Our prior work has shown that calcium (Ca) stone formers (SF) with idiopathic hypercalciuria (IH) have decreased renal tubule Ca reabsorption which is most marked after meals. Proximal tubule (PT) Ca reabsorption appears to be decreased in Ca oxalate SF (ICSF) but not Ca phosphate (CaP) SF (IPSF), meaning that other tubule sites must be affected in IPSF. ICSF and IPSF also differ in the site of mineral deposition in their kidneys - interstitial plaque vs. tubule plugs. These experiments use a Gerneral Clinical Research Center protocol to study the sites of abnormal Ca reabsorption in ICSF and IPSF compared with normals (N). We hypothesize that TAL Ca reabsorption will be increased in ICSF, fostering plaque via vas wash-down. We use furosemide (Fur) blockade of thick ascending limb (TAL) transport to confirm the decreased PT transport discovered using lithium clearnace (Aim 1.1a), and to gauge absolute TAL Ca reabsorption (Aim 1.1b). We also predict that TAL Ca reabsorption is decreased in IPSF, and also results in decreased TAL bicarbonate absorption, resulting in increased urine pH and CaP SS which promotes tubule plugging (Aim 1.1c). We test several potential signallers of renal Ca reabsorption for a relationship to Ca transport, looking for dyssynchrony with transport changes in a time resolved protocol, and differences in regression of signaller levels and Ca reabsorption between ICSF, IPSF, and N (Aim 1.2a,b), seeking potential drug targets. Thiazide (TZ) is a main treatment for Ca stone prevention and lowers urine Ca;animal experiments suggest that PT Ca reabsorption is increased with TZ. If PT reabsorption is increased by TZ in humans, it may reduce plaque formation as well as stone recurrence (Aim 1.3). Calcitriol levels are elevated in many Ca SF, and administration of calcitriol to N in non-hypercalcemic doses can reproduce findings of IH, including inability to conserve Ca on a low Ca diet. We will test whether calcitriol can decrease PT Ca reabsorption as seen in IH (Aim 1.4). All SF studied in Project 1 will have biopsy and tissue studies in Projects 2 and 3, so results of physiology studies can be combined with histopathologic data to test project aims (PI-6) relating Ca transport to tissue Ca levels, mineral deposits, transporters and receptors.

Public Health Relevance

Calcium (Ca) kidney stones are common, and can cause kidney damage as well as need for surgery and hospitalization. Abnormal renal Ca transport is the major abnormality leading to stones and to the associated bone disease. Clarification of the mechanisms for abnormal Ca reabsorption will lead to potential drug and gene targets and improvements in prevention of calcium kidney stones.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-R)
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University of Chicago
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Williams Jr, James C; Borofsky, Michael S; Bledsoe, Sharon B et al. (2018) Papillary Ductal Plugging is a Mechanism for Early Stone Retention in Brushite Stone Disease. J Urol 199:186-192
Worcester, Elaine M; Bergsland, Kristin J; Gillen, Daniel L et al. (2018) Mechanism for higher urine pH in normal women compared with men. Am J Physiol Renal Physiol 314:F623-F629
Bergsland, Kristin J; Coe, Fredric L; Parks, Joan H et al. (2018) Evidence for a role of PDZ domain-containing proteins to mediate hypophosphatemia in calcium stone formers. Nephrol Dial Transplant 33:759-770
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Winfree, Seth; Ferkowicz, Michael J; Dagher, Pierre C et al. (2017) Large-scale 3-dimensional quantitative imaging of tissues: state-of-the-art and translational implications. Transl Res 189:1-12
Cohen, Andrew J; Borofsky, Michael S; Anderson, Blake B et al. (2017) Endoscopic Evidence That Randall's Plaque is Associated with Surface Erosion of the Renal Papilla. J Endourol 31:85-90
Gilad, Ron; Williams Jr, James C; Usman, Kalba D et al. (2017) Interpreting the results of chemical stone analysis in the era of modern stone analysis techniques. J Nephrol 30:135-140

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