MECHANISM OF DECREASED CALCITRIOL DEGRADATION IN RENAL-FAILURE

Metabolic clearance rate (MCR) of calcitriol is decreased in renal failure, and uremic toxins play a major role in the suppression of calcitriol degradation. In this experiment, we studied the effect of uremic toxins on renal 24- and 26-hydroxylase (HX) activities. Normal rats were infused for 20 h with 30 ml of normal or uremic plasma ultrafiltrates. At the end of infusion, renal enzymes activities were measured by the generations of 1,24,25- and 1,25,26-trihydroxyvitamin D3 10 min after the addition of 25 nM or 1-mu-M calcitriol. Renal 24-HX activity decreased approximately 50%, whereas 26-HX activity did not decrease in rats infused with uremic plasma ultrafiltrate. The induction of 24-HX activity by 100 ng calcitriol also decreased in rats infused with uremic ultrafiltrate. To examine whether uremic ultrafiltrate could directly inhibit the degradation enzymes, 24- and 26-HX activities were measured in kidney homogenates preincubated for 3 h with either normal or uremic ultrafiltrate. Uremic ultrafiltrate did not directly suppress 24- and 26-HX activities. Furthermore, the disappearance rate of calcitriol was similar for 90 min in kidney homogenates after they were preincubated for 3 h with uremic and normal ultrafiltrates. Because 24-HX synthesis is induced by the calcitriol-receptor complex binding to nuclear chromatin and activating genes coding for the enzyme, we studied the effect of uremic toxins on the binding affinity of calcitriol-receptor complex for DNA-cellulose. Uremic ultrafiltrate significantly reduced the binding affinity of the hormone receptor complex for DNA when the receptor was preincubated with the ultrafiltrate for 3 h. We conclude that uremic toxins suppress genomic synthesis of 24-HX, perhaps via a receptor-mediated process, thereby reducing the MCR of calcitriol.