Pathophysiological Studies in Idiopathic Hypercalciuria: Use of an Oral Calcium Tolerance Test to Characterize Distinctive Hypercalciuric Subgroups*

Abstract

Twenty-one unselected patients with recurrent nephrolithiasis and normocalcemic hypercalciuria with or without hypophosphatemia and 18 normal subjects were studied with an oral calcium tolerance test and for 3- to 5-day periods while consuming a lownormal (400 mg) and high-normal (1000 mg) calcium intake. The oral calcium tolerance test consisted of the measurement of the calcemic, calciuric, and parathyroid (assessed by determinations of serum immunoreactive parathyroid hormone and nephrogenous cAMP) responses to acute 1000- or 350-mg doses of calcium. Nineteen patients displayed normal results for basal serum calcium, parathyroid function, and fasting calcium excretion, and striking calcemic (mean increase in serum calcium, 0.9 us. 0.2 mg/dl in the normal subjects) and calciuric (mean increase in urinary calcium, 0.33 vs. 0.15 mg calcium/100 ml GF in the normal subjects) responses to the 1000-mg calcium tolerance test, associated with a mean 54% suppression in nephrogenous cAMP. These patients were operationally defined as having “absorptive” hypercalciuria. The variable occurrence of hypophosphatemia in this group suggested that the pathogenesis of “absorptive” hypercalciuria may be complex and/or multifactorial. There were strong positive correlations between the calciuric response to the calcium tolerance test and fractional isotopic calcium absorption (r = 0.75, P < 0.001), the calcemic responses to the test (r = 0.71, P < 0.001) and the calciuric responses noted on the 1000- vs. the 400-mg daily calcium intake (r = 0.78, P < 0.001). Two patients displayed low or low normal basal serum calcium, increased parathyroid function, increased fasting calcium excretion, and a striking calciuric but minimal calcemic response to the 1000-mg calcium tolerance test, associated with a moderate suppression in nephrogenous cAMP. These patients were operationally defined as having "renal" hypercalciuria. Several lines of evidence indicated that the hyperparathyroidism in these patients was physiological or secondary, including the near normalization of parathyroid function on the daily 1000-mg calcium intake. A steep slope of calcium excretion on calcium intake (due to increased calcium absorption) was noted in all hypercalciuric patients and accounted for the significantly improved diagnostic accuracy of screening patients for hypercalciuria on the high-normal calcium intake. The simple measurement of total cAMP excretion (nanomoles per 100 ml GF) and urinary calcium on the 1000-mg daily calcium intake seemed to provide reliable separation of patients with "renal" from those with "absorptive" hypercalciuria. A physiological (350 mg) dose of oral calcium produced a 30% suppression of nephrogenous cAMP in normal subjects; this suggests that dietary calcium exerts an important control of parathyroid function under physiological circumstances.