A test of the hypothesis that the collecting duct calcium-sensing receptor limits rise of urine calcium molarity in hypercalciuric calcium kidney stone formers

Abstract

The process of kidney stone formation depends on an imbalance between excretion of water and insoluble stone-forming salts, leading to high concentrations that supersaturate urine and inner medullary collecting duct (IMCD) fluid. For common calcium-containing stones, a critical mechanism that has been proposed for integrating water and calcium salt excretions is activation of the cell surface calcium-sensing receptor (CaSR) on the apical membranes of IMCD cells. High deliveries of calcium into the IMCD would be predicted to activate CaSR, leading to reduced membrane abundance of aquaporin-2, thereby limiting water conservation and protecting against stone formation. We have tested this hypothesis in 16 idiopathic hypercalciuric calcium stone formers and 14 matched normal men and women in the General Clinical Research Center. Subjects were fed identical diets; we collected 14 urine samples at 1-h intervals during a single study day, and one sample overnight. Hypercalciuria did not increase urine volume, so urine calcium molarity and supersaturation with respect to calcium oxalate and calcium phosphate rose proportionately to calcium excretion. Thus CaSR modulation of urine volume via IMCD CaSR activation does not appear to be an important mechanism of protection against stone formation. The overnight period, one of maximal water conservation, was a time of maximal stone risk and perhaps a target of specific clinical intervention.

Fig. 1.

Estimated vs. measured urine osmolality. Estimated urine osmolality (U_OSM = [Na]·2 + [K]·2 + [NH₄]·2 + [Ca]·2.5 + [Mg]·3 + urea) was plotted against osmolality measured in the same urine samples. Diagonal line is the line of identity. Estimated results correlated well with measured values (r² = 0.99, P < 0.001).

Fig. 2.

Determinants of supersaturation throughout the day. Hourly excretions of calcium (top left), oxalate (top middle), phosphorus (top right), magnesium (bottom left), citrate (bottom middle), and sodium (bottom right) are shown fasting and in the periods from breakfast to lunch (B to L), lunch to supper (L to S), supper to the end of the protocol (S to H) and overnight (ON). Cross-hatched bars, normal subjects (N); gray bars, stone formers with idiopathic hypercalciuria (IHSF). Values are means ± SE, adjusted for repeated measures. Significant differences between IHSF and N by time period: *P < 0.001, #P < 0.01, †P < 0.05.

Fig. 3.

Urine supersaturation for calcium oxalate (CaOx) and calcium phosphate (CaP) throughout the day. CaOx supersaturation (SS; top right) and CaP SS (bottom right) are shown during fasting and in the periods from B to L, L to S, S to H, and ON. Horizontal lines indicate SS of 1. Concentrations of urine calcium (top left) and oxalate (top middle), as well as urine pH (bottom left) and urine flow rate (bottom middle), during the same periods are indicated. Cross-hatched bars, N; gray bars, IHSF. Values are means ± SE adjusted for repeated measures. Significant differences between IHSF and N by time period: *P < 0.001, #P < 0.01, †P < 0.05.

Fig. 4.

Urine osmolality throughout the day. Estimated osmolar excretion (left) and estimated urine osmolality (right) are shown fasting and in the periods B to L, L to S, S to H, and ON. Cross-hatched bars, N; gray bars, IHSF. Values are means ± SE, adjusted for repeated measures.