A consideration of the hormonal basis and phosphate leak hypothesis of absorptive hypercalciuria

Fifty patients with absorptive hypercalciuria (AH), 25 normal subjects (NS), and 25 nonhypercalciuric patients with stone disease (NHSF) were studied using an oral calcium tolerance test and 24-h urine collections on both a restricted and an unrestricted calcium intake. Mean (+/- SD) fasting fractional calcium excretion was increased in the patients with AH (2.7 +/- 1.1% vs. 1.4 +/- 0.6% in the NS; P less than 0.001) and was negatively correlated with fasting nephrogenous cAMP, suggesting that this renal calcium leak was secondary to parathyroid suppression. Plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] was elevated in 80% of patients with AH and was high normal in the remaining 20%. Ten patients, selected on the basis of results for 1,25-(OH)2D greater than 4 SD from the normal mean, displayed a particularly severe pattern of abnormalities, including mild hypercalcemia in two patients. Pooled data from the NS and patients with AH revealed a significant negative correlation between the plasma concentration of 1,25-(OH)2D and the renal phosphate threshold (r = -0.40; P less than 0.001), but this correlation lost significance when the NHSF were substituted for the NS as a control group (r = -0.07; P = NS). These findings 1) provide a pathophysiological basis for the increase in fasting calcium excretion commonly observed in hypercalciuric patients, and 2) stress the importance of circulating 1,25-(OH)2D in the pathogenesis of the syndrome, but 3) fail to support the phosphate leak theory of pathogenesis.