To detect the source of relevant acute intrarenal side effects after extracorporeal piezoelectric lithotripsy and its impact on repeat treatment, urinary excretion of highly specific marker proteins was determined before (day-1) and after (days 0, 1, 4, 7, 14 and 21) treatment. Marker proteins included high molecular weight alpha-2-macroglobulin, immunoglobulin G, albumin, alpha-1-microglobulin as well as the enzyme N-acetyl-beta-glucosaminidase. Of 50 patients who underwent 4,000 shock waves to caliceal stones (group 1) 15 were identically retreated after 5 (group 2) or 15 (group 3) days, respectively, to determine the shortest safe interval to repeat extracorporeal piezoelectric lithotripsy. The course of lithotripsy damage was also evaluated in 15 pre-damaged kidneys (group 4). The alpha-2-macroglobulin enhancement found in all groups on day 0 (p less than 0.005 to p less than 0.05) documented intrarenal bleeding from ruptured vessels. Ratios of alpha-2-macroglobulin/albumin greater than 2.00 on days 0 and 1 exclude a glomerular source of gross hematuria (groups 1 to 4). There was only slight acute tubular damage after extracorporeal piezoelectric lithotripsy (N-acetyl-beta-glucosaminidase increase, p less than 0.05 for groups 1 to 4). Retreatment after 5 days did not enhance the amount of proteinuria compared to the same patients from group 1 (statistically significant at p less than 0.45 to p less than 0.10). Group 3 also showed a similar elevation of proteinuria as the identical patients pretreated 15 days previously. Thus, the data seem to suggest that early repeat sessions of extracorporeal piezoelectric lithotripsy are as safe as delayed retreatments. The course of proteinuria in group 4 did not suggest enhancement of extracorporeal piezoelectric lithotripsy damage in pre-injured kidneys. The urinary marker alpha-2-macroglobulin detects intrarenal vessel ruptures, which are responsible for intrarenal hematomas, as evidenced by animal and human histology. A model is offered to understand and detect the most important parenchymal bioeffects to minimize the risk of injury.