Endothelin receptor blockade during hypothermic perfusion preservation mitigates the adverse effect of preretrieval warm ischemic injury on posttransplant glomerular filtration rate

Background. Preretrieval warm ischemic injury predisposes to both short-term and long-term dysfunction of cadaveric renal allografts. We previously reported that the excretion of the vasoactive peptide, endothelin (ET), is significantly increased during hypothermic perfusion preservation (HPP) of kidneys subjected to preretrieval warm ischemia compared with nonischemic controls. As such, the purpose of this study was to determine if endothelin receptor (ET-R) blockade during HPP would improve glomerular filtration rate (GFR) of kidneys subjected to preretrieval warm ischemia when measured in situ at 2 weeks after transplantation (Tx). Methods. The left kidney was retrieved from 300-g Lewis rats after in situ cold perfusion and transplanted after 2 hr of HPP. A 30-min period of preretrieval warm ischemia was induced. Kidneys were divided into four groups: nonischemic controls (n=9), ischemic (isch) kidneys not receiving ET-R blockade during HPP (n=7), isch kidneys receiving the ETA receptor antagonist (n=7), and isch kidneys receiving the ET_A/B receptor antagonist (n=8). ET-R blockade was induced by adding the ET_A, A-147627, or the ET_A/B, A-182086, receptor antagonist (Abbott Laboratories, Abbott Park, IL) directly to the preservation solution (5x10^-6M). The kidneys were then isografted into genetically identical Lewis rats and GFR, determined by measurement of urinary iohexol clearance, measured 2 weeks after Tx. Results. Two-week GFRs (mL/min) for each of the study cohorts are as follows: nonischemic controls, 1.18±0.11; ischemic (isch) only, 0.57±0.08 (P≤0.05 vs. nonischemic controls); isch + ET_A blockade, 0.95±0.15 (P≤0.05 vs. isch only); isch + ET_A/B blockade, 0.90±0.08 (P≤0.05 vs. isch only). Conclusion. Addition of an ET_A, A-147627, or an ET_A/B, A-182086, receptor antagonist to preservation solution used during HPP of kidneys subjected to preretrieval warm ischemia resulted in a normalization of GFR measured 2 weeks after Tx. The data provide a basis for further investigation of the impact of ET-R blockade on both the short- and long-term adverse effects of preretrieval warm ischemic injury in cadaveric renal Tx.