Modeling hypercalciuria in the genetic hypercalciuric stone-forming rat

Frick, Kevin K.; Krieger, Nancy S.; Bushinsky, David A.

doi:10.1097/mnh.0000000000000130

Cited by 9 publications

(17 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GHS rats have alterations in Ca homeostasis including increased intestinal absorption, reduced renal tubular reabsorption, and increased bone resorption, similar to those of many patients with idiopathic IH [24]. Hypercalciuria in the GHS rats leads directly to stone formation as it does in humans [1,37,39].…”

Section: Discussionmentioning

confidence: 99%

“…GHS rats were generated by selectively inbreeding Sprague-Dawley rats for increased uCa excretion [24]. When fed a standard, ample Ca diet, each GHS rat now consistently excretes over tenfold more uCa than Sprague-Dawley rat controls [24].…”

Section: Introductionmentioning

confidence: 99%

“…To examine the effect of a low Na diet on urine supersaturation (SS), stone formation and bone quality, we utilized a model of human idiopathic IH, the genetic hypercalciuric stone-forming (GHS) rat [24]. GHS rats were generated by selectively inbreeding Sprague-Dawley rats for increased uCa excretion [24].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Low Sodium Diet Decreases Stone Formation in Genetic Hypercalciuric Stone-Forming Rats

Krieger

Grynpas

VandenEynde

et al. 2019

Nephron

View full text Add to dashboard Cite

Background: Urine (u) calcium (Ca) excretion is directly dependent on dietary sodium (Na) intake leading to the recommendation for Na restriction in hypercalciuric kidney stone formers. However, there is no direct evidence that limiting Na intake will reduce recurrent stone formation. Materials and Methods: We used genetic hypercalciuric stone-forming (GHS) rats, which universally form Ca phosphate (P) kidney stones, fed either a low Na (LNa, 0.05%) or normal Na (NNa, 0.4%) Na diet (D) for 18 weeks. Urine was collected at 6-week intervals. Radiographic analysis for stone formation and bone analyses were done at the conclusion of the study. Results: Mean uCa was lower with LNaD than NNaD as was uP and LNaD decreased mean uNa and uChloride. There were no differences in urine supersaturation (SS) with respect to calcium phosphate (CaP) or Ca oxalate (CaOx). However, stone formation was markedly decreased with LNaD by radiographic analysis. The LNaD group had significantly lower femoral anterior-posterior diameter and volumetric bone mineral density (vBMD), but no change in vertebral trabecular vBMD. There were no differences in the bone formation rate or osteoclastic bone resorption between groups. The LNaD group had significantly lower femoral stiffness; however, the ultimate load and energy to fail was not different. Conclusion: Thus, a low Na diet reduced uCa and stone formation in GHS rats, even though SS with respect to CaP and CaOx was unchanged and effects on bone were modest. These data, if confirmed in humans, support dietary Na restriction to prevent recurrent Ca nephrolithiasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Low Sodium Diet Decreases Stone Formation in Genetic Hypercalciuric Stone-Forming Rats

Krieger

Grynpas

VandenEynde

et al. 2019

Nephron

View full text Add to dashboard Cite

show abstract

“…Recent evidence has identified loss of function mutations in CYP24A1, encoding the vitamin D-24-hydroxylase which regulates the catabolism of 1,25(OH) 2 D, can result in high circulating levels of 1,25(OH) 2 D, hypercalcemia, hypercalciuria, and nephrolithiasis in humans [50]. Our, and other team’s, studies using genetic hypercalciuric stone-forming rats showed that vitamin D could take part in the pathogenesis of urolithiasis [51,52,53]. Vitamin D receptor knockdown in genetic hypercalciuric rats reduced calcium phosphate deposits in the kidneys [52].…”

Section: Discussionmentioning

confidence: 99%

Association between Circulating Vitamin D Level and Urolithiasis: A Systematic Review and Meta-Analysis

Zhang

et al. 2017

Nutrients

View full text Add to dashboard Cite

Many studies compared the serum/plasma 1,25 dihydroxyvitamin D3 (1,25(OH)2D) and 25 hydroxyvitamin D3 (25(OH)D) between people with and without nephrolithiasis, and their results were conflicting. After systematically searching PubMed, Web of Science, The Cochrane Library, CNKI, and the Wanfang Database, we conducted a meta-analysis. Thirty-two observational studies involving 23,228 participants were included. Meta-analysis of these studies showed that of stone formers (SFs), calcium SFs had significantly higher concentrations of 1,25(OH)2D (weighted mean difference (WMD), 10.19 pg/mL; 95% confidence interval (CI), 4.31–16.07; p = 0.0007 and WMD, 11.28 pg/mL; 95% CI, 4.07–18.50; p = 0.002, respectively) than non-stone formers, while the levels of 25(OH)D (WMD, 0.88 ng/mL; 95% CI, −1.04–2.80; p = 0.37 and WMD, −0.63 ng/mL; 95% CI, −2.72–1.47; p = 0.56, respectively) are similar. Compared with controls and normocalciuria SFs, hypercalciuria SFs had increased circulating 1,25(OH)2D (WMD, 9.41 pg/mL; 95% CI, 0.15–18.67; p = 0.05 and WMD, 2.75 pg/mL; 95% CI, −0.20–5.69; p = 0.07, respectively) and markedly higher 25(OH)D (WMD, 5.02 ng/mL; 95% CI, 0.99–9.06; p = 0.01 and WMD, 5.02 ng/mL; 95% CI, 2.14–7.90; p = 0.0006, respectively). Normocalciuria SFs had elevated 1,25(OH)2D level (WMD, 6.85 pg/mL; 95% CI, −5.00–18.71; p = 0.26) and comparable 25(OH)D (WMD, 0.94 ng/mL; 95% CI, −3.55–5.43; p = 0.68). Sensitivity analysis generated similar results. Current evidence suggests that increased circulating 1,25(OH)2D is associated with urinary stones and a higher level of circulating 25(OH)D is significantly associated with hypercalciuria urolithiasis. Further studies are still needed to reconfirm and clarify the role of vitamin D in the pathogenesis of stones.

show abstract

“…To determine the cellular and molecular basis for alterations in bone formation and resorption in hypercalciuria while controlling for genetic, nutritional, and hormonal factors, we conducted studies in rats from an inbred colony of hypercalciuric rats . These genetic hypercalciuric stone‐forming (GHS) rats are the result of over 100 generations of selective inbreeding of hypercalciuric offspring of the original spontaneously hypercalciuric male and female Sprague–Dawley (SD) rats.…”

Section: Introductionmentioning

confidence: 99%

Increased Osteoclast and Decreased Osteoblast Activity Causes Reduced Bone Mineral Density and Quality in Genetic Hypercalciuric Stone‐Forming Rats

et al. 2020

View full text Add to dashboard Cite

To study human idiopathic hypercalciuria (IH), we developed an animal model, genetic hypercalciuric stone‐forming (GHS) rats, whose pathophysiology parallels that in IH. All GHS rats form kidney stones and have decreased BMD and bone quality compared with the founder Sprague–Dawley (SD) rats. To understand the bone defect, we characterized osteoclast and osteoblast activity in the GHS compared with SD rats. Bone marrow cells were isolated from femurs of GHS and SD rats and cultured to optimize differentiation into osteoclasts or osteoblasts. Osteoclasts were stained for TRAcP (tartrate resistant acid phosphatase), cultured to assess resorptive activity, and analyzed for specific gene expression. Marrow stromal cells or primary neonatal calvarial cells were differentiated to osteoblasts, and osteoblastic gene expression as well as mineralization was analyzed. There was increased osteoclastogenesis and increased resorption pit formation in GHS compared with SD cultures. Osteoclasts had increased expression of cathepsin K, Tracp, and MMP9 in cells from GHS compared with SD rats. Osteoblastic gene expression and mineralization was significantly decreased. Thus, alterations in baseline activity of both osteoclasts and osteoblasts in GHS rats, led to decreased BMD and bone quality, perhaps because of their known increase in vitamin D receptors. Better understanding of the role of GHS bone cells in decreased BMD and quality may provide new strategies to mitigate the low BMD and increased fracture risk found in patients with IH. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

show abstract

Modeling hypercalciuria in the genetic hypercalciuric stone-forming rat

Cited by 9 publications

References 72 publications

Low Sodium Diet Decreases Stone Formation in Genetic Hypercalciuric Stone-Forming Rats

Low Sodium Diet Decreases Stone Formation in Genetic Hypercalciuric Stone-Forming Rats

Association between Circulating Vitamin D Level and Urolithiasis: A Systematic Review and Meta-Analysis

Increased Osteoclast and Decreased Osteoblast Activity Causes Reduced Bone Mineral Density and Quality in Genetic Hypercalciuric Stone‐Forming Rats

Contact Info

Product

Resources

About