Pathogenesis of Calcium Nephrolithiasis

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Idiopathic calcium (Ca) stone formers (ICSF) have papillary calcifications: interstitial plaque or ductal plugging (DP), which may anchor stone growth. Ca oxalate (CaOx) stones associate with plaque, apatite (AP) stones with DP. Decreased renal Ca reabsorption (rCa) is characteristic of idiopathic hypercalciuria (IH); how decreased rCa promotes plaque and DP, as well as stones, is a theme of the PPG. In Project 2 a papillary grading scale (PGS) will be used to quantify plaque and DP during endoscopic stone surgery, and to select ICSF with IH as subjects for Projects 1 and 3, so that physiology (Project 1) and tissue studies (Project 3) will be done on similar ICSF, chosen for high scores for either plaque or DP. The ability of the PGS to correlate with clinical and histopathologic features of stone formation, and with risk of stone recurrence will be tested in aims 2.1 and 2.5. Whether papillary appearance in pediatric stone formers is similar to adults will be tested in aim 2.2. Aims 1.1a and 3.1a-b will test whether plaque is caused by decreased rCa in proximal tubule. Animal models suggest that inflammatory mediators or reactive oxygen species play a role in stone formation, and we will test this in urine (aim 1.3) and tissue (3.2.1a-c, 3.2.2, 3.3a-b) of ICSF with plaque or DP. Whether DP can propagate via an inflammatory "field effect" will be tested in aim 3.3c. We predict DP will associate with Ca phosphate supersaturation in urine (aim 1.1b), with presence of AP in stones (aim 2.3), and with renal impairment (aim 2.4). The possibility that DP-induced inflammation causes pain will be explored in aim 2.6. We will compare the effects of 2 common stone treatments, low Na diet with or without Kcitrate, on segmental rCa in controls and ICSF, using endogenous lithium clearance and urine exosomal markers to study effects on both proximal (aim 1.2) and distal (aim 1.4) nephron rCa, as well as effects on overnight urine Ca (aim 1.5), and on urine SS and upper limit of metastability (aim 1.6).