:83-97. PMID: 9459291

KEYPOINTS

• Determination of the plasma pH reveals the primary acid–base disturbance. • The expected change in bicarbonate concentration or PCO2 compared with the actual change indicates whether compensation is appropriate. • The anion gap should be calculated regardless of the primary disturbance.

Delta–Delta The ratio between the change in anion gap and the change in plasma HCO3 concentration (∆ anion gap –∆ bicarbonate concentration) in an uncomplicated anion gap metabolic acidosis is usually 1 to 2. The patient in case 9 has an anion gap of 20. If a normal anion gap is assumed to be 12, the change in the anion gap is 8. The change in the serum bicarbonate concentration is 14 (24 – 10). The change in the anion gap (8) divided by the change in the bicarbonate (14) yields a ratio of less than 1. The metabolic acidosis is more severe than would be expected from the isolated presence of an acid with its unmeasured anion. This finding suggests the presence of a concurrent non–anion gap metabolic acidosis. A ratio between the change in the anion gap and the change in plasma bicarbonate concentration that exceeds 2 suggests that the decrease in this concentration is less than expected because of a concurrent metabolic alkalosis.

KEYPOINTS

• In anion gap metabolic acidosis, the ratio between the change in anion gap and the change in bicarbonate concentration should be 1 to 2.

Metabolic Acidosis Metabolic acidosis is discussed here in the context of non–anion gap metabolic acidosis, anion gap acidosis, lactic acidosis, and ketoacidosis.

Non–Anion Gap Metabolic Acidosis When metabolic acidosis reduces the bicarbonate concentration and the anion gap remains normal, hyperchloremic metabolic acidosis is present; that is, the chloride concentration is high relative to the sodium concentration. Hyperchloremic metabolic acidosis develops in one of two ways: Fluids containing high concentrations of sodium bicarbonate or potential sodium bicarbonate are lost from the extracellular fluid, or hydrogen chloride or potential hydrogen chloride is added to the extracellular fluid. Either condition will cause an increase in chloride concentration and decrease in bicarbonate concentration. The ensuing hyperchloremic metabolic acidosis will not change the anion gap, because the reduction in the bicarbonate concentration is offset by the increase in chloride. Table 17 lists the causes of non–anion gap metabolic acidosis, of which the most common is diarrhea. Diarrhea leads to loss of sodium bicarbonate, as the intestinal fluid below the stomach is relatively alkaline. In case 9, diarrhea accounts for the non–anion gap portion of the metabolic acidosis. When gastrointestinal epithelium is exposed to urine, as in ureterosigmoidostomy or ileal loop bladders, it will absorb chloride from and secrete bicarbonate and potassium into the urine. This process results in hypokalemic hyperchloremic metabolic acidosis. Administration of sodium bicarbonate and sodium chloride cor-

47

Metabolic Acidosis

TA B L E 1 7 Causes of Hyperchloremic (Normal Anion Gap) Metabolic Acidosis

Gastrointestinal loss of HCO3 Diarrhea Ureterosigmoidostomy Renal HCO3 loss Proximal renal tubular acidosis Isolated—sporadic, familial Fanconi’s syndrome—with phosphaturia, glucosuria, uricosuria, aminoaciduria Familial, cystinosis, tyrosinemia, multiple myeloma, Wilson’s disease, ifosfamide, osteopetrosis Carbonic anhydrase inhibitors Ileal bladder Reduced renal H+ secretion Distal renal tubular acidosis Familial, hypercalcemic-hypercalciuric states, Sjögren’s syndrome, autoimmune diseases, amphotericin B, renal transplant Type 4 renal tubular acidosis Hyporeninemic-hypoaldosterone—diabetes mellitus, tubulointerstitial diseases, NSAIDs Defective mineralocorticoid synthesis or secretion—long-term heparin therapy, Addison’s disease, congenital adrenal defects Inadequate renal response to mineralocorticoids—sickle-cell disease, systemic lupus erythematosus, potassium-sparing diuretics, “chloride shunts” Early uremia HCl/HCl precursor ingestion/infusion HCl NH4Cl Arginine HCl Other Status post chronic hyperventilation Recovery from diabetic ketoacidosis Toluene inhalation NSAIDs = nonsteroidal anti-inflammatory drugs.

rects the metabolic acidosis and volume depletion produced by diarrhea or ureterosigmoidostomy. All types of renal tubular acidosis cause hyperchloremic metabolic acidosis. Proximal renal tubular acidosis is caused by a reduced capacity of the kidney to reabsorb sodium bicarbonate, causing the serum bicarbonate concentration to decrease to 14 to 20 meq/L. If the serum bicarbonate concentration is increased above the abnormally low renal tubule threshold for bicarbonate reabsorption (for example, when exogenous sodium bicarbonate is administered), sodium bicarbonate is excreted in the urine. However, the urine is appropriately acidified when the serum bicarbonate concentration decreases below this threshold level and a steady state is present. Urinary potassium wasting and resultant hypokalemia often accompany proximal renal tubular acidosis and may worsen with sodium bicarbonate therapy. Distal renal tubular acidosis results from an inability of the renal tubules to generate or maintain a normal pH gradient (normal minimal urinary pH is less than 5.5). This inability to excrete the 50 to 100 meq of hydrogen ions generated during metabolism of the usual western diet results in a severe (<10 meq/L) decrease in serum bicarbonate concentration. Patients with distal renal tubular acidosis excrete inappropriately alkaline urine. Distal renal tubular acidosis frequently leads to medullary calcifications 48

Metabolic Acidosis

TA B L E 1 8 Causes of High-Anion-Gap Metabolic Acidosis

Condition

Unmeasured Anion

Lactic acidosis

Lactate

Ketoacidosis Ethanol Starvation Diabetes Uremia

β-Hydroxybutyrate β-Hydroxybutyrate β-Hydroxybutyrate, acetoacetate Sulfates Phosphate Urate Hippurate

Methanol ingestion Ethylene glycol ingestion Salicylate poisoning

Formate Glycolate Oxalate Salicylate Ketones Lactate

and calcium kidney stones (due to hypercalciuria and deficient excretion of urinary citrate). The presence of hyperchloremic metabolic acidosis and an alkaline urinary pH suggests the diagnosis of renal tubular acidosis. However, urinary tract infections can also alkalinize the urine, because certain bacteria will metabolize urea to ammonium and carbon dioxide. Distal renal tubular acidosis can generally be treated with 60 to 100 meq of sodium bicarbonate daily. Sodium bicarbonate simultaneously corrects the acidosis, ameliorates renal potassium wasting, and increases urinary citrate levels. Increased urinary citrate excretion protects against renal papillary calcification and kidney stone formation. Type 4 renal tubular acidosis is a hyperkalemic hyperchloremic metabolic acidosis that is usually due to hypoaldosteronism or an inadequate renal tubular response to aldosterone. This state leads to a reduction in urinary excretion of potassium and a resultant hyperkalemia, which interferes with renal production of NH4+. This condition, along with inhibition of renal hydrogen ion excretion caused by aldosterone deficiency, leads to development of metabolic acidosis. Some patients with type 4 renal tubular acidosis require administration of exogenous mineralocorticoids, others respond well to diuretics, and still others require treatment with exogenous sodium bicarbonate. The underlying pathology can sometimes also be corrected (for example, obstructive uropathy).

Anion Gap Metabolic Acidosis Anion gap metabolic acidosis results when hydrogen ions accumulate with an anion other than chloride. The accompanying unmeasured anion elevates the anion gap. Table 18 lists the causes of an anion gap metabolic acidosis, along with the unmeasured anion.

Lactic Acidosis In the process of gluconeogenesis, lactic acid is generated from metabolism of pyruvate. Lactic acid is transiently buffered by the bicarbonate buffer system and is then converted back to pyruvate, primarily in the liver. This process requires functional mitochondria and normal oxidative metabolism and results in the regeneration of the buffered bicarbonate. A decrease in bicarbonate concentration and resultant gap metabolic acidosis occur when lactic acid accumulates, as seen most commonly in states of tissue hypoperfusion (Adrogue and Madias). In case 9, the anion gap portion of the metabolic acidosis is most

Adrogue HJ, Madias NE. Medical progress: management of life-threatening acid-base disorders. First of two parts. N Engl J Med. 1998;338:26-34. PMID: 9414329

49

Metabolic Alkalosis

Adrogue, HJ, Madias NE. Medical progress: management of life-threatening acid-base disorders. Second of two parts. N Engl J Med. 1998;338:107-11. PMID: 9420343

likely due to lactic acidosis from tissue hypoperfusion. Drug-induced mitochondrial dysfunction, as seen with nucleoside therapy in treatment of AIDS, can lead to lactic acidosis in the absence of obvious tissue hypoxia. Grand mal seizures, caused by an increased metabolic rate, result in a lactic acidosis that quickly reverses. Use of bicarbonate to treat lactic acidosis caused by tissue hypoxia remains controversial. Correction of the underlying disorder allows the accumulated lactate to be regenerated back to bicarbonate. Consequently, a true bicarbonate deficit may not exist. If the bicarbonate concentration is very low and the pH is less than 7.1, administration of sodium bicarbonate may be helpful (Adrogue and Madias). Ethylene glycol is present in antifreeze. When ingested, it is metabolized by alcohol dehydrogenase to glyoxylate and oxalic acid. The oxalate derived from ethylene glycol precipitates with calcium and is deposited in the brain, lungs, peripheral nerves, and kidneys. Renal failure frequently occurs. A plasma osmolal gap and abundant urinary calcium oxalate crystals are important diagnostic clues suggesting ethylene glycol poisoning. Methanol, commonly referred to as wood alcohol, is present in many commercially available solvents. Ingested methanol is converted by alcohol dehydrogenase to formaldehyde and formic acid, which can cause blindness, coma, and death. Methanol ingestion will also cause an osmolar gap. Treatment of both methanol and ethylene glycol poisoning requires inhibition of alcohol dehydrogenase. This inhibition will block conversion of the ingested compound to organic acids and other toxic metabolites. Inhibition is accomplished by administration of ethanol or fomepizole. Hemodialysis effectively removes the ingested poison and its toxic metabolites and simultaneously corrects the metabolic acidosis and electrolyte abnormalities. An osmolal gap is present when the measured plasma osmolality exceeds the calculated plasma osmolality by 10 mosmol/kg. Plasma osmolality is calculated as follows: plasma osm = 2 × [Na+] + [glucose level]/18 + [blood urea nitrogen level]/2.8

Ketoacidosis When glucose is in short supply or cannot be utilized, the liver converts free fatty acids into ketones to be used as an alternative energy source. Decreased insulin activity and increased glucagon activity lead to formation of acetoacetic acid and β-hydroxybutyric acid. The presence of these ketoacids decreases the serum bicarbonate concentration and increases the anion gap. As in lactic acidosis, alkali therapy in ketoacidosis is controversial. Enhancement of glucose utilization will allow regeneration of bicarbonate from ketoacid anions and correction of the acidosis. Occasionally, excretion of the ketoacid anions in the urine will limit the amount of bicarbonate that can be generated through therapy with glucose or insulin. In this case, the patient will have a normal anion gap and may benefit from exogenous alkali therapy.

Metabolic Alkalosis Case 10 A 36-year-old woman presents to the emergency department because of generalized weakness. She takes no prescribed medications or any other drugs. On physical examination, her blood pressure is 105/75 mm Hg. Laboratory studies show blood urea nitrogen, 40 mg/dL; serum creatinine, 1.9 mg/dL; serum 50

Metabolic Alkalosis

sodium, 130 meq/L; serum potassium, 3.0 meq/L; serum chloride, 85 meq/L; serum bicarbonate, 35 meq/L. Arterial blood gas studies on room air reveal pH 7.49 and Pco2 48 mm Hg. The urinary sodium concentration is 50 meq/L, potassium concentration is 30 meq/L, and chloride concentration is 2 meq/L (Table 19). TA B L E 1 9 Acid–Base Problem Solving: Case 10

Arterial blood gases: pH 7.49, PCO2 48 mm Hg, HCO335 meq/L Electrolytes: Na 130 meq/L, K 3.0 meq/L, Cl 85 meq/L, CO2 35 meq/L What is the primary disturbance? The pH is > 7.4; thus, an alkalosis is present. Because the HCO3 concentration is high, the primary disturbance is a metabolic alkalosis. Is compensation appropriate? Given the 11-meq/L increase in the serum HCO3 concentration, the PCO2 is expected to increase by approximately 8 mm Hg and be close to 48 mm Hg, (see table 17). Compensation is therefore appropriate. What is the anion gap? 130 – (85 + 30) = 15. Could a “hidden” gap metabolic acidosis be present? This is not likely. A small (1–5 meq/L) increase in the anion gap is common in metabolic alkalosis. This increase is thought to be multifactorial but mostly associated with both changes in the amount of protein and the amount of negative charges on proteins that result from the alkalosis. What is the delta–delta? This question is useful only in primary metabolic acidosis.

A primary increase in the bicarbonate concentration can result from loss of hydrogen chloride or, less commonly, addition of bicarbonate. Once generated, the metabolic alkalosis is corrected through urinary excretion of the excess bicarbonate. Alkalosis is maintained only when renal bicarbonate excretion is limited owing to a reduction in renal function or stimulation of renal tubule bicarbonate reabsorption. Increased reabsorption is caused by extracellular fluid volume contraction, chloride depletion, hypokalemia, or elevated mineralocorticoid activity. The most common causes of metabolic alkalosis are vomiting, nasogastric suction, and diuretic therapy. In these cases, which are classified as chloride responsive, administration of sodium chloride reverses the alkalosis by expanding the intravascular volume (Table 20). TA B L E 2 0 Differential Diagnosis of Metabolic Alkalosis

Low Urinary [CI] (<20 meq/L) Chloride Responsive Diuretics (Remote) Vomiting/nasogastric tube suction Status post chronic hypercarbia

High Urinary [CI] (>20 meq/L) Chloride Unresponsive Diuretics (Recent) High blood pressure Primary hyperaldosteronism Cushing’s disease Ectopic ACTH production Exogenous mineralocorticoid production Mineralocorticoid-like substances Liddle’s syndrome Low blood pressure Bartter’s syndrome Gitelman’s syndrome Severe potassium depletion

ACTH = adenocorticotropic hormone.

51

Metabolic Alkalosis

FIGURE 5. Diuretic-induced metabolic alkalosis. Loop diuretics wil reduce Na and CI reabsorption in the thick ascending limb of Henle and thiazide diuretics reduce Na and CI reabsorption at more distal sites (the diluting segment). Both diuretics cause increased delivery of Na and CI to the collecting tubules where Na reabsorption increases H and K secretion.

KEYPOINTS

• Metabolic alkalosis is often caused by upper gastrointestinal loss of hydrogen chloride or by renal loss of hydrogen chloride with diuretic therapy. • Metabolic alkalosis is maintained by extracellular fluid volume contraction, chloride depletion, hypokalemia, or elevated mineral corticoid activity.

52

NaCl

Na+

Na+

Na+

H+

K+

The key pathophysiologic mechanisms responsible for the development and maintenance of gastric alkalosis are as follows. The stomach secretes hydrogen chloride and sodium chloride, which are lost in vomitus. Because no hydrogen chloride enters the duodenum, the pancreas does not excrete bicarbonate. Because hydrogen chloride is lost but bicarbonate is not lost concomitantly, the plasma bicarbonate concentration increases. This process represents the generation phase of metabolic alkalosis. Extracellular fluid contraction and chloride depletion simultaneously develop. The renal filtered load of bicarbonate increases, and some sodium bicarbonate is excreted, resulting in the unexpected finding of a normal urinary sodium level despite extracellular fluid volume contraction. The bicarbonaturia partially corrects the alkalosis. With additional extracellular fluid volume contraction and chloride depletion, no further sodium bicarbonate is lost in the urine and the alkalosis is maintained. The reabsorption of sodium bicarbonate in the distal tubule is associated with potassium secretion, resulting in hypokalemia that helps to maintain alkalosis. Saline expansion of the extracellular fluid and correction of the hypokalemia will reverse all of the factors that drive bicarbonate reabsorption and rapidly correct the alkalosis. Another frequent cause of metabolic alkalosis is administration of thiazide and loop diuretics. These diuretics increase renal excretion of sodium chloride and water and thereby contract the extracellular fluid and activate the renin–angiotensin–aldosterone axis. Persistent distal delivery of sodium chloride in the presence of aldosterone results in urinary loss of potassium and hydrogen (Figure 5). This process generates hypokalemia and metabolic alkalosis. The combination of hypokalemia and extracellular fluid contraction maintain the metabolic alkalosis. Thus, the kidney is the site of both bicarbonate generation and maintenance in patients with diuretic-induced metabolic alkalosis. In diuretic-induced metabolic alkalosis, soon after ingestion or infusion of a diuretic, the urinary chloride concentration increases to greater than 20 meq/L as a result of the diuretic effect. The urinary chloride concentration will then decrease to less than 20 meq/L when the effect of the diuretic wanes. This alkalosis is classified as a volume-sensitive, or low urinary chloride concentration, metabolic alkalosis even though the measured urinary chloride concentration may be low or high. The very low urinary chloride concentration in case 10 suggests vomiting or remote diuretic ingestion. It also suggests that sodium chloride volume expansion will correct the alkalosis. Less commonly, a generated metabolic alkalosis is maintained in the absence of volume depletion. Patients with metabolic alkalosis and a high urinary chloride level (>20 meq/L) have maintenance mechanisms related to persistent mineralocorticoid effect in the absence of extracellular fluid contraction or hypokalemia. In general, infusion of sodium chloride does not correct metabolic alkaloses in patients with high urinary levels of chloride. Consequently, these disorders are also called chloride-unresponsive, or chloride-resistant, metabolic alkaloses. Examples are primary hyperaldosteronism and Cushing’s syndrome.

Respiratory Acidosis

Respiratory Acidosis Respiratory acidosis is due to a primary increase in arterial Pco2, which accumulates when ventilation is inadequate. Hypoventilation can result from disorders or medications that affect the central nervous system respiratory center, respiratory muscles, and chest wall; obstruction of the airway; or ventilation–perfusion mismatch. Table 21 shows the most common causes of respiratory acidosis. Acute respiratory acidosis involves a small increase in bicarbonate concentration as a result of cellular buffering. In chronic respiratory acidosis, the increase in bicarbonate concentration is larger because renal generation of bicarbonate is stimulated. Table 16 shows the expected level of compensation.

Respiratory Alkalosis Hyperventilation reduces the arterial Pco2, which increases the pH. Table 22 shows the causes of respiratory alkalosis. The expected compensatory responses for acute and chronic respiratory alkalosis are shown in Table 16.

Mixed Acid–Base Disorders

TA B L E 2 1 Causes of Respiratory

Acidosis Central nervous system depression Sedatives Central nervous system lesions Neuromuscular disorders Myopathies Neuropathies Thoracic cage restriction Kyphoscoliosis Scleroderma Impaired lung motion Pleural effusion Pneumothorax Acute obstructive pulmonary disease Aspiration Tumor Bronchospasm Chronic obstructive pulmonary disease Miscellaneous Ventilator malfunction

Case 11 A 38-year-old man with diabetes presents with 4-day history of persistent vomiting. His body temperature is 39 °C (102 °F), pulse rate 88/min, and blood pressure 98/56 mm Hg. Laboratory studies show serum sodium, 138 meq/L; serum potassium, 3.0 meq/L; serum chloride, 80 meq/L; serum bicarbonate, 34 meq/L; serum glucose, 510 mg/dL; room air arterial blood gas, pH 7.5; Pco2, 42 mm Hg; Po2, 80 mm Hg. Often, more than one acid–base disturbance is present simultaneously. Diagnosis of mixed disturbances requires calculation of renal and respiratory compensation. Calculation of the anion gap and the ratio of the change in anion gap to change in bicarbonate concentration (“delta–delta”) may also be helpful (Table 23). Mixed metabolic and respiratory acidosis frequently occurs during cardiopulmonary arrest. If a patient with metabolic acidosis has an inappropriately low arterial Pco2, respiratory alkalosis may coexist. This mixed disorder will tend to normalize the pH. Sepsis often causes this particular mixed disorder, because endotoxin directly stimulates the respiratory center while hypotension leads to lactic acidosis. Salicylate poisoning also causes mixed metabolic acidoTA B L E 2 3 Acid–Base Problem Solving: Case 11

Arterial blood gases: pH 7.5, PCO2 42 mm Hg, PO2 80 mm Hg, HCO3 34 Serum electrolytes: Na 138 meq/L, K 3.0 meq/L, Cl 80 meq/L, HCO3 34 meq/L, glucose 510 mg/dL What is the primary disturbance? Metabolic alkalosis, generated by loss of HCl from the stomach and maintained by the intravascular volume depletion. Is compensation appropriate? No. For the 10-meq increase in HCO3, the expected PCO2 would be 47 mm Hg. Thus, there is a concomitant respiratory alkalosis, perhaps due to infection. What is the anion gap? 24. Although the anion gap may be slightly elevated in a metabolic acidosis, the extent of this anion gap suggests the presence of an anion gap metabolic acidosis, perhaps due to diabetic ketoacidosis or lactic acidosis from tissue underperfusion.

Cardiopulmonary resuscitation

TA B L E 2 2 Causes of Respiratory

Alkalosis Anxiety Central nervous system disorders Stroke Tumor Infection Hormones Progesterone Catecholamines Drugs Salicylates Analeptics Sepsis and endotoxemia Hyperthyroidism Hypoxia Pregnancy Cirrhosis Pulmonary edema Lung diseases Pulmonary emboli Restrictive lung disorders Pneumonia Ventilator-induced

53

Prerenal Azotemia

sis and respiratory alkalosis, because toxic salicylate levels directly stimulate respiration and simultaneously uncouple cellular oxidative metabolism and generate an anion gap acidosis. One of the most challenging diagnostic problems is a patient with an elevated Pco2. The difficulty lies in the different compensatory responses in acute and chronic respiratory acidosis. For example, in a patient with a Pco2 of 60 mm Hg, the expected compensatory response in acute respiratory acidosis would be an increase in bicarbonate concentration to 26 meq/L. The expected response in chronic respiratory acidosis is an increase in bicarbonate concentration to 32 meq/L. Intermediate bicarbonate values, such as 29 meq/L, may mean that a metabolic alkalosis is present with an acute respiratory acidosis or that a metabolic acidosis is complicating a chronic respiratory acidosis. In this case, history and physical examination allow the clinician to distinguish between these possibilities.

Acute Renal Failure

Gastaldello K, Melot C, Kahn RJ, Vanherweghem JL, Vincent JL, Tielemans C. Comparison of cellulose diacetate and polysulfone membranes in the outcome of acute renal failure. A prospective randomized study. Nephrol Dial Transplant. 2000;15:224-30. PMID: 10648669

Acute renal failure is defined as a sudden decrease in the glomerular filtration rate. The diagnosis is usually associated with an increased blood urea nitrogen concentration (azotemia) and increased serum creatinine concentration. Acute renal failure can be diagnosed with certainty when the patient’s previous renal function is known and a decline is documented. Before intrinsic renal disease is diagnosed, disorders of extracellular fluid volume (prerenal azotemia) and obstructive causes of renal insufficiency (postrenal azotemia) must be excluded (Figure 6). The evaluation of patients with acute renal failure should include a history of recent medications and procedures and examination of hemodynamic and volume status, the bladder and the prostate, urinalysis, and urinary diagnostic indices (Gastaldello et al.). Renal ultrasonography is useful in detecting urinary tract obstruction or chronic renal insufficiency by estimating the size of the kidneys. Renal biopsy may be valuable in the few patients in whom the diagnosis remains unclear. Acute renal failure occurs in as many as 7% of patients in tertiary care centers and in up to one third of patients in intensive care units. It rarely occurs in outpatients. Prerenal azotemia, however, is the most common cause of acute renal failure in both outpatients and hospitalized patients.

Prerenal Azotemia • When do angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers cause acute renal failure? • What is the hemodynamic cause of acute renal failure in such patients?

Prerenal azotemia due to decreased renal perfusion is found in patients with volume depletion and those with volume overload. The most frequent cause of prerenal azotemia is extracellular fluid volume depletion. Volume depletion causes stimulation of the sympathetic nervous system and the renin– angiotensin–aldosterone system. This results in increased renal tubular reabsorption of sodium in the proximal and distal portions of the nephron and increased release of antidiuretic hormone, which results in increased water reabsorption. Therefore, the urine of patients with prerenal azotemia is characterized by low volume, low urinary sodium concentration, increased urinary creatinine concentration, and high osmolality. Under microscopic examination, the urine is generally normal. The use of nonsteroidal anti-inflammatory drugs, including cyclooxygenase-2 inhibitors, may be associated with functional reversible decrements in 54

Prerenal Azotemia

renal blood flow and glomerular filtration rate secondary to inhibition of renal afferent arteriolar vasodilatation. This is particularly evident in patients with preexisting renal insufficiency or concurrent volume depletion. Hypercalcemia may cause renal vasoconstriction and a decreased glomerular filtration rate but is also associated with renal tubular defects that may cause polyuria, worsening of volume depletion, and increase in serum calcium concentration. This can lead to a vicious circle of volume depletion and increasing hypercalcemia in the absence of intrinsic renal disease. Patients who have acute renal failure have increased morbidity and a 10- to 15-fold increase in mortality compared with patients who do not have acute renal failure. Patients with prerenal azotemia generally have a favorable prognosis. The mortality rate for patients with prerenal azotemia requiring nephrology consultation or treatment in an intensive care unit may be higher than in patients treated in other settings, probably because of the severity of the underlying presenting condition. Increased blood urea nitrogen and creatinine concentration

Determine if new or old

Yes

Rule out prerenal azotemia (history, physical examination, urinalysis, and urinary indices)

Chronic renal failure

No Treat underlying cause Rule out obstructive uropathy (history, physical examination, urinalysis radiologic studies)

Yes

Treat

No Examination of urine

Muddy brown casts Increased urinary sodium concentration Decreased urinary creatinine concentration Increased fractional excretion of sodium

Increased urinary protein concentration Hematuria Erythrocyte casts

Crystalluria

Pyuria Leukocyte casts Eosinophiluria

Dipstick hematuria without erythrocytes

Drug nephrotoxicity Rhabdomyolysis

Nephritic syndrome

Interstitial nephritis

Acute tubular necrosis

FIGURE 6. Approach to the Patient with Prerenal Azotemia.

55

Prerenal Azotemia

Determination of the fractional excretion of sodium (FENa) may be useful in patients with oliguria. The FENa represents the percentage of the total filtered sodium that is ultimately excreted in the final urine. The FENa can be determined from a spot urine specimen, with simultaneous determination of plasma sodium and creatinine concentrations: Where: Una = urines FeNa = UNa/PNa × 100% ________

Ucr/Pcr The FENa is characteristically less than 1% in patients with prerenal azotemia. In patients with acute renal failure, a FENa greater than 1% usually indicates an intrinsic renal cause of azotemia, but a high value is never normal in patients with oliguria. Diuretic use and osmotic diuresis due to glycosuria in patients with diabetes mellitus may be associated with natriuresis, volume depletion, and subsequent prerenal azotemia. Urinary sodium concentration and FENa may be high in such patients and therefore may be unreliable indicators of the volume-depleted state during diuresis. Determination of the FENa is most useful in patients with oliguria and acute renal failure. Case 12 A 54-year-old woman is admitted to the hospital because of increasing edema and dyspnea. She has a history of congestive heart failure due to ischemic heart disease. She was treated with digoxin and hydrochlorothiazide, but her symptoms worsened. On physical examination, her pulse rate is 118/min and regular, and blood pressure is 106/85 mm Hg. Neck veins are distended 6 cm at 45 degrees, and hepatojugular reflux is present. Bilateral crackles are heard, and an S3 gallop is auscultated. She has bilateral lower extremity edema. On admission, laboratory values are as follows: blood urea nitrogen, 72 mg/dL; serum creatinine, 1.3 mg/dL; sodium, 128 meq/L; potassium, 3.2 meq/L; chloride, 102 meq/L; and bicarbonate, 22 meq/L. Urinalysis shows a specific gravity of 1.020, trace protein, trace ketones, and no glucose. Microscopic examination is normal. Urinary sodium concentration is 8 meq/L, and urine osmolality is 530 mosm/kg H2O. A 24-hour urine volume is 310 mL on the first hospital day. Patients with decreased renal blood flow despite clinical volume overload (such as those with congestive heart failure, other cardiovascular diseases, or ascites) have renal responses similar to the responses of patients with volume depletion. Findings on urinalysis and microscopic examination are also similar to those in patients with volume depletion. Therapy consists of normalizing the extracellular fluid volume and treating the underlying disease with diuretics, if possible. The FENa may still be a useful measurement in patients with acute renal failure who are receiving diuretics, since a low value substantiates the diagnosis of prerenal azotemia and suggests resistance to diuretic action. A high FENa alone cannot distinguish an intrinsic renal cause of azotemia from prerenal azotemia treated with diuretics. Patients with decreased renal blood flow secondary to various forms of renal vascular disease (such as severe unilateral or bilateral renal artery stenosis, renal artery thrombosis, and renal embolic disease) may have decreased renal perfusion. The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may also be associated with functional reversible 56

Postrenal Azotemia (Urinary Tract Obstruction)

decrements in renal blood flow and glomerular filtration rate, particularly in patients with preexisting renal insufficiency, bilateral renal vascular disease, or concurrent volume depletion. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decrease resistance of the postglomerular efferent arterioles and decrease net glomerular filtration pressure. This causes a decreased glomerular filtration rate in patients with renal insufficiency or renal artery stenosis. A net decrease in glomerular filtration pressure results, especially in patients with preexisting volume depletion or renal insufficiency. Initial treatment of prerenal azotemia consists of optimizing volume status. The most appropriate management of patients with congestive heart failure or ascites is treatment of the underlying disease, use of inotropic drugs to improve cardiac output, and normalization of extracellular fluid volume (frequently with diuretics) to improve cardiac output and renal perfusion. In patients in whom drug effects are suspected to cause the prerenal azotemia, treatment with the drug in question should be discontinued and the clinical course should be observed. In patients treated with angiotensin-converting enzyme inhibitors, the development of acute renal failure should prompt investigation of the patency of the renal vasculature. Patients with hypercalcemia should be treated with volume repletion and a loop diuretic, such as furosemide, to maximize urinary calcium excretion.

Postrenal Azotemia (Urinary Tract Obstruction) Obstruction of the urinary outflow tract may also cause acute renal failure. To cause azotemia, obstruction must involve the outflow tracts of two normal kidneys or of one kidney if bilateral renal dysfunction was present previously. The diagnosis of acute or chronic urinary tract obstruction should be considered strongly in patients who have had abdominal or pelvic surgery, gynecologic or prostate gland neoplasms, or radiation therapy. Chronic urinary tract obstruction is often asymptomatic. The presence of anuria suggests complete obstruction, whereas urinary frequency, polyuria, oliguria, and nocturia may often accompany partial urinary tract obstruction. Urine indices and sodium concentration are not reliable findings in patients with urinary tract obstruction. The ratio of blood urea nitrogen to serum creatinine may be elevated as a result of decreased tubular flow and increased tubular reabsorption of urea. Hydronephrosis on ultrasonography is sensitive and specific in confirming the diagnosis of urinary tract obstruction. If periureteral metatastic disease or retroperitoneal fibrosis encases the ureters or if the results of ultrasonography are equivocal, computed tomography or magnetic resonance imaging may provide better diagnostic discrimination. Antegrade or retrograde intravenous pyelography or percutaneous nephrostomy is only rarely used to diagnose urinary tract obstruction. Polyuria may occur as a physiologic response after correction of urinary tract obstruction, or postobstructive diuresis may occur because of sodium and water retention and abnormal renal tubular handling of sodium and water.

KEYPOINTS

• In hospitalized patients, prerenal azotemia is associated with increased mortality if it complicates a disease with substantial morbidity. • Nonsteroidal anti-inflammatory drugs may worsen renal function in patients with volume depletion or volume overload and prerenal azotemia. • Determination of the fractional excretion of sodium is most useful in patients with oliguria and acute renal failure. • A fractional excretion of sodium greater than 1% is never physiologic in patients with oliguria. • The acute renal failure associated with administration of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is a result of disordered hemodynamics that initiates a type of prerenal azotemia secondary to decreased renal perfusion. Azotemia is frequently reversible after discontinuation of the drug. • Patients with acute renal failure who are receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and who have an evaluation suggesting prerenal azotemia should be screened for a solitary kidney or renal vascular disease.

Intrinsic Acute Renal Failure • Does the clinical setting provide clues to the diagnosis and prognosis in patients with intrinsic acute renal failure? • What therapeutic strategies may be used to limit the development of contrastmediated nephropathy? • How does acute interstitial nephritis differ from nephrotoxic renal disease?

57

Intrinsic Acute Renal Failure

Case 13 A 52-year-old man with crescendo angina is transferred to the intensive care unit because of hypotension after coronary artery bypass grafting. He has had hypertension for 16 years and hypercholesterolemia for 12 years, both of which are well controlled by various medications. On physical examination, his pulse rate is 110/min and regular and blood pressure is 78/54 mm Hg. Temperature is 39 °C (102.2 °F). His chest is clear, and no murmurs or gallops are heard. His abdomen is not tender. Trace bilateral lower extremity edema is present. Blood urea nitrogen concentration is 29 mg/dL, and serum creatinine concentration is 1.4 mg/dL. Urinalysis shows a specific gravity of 1.018, trace protein, and no glucose or ketones. On microscopic examination, the urine is normal. The patient is treated with nafcillin and gentamicin. On the second day in the intensive care unit, his blood pressure is 140/70 mm Hg and he is afebrile. The 24-hour urine output is 245 mL. Blood urea nitrogen is 72 mg/dL, and serum creatinine is 3.0 mg/dL. Urinalysis reveals a specific gravity of 1.009. Microscopic examination shows granular casts and debris.

Albright RC Jr. Acute renal failure: a practical update. Mayo Clin Proc. 2001;76:67-74. PMID: 1115541

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Acute tubular necrosis, secondary to renal ischemia and/or nephrotoxins, is common in patients in intensive care units and is the most common cause of acute renal failure due to intrinsic renal disease in hospitalized patients (Albright). The decreased glomerular filtration rate has been ascribed to vasoconstriction, intratubular obstruction secondary to swollen necrotic cells, backleak of glomerular filtrate through disrupted proximal tubules, and decreased glomerular permeability. Most patients with acute tubular necrosis have multiple associated conditions, such as hypotension, sepsis, or administration of nephrotoxic agents. Renal insufficiency may be insidious or sudden. Patients with acute tubular necrosis typically have an initial oliguric phase that varies in degree and duration. It may be so brief as to be clinically inapparent, or it may continue for as long as 10 to 14 days. Occasionally, oliguria is irreversible, and chronic renal failure or end-stage renal disease results. More often, the oliguric phase is followed by a diuretic phase, which is sometimes characterized by large increases in urine flow. The diuresis is a consequence of the increasing glomerular filtration rate coupled with the inability of regenerating tubules to reabsorb sodium and water normally. Fluid and electrolyte disorders, such as volume depletion, hyponatremia, hypernatremia, hypokalemia, hyperkalemia, or hypomagnesemia, may result. If recovery occurs, the long-term prognosis is good, but abnormal renal function is often present and may persist for years. The urine in patients with acute tubular necrosis is typically abnormal, with pigmented tubular epithelial cell casts and debris. The urinary sodium concentration and FENa are usually high, whereas the urine osmolality is not increased compared with the plasma osmolality. The latter reflects the inability of the tubules to reabsorb sodium and water. The urinary creatinine concentration is typically low, reflecting both the decrease in glomerular filtration rate and reabsorption of tubular fluid. In patients with nonoliguric acute renal failure, urinary diagnostic indices are unreliable and should not be used. After establishing the diagnosis of acute renal failure related to intrinsic renal disease, the clinician must attempt to minimize renal parenchymal injury, prevent symptoms of uremia, ensure metabolic balance, and promote recovery

Intrinsic Acute Renal Failure

of renal function. Optimization of the patient’s clinical volume status is imperative. Sodium and water restriction may be necessary, especially in patients with oliguria and acute tubular necrosis. Protein restriction, administration of essential amino acids, and maintenance of carbohydrate intake may limit catabolism but maintain nitrogen balance. Potassium and phosphorus intake should be restricted. Hyperkalemia and acidemia should be identified and treated. Medications that can reduce the glomerular filtration rate or interfere with potassium disposition and magnesium-containing antacids should be discontinued. Dosages of these medications should be adjusted according to the patient’s degree of renal insufficiency. Hemodialysis, peritoneal dialysis, continuous arteriovenous hemofiltration, and continuous venovenous hemofiltration may be necessary to treat complications of acute renal failure. Each of these therapies has specific advantages and disadvantages. Some indications for emergent dialysis in patients with acute renal failure are hyperkalemia, acidemia, and hypoxemia from volume overload that is refractory to treatment. Hemodialysis provides rapid systemic treatment of hyperkalemia and volume overload, but the procedure is limited by the patient’s mean arterial pressure and cardiovascular status. Hemodialysis also requires systemic anticoagulation and access to the circulation through relatively large blood vessels. Peritoneal dialysis is easily initiated, is useful in the hemodynamically unstable patient, and does not require systemic anticoagulation. It may be less useful than hemodialysis in the emergent treatment of hyperkalemia or acidemia but provides good long-term control of fluid balance. However, peritoneal dialysis is relatively contraindicated in patients who have recently undergone abdominal surgery. Continuous arteriovenous hemofiltration and continuous venovenous hemofiltration are useful in hemodynamically unstable patients with hypotension. Both of these techniques provide excellent fluid control and allow administration of large amounts of fluid, particularly for total parenteral nutrition. However, these continuous therapies are relatively inefficient in treating patients with uremia and its complications. Clearance of uremic toxins may be increased by adding a dialytic component (continuous arteriovenous hemodiafiltration or continuous venovenous hemodiafiltration). Although continuous filtration procedures have been advocated to clear vasoactive substances such as cytokines in patients with sepsis and multiple organ system failure, a welldesigned, prospective, controlled clinical trial of continuous hemodiafiltration compared with intermittent hemodialysis for patients with acute renal failure in the intensive care unit did not demonstrate a survival advantage with the novel therapy (Mehta et al.). The mortality rate in patients with acute renal failure has been relatively unchanged over the past four decades and is as high as 80% in studies of patients in intensive care units. These findings may reflect the growth of an aging population with preexisting chronic illnesses. Hospitalized surgical patients or patients in intensive care units who develop acute renal failure and patients with oliguria have consistently poorer survival than do outpatients, hospitalized medical patients, patients treated in less intensive care settings, and patients with nonoliguric acute renal failure. As many as 15% of patients undergoing cardiac surgery may develop acute renal failure, with a 13% mortality rate. Higher mortality rates occur in elderly patients and in patients with more severe oliguric acute renal failure, preexisting chronic disease, respiratory failure requiring mechanical ventilation, multiple organ system failure, jaundice, hepatic failure, neoplasms, hypotension, and coma. Mortality due to acute renal failure is related to the severity of the underlying illness and the patient’s previous health

Mehta RL, McDonald B, Gabbai FB, Pahl M, Pascual MT, Farkas A, et al. A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Collaborative Group for Treatment of acute renal failure in the ICU. Kidney Int. 2001;60:1154-63. PMID: 11532112

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Intrinsic Acute Renal Failure

Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet. 2000;356:26-30. PMID: 10892761 Schiffl A, Lange S, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med. 2002;346:305-10. PMID: 11821506 Lassnigg A, Donner E, Grubhofer G, Presterl E, Druml W, Hiesmayr M. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am Soc Nephrol. 2000;11:97-104. PMID: 10616845 Lamiere N, Vanholder R. Pathophysiologic features and prevention of human and experimental acute tubular necrosis. J Am Soc Nephrol. 2001;12 Suppl 17:S20-S32. Acker CG, Singh AR, Flick RP, Bernardini J, Greenberg A, Johnson JP. A trial of thyroxine in acute renal failure. Kidney Int. 2000; 57:293-8. PMID: 10620211 KEYPOINTS

• Acute tubular necrosis is a common cause of acute renal failure in patients in the intensive care unit. • Urinary indices are most sensitive in diagnosing acute tubular necrosis in patients with oliguria. • What is the prognosis for hospitalized patients with acute renal failure due to acute tubular necrosis? • What therapy provides the best outcome in hospitalized patients with acute renal failure due to acute tubular necrosis? • Continuous renal replacement therapies are now used almost as often as peritoneal dialysis and hemodialysis in patients with acute renal failure who are treated in intensive care units. • Pathways to decreasing the incidence of contrast-mediated nephropathy in patients with renal insufficiency include performing procedures in carefully selected patients using the minimum amount of contrast agent; ensuring optimal fluid balance; discontinuing concurrent administration of nephrotoxic medications, if possible; ensuring volume repletion by administration of saline solutions; and administering acetylcysteine. • Common risk factors for nephrotoxicity include advanced age, volume depletion, underlying renal insufficiency, prolonged drug therapy, and administration of more than one nephrotoxic agent.

60

status, as measured by several scoring systems. Some surviving patients will require long-term renal replacement therapy. Conservative management of the complications of acute renal failure is easier in nonoliguric patients because of their high urine output and their less frequent need for dialysis. Whether the type of membrane used for dialysis of patients with acute renal failure is independently associated with outcome is controversial. So-called “biocompatible” dialysis membranes are not associated with complement activation, whereas bioincompatible membranes often result in activation of complement and can be associated with an anaphylactic-like response. Prospective studies of patients with acute renal failure who were treated with biocompatible dialysis membranes compared with bioincompatible membranes have had varying results. The reasons for these disparities are unknown, but neutrophil activation by dialysis membranes may be a more important determinant of deleterious effects than is activation of the complement cascade. At present, the relative merits of the use of different membranes in patients with acute renal failure have not been conclusively determined. There are few data to guide the provision, delivery, and timing of fluid and solute removal by intermittent and continuous techniques. One study showed that increased ultrafiltration volume, typically associated with increased clearance of uremic toxins, was associated with improved survival in patients with acute renal failure treated with continuous venovenous hemofiltration (Ronco et al.). Another study showed greater survival in patients with acute renal failure treated with daily intermittent hemodialysis compared with patients treated with hemodialysis on alternate days (Schiffl et al.). The generalizability of this finding is, however, uncertain. In patients with established acute renal failure, the therapeutic effects of vasodilators (including calcium channel blockers), atrial natriuretic peptide, and growth factors, are also inconclusive. No study has provided convincing evidence that administration of dopamine enhances clinically significant outcomes in patients with acute renal failure (Lassnigg et al.; Lamiere and Vanholder). A recent study in patients with acute renal failure failed to confirm results from animal models concerning the benefits of supplementation with thyroid hormone (Acker et al.). The use of these agents therefore cannot be recommended.

Nephrotoxicity The overall incidence of contrast-mediated nephropathy is low but may be markedly increased in high-risk patients with diabetes mellitus or renal insufficiency. Contrast-mediated nephropathy typically results in acute renal failure 24 to 48 hours after exposure. The serum creatinine concentration peaks at 3 to 5 days. Contrast-mediated nephropathy comprises a range of disorders, from inconsequential enzymuria or a slight transient decrease in the glomerular filtration rate to severe irreversible oliguric acute renal failure. Renal function usually returns to baseline in 10 to 14 days. However, renal impairment may be prolonged and may require temporary or, rarely, permanent dialysis. Renal dysfunction is usually not associated with oliguria. Urinalysis typically shows only casts and is nondiagnostic. Unlike most other causes of acute renal failure due to intrinsic renal disease, the urine osmolality in patients with contrast-mediated nephropathy is usually high and the FENa is often low. Contrast-mediated nephropathy generally is associated with low morbidity and mortality. Prevention of contrast-mediated nephropathy is best accomplished by avoiding administration of contrast agents in high-risk patients and by choosing alternative diagnostic procedures, such as radionuclide or magnetic resonance imaging scans and ultrasonography, if possible. In high-risk patients, lim-

Intrinsic Acute Renal Failure

iting the dose of the contrast agent and providing volume expansion with 5% dextrose and half-normal saline decrease the incidence of nephropathy. Administration of acetylcysteine in a randomized controlled trial of patients with renal insufficiency undergoing computed tomographic procedures dramatically decreased the proportion of patients who experienced worsening renal insufficiency after the administration of a nonionic low-osmolality contrast agent (Tepel et al.). These findings, however, have only been variably reproduced (Durham et al.; Shyu et al.; Briguori et al.). Differences between outcomes of treatment with acetylcysteine in studies of contrast nephropathy may depend on the population assessed, the severity of comorbid illness, the dose and type of contrast, the outcome measures, or the procedures used. In a large randomized controlled study, administration of normal saline significantly reduced the incidence of contrast media–associated nephropathy compared with infusion of 5% dextrose and half-normal saline (Mueller et al.). Although other approaches to decreasing contrast-mediated nephropathy have been studied (for example, administration of calcium channel blockers and theophylline), their role has not been rigorously defined, nor has their superiority to administration of half-normal saline been shown. In a recent study, the use of dialysis to remove contrast agents in patients with renal insufficiency did not improve outcomes.

Drug-Induced Nephrotoxicity Nephrotoxic drugs, often antibiotics, are typically eliminated by the kidneys and tend to accumulate when the glomerular filtration rate is decreased. Nephrotoxicity due to a drug alone is often insidious and occurs more commonly in settings outside the intensive care unit. Seven percent to 29% of cases of hospital-acquired acute renal failure are related to the use of aminoglycoside antibiotics. The risk of nephrotoxicity due to aminoglycoside antibiotics increases with patient age, duration of therapy, and presence of volume depletion or hypotension and preexisting renal disease. Aminoglycoside antibiotic nephrotoxicity may be associated with renal potassium and magnesium wasting, resulting in development of hypokalemia, hypomagnesemia, and hypocalcemia. Polyuria and nephrogenic diabetes insipidus may result. A decreased glomerular filtration rate may not become clinically apparent until 1 to 2 weeks after initiation of therapy. Urinary sodium concentration and FENa are typically high. In patients with multiple risk factors, the time course for developing acute renal failure may be shorter. Because the therapeutic-to-toxic ratio for aminoglycoside antibiotics is low, monitoring of serum peak and trough drug levels is advised. When administering gentamicin and tobramycin, avoidance of peak and trough concentrations of greater than 10 µg/mL and 2 µg/mL, respectively, is associated with lower rates of nephrotoxicity. Maintenance of volume status and repletion of electrolytes are important for patients receiving aminoglycoside antibiotics. If acute renal failure develops, the drug should be discontinued if clinically feasible. Irreversible nephrotoxicity due to amphotericin B is related to the total cumulative dose administered and rarely develops unless the total dose exceeds 2 g (Deray). Concomitant use of cyclosporine may increase the risk for renal disease. Amphotericin B reacts with cell membrane sterols, causing renal vasoconstriction and structural renal arteriolar and tubular damage. Elderly and volume-depleted patients are at greatest risk. Volume repletion and use of lipidcomplexed preparations may reduce toxicity. Acute renal failure is usually nonoliguric and is slowly progressive but causes little proteinuria. Tubular disorders, such as distal renal tubular acidosis and abnormal water and cation reabsorp-

Tepel M, van der Giet M, Scwartzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiocontrast agent induced reductions in renal function by acetylcysteine. N Engl J Med. 2000;343:180-4. PMID: 10900277 Durham JD, Caputo C, Dokko J, Zaharakis T, Pahlavan M, et al. A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int. 2002;62:2202-7. PMID: 12427146 Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol. 2002;40:1383-8. PMID: 12392825 Briguori C, Manganelli F, Scarpato P, Elia PP, Golia B, Riviezzo G, et al. Acetylcysteine and contrast agent-associated nephropathy. J Am Coll Cardiol 2002;40:298-303. PMID: 12106935 Mueller C, Buerkle G, Buettner HJ, Petersen J, Perruchoud AP, Eriksson U, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med. 2002;162:329-36. PMID: 11822926

Deray G. Amphotericin B nephrotoxicity. J Antimicrob Chemother. 2002;749 Suppl 1:37-41. PMID: 11801579

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tion, may be noted. Newer antifungal preparations may be less toxic than amphotericin B. Pentamidine and vancomycin may also cause nephrotoxicity. Long-term use of high-dose lithium to treat bipolar disorder may result in prerenal azotemia accompanied by tubular disease. Chinese herbs and other alternative therapeutics may cause acute renal failure in outpatients. Clinicians should be aware of the nephrotoxic effects of these preparations. Case 14 A 35-year-old man has HIV infection that was diagnosed 2 years ago. His serum creatinine concentration at that time was 0.6 mg/dL. Initially, he received highly active antiretroviral therapy with zidovudine, lamivudine, and abacavir. His regimen was switched to stavudine, delavirdine, and ritonavir 2 months ago. Two months later, he presents for a routine visit. Physical examination reveals blood pressure of 110/70 mm Hg and a regular heart rate of 100/min without orthostatic changes. The chest is clear, with no cardiac murmur or gallop, and the abdomen is normal. He has moderate bilateral lower extremity edema. Laboratory values are as follows: sodium, 136 meq/L; potassium, 5.2 meq/L; chloride, 99 meq/L; bicarbonate, 22 meq/L; creatinine, 2.7 mg/dL; blood urea nitrogen, 37 mg/dL. Urinalysis reveals a specific gravity of 1.030, no hematuria, trace proteinuria, trace ketonuria, and no glucosuria. Urinary microscopic examination shows tubular cell casts but no erythrocyte casts.

HIV Infection

Weiner NJ, Goodman JW, Kimmel PL. The HIV-associated renal diseases: current insight into pathogenesis and treatment. Kidney Int. 2003;63:1618-31. PMID: 12675837. Woywodt A, Schwarz A, Mengel M, Haller H, Zeidler H, Kohler L. Nephrotoxicity of selective COX-2 inhibitors. J Rheumatol. 2001;28:2133-5. PMID: 11550988

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Patients with HIV infection develop acute renal failure for the same reasons as patients without HIV infection. Protease inhibitors have been associated with development of acute renal failure. An acute reversible decrease in renal function may occur shortly after initiation of therapy with ritonavir. Indinavir is also associated with the development of acute renal failure. Indinavir is excreted by the kidneys, and indinavir crystals form in the urine, especially if the urine is concentrated or of low volume. The crystals may precipitate in renal tissue and lead to acute renal failure. In addition, patients treated with indinavir may have such symptoms as dysuria, colic, and back pain, since indinavir kidney stones can be associated with urinary tract obstruction and postrenal azotemia. Such abnormalities as hematuria or crystalluria provide clues to the diagnosis. In many patients, therapy with indinavir can be restarted after volume repletion. Crystalluria and intrarenal obstruction may also be the cause of acute renal failure in patients treated with sulfadiazine and acyclovir. Recently, rhabdomyolysis and thrombotic microangiopathic renal disease have been noted as relatively frequent causes of acute renal failure in HIV-infected patients (Weiner et al.). Although infections and immunologic diseases may cause acute interstitial nephritis, this disorder is most frequently associated with medications. Penicillins, quinolones, nonsteroidal anti-inflammatory drugs, diuretics, cimetidine, phenytoin, phenobarbital, allopurinol, cephalosporins, interferon-α, and other drugs have been implicated in the development of acute interstitial nephritis (Woywodt et al.). The diagnosis is suggested by the presence of nonoliguric acute renal failure, especially in association with signs of systemic hypersensitivity, such as fever, rash, and eosinophilia. Sterile pyuria and microscopic hematuria are common findings, and non–nephrotic-range proteinuria may be present. Eosinophiluria is a supportive finding and often differentiates

Acute Renal Failure in Patients with Cancer

acute interstitial nephritis from acute tubular necrosis, nephrotoxicity, and pyelonephritis. Eosinophiluria may be demonstrated by Wright’s stain or the more specific Hansel’s stain, although the finding is nonspecific. Eosinophiluria may also occur in patients with acute prostatitis, rapidly progressive glomerulonephritis, and cholesterol emboli. Renal histologic specimens demonstrate an acute interstitial infiltrate composed of mononuclear cells and, less often, of eosinophils. Therapy involves discontinuation of the causative agent or treatment of the underlying disease. Although glucocorticoids are often used to treat acute interstitial nephritis, no data from prospective clinical trials are available on the efficacy of this therapy. Time to recovery varies, and dialysis may be necessary.

Acute Renal Failure in Patients with Cancer • What are the most common nephrotoxic drugs given to patients who are being treated for cancer? • What therapeutic strategies may be used to limit the development of acute renal failure in patients with cancer?

In patients with cancer, the usual causes of acute renal failure should be considered, in addition to unique causes related to the particular type of cancer and its treatment (Kapoor and Chan). Urinary tract obstruction should always be considered in patients with cancer, especially those with lymphoma or pelvic organ neoplasms. Acute oliguric urate nephropathy, a consequence of intratubular deposition of urate crystals, occurs most often in patients with lymphoproliferative and hematologic disorders during chemotherapy. Acute renal failure due to tumor cell lysis is accompanied by the release of other ions from neoplastic cells, resulting in hyperphosphatemia, hypocalcemia, and hyperkalemia. Uric acid crystalluria and a high ratio of urinary uric acid to urine creatinine (greater than 1.0) are found. Preventive therapy includes administration of allopurinol before chemotherapy is started, volume repletion, and alkalinization of the urine with sodium bicarbonate in an attempt to maintain urine pH above 6.5. Treatment of acute renal failure and other metabolic derangements is associated with a good prognosis. Hemolytic–uremic syndrome may occur after bone marrow transplantation. Its clinical presentation is often that of the nephritic syndrome (hypertension, renal insufficiency, proteinuria, and hematuria, often with erythrocyte casts) that occurs 4 to 12 months after bone marrow transplantation. The diagnosis of hemolytic–uremic syndrome should be suspected in patients with microangiopathic hemolytic anemia, thrombocytopenia, and central nervous system dysfunction. Therapy is supportive, and some patients develop end-stage renal disease. The clinical syndrome of radiation nephropathy includes hypertension, renal insufficiency, renal vascular damage, proteinuria, and anemia. The syndrome develops in patients who received radiation exposure to the kidneys of greater than 23 Gy and often occurs months after completion of the radiation therapy. Cisplatin (formerly called cis-platinum) nephrotoxicity may present as polyuria without azotemia during the first 2 days after drug administration. Nephrogenic diabetes insipidus and a decreased glomerular filtration rate may occur 72 to 96 hours after administration of cisplatin. Recovery usually occurs within 2 to 4 weeks, but renal abnormalities may persist. Cisplatin nephrotoxicity is dose-dependent and cumulative. Methotrexate causes both acute tubular necrosis and renal failure because of crystal precipitation in the renal tubules. Antineoplastic antibiotics, such as

Kapoor M, Chan GZ. Malignancy and renal disease. Crit Care Clin. 2001;17:57198. PMID: 11525049

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Other Causes of Acute Renal Failure

KEYPOINTS

• Urinary tract obstruction should always be considered in patients with cancer. It is often associated with lymphoma, gastrointestinal neoplasms, and tumors of the genitourinary system.

plicamycin, may cause acute tubular necrosis. Dose-related mitomycin C toxicity is usually associated with the hemolytic–uremic syndrome. Biological response modifiers are increasingly used to treat various neoplastic diseases. Interleukin-2 causes a capillary leak–like syndrome, associated with edema, ascites, and oliguria. Patients have a low FENa, consistent with prerenal azotemia. Renal function usually returns to normal within 30 days after cessation of therapy. Interstitial nephritis, minimal change nephropathy, and immune complex nephropathy have been reported in patients receiving interferon-α, and acute renal failure has occurred in a few patients. Interferon-γ sometimes causes acute renal failure (focal segmental glomerulosclerosis and acute tubular necrosis) and proteinuria. Immunoglobulin therapy has been associated with a spectrum of renal disorders including acute renal failure, but the abnormalities are usually reversible. Advanced age, volume depletion, and renal insufficiency are risk factors for this complication. In addition to drugs given to treat opportunistic infections in immunocompromised hosts, immunosuppressive medications, such as tacrolimus and cyclosporine, can result in the development of renal insufficiency. Acute renal failure occurs frequently, is usually dose dependent, and is manifested by vasoconstriction, which is generally reversible if the dose is decreased or the drug is discontinued. Rarely, these drugs may cause a thrombotic microangiopathic acute renal failure.

Other Causes of Acute Renal Failure • What are the most frequent causes of acute renal failure in patients with alcoholic liver disease?

Case 15 A 61-year-old man is admitted to the hospital because of increasing abdominal girth and edema. He has a 30-yearhistory of alcohol use and was told 1 year ago that he had liver disease. He has received furosemide for the past 3 months to treat the edema. On physical examination, his pulse rate is 112/min and regular, and blood pressure is 96/70 mm Hg. The chest is clear, and cardiac examination is normal. The abdomen is distended and tense, and a fluid wave can be elicited. No rebound or rigidity is present. He has bilateral lower extremity edema. On admission, laboratory values are as follows: serum creatinine, 1.2 mg/dL; serum sodium, 122 meq/L; serum potassium, 3.1 meq/L; serum chloride, 102 meq/L; serum bicarbonate, 20 meq/L; and blood urea nitrogen, 42 mg/dL. Urinalysis shows a specific gravity of 1.020, trace protein, trace ketones, and no glucose. Microscopic examination is normal. Urinary sodium concentration is 6 meq/L, and urine osmolality is 670 mosm/kg H2O. Patients with alcoholic liver disease are at risk for several types of acute renal failure. The most common cause is prerenal azotemia in patients with cirrhosis and ascites. Patients with end-stage liver disease may also develop acute tubular necrosis during periods of hemodynamic instability or sepsis, or secondary to use of nephrotoxic drugs or rhabdomyolysis. The hepatorenal syndrome is a form of progressive decreased renal perfusion that occurs in patients with advanced liver disease in whom no other causes sufficiently explain the severity and persistence of the renal dysfunction (such as drug toxicity, infection, or 64

Other Causes of Acute Renal Failure

other underlying systemic illness) (Arroyo et al.). The hepatorenal syndrome is thought to be a physiologic renal response to systemic complications of the liver disease. The mortality rate for patients with the hepatorenal syndrome is extremely high. Spontaneous recovery occurs rarely, and typically only if the hepatic disease improves. The severity of the liver disease is probably the most important determinant of survival. Liver transplantation may successfully reverse the hepatorenal syndrome in these high-risk patients. Although the hepatorenal syndrome usually occurs in patients with cirrhosis, it may develop in patients with fulminant hepatitis or hepatic cancer. Patients usually have ascites, portal hypertension, jaundice, hypoalbuminemia, and some degree of hypotension. The hepatorenal syndrome frequently occurs in conjunction with diuresis, paracentesis, surgical procedures, gastrointestinal bleeding, or infection. To diagnose the hepatorenal syndrome, volume status, usually measured by central venous pressure and/or cardiac hemodynamic parameters, must be adequate. The urinary sodium concentration is usually less than 10 meq/L, and the FENa is generally less than 1%. A high urinary sodium concentration in the absence of diuretic administration strongly suggests another diagnosis. Azotemia and oliguria are progressive. The pathogenesis of the hepatorenal syndrome is unknown, but abnormalities of leukotriene and endothelin metabolism, shunting of renal plasma flow from cortical to medullary segments, and intense renal vasoconstriction in the presence of systemic and splanchnic vasodilatation have all been implicated. Renal histology is usually normal, which suggests that structural renal disease is not the cause of the hepatorenal syndrome. Treatment consists of identifying and discontinuing possible inciting agents and maintaining central and renal hemodynamic variables, often by using albumin infusions to enhance oncotic pressure. Acute renal failure due to rhabdomyolysis is associated with high serum levels of creatine kinase and creatinine, hyperuricemia, hyperkalemia, and hyperphosphatemia. This form of acute renal failure may be precipitated by muscle trauma, strenuous exercise, influenza, potassium or phosphorus depletion, drug overdose, or alcohol use. Such drugs as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors may also cause acute renal failure due to rhabdomyolysis, especially in patients with inborn errors of muscle metabolism (Omar et al.). Reports of acute renal failure associated with rhabdomyolysis after cocaine use have described associated hepatic failure and disseminated intravascular coagulation. The serum creatinine level may be markedly increased or rise by more than 2 mg/dL per day as a result of muscle injury and decreased renal excretion. Urinalysis shows dipstick-positive heme in the absence of erythrocytes on microscopic examination, reflecting myoglobinuria. Pigmented casts are also seen. Other microscopic findings are the same as those of acute tubular necrosis. Volume repletion, administration of mannitol, and administration of bicarbonate to alkalinize the urine have been recommended, even though studies showing that these therapeutic measures are effective after the onset of renal injury are lacking. Administration of furosemide early in the course of acute renal failure has been suggested in patients with oliguria. The ultimate prognosis is good, although dialysis may be necessary, especially if severe hyperkalemia is present. Patients with atherosclerotic heart disease and peripheral vascular disease may be at risk for several types of renal disease (Alcazar and Rodicio). The most common type is prerenal azotemia in patients with congestive heart failure, although patients with heart disease may develop acute tubular necrosis during periods of hemodynamic instability or sepsis, after receiving nephrotoxic drugs, or after administration of contrast agents during coronary angiography

Arroyo V, Guevara M, Gines P. Hepatorenal syndrome in cirrhosis: pathogenesis and treatment. Gastroenterology. 2002;122:1658-76. PMID: 12016430

Omar MA, Wilson JP, Cox TS. Rhabdomyolyis and HMG-CoA reductase inhibitors. Ann Pharmacother. 2001;35:1096-107. PMID: 11573861

Alcazar JM, Rodicio JL. Ischemic nephropathy: clinical characteristics and treatment. Am J Kidney Dis. 2000;36: 883-93. PMID: 11054344

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Other Causes of Acute Renal Failure

Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002; 105:2259-64. PMID: 12010907

or peripheral arteriography. In a large retrospective study, approximately 3% of patients experienced acute renal failure after percutaneous coronary intervention (Rihal et al.). The presence of diabetes and increased serum creatinine concentration were risk factors. Atheroembolic renal disease occurs in patients with atherosclerosis, especially after angiography, angioplasty, vascular surgery, treatment with intra-aortic balloon pumps, anticoagulation, or thrombolysis. Renal atheroemboli rarely occur spontaneously. The clinical findings are a result of cholesterol crystals or debris from atheromatous plaques obstructing small renal vessels and causing local inflammation, ischemia, hypertension, and progressive renal insufficiency. Other organ system dysfunction, such as cerebral ischemia, ocular abnormalities, and intestinal vascular insufficiency, may occur concomitantly and are clues to the diagnosis. Refractile plaques in retinal arteries (Hollenhorst plaques), livedo reticularis, petechial lesions, and cyanosis of the lower extremity digits may be noted. Leukocytosis, eosinophilia, eosinophiluria, hypocomplementemia, and an increased erythrocyte sedimentation rate may also be present but are not diagnostic. The diagnosis may be confirmed by biopsy of muscle, skin, or kidney that shows the typical biconcave clefts in small vessels. The course of renal insufficiency varies but frequently progresses over days to months. No treatment has been shown to be beneficial. Therapy consists of treatment of hypertension, discontinuation of anticoagulation, and preparation for dialysis if necessary. The prognosis for recovery of renal function and patient survival is poor.

Chronic Kidney Disease

NKF–K/DOQI Clinical Practice Guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis. 2002;39(2 Suppl 2):S1–246. PMID: 11904577

The National Kidney Foundation launched the Kidney Disease Outcomes Quality Initiative (K/DOQI) to evaluate, classify, and stratify patients with chronic kidney disease, which is defined by the presence of kidney damage or decreased kidney function (glomerular filtration rate <60 mL/min) for 3 months or more, irrespective of diagnosis (NKF-K/DOQI Clinical Practice Guidelines). Table 24 summarizes the overall clinical action plan for the different stages of chronic kidney disease. The disease is staged according to the glomerular filtration rate, which may be calculated by using either the Cockcroft–Gault or Modification of Diet in Renal Disease formula. The National Kidney

TA B L E 2 4 Chronic Kidney Disease: A Clinical Action Plan

Stage

Description

GFR (mL/min)

Action

1

At increased risk Kidney damage with normal or increased GFR

≥ 90, with CKD risk factors ≥ 90

Screening, CKD risk reduction Diagnosis and treatment, treatment of comorbid conditions, slowing of progression, cardiovascular risk reduction

60–89

Estimation of progression

3

Kidney damage with mildly decreased GFR Moderate decreased GFR

30–59

Evaluation and treatment of complications

4

Severely decreased GFR

15–29

Preparation for kidney replacement therapy

5

Kidney failure

<15, or dialysis

Replacement (if uremia present)

2

CKD = chronic kidney disease; GFR = glomerular filtration rate. Adapted from: K/DOQI Clinical Practice Guidelines on Chronic Kidney Disease: evaluation, classification, and stratification. K/DOQI Clinical Practice Guidelines on Chronic Kidney Disease Work Group. Part I. Executive Summary. Am J Kidney Dis. 2002;39(2 Suppl 1):S17-S31.

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Management Issues

KEYPOINTS

• Early referral to a nephrologist for patients with azotemia (serum creatinine concentration >2 mg/dL in men and >1.5 mg/dL in women) is recommended in an attempt to reduce the substantial morbidity and mortality of patients with renal disease. • Adequate control of systemic hypertension is the most important intervention to slow the progression of renal insufficiency. Target blood pressure should be less than 130/85 mm Hg in all patients with renal disease and less than 125/75 mm Hg in patients with proteinuria greater than 1 g/d. Angiotensin-converting enzyme inhibitors appear to have a renoprotective effect. • Therapy with erythropoietin is efficacious in correcting the anemia of chronic kidney disease in patients with pre-end-stage renal disease and those with end-stage renal disease. • The three types of renal bone disease are osteitis fibrosa, in which bone turnover is increased owing to hyperparathyroidism; osteomalacia, in which bone turnover is decreased and osteoid levels are increased secondary to aluminum deposition in bone; and adynamic bone disease. • Management strategies to prevent renal osteodystrophy include dietary phosphorus restriction, oral calcium-containing phosphorus binders, and calcitriol supplements to increase serum calcium and suppress parathyroid hormone secretion.

Management Issues • What is the most important intervention known to slow the progression of diabetic nephropathy?

Recommendations from a National Institutes of Health conference on optimization of care for chronic kidney disease patients advocate nephrology consultation for women with a serum creatinine concentration greater than 1.5 mg/dL and men with a serum creatinine concentration greater than 2.0 mg/dL. Benefits of referral include confirmation of the diagnosis, identification of reversible causes of kidney dysfunction, initiation of therapy likely to slow disease progression, and timely preparation of the patient for renal replacement therapy. Early nephrology referral has also been shown to reduce initial treatment costs.

Progression of Kidney Disease Kidney function declines progressively in approximately 85% of patients with kidney damage once the serum creatinine concentration increases to greater than 1.5 to 2.0 mg/dL. After the correct diagnosis is established, initial efforts should be directed at evaluating and correcting potential reversible conditions that may be superimposed on the underlying disease process (Table 26). In case 16, the clinical presentation is consistent with diabetic nephropathy; treatment with nonsteroidal anti-inflammatory drugs was discontinued because these agents are potential nephrotoxins. In many cases, the subsequent decline in kidney function appears to evolve from a series of secondary events or metabolic changes unrelated to the original insult. Appropriate management of these derangements may slow the rate of continued renal injury. The most important independent predictors of accelerated kidney dysfunction are poorly controlled hypertension and the level of urinary protein excretion. In most kidney diseases, the decrease in glomerular filtration rate is linear. Chronic kidney disease may progress to end-stage renal disease because of secondary factors unrelated to the original disease. Such factors include systemic and intraglomerular hypertension; hyperlipidemia; metabolic acidosis; precipitation of calcium phosphate in the renal interstitium; interstitial fibrosis; enhanced production of growth factors, such as transforming growth factor-α and platelet-derived growth factor; and activation of the renin–angiotensin system. Control of systemic hypertension is the most important maneuver to slow the progression of established nephropathy. Adherence to a renal diet (protein restriction) is less efficacious. In diabetic patients, optimal glycemic control will reduce the initial development of microalbuminuria or overt nephropathy.

Hypertension

Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, et al. Angiotensinconverting enzyme inhibitors and progression of nondiabetic renal disease. A metaanalysis of patient-level data. Ann Intern Med. 2001;135:73-87. PMID: 11453706

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Hypertension usually accompanies progressive kidney disease. Systemic hypertension may increase intraglomerular capillary pressure and capillary wall stress, induce endothelial cell damage, increase glomerular permeability, and activate the renin–angiotensin system and other local growth factors, resulting in glomerular hypertrophy and glomerulosclerosis. Angiotensin-converting enzyme inhibitors appear to be especially effective in reducing the rate of progression of diabetic and nondiabetic renal disease. This effect is most pronounced in patients with urinary protein excretion rates greater than 3 g/d (Jafar et al.). Beneficial effects of angiotensin-converting enzyme inhibitors do not result solely from their actions on systemic pressure. For equivalent reductions in mean arterial pressure, angiotensin-converting enzyme inhibitors retard progression of renal disease more effectively than do calcium channel blockers in

Management Issues

hypertensive nephrosclerosis (Agodoa et al.). In hypertensive or normotensive patients with type 1 diabetes, angiotensin-converting enzyme inhibitors reduce the frequency of progression from microalbuminuria to overt diabetic nephropathy. Patients with type 2 diabetes also appear to benefit from treatment with angiotensin-converting enzyme inhibitors, but recent studies document a similar renoprotective effect of angiotensin receptor blockers in this group (Parving et al.; Lewis et al.; Brenner et al.). Nondihydropyridine calcium channel blockers (verapamil or diltiazem) have also been shown to retard progression of kidney disease in patients with type 2 diabetes mellitus. Target blood pressure should be less than 130/85 mm Hg for all patients with kidney disease and less than 125/75 mm Hg for patients with urinary protein excretion greater than 1 g/24 h. Optimal glycemic control in diabetes will also reduce the development of microalbuminuria or overt nephropathy.

Dietary Protein The benefit of dietary protein restriction in chronic kidney disease remains controversial (Pedrini et al.). Hypoalbuminemia in patients beginning dialysis is a strong predictor of early death. Thus, any component of this abnormality that is due to inadequate protein intake should be corrected. Dietary protein intake of 0.6 to 1 g/kg daily appears to be safe, as it is well tolerated and does not lead to malnutrition, unless severe nephrotic syndrome or advanced chronic kidney disease exists. The favorable effect of protein restriction in experimental animal models and studies in diabetic patients was not confirmed in two large controlled trials of nondiabetic patients in Italy and the United States. A reasonable clinical recommendation for patients with chronic kidney disease would include rigorous blood pressure control and moderate protein intake. As chronic kidney disease progresses, the typical renal diet should contain 2 g/d restriction of potassium and 2 g/d restriction of sodium with usual fluid intake.

Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;285:2719-28. PMID: 11386927 Parving HH, Lehnert H, BrochnerMortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-8. PMID: 11565519 Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-60. PMID: 11565517 Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-9. PMID: 11565518 Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Ann Intern Med. 1996;124:627-32. PMID: 8607590

TA B L E 2 6 Potentially Reversible

Anemia A normochromic, normocytic anemia may accompany progressive chronic kidney disease. In most cases, the anemia is due to a deficiency of erythropoietin. The interstitial cells of the normal kidney are the primary sites of erythropoietin synthesis in response to decreased renal tissue oxygenation. The anemia of chronic kidney disease is attributable to reduced erythropoietin production due to a reduction in functioning renal mass. Other causes of anemia, such as gastrointestinal bleeding, iron or folate deficiency, and hemolysis, should be excluded. Use of recombinant erythropoietin has nearly eliminated anemia as a major cause of morbidity in patients with end-stage renal disease or pre–endstage renal disease. The optimal target hemoglobin values remain to be determined in patients with pre–end-stage renal disease. However, target hemoglobin values of 11 to 12 g/dL may improve energy and physical function and reduce left ventricular mass. A large survey of patients with end-stage renal disease showed that administration of erythropoietin before initiation of dialysis provided a survival benefit during the first 19 months of dialysis therapy (Fink et al.). Reductions in mortality remain to be demonstrated in large, randomized clinical controlled trials. Erythropoietin therapy may worsen hypertension in approximately 30% of patients. Headaches and flu-like symptoms occur less frequently. No evidence indicates that erythropoietin therapy accelerates progression of kidney disease, as long as blood pressure is adequately controlled. Patients with chronic kidney disease who have hemoglobin levels less than 10 g/dL are candidates for recombinant erythropoietin therapy, once iron defi-

Causes of Worsening Renal Failure Hypotension/renal hypoperfusion Volume depletion Uncontrolled hypertension Congestive heart failure Nephrotoxic drugs or radiocontrast agents Urinary tract obstruction Hypercalcemia Sepsis Urosepsis or obstruction

Fink J, Blahut S, Reddy M, Light P. Use of erythropoietin before the initiation of dialysis and its impact on mortality. Am J Kidney Dis. 2001;37:348–55. PMID: 11157377

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Medical Management of the Uremic State

ciency has been excluded. For adult patients with severe anemia or anemiadependent angina, 75 to 125 U/kg weekly, should be administered subcutaneously in divided doses. Low iron stores, inflammation or chronic infection, hemoglobinopathies, bone marrow fibrosis, aluminum toxicity, and vitamin B12 or folate deficiency may limit response.

Hyperparathyroidism and Renal Osteodystrophy Secondary hyperparathyroidism is almost universal in patients with chronic kidney disease. Phosphate retention occurs soon after the glomerular filtration rate decreases to less than 60 to 80 mL/min and plays a central role in stimulating the increase in parathyroid hormone synthesis. Phosphate retention is now thought to promote parathyroid hormone release by a direct effect of hypocalcemia, decreased formation and effect of calcitriol (1,25-dihydroxy vitamin D), or a direct effect of hyperphosphatemia on parathyroid hormone gene expression. Since a calcium-sensing receptor, with its attendant messenger RNA and protein, has been identified in the parathyroid gland, it now appears that this receptor may directly sense hypocalcemia. The suppression of renal calcitriol synthesis may increase parathyroid hormone by decreasing the serum calcium level or by removing the inhibitory effect of calcitriol on the parathyroid gland. Independent of the mechanism, this secondary hyperparathyroid response is a “trade-off” in which serum levels of calcium and phosphorus normalize at the cost of a persistently elevated parathyroid hormone level and potential bone disease. To mitigate these changes, dietary phosphorus restriction should be initiated if the glomerular filtration rate decreases to less than 60 mL/min. Oral calcium-containing phosphate binders (calcium acetate or calcium carbonate, taken with meals) should be administered as necessary to normalize serum levels of calcium and phosphorus. New calcium-free phosphate binders are currently available, but the role of these agents remains to be determined in chronic kidney disease. Calcitriol can be administered to suppress parathyroid hormone and retard the development of renal bone disease. Calcitriol may be useful in patients with persistent hypocalcemia or severe hyperparathyroidism as long as hypercalcemia and elevation of the serum calcium–phosphorus product are avoided. The goal of therapy is to maintain parathyroid hormone levels at two to three times the normal values. In assessing parathyroid hormone activity, intact parathyroid hormone (or N-terminal parathyroid hormone molecule) should be measured because inactive C-terminal parathyroid hormone molecules accumulate in patients with kidney failure. The three types of renal bone disease are osteitis fibrosa, in which bone turnover is increased because of secondary hyperparathyroidism; osteomalacia, which is characterized by low bone turnover and increased osteoid levels secondary to aluminum deposition in bone; and adynamic bone disease, which may be more prevalent in elderly persons, diabetic patients, persons treated with aluminum hydroxide, and those receiving continuous ambulatory peritoneal dialysis. The pathophysiology of adynamic bone disease may relate to excessive suppression of parathyroid hormone by calcitriol therapy. Patients with renal osteodystrophy may present with bone pain or fractures. Radiographic signs of osteitis fibrosa include subperiosteal bone resorption of phalanges, distal clavicles, and skull. Osteopenia and pseudofractures are more suggestive of osteomalacia.

Medical Management of the Uremic State Kidney function continues to decline with time in most patients with chronic kidney disease. Inadequate sodium excretion leads to hypertension and edema, necessitating dietary sodium restriction and therapy with diuretics. Hyperkalemia 70

Medical Management of the Uremic State

may be induced by use of angiotensin-converting enzyme inhibitors and salt substitutes and becomes more likely as the glomerular filtration rate decreases to less than 20 mL/min. Dietary potassium should be restricted, and other sources of potassium should be discontinued. Correction of metabolic acidosis may improve muscle strength and lessen the effects of secondary hyperparathyroidism on bone. Medications should be reviewed, and doses should be adjusted as necessary to compensate for reduced renal metabolism and removal. Hypermagnesemia is a potential problem for patients using magnesiumcontaining antacids and cathartics. Uremia is the clinical state in which patients with advanced renal failure develop signs and symptoms related to azotemia. Uremic symptoms are presumed to be caused by poorly identified “uremic toxins,” which accumulate as a result of inadequate removal by the kidney. These symptoms include anorexia, nausea, vomiting, pruritus, impaired cognitive functions, fatigue, sleep disturbances, sensory and motor neuropathy, asterixis, pericarditis, impaired myocardial contractility, and seizures. The improvement in symptoms with effective dialysis supports the hypothesis that retained toxins are responsible. Table 27 lists absolute and relative indications for and contraindications to renal replacement therapy. Uremia is accompanied by several endocrine disorders. Levels of total thyroxine, triiodothyronine, and free triiodothyronine are decreased, whereas levels of thyroid-stimulating hormone and free thyroxine levels are usually normal. Plasma levels of prolactin and growth hormone are elevated. Peripheral resistance to insulin is present, yet renal insulin clearance is impaired, allowing many diabetic patients to reduce or discontinue insulin use. Gonadal dysfunction occurs in both men and women, resulting in testicular atrophy, amenorrhea, sexual dysfunction, and infertility. Luteinizing hormone levels are elevated in men and women. Growth retardation frequently occurs in children with endstage renal disease.

TA B L E 2 7 Indications and Contraindications for Renal Replacement

Therapy in End-Stage Renal Disease Absolute indications Hyperkalemia Respiratory or congestive heart failure Refractory metabolic acidosis Pericarditis Relative indications Glomerular filtration rate < 10 mL/min (< 15 mL/min in a patient with diabetes mellitus) Serum creatinine > 8 mg/dL (> 6 mg/dL in a patient with diabetes mellitus) Uremic symptoms Relative contraindications Severe, irreversible dementia Debilitating chronic disease

71

Treatment of End-Stage Renal Disease

KEYPOINTS

• For patients undergoing dialysis, overall mortality rates among those without diabetes approximate 22% at 1 year and 60% to 70% at 5 years. Rates are worse among diabetic patients. • After renal transplantation, patient survival rates of 95% at 1 year and 88% at 5 years are expected. Continuing cadaveric graft survival rates of 85% at 1 year and 70% at 5 years can be expected with use of newer immunosuppressant agents.

Treatment of End-Stage Renal Disease Case 17 The patient in case 16 has a healthy brother who has volunteered to be a kidney donor. The patient requests your guidance regarding the merits of renal transplantation and dialysis. Patients requiring renal replacement therapy can undergo dialysis (peritoneal or hemodialysis) or renal transplantation. Without replacement therapy, these patients will die. The primary internist plays a key role in initiating the treatment process and in counseling patients who decline dialysis. Early referral to a nephrologist is essential for adequate patient education and preparation for various treatment options.

Dialysis versus Renal Transplantation

TA B L E 2 8 Exclusion Criteria for Renal Transplantation

Active infection* (including HIV) Recent active cancer Dementia Significant cardiopulmonary or hepatic disease Chronic debilitated state Habitual substance abuse or noncompliance * Hepatitis C is controversial.

72

All patients should be counseled about their options for dialysis or transplantation and receive information comparing survival and quality of life with both methods. Cadaveric kidney transplantation has been shown to have a survival advantage over long-term dialysis in suitable patients matched for age and renal disease. Transplantation also offers superior quality of life and is less expensive than long-term dialysis. However, many patients are not medically suitable for surgery and long-term immunosuppression (Table 28). Currently, 5-year survival rates with long-term dialysis are 30% to 40% in patients without diabetes and 20% in diabetic patients. In comparison, 5-year survival rates are 88% after transplantation. The current shortage of donor organs in the United States severely limits patient access to transplantation, despite its superior results and reduced long-term costs. Patients are encouraged to find their own donors, both to avoid prolonged waiting and because excellent results are achieved with transplantation of kidneys from living related or unrelated donors.

Dialysis Techniques Home hemodialysis, in-center hemodialysis, and home peritoneal dialysis (chronic ambulatory or cycler peritoneal dialysis) are the treatments available to most U.S. patients with end-stage renal disease. Almost 85% of patients receive in-center hemodialysis; despite better survival statistics, only 1% of patients receive home hemodialysis. High-efficiency (cellulose-type membranes with large surface area) and high-flux (noncellulose membranes with larger pore size) hemodialysis membranes have been proposed to decrease symptoms associated with dialysis. Long-term use of high-flux membranes has been proposed to reduce morbidity in several reports. Peritoneal dialysis, which is used in about 15% of patients, has patient survival equivalent to in-center hemodialysis in patients who do not have diabetes mellitus. Data from the U.S. Renal Data System show a slight increase in mortality in diabetic and elderly patients treated with chronic ambulatory peritoneal dialysis. However, this finding is not universal, and peritoneal dialysis is frequently offered to independent diabetic patients and elderly patients with hemodynamic instability. Maintenance of access to dialysis is a major challenge with both hemodialysis and peritoneal dialysis. For peritoneal dialysis, placement of a peritoneal catheter should optimally occur 2 to 4 weeks before therapy is started. Peritonitis caused by gram-positive organisms may be a common problem. For hemodialysis, an arteriovenous fistula or a prosthetic vascular graft should be placed weeks to months before initiation of dialysis. Cuffed double-lumen subcutaneous catheters have been used, but they have a higher failure rate from infection and thrombosis. In addition, they tend to deliver a lower dose of dialysis.

Treatment of End-Stage Renal Disease

Medical Problems in Patients Undergoing Dialysis Cardiovascular disease, infection, and withdrawal from dialysis are the primary causes of death in patients undergoing dialysis. Cardiovascular disease accounts for almost 50% of deaths in patients on dialysis, and coronary artery disease is responsible for 30%. Patients undergoing dialysis have many cardiovascular risk factors, including hypertension, hyperlipidemia, and hyperhomocystinemia, and many have diabetes as an underlying disorder. Dialysis-induced hypotension, increased oxidant stress, and an increased calcium intake may also contribute to atherosclerotic risk. Cardiomyopathy and left ventricular hypertrophy may also occur. The 1-year mortality rate after an acute myocardial infarction is more than 50%. Coronary angioplasty is less effective in patients undergoing dialysis because rates of restenosis are 70% to 80% at 6 months. Thus, the invasive treatment in these patients should be coronary artery bypass grafting. The longterm outcomes of percutaneous transluminal angioplasty with stent placement remain to be determined. Infection accounts for 15% to 20% of all deaths. Infection of the vascular access may occur, with few local findings. Common organisms predominate, and infection of the vascular access site is a frequent problem. Although 1-year survival rates have improved (approximately 80%), they remain lower than survival rates for patients undergoing dialysis in countries other than the United States. Multiple explanations have been proposed, but strong emphasis has been placed on insufficient doses of dialysis. Dialysis doses are now monitored frequently and adjusted accordingly.

Kidney Transplantation Kidney transplantation is considered successful if the glomerular filtration rate after transplantation is greater than 50 mL/min. Advantages of successful transplantation include better survival and restoration of normal energy levels, hematocrit, and endocrine function, which allow a return to an unrestricted lifestyle. Kidney transplantation stabilizes or improves autonomic neuropathy, retinopathy, and gastroenteropathy in diabetic patients in whom these conditions worsened on dialysis. A lack of adequate numbers of donor organs, surgical risk, complications, and the cost of immunosuppression are the major barriers to wider use of transplantation.

Contraindications Table 28 shows the most commonly agreed-on criteria used to exclude patients from consideration for renal transplantation. Chronological age is no longer considered an exclusion criterion per se if the patient has few comorbid conditions.

Patient and Graft Survival Patient survival after kidney transplantation is significantly influenced by the source of the organ. Recipients of a living-related kidney have survival rates of 97% at 1 year and 90% at 5 years. Recipients of a living-unrelated kidney have survival rates of 96% at 1 year and 84% at 5 years. Recipients of a cadaveric kidney have survival rates of 93% at 1 year and 81% at 5 years. Diabetic patients and patients older than 60 years of age have 1-year survival rates of approximately 90% but 5-year survival rates of 45% to 70%. Cardiovascular disease is the most frequent cause of death in adults. Acute myocardial infarction accounts for one third of cardiovascular deaths. Infection accounts for 18% of deaths, and 10% of deaths are from cancer. Kidney graft survival is categorized as short term (<1 year after transplantation) or long term (≥1 year). Short-term cadaveric transplant survival exceeds 85% in many centers. Although short-term survival is influenced by many fac73

Treatment of End-Stage Renal Disease

Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000;342:605-12. PMID: 10699159

tors (for example, source of the kidney, HLA mismatch and panel-reactive antibody status, and dialysis history), acute rejection is the primary cause of shortterm renal allograft loss. Long-term survival is measured in half-lives (time beyond the first post-transplantation year in which 50% of grafts are no longer functioning) and is also influenced by numerous factors (such as HLA matching, episodes of acute rejection, hypertension, and recurrent or new glomerular disease). Use of newer immunosuppressive agents has significantly improved short-term graft survival. Long-term survival has improved slightly. For transplants performed in the United States between 1988 and 1996, the half-life was 18.8 years for cadaveric allografts and 21.6 years for one-haplotype– mismatched living-related grafts (Hariharan et al.).

Special Problems in Renal Transplant Recipients The calcineurin inhibitors cyclosporine and tacrolimus, which inhibit interleukin-2 production, are the cornerstones of immunosuppressive therapy. Both drugs may produce hypertension, hyperkalemia, and nephrotoxicity. Unlike cyclosporine, tacrolimus does not cause hirsutism or gum hypertrophy but it can induce seizures, encephalopathy, diarrhea, and glucose intolerance. Nephrotoxicity limits the use of calcineurin inhibitors as sole agents. Thus, most immunosuppressive regimens add steroids or an inhibitor of purine metabolism, such as mycophenolate mofetil or azathioprine. Mycophenolate mofetil acts more selectively on lymphocytes than does azathioprine, but it induces dose–related diarrhea and leukopenia and may be associated with a higher frequency of viral infections. In contrast to azathioprine, mycophenolate mofetil does not prolong the half-life of allopurinol. Antimicrobial prophylaxis for common opportunistic infections, such as cytomegalovirus; Epstein–Barr virus; Pneumocystis, Candida, and Aspergillus species; and mycobacteria, is now routinely administered to transplant recipients. Cardiovascular disease, especially myocardial infarction, is the most common cause of morbidity and mortality. Cutaneous and lymphoid neoplasms occur at a significantly higher rate in transplant recipients than in the general population. Aseptic necrosis of the hips and knees and cataracts related to use of high–dose steroids were formerly a significant problem but are now decreasing in frequency.

Nephrolithiasis Pak CY. Kidney stones. Lancet. 1998;351:1797-801. PMID: 9635968

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Nephrolithiasis affects 1% to 5% of the population. Men have twice the risk of women (Pak). Table 29 shows the composition, frequency, and causes of nephrolithiasis. The clinical presentation of patients with nephrolithiasis usually includes moderate to severe colicky flank pain with radiation into the lower abdomen or perineal area, urinary symptoms of urgency or frequency, and microscopic or gross hematuria. Some patients present with silent ureteral obstruction, unexplained persistent urinary infection, or painless hematuria. The diagnosis may be confirmed either by renal ultrasonography, intravenous pyelography, or spiral computed tomography. Stone analysis is rarely indicated with first stone passage, because most stones are calcium containing and will have a typical appearance on radiography. When kidney–ureter–bladder imaging or intravenous pyelography fails to demonstrate a stone in the course of the urinary tract in a patient with typical renal colic, the clinician should suspect radiolucent stone disease (uric acid); calcium stones less than 1 to 3 mm in diameter; or nonstone causes, such as obstruction by blood clots or tumors.

Calcium Stone Disease

TA B L E 2 9 Nephrolithiasis: Composition, Frequency, and Causes

Composition

Frequency

Calcium oxalate or phosphate

75%

Cause Hypercalciuria High dietary sodium and protein Hypercalcemia Idiopathic Low urine volume Chronic dehydration, hot climate Hyperuricosuria Hyperoxaluria Low dietary calcium

Uric acid

10%–15%

Struvite

10%–15%

Cystine

<1%

Low urinary citrate level Chronic metabolic acidosis Renal tubular acidosis Inflammatory bowel disease Low urinary pH Chronic metabolic acidosis Hyperuricosuria Urine infection (urease-splitting bacteria) Cystinuria (single-gene defect)

Nephrolithiasis results from abnormal urinary concentration and/or composition of stone-forming salts that is metabolic or dietary in origin. Metabolic disorders include idiopathic hypercalciuria, hyperparathyroidism, hereditary hyperoxaluria, and cystinosis. Dietary risk factors include low dietary intake of calcium; high dietary intake of sodium, purine (uric acid), animal protein (which causes increased urinary calcium excretion), and oxalate; and enteric hyperoxaluria associated with inflammatory bowel disease or short-bowel syndromes.

Calcium Stone Disease Calcium stone disease occurs most often in the third to fifth decade of life. Most patients with calcium stones have hypercalciuria (defined as 24-hour urinary calcium excretion greater than 300 mg in men, greater than 250 mg in women, or greater than 4 mg/kg in men or women). The hypercalciuria may be associated with hyperparathyroidism or sarcoidosis, with or without hypercalcemia. More often, the hypercalciuria occurs in the setting of a normal calcium level and in the absence of systemic diseases; in this case, it is called idiopathic hypercalciuria. Most patients with hypercalciuria have excessive gastrointestinal absorption of calcium. In many of these cases, the level of 1,25 vitamin D is elevated, and the serum phosphorus level is slightly low; the mechanism for these derangements is not known. Because these patients also have inappropriate calciuria while consuming a calcium-restricted diet, such a diet is not advised. Hypercalciuria is worsened by high dietary intake of sodium, high intake of animal protein, and use of loop diuretics; it is reduced by use of distally acting thiazide diuretics and amiloride. In patients with recurrent hypercalciuric stones, treatment should consist of high fluid intake, dietary sodium restriction, and thiazide diuretics. Dietary calcium restriction is not advised because negative calcium balance may occur and because a low-calcium diet increases gastrointestinal absorption of oxalate and oxaluria. This increase in urinary oxalate can substantially increase supersaturation of the urine by calcium oxalate, which in turn increases the rate of stone formation. 75

Struvite (Infection) Stone Disease

Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993;328:833-8. PMID: 8441427 Curhan GC, Willett WC, Speizer FE, Speigelman D, Stampfer MJ. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126:497-504. PMID: 9092314 Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346:77-84. PMID: 11784873

KEYPOINTS

• Hypercalciuria is the most common risk factor for calcium nephrolithiasis. • Hypercalciuria is significantly worsened by a high-sodium diet. • Treatment for hypercalciuric stone formers includes low dietary sodium, high fluid intake, normal calcium intake, and, in some patients, hydrochlorothiazide therapy.

Several studies have shown that a higher dietary intake of calcium is associated with fewer calcium stone events in both men and women (Curhan et al., 1993; Curhan et al., 1997). Furthermore, a recent study in 120 Italian patients with hypercalciuric calcium oxalate stones demonstrated that a diet consisting of a normal amount of calcium but low in sodium and animal protein was associated with reduced frequency of calcium stones compared with a low-calcium diet (Borghi et al.). In this study, both diets were associated with a reduction in the urinary calcium level; however, urinary oxalate excretion increased in the group receiving a low-calcium diet and decreased in the group receiving a high-calcium diet. The reduction in urinary oxalate excretion in patients consuming a normal-calcium diet is attributed to intestinal binding of dietary oxalate by dietary calcium, thus lessening the amount of free oxalate available for absorption. Although both groups had reduced calcium oxalate saturation of the urine, participants who consumed the normal-calcium diet had a greater reduction. Compared with patients receiving a low-calcium diet, those receiving the normal-calcium, low-sodium, low-protein diet had a 50% reduction in risk for stone formation at 5 years. Other risk factors for calcium stones include chronic low urine output; hyperoxaluria, which is seen in patients with inflammatory bowel disease, those who consume large amounts of leafy green vegetables, or, rarely, those with a recessively inherited disorder of oxalate metabolism; hyperuricosuria; and low urine citrate level, which occur most often in patients with inflammatory bowel disease and renal tubular acidosis. Renal stones that occur in the distal form of renal tubular acidosis are frequently composed of calcium phosphate, present as multiple stones on radiography (nephrocalcinosis), and develop in the presence of persistently alkaline urine (pH >5.5) despite metabolic acidosis.

Struvite (Infection) Stone Disease KEYPOINTS

• Struvite, or infection, stones form in the presence of active urinary infection. Thus, a urine examination showing no leukocytes or bacteria rules out this type of stone disease.

Struvite (infection) stones, composed of magnesium ammonium phosphate, occur only in the presence of urine that is chronically infected with urease-producing bacteria. These organisms split urea and cause persistently alkaline urine. Struvite stones, which are often branched (“staghorn-shaped”), occur more commonly in women than men. Treatment consists of eradication of infection with antibiotics and removal of the bacteria-laden stones.

Uric Acid Stone Disease

KEYPOINTS

• Uric acid stones can frequently be dissolved by alkalinization of the urine by administering potassium citrate or sodium bicarbonate orally so that the urine pH is above pH 6.5.

Uric acid stones occur especially in patients with unusually low urine pH and hyperuricosuria. In some patients, this very low urinary pH is due to a defect in renal ammonia secretion that results in less buffering of secreted hydrogen ion. Urate stones are radiolucent but are visualized by ultrasonography and computed tomography. Since the solubility of uric acid is greatly increased when urine pH is raised, treatment should consist of alkalinization of urine to a pH greater than 6.5 by administration of oral sodium bicarbonate or citrate solution and hydration. In patients with hyperuricosuria, allopurinol can be used.

Cystine Stone Disease Cystine stone disease occurs in patients who have inherited an autosomally recessive gastrointestinal and renal tubular transport disorder of four amino acids: cystine, ornithine, arginine, and lysine. Of these, cystine is the most insoluble in normally acid urine and thus precipitates into stones. Onset occurs at a

76

Normal Renal Function

younger age than does calcium disease, and stones are radioopaque. Treatment consists of hydration, alkalinization of the urine to a pH greater than 6.5, and administration of D-penicillamine or α-mercaptopropionyl glycine to convert the cystine to a more soluble cysteine-drug disulfide complex. Captopril has been shown to have similar effects as D-penicillamine.

Work-up and Management of Nephrolithiasis Table 30 shows the work-up and management of nephrolithiasis. Most renal stones are composed of calcium, are smaller 5 mm, and will readily pass without instrumentation. Evaluation for the first stone event in an adult should be limited to a routine chemistry panel; urinalysis; stone analysis, if possible; and intravenous pyelography or renal ultrasonography to detect multiple stones or anatomic abnormalities of the urinary tract. Treatment of a first uncomplicated calcium stone is hydration and observation. However, nephrolithiasis recurs in many patients: Additional stones form in 35% of patients at 2 years and 52% at 10 years. Work-up for recurrent or complicated stones includes questioning about family history, use of over-the-counter vitamins, chronic dehydration, diarrheal disorders, sarcoidosis, and conditions associated with renal tubular acidosis (e.g., Sjögren’s syndrome). Intravenous pyelography; a chemistry profile for creatinine, calcium, uric acid, electrolytes (to detect renal tubular acidosis), and serum parathyroid hormone (especially in hypercalcemia); urine culture; and 24-hour urine collection for sodium, calcium, oxalate, urate, and citrate should be done. Nephrocalcinosis on radiography suggests hyperparathyroidism, medullary sponge kidney, or renal tubular acidosis. Hypercalcemia developing after treatment with a thiazide for hypercalciuria suggests latent hyperparathyroidism. Onset of stone disease in patients younger than 20 years of age suggests cystinuria or renal tubular acidosis, and a family history of renal stones is more common in idiopathic hypercalciuria and cystinuria. Basic treatment regardless of the type of stone includes high fluid intake, relief of persistent obstruction, and treatment of infection. In idiopathic calcium stone disease, hypercalciuria is managed by dietary sodium restriction (but not calcium restriction), thiazide diuretics, or amiloride or a combination of these measures. Hyperoxaluria may respond to dietary oxalate restriction. Treatment of hyperuricosuria with a low-purine diet or allopurinol reduces recurrent calcium stones. Treatment of idiopathic hypocitraturia with oral citrate is not of proven benefit.

TA B L E 3 0 Work-up of

Nephrolithiasis Medical history: diarrhea, urinary tract infection, gout Family history: cystinuria, oxalosis Urine pH Urine culture (if indicated) Stone analysis Serum calcium, phosphorus, parathyroid hormone, electrolytes, creatinine, and uric acid 24-hour urine calcium, sodium, oxalate, citrate, urate, creatinine, and (when indicated) cystine Renal imaging: ultrasonography, intravenous pyelography, spiral computed tomography

KEYPOINTS

• The differential diagnosis for multiple, bilateral calcium nephrolithiasis (nephrocalcinosis) includes primary hyperparathyroidism, distal renal tubular acidosis, medullary sponge kidney, and primary hyperoxaluria.

Renal Function and Disease in Pregnancy Pregnancy is accompanied by physiologic changes that can adversely affect renal function and that may exacerbate renal disease. The management of new-onset and preexisting hypertension in pregnancy is a major issue.

Normal Renal Function • What is the significance of electrolyte abnormalities and increased urinary protein excretion in pregnant women? • What is the significance of and clinical approach to asymptomatic bacteriuria in pregnant women?

In normal pregnancy, blood pressure decreases soon after conception and reaches a nadir at about 20 weeks. This decrease in blood pressure results from an imbalance between peripheral vasodilatation, which is associated with

77

Hypertension during Pregnancy

Maclean AB. Urinary tract infection in pregnancy. Int J Antimicrob Agents. 2001;17:273-6. PMID: 11295407 Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183:S1-S22. PMID: 10920346

KEYPOINTS

• Normal levels of blood urea nitrogen and serum creatinine may be associated with significant renal dysfunction in pregnant patients. • Urinary protein excretion rarely exceeds 200 mg/24 h during pregnancy. • Asymptomatic bacteriuria is common in pregnant patients and should be treated.

increased synthesis of vasodilatory prostacyclin (prostaglandin I2), and vasoconstriction, which is mediated by increased thromboxane synthesis. Cardiac output, blood and plasma volume, and sodium retention increase during pregnancy. Edema commonly occurs. Renal size increases, and ureteral dilatation develops. Renal plasma flow increases 50% to 70% above normal during the first trimester and remains elevated during the third trimester. The glomerular filtration rate increases at the end of the first month of pregnancy, reaches values greater than 150% of normal, and remains elevated until term. These hemodynamic events cause a low-normal blood urea nitrogen level (mean, 7.5 to 10.0 mg/dL) and serum creatinine concentration (mean, 0.5 to 0.8 mg/dL) and a low uric acid level. Therefore, serum creatinine concentrations and blood pressures at the upper limits of normal are abnormal in pregnant patients. Urinary protein excretion rarely exceeds 200 mg/24 h, but glucosuria in the absence of hyperglycemia is common. Asymptomatic bacteriuria develops in approximately 5% of pregnant women (Maclean). Although clinical trials have been inconclusive, bacteriuria should be treated, since it may be associated with premature labor and delivery and infants who are small for gestational age. Bacteriuria may progress to pyelonephritis in up to one quarter to one third of patients. Pyelonephritis is associated with an increased risk of intrauterine death and premature labor. Cephalosporins and amoxicillin have been used in pregnant patients, but quinolones are to be avoided. Women with asymptomatic bacteriuria should have regular urine cultures after completion of antibiotic therapy, whereas women with pyelonephritis should receive long-term suppressive antibiotic therapy.

Hypertension during Pregnancy KEYPOINTS

• Hypertension present before pregnancy or developing before 20 weeks of gestation must be differentiated from hypertension complicating pregnancy after the 20th week because of the different prognosis and treatment of preeclampsia. • Preexisting hypertension increases the risk of preeclampsia and maternal and infant morbidity. • Severe hypertension should be treated because therapy may improve maternal and fetal outcomes. However, treatment of hypertension in pregnant patients has not reduced the incidence of preeclampsia or premature delivery. • Methyldopa is the drug that has been used the longest to treat hypertension in pregnant patients. • Treatment with drugs that interfere with the action of angiotensin should be discontinued in pregnant patients.

• What is the differential diagnosis of and the complications associated with hypertension during pregnancy?

Hypertension in pregnancy is defined as blood pressure of 140/90 mm Hg or greater (National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy). Systolic or diastolic blood pressure less than 140/90 mm Hg has not been associated with meaningful adverse clinical outcomes. Hypertension affects up to 10% of pregnant women in different populations. The differential diagnosis includes 1) chronic hypertension (preexisting essential or secondary hypertension), which may be masked by the vasodilatation of pregnancy; 2) gestational hypertension; 3) preeclampsia, a multisystem disease unique to pregnancy that involves both hypertension and renal disease and is manifested by proteinuria and renal insufficiency (see below); and 4) preeclampsia superimposed on chronic hypertension. Hypertension that was present before pregnancy or that developed before 20 weeks of gestation must be differentiated from hypertension complicating pregnancy after the 20th week (usually preeclampsia) because of the different prognosis and treatment of preeclampsia compared with other hypertensive disorders of pregnancy. The presence of hypertensive retinopathy and electrocardiographic changes or the absence of nephrotic-range proteinuria may be helpful in confirming the diagnosis of chronic hypertension, while signs of systemic illness suggest preeclampsia.

Chronic Hypertension Chronic hypertension is hypertension that is present before the onset of pregnancy or that is diagnosed before the 20th week of gestation. It occurs in 1% to 5% of pregnant patients and is more common in older, obese, and black 78

Hypertension during Pregnancy

women. Blood pressure greater than 120/75 mm Hg is associated with increased fetal and maternal morbidity and mortality. Chronic hypertension increases the risk of preeclampsia, abruptio placentae, fetal growth retardation, and fetal death. Patients with chronic hypertension have a 25% to 27% risk for superimposed preeclampsia, but the frequency of preeclampsia is unrelated to the presence of proteinuria during the first trimester or to subsequent treatment with low-dose aspirin. Treatment of chronic hypertension in pregnant women must be individualized. However, relevant studies to guide therapy are few, are often underpowered, and have yielded contradictory data (Umans and Lindheimer). There is little evidence from rigorously controlled prospective studies that drug treatment of hypertension (blood pressure >140 to 179/90 to 109 mm Hg) in pregnant patients with normal renal function and no proteinuria improves neonatal outcomes. However, antihypertensive therapy may prevent progression of hypertension to more severe levels. This is important because the severity of hypertension is associated with preterm delivery and small-for-gestationalage infants. Preexisting essential hypertension should be treated because treatment may improve several aspects of maternal and fetal outcomes; however, such treatment has not been shown to reduce the incidence of preeclampsia or premature delivery. Bed rest often is effective in decreasing diastolic blood pressure to 90 to 100 mm Hg. Sodium restriction is controversial but should be considered if it was useful during a patient’s prior pregnancy. Clinicians have the most experience with methyldopa as an antihypertensive agent for the treatment of hypertension in pregnancy. Labetalol; hydralazine; β-blockers (other than atenolol; see below); and, more recently, calcium channel blockers have also been used to treat women with chronic hypertension during pregnancy. Therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be discontinued or not used because fetal complications occur when these medication are taken during the second and third trimesters. The use of atenolol has been associated with fetal growth restriction. The use of diuretics in the treatment of pregnant patients with chronic hypertension is controversial, although such treatment is often continued in patients with chronic hypertension who were receiving these agents before the beginning of pregnancy. Some studies have reported that calcium supplementation during pregnancy has beneficial effects on blood pressure and reduces the risk for preeclampsia, but these findings may be limited to a subset of patients with low calcium intake. Calcium supplementation has no effect on the frequency of preterm or cesarean delivery, intrauterine growth retardation, or intrauterine or perinatal death. The use of calcium supplements is still controversial. Women with chronic hypertension should be monitored frequently after the 20th week for signs of preeclampsia.

Umans JG, Lindheimer MD. Antihypertensive therapy in pregnancy. Curr Hypertens Rep. 2001;3:392-9. PMID: 11551373

Gestational Hypertension Gestational hypertension is blood pressure greater than 140/90 mm Hg in the absence of proteinuria in a woman who was normotensive before 20 weeks of pregnancy. Gestational hypertension, also known as transient hypertension of pregnancy, is not associated with signs of preeclampsia and resolves after delivery. It is more common in multiparous or overweight patients and in women with a family history of hypertension. It is sometimes difficult to differentiate gestational hypertension from chronic hypertension until the postpartum period, when gestational hypertension resolves whereas chronic hypertension persists.

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Hypertension during Pregnancy

Walker JJ. Pre-eclampsia. Lancet. 2001;356:1260-5. PMID: 11072961 Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J, et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med. 2001;344:867-72. PMID: 11259719

Buchbinder A, Sibai BM, Caritis S, Macpherson C, Hauth J, Lindheimer MD, et al. Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia. Am J Obstet Gynecol. 2002;18666-71. PMID: 11810087 Dekker G, Sibai B. Primary, secondary and tertiary prevention of preeclampsia. Lancet. 2001;357:209-15. PMID: 11213110 Belfort MA, Anthony J, Saade GR, Allen JC Jr. A comparison of magnesium sulfate and nimodipine for the prevention of preeclampsia. N Engl J Med. 2003;348: 304-11. PMID: 12540643

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Preeclampsia and Eclampsia Preeclampsia is a multisystem disease unique to pregnancy (Walker). It is characterized by both hypertension and renal disease and is manifested by proteinuria and renal insufficiency. Preeclampsia is occasionally accompanied by abnormalities of coagulation, but hematuria is unusual. The occurrence of convulsions in patients with preeclampsia defines eclampsia. Preeclampsia usually occurs after the 20th week of gestation, most commonly in women who are pregnant for the first time. When preeclampsia occurs in the first trimester, it strongly suggests that the patient has a hydatidiform mole. The pathogenesis of the disease is not fully understood, but it may be related to abnormal cytotrophoblast invasion of spiral arterioles, decreased uteroplacental hypoperfusion, an imbalance between increased synthesis of thromboxane and decreased production of prostaglandin I2, increased oxidative stress, disordered endothelin metabolism, or endothelial cell dysfunction. The signs and symptoms are the result of widespread effects on endothelial cells. Both maternal and paternal factors may be associated with susceptibility to preeclampsia (Esplin et al.). Diagnosis of preeclampsia is difficult in patients with preexisting renal disease because of the similarity of signs and symptoms. Reduced clearance of creatinine and uric acid is common and results in elevated serum levels of creatinine and uric acid. Weight gain and edema formation may be related to changes in capillary permeability as well as to sodium retention. Serum uric acid levels greater than 5.5 mg/dL are usually associated with preeclampsia. The level correlates directly with the severity of clinical and pathologic disease and inversely with fetal survival. Patients with preeclampsia may have abnormalities associated with the development of vascular thrombosis, such as activated protein C resistance, antiphospholipid antibodies, protein S deficiency, and increased levels of homocysteine. The renal lesion endotheliosis consists of swelling of glomerular endothelial cells, accompanied by glomerular deposition of fibrinogen and infiltration of lipid-laden macrophages. These changes resolve soon after delivery (Buchbinder et al). Patients with preeclampsia should have frequent monitoring of platelet count, liver enzymes, renal function and urinary protein excretion. Therapy consists of bed rest, antihypertensive agents, seizure prophylaxis as necessary, and, ultimately, delivery. Although antihypertensive treatment does not improve perinatal outcomes, it should be instituted when diastolic blood pressure exceeds 100 to 110 mm Hg if delivery is not desirable. Hydralazine, labetalol, and methyldopa have been used, as have calcium channel blockers, β-blockers (except atenolol), and clonidine. Hydralazine, labetalol, nifedipine, and, rarely, sodium nitroprusside have been used to treat acute severe hypertension in preeclampsia. Magnesium sulfate, a vasodilator that increases prostaglandin I2 levels, is both an effective prophylactic and anticonvulsant in patients with preeclampsia, compared with both phenytoin and nimodipine as prophylactic agents (Dekker and Sibai; Belfort et al.). Fetal outcomes are also better in mothers treated with magnesium sulfate than in mothers treated with other anticonvulsants, for reasons that remain unclear. Magnesium supplementation has been associated with respiratory paralysis and maternal death. Synergism between magnesium and calcium channel blockers, such as nifedipine, can cause severe hypotension, which should be avoided because of the risk of increasing uteroplacental ischemia. Management of magnesium supplementation may be problematic in pregnant patients with renal disease. Such patients need frequent assessment of neurologic status and serum magnesium concentration. Fetal monitoring is an important part of the management of patients with preeclampsia. If blood pressure cannot be controlled or if hyperuricemia, proteinuria, or increasing renal insufficiency develops, delivery should be considered even if the fetus is less than 32 weeks of age. If eclampsia or the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) develops, immediate delivery is indicated.

Chronic Renal Insufficiency in Pregnant Patients

In patients at high risk for preeclampsia (those with hypertension, diabetes mellitus, preexisting renal disease, multiple pregnancies, poor previous obstetric history, or family or personal history of preeclampsia), preventive treatment with aspirin, 60 mg/d, may be effective, perhaps by reversing disordered prostaglandin metabolism. Aspirin therapy was reported to decrease the incidence of preeclampsia in healthy women who had never been pregnant before, but it was associated with a higher incidence of abruptio placentae. The findings of a benefit associated with aspirin in other populations, including nulliparous women, have not been confirmed. Such therapy in patients without risk factors for preeclampsia is usually not recommended. Administration of the antioxidant vitamins C and E may decrease the incidence of preeclampsia in high-risk patients, but further studies are necessary to confirm the findings. The frequency of abruptio placentae and the incidence of preterm delivery, neonatal complications (including rate of admission to neonatal intensive care units), neonatal intraventricular hemorrhage, and perinatal death are higher in women with chronic hypertension with superimposed preeclampsia than in women who do not develop this complication.

Chronic Renal Insufficiency in Pregnant Patients • What is the effect of chronic renal disease on pregnancy?

Proteinuria greater than 300 mg/24 h during the first trimester in pregnant women with chronic hypertension is associated with a higher incidence of delivery of infants at less than 35 weeks of gestation, birth weights that are low for gestational age, neonatal intraventricular hemorrhage, and more frequent admission to neonatal intensive care units. Proteinuria may be an indication of underlying renal disease as a cause of the chronic hypertension and is a risk factor for adverse outcomes regardless of whether hypertension is controlled. Survival of infants of women with chronic renal insufficiency ranges from 70% to 100%, although prematurity and intrauterine growth retardation are common. Pregnant women with preexisting nephropathy develop increased proteinuria and hypertension. Pregnant women with mild renal insufficiency may not develop impaired renal function as frequently do those with a lower glomerular filtration rate, but few prospective data are available to substantiate this claim. Women with a serum creatinine concentration greater than 1.4 mg/dL in the first trimester have decreased fertility, and almost 50% may lose renal function during pregnancy or during the postpartum period. Women with more advanced renal disease, with a serum creatinine concentration greater than 2.0 mg/dL in the first trimester, have a higher risk of pregnancy-associated progressive renal insufficiency. Similar outcomes occur in women with diabetic nephropathy. Flares of systemic lupus erythematosus may occur during pregnancy and the postpartum period and increase the risk for renal failure. Prednisone and azathioprine are used to treat these flares, but cyclophosphamide is teratogenic and must be avoided. Most women with end-stage renal disease who undergo dialysis are infertile, although pregnancy may occur in such patients. Infant survival is improving, but only about 50% of women maintain pregnancy to term. Many infants are premature or small for gestational age. Two percent of women of childbearing age with a functioning renal transplant may conceive. Transplant recipients with a serum creatinine concentration less than 2.0 mg/dL may have infants who are small for gestational age. Intensive dialysis has been used in an attempt to maximize the chances of successful delivery in pregnant women with renal insufficiency or end-stage renal disease, but no controlled studies are available to guide therapy.

KEYPOINTS

• Proteinuria in pregnant patients with chronic hypertension is a risk factor for adverse outcomes, regardless of whether hypertension is controlled. • Women with a serum creatinine concentration greater than 1.4 mg/dL in the first trimester have decreased fertility and may experience increased renal insufficiency during pregnancy or during the postpartum period. • Women with a serum creatinine concentration greater 2.0 mg/dL in the first trimester have an increased risk of pregnancy-associated progressive renal insufficiency.

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Acute Renal Failure in Pregnant Patients

Acute Renal Failure in Pregnant Patients

KEYPOINTS

• All patients with a decreased glomerular filtration rate are at risk for preeclampsia and worsening renal function and should seek preconception counseling. • Most women with end-stage renal disease who require dialysis are infertile. Infertility is usually reversible after successful transplantation.

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Prerenal azotemia and urinary tract obstruction should be considered in all pregnant women with acute renal failure. Although urinary tract obstruction is rare, it may be difficult to diagnose because of the physiologic hydronephrosis of pregnancy. Acute renal failure in pregnancy is associated with abruptio placentae, septic abortion, severe preeclampsia, amniotic fluid embolism, and retained fetus. Intrinsic acute renal failure in pregnancy is usually due to acute tubular necrosis or acute cortical necrosis. Anuria and hematuria, or the persistence of oliguria or anuria for more than 1 week, suggest cortical necrosis. The prognosis for recovery of renal function in patients with acute cortical necrosis is poor. Postpartum acute renal failure is a rare but serious complication that can occur several days to 10 weeks after delivery. Findings include hypertension, renal insufficiency, and microangiopathic hemolytic anemia. The syndrome is related to the thrombotic microangiopathies, thrombotic thrombocytopenic purpura, and the hemolytic–uremic syndrome. A peripheral blood smear that shows signs of microangiopathic hemolytic anemia in the setting of thrombocytopenia and acute renal failure after delivery is diagnostic. Patients have been treated with plasma exchange, but renal failure often persists in survivors.