Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Nephrotic syndrome in adults Michael A. Carome MD & Jack Moore Jr MD To cite this article: Michael A. Carome MD & Jack Moore Jr MD (1992) Nephrotic syndrome in adults, Postgraduate Medicine, 92:2, 209-220, DOI: 10.1080/00325481.1992.11701426 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701426
Published online: 17 May 2016.
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Date: 19 June 2016, At: 17:05
-@CME credit article
Nephrotic syndrome in adults A diagnostic and management challenge
Michael A. Carome, MD Jack Moore Jr, MD
Downloaded by [RMIT University Library] at 17:05 19 June 2016
Preview Faced with the spectrum of disorders that can manifest as nephrotic syndrome, where does the primary care physician begin when evaluating a patient? Is renal biopsy called for, or is empirical therapy enough? In this article, Drs Carome and Moore address the challenges posed by the nephrotic patient.
The nephrotic syndrome is one of the more common kidney problems encountered by primary care physicians. Diagnostic criteria include heavy proteinuria (>3.5 g/day), hypoalbuminemia, edema, hyperlipidemia, and lipiduria. Although the majority of nephrotic patients manifest each of these symptoms at some time during their illness, the diagnosis may be made on the basis of heavy proteinuria alone. While patients who have only heavy proteinuria may not meet the classic criteria for nephrotic syndrome, the same underlying disease processes are at work, and the clinical evaluation should be the same. The nephrotic syndrome results from glomerular disease. Changes in the physicochemical characteristics of the glomerular basement membrane, which serves as a filtration barrier, result in a marked increase in the filtration of albumin and other large
proteins into Bowman's space. 1 The glomerular basement membrane may be altered by immune complexes, nephrotoxic antibodies, and nonimmune mechamsms.
Differential diagnosis The adult nephrotic syndrome can be divided into two major groups of disorders, depending on whether it is primary (idiopathic) or secondary. The spectrum of lesions in primary nephrotic syndrome includes the following: minimal change disease, membranous glomerulonephritis, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and a group of miscellaneous proliferative glomerulonephropathies (figure 1).2 The cause of these primary lesions is unknown. They are defined by specific histologic characteristics of tissue obtained at renal biopsy. Each form of primary nephrotic syndrome should be
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • NEPHROTIC SYNDROME
considered a distinct clinicopathologic entity with characteristic clinical features and natural history. Their prevalence and the extent to which they are related to age are depicted in figure 2. Collectively, the variety of disorders that cause primary nephrotic syndrome may seem overwhelming. However, the vast majority of cases are caused by the relatively few disorders depicted in figures 1 and 2. Disorders that are morphologically similar to primary forms of nephrotic syndrome can be caused by systemic illness, drugs, toxins, or infection. Primary nephrotic syndrome with a coexisting systemic illness (eg, minimal change disease with Hodgkin's disease) is considered a form of secondary nephrotic syndrome. Some of these associations are listed in table 1. Other forms of secondary nephrotic syndrome, most notably diabetic nephropathy and amyloidosis, have histologic characteristics distinct from any of the glomerular lesions listed in table 1. These two, together with systemic lupus erythematosus associated with proliferative glomerulonephritis, are, in our experience, the most common continued
209
Although the variety of disorders that cause nephrotic syndrome may seem overwhelming, the vast majority of cases are caused by relatively few disorders.
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Figure 1. Distribution of major causes of primary nephrotic syndrome in adults. Adapted from Glassock et a/. 2
forms of secondary nephrotic syndrome. The incidence of diabetic nephropathy, which is the most common cause of both nephrotic syndrome and endstage renal disease in the United States, is almost certainly underrepresented by biopsy data, since many patients with diabetes never undergo renal biopsy.
Manifestations of nephrotic syndrome The clinical manifestations of nephrotic syndrome result from heavy proteinuria. Hypoalbuminemia is a cardinal finding in severe or chronic cases. Albumin
210
and other proteins that enter the urinary space are taken up and catabolized by proximal tubular cells. This uptake process quickly becomes saturated when excess protein is filtered at the glomerulus, and protein is then excreted directly into the urine. 3 Moreover, nephrotic patients may not have the capacity to increase the synthesis of hepatic albumin maximally. These factors ultimately lead to the development of hypoalbuminemia. Edema is a major sign identifYing the nephrotic patient. Hypoalbuminemia, which lowers plasma oncotic pressure, results
in a net movement of fluid from the intravascular to the extravascular space. 4 Intravascular volume depletion and decreased renal blood flow trigger a number of homeostatic mechanisms, including increased activity of the renin-angiotensin-aldosterone system, increased antidiuretic hormone release, and decreased atrial natriuretic peptide secretion. The net effect of these changes is secondary retention of sodium and water by the kidneys.' Alternatively, primary renal sodium and water retention may contribute to edema formation in some nephrotic patients with significant hypoalbuminemia who actually have an expanded intravascular volume. Hyperlipidemia is a common laboratory abnormality in patients with nephrotic syndrome. 6 The levels of total cholesterol, triglycerides, low-density lipoprotein (LDL), and very-lowdensity lipoprotein (VLDL) are increased, while high-density lipoprotein (HDL) levels are decreased. These abnormalities result from an increase in hepatic cholesterol and lipoprotein synthesis, a decrease in peripheral and hepatic catabolism of serum lipoproteins, and an increase in urinary excretion ofHDL.
NEPHROTIC SYNDROME • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
The clinical manifestations of nephrotic syndrome include heavy proteinuria, hypoalbuminemia, edema, hyperlipidemia, and lipiduria.
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Figure 2. Prevalence of major causes of primary nephrotic syndrome in adults, by age. Adapted from Glassock et a/. 2
Hyperlipidemia is of concern, since its presence may lead to accelerated coronary atherosclerosis as well as to progression of renal disease.
Clinical evaluation Evaluation of the adult with nephrotic syndrome is outlined in table 2. HISlORY-The most important factor in evaluation is a carefully directed history. A primary form of nephrotic syndrome is more likely when the history is unremarkable, whereas a secondary form may be present if the history suggests a connec-
tive tissue disorder, malignant disease, sexually transmitted disease, hepatitis, infection with human immunodeficiency virus, or ingestion of over-the-counter or prescription medication. Diabetes mellitus has usually been present for years before nephrotic syndrome develops. Complications such as proliferative retinopathy or vascular disease provide strong evidence for underlying diabetic nephropathy. PHYSICAL EXAMINATION-The physical examination is directed at uncovering physical signs of potential secondary causes of nephrosis, such as evidence of
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • NEPHROTIC SYNDROME
diabetic complications, the stigmata of systemic lupus erythematosus, or features indicative of an underlying malignant disease. The severity and duration of edema are not helpful indicators, since some patients may have no edema and are only discovered to be nephrotic on routine urine screening for proteinuna. DIAGNOSTIC TESTING-This is divided into two phases: baseline laboratory testing and serologic testing for specific systemic disorders. BASELINE TESTs-These tests should be performed on all continued
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A primary form of nephrotic syndrome is more likely when the history is unremarkable.
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Table 1. Some types of secondary nephrotic syndrome Nephrotic syndrome*
Coexisting condition
Minimal change disease
Hodgkin's disease
Membranous glomerulonephritis
Solid tumors Hepatitis B infection
Focal segmental glomerulosclerosis
Vesicoureteral reflux Heroin abuse Infection with human immunodeficiency virus
Miscellaneous proliferative glomerulonephropathies
Systemic lupus erythematosus
*Based on morphologic changes on renal biopsy.
nephrotic patients. They include a multiphasic biochemical analysis of serum, a complete blood cell count, a lipid profile, urinalysis, and timed urine collection for the assessment of protein excretion and creatinine clearance. The nephrotic patient usually has low serum albumin, total protein, and calcium concentrations, while total cholesterol, LDL, and VLDL concentrations are elevated. The blood urea nitrogen and creatinine concentrations may be normal or elevated,
212
depending on the underlying disease. Urinalysis usually reveals lipid bodies (macrophages and renal tubular epithelial cells filled with lipid droplets), as well as free lipid droplets. Lipid is best visualized under polarized light. The importance of a careful urinalysis cannot be overemphasized. Total urinary protein should exceed 3.5 g/day to support the diagnosis. The problems associated with timed urine collections can be avoided by measuring the ratio of protein to ere-
atinine in a randomly collected urine sample" and calculating the creatinine clearance. The latter can be done using a variety of formulas based on the patient's serum creatinine concentration, age, and weight. 8 Both timed and random methods of urine collection have been shown to yield extremely precise results. All of the aforementioned parameters can be monitored to assess disease activity and response to treatment. Thus, baseline measurements are important. SEROLOGIC TESTs-The second stage of the diagnostic evaluation traditionally has comprised an array of serologic tests to identifY various systemic disorders. These include tests for fluorescent antinuclear antibody, rheumatoid factor, components of the complement system, hepatitis B surface antigen, venereal disease serology, cryoglobulins, protein electrophoresis, and erythrocyte sedimentation rate, as well as urine protein electrophoresis. A study of 87 adult patients with nephrotic syndrome was recently conducted at the Walter Reed Army Medical Center to determine the value of performing such empirical serologic test-
NEPHROTIC SYNDROME • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
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The importance of a careful urinalysis in the clinical evaluation of a patient with nephrotic syndrome cannot be overemphasized.
ing in the absence of specific clinical indications. 9 Diagnostic accuracy of the combination of a thorough history, physical examination, and baseline laboratory studies for determining whether the patient had primary or secondary nephrotic syndrome and for identifYing the specific histopathologic type was found to be the same whether or not empirical serologic data were available. Serologic findings were rarely abnormal without clinical suspicion, and the tests cost several hundred dollars. Thus, the second phase of the diagnostic evaluation should include only specific testing to help confirm a diagnosis already suspected on the basis of the initial clinical evaluation. For example, only nephrotic patients with symptoms and signs consistent with systemic lupus erythematosus should be tested for fluorescent antinuclear antibody and complement levels, and only patients with clinical evidence of an underlying cancer should undergo further evaluation for malignancy. In the absence of clinical suspicion, a wide battery of screening or radiologic tests aimed at blindly searching for multiple causes of secondary nephrotic syndrome is not cost-
Table 2. Initial evaluation of adults with nephrotic syndrome
History: hypertension, diabetes, cancer, drugs, infection, collagen vascular disease Physical examination: evidence of cancer, diabetes, collagen vascular disease Initial laboratory tests: complete blood cell count, chemistry profile Urinalysis (by physician) Measurement of renal function and protein excretion
effective, and this approach should not be pursued.
Role of renal biopsy Renal biopsy is an important part of our evaluation of most patients with primary nephrotic syndrome. Other clinicians, using the results of decision analysis, have questioned its utility10 and suggested that biopsy be reserved for patients who do not respond to a short (2-month) course of corticosteroids. Since minimal change disease is the only form of primary nephrotic syndrome likely to respond to such a regimen, we agree that a priori treatment is an acceptable strategy. We treat patients who are suspected on
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clinical grounds of having minimal change disease with a short course of corticosteroids and reserve biopsy for those who do not respond. We feel that minimal change disease is likely in patients in whom the nephrotic syndrome develops quite rapidly, in whom massive proteinuria (>10 g/day) is noted, and in whom the other features of nephrotic syndrome are striking in their severity. When decision-analysis techniques have been used to study the role of renal biopsy for all patients with primary nephrotic syndrome, assumptions have been made about the prevalence and natural history of different histologic entities, the risks and continued
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In the absence of clinical suspicion, a wide battery of tests aimed at blindly searching for multiple causes of secondary nephrotic syndrome is not cost-effective and should not be pursued.
Table 3. Therapeutic options for adults with nephrotic syndrome Corticosteroids Cytotoxic agents Angiotensin-converting enzyme inhibitors* Calcium channel blockers* Cyclosporine (Sandimmune)* Nonsteroidal anti-inflammatory drugs* Dietary protein restriction*
*May result in diminution of proteinuria and attenuate severity of nephrotic syndrome but will not target primary disease.
benefits of biopsy and various treatment options (based on semi-quantitative assessments), and response to treatment. Since optimum treatment regimens for most disorders that result in nephrotic syndrome remain undefined and are the subject of active clinical investigation, we feel that most patients should be afforded the opportunity to undergo biopsy. The results
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permit us to establish a specific diagnosis, provide patients with information about their disease and its likely prognosis, and select a specific therapeutic regimen. However, we do not generally offer biopsy to patients who have long-standing diabetes, shrunken kidneys, or other contraindications, such as uncontrolled hypertension or a bleeding diathesis. For some forms of secondary nephrotic syndrome, renal biopsy is critical. Patients with systemic lupus erythematosus who have clinical renal involvement, for example, may have one of several forms of lupus nephritis. Precise definition of the histologic subtype, which is largely impossible clinically, allows for specific therapy and provides the best information to guide both the intensity and duration of therapy. 11
Management of nephrotic syndrome in adults Management of the nephrotic adult consists of treating the underlying glomerular disease as well as managing the complications of nephrotic syndrome. 12 Treatment depends on whether the disease is primary or secondary and whether specific therapy may be required.
PRIMARY NEPHROTIC SYN-
DROME-Specific therapeutic options for primary nephrotic syndrome are listed in table 3. The two most common forms of the syndrome, minimal change disease and membranous glomerulonephritis, often respond to immunosuppressive therapy. We treat minimal change disease with prednisone, 2 mg/kg of body weight daily for 1 week, then every other day for 7 weeks. This regimen brings about remission in approximately 80% of adults. Up to 16 weeks of therapy may be required. l.l We have not found longer treatment courses to be helpful. We offer a second biopsy to patients who do not respond, and generally we discover focal segmental glomerulosclerosis that was not detected on the original biopsy specimen. We treat membranous glomerulonephritis with month-long courses of prednisone alternating with month-long courses of chlorambucil (Leukeran) for a total of 6 months. This treatment regimen, designed by Ponticelli and associates, 14 appears to benefit many patients. We and others have not been impressed with the response of other forms of primary nephrotic syndrome to steroids or to com-
NEPHROTIC SYNDROME • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
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Renal biopsy for patients with nephrotic syndrome permits the clinician to establish a specific diagnosis and select a specific therapeutic regimen.
binations of steroids, cytotoxic agents, and antiplatelet agents. Patients with these disorders may be candidates for treatment with angiotensin-converting enzyme inhibitors, calcium channel blockers, cyclosporine (Sandimmune), or nonsteroidal antiinflammatory drugs to lessen the severity of proteinuria. Clearly, further research into these disorders is required to determine effective treatment strategtes.
Table 4. Major complications of nephrotic syndrome and their clinical effects Complication
Clinical effects
Hypovolemia
Hypotension, acute renal failure
Anasarca
Infection, immobility
Hyperlipidemia
Early vascular disease
Hypercoagulability
Renal vein thrombosis, pulmonary embolism
SECONDARY NEPHRaTIC SYN-
DROME-Patients with secondary nephrotic syndrome require management of the associated disorder. Removal of the underlying malignant lesion, treatment of the underlying connective tissue disorder, or removal of the offending toxin or drug is necessary. NONSPECIFIC TRFATMENT-
All patients with nephrotic syndrome should be afforded nonspecific treatment to limit complications (table 4), which often result in as much morbidity as the glomerular lesion. 15 One serious complication is the development of a hypercoagulable state, with lower extremity deep vein thrombosis, pulmonary embolism, and renal vein thrombosis.16
Another serious complication is the development of acute renal failure. 17 A profound, rapid fall in the plasma albumin level may lead to dramatic fluid shifts, intravascular volume depletion, prerenal azotemia, and if prolonged, ischemic renal damage. Aggressive diuretic treatment for edema can also have similar consequences, as can renal vein thrombosis. The goals of nonspecific treatment include the control of edema, hypertension, hypoalbuminemia, and hyperlipidemia. Control of edema and hypertension involves adherence to a sodium-restricted diet, judicious use of diuretics, and bed rest. The loop diuretic furosemide (Lasix) should be given initially,
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • NEPHROne SYNDROME
and the dose should be titrated until a response is seen. Diuresis can be augmented with low-dose metolazone (Diulo, Mykrox, Zaroxolyn) .18 Volume depletion can be avoided by monitoring the patient's weight and ensuring that the rate of diuresis is not too rapid. Hypoalbuminemia is best managed with a diet that includes high-biologic-value protein in modest quantities. We restrict daily protein intake to 0.8 g/kg of ideal body weight, since protein loading has been shown to increase urinary protein excretion and worsen hypoalbuminemia. 19 Whether protein restriction exerts a salutary effect on the progression of renal disease in humans is the subject of continued on page 218
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Minimal change disease and membranous glomerulonephritis often respond to immunosuppressive therapy.
Michael A. Carome, MD Jack Moore Jr, MD Dr Carome (left) is a major in the US Army Medical Corps: a research fellow in nephrology, Walter Reed Army Medical Center, Washington, DC: and an instructor in medicine, Uniformed Services University of the Health Sciences, Bethesda. Dr Moore (right) is a colonel in the US Army Medical Corps: chief, nephrology service, Walter Reed Army Medical Center: and associate professor of medicine, Uniformed Services University of the Health Sciences.
clinical investigation. Some patients respond to administration of a low dose of an angiotensinconverting enzyme inhibitor or calcium channel blocker with a reduction in proteinuria, although treatment with these agents has been demonstrated to be efficacious only in patients
with diabetic nephropathy.~o Patients who have significant hyperlipidemia from chronic nephrotic syndrome are candidates for dietary manipulation and therapy with bile acid resin and lovastatin (Mevacor). 6 The latter agent should be used cautiously, since it has been associat-
continued
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NEPHROTIC SYNDROME • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
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ed with rhabdomyolysis in some nephrotic patients.
The views expressed herein are those of the authors and do not necessarily reflect the views of the US Army or the Department of Defense.
Summary and conclusions The adult with nephrotic syndrome presents diagnostic and treatment challenges for the primary care physician. Early consultation with a nephrologist is advisable to assist in choosing between empirical therapy or renal biopsy to identify the specific causative lesion. Some patients respond to treatment of either the specific disorder or the underlying cause. All patients should be afforded specific therapy, where available, and nonspecific therapy to minimize the severity of the nephrosis and attenuate the incidence and severity of complications. Although the cause of most disorders resulting in nephrotic syndrome remains unclear, active research into the syndrome's pathogenesis and treatment options should prove fruitful. FUll
--®
Earn credit on this article. See CME Quiz.
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Address for correspondence: Michael
A Carome, MD, Nephrology Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20307-5001.
References I. Brenner BM, Hostetter TH, Humes HD. Molecular basis of proteinuria of glomerular origin. N Eng! J Med 1978;298:826-33 2. Glassock RJ, Adler SG, Ward HJ, et al. Primary glomerular diseases. In: Brenner BR, Rector FC, eds. The kidney. Philadelphia: WB Saunders, 1991:1182-279 3. Strober W, Waldmann 11\. The role of the kidney in the metabolism of plasma proteins. Nephron 1974;13:35-66 4. Mees EJ, Roos JC, Boer P, et al. Observations on edema formation in the nephrotic syndrome in adults with minimal lesions. Am J Med 1979;67:378-84 5. Meltzer JI, Keirn HJ, Laragh JH, et al. Nephrotic syndrome: vasoconsuiction and hypervolemic types indicated by renin-sodi urn profiling. Ann Intern Med 1979;91:688-96 6. Grundy SM, Vega GL Rationale and management of hyperlipidemia of the nephrotic syndrome. Am] Med 1989;87:3-llN 7. GinsbergJM, Chang BS, Matarese RA, et al. Use of single voided urine samples to estimate quantitative proteinuria. N Eng! J Med 1983;309: 1543-6 8. Boyce EG, Dickerson RN, Cooney GF, et al. Creatinine clearance estimation in proteinmalnourished patients. Clin Pharm 1989;8: 721-6 9. Howard AD, Moore J, Gouge SF, et al. Routine serologic tests in the differential diagnosis of the adult nephrotic syndrome. Am J Kidney Dis 1990; 15:24-30 10. Levey AS, LauJ, Pauker SG, et al. Idiopathic nephrotic syndrome: puncturing the biopsy myth. Ann Intern Med 1987;107:697713
ll. Steinberg AD. The ueaunent oflupus nephritis. Kidney Int 1986;30:769-87 12. Cameron JS. The nephrotic syndrome and its complications. Am J Kidney Dis 1987;10: 157-71 13. Nolasco F, Cameron JS, Heywood EF, et al. Adult-onset minimal change nephrotic syndrome: a long-term follow-up. Kidney Int 1986;29: 1215-33 14. Ponticelli C, Zucchdli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Eng! J Med 1989;320:8-13 15. Bernard DB. Extrarenal complications of the nephrotic syndrome. Kidney Int 1988;33: 1184-202 16. Uach F. Nephrotic syndrome: hypercoagulability, renal vein thrombosis, and other thromboembolic complications. In: Brenner BM, Stein JH, eds. Contemporary issues in nephrology. 9. Nephrotic syndrome. New York: Churchill Livingstone, 1982:121-44 17. Jennette JC, Falk RJ. Adult minimal change glomerulopathy with acute renal failure. Am J Kidney Dis 1990; 16:432-7 18. Oster JR, Epstein M, Smoller S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. (Editorial) Ann Intern Med 1983;99:405-6 19. Kaysen GA. Albumin metabolism in the nephrotic syndrome: the effect of dietary protein intake. AmJ Kidney Dis 1988;12:461-80 20. Bakris GL Effects of diltiazem or lisinopril on massive proteinuria associated with diabetes mellitus. Ann Intern Med 1990;112:707-8
NEPHROTIC SYNDROME • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Nephrotic syndrome in adults Michael A. Carome MD & Jack Moore Jr MD To cite this article: Michael A. Carome MD & Jack Moore Jr MD (1992) Nephrotic syndrome in adults, Postgraduate Medicine, 92:2, 209-220, DOI: 10.1080/00325481.1992.11701426 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701426
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [RMIT University Library]
Date: 19 June 2016, At: 17:05
-@CME credit article
Nephrotic syndrome in adults A diagnostic and management challenge
Michael A. Carome, MD Jack Moore Jr, MD
Downloaded by [RMIT University Library] at 17:05 19 June 2016
Preview Faced with the spectrum of disorders that can manifest as nephrotic syndrome, where does the primary care physician begin when evaluating a patient? Is renal biopsy called for, or is empirical therapy enough? In this article, Drs Carome and Moore address the challenges posed by the nephrotic patient.
The nephrotic syndrome is one of the more common kidney problems encountered by primary care physicians. Diagnostic criteria include heavy proteinuria (>3.5 g/day), hypoalbuminemia, edema, hyperlipidemia, and lipiduria. Although the majority of nephrotic patients manifest each of these symptoms at some time during their illness, the diagnosis may be made on the basis of heavy proteinuria alone. While patients who have only heavy proteinuria may not meet the classic criteria for nephrotic syndrome, the same underlying disease processes are at work, and the clinical evaluation should be the same. The nephrotic syndrome results from glomerular disease. Changes in the physicochemical characteristics of the glomerular basement membrane, which serves as a filtration barrier, result in a marked increase in the filtration of albumin and other large
proteins into Bowman's space. 1 The glomerular basement membrane may be altered by immune complexes, nephrotoxic antibodies, and nonimmune mechamsms.
Differential diagnosis The adult nephrotic syndrome can be divided into two major groups of disorders, depending on whether it is primary (idiopathic) or secondary. The spectrum of lesions in primary nephrotic syndrome includes the following: minimal change disease, membranous glomerulonephritis, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and a group of miscellaneous proliferative glomerulonephropathies (figure 1).2 The cause of these primary lesions is unknown. They are defined by specific histologic characteristics of tissue obtained at renal biopsy. Each form of primary nephrotic syndrome should be
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • NEPHROTIC SYNDROME
considered a distinct clinicopathologic entity with characteristic clinical features and natural history. Their prevalence and the extent to which they are related to age are depicted in figure 2. Collectively, the variety of disorders that cause primary nephrotic syndrome may seem overwhelming. However, the vast majority of cases are caused by the relatively few disorders depicted in figures 1 and 2. Disorders that are morphologically similar to primary forms of nephrotic syndrome can be caused by systemic illness, drugs, toxins, or infection. Primary nephrotic syndrome with a coexisting systemic illness (eg, minimal change disease with Hodgkin's disease) is considered a form of secondary nephrotic syndrome. Some of these associations are listed in table 1. Other forms of secondary nephrotic syndrome, most notably diabetic nephropathy and amyloidosis, have histologic characteristics distinct from any of the glomerular lesions listed in table 1. These two, together with systemic lupus erythematosus associated with proliferative glomerulonephritis, are, in our experience, the most common continued
209
Although the variety of disorders that cause nephrotic syndrome may seem overwhelming, the vast majority of cases are caused by relatively few disorders.
Downloaded by [RMIT University Library] at 17:05 19 June 2016
Figure 1. Distribution of major causes of primary nephrotic syndrome in adults. Adapted from Glassock et a/. 2
forms of secondary nephrotic syndrome. The incidence of diabetic nephropathy, which is the most common cause of both nephrotic syndrome and endstage renal disease in the United States, is almost certainly underrepresented by biopsy data, since many patients with diabetes never undergo renal biopsy.
Manifestations of nephrotic syndrome The clinical manifestations of nephrotic syndrome result from heavy proteinuria. Hypoalbuminemia is a cardinal finding in severe or chronic cases. Albumin
210
and other proteins that enter the urinary space are taken up and catabolized by proximal tubular cells. This uptake process quickly becomes saturated when excess protein is filtered at the glomerulus, and protein is then excreted directly into the urine. 3 Moreover, nephrotic patients may not have the capacity to increase the synthesis of hepatic albumin maximally. These factors ultimately lead to the development of hypoalbuminemia. Edema is a major sign identifYing the nephrotic patient. Hypoalbuminemia, which lowers plasma oncotic pressure, results
in a net movement of fluid from the intravascular to the extravascular space. 4 Intravascular volume depletion and decreased renal blood flow trigger a number of homeostatic mechanisms, including increased activity of the renin-angiotensin-aldosterone system, increased antidiuretic hormone release, and decreased atrial natriuretic peptide secretion. The net effect of these changes is secondary retention of sodium and water by the kidneys.' Alternatively, primary renal sodium and water retention may contribute to edema formation in some nephrotic patients with significant hypoalbuminemia who actually have an expanded intravascular volume. Hyperlipidemia is a common laboratory abnormality in patients with nephrotic syndrome. 6 The levels of total cholesterol, triglycerides, low-density lipoprotein (LDL), and very-lowdensity lipoprotein (VLDL) are increased, while high-density lipoprotein (HDL) levels are decreased. These abnormalities result from an increase in hepatic cholesterol and lipoprotein synthesis, a decrease in peripheral and hepatic catabolism of serum lipoproteins, and an increase in urinary excretion ofHDL.
NEPHROTIC SYNDROME • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
The clinical manifestations of nephrotic syndrome include heavy proteinuria, hypoalbuminemia, edema, hyperlipidemia, and lipiduria.
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Figure 2. Prevalence of major causes of primary nephrotic syndrome in adults, by age. Adapted from Glassock et a/. 2
Hyperlipidemia is of concern, since its presence may lead to accelerated coronary atherosclerosis as well as to progression of renal disease.
Clinical evaluation Evaluation of the adult with nephrotic syndrome is outlined in table 2. HISlORY-The most important factor in evaluation is a carefully directed history. A primary form of nephrotic syndrome is more likely when the history is unremarkable, whereas a secondary form may be present if the history suggests a connec-
tive tissue disorder, malignant disease, sexually transmitted disease, hepatitis, infection with human immunodeficiency virus, or ingestion of over-the-counter or prescription medication. Diabetes mellitus has usually been present for years before nephrotic syndrome develops. Complications such as proliferative retinopathy or vascular disease provide strong evidence for underlying diabetic nephropathy. PHYSICAL EXAMINATION-The physical examination is directed at uncovering physical signs of potential secondary causes of nephrosis, such as evidence of
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • NEPHROTIC SYNDROME
diabetic complications, the stigmata of systemic lupus erythematosus, or features indicative of an underlying malignant disease. The severity and duration of edema are not helpful indicators, since some patients may have no edema and are only discovered to be nephrotic on routine urine screening for proteinuna. DIAGNOSTIC TESTING-This is divided into two phases: baseline laboratory testing and serologic testing for specific systemic disorders. BASELINE TESTs-These tests should be performed on all continued
211
A primary form of nephrotic syndrome is more likely when the history is unremarkable.
Downloaded by [RMIT University Library] at 17:05 19 June 2016
Table 1. Some types of secondary nephrotic syndrome Nephrotic syndrome*
Coexisting condition
Minimal change disease
Hodgkin's disease
Membranous glomerulonephritis
Solid tumors Hepatitis B infection
Focal segmental glomerulosclerosis
Vesicoureteral reflux Heroin abuse Infection with human immunodeficiency virus
Miscellaneous proliferative glomerulonephropathies
Systemic lupus erythematosus
*Based on morphologic changes on renal biopsy.
nephrotic patients. They include a multiphasic biochemical analysis of serum, a complete blood cell count, a lipid profile, urinalysis, and timed urine collection for the assessment of protein excretion and creatinine clearance. The nephrotic patient usually has low serum albumin, total protein, and calcium concentrations, while total cholesterol, LDL, and VLDL concentrations are elevated. The blood urea nitrogen and creatinine concentrations may be normal or elevated,
212
depending on the underlying disease. Urinalysis usually reveals lipid bodies (macrophages and renal tubular epithelial cells filled with lipid droplets), as well as free lipid droplets. Lipid is best visualized under polarized light. The importance of a careful urinalysis cannot be overemphasized. Total urinary protein should exceed 3.5 g/day to support the diagnosis. The problems associated with timed urine collections can be avoided by measuring the ratio of protein to ere-
atinine in a randomly collected urine sample" and calculating the creatinine clearance. The latter can be done using a variety of formulas based on the patient's serum creatinine concentration, age, and weight. 8 Both timed and random methods of urine collection have been shown to yield extremely precise results. All of the aforementioned parameters can be monitored to assess disease activity and response to treatment. Thus, baseline measurements are important. SEROLOGIC TESTs-The second stage of the diagnostic evaluation traditionally has comprised an array of serologic tests to identifY various systemic disorders. These include tests for fluorescent antinuclear antibody, rheumatoid factor, components of the complement system, hepatitis B surface antigen, venereal disease serology, cryoglobulins, protein electrophoresis, and erythrocyte sedimentation rate, as well as urine protein electrophoresis. A study of 87 adult patients with nephrotic syndrome was recently conducted at the Walter Reed Army Medical Center to determine the value of performing such empirical serologic test-
NEPHROTIC SYNDROME • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
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The importance of a careful urinalysis in the clinical evaluation of a patient with nephrotic syndrome cannot be overemphasized.
ing in the absence of specific clinical indications. 9 Diagnostic accuracy of the combination of a thorough history, physical examination, and baseline laboratory studies for determining whether the patient had primary or secondary nephrotic syndrome and for identifYing the specific histopathologic type was found to be the same whether or not empirical serologic data were available. Serologic findings were rarely abnormal without clinical suspicion, and the tests cost several hundred dollars. Thus, the second phase of the diagnostic evaluation should include only specific testing to help confirm a diagnosis already suspected on the basis of the initial clinical evaluation. For example, only nephrotic patients with symptoms and signs consistent with systemic lupus erythematosus should be tested for fluorescent antinuclear antibody and complement levels, and only patients with clinical evidence of an underlying cancer should undergo further evaluation for malignancy. In the absence of clinical suspicion, a wide battery of screening or radiologic tests aimed at blindly searching for multiple causes of secondary nephrotic syndrome is not cost-
Table 2. Initial evaluation of adults with nephrotic syndrome
History: hypertension, diabetes, cancer, drugs, infection, collagen vascular disease Physical examination: evidence of cancer, diabetes, collagen vascular disease Initial laboratory tests: complete blood cell count, chemistry profile Urinalysis (by physician) Measurement of renal function and protein excretion
effective, and this approach should not be pursued.
Role of renal biopsy Renal biopsy is an important part of our evaluation of most patients with primary nephrotic syndrome. Other clinicians, using the results of decision analysis, have questioned its utility10 and suggested that biopsy be reserved for patients who do not respond to a short (2-month) course of corticosteroids. Since minimal change disease is the only form of primary nephrotic syndrome likely to respond to such a regimen, we agree that a priori treatment is an acceptable strategy. We treat patients who are suspected on
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clinical grounds of having minimal change disease with a short course of corticosteroids and reserve biopsy for those who do not respond. We feel that minimal change disease is likely in patients in whom the nephrotic syndrome develops quite rapidly, in whom massive proteinuria (>10 g/day) is noted, and in whom the other features of nephrotic syndrome are striking in their severity. When decision-analysis techniques have been used to study the role of renal biopsy for all patients with primary nephrotic syndrome, assumptions have been made about the prevalence and natural history of different histologic entities, the risks and continued
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In the absence of clinical suspicion, a wide battery of tests aimed at blindly searching for multiple causes of secondary nephrotic syndrome is not cost-effective and should not be pursued.
Table 3. Therapeutic options for adults with nephrotic syndrome Corticosteroids Cytotoxic agents Angiotensin-converting enzyme inhibitors* Calcium channel blockers* Cyclosporine (Sandimmune)* Nonsteroidal anti-inflammatory drugs* Dietary protein restriction*
*May result in diminution of proteinuria and attenuate severity of nephrotic syndrome but will not target primary disease.
benefits of biopsy and various treatment options (based on semi-quantitative assessments), and response to treatment. Since optimum treatment regimens for most disorders that result in nephrotic syndrome remain undefined and are the subject of active clinical investigation, we feel that most patients should be afforded the opportunity to undergo biopsy. The results
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permit us to establish a specific diagnosis, provide patients with information about their disease and its likely prognosis, and select a specific therapeutic regimen. However, we do not generally offer biopsy to patients who have long-standing diabetes, shrunken kidneys, or other contraindications, such as uncontrolled hypertension or a bleeding diathesis. For some forms of secondary nephrotic syndrome, renal biopsy is critical. Patients with systemic lupus erythematosus who have clinical renal involvement, for example, may have one of several forms of lupus nephritis. Precise definition of the histologic subtype, which is largely impossible clinically, allows for specific therapy and provides the best information to guide both the intensity and duration of therapy. 11
Management of nephrotic syndrome in adults Management of the nephrotic adult consists of treating the underlying glomerular disease as well as managing the complications of nephrotic syndrome. 12 Treatment depends on whether the disease is primary or secondary and whether specific therapy may be required.
PRIMARY NEPHROTIC SYN-
DROME-Specific therapeutic options for primary nephrotic syndrome are listed in table 3. The two most common forms of the syndrome, minimal change disease and membranous glomerulonephritis, often respond to immunosuppressive therapy. We treat minimal change disease with prednisone, 2 mg/kg of body weight daily for 1 week, then every other day for 7 weeks. This regimen brings about remission in approximately 80% of adults. Up to 16 weeks of therapy may be required. l.l We have not found longer treatment courses to be helpful. We offer a second biopsy to patients who do not respond, and generally we discover focal segmental glomerulosclerosis that was not detected on the original biopsy specimen. We treat membranous glomerulonephritis with month-long courses of prednisone alternating with month-long courses of chlorambucil (Leukeran) for a total of 6 months. This treatment regimen, designed by Ponticelli and associates, 14 appears to benefit many patients. We and others have not been impressed with the response of other forms of primary nephrotic syndrome to steroids or to com-
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Renal biopsy for patients with nephrotic syndrome permits the clinician to establish a specific diagnosis and select a specific therapeutic regimen.
binations of steroids, cytotoxic agents, and antiplatelet agents. Patients with these disorders may be candidates for treatment with angiotensin-converting enzyme inhibitors, calcium channel blockers, cyclosporine (Sandimmune), or nonsteroidal antiinflammatory drugs to lessen the severity of proteinuria. Clearly, further research into these disorders is required to determine effective treatment strategtes.
Table 4. Major complications of nephrotic syndrome and their clinical effects Complication
Clinical effects
Hypovolemia
Hypotension, acute renal failure
Anasarca
Infection, immobility
Hyperlipidemia
Early vascular disease
Hypercoagulability
Renal vein thrombosis, pulmonary embolism
SECONDARY NEPHRaTIC SYN-
DROME-Patients with secondary nephrotic syndrome require management of the associated disorder. Removal of the underlying malignant lesion, treatment of the underlying connective tissue disorder, or removal of the offending toxin or drug is necessary. NONSPECIFIC TRFATMENT-
All patients with nephrotic syndrome should be afforded nonspecific treatment to limit complications (table 4), which often result in as much morbidity as the glomerular lesion. 15 One serious complication is the development of a hypercoagulable state, with lower extremity deep vein thrombosis, pulmonary embolism, and renal vein thrombosis.16
Another serious complication is the development of acute renal failure. 17 A profound, rapid fall in the plasma albumin level may lead to dramatic fluid shifts, intravascular volume depletion, prerenal azotemia, and if prolonged, ischemic renal damage. Aggressive diuretic treatment for edema can also have similar consequences, as can renal vein thrombosis. The goals of nonspecific treatment include the control of edema, hypertension, hypoalbuminemia, and hyperlipidemia. Control of edema and hypertension involves adherence to a sodium-restricted diet, judicious use of diuretics, and bed rest. The loop diuretic furosemide (Lasix) should be given initially,
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and the dose should be titrated until a response is seen. Diuresis can be augmented with low-dose metolazone (Diulo, Mykrox, Zaroxolyn) .18 Volume depletion can be avoided by monitoring the patient's weight and ensuring that the rate of diuresis is not too rapid. Hypoalbuminemia is best managed with a diet that includes high-biologic-value protein in modest quantities. We restrict daily protein intake to 0.8 g/kg of ideal body weight, since protein loading has been shown to increase urinary protein excretion and worsen hypoalbuminemia. 19 Whether protein restriction exerts a salutary effect on the progression of renal disease in humans is the subject of continued on page 218
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Minimal change disease and membranous glomerulonephritis often respond to immunosuppressive therapy.
Michael A. Carome, MD Jack Moore Jr, MD Dr Carome (left) is a major in the US Army Medical Corps: a research fellow in nephrology, Walter Reed Army Medical Center, Washington, DC: and an instructor in medicine, Uniformed Services University of the Health Sciences, Bethesda. Dr Moore (right) is a colonel in the US Army Medical Corps: chief, nephrology service, Walter Reed Army Medical Center: and associate professor of medicine, Uniformed Services University of the Health Sciences.
clinical investigation. Some patients respond to administration of a low dose of an angiotensinconverting enzyme inhibitor or calcium channel blocker with a reduction in proteinuria, although treatment with these agents has been demonstrated to be efficacious only in patients
with diabetic nephropathy.~o Patients who have significant hyperlipidemia from chronic nephrotic syndrome are candidates for dietary manipulation and therapy with bile acid resin and lovastatin (Mevacor). 6 The latter agent should be used cautiously, since it has been associat-
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ed with rhabdomyolysis in some nephrotic patients.
The views expressed herein are those of the authors and do not necessarily reflect the views of the US Army or the Department of Defense.
Summary and conclusions The adult with nephrotic syndrome presents diagnostic and treatment challenges for the primary care physician. Early consultation with a nephrologist is advisable to assist in choosing between empirical therapy or renal biopsy to identify the specific causative lesion. Some patients respond to treatment of either the specific disorder or the underlying cause. All patients should be afforded specific therapy, where available, and nonspecific therapy to minimize the severity of the nephrosis and attenuate the incidence and severity of complications. Although the cause of most disorders resulting in nephrotic syndrome remains unclear, active research into the syndrome's pathogenesis and treatment options should prove fruitful. FUll
--®
Earn credit on this article. See CME Quiz.
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Address for correspondence: Michael
A Carome, MD, Nephrology Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20307-5001.
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ll. Steinberg AD. The ueaunent oflupus nephritis. Kidney Int 1986;30:769-87 12. Cameron JS. The nephrotic syndrome and its complications. Am J Kidney Dis 1987;10: 157-71 13. Nolasco F, Cameron JS, Heywood EF, et al. Adult-onset minimal change nephrotic syndrome: a long-term follow-up. Kidney Int 1986;29: 1215-33 14. Ponticelli C, Zucchdli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Eng! J Med 1989;320:8-13 15. Bernard DB. Extrarenal complications of the nephrotic syndrome. Kidney Int 1988;33: 1184-202 16. Uach F. Nephrotic syndrome: hypercoagulability, renal vein thrombosis, and other thromboembolic complications. In: Brenner BM, Stein JH, eds. Contemporary issues in nephrology. 9. Nephrotic syndrome. New York: Churchill Livingstone, 1982:121-44 17. Jennette JC, Falk RJ. Adult minimal change glomerulopathy with acute renal failure. Am J Kidney Dis 1990; 16:432-7 18. Oster JR, Epstein M, Smoller S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. (Editorial) Ann Intern Med 1983;99:405-6 19. Kaysen GA. Albumin metabolism in the nephrotic syndrome: the effect of dietary protein intake. AmJ Kidney Dis 1988;12:461-80 20. Bakris GL Effects of diltiazem or lisinopril on massive proteinuria associated with diabetes mellitus. Ann Intern Med 1990;112:707-8
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