Allograft kidney transplantation, which triggers host cellular- and antibody-mediated rejection of the kidney, is a major contributor to kidney damage during transplant. Here, we asked whether PrC-210 would suppress damage seen in allograft kidney transplant. Brown Norway (BN) rat kidneys were perfused in situ (UW Solution) with or without added 30 mM PrC-210, and then immediately transplanted into Lewis (LEW) rats. 20 h later, the transplanted BN kidneys and LEW rat plasma were analyzed. Kidney histology, and kidney/serum levels of several inflammation-associated cytokines, were measured to assess mismatch-related kidney pathology, and PrC-210 protective efficacy. Twenty hours after the allograft transplants: (i) significant histologic kidney tubule damage and mononuclear inflammatory cell infiltration were seen in allograft kidneys; (ii) kidney function metrics (creatinine and BUN) were significantly elevated; (iii) significant changes in key cytokines, i.e., TIMP-1, TNF-alpha and MIP-3A/CCL20, and kidney activated caspase levels were seen. In PrC-210-treated kidneys and recipient rats, (i) kidney histologic damage (Banff Scores) and mononuclear infiltration were reduced to untreated background levels; (ii) creatinine and BUN were significantly reduced; and (iii) activated caspase and cytokine changes were significantly reduced, some to background. In conclusion, the results suggest that PrC-210 could provide broadly applicable organ protection for many allograft transplantation conditions; it could protect transplanted kidneys during and after all stages of the transplantation process—from organ donation, through transportation, re-implantation and the post-operative inflammation—to minimize acute and chronic rejection.

Background Vascularized composite allotransplantation (VCA) represents a promising reconstructive solution primarily conducted to improve quality of life. However, tissue damage caused by cold-ischemia (CI) storage prior to transplant represents a major factor limiting widespread application. This study investigates the addition of the novel free radical scavenger PrC-210 to UW Organ Preservation Solution (UW Solution) to supress CI-induced skeletal muscle injury in a rat hind limb amputation model. Methods Lewis rats received systemic perfusion of UW solution +/- PrC-210 (0mM control, 10mM, 20mM, 30mM, or 40mM), followed by bilateral transfemoral amputation. Limbs were stored in 40mL of the same perfusate at 4°C for 48 hours. Muscle punch biopsies were taken at set times over the 48 hour cold-storage period and analyzed for caspase-3,7 activity, cytochrome C levels, and qualitative histology. Results A single 15 second perfusion of PrC-210-containing UW Solution conferred a dose-dependent reduction of CI-induced muscle cell death over 48 hr. In the presence of PrC-210, muscle cell mitochondrial Cytochrome C release was equivalent to 0 hr controls, with profound reductions in the Caspase 3,7 apoptotic marker that correlated with limb histology. PrC-210 conferred complete prevention of ROS-induced mitochondrial lysis in vitro, as measured by Cytochrome C release. Conclusion The addition of 30mM PrC210 to UW Solution conffered the most consistent reduction in CI limb damage, and it warrants further investigation for clinical application in the VCA setting.