The present study is designed to study the effects of renal transplantation on the regulation of vitamin D metabolism. Abnormal vitamin D metabolism and calcium homeostasis are invariable concomitants of end stage renal failure. While renal transplantation generally results in improved vitamin D/calcium metabolism, insufficient data are available to assess if normal function ensues. Indeed, complications which often manifest, and therapy employed, post-transplantation have precluded controlled evaluation of 1,25(OH)2D production. However, defective regulation of vitamin D metabolism may underlie many of the metabolic abnormalities exhibited by patients with renal transplants. We plan to employ a rat model system of renal transplantation to initiate controlled investigation of renal 25(OH)D-1yield(and 24R)-hydroxylase activity. Initially, the effects of organ preservation methods, tubular necrosis and immunosuppressive drug therapy on vitamin D metabolism will be examined in ACI rats with renal isografts. The circulating concentration of vitamin D metabolites before and after hormonal and/or metabolic pertubation which normally affect the production of 1,25(OH)2D3 [and24,25(OH)2D3] will be examined in transplanted rats treated or untreated and bearing organs subjected to various methods of preservation. In addition, we will directly assay 25(OH)D-1yield(and 24R)-hydroxylase activity in the transplanted kidney to determine whether hormonal/metabolic regulation of vitamin D metabolism is normal. In complementary studies we will examine the effects of rejection on maintenance of 1,25(OH)2D production. Using PVGI kidneys transplanted to PVG rats, we will assess the time course effects of mild chronic rejection on vitamin D metabolism. We will also examine whether immunosuppressive drugs successfully interrupt the potential adverse effects of rejection on 1,25(OH)2D production. Our studies should provide important data relative to the adequacy of vitamin D metabolism post renal transplantation and provide insight into the pathophysiology and therapy of many metabolic abnormalities common to patients with renal allografts.
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