This proposal focuses on abnormalities of the PTH-1,25-(OH)2D axis which form the basis of two important hypercalciuric syndromes, absorptive hypercalciuria and primary hyperparathyroidism. Previous studies have provided a reasonably clear picture of the key pathophysiological features of each syndrome, such that the present proposal represents a number of new initiatives designed to pinpoint primary pathogenetic mechanisms. Preliminary data are presented which indicate that the techniques and study designs involved in these initiatives are sound and that the proposed studies should generate basic information concerning the fundamental basis of each syndrome.
The specific aims of the proposal include: 1) an infusion equilibrium study of 1,25-(OH)2D clearance and production in normal subjects and patients with absorptive hypercalciuria, in order to a) clarify existing disagreement concerning normal 1,25-(OH)2D kinetics and b) examine the basis of the increased circulating 1,25-(OH)2D observed in absorptive hypercalciuria, which is in our experience almost uniformly a 1,25-(OH)2D-mediated syndrome, 2) further investigation of the striking influence of an acute (days) increase in calcium intake on the production and/or clearance of 1,25-(OH)2D in patients with absorptive hypercalciuria, as well as the apparent """"""""escape"""""""" phenomenon which is observed when an unrestricted calcium intake is maintained for a longer period (weeks), 3) the testing of a specific hypothesis concerning the pathogenesis of absorptive hypercalciuria, this being that the syndrome has as its basis a proximal tubular hypersensitivity to the effects of PTH, 4) further investigation of the disordered control of 1,25-(OH)2D metabolism in absorptive hypercalciuria by examining the effects of short-term phosphorous deprivation, 5) an examination of skeletal participation and/or involvement in 1,25-(OH)2D-mediated hypercalciuria, 6) further study of the marked and unexpected sensitivity of the PTH-1,25-(OH)2D axis to net calcium absorption in patients with primary hyperparathyroidism, with emphasis on longer term studies (weeks), and 7) an examination of both kinetic and production rate hypotheses as explanations(s) for the fourfold range of values for circulating 1,25-(OH)2D observed in untreated patients with primary hyperparathyroidism.
