A 65-Year-Old Man with Chronic Back Pain and Shortness of Breath

A 65-Year-Old Man with Chronic Back Pain and Shortness of Breath

Case Records of the VA Maryland Healthcare System/ University of Maryland Medicine HEALTH CARE SYSTEM Editor Philip A. Mackowiak, MD Assistant Edit...

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Case Records of the VA Maryland Healthcare System/ University of Maryland Medicine

HEALTH CARE SYSTEM

Editor

Philip A. Mackowiak, MD Assistant Editors

Douglas H. Pogue, MD Christopher B. McFadden, MD

A 65-Year-Old Man with Chronic Back Pain and Shortness of Breath Presenters

Thomas L. Pallone, MD John C. Papadimitriou, MD, PhD

Presentation of Case

A 65-year-old man presented with shortness of ~reath preceded by 8 months of leg edema and intermittent dyspnea. He also complained of recent two-pillow orthopnea, episodic paroxysmal nocturnal dyspnea, and a 15-pound weight loss. He had had low back pain for many years, treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy. Lumbosacral spine films showed degenerative changes at L4-L5 and L5-S1 with bilateral foraminal narrowing. The patient declined surgical decompression. He had had an appendectomy at age 12 and had been exposed to tuberculosis in the distant past. Current medication included only lorazepam. The family history was unremarkable. The patient was a nonsmoker and a social drinker. He denied use of illicit drugs. On admission, the temperature was 97°F, pulse was 87/min, and blood pressure was 96/71 mm Hg. There was periorbital edema. The jugular veins were not distended. Bibasilar rales, a 2/6 holosystolic murmur at the cardiac apex, and an S3 gallop were present. The abdomen was normal. There was From the Medical Care Clinical Center, VA Maryland Health Care System and the Departments of Medicine and Pathology, University of Maryland School of Medicine, Baltimore, Maryland. Correspondence: Philip A. Mackowiak, M.D., Medical Service (111), VA Medical Center, 10 N. Greene St., Baltimore, MD 21201. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

pitting edema of both lower extremities to the midthigh. The skin was normal. There was decreased sensation to light touch below the knees bilaterally. Details of the laboratory evaluation are provided in Tables 1 and 2. Chest radiograph demonstrated blunting of the costophrenic angles and an enlarged cardiac silhouette. Electrocardiogram revealed a heart rate of 90 beats/min, normal axis, 10 atrioventricular conduction delay, poor R wave progression, and T wave inversions in V5-6. Echocardiogram showed an enlarged left atrium, mild left ventricular hypertrophy, moderate tricuspid and mitral regurgitation, and an ejection fraction of greater than 60%. A multigated acquisition scan showed an ejection fraction of 73%. Nuclear magnetic resonance imaging of the spine demonstrated degenerative changes with compression fractures of the 8th and 9th thoracic vertebrae. A bone scan showed increased tracer uptake by the lower thoracic and lower lumbar vertebrae. Evaluation of pleural fluid obtained by thoracentesis revealed a transudate. Bone marrow biopsy showed 9% plasma cells. Differential Diagnosis

Dr. Thomas L. Pallone In summary, this is the case of an elderly man with the symptoms, signs, and laboratory findings of nephrotic syndrome. He has extracellular fluid volume expansion, as evidenced by the presence of peripheral edema and pleural effusions. His urinary protein excretion is markedly elevated at 8.25 g/24 hours and is accompanied by hyperlipidemia. The urinalysis reveals bland sediment with few formed elements. Renal function is fairly well preserved, as reflected by a serum creatinine concentration of 1.2 mg/dL. Interestingly, there is glycosuria in the absence of significant hyperglycemia (Table 1). The glycosuria might be explained by subclinical diabetes mellitus if the serum glucose had exceeded the reabsorptive capacity of the proximal convoluted tubule (180 mg/dL) at some time before the serum glucose sample reported in Table 1 was obtained. Alternate explanations include incorrect reporting of the urinary dipstick measurement (owing to an interfering substance) or dysfunction of the proximal tubule with impaired reabsorptive capacity for glucose because of tubulointerstitial renal disease. The history of a 14-pound weight loss raises the specter of a paraneoplastic glomerulopathy. A reasonably complete evaluation of this patient was performed. Nevertheless, some additional information would have been helpful, such as the hemoglobin Ale level and the results of the funduscopic examination. If these were normal, diabetes mellitus could be excluded. Additionally, given the patient's shortness of breath, a ventilation perfusion scan, or possibly a pulmonary angiogram, might have been performed, because some forms of the nephrotic syndrome are associated with a hypercoagulable state and, hence, thromboembolic disease. 1 ,2 195

Case Records of the VA Maryland Healthcare System/University of Maryland Medicine

Table 1. Laboratory Values Variable

Value

Hematocrit Mean corpuscular volume Platelet count (per mm3 ) White cell count (per mm 3 ) Differential count (%) Neutrophils Lymphocytes Monocytes Eosinophils Basophils Sodium (mEqlL) Potassium (mEqlL) Chloride (mEqlL) Bicarbonate (mmollL) Urea nitrogen (mgldL) Creatinine (mgldL) Glucose (mg/dL) Calcium (mg/dL) Phosphorus (mg/dL) Magnesium (mgldL) Protein (g/dL) Albumin (g/dL) Thyroid stimulating hormone (uIU/mL) Cholesterol (mg/dL) Serum protein electrophoresis

.370 86 405,000 8,600 68

23 6 2 1 138 4.4 104

26 20 1.2

122 8.3 4.1 2.2 4.8

2.3 3.6 341 No monoclonal spike

Before proceeding to categorize the specific pathological lesions that might be responsible for this patient's nephrotic syndrome, let me comment on the "sodium avid" nature of glomerular disease. Our patient presented with edema, rales, and transudative pleural effusions. The mechanisms responsible for sodium retention and the associated expanded extracellular fluid (ECF) volume in the presence of adequate left ventricular function are uncertain. Is there relative "intravascular" hypovolemia despite overall ECF expansion (ie, "underfilling" stimulating neurohormonal signals to the kidney that promote sodium retention), or does abnormal sodium retention by the kidney occur despite conditions that should Table 2. Serologic and Urine Studies Variable Hepatitis B surface antigen Hepatitis C antibody Antinuclear antibody Rapid plasma reagin Urinalysis

Urine chemistry

WBe, white blood cell.

196

Value Negative Negative Negative Negative Specific Gravity 1.009 pH 5.0 Protein 4+ Occasional WBCs Occasional RBCs Protein excretion 8.25 g/24 hours Negative electrophoresis for Bence-Jones proteins

favor natriuresis (ie, is there "overfilling")? Considerable evidence favors the overfilling hypothesis. Measurements of plasma volume, though notoriously difficult, have most often yielded normal or elevated values. 3 Hypertension is common in cases of glomerulonephritis and inhibition of the renin angiotensin system does not consistently produce natriuresis. In addition, atrial natriuretic peptide (ANP), a hormone released by the cardiac atria and other sites4 in response to ECF volume expansion, has been shown not to induce natriuresis in the nephrotic kidney. Normally, ANP increases the glomerular filtration rate, blocks renin secretion, and inhibits both proximal and distal sodium reabsorption. 5 Perico et al 6 have shown that in rats with unilateral, doxorubicin-induced nephrotic injury, infusion of ANP produces diuresis and natriuresis in the protected kidney but not in the doxorubicintreated nephrotic kidney (Figure 1). In related experiments, Peterson et aF showed that nephrotic patients exhibit an exaggerated ANP response to head out water immersion accompanied by blunted natriuresis. These observations not withstanding, the precise mechanisms responsible for ECF expansion in nephrotic syndrome have yet to be defined. 8 There are a number of fundamental questions that need to be addressed in every patient with nephrotic syndrome. What is the likely histological lesion? Is the renal disease a primary, idiopathic disease, or is it secondary to some systemic disease process? Will knowing the histology influence treatment sufficiently to warrant the risk of a percutaneous renal biopsy? The many causes of nephrotic syndrome can be codified according to two general schemes. The first divides glomerulonephritis into "primary" diseases that primarily affect the kidney and "secondary" diseases in which glomerular inflammation occurs as part of a more generalized disease process (Table 3). As summarized in Table 3, primary glomerulonephritis is classified according to its appearance on light and electron microscopy. For example, if there is no obvious pathology, the lesion is designated as "minimal change"; if there is thickening of the capillary basement membrane, it is categorized as "membranous"; and if increased numbers of mesangial cell nuclei are present, it is classified "proliferative." Despite the seeming lack of a pathophysiological basis, this method of classification has proved to be enormously useful. It helps to predict natural history, and, hence, prognosis; it characterizes histologic subtypes into age-stratified subgroups (Figure 2)9; and it predicts the potential for response to immunosuppressive therapy. Secondary glomerulonephritis has a histological appearance similar to that of primary glomerulonephritis but varies with respect to prognosis and response to therapy. Excellent reviews of this topic are available.lO,n September 2000 Volume 320 Number 3

Pallone and Papadimitriou

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Another classification scheme is based on the amount of the protein and formed elements, especially red blood cells, in the urine (Table 4). According to this scheme, disorders characterized by heavy proteinuria with few red blood cells (RBCs) or RBC casts are designated "nephrotic." Urine sediment dominated by hematuria and RBC casts is designated as "nephritic." "Nephritic/nephrotic" disorders with heavy proteinuria and hematuria are common. Urinary oval fat bodies and fatty casts frequently accompany heavy proteinuria, regardless of cause. When hematuria, as opposed to proteinuria, is the predominant urinary abnormality, the question arises as to whether the RBCs reflect a urological or a glomerular disorder. RBC casts are prima facie evidence of glomerulopathic renal disease. However, they can be difficult to identify. Dysmorphic RBCs also suggest that hematuria is glomerular in origin.12 Given this background, what can be said of the patient in question? His age, the nephrotic/nonnephritic character of his urine sediment, and the THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

relatively well preserved renal function all help to narrow the list of possibilities enumerated in Table 3. Ofthe primary glomerular diseases, membranous nephropathy, focal sclerosis, and, possibly, IgA nephropathy are most likely. Minimal change disease, although consistent with the heavy proteinuria, is unlikely because of the patient's age. Of the secondary disorders worthy of consideration, diabetic nephropathy must be included becau:se of the glycosuria and the absence of hemoglobin Ale determination. Amyloidosis must also be considered. In the United States, membranous glomerulonephritis (MGN) is the most common, primary glomerular disorder identified by renal biopsy in adults (Figure 2). It is also the glomerulopathy most often associated with thromboembolic complications such as renal vein thrombosis and pulmonary emboli. l ,2 Llach et al 2 examined the incidence of renal vein thrombosis in 151 patients with nephrotic syndrome of various causes. MGN was present in 69 (46%) patients and accounted for 20 (61%) of the cases of 197

Case Records of the VA Maryland Healthcare System/University of Maryland Medicine

Table 4. The NephriticlNephrotic Classification Scheme

Table 3. Classification of Glomerulonephritis Primary Glomerulonephritis Minimal change nephropathy (lipoid nephrosis) Membranous nephropathy Focal segmental glomerulosclerosis IgA nephropathy (Berger disease) Proliferative glomerulonephritis Membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis) Fibrillary glomerulonephritis Immunotachtoid glomerulonephritis Secondary Glomerulonephritis Diabetic nephropathy Amyloidosis Systemic lupus erythmatosus (many histological variants) Infection (poststreptococcal, hepatitis-related, HIV, many others) Cryoglobulinemia (hepatitis C, paraproteinemias) Neoplasms Drug-related Antiglomerular basement membrane antibody disease Wegener granulomatosis Alport syndrome

renal vein thrombosis. "Primary" MGN is also notable for its association with malignant neoplasms-most commonly, solid tumors of the lung, urogenital system, or gastrointestinal tract. 13 ,14 Given our patient's history of weight loss, I think consideration should be given to an underlying malignant neoplasm. The course of membranous nephropathy can involve either spontaneous exacerbations/remissions or relentlessly progressive disease. In approximately 50% of cases, renal function is preserved (Figure 3).15 The probability of progression to end-stage renal disease depends on histologic stage and the presence of hypertension and heavy proteinuria. 16 Treatment with corticosteroids has not been shown to be of benefit. However, alternating monthly courses of pred-

Urinalysis

Disease Process

Nephrotic

Minimal change glomerulonephritis Amyloidosis Focal segmental glomerulosclerosis Diabetic nephropathy Membranous nephropathy IgA nephropathy Proliferative glomerulonephritis Poststreptococcal glomerulonephritis Cryloglobulinemia Membranoproliferative glomerulonephritis Crescentic or rapidly progressive glomerulonephritis

Nephritic

nisone and chlorambucil can induce remission and help preserve renal functionP-21 A recent meta-analysis of 10 prospective, randomized trials showed that whereas function was not clearly improved by treatment, regimens that included an alkylating agent did have a beneficial effect on proteinuria. 22 Cyclosporin also improves proteinuria and is more effective in this regard than an angiotensin-converting enzyme inhibitor alone. Unfortunately, proteinuria frequently recurs once cyclosporin is withdrawn. 23 In our patient, confirmation of the diagnosis of MGN by renal biopsy would be important prognostically and would justify treatment with prednisone and chlorambucil, or possibly cyclosporin, especially if conservative therapy with diuretics and lipid-lowering agents proved ineffective. Focal segmental glomerulosclerosis (FSGS) is an adult kidney disorder involving heavy proteinuria and a variable prognosis. It can be either primary or Patients l00~~-------;~--------~----~

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Pallone and Papadimitriou

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secondary; the latter is caused by intravenous drug abuse, obesity, or HIV infection. HIV nephropathy is an especially aggressive subtype ofFSGS that sometimes responds to antiretroviral drugs. 24,25 Our patient's age, heavy proteinuria, and bland urine sediment all suggest FSGS, the prognosis of which correlates with level of proteinuria (Figure 4).26 Patients with hypertension and heavy proteinuria generally progress to end-stage renal disease in several years. Although FSGS was previously thought to be steroid-resistant, a recent reevaluation of the literature suggests that courses of prednisone (0.5 to 2 mg/kg/day) lasting 3 to 6 months induce remission in 35% of cases and that remission of proteinuria is associated with markedly improved renal surviva1. 26 - 28 IgA nephropathy, the most common glomerular disease worldwide, typically begins in the 3rd to 5th decade oflife. 29,30 It is more often nephritic than FSGS but can produce isolated, heavy proteinuria. Secondary forms of IgA nephropathy are seen in cirrhosis, inflammatory bowel disease, and cancer. Although neither Warfarin nor cytotoxic agents have been used successfully to treat IgA nephropathy, high-dose fish oil may improve its prognosis (Figure 5).31-33 I believe IgA nephropathy is less likely than MGN or FSGS as a cause of our patient's renal dysfunction. Secondary glomerulopathies causing heavy proteinuria include diabetes, amyloidosis, and membranous glomerulopathy. As discussed above, in our patient, subclinical diabetes cannot be excluded because of inadequate clinical information. His weight loss raises the possibility of a paraneoplastic glomerulopathy such as MGN or amyloidosis. Drugrelated proteinuria, such as that associated with NSAID use, is another possibility. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

Diabetic nephropathy has a reasonably predictable course. Hyperfiltration, increased glomerular filtration rate (GFR), and possibly large kidney size precede the onset of microalbuminuria. 34 Frank nephrotic syndrome is most often accompanied by retinopathy and occurs in 30 to 40% of patients after 18 years of disease. 35 Renal dysfunction can be prevented by rigorous and early control of the serum

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Case Records of the VA Maryland Healthcare System/University of Maryland Medicine

prolonged corticosteroid therapy for FSGS, or chlorambucil in the case ofMGN, or was anxious for objective prognostic information, I would have advised him to undergo a renal biopsy. Elderly patients with idiopathic nephrotic syndrome most often have MGN. However, FSGS and amyloidosis are also important causes 38 and a renal biopsy would be the only way to determine which of these renal disorders were the cause of this patient's nephrotic syndrome. Diagnosis. Membranous glomerulonephritis. Pathological Discussion Figure 6. H&E stain of the renal biopsy.

glucose and blood pressure and by treatment with a angiotensin-converting enzyme inhibitor unless otherwise contraindicated. Our patient's glycosuria in the absence of hyperglycemia might represent the proximal tubular dysfunction of Fanconi syndrome or light chain nephropathy.36 His peripheral neuropathy might be the result of longstanding subclinical type II diabetes or amyloidosis. Amyloidosis generally causes heavy proteinuria without hematuria in patients over 50 years of age. It results from glomerular deposition of light chains (AL type), generated in response to chronic inflammation (AA), or as a result of a familial disorder (AF).37 In summary, I believe this patient should have been examined for diabetes with serum glucose determinations, a hemoglobin Ale level, and a careful funduscopic examination. I would also have searched carefully for lymphadenopathy and performed repeated tests for fecal occult blood in an effort to exclude an occult cancer. If the patient had been taking NSAIDs, I would have asked him to stop. If he were willing to submit to the risk of

Dr. John C. Papadimitriou On examination by light microscopy, 28 glomeruli were identified, 3 of which were globally sclerosed. Hematoxylin and eosin (H&E) staining of the nonsclerosed glomeruli showed extensive deposition of eosinophilic, acellular, amorphous material. These deposits involved the mesangium diffusely, forming nodular masses protruding within the glomerular capillaries (Figure 6). The deposited material was only weakly PAS-positive, distinguishing it from the surrounding mesangial matrix and glomerular basement membranes. The deposited material did not take up silver stain and had a pale "dirty" green coloration on Masson's trichrome stain. Congo red stained the material a pale rose color, which, when examined under polarized light, exhibited an applegreen birefringence. Extensive deposition of Congo red-positive material was also noted in the walls of arterioles. The interstitium appeared moderately fibrotic. There was associated tubular atrophy. Electron microscopic examination of two nonsclerotic glomeruli showed massive mesangial deposits of randomly arranged, nonbranching fibrils of 10- to 12-mm diameter (Figure 7). The fibrillar deposits extended into the subendothelial spaces and were overlaid by new layers of basement membrane. All of these findings are characteristic of renal amyloidosis with a nodular and diffuse mesangial pattern. The morphologic abnormalities visible in the H&E sections can also be seen in monoclonal immunoglobulin deposition disease, diabetic nephropathy, and membranoproliferative glomerulonephritis, all of which can produce a similar picture of mesangial expansion and nodule formation by deposits of amorphous material. However, the histochemical findings and the distinctive fibrillar deposits evident on electron microscopy are seen only in amyloidosis. Anatomical Diagnosis. Renal amyloidosis. References

Re, Ismail N. Extrarenal complications of the nephrotic syndrome. Am J Kidney Dis 1994;23:477-97. 2. Llach F, Papper S, Massry SG. The clinical spectrum of renal vein thrombosis: acute and chronic. Am J Med 1980;69: 819-27. 1. Harris

Figure 7. Electron microscope examination of the renal biopsy.

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3. Palmer BF, Alpern RJ. Pathogenesis of edema formation in the nephrotic syndrome. Kidney Int 1997;59:S21-7. 4. Weidmann P, Saxenhofer H, Shaw SG, et al. Atrial natriuretic peptide in man. J Steroid Biochem 1989;32:229-41. 5. Maack T. Role of atrial natriuretic factor in volume control. Kidney Int 1996;49:1732-7. 6. Perico N, Delaini F, Lupini C, et al. Blunted excretory response to atrial natriuretic peptide in experimental nephrosis. Kidney Int 1989;36:57-64. 7. Peterson C, Madsen B, Perlman A, et al. Atrial natriuretic peptide and the renal response to hypervolemia in nephrotic humans. Kidney Int 1988;34:825-31. 8. Schrier RW, Fassett RG. A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome. Kidney Int 1998;53:1111-7. 9. Moxey-Mims MM, Stapleton FB, Feld FG. Applying decision analysis to management of adolescent idiopathic nephrotic syndrome. Pediatr Nephrol 1994;8:660-4. 10. Glassock RJ, Cohen AB. The primary glomerulopathies. Dis Mon 1996;42:329-83. 11. O'Meara YM, Salant DJ. Management of glomerular diseases of primary and secondary origin. CUIT Opin Nephrol Hypertens 1992;1:124-32. 12. Saad TF. Images in clinical medicine. Dysmorphic urinary erythrocytes. N Engl J Med 1996;334:1440. 13. Brueggemeyer CD, Ramirez G. Membranous nephropathy: a concern for malignancy. Am J Kidney Dis 1987;9:23-6. 14. Burstein DM, Korbet SM, Schwartz MM. Membranous glomerulonephritis and malignancy. Am J Kidney Dis 1993;22:5-10. 15. Cameron JS. Pathogenesis and treatment of membranous nephropathy. Kidney Int 1979;15:88-103. 16. Ponticelli C. Prognosis and treatment of membranous nephropathy. Kidney Int 1986;29:927-40. 17. Ponticelli C, Zucchelli P, Imbasciati E, et aI. Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1984;310:946-50. 18. Ponticelli C, Zucchelli P, Passerini P, et aI. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1989;320:8-13. 19. Ponticelli C, Zucchelli P, Passerini P, et al. Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. The Italian Idiopathic Membranous Nephropathy Treatment Study Group. N Engl J Med 1992;327:599603. 20. Ponticelli C, Zucchelli P, Passerini P, et aI. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int 1995;48:1600-4. 21. Muirhead N. Management of idiopathic membranous nephropathy: evidence-based recommendations. Kidney Int Suppl 1999;70:S47-55.

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22. Hogan SL, Muller KE, Jennette JC, et al. A review of the therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis 1995;25:862-75. 23. Amabalavanan S, Fauvel JP, Sibley RK, et al. Mechanism of the antiproteinuric effect of cyclosporine in membranous nephropathy. J Am Soc Nephrol 1996;7:290-8. 24. WaH RK, Drachenberg CI, Papadimitriou JC, et aI. HN-1-associated nephropathy and response to highly-active antiretroviral therapy. Lancet 1998;352:783-4. 25. Viani RM, Dankner WM, Muelenaer P A, et aI. Resolution of HIV-associated nephrotic syndrome with highly active antiretroviral therapy delivered by gastrostomy tube. Pediatrics 1999;104:1394-6. 26. Korbet SM, Schwartz MM, Lewis EJ. Primary focal segmental glomerulosclerosis: clinical course and response to therapy. Am J Kidney Dis 1994;23:773-83. 27. Rydel JJ, Korbet SM, Borok RZ, et al. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am J Kidney Dis 1995;25:534-42. 28. Ponticelli C, Villa M, Banfi G, et al. Can prolonged treatment improve the prognosis in adults with focal segmental glomerulosclerosis? Am J Kidney Dis 1999;34:618-25. 29. Galla JH. IgA nephropathy. Kidney Int 1995;47:377-87. 30. Pettersson E. IgA nephropathy: 30 years on. J Intern Med 1997;242:349-53. 31. Donadio JV Jr, Bergstralh EJ, Offord KP, et al. A controlled trial offish oil in IgA nephropathy. Mayo Nephrology Collaborative Group. N Engl J Med 1994;331:1194-9. 32. Glassrock RJ. The treatment ofIgA nephropathy: status at the end of the millennium. J Nephrol 1999;12:288-96. 33. Nolin L, Courteau M. Management of IgA nephropathy: evidence-based recommendations. Kidney Int Suppl 1999;70: S56-62. 34. Nelson RG, Bennett PH, Beck GJ, et al. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med 1996;335:1636-42. 35. Bennett PH, Haffner S, Kasiske BL, et al. Screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis 1995;25:107-12. 36. Rikitake 0, Sakemi T, Yoshikawa Y, et al. Adult Fanconi syndrome in primary amyloidosis with lambda light-chain proteinuria. Jpn J Med 1989;28:523-6. 37. Browning MJ, Banks RA, Tribe CR, et al. Ten year's experience of an amyloid clinic-a clinicopathological survey. Q J Med 1985;54:213-27. 38. Cameron JS. Nephrotic syndrome in the elderly. Semin Nephrol 1996;16:319-29.

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