Thirty-six renal transplant biopsies were obtained from 20 diabetic patients 1-6.5 years after successful combined pancreatic and renal transplantation (PKtx). An additional 36 renal transplant biopsies were obtained from 30 diabetic recipients 1-6.8 years after kidney transplantation only (Ktx). Light microscopic lesions indicating diabetic nephropathy were evaluated by a semiquantitative score ranging from 0 to 9. Within 2.5 years after transplantation, light microscopy showed no or only slight diabetic changes in both groups (nephropathy score = 0-2). Later, a nephropathy score > or = 3 was seen in only 1 of 15 biopsies (6.7%) in the combined PKtx group, but in 11 of 24 biopsies (45.8%) in the Ktx group (P < 0.05). Twenty-eight of the biopsies from the PKtx group and 26 of them from the Ktx patients were examined with electron microscopic morphometry to evaluate the glomerular basement membrane thickness (BMT) and the relative volume of the mesangial tissue (Vv). Of the biopsies taken < 2 1/2 years after transplantation in PKtx patients, and of those similarly taken in the Ktx patients, 93.8% vs. 88.9% had BMT values within 2 SD of the normal (NS). Of the kidney biopsies taken > or = 2.5 years after transplantation, 91.7% in the PKtx group still had a normal BMT, while only 35.3% of the biopsies in the Ktx group had a normal BMT (P < 0.01). In the PKtx group, the Vv was normal in 12/16 (75.0%) of the biopsies taken < 2 1/2 years after transplantation, and in 9/11 (81.8%) of the biopsies obtained > or = 2.5 years after transplantation. In contrast, the Vv was normal in only 1/9 (11.1%) and 2/17 (11.8%) of correspondingly obtained biopsies from Ktx patients (biopsies < 2.5 years after transplantation, P < 0.01, and biopsies > or = 2.5 years after transplantation, P < 0.001, respectively). We conclude that a functioning pancreatic transplant can prevent or reduce the various signs of diabetic nephropathy that eventually develop in diabetic patients with a kidney graft only.