scholarly journals 1,25(OH)2D3-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet

2013 ◽  
Vol 305 (8) ◽  
pp. F1132-F1138 ◽  
Author(s):  
Kevin K. Frick ◽  
John R. Asplin ◽  
Nancy S. Krieger ◽  
Christopher D. Culbertson ◽  
Daniel M. Asplin ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Cells ◽  
Idiopathic Hypercalciuria ◽  
Sprague Dawley ◽  
Vitamin D Receptors ◽  
Low Calcium Diet ◽  
Calcium Reabsorption ◽  
Renal Tubular ◽  
Intestinal Ca Absorption ◽  
Tubular Calcium Reabsorption

The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 ± 0.1 to 9.3 ± 0.9 mg/day and increased more in GHS from 4.7 ± 0.3 to 21.5 ± 0.9 mg/day ( P < 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption.

scholarly journals Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet

2014 ◽  
Vol 306 (9) ◽  
pp. F1081-F1087 ◽  
Author(s):  
Kevin K. Frick ◽  
John R. Asplin ◽  
Christopher D. Culbertson ◽  
Ignacio Granja ◽  
Nancy S. Krieger ◽  
...  
Keyword(s):  
Vitamin D ◽  
Bone Density ◽  
Bone Resorption ◽  
Mrna Expression ◽  
Kidney Stones ◽  
Sprague Dawley ◽  
Vitamin D Receptors ◽  
Low Calcium Diet ◽  
Renal Tubular ◽  
Intestinal Ca Absorption

Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients.

Increased sensitivity to 1,25(OH)2D3 in bone from genetic hypercalciuric rats

1996 ◽  
Vol 271 (1) ◽  
pp. C130-C135 ◽  
Author(s):  
N. S. Krieger ◽  
V. M. Stathopoulos ◽  
D. A. Bushinsky
Keyword(s):  
Bone Resorption ◽  
Calcium Absorption ◽  
Immunoblot Analysis ◽  
Calcium Excretion ◽  
Sprague Dawley ◽  
Urine Calcium ◽  
Fourfold Increase ◽  
Low Calcium Diet ◽  
Slot Blot Analysis ◽  
Urine Calcium Excretion

As a model of human hypercalciuria, we have selectively inbred genetic hypercalciuric stone-forming (GHS) Sprague-Dawley rats whose mean urine calcium excretion is eight to nine times greater than that of controls. A large component of this excess urine calcium excretion is secondary to increased intestinal calcium absorption, which is not due to an elevation in serum 1,25(OH)2D3, but appears to result from an increased number of intestinal 1,25(OH)2D3 receptors (VDR). When GHS rats are fed a low-calcium diet, the hypercalciuria is only partially decreased and urine calcium excretion exceeds intake, suggesting that an additional mechanism contributing to the hypercalciuria is enhanced bone demineralization. To determine if GHS rat bones are more sensitive to exogenous 1,25(OH)2D3, we cultured calvariae from neonatal (2- to 3-day-old) GHS and control rats with or without 1,25(OH)2D3 or parathyroid hormone (PTH) for 48 h at 37 degrees C. There was significant stimulation of calcium efflux from GHS calvariae at 1 and 10 nM 1,25(OH)2D3, whereas control calvariae showed no significant response to 1,25(OH)2D3 at any concentration tested. In contrast, PTH induced similar bone resorption in control and GHS calvariae. Immunoblot analysis demonstrated a fourfold increase in the level of VDR in GHS calvariae compared with control calvariae, similar to the increased intestinal receptors described previously. There was no comparable change in VDR RNA levels as measured by slot blot analysis, suggesting the altered regulation of the VDR occurs posttranscriptionally. That both bone and intestine display an increased amount of VDR suggests that this may be a systemic disorder in the GHS rat and that enhanced bone resorption may be responsible, in part, for the hypercalciuria in the GHS rat.

Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis

2007 ◽  
Vol 292 (1) ◽  
pp. F66-F75 ◽  
Author(s):  
Elaine M. Worcester ◽  
Daniel L. Gillen ◽  
Andrew P. Evan ◽  
Joan H. Parks ◽  
Katrina Wright ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Serum Magnesium ◽  
Normal Subjects ◽  
Urinary Calcium ◽  
Idiopathic Hypercalciuria ◽  
Calcium Excretion ◽  
Stone Formers ◽  
Calcium Reabsorption ◽  
Renal Tubular ◽  
Filtered Load

Idiopathic hypercalciuria (IH) is common among calcium stone formers (IHSF). The increased urinary calcium arises from increased intestinal absorption of calcium, but it is unclear whether increased filtered load or decreased renal tubular reabsorption of calcium is the main mechanism for the increased renal excretion. To explore this question, 10 IHSF and 7 normal subjects (N) were studied for 1 day. Urine and blood samples were collected at 30- to 60-min intervals while subjects were fasting and after they ate three meals providing known amounts of calcium, phosphorus, sodium, protein, and calories. Fasting and fed, ultrafiltrable calcium levels, and filtered load of calcium did not differ between N and IHSF. Urine calcium rose with meals, and fractional reabsorption fell in all subjects, but the change was significantly higher in IHSF. The changes in calcium excretion were independent of sodium excretion. Serum parathyroid hormone levels did not differ between N and IHSF, and they could not account for the greater fall in calcium reabsorption in IHSF. Serum magnesium and phosphorus levels in IHSF were below N throughout the day, and tubule phosphate reabsorption was lower in IHSF than N after meals. The primary mechanism by which kidneys ferry absorbed calcium into the urine after meals is via reduced tubule calcium reabsorption, and IHSF differ from N in the magnitude of the response. Parathyroid hormone is not likely to be a sufficient explanation for this difference.

Renal tubular reabsorption of calcium in familial hypocalciuric hypercalcaemia

1986 ◽  
Vol 112 (4) ◽  
pp. 541-546 ◽  
Author(s):  
J. H. Kristiansen ◽  
J. Brøchner-Mortensen ◽  
K. O. Pedersen
Keyword(s):  
Plasma Clearance ◽  
Renal Tubule ◽  
Distal Tubule ◽  
Significant Linear Correlation ◽  
Calcium Reabsorption ◽  
Renal Tubular Reabsorption ◽  
Proximal Tubular ◽  
The Absolute ◽  
Renal Tubular ◽  
Tubular Calcium Reabsorption

Abstract. To investigate the nephron site of the enhanced tubular calcium reabsorption in familial hypocalciuric hypercalcaemia (FHH), the renal plasma clearance of lithium and calcium and the glomerular filtration rate were determined simultanously after an overnight fast in nine FHH patients and ten healthy controls. As the renal plasma clearance of lithium equals the rate of the proximal tubular fluid delivered into the thin descending loop of Henle's loop, the reabsorption of calcium in the proximal and distal tubule, respectively, could be calculated. We found that the FHH patients had a significantly higher fractional calcium reabsorption in the proximal tubule (77.6 ± 4.7 (%) vs 73.3 ± 3.1, P < 0.05). The same held true for the absolute proximal calcium reabsorption (1.49 ± 0.12 (mmol/l) vs 1.07 ± 0.05, P < 0.001). There was a significant linear correlation between the increased tubular capacity for calcium reabsorption and the absolute proximal calcium reabsorption (r = 0.70, P < 0.05). The distal tubular calcium reabsorption did not differ in the two groups. Our results therefore suggest that the enhanced tubular calcium reabsorption in FHH takes place exclusively in the proximal renal tubule.

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