Studies conducted to date by Project 1 have characterized the acute renal injury and functional impairment caused by shock wave lithotripsy (SWL), with identification of potentially harmful risk factors for SWL and strategies to reduce acute tissue injury. The studies proposed in this PPG renewal will extend these results into the long-term effects of SWL. The Mayo clinic recently released information on a 19 year follow-up study on patients whose kidney stones were treated with SWL, the results of which raised concerns that SWL might be a risk factor for the onset of diabetes mellitus. We will use pig models ofthe pre-diabetic (metabolic syndrome) and diabetic (type 2 diabetes) phenotype and perform glucose regulation tests to determine whether SWL is indeed a risk factor for the onset, or increasing the severity, of diabetes mellitus; as well as investigate the influence of renal sidedness oftreatment and lithotripter type (Aim 1). Our research group has identified SWL protocols that protect the kidney from the injurous effects of shock waves, and we propose to determine the mechanism(s) by which these SWL protection procotols initiate their protective effect (Aims 2 and 3). Longitudinal studies have shown that patients are converting from calcium oxalate stone formers to brushite stone formers and that this is correlated with the number of SWL treatments. This is worrisome as brushite stones are hard stones that are difficult to fragment with SWL. A pig model will be used to test whether SWL-induced damage ofthe papilla results in long-term changes in nephron structure and function, leading to an impairment of papillary urine acidification and the production of a more alkaline urine, a milieu which would favor brushite stone formation; and to determine whether SWL protection protocols can prevent such adverse changes in renal structure and function (Aim 4). These aims have significant translational implications and will make SWL safer as they will identify what types of SWL treatments will lead to long-term adverse effects; optimize and determine the mechanisms of lithotripsy protocols that are protective from shock wave-induced injury, and the use of such SWL protection protocols to lessen/prevent the long-term complications of SWL. RELEVANCE (See instructions): Potential long-term adverse complications of SWL are becoming apparent in the stone forming population (e.g. diabetes, conversion to kidney stones that are resistant to SWL therapy). The proposed research will clarify whether SWL is responsible for these chronic adverse effects, and provide strategies to lessen and/or avoid such complications. These new observations will improve the safety of SWL for all patients.