Abstract 15990: Cardiac Arrest and Cardiopulmonary Resuscitation in the Mouse Induces Renal Fibrosis: Contribution of Proximal Tubular Endocytosis

Introduction: Cardiac arrest and cardiopulmonary resuscitation (CA/CPR) causes acute cardiorenal syndrome in the mouse. Recent studies demonstrate that in humans, cardiorenal syndrome may initiate chronic kidney disease (CKD). Clinical studies of cardiorenal acute kidney injury(AKI)-to-CKD transition report higher incidence of CKD than studies of all-cause AKI-to-CKD transition, but no animal model of AKI-CKD transition includes cardiac injury. Hypothesis: We hypothesized that CKD is a potentially preventable, long-term outcome of cardiac arrest. Methods: Male C57Bl/6 mice, and mice with proximal tubule-specific deletion of the proximal tubular (PT) endocytosis receptor, megalin, (PTmegKO and littermate controls) were subjected to CA/CPR (induced with potassium chloride, resuscitated 8 min later with chest compressions and epinephrine). Urine mass spectrometry was performed 24h before and 24h after CA/CPR in PTmegKO and control mice. After 28 days, renal function (glomerular filtration rate, GFR and serum urea nitrogen, sUN) were assessed, and kidney sections stained and quantified for alpha-smooth muscle actin (aSMA) and collagen. Results: Time to return of spontaneous circulation, epinephrine dose, and survival to 28d (66%) were not different. WT CA/CPR-treated mice developed CKD with elevated sUN, reduced GFR and renal fibrosis compared to sham (renal interstitial aSMA burden 14.4±4.5 vs 0.8±0.5%, p Conclusions: AKI to CKD transition occurs after CA/CPR in the mouse. Deletion of PT megalin reveals cardiac protein in the urine following CA/CPR compared to littermates suggesting cardiac protein is taken up by PT cells after CA/CPR. Deletion of PT megalin likely reduced renal fibrosis 1 month after CA/CPR. Investigation of pharmacologic inhibition of megalin to reduce transition to CKD after CA/CPR is warranted.