A B S T R A C T The causes for the hypercalciuria and diagnostic criteria for the various forms of hypercalciuria were sought in 56 patients with hypercalcemia or nephrolithiasis (Ca stones), by a careful assessment of parathyroid function and calcium metabolism. A study protocol for the evaluation of hypercalciuria, based on a constant liquid synthetic diet, was developed. In 26 cases of primary hyperparathyroidism, characteristic features were: hypercalcemia, high urinary cyclic AMP (cAMP, 8.58+3.63 SD gmol/g creatinine; normal, 4.02±0.70 umol/g creatinine), high immunoreactive serum parathyroid hormone (PTH), hypercalciuria, the urinary Ca exceeding absorbed Ca from intestinal tract (CaA), high fasting urinary Ca (0.2 mg/mg creatinine or greater), and low bone density by 'I photon absorption. The results suggest that hypercalciuria is partly secondary to an excessive skeletal resorption (resorptive hypercalciuria). The 22 cases with renal stones had normocalcemia, hypercalciuria, intestinal hyperabsorption of calcium, normal or low serum PTH and urinary cAMP, normal fasting urinary Ca, and normal bone density. Since their CaA exceeded urinary Ca, the hypercalciuria probably resulted from an intestinal hyperabsorption of Ca (absorptive hypercalciuria). The primacy of intestinal Ca hyperabsorption was confirmed by responses to Ca load and deprivation under a metabolic dietary regimen. During a Ca load of 1,700 mg/day, there was an exaggerated increase in the renal excretion.of Ca and a suppression of cAMP excretion. The urinary Ca of 453±+154 SD mg/day was significantly higher than the control group's 211+42 mg/ day. The urinary cAMP of 2.26±0.56 umol/g creatinine was significantly lower than in the control group. In contrast, when the intestinal absorption of calcium was limited by cellulose phosphate, the hvpercalciuria was kc'ceiz(l for plblicatifn 9 July 1073 and in rezxsed form 11 September 1973. corrected and the suppressed renal excretion of cAMP returned towards normal. Two cases with renal stones had normocalcemia, hypercalciuria, and high urinary cAMP or serum PTH. Since CaA was less than urinary Ca, the hypercalciuria may have been secondary to an impaired renal tubular reabsorption of Ca (renal hypercalciuria). Six cases with renal stones had normal values of serum Ca, urinary Ca, urinary cAMP, and serum PTH (normocalciuric nephrolithiasis). Their CaA exceeded urinal Ca, and fasting urinary Ca and bone density were normal. The results support the proposed mechanisms for the hypercalciuria and provide reliable diagnostic criteria for the various forms of hypercalciuria.
SynopsisThe activity of an enzyme preferentially hydrolyzing parathyroid hormone in rat kidney homogenate was evaluated at various levels of parathyroid hormone activity and calcium metabolism.Transient hypercalcemia, hypocalcemia, increase and absence of parathyroid hormone for a short duration did not influence the enzyme activity. However, the enzyme activity showed a slight but significant decrease in parathyrordectomized rat in which sustained hypocalcemia was produced for 8 days. Hypercalcemia induced by the administration of dihydrotachysterol for 4 weeks provoked an increase in the enzyme activity.Following the reports by Orimo et al. (1965a, b) on the enzymatic inactivation of parathyroid hormone (PTH) by rat kidney slices, the nature of such inactivation has been gradually clarified through enzymological approach (Fujita et al., 1969;Maruyama et al., 1970;Fujita et al., 1970). However, the physiological significance in vivo of such enzymes in rat kidney preferentially, hydrolyzing parathyroid hormone (PTH ase) has scarcely been studied. In the present study, attempts were made to elucidate the role of these enzymes in the control of calcium homeostasis by studying the enzyme activity of the kidney at various states of altered calcium metabolism. Matetrials and MethodsAssay of PTH'ase Labelling of PTH with125 I was carried out according to Hunter and Greenwood (1962). The assay of PTH'ase was performed at pH8.5 as described by Fujita et al. (1969), except for the amount of carrier TCH-PTH which was different in each experiment. Protein was determined by the Lowry's method (Lowry et al., 1951). Experiment 1 (a) Eight male Wistar rats of about 150g body weight were parathyroidectomized by hot wire cautery and maintained on Oriental rat chow and water ad libitum. The animals were sacrificed at 24 hr and 72 hr after the operation, while four intact rats were sacrified on the day of the operation to serve as controls. The bilateral kidneys were removed and immediately homogenized in 0.15 M KCl with a Waring blendor to make 5% homogenate. Experiment 1 (b) Nine male Wistar rats weighing approximatly 200 g were divided into two groups. The animals of one group were parathyroidectomized, while those of the other group were sham-operated at the same time. Fhey were sacrificed at 8 days after the operation and blood samples and the right kidneys were obtained for the determination of serum calcium and PTH'ase activity (using 90 min incubation). Experiment 2Ten male Wistar rats of about 200g body weight were divided into two equal groups. One group was injected intraperitoneally with 1ml/100g b.w. of 0.11 M CaCl2 every two hr to produce hypercalcemia, while normal saline was injected to control animals. At 6hr after the first injection, the animals of both groups were sacrificed and the right kidneys were removed for the assay of PTH'ase activity.
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