Shock wave lithotripsy (SWL) is clearly an effective noninvasive treatment for a wide variety of upper urinary tract calculi. However, compelling clinical data now suggest that exposure to shock waves in therapeutic doses may be associated with 1) acute renal injury in a majority, if not all SWL patients, 2) at least two chronic effects; a rise in diastolic blood pressure and a decrease in renal function and 3) renal trauma enhanced by pre-existing risk factors. Thus, there is a growing, well founded concern regarding the potential for increased and significant patient morbidity as SWL continues to gain in popularity. Concern regarding the adverse effects of SWL is heightened by the prospect that little is known about the mechanical stresses of shock waves that contribute to stone comminution but induce extensive cell/tissue injury. To address these concerns, this Program Project will test a unifying hypothesis which states that, 1) the mechanical stresses generated by SWL facilitate stone comminution but induce cellular damage, 2) acute cellular injury in the kidney, transiently alters renal function, and 3) that pre-existing risk factors predispose the SWL treated kidney to chronic complications. Four projects are presented. A whole-animal study (Project 1) will identify and characterize risk factors thought to lead to acute and chronic impairment of renal hemodynamics and function, permanent alteration of renal structure and chronic hypertension. An in vitro study (Project 2) will determine the role of cavitation in SWL-induced injury to renal tubular epithelial and vascular endothelial cells. Two biophysical studies (Projects 3 & 4) will determine how the mechanical stresses (i.e. cavitation, shear, spall) generated by shock waves contribute to stone comminution but at the same time cause cellular damage. For the first time, biomechanical determinations to characterize shock waves will be performed in minipigs and under in vitro conditions. The new data generated by this Program Project will provide objectively determined criteria for the safe clinical use of SWL.