Abstract 20869: Preservation of Transplant Organ Function and Recipient Survival With Thrombin-Targeted Perfluorocarbon Nanoparticles Perfused Ex Vivo
Introduction: Methods to improve functionality of excised organs harvested for transplant could extend the time available for selection and implantation and enhance transplant opportunities for millions of potential organ recipients. For proof of concept, we elected to test kidney preservation with use of methods that could be applicable to all other tissues such as the heart, liver and lungs.
Hypothesis: We hypothesized that perfusion of explanted allografts with thrombin-targeted perfluorocarbon nanoparticles (PFC-NP) could attenuate organ inflammation, prevent ischemic injury by inhibiting microvascular thrombosis, and thereby improve graft function.
Methods: Male Lewis rats underwent left renal explantation followed by perfusion with 0.3 ml of untargeted PFC-NP (N=4), 0.3 ml thrombin-targeted PFC NP functionalized with the anti-thrombin molecule PPACK (phenylalanine-proline-arginine-chloromethylketone), an irreversible thrombin inhibitor, (N=4) or standard perfusate (N=3). Kidneys then underwent 60 minutes of warm ischemia and 6 hours of cold incubation, followed by transplantation into recipients and native nephrectomy. Blood was collected at 48 hours post-transplant and the animals were euthanized. Kidney biopsies were processed for blinded histologic analysis. A survival experiment was then performed using the protocol as above in Male Lewis rats with standard perfusate (N=3), empty nanoparticle (N=3) and PFC-PPACK (N=6).
Results: Serum Cr at 48 hrs was substantially improved for the PPACK PFC NP groups as compared to control groups: 6.3 vs 5.2 vs 1.9 mg/dl for control, PFC-NP, and PPACK NP (p<0.01 by ANOVA). Kaplan-Meier survival curves also indicated improved survival despite the extreme injury that ultimately eventuates in demise for all subjects. Blinded histologic scoring revealed markedly attenuated renal damage in the PFC NP PPACK group compared to untreated animals (2.75 +/- 1.60 versus 83 +/- 3.89 (P=.0001)).
Conclusions: Nanoparticles targeted to thrombin preserved explanted organ function in a syngeneic transplant model and extended survival, offering a simple approach for preserving tissue integrity under conditions of even extreme prolonged ischemia.
Author Disclosures: C. Vemuri: None. A. Upadhya: None. B. Arif: None. J. Jia: None. J. Gaut: None. P. Manning: Employment; Modest; Vasculox, inc.. Y. Lin: None. S. Wickline: Research Grant; Modest; NIH. Ownership Interest; Modest; AcuPlaq LLC. W. Chapman: None.
- © 2016 by American Heart Association, Inc.