Prepared by Salman Singapuri, MD, Chief Resident, Department of Internal Medicine, University of Alabama at Birmingham, Health Center Montgomery; and Anna Schuler, MD, Fellow, and Zvi Talor, MD, Professor of Medicine, Department of Nephrology and Hypertension, Shands Hospital, University of Florida, Gainesville
A 61-year-old white man presents to our clinic complaining of anasarca, 15-lb weight gain over the past 4 weeks, excessive fatigue, and orthopnea of 1 month?s duration. His medical history includes poorly controlled hypertension, hyperlipidemia, prostatectomy done for prostate cancer (with recent elevation of prostate-specific antigen), and thyroidectomy performed for hypothyroidism. He has been taking ibuprofen for repeat headaches. His regular medications include spironolactone, lactulose, irbesartan, bisoprolol/hydrochlorothiazide, levothyroxine, atorvastatin, and amlodipine. Physical examination shows: hypertension, ascites, and 3 pitting edema of the lower extremities. Serum liver function testing reveals only severe hypoalbuminemia. Additional testing shows: 14.8 g of protein on 24-hour urine collection; creatinine clearance of 52 mL/min; and significantly elevated thyroid-stimulating hormone level (7.4 mIU/L). Results of a renal biopsy pointed out the diagnosis (Figures 1-3).
Membranous nephropathy—Results of the renal biopsy revealed the characteristic features of membranous nephropathy: light microscopy (Figure 1) showed diffuse thickening of the glomerular basement membrane, with normal cellularity. Immunofluorescence (Figure 2) revealed granular immunoglobulin G deposition and subepithelial deposits on electron microscopy (Figure 3).
Membranous nephropathy and focal-segmental glomerulosclerosis are among the most common causes of the nephrotic syndrome in nondiabetic adults.1 Membranous nephropathy is frequently idiopathic in adults but can be secondary to other conditions. Clinical, laboratory, and histologic features can distinguish between these 2 diagnoses. The causes of membranous nephropathy include rheumatoid arthritis; medications, such as gold and penicillamine; hepatitis B virus (HBV) and hepatitis C virus (HCV) infections; and systemic lupus erythematosus. Malignancy (primarily solid tumors) has been suggested as a cause in as many as 5% to 10% of cases in adults.2
Therapy with immunosuppressive agents is indicated in patients with membranous nephropathy who have elevated creatinine levels or in those with progressive disease or severe, symptomatic or persistent nephrotic syndrome, thromboembolism, and age older than 50 years. Diuretics help control edema, and angiotensin-converting-enzyme inhibitors decrease proteinuria and control hypertension, 3 conditions that may be present with membranous nephropathy. The risk of renal-vein thrombosis and other deep-vein thromboses is significant in these patients, and routine use of anticoagulation is controversial.
Focal-segmental glomerulosclerosis can be primary or secondary; secondary disease typically presents with non-nephrotic proteinuria and renal insufficiency. Its causes include toxins; genetic abnormalities; and/or infections, such as HIV-associated nephropathy, heroin nephropathy, or drug toxicity. On light microscopy, this condition is characterized by the presence, in some (but not all) glomeruli, of segmental areas of mesangial collapse and sclerosis.3 Electron microscopy shows diffuse fusion of the epithelial-cell foot processes.3 Immunofluorescence usually reveals no immune deposits. Membranoproliferative glomerulonephritis is an uncommon cause of glomerular disease that, in its idiopathic form, primarily occurs between the ages of 8 and 30 years. It has been associated with HBV and HCV infections, subacute bacterial endocarditis, and ventriculoatrial shunt infection. On light microscopy, the glomeruli are generally enlarged and hypercellular. Irregular new basement membrane material is formed around the subendothelial deposits, producing the "tram-track appearance." Electron microscopy characteristically shows electron-dense deposits in subendothelial sites. Immunofluorescence reveals prominent C3 deposition in a granular pattern.
Minimal-change disease, also known as lipoid nephrosis or nil disease, is the most common form of nephrotic syndrome in children. It also accounts for between 10% and 15% of cases in adults.4 Almost all cases are idiopathic, with some exceptions. Immunofluorescence and light microscopy typically show no evidence of immune complex deposition. The characteristic histologic finding is diffuse effacement of the epithelial-cell foot processes on electron microscopy.