Exertional Heat Stroke (EHS) occurs with rapid onset during strenuous exertion and results in hospitalization that is often associated with renal and hepatic injury. EHS may increase susceptibility to a subsequent EHS collapse if organ injury has not completely resolved prior to the second heat exposure. We investigated renal filtration and mitochondrial oxidative phosphorylation (OP) changes in radiotelemetered C57BL/6J mice that were forced to run in a heat chamber (37.5°C) until collapse (core temperature ~42.7°C). Mice were exposed to one (EHS) or two EHS events separated by 1 (EHS1), 3 (EHS3) or 7 (EHS7) days of recovery. Samples were collected 30 min, 3h, 1, or 7d after the first or second EHS exposure. Blood urea nitrogen (BUN; Abaxis VetScan analyzer) and a Mitochondrial Function Assay MitoPlate (Biolog) were used to assess renal filtration and OP changes, respectively. EHS1 mice experienced significantly greater thermal load (area under the heat curve) and dehydration compared to EHS, EHS3 and EHS7 mice (p<0.001), but hypothermia depth during recovery was significant less pronounced than the other groups (~35°C vs. 32°C, respectively; p<0.01). EHS1 mice showed 103% and 95% BUN decrease at 30 min and 3h of recovery compared with EHS, EHS3, and EHS7 groups, respectively (ANOVA, p<0.001). Analysis of OP kinetics revealed that the following Citric Acid Cycle enzymes increased: Pyruvate Dehydrogenase (78%), Citrate Synthase (77%), Isocitrate Dehydrogenase (66%), Aconotase (59%) Alpha‐Ketoglutarate Dehydrogenase (50%), Succinate Dehydrogenase (18%), Fumurase (37%), and Malate Dehydrogenase (50%) 3h following EHS1, EHS3 or EHS7 (p<0.05). All values were compared and normalized to naive control animals. The core temperature data indicate that EHS mice were partially acclimated prior to the second exposure on day 1 and this was sufficient to improve thermal tolerance (time in the heat before collapse) and reduce the severe sequelae during recovery. The minimal BUN changes EHS1 mice may be a consequence of increased glomerular filtration promoting normal renal hemodynamics. However, the kidney of EHS3 mice appeared to recover prior to the second exposure such that renal function was no longer adversely affected. The potential mechanism of these changes may be attributed to citric acid cycle kinetics of the renal mitochondria. These are the first data to indicate that partial heat acclimation in mice is sufficient to protect them against renal injury following a second heat exposure and this response has a 3d decay rate.Support or Funding InformationThe views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government. This abstract has been approved for public release with unlimited distribution.