The project's broad objective is an understanding of the impact of two common treatments for stone disease on renal calcium (Ca) handling, and the links between renal physiology and tissue calcifications in stone formers (SF). Stone formation requires urine supersaturation (SS) with calcium oxalate (CaOx) and calcium phosphate (CaP); idiopathic hypercalciuria (IH) is a common cause of increased SS. Prevention of stone recurrence relies on decreasing SS, but the optimal means of doing this in a given patient is not clear. Decreased tubular Ca reabsorption (rCa), in both proximal and distal nephron, is characteristic of IH. We hypothesize that renal tubule transport alterations are linked to pathogenesis of the tissue calcifications found in SF, as well as to their stones, and propose to study Ca SF with IH (IHSF) who have undergone papillary mapping during endoscopy who will be selected for one of two papillary appearances: 1) papillae with abundant plaque but no plugging (typical of many CaOx SF) or 2) plugs with modest plaque (typical of apatite SF). We will test the hypothesis that plaque surface area correlates with decreased proximal tubule rCa, and plug area correlates with increased CaP SS (Aim 1.1a,b). Having demonstrated differences between IHSF and normals (N) in rCa on a stable diet, both fasting and fed, we propose to explore these findings using high and low Na intake, with or without Kcitrate. We will study the effects on rCa, fasting, fed and overnight (a high risk period for stone formation), using lithium clearance and urine stone risk factors (Aims 1.2a, 1.4a, 1.5). To understand the mechanisms of the changes in rCa that we expect with low Na diet and K citrate, we will measure urine exosomes for both proximal and distal nephron transporters (Aims 1.2b, 1.4, and 1.5). SS and upper limit of metastability will be measured to gain a better understanding of how K citrate and low Na diet affects these important treatment parameters (Aim 1.5, 1.6). To gain further insight into plaque and plug formation the role of inflammation (Aim 1.3).
Calcium kidney stones are common and a significant cause of morbidity, causing hospitalization, surgery, and kidney damage. While we have discovered that abnormal renal calcium transport is key to the pathogensesis of stone formation, the sites of abnormal renal tubule transport, the effects of inflammation, and effects of common treatments upon renal calcium transport are not well understood. An understanding of these will directly impact both our scientific understanding of the disease and patient care.
| 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 |
| Kleinguetl, Colin; Williams Jr, James C; Ibrahim, Samar A et al. (2017) Calcium Tartrate Tetrahydrate, Case Report of a Novel Human Kidney Stone. J Endourol Case Rep 3:192-195 |
| Mulay, Shrikant R; Eberhard, Jonathan N; Desai, Jyaysi et al. (2017) Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease. J Am Soc Nephrol 28:761-768 |
| Winfree, Seth; Khan, Shehnaz; Micanovic, Radmila et al. (2017) Quantitative Three-Dimensional Tissue Cytometry to Study Kidney Tissue and Resident Immune Cells. J Am Soc Nephrol 28:2108-2118 |
| Borofsky, Michael S; Dauw, Casey A; York, Nadya et al. (2017) Accuracy of daily fluid intake measurements using a ""smart"" water bottle. Urolithiasis : |
| 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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