CLINICAL PATHOPHYSIOLOGY OF NEPHROLITHIASIS

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This project seeks to define mechanisms by which kidneys produce interstitial apatite plaque and inner medullary collecting duct plugging. Since apatite plaque is thought to be the anchored nidus on which calcium oxalate stones grow, understanding mechanisms of its production is essential for progress in stone research. Likewise, understanding mechanisms that cause abnormally high urine pH and foster calcium phosphate stones and collecting duct apatite plugging may disclose clinical approaches to preventing the renal damage apatite plugging appears to produce. The discovery of an origin of renal interstitial apatite plaque in basement membranes of thin limbs of Henle's loops in the common calciumoxalate stone forming patient, and that brushite stone formers plug inner medullary collecting ducts with apatite crystals and develop renal disease with nephron obsolescence has led us to delineate the pathophysiological basis for both crystallization phenomina. Interstitial plaque abundance is directly related to urine calcium excretion and inverse to urine volume, suggesting a link to calcium concentrations in the thin limb lumens or the interstitium. This project uses multiple measurements of renal mineral excretion and fractional reabsorption along with blood hormone levels during the course of a three meal day to quantify the contributions of increased calcitrol and insulin and reduced parathyroid hormone to estimated thin loop and urine calcium concentration in hypercalciuric stone formers. Collecting duct plugging appears related to abnormally high urine pH. Using the same basic protocol we explore effects of diet and insulin on postprandial urine pH regulation. The specific aims of the project seek to: (1) Estimate the relative magnitudes of two alternative plaque mechanisms; (2) Explore the role of insulin, PTH, calcitriol and renal calcium receptor signalling in regulating post prandial renal calcium reabsorption in stone formers with genetic hypercalciuria; (3) Determine human kidney tissue levels of the vitamin D receptor and calcium receptor in genetic hypercalciuria; (4) Explore the role of insulin and diet in regulating postprandial urine pH; (5) determine the role of oxalate and oxalate ion in inner medullary collecting duct apatite plugging in stone formers with intestinal bypass for obesity.