Reversal of Mesangial Enlargement in Rats With Long-standing Diabetes by Whole Pancreas Transplantation

Abstract

An important unanswered question about clinical use of pancreas transplantation is: can pancreas transplants reverse or, at least, stabilize well-established lesions of insulin-dependent diabetes mellitus (IDDM)? To answer this question, we performed whole pancreas transplantations in 190 highly inbred rats 6, 9,12,15,18, and 21 mo after induction of diabetes mellitus (DM) with alloxan. We then studied the effect on renal mesangial enlargement (ME) for 24 mo after onset of DM by a quantitative morphologic technique in which camera lucida tracings of the mesangium were made at × 1250 and were analyzed using an electronic planimeter connected to a calculator/computer. A pretransplant kidney biopsy was obtained so that the rats served as their own controls. In addition, studies were performed for 28 mo in 57 untreated diabetic controls and in 55 nondiabetic controls. Monthly metabolic studies showed that whole pancreas transplantation maintained very tight, lifelong metabolic control of diabetes. Kidney sections obtained for 2 yr from diabetic controls and for 21 mo from diabetic rats before transplantation showed highly significant increases in total mesangial area, nuclear-free mesangial area, and percentage of glomerular area occupied by nuclear-free mesangial area. Pancreas transplantation consistently produced a highly significant reversal of well-established ME, regardless of when it was performed. In most instances, the mesangial area was reduced to a size smaller than that measured at 6 mo. ME, one of the hallmark lesions of diabetic glomerulosclerosis, was selected as the target lesion on which to test the effectiveness of pancreas transplantation because kidney disease is a very important cause of mortality and morbidity in IDDM, and because there is a striking similarity between diabetic kidney lesions of rats and those of humans. Our results demonstrate that whole pancreas transplants are very capable of reversing one of the main lesions of well-established diabetic nephropathy.