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Frick K.K.,University of Rochester | Asplin J.R.,Litholink Corporation | Krieger N.S.,University of Rochester | Culbertson C.D.,University of Rochester | And 2 more authors.
American Journal of Physiology - Renal Physiology | Year: 2013

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. © 2013 by the American Physiological Society.


Frick K.K.,University of Rochester | Asplin J.R.,Litholink Corporation | Favus M.J.,University of Chicago | Culbertson C.,University of Rochester | And 2 more authors.
American Journal of Physiology - Renal Physiology | Year: 2013

Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (U) calcium (Ca) excretion, have increased intestinal Ca absorption and bone Ca resorption and reduced renal Ca reabsorption, leading to increased UCa compared with the Sprague-Dawley (SD) rats. GHS rats have increased vitamin D receptors (VDR) at each of these sites, with normal levels of 1,25(OH)2D3 (1,25D), indicating that their VDR is undersaturated with 1,25D. We tested the hypothesis that 1,25D would induce a greater increase in UCa in GHS rats by feeding both strains ample Ca and injecting 1,25D (25 ng · 100 g body wt-1 · day-1) or vehicle for 16 days. With 1,25D, UCa in SD increased from 1.7 ± 0.3 mg/day to 24.4 ± 1.2 (Δ = 22.4 ± 1.5) and increased more in GHS from 10.5 ± 0.7 to 41.9 ± 0.7 (Δ = 29.8 ± 1.8; P = 0.003). To determine the mechanism of the greater increase in UCa in GHS rats, we measured kidney RNA expression of components of renal Ca transport. Expression of transient receptor potential vanilloid (TRPV)5 and calbindin D28K were increased similarly in SD + 1,25D and GHS + 1,25D. The Na+/Ca2+ exchanger (NCX1) was increased in GHS + 1,25D. Klotho was decreased in SD + 1,25D and GHS + 1,25D. TRPV6 was increased in SD + 1,25D and increased further in GHS + 1,25D. Claudin 14, 16, and 19, Na/K/2Cl transporter (NKCC2), and secretory K channel (ROMK) did not differ between SD + 1,25D and GHS + 1,25D. Increased UCa with 1,25D in GHS exceeded that of SD, indicating that the increased VDR in GHS induces a greater biological response. This increase in UCa, which must come from the intestine and/or bone, must exceed any effect of 1,25D on TRPV6 or NCX1-mediated renal Ca reabsorption. © 2013 the American Physiological Society.


Moe S.M.,Indiana University | Moe S.M.,Roudebush Veterans Affairs Medical Center | Zidehsarai M.P.,Indiana University | Chambers M.A.,Indiana University | And 5 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2011

Background and objectives: Patients with advanced chronic kidney disease (CKD) are in positive phosphorus balance, but phosphorus levels are maintained in the normal range through phosphaturia induced by increases in fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH). This provides the rationale for recommendations to restrict dietary phosphate intake to 800 mg/d. However, the protein source of the phosphate may also be important. Design, setting, participants, & measurements: We conducted a crossover trial in nine patients with a mean estimated GFR of 32 ml/min to directly compare vegetarian and meat diets with equivalent nutrients prepared by clinical research staff. During the last 24 hours of each 7-day diet period, subjects were hospitalized in a research center and urine and blood were frequently monitored. Results: The results indicated that 1 week of a vegetarian diet led to lower serum phosphorus levels and decreased FGF23 levels. The inpatient stay demonstrated similar diurnal variation for blood phosphorus, calcium, PTH, and urine fractional excretion of phosphorus but significant differences between the vegetarian and meat diets. Finally, the 24-hour fractional excretion of phosphorus was highly correlated to a 2-hour fasting urine collection for the vegetarian diet but not the meat diet. Conclusions: In summary, this study demonstrates that the source of protein has a significant effect on phosphorus homeostasis in patients with CKD. Therefore, dietary counseling of patients with CKD must include information on not only the amount of phosphate but also the source of protein from which the phosphate derives. Copyright © 2011 by the American Society of Nephrology.


Bushinsky D.A.,University of Rochester | Willett T.,Samuel Lunenfeld Research Institute | Willett T.,University of Toronto | Asplin J.R.,Litholink Corporation | And 3 more authors.
Journal of Bone and Mineral Research | Year: 2011

We have bred a strain of rats to maximize urine (u) calcium (Ca) excretion and model hypercalciuric nephrolithiasis. These genetic hypercalciuric stone-forming (GHS) rats excrete more uCa than control Sprague-Dawley rats, uniformly form kidney stones, and similar to patients, demonstrate lower bone mineral density. Clinically, thiazide diuretics reduce uCa and prevent stone formation; however, whether they benefit bone is not clear. We used GHS rats to test the hypothesis that the thiazide diuretic chlorthalidone (CTD) would have a favorable effect on bone density and quality. Twenty GHS rats received a fixed amount of a 1.2% Ca diet, and half also were fed CTD (4 to 5mg/kg/d). Rats fed CTD had a marked reduction in uCa. The axial and appendicular skeletons were studied. An increase in trabecular mineralization was observed with CTD compared with controls. CTD also improved the architecture of trabecular bone. Using micro-computed tomography (μCT), trabecular bone volume (BV/TV), trabecular thickness, and trabecular number were increased with CTD. A significant increase in trabecular thickness with CTD was confirmed by static histomorphometry. CTD also improved the connectivity of trabecular bone. Significant improvements in vertebral strength and stiffness were measured by vertebral compression. Conversely, a slight loss of bending strength was detected in the femoral diaphysis with CTD. Thus results obtained in hypercalciuric rats suggest that CTD can favorably influence vertebral fracture risk. CTD did not alter formation parameters, suggesting that the improved vertebral bone strength was due to decreased bone resorption and retention of bone structure. Copyright © 2011 American Society for Bone and Mineral Research.


Leaf D.E.,Columbia University | Leaf D.E.,Brigham and Women's Hospital | Korets R.,Columbia University | Taylor E.N.,Maine Medical Center | And 5 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2012

Background and objectives Despite the important role of vitamin D in maintaining bone health, many clinicians are reluctant to treat vitamin D deficiency in kidney stone formers because of the theoretical risk of increasing urinary calcium excretion. This study examined the effect of vitamin D repletion on urinary calcium excretion among stone formers. Design, setting, participants, & measurements Participants (n=29) were recruited from urology clinics affiliated with New York Presbyterian Hospital. Enrollment criteria included a history of nephrolithiasis, urinary calcium excretion between 150 and 400 mg/d, and a serum 25-hydroxyvitamin D level <30 ng/ml. Participants were given oral ergocalciferol (50,000 IU/wk) for 8 weeks. Serumand 24-hour urine tests were repeated after 8weeks. Results Levels of 25-hydroxyvitaminDincreased significantly after vitamin Drepletion (17±6 and35±10 ng/ml, P<0.001), but mean 24-hour urinary calcium excretion did not change (257±54 and 255±88 mg/d at baseline and follow-up, respectively, P=0.91). However, 11 participants had an increase in urinary calcium excretion ≥20 mg/d; these participants also had an increase in urine sodiumexcretion, likely reflecting dietary variability. No participant experienced adverse effects from vitamin D, including hypercalcemia. Conclusions Among stone formers with vitamin D deficiency, a limited course of vitamin D repletion does not seem to increase mean urinary calcium excretion, although a subset of individuals may have an increase. These data suggest that vitamin D therapy, if indicated, should not be withheld solely on the basis of stone disease, but 24-hour urinary calcium excretion should be monitored after repletion. © 2012 by the American Society of Nephrology.


Block G.A.,Denver Nephrology | Wheeler D.C.,University College London | Persky M.S.,Denver Nephrology | Kestenbaum B.,University of Washington | And 11 more authors.
Journal of the American Society of Nephrology | Year: 2012

Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m 2 to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2mg/dl in both active and placebo arms to 3.9mg/dl with active therapy and 4.1mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain. Copyright © 2012 by the American Society of Nephrology.


Bergsland K.J.,University of Chicago | Coe F.L.,University of Chicago | White M.D.,Urological Institute of Northeastern New York | Erhard M.J.,Nemours Childrens Clinic | And 4 more authors.
Kidney International | Year: 2012

Calcium nephrolithiasis in children is increasing in prevalence and tends to be recurrent. Although children have a lower incidence of nephrolithiasis than adults, its etiology in children is less well understood; hence, treatments targeted for adults may not be optimal in children. To better understand metabolic abnormalities in stone-forming children, we compared chemical measurements and the crystallization properties of 24-h urine collections from 129 stone formers matched to 105 non-stone-forming siblings and 183 normal, healthy children with no family history of stones, all aged 6 to 17 years. The principal risk factor for calcium stone formation was hypercalciuria. Stone formers have strikingly higher calcium excretion along with high supersaturation for calcium oxalate and calcium phosphate, and a reduced distance between the upper limit of metastability and supersaturation for calcium phosphate, indicating increased risk of calcium phosphate crystallization. Other differences in urine chemistry that exist between adult stone formers and normal individuals such as hyperoxaluria, hypocitraturia, abnormal urine pH, and low urine volume were not found in these children. Hence, hypercalciuria and a reduction in the gap between calcium phosphate upper limit of metastability and supersaturation are crucial determinants of stone risk. This highlights the importance of managing hypercalciuria in children with calcium stones. © 2012 International Society of Nephrology.


Farmanesh S.,University of Houston | Ramamoorthy S.,Rensselaer Polytechnic Institute | Chung J.,University of Houston | Asplin J.R.,Litholink Corporation | And 2 more authors.
Journal of the American Chemical Society | Year: 2014

The molecular recognition and interactions governing site-specific adsorption of growth inhibitors on crystal surfaces can be tailored in order to control the anisotropic growth rates and physical properties of crystalline materials. Here we examine this phenomenon in calcium oxalate monohydrate (COM) crystallization, a model system of calcification with specific relevance for pathological mineralization. We analyzed the effect of three putative growth inhibitors - chondroitin sulfate, serum albumin, and transferrin - using analytical techniques capable of resolving inhibitor-crystal interactions from interfacial to bulk scales. We observed that each inhibitor alters surface growth by adsorbing on to distinct steps emanating from screw dislocations on COM surfaces. Binding of inhibitors to different crystallographic faces produced morphological modifications that are consistent with classical mechanisms of layer-by-layer crystal growth inhibition. The site-specific adsorption of inhibitors on COM surfaces was confirmed by bulk crystallization, fluorescent confocal microscopy, and atomic force microscopy. Kinetic studies of COM growth at varying inhibitor concentrations revealed marked differences in their efficacy and potency. Systematic analysis of inhibitor combinations, quantified via the combination index, identified various binary pairings capable of producing synergistic, additive, and antagonistic effects. Collectively, our investigation of physiologically relevant biomolecules suggests potential roles of COM inhibitors in pathological crystallization and provides guiding principles for biomimetic design of molecular modifiers for applications in crystal engineering. © 2013 American Chemical Society.


Chung J.,University of Houston | Granja I.,Litholink Corporation | Taylor M.G.,University of Pittsburgh | Mpourmpakis G.,University of Pittsburgh | And 2 more authors.
Nature | Year: 2016

Crystalline materials are crucial to the function of living organisms, in the shells of molluscs, the matrix of bone, the teeth of sea urchins, and the exoskeletons of coccoliths. However, pathological biomineralization can be an undesirable crystallization process associated with human diseases. The crystal growth of biogenic, natural and synthetic materials may be regulated by the action of modifiers, most commonly inhibitors, which range from small ions and molecules to large macromolecules. Inhibitors adsorb on crystal surfaces and impede the addition of solute, thereby reducing the rate of growth. Complex inhibitor-crystal interactions in biomineralization are often not well elucidated. Here we show that two molecular inhibitors of calcium oxalate monohydrate crystallization - citrate and hydroxycitrate - exhibit a mechanism that differs from classical theory in that inhibitor adsorption on crystal surfaces induces dissolution of the crystal under specific conditions rather than a reduced rate of crystal growth. This phenomenon occurs even in supersaturated solutions where inhibitor concentration is three orders of magnitude less than that of the solute. The results of bulk crystallization, in situ atomic force microscopy, and density functional theory studies are qualitatively consistent with a hypothesis that inhibitor-crystal interactions impart localized strain to the crystal lattice and that oxalate and calcium ions are released into solution to alleviate this strain. Calcium oxalate monohydrate is the principal component of human kidney stones and citrate is an often-used therapy, but hydroxycitrate is not. For hydroxycitrate to function as a kidney stone treatment, it must be excreted in urine. We report that hydroxycitrate ingested by non-stone-forming humans at an often-recommended dose leads to substantial urinary excretion. In vitro assays using human urine reveal that the molecular modifier hydroxycitrate is as effective an inhibitor of nucleation of calcium oxalate monohydrate nucleation as is citrate. Our findings support exploration of the clinical potential of hydroxycitrate as an alternative treatment to citrate for kidney stones. © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.


Bergsland K.J.,University of Chicago | Zisman A.L.,University of Chicago | Asplin J.R.,Litholink Corporation | Worcester E.M.,University of Chicago | Coe F.L.,University of Chicago
American Journal of Physiology - Renal Physiology | Year: 2011

Little is known about the renal handling of oxalate in patients with idiopathic hypercalciuria (IH). To explore the role of tubular oxalate handling in IH and to evaluate whether differences exist between IH and normal controls, we studied 19 IH subjects, 8 normal subjects, and 2 bariatric stone formers (BSF) during a 1-day General Clinical Research Center protocol utilizing a low-oxalate diet. 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, oxalate, and calories. Plasma oxalate concentrations and oxalate-filtered loads were similar between patients (includes IH and BSF) and controls in both the fasting and fed states. Urinary oxalate excretion was significantly higher in patients vs. controls regardless of feeding state. Fractional excretion of oxalate (FEOx) was >1, suggesting tubular secretion of oxalate, in 6 of 19 IH and both BSF, compared with none of the controls (P < 0.00001). Adjusted for water extraction along the nephron, urine oxalate rose more rapidly among patients than normal subjects with increases in plasma oxalate. Our findings identify tubular secretion of oxalate as a key mediator of hyperoxaluria in calcium stone formers, potentially as a means of maintaining plasma oxalate in a tight range. Copyright © 2011 the American Physiological Society.

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