Enlarged nephrons and severe nondiabetic nephropathy in hepatocyte nuclear factor-1beta (HNF-1beta) mutation carriers.

BACKGROUND: Mutations in hepatocyte nuclear factor-1beta (HNF-1beta) lead to a syndrome with diabetes and urogenital malformations [maturity onset of diabetes of the young, type 5 (MODY5)]. The aim of this study was to perform a clinicopathologic investigation of the renal disease in members of a Norwegian family with the HNF-1beta mutation R137-K161del.

METHODS: The study was based on long-term clinical observations of five mutation carriers, combined with renal biopsies from four of these. The biopsies were examined by light microscopy, immunohistochemistry, and transmission electron microscopy. The diameter of the glomerulus, proximal and distal tubules, in addition to thickness of the glomerular basement membrane (GBM), were measured in light microscopic slides and transmission electron micrographs. The results were compared with biopsies from adult patients with diabetic glomerulopathy, glomerulonephritis, and/or benign nephrosclerosis, and children with minimal-change glomerulopathy or glomerulonephritis, respectively.

RESULTS: Clinically, there was a wide intrafamilial variation from stable or slightly increasing serum creatinine to progressive renal failure and end-stage renal disease (ESRD). In all cases, the kidney disease was diagnosed prior to diabetes. Hypertrophy of the proximal and distal tubules as well as enlarged glomeruli were found in three of four mutation carriers. Essentially normal nephrons were found in the 10-year-old boy. The thickness of the GBM was considered near normal in all mutation carriers. Oligomeganephronia was found in one patient.

CONCLUSION: Histopathologic and morphometric studies of kidney biopsies from four carriers of an HNF-1beta mutation revealed enlarged glomeruli and tubular structures. Long-term clinical follow-up demonstrated that the renal disease developed prior to and independently of diabetes. Finally, there is a wide phenotypic variation of the renal disease caused by HNF-1beta mutations.