Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats

David A. Bushinsky, John R. Asplin, Marc D. Grynpas, Andrew Evan, Walter R. Parker, Kristen M. Alexander, Fredric L. Coe

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Background. Over 54 generations, we have successfully bred a strain of rats that maximizes urinary calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls, uniformly form poorly crystalline calcium phosphate kidney stones, and are termed genetic hypercalciuric stone-forming (GHS) rats. These rats were used to test the hypothesis that increasing urinary oxalate excretion would not only increase the supersaturation with respect to the calcium oxalate solid phase, but also would increase the ratio of calcium oxalate-to-calcium phosphate supersaturation and result in calcium oxalate stone formation. Methods. To increase urine oxalate excretion an oxalate precursor, hydroxyproline, was added to the diet of male GHS rats. The GHS rats were fed a standard 1.2% calcium diet alone or with 1%, 3% or 5% trans-4-hydroxy-L-proline (hydroxyproline). Results. The addition of 1% hydroxyproline to the diet of GHS rats led to an increase in urinary oxalate excretion, which did not increase further with the provision of additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter calcium excretion while the provision of 5% hydroxyproline led to a decrease in urine calcium excretion. The addition of 1% hydroxyproline led to an increase in urinary calcium oxalate supersaturation, which did not further increase with additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter urinary supersaturation with respect to calcium hydrogen phosphate while the addition of 5% hydroxyproline tended to lower this supersaturation. Compared to rats fed the control and the 3% hydroxyproline diet the addition of 5% hydroxyproline increased the ratio of calcium oxalate supersaturation to calcium phosphate supersaturation. Virtually all rats formed stones. In the control and 1% hydroxyproline group, all of the stones were composed of calcium and phosphate (apatite), in the 3% hydroxyproline group the stones were a mixture of apatite and calcium oxalate, while in the 5% hydroxyproline group all of the stones were calcium oxalate. Conclusions. The provision of additional dietary hydroxyproline to GHS rats increases urinary oxalate excretion, calcium oxalate supersaturation and the ratio of calcium oxalate-to-calcium phosphate supersaturation, resulting in the formation of calcium oxalate kidney stones. Thus, with the addition of a common amino acid, the GHS rats now not only model the most common metabolic abnormality found in patients with nephrolithiasis, hypercalciuria, but form the most common type of kidney stone, calcium oxalate.

Original languageEnglish (US)
Pages (from-to)975-987
Number of pages13
JournalKidney International
Volume61
Issue number3
DOIs
StatePublished - 2002

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Calcium Oxalate
Proline
Oxalates
Kidney Calculi
Calcium
Diet
Apatites
Urine
Hypercalciuria
Nephrolithiasis
Hydroxyproline

Keywords

  • Hydroxyproline
  • Hypercalciuria
  • Kidney stones
  • Nephrolithiasis

ASJC Scopus subject areas

  • Nephrology

Cite this

Bushinsky, D. A., Asplin, J. R., Grynpas, M. D., Evan, A., Parker, W. R., Alexander, K. M., & Coe, F. L. (2002). Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats. Kidney International, 61(3), 975-987. https://doi.org/10.1046/j.1523-1755.2002.00190.x

Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats. / Bushinsky, David A.; Asplin, John R.; Grynpas, Marc D.; Evan, Andrew; Parker, Walter R.; Alexander, Kristen M.; Coe, Fredric L.

In: Kidney International, Vol. 61, No. 3, 2002, p. 975-987.

Research output: Contribution to journalArticle

Bushinsky, DA, Asplin, JR, Grynpas, MD, Evan, A, Parker, WR, Alexander, KM & Coe, FL 2002, 'Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats', Kidney International, vol. 61, no. 3, pp. 975-987. https://doi.org/10.1046/j.1523-1755.2002.00190.x
Bushinsky, David A. ; Asplin, John R. ; Grynpas, Marc D. ; Evan, Andrew ; Parker, Walter R. ; Alexander, Kristen M. ; Coe, Fredric L. / Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats. In: Kidney International. 2002 ; Vol. 61, No. 3. pp. 975-987.
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abstract = "Background. Over 54 generations, we have successfully bred a strain of rats that maximizes urinary calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls, uniformly form poorly crystalline calcium phosphate kidney stones, and are termed genetic hypercalciuric stone-forming (GHS) rats. These rats were used to test the hypothesis that increasing urinary oxalate excretion would not only increase the supersaturation with respect to the calcium oxalate solid phase, but also would increase the ratio of calcium oxalate-to-calcium phosphate supersaturation and result in calcium oxalate stone formation. Methods. To increase urine oxalate excretion an oxalate precursor, hydroxyproline, was added to the diet of male GHS rats. The GHS rats were fed a standard 1.2{\%} calcium diet alone or with 1{\%}, 3{\%} or 5{\%} trans-4-hydroxy-L-proline (hydroxyproline). Results. The addition of 1{\%} hydroxyproline to the diet of GHS rats led to an increase in urinary oxalate excretion, which did not increase further with the provision of additional hydroxyproline. The addition of 1{\%} and 3{\%} hydroxyproline did not alter calcium excretion while the provision of 5{\%} hydroxyproline led to a decrease in urine calcium excretion. The addition of 1{\%} hydroxyproline led to an increase in urinary calcium oxalate supersaturation, which did not further increase with additional hydroxyproline. The addition of 1{\%} and 3{\%} hydroxyproline did not alter urinary supersaturation with respect to calcium hydrogen phosphate while the addition of 5{\%} hydroxyproline tended to lower this supersaturation. Compared to rats fed the control and the 3{\%} hydroxyproline diet the addition of 5{\%} hydroxyproline increased the ratio of calcium oxalate supersaturation to calcium phosphate supersaturation. Virtually all rats formed stones. In the control and 1{\%} hydroxyproline group, all of the stones were composed of calcium and phosphate (apatite), in the 3{\%} hydroxyproline group the stones were a mixture of apatite and calcium oxalate, while in the 5{\%} hydroxyproline group all of the stones were calcium oxalate. Conclusions. The provision of additional dietary hydroxyproline to GHS rats increases urinary oxalate excretion, calcium oxalate supersaturation and the ratio of calcium oxalate-to-calcium phosphate supersaturation, resulting in the formation of calcium oxalate kidney stones. Thus, with the addition of a common amino acid, the GHS rats now not only model the most common metabolic abnormality found in patients with nephrolithiasis, hypercalciuria, but form the most common type of kidney stone, calcium oxalate.",
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T1 - Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats

AU - Bushinsky, David A.

AU - Asplin, John R.

AU - Grynpas, Marc D.

AU - Evan, Andrew

AU - Parker, Walter R.

AU - Alexander, Kristen M.

AU - Coe, Fredric L.

PY - 2002

Y1 - 2002

N2 - Background. Over 54 generations, we have successfully bred a strain of rats that maximizes urinary calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls, uniformly form poorly crystalline calcium phosphate kidney stones, and are termed genetic hypercalciuric stone-forming (GHS) rats. These rats were used to test the hypothesis that increasing urinary oxalate excretion would not only increase the supersaturation with respect to the calcium oxalate solid phase, but also would increase the ratio of calcium oxalate-to-calcium phosphate supersaturation and result in calcium oxalate stone formation. Methods. To increase urine oxalate excretion an oxalate precursor, hydroxyproline, was added to the diet of male GHS rats. The GHS rats were fed a standard 1.2% calcium diet alone or with 1%, 3% or 5% trans-4-hydroxy-L-proline (hydroxyproline). Results. The addition of 1% hydroxyproline to the diet of GHS rats led to an increase in urinary oxalate excretion, which did not increase further with the provision of additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter calcium excretion while the provision of 5% hydroxyproline led to a decrease in urine calcium excretion. The addition of 1% hydroxyproline led to an increase in urinary calcium oxalate supersaturation, which did not further increase with additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter urinary supersaturation with respect to calcium hydrogen phosphate while the addition of 5% hydroxyproline tended to lower this supersaturation. Compared to rats fed the control and the 3% hydroxyproline diet the addition of 5% hydroxyproline increased the ratio of calcium oxalate supersaturation to calcium phosphate supersaturation. Virtually all rats formed stones. In the control and 1% hydroxyproline group, all of the stones were composed of calcium and phosphate (apatite), in the 3% hydroxyproline group the stones were a mixture of apatite and calcium oxalate, while in the 5% hydroxyproline group all of the stones were calcium oxalate. Conclusions. The provision of additional dietary hydroxyproline to GHS rats increases urinary oxalate excretion, calcium oxalate supersaturation and the ratio of calcium oxalate-to-calcium phosphate supersaturation, resulting in the formation of calcium oxalate kidney stones. Thus, with the addition of a common amino acid, the GHS rats now not only model the most common metabolic abnormality found in patients with nephrolithiasis, hypercalciuria, but form the most common type of kidney stone, calcium oxalate.

AB - Background. Over 54 generations, we have successfully bred a strain of rats that maximizes urinary calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls, uniformly form poorly crystalline calcium phosphate kidney stones, and are termed genetic hypercalciuric stone-forming (GHS) rats. These rats were used to test the hypothesis that increasing urinary oxalate excretion would not only increase the supersaturation with respect to the calcium oxalate solid phase, but also would increase the ratio of calcium oxalate-to-calcium phosphate supersaturation and result in calcium oxalate stone formation. Methods. To increase urine oxalate excretion an oxalate precursor, hydroxyproline, was added to the diet of male GHS rats. The GHS rats were fed a standard 1.2% calcium diet alone or with 1%, 3% or 5% trans-4-hydroxy-L-proline (hydroxyproline). Results. The addition of 1% hydroxyproline to the diet of GHS rats led to an increase in urinary oxalate excretion, which did not increase further with the provision of additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter calcium excretion while the provision of 5% hydroxyproline led to a decrease in urine calcium excretion. The addition of 1% hydroxyproline led to an increase in urinary calcium oxalate supersaturation, which did not further increase with additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter urinary supersaturation with respect to calcium hydrogen phosphate while the addition of 5% hydroxyproline tended to lower this supersaturation. Compared to rats fed the control and the 3% hydroxyproline diet the addition of 5% hydroxyproline increased the ratio of calcium oxalate supersaturation to calcium phosphate supersaturation. Virtually all rats formed stones. In the control and 1% hydroxyproline group, all of the stones were composed of calcium and phosphate (apatite), in the 3% hydroxyproline group the stones were a mixture of apatite and calcium oxalate, while in the 5% hydroxyproline group all of the stones were calcium oxalate. Conclusions. The provision of additional dietary hydroxyproline to GHS rats increases urinary oxalate excretion, calcium oxalate supersaturation and the ratio of calcium oxalate-to-calcium phosphate supersaturation, resulting in the formation of calcium oxalate kidney stones. Thus, with the addition of a common amino acid, the GHS rats now not only model the most common metabolic abnormality found in patients with nephrolithiasis, hypercalciuria, but form the most common type of kidney stone, calcium oxalate.

KW - Hydroxyproline

KW - Hypercalciuria

KW - Kidney stones

KW - Nephrolithiasis

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