Summary Project 2 will test the hypothesis that injury to the renal papilla as documented by our papillary injury grading system (PGS) will reflect and predict stone disease, specifically we will determine the influence of intrinsic patient factors such as renal physiology and stone passage events, as well as on the influence of extrinsic patient factors, particularly surgical treatments. To investigate the time course of papillary disease, we will quantify the extent of papillary changes in a co-hort of pediatric calcium stone formers. We will test the hypothesis that our PGS will predict calcium stone type, as well as the relative percentage of calcium phosphate present in stones. In a related hypothesis, we will test whether application of the PGS is able to predict calcium stone type as classified by formation pattern (tubular plugging vs plaque overgrowth). We hypothesize that papilla with high injury scores will correlate with renal injury as quantified by cimetidine blocked creatinine clearance and microalbuminuria. We have documented that tubular plugging is histologically associated with significant inflammatory changes in the papilla. We will test the hypothesis that these changes will be reflected by elevated levels of inflammatory markers in urine, as well as tissue. We have previously documented that percantage of Randall's plaque papillary coverage correlates directly with stone activity. We will determine whether papillary injury is also associated with stone activity. Finally, we will test the hypothesis that inflammation secondary to ductal plugging is associated with chronic flank pain in the setting of non-obstructing renal stones and, further, whether the treatment of such stones is associated with improvement in patient symptoms. RELEVANCE