Mechanism of urinary calcium regulation by urinary magnesium and pH

Abstract

Urinary magnesium and pH are known to modulate urinary calcium excretion, but the mechanisms underlying these relationships are unknown. In this study, the data from 17 clinical trials in which urinary magnesium and pH were pharmacologically manipulated were analyzed, and it was found that the change in urinary calcium excretion is directly proportional to the change in magnesium excretion and inversely proportional to the change in urine pH; a regression equation was generated to relate these variables (R(2) = 0.58). For further exploration of these relationships, intravenous calcium chloride, magnesium chloride, or vehicle was administered to rats. Magnesium infusion significantly increased urinary calcium excretion (normalized to urinary creatinine), but calcium infusion did not affect magnesium excretion. Parathyroidectomy did not prevent this magnesium-induced hypercalciuria. The effect of magnesium loading on calciuria was still observed after treatment with furosemide, which disrupts calcium and magnesium absorption in the thick ascending limb, suggesting that the effect may be mediated by the distal nephron. The calcium channel TRPV5, normally present in the distal tubule, was expressed in Xenopus oocytes. Calcium uptake by TRPV5 was directly inhibited by magnesium and low pH. In summary, these data are compatible with the hypothesis that urinary magnesium directly inhibits renal calcium absorption, which can be negated by high luminal pH, and that this regulation likely takes place in the distal tubule.

Figure 1.

Three-dimensional representation of the simultaneous effect of various treatments on urinary pH, magnesiuria, and calciuria. Studies involving treatment by magnesium oxide or citrate (gray circles), potassium bicarbonate or citrate (black squares), or magnesium potassium citrate (white triangles) are plotted to three variables: Change of urinary pH, calcium, and magnesium between values before and after treatment. The change in urinary calcium can be numerically fitted into the equation ΔU_calcium × V = 0.70 + 0.26 × (ΔU_magnesium× V) − 2.06 × ΔU_pH. The R² for the regression was 0.58.

Figure 2.

Perfusion of MgCl₂, CaCl₂, or vehicle in normal or PTX rats: Effect on calcium-creatinine and magnesium-creatinine ratios. Normal rats (A through C) or PTX rats (D through F) received an intravenous load of 20 μmol/100 g body weight MgCl₂ (A and D) or CaCl₂ (B and E) or an equivalent volume of 0.45% NaCl (vehicle; C and F) in 1 h. Urine was collected by 30-min periods and analyzed for calcium, magnesium, and creatinine. Results are reported as calcium-creatinine (▴) or magnesium-creatinine (•) ratio related to the baseline value. Each point represents the mean ± SEM of values obtained from three to eight rats.

Figure 3.

Effect of furosemide on magnesium-induced calciuria. Normal rats (A and B) or PTX rats (C and D) were administered a unique bolus of 10 mg/kg furosemide immediately before starting to receive an intravenous load of 20 μmol/100 g body weight MgCl₂ in 1 h. Urine was collected by 30-min periods and analyzed for calcium, magnesium, and creatinine. Results are presented as calcium-creatinine ratio of rats treated (gray triangles) or not (black triangles) with furosemide or as magnesium-creatinine ratio of rats that were treated (gray dots) or not (black dots) with furosemide, related to the baseline value. Each point represents the mean ± SEM of values obtained from four to five rats.

Figure 4.

Magnesium concentration and pH modulate ⁴⁵calcium uptake in oocytes expressing TRPV5. X. laevis oocytes were injected with TRPV5 cRNA and subjected to ⁴⁵calcium uptake assay with the uptake solution containing 1 to 10 mM MgCl₂ at pH 5 or 8, as indicated. The results are presented as mean ± SEM of three different experiments with a total of 28 to 35 oocytes per condition and are related to 1 mM MgCl₂ and pH 5.