Alendronate decreases urine calcium and supersaturation in genetic hypercalciuric rats

Bushinsky, David A.; Neumann, Krystof J.; Asplin, John R.; Krieger, Nancy S.

doi:10.1046/j.1523-1755.1999.00247.x

Cited by 90 publications

(84 citation statements)

References 40 publications

(2 reference statements)

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“…This dose was calculated to provide approximately 4 to 5 mg/kg body wt per 24 h Thz, a dose that we have previously shown to be effective in reducing calcium excretion in rats (28). Male rats, as opposed to the female rats that were used in a number of previous studies (7)(8)(9)(10)12,13,15), were used because of their greater baseline oxalate excretion when fed this standard calcium diet (6,16,20). Previously, we have shown that GHS rats develop calcium phosphate (apatite) stones when fed this 1.2% calcium diet (8,10,12,15,20).…”

Section: Study Protocolmentioning

confidence: 99%

Thiazides Reduce Brushite, but not Calcium Oxalate, Supersaturation, and Stone Formation in Genetic Hypercalciuric Stone–Forming Rats

Bushinsky¹,

Asplin²

2005

Journal of the American Society of Nephrology

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Over 59 generations, a strain of rats has been inbred to maximize urine calcium excretion. The rats now excrete eight to 10 times as much calcium as controls. These rats uniformly form calcium phosphate (apatite) kidney stones and have been termed genetic hypercalciuric stone-forming (GHS) rats. The addition of a common amino acid and oxalate precursor, hydroxyproline, to the diet of the GHS rats leads to formation of calcium oxalate (CaOx) kidney stones. Hydroxyproline-supplemented GHS rats were used to test the hypothesis that the thiazide diuretic chlorthalidone would decrease urine calcium excretion, supersaturation, and perhaps stone formation. All GHS rats received a fixed amount of a standard 1.2% calcium diet with 5% trans-4-hydroxy-L-proline (hydroxyproline) so that the rats would exclusively form CaOx stones. Half of the rats had chlorthalidone (Thz; 4 to 5 mg/kg per d) added to their diets. Urine was collected weekly, and at the conclusion of the study, the kidneys, ureters, and bladders were radiographed for the presence of stones. Compared with control, the addition of Thz led to a significant reduction of urine calcium and phosphorus excretion, whereas urine oxalate excretion increased. Supersaturation with respect to the calcium hydrogen phosphate fell, whereas supersaturation with respect to CaOx was unchanged. Rats that were fed Thz had fewer stones. As calcium phosphate seems to be the preferred initial solid phase in patients with CaOx kidney stones, the reduction in supersaturation with respect to the calcium phosphate solid phase may be the mechanism by which thiazides reduce CaOx stone formation.

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Section: Study Protocolmentioning

confidence: 99%

Thiazides Reduce Brushite, but not Calcium Oxalate, Supersaturation, and Stone Formation in Genetic Hypercalciuric Stone–Forming Rats

Bushinsky¹,

Asplin²

2005

Journal of the American Society of Nephrology

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“…There was no comparable change in vitamin D receptor RNA levels as measured by slot blot analysis, suggesting the altered regulation of the vitamin D receptor occurs posttranscriptionally. We then determined if alendronate, an inhibitor of bone resorption, would decrease urine calcium excretion by retarding bone resorption (29). On the low-calcium diet, the urine calcium of the GHS rats exceeded their calcium intake, indicating that some of the urine calcium was from bone mineral stores.…”

Section: Genetic Hypercalciuric Stone-forming Ratsmentioning

confidence: 99%

“…We have shown evidence for both primary bone dissolution apparently due to augmented vitamin D receptor number in GHS rat osteoblasts leading to enhanced bone resorption and a primary defect in renal tubular reabsorption of calcium. Though the renal tubular defect would necessitate bone resorption to maintain normal serum calcium levels, both the renal and bone defects have been shown to be independent of each other (25,28,29). The independent defects in calcium handling by the intestine, kidney, and bone suggest a systemic defect in calcium handling resulting in hypercalciuria.…”

Section: Genetic Hypercalciuric Stone-forming Ratsmentioning

confidence: 99%

Molecular Mechanisms of Primary Hypercalciuria

Frick¹,

Bushinsky²

2003

Journal of the American Society of Nephrology

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127

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“…17 The pathophysiology of the hypercalciuria seems similar to that in humans in that it involves intestinal hyperabsorption, 18,19 reduced renal tubular reabsorption, 20 and increased bone mineral lability. 21,22 Virtually all of the GHS rats form kidney stones, whereas control rats have no evidence of stone formation. 23 On a standard rat diet, the kidney stones formed contain only calcium and phosphate.…”

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confidence: 99%

Thiosulfate Reduces Calcium Phosphate Nephrolithiasis

Asplin

Donahue

Lindeman

et al. 2009

Journal of the American Society of Nephrology

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An uncontrolled trial reported that sodium thiosulfate reduces formation of calcium kidney stones in humans, but this has not been established in a controlled human study or animal model. Using the genetic hypercalciuric rat, an animal model of calcium phosphate stone formation, we studied the effect of sodium thiosulfate on urine chemistries and stone formation. We fed genetic hypercalciuric rats normal food with or without sodium thiosulfate for 18 wk and measured urine chemistries, supersaturation, and the upper limit of metastability of urine. Eleven of 12 untreated rats formed stones compared with only three of 12 thiosulfate-treated rats (P Ͻ 0.002). Urine calcium and phosphorus were higher and urine citrate and volume were lower in the thiosulfate-treated rats, changes that would increase calcium phosphate supersaturation. Thiosulfate treatment lowered urine pH, which would lower calcium phosphate supersaturation. Overall, there were no statistically significant differences in calcium phosphate supersaturation or upper limit of metastability between thiosulfate-treated and control rats. In vitro, thiosulfate only minimally affected ionized calcium, suggesting a mechanism of action other than calcium chelation. In summary, sodium thiosulfate reduces calcium phosphate stone formation in the genetic hypercalciuric rat. Controlled trials testing the efficacy and safety of sodium thiosulfate for recurrent kidney stones in humans are needed.

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Alendronate decreases urine calcium and supersaturation in genetic hypercalciuric rats

Cited by 90 publications

References 40 publications

Thiazides Reduce Brushite, but not Calcium Oxalate, Supersaturation, and Stone Formation in Genetic Hypercalciuric Stone–Forming Rats

Thiazides Reduce Brushite, but not Calcium Oxalate, Supersaturation, and Stone Formation in Genetic Hypercalciuric Stone–Forming Rats

Molecular Mechanisms of Primary Hypercalciuria

Thiosulfate Reduces Calcium Phosphate Nephrolithiasis

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