Renal Ca Handling Research Articles

Serial Follow-Up Study on Renal Handling of Calcium and Phosphorus After Soil Replacement in Cd-Polluted Rice Paddies Estimated Using a General Linear Mixed Model

A 10-year follow-up study was conducted to investigate the effects of renal handling of calcium (Ca) and phosphorus (P) after the removal of cadmium-polluted soil in rice paddies and replacing it with nonpolluted soil. Using a general linear mixed model, serial changes of Ca and P concentrations in urine and serum (Ca-U/S, P-U/S), fractional excretion of Ca (FECa), and percent tubular reabsorption of P (%TRP) were determined in 37 persons requiring observation in the Cd-polluted Kakehashi River Basin, Japan. Ca-U and Ca-S remained within the normal range in both sexes. FECa in men returned to the normal level within 3.3 years from the completion of soil replacement. Overall, it is suggested that the renal handling of Ca showed no or only a slight change throughout the observation period in both sexes. P-U decreased gradually. P-S showed lower than normal values in the men and values at the lower end of the normal range in women, although the values recovered gradually to normal. %TRP values remained low throughout the observation period and the values did not recover in either sex. However, the results of P-U and P-S suggested that the renal handling of P may recover after the completion of soil replacement.

Ethnic Differences in Renal Responses to Furosemide

Blacks have a greater tendency to retain Na than whites. The present study sought evidence for ethnic differences in parameters reflective of Na uptake by the Na,K,2Cl cotransporter in the thick ascending limb, namely, the urine concentration and urinary excretion of certain cations before and after furosemide administration (40 mg IV). Subjects were healthy (ages 18 to 36 years). During the preceding overnight period, urine volume was lower, and osmolality was higher in blacks than in whites, an ethnic difference that disappeared when water intake was restricted to infused normal saline (60 mL/h). Plasma vasopressin levels were higher in black males than in other sex/ethnic groups. Baseline urinary excretion rates of K, Ca, and Mg were significantly lower in blacks than in whites. After furosemide (0 to 1 hour), K and Ca excretion rates increased, but the proportionate ethnic difference decreased from 44% to 22% and from 22% to 10%, respectively, consistent with blacks having more basal Na,K,2Cl cotransporter activity to inhibit. During a later postfurosemide period (1 to 5 hours), urinary concentrations of Ca and Mg recovered more slowly in blacks, consistent with greater reuptake in the thick ascending limb. In summary, there were distinct ethnic differences in renal handling of Ca and Mg basally and in response to furosemide that were consistent with a more active Na,K,2Cl cotransporter in the thick ascending limb in blacks. An increase in vasopressin levels appeared to explain greater urine concentrations in black males but not black females.

Dosing time-dependent variation of bone resorption by cyclosporin A in rats’ femurs

The dosing time-dependent difference of bone resorption by cyclosporin A was determined in normal rats. Rats were kept in rooms with a 12-h light/dark cycle. Cyclosporin A (3 mg/kg, once a day) or vehicle was given at either 2 h after light on (2 HALO) or 8 HALO, 14 HALO, 20 HALO for 24 weeks. Serum and 4-h urine samples were obtained before and at 12 and 24 weeks after the treatment. Body weight, creatinine clearance, serum parathyroid hormone, the trough level of cyclosporin A in whole blood and urinary excretion of Ca and P were not changed by the drug at every any dosing time. Serum Ca and P concentrations by the vehicle treatment differed with the dosing time. Furthermore, increases of these two parameters by the drug varied with dosing time; most prominently at the 2 HALO dosing, and were not seen at the 8 and 14 HALO dosings. Degree of bone resorption of the femur determined by dual-energy X-ray absorption, also varied with dosing time, most prominently at 2 HALO and less prominently at 14 HALO. Increase of urine deoxypyridinoline excretion, a marker of osteoclast activity, by the drug was highest at 2 HALO and lowest at 14 HALO, however parathyroid hormone and osteocalcin concentrations after cyclosporin A treatment did not vary with dosing time. Reduction of urinary nitric oxide (NO) was most prominent at 2 HALO and negligible at 14 HALO. We concluded that cyclosporin A-induced bone resorption and serum Ca and P increases were varied with dosing time. Sensitivity of osteoclasts by the drug was the major mechanisms of the phenomenon, while differences in pharmacokinetics, the parathyroid gland, osteoblasts and renal handling of Ca and P did not contribute to the phenomenon.

Defect in parathyroid-hormone-induced luminal calcium absorption in connecting tubules of Klotho mice

Homozygous Klotho mutant mice (KL(-/-) mice) exhibit multiple phenotypes resembling human ageing. Increases in the ratio of urinary calcium to urinary creatinine (uCa/uCr) and in serum Ca concentration and decreases in urinary Cr excretion and serum parathyroid hormone (PTH) concentration were reported; however, precise information about renal Ca handling was not reported in these animals. We evaluated the PTH-induced increase in intracellular Ca(2+) concentration ([Ca(2+)]i) in cells of isolated perfused connecting tubules (CNTs) of KL(-/-) mice. We also determined fractional excretion of Ca from the urine and serum samples of the same animals (n = 7), and compared them with KL(+/+) mice and hemi-nephrectomized KL(-+/+) mice (n = 10 in each) as controls. FECa was significantly higher in KL(-/-) mice than in controls (0.67 +/- 0.13 vs 0.20 +/- 0.04%). The PTH (10 nM)-induced increase in [Ca(2+)]i was diminished in KL(-/-) mice (58 +/- 5 vs 231 +/- 15 nM). Addition of 10 nM of 8-(4-chlorophenylthio)-cyclic adenosine 3',5'-monophosphate had a similar effect. The PTH-induced increase had completely disappeared by the removal of Ca from lumen and bath in both groups of animals. Removal of sodium (Na) from the solution increased [Ca(2+)]i to a similar extent in both groups. Conclusion. We conclude that renal Ca excretion estimated by determining FECa was defective in the KL(-/-) mice. Impairment of Ca absorption from the lumen by stimulation of PTH in CNTs is one of the mechanisms of this defect. Activity of the basolateral Na/Ca exchanger was preserved in this strain. Therefore, the pathway downstream after generation of second messengers following stimulation of PTH (such as the sorting of transporters of Ca absorption) might be impaired by disruption of the Klotho gene.

Defective renal calcium reabsorption in genetic hypercalciuric rats

Idiopathic hypercalciuria is a frequent cause of calcium (Ca) containing kidney stones. We have previously shown that there is increased intestinal Ca absorption in selectively inbred genetic hypercalciuric stone forming (GHS) rats; however, excess Ca excretion persists when the rats are fed a low Ca diet indicating a defect in renal Ca reabsorption and/or increased bone resorption. To determine if GHS rats have a defect in renal Ca reabsorption we performed 14C-inulin clearance studies on parathyroidectomized female GHS and control (Ctl) rats. After three baseline collections, chlorothiazide (CTZ) or furosemide (FUR) was infused and three more collections were obtained. Both GFR and filtered load of Ca did not differ among the groups; however, fractional and absolute excretion (UcaV) of Ca was three times higher in GHS rats. The increased Ca excretion was not diminished by a low Ca diet. Urine flow rate nearly tripled in all rats after either FUR or CTZ. After CTZ, UcaV was decreased to a greater extent in GHS compared to Ctl rats. After FUR, UcaV was increased to a greater extent in Ctl rats compared to GHS rats. These data indicate that GHS rats have a defect in renal Ca reabsorption, in addition to increased intestinal Ca absorption. The effect of CTZ was greater, and that of FUR was smaller, in GHS compared with Ctl rats, suggesting that the defect in renal Ca handling might be at the level of the thick ascending limb.

Inhibition of bone resorption by the bisphosphonate BM 21.0955 is not associated with an alteration of the renal handling of calcium in rats infused with parathyroid hormone-related protein

Hypercalcaemia of malignancy is determined by an increase of bone resorption and/or renal tubular reabsorption of calcium (Ca). However, this latter component has been found to vary in certain patients during therapy with bone resorption inhibitors such as bisphosphonates. We investigated the possible effects of the highly potent bisphosphonate BM 21.0955 on the renal handling of Ca in thyroparathyroidectomized rats made hypercalcaemic by the stimulation of both bone resorption and renal tubular reabsorption of Ca induced by the chronic infusion of parathyroid hormone-related protein (PTHrP). Dose-dependent inhibition of bone resorption by BM 21.0955, as indicated by the decrease in fasting urinary Ca excretion from 64.0 ± 7.3 to 6.7 ± 3.1 nmol ml GFR, was associated with a change in plasma Ca from 2.97 ± 0.10 to 2.63 ± 0.16 mmol l . However, the relationship between urinary Ca excretion and plasma Ca was not altered, either at endogenous plasma Ca concentration or during the acute infusion of Ca. Similarly, an index of renal tubular reabsorption of Ca calculated from the slope of the linear portion of the relationship between urinary Ca and plasma Ca, which was increased by PTHrP administration, was not influenced by BM 21.0955 therapy (2.59 ± 0.15 vs. 2.55 ± 0.11 mmol l GFR). These results indicate that BM 21.0955, which is one of the most potent bisphosphonates inhibiting bone résorption, did not affect the renal tubular reabsorption of Ca enhanced by PTHrP.

Renal handling of sodium and calcium in hypercalciuria.

The renal handling of Ca in response to Na intake was evaluated in 12 patients with hypercalciuria and active kidney stone disease. There was no depression of urinary Ca excretion in response to the hypocalciuric effect of metolazone. Patients were hospitalized and their Ca and Na excretions measured while on a 190-mEq Na, 800-mg Ca, 1200-mg PO4- diet. These measurements were then repeated after Na intake decreased to 35 mEq/day while other variables, including diuretic dose and Ca intake, were unchanged. Two distinct responses were elicited by patients after Na restriction. In group I or the "responders" (n = 4), Ca excretion was reduced from 255 +/- 31 to 62 +/- 6 mg/24 hr. In the control group (n = 4), Ca excretion decreased from 95 +/- 8 to 57 +/- 11 mg/24 hr at similar levels of Na excretion. In group II or the "nonresponders" (n = 8), Ca excretion fell from 317 +/- 31 to 154 +/- 17 mg/24 hr when Na excretion was less than 50 mEq/24 hr. Metolazone with Na restriction normalized urine Ca excretion to the same order as in control subjects in group I. This is indicative of a mild Ca leak or a salt-sensitive leak. Despite diuretic and Na restriction most of the patients with hypercalciuria (group II) did not reabsorb Ca in a normal manner. This is indicative of a severe reabsorptive defect for Ca despite normal Na handling.

Renal handling of calcium: influence of parathyroid hormone and 1,25-dihydroxyvitamin D3

The influence of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the renal Ca handling was studied in vitamin D-replete rats. The relation between plasma concentration ([Ca]P) and urinary Ca (UCaV/ml GF) was ascertained by clearance techniques over the [Ca]P range of 1.4-3.4 mM varied by infusion of Ca gluconate. Chronic thyroparathyroidectomy (TPTX) decreased the plasma Ca threshold from about 2.3 to 1.5 mM. Between [Ca]P 1.4 and 3.4 mM there was a linear increase in UCaV/ml GF corresponding to 35-50% of the increment in filtered load. In TPTX, PTH (2.5 IU/h i.v.) shifted the Ca threshold from 1.5 to 2.3 mM, without changing the slope of UCaV/ml GF on [Ca]P. The effect of TPTX on the renal Ca handling was not corrected by doses of 1,25(OH)2D3, which increased the intestinal Ca absorption of TPTX rats to normal level. In intact and TPTX rats disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) given at doses which inhibit the production of 1,25(OH)2D3 did not change the tubular Ca handling. Furthermore, 1,25(OH)2D3 had no effect in EHDP-treated TPTX rats. Therefore, tubular Ca handling does not appear to be altered in response to chronic endogenous variation or physiologic supplementation of 1,25(OH)2D3 in vitamin D-replete rats. This is in contrast to the marked alteration observed after TPTX or PTH administration.