Minimal change disease with acute renal failure: a case against the nephrosarca hypothesis

Mary Ann Cameron 0 Usha Peri 0 Thomas E. Rogers 0 1 Orson W. Moe 0 0 Department of Internal Medicine, University of Texas Southwestern Medical Center , 5323 Harry Hines Blvd, Dallas 1 Pathology, Department of Veterans Affairs Medical Center and The University of Texas Southwestern Medical Center , Dallas, TX, USA An unusual but well-documented presentation of minimal change disease is nephrotic proteinuria and acute renal failure. One pathophysiological mechanism proposed to explain this syndrome is nephrosarca, or severe oedema of the kidney. We describe a patient with minimal change disease who presented with heavy proteinuria and acute renal failure but had no evidence of renal interstitial oedema on biopsy. Aggressive fluid removal did not reverse the acute renal failure. Renal function slowly returned concomitant with resolution of the nephrotic syndrome following corticosteroid therapy. The time profile of the clinical events is not compatible with the nephrosarca hypothesis and suggests an alternative pathophysiological model for the diminished glomerular filtration rate seen in some cases of minimal change disease. Introduction Minimal change disease with acute renal failure has been described since 1966, with >85 cases reported in the literature [1,2]. It has been associated with older age, systolic hypertension, vascular disease and more severe nephrotic syndrome [3,4]. However, the underlying pathophysiology that distinguishes this entity from the majority of minimal change disease with preserved glomerular filtration rate (GFR) has thus far remained elusive. Lowenstein and colleagues proposed a theory of nephrosarca, or interstitial oedema of the kidney, which physically causes vascular and/or tubular occlusion and consequent filtration failure [5]. Data in support of this hypothesis include the finding of severe interstitial oedema on biopsy in some [3,5] but not all reports [2,4]. A central tenet of this hypothesis is that the acute renal failure should and would improve simply with removal of excess extracellular fluid. Therefore, one would expect resolution of acute renal failure without, or prior to corticosteroid-induced disease remission as long as the excess oedematous fluid is removed. Functional data of this type have never been documented unequivocally in the literature [2]. We present a case of minimal change disease with acute renal failure which failed to undergo remission despite 16 l of ultrafiltration. The acute renal failure subsequently resolved along with remission of proteinuria following corticosteroid therapy without further reduction in extracellular fluid volume. We propose that reduction in glomerular ultrafiltration is part of the underlying defect in minimal change disease and is due to factors other than nephrosarca. A 61-year-old Caucasian male without any significant past history presented to his physician with swelling of his hands and feet, progressive dyspnoea and weight gain in excess of 10 kg in the week prior to admission. He also noted decreased frequency and quantity of urine during this period. He denied any chest pain or symptoms of cerebral or peripheral vascular disease. He reported no ingestion of nephrotoxic agents, no preceding history of sore throat, arthralgias, myalgias, skin rashes, nasal symptoms, haemoptysis, haematuria or dysuria. The patient denied a history of tobacco use. The physical examination indicated a blood pressure of 166/80 mmHg, heart rate of 90 and respiratory rate of 16/min. There were no skin lesions or lymphadenopathy, and all pulses were palpable. There was 3 pitting pedal oedema to the upper thighs and periorbital oedema. Other than decreased breath sounds at lung bases, the remainder of the physical examination was unremarkable. On admission, his plasma creatinine (PCr) was 645 mmol/l (7.3 mg/dl) with a BUN of 39 mmol/l (110 mg/dl). His serum electrolytes, calcium, phosphorus and magnesium were within normal limits. His urinalysis at presentation had a specific gravity of 1.020, pH of 5.5, 2025 white blood cells (WBCs), 1520 red blood cells, and distinct red blood cell and haemoglobin casts. The haematology panel included WBCs, 11 000/mm3 (20% lymphocytes, 7.4% monocytes, 68% granulocytes and 4% eosinophils), haematocrit of 37% and normal red cell morphology. Arterial blood gases revealed pH 7.46, pCO2 33.5 mmHg and pO2 75.9 mmHg. A renal sonogram on admission showed normal echogenicity and no hydronephrosis. The linear dimensions of the kidneys were as follows: (i) longitudinal renal length of 12.2 cm (right) and 12.5 cm (left); (ii) anterio-posterior thickness at mid-section of 5 cm (right) and 5.5 cm (left); and (iii) transverse length of 3 cm bilaterally. The plasma albumin concentration was 18 g/l and low-density lipoprotein (LDL) was 6.47 mmol/l (250 mg/dl). A 24 h urine collection with a Foley catheter showed 9.8 g of protein and a creatinine clearance (ClCr) of 9 ml/min. Serum protein electrophoresis indicated hypoalbuminaemia, and urine protein electrophoresis showed primarily albuminuria. A complete serological work-up (rheumatoid factor, anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, hepatitis B and C panel, anti-glomerular basement membrane antibody, human immunodeficiency virus, RPR, cryoglobulins, and complements C3 and C4) was negative. A percutaneous renal biopsy was performed the morning after admission and it included a total of 17 glomeruli, two of which were globally sclerosed. The remaining glomeruli were normal in appearance on light microscopy without focal or segmental sclerosis and with normal vasculature. No evidence of interstitial oedema, interstitial infiltrate or tubular necrosis was observed. Immunofluorescence was negative (not shown). Ultrastructural examination showed large areas of visceral epithelial foot process effacement without evidence of immune deposits. A diagnosis of minimal change disease with acute renal failure was made and treatment with 2 mg/kg of prednisone per day was initiated. Over the week following admission, PCr progressed to 981 mmol/l (11.1 mg/dl), and the volume overload progressed despite salt restriction. High-dose intravenous diuretic therapy was basically ineffective. Haemodialysis was initiated on day 7 of hospitalization. The patient required a net negative 16 l of ultrafiltration before he was clinically deemed to have achieved dry weight. A repeat sonogram obtained after the patient achieved his dry weight showed that the kidneys were exactly the same size as before ultrafiltration with normal echogenicity. Haemodialysis was continued for a total of 6 weeks. The proteinuria and renal function both improved after 56 weeks of prednisone therapy. At the time of discontinuation of haemodialysis, the endogenous ClCr was 31 ml/min (Figure 1). The prednisone was gradually tapered over a period of 1 year. At the time steroids were discontinued, the patient had a PCr of 115 mmol/l (1.3 mg/dl), a 24 h urine (...truncated)