Metformin Preconditioning and Postconditioning to Reduce Ischemia Reperfusion Injury in an Isolated Ex Vivo Rat and Porcine Kidney Normothermic Machine Perfusion Model

Abstract

Metformin may act renoprotective prior to kidney transplantation by reducing ischemia-reperfusion injury (IRI). This study examined whether metformin preconditioning and postconditioning during ex vivo normothermic machine perfusion (NMP) of rat and porcine kidneys affect IRI. In the rat study, saline or 300 mg/kg metformin was administered orally twice on the day before nephrectomy. After 15 minutes of warm ischemia, kidneys were preserved with static cold storage for 24 hours. Thereafter, 90 minutes of NMP was performed with the addition of saline or metformin (30 or 300 mg/L). In the porcine study, after 30 minutes of warm ischemia, kidneys were preserved for 3 hours with oxygenated hypothermic machine perfusion. Subsequently, increasing doses of metformin were added during 4 hours of NMP. Metformin preconditioning of rat kidneys led to decreased injury perfusate biomarkers and reduced proteinuria. Postconditioning of rat kidneys resulted, dose-dependently, in less tubular cell necrosis and vacuolation. Heat shock protein 70 expression was increased in metformintreated porcine kidneys. In all studies, creatinine clearance was not affected. In conclusion, both metformin preconditioning and postconditioning can be done safely and improved rat and porcine kidney quality. Because the effects are minor, it is unknown which strategy might result in improved organ quality after transplantation.

Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials

“…However, no significant differences were observed comparing pre and post conditioning effects. In porcine study, creatinine clearance did not differ between kidneys perfused in NMP with metformin and without drug, even if there was a tendency toward lower creatinine levels in metformin-treated group ( 112 ). Histological analysis of porcine renal biopsies reported no differences in morphological lesions of renal parenchyma between two NMP groups ( 112 ).…”

“…In porcine study, creatinine clearance did not differ between kidneys perfused in NMP with metformin and without drug, even if there was a tendency toward lower creatinine levels in metformin-treated group ( 112 ). Histological analysis of porcine renal biopsies reported no differences in morphological lesions of renal parenchyma between two NMP groups ( 112 ). Therefore, metformin can be used in renal transplantation setting but it remains unclear whether addition of this drug during machine perfusion results in improved organ quality after transplantation ( 112 ).…”

“…However, no significant results were obtained in randomized clinical studies in myocardial setting (205,206). Recently, Huijink T M et al tested the effects of metformin in a rat model of renal I/R injury and in NMP with ischemic porcine kidneys (112). In rat experimental model, pre-and postconditioning with metformin significantly reduced tubular cell necrosis and endothelial dysfunction and improved organ quality (112).…”

“…Histological analysis of porcine renal biopsies reported no differences in morphological lesions of renal parenchyma between two NMP groups (112). Therefore, metformin can be used in renal transplantation setting but it remains unclear whether addition of this drug during machine perfusion results in improved organ quality after transplantation (112).…”

Ex-vivo Kidney Machine Perfusion: Therapeutic Potential

“…Huijink et al investigated the potential beneficial effect of metformin on kidney graft injury by the donor pre-treating and/or adding it to NMP solution in rats and pigs experiments (120). Metformin is not only known as an antihyperglycemic agent but also has some pleiotropic effects, due to its ability to inhibit the complex 1 of the mitochondrial respiratory chain, coordinate cellular energy state, inhibit apoptosis, and regulate endothelial function via NO production (175,176).…”