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Proteinuric Nephropathy in Acquired and Congenital Generalized Lipodystrophy: Baseline Characteristics and Course during Recombinant Leptin Therapy

National Institute of Diabetes and Digestive and Kidney Diseases (E.D.J., S.A.M., J.R.Y., E.K.C., E.A.O., J.E.B., P.G.), National Institutes of Health, Bethesda, Maryland 20892; Amgen (A.M.D.), Thousand Oaks, California 91320; Department of Pediatrics (M.A.T., P.R.B.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104; and Department of Medicine (D.B.S., S.O.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: Edward D. Javor, 10 Center Drive, Room 8D20, Bethesda, Maryland 20892-1770. E-mail: edwardj{at}intra.niddk.nih.gov.

Generalized lipodystrophy is characterized by adipose tissue absence, hypoleptinemia, hypertriglyceridemia, insulin resistance, diabetes, hepatomegaly, and nonalcoholic steatohepatitis. In the course of recruiting patients for treatment with recombinant leptin, we were struck by the frequency and severity of proteinuria. We evaluated 25 patients with generalized lipodystrophy. Eighteen were treated with recombinant leptin, and we have followed 15 on leptin for 4–36 months. We followed renal parameters at baseline and during follow-up visits. Renal biopsies were performed as clinically indicated. At baseline, 22 of 25 patients (88%) had elevated urine albumin excretion (>30 mg/24 h), 15 (60%) had macroalbuminuria (>300 mg/24 h), and five (20%) had nephrotic-range proteinuria (>3500 mg/24 h). Twenty-three (92%) had elevated creatinine clearance (>125 ml/min·1.73 m²). Eleven of 15 patients (73%) treated with recombinant leptin exhibited reduction in proteinuria, associated with reduction of hyperfiltration. Four patients who did not improve are discussed individually. Renal biopsy findings were remarkable for focal segmental glomerulosclerosis in four patients, membranoproliferative glomerulonephritis in two patients, and diabetic nephropathy in one patient. In conclusion, generalized lipodystrophy is associated with proteinuria and unique renal pathologies, including focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis. The majority treated with recombinant leptin demonstrated reduction in proteinuria and hyperfiltration.

Abbreviations: AGL, Acquired generalized lipodystrophy; CGL, congenital generalized lipodystrophy; FSGS, focal segmental glomerulosclerosis; HbA1c, glycosylated hemoglobin; MPGN, membranoproliferative glomerulonephritis.

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