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 ETA/B receptor antagonist (n=8). ET-R blockade was induced by adding the ETA, A-147627, or the ETA/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< or =0.05 vs. nonischemic controls); isch + ETA blockade, 0.95+/-0.15 (P< or =0.05 vs. isch only); isch + ETA/B blockade, 0.90+/-0.08 (P< or =0.05 vs. isch only).


CONCLUSIONS
Addition of an ETA, A-147627, or an ETA/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.
Inman
Sharon R
SR
Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, Ohio 45701, USA.
Burns
Thomas E
TE
Plott
Wanda K
WK
Pomilee
Ray A
RA
Antonelli
Jodi A
JA
Lewis
Richard M
RM
D000818:Animals; D000077868:Atrasentan; D065128:Endothelin Receptor Antagonists; D005919:Glomerular Filtration Rate; D007036:Hypothermia, Induced; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000098:blood supply* / Q000503:physiopathology; D016030:Kidney Transplantation; D009926:Organ Preservation / Q000009:adverse effects*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D017466:Receptors, Endothelin / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D017466:Receptors, Endothelin; D000077868:Atrasentan