Islet cell damage associated with tacrolimus and cyclosporine: Morphological features in pancreas allograft biopsies and clinical correlation

Background. The introduction of the potent immunosuppressive drugs tacrolim us (FK) and cyclosporine (CSA) has markedly improved the outcome of solid o rgan transplantation. However, these drugs can cause posttransplantation di abetes mellitus. Abnormalities in the glucose metabolism are of particular significance in pancreas transplantation. Methods. We studied 26 pancreas allograft biopsies, performed 1-8 months po sttransplantation, from 20 simultaneous kidney-pancreas transplant recipien ts, randomized to receive either FK or CSA. The biopsies were studied by li ght microscopy, immunoperoxidase stains for insulin and glucagon, in situ D NA-end labeling for detection of apoptosis, and electron microscopy, The is let morphology was correlated with the mean and peak levels of CSA and FK i n serum, with corticosteroid administration and with glycemia, Results. On light microscopy cytoplasmic swelling, vacuolization, apoptosis , and abnormal immunostaining for insulin were seen in biopsies from patien ts receiving either FK or CSA. The islet cell damage was more frequent and severe in the group receiving FK than in the group receiving CSA (10/13 and 5/13, respectively) but the differences were not statistically significant . Significant correlation was seen between the presence of islet cell damag e and serum levels of CSA or FK during the 15 days previous to the biopsy, as well as with the peak level of FK, Toxic levels of CSA or FK and adminis tration of pulse steroids were associated with hyperglycemia when these occ urred concurrently (P = 0.005), Toxic levels of CSA or FK by themselves wer e associated with hyperglycemia in a minority of cases (8 and 26%, respecti vely), Electron microscopy showed cytoplasmic swelling and vacuolization, a nd marked decrease or absence of dense-core secretory granules in beta cell s; the changes were more pronounced in patients on FK, Serial biopsies from two hyperglycemic patients receiving FK and evidence of islet cell damage demonstrated reversibility of the damage when EE was discontinued. Conclusions. The structural damage to beta cells demonstrated in this study is similar to morphological and functional abnormalities previously descri bed in experimental animal models and can at least partially account for th e glucose metabolism abnormalities seen in patients receiving these drugs. Toxic levels of CSA or FK and higher steroid doses potentiate each others' diabetogenic effects.