ISLET CELL DAMAGE ASSOCIATED WITH TACROLIMUS AND CYCLOSPORINE. MORPHOLOGICAL FEATURES IN PANCREAS ALLOGRAFT BIOPSIES AND CLINICAL CORRELATION

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810 The introduction of tacrolimus (FK) and cyclosporine (CSA) has markedly improved the outcome of solid organ transplantation. These drugs can cause, however, post-transplantation diabetes mellitus. Abnormalities in the glucose metabolism are of particular significance in pancreas transplantation. We studied 26 pancreas allograft biopsies, performed 1-8 months post-transplantation, from 20 SPK transplant recipients, randomized to receive either FK or CSA (10 patients each group). The biopsies were studied with H&E stain, immunoperoxidase stains for insulin and glucagon, in-situ DNA-end labeling for detection of apoptosis, and electron microscopy. The islet morphology was correlated with the mean and peak levels of CSA and FK in serum, with corticosteroid administration and with glycemia. On light microscopy cytoplasmic swelling, vacuolization, apoptosis and decreased immunostaining for insulin were seen in biopsies from patients receiving either FK or CSA. All the morphological features were 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 and degree of islet cell damage and serum levels of CSA or FK during the 15 days previous to the biopsy (p.045), as well as with the peak level of FK(p.04). Toxic levels of either CSA or FK and concurrent administration of pulse steroids were associated with hyperglycemia to a significant degree (p.005). Toxic levels of CSA or FK by themselves were associated with hyperglycemia in a minority of cases (8% and 26% respectively). Electron microscopy showed cytoplasmic swelling and vacuolization, and decrease or absence of endocrine secretory granules in beta cells; the changes were more pronounced in patients on FK. Serial biopsies from 2 hyperglycemic patients receiving FK and evidence of islet cell damage on biopsies, demonstrated reversibility of the damage when FK was discontinued. The structural damage to beta cells demonstrated in this study is similar to morphological abnormalities described in animals studies and can at least in part account for the hyperglycemia seen in patients receiving these drugs. Toxic levels of CSA or FK and higher steroid doses potentate each others' diabetogenic effects.