Abstract
Objective. Ischemia-reperfusion injury (IRI) is inevitable after kidney transplantation (KT), impairing outcomes. Relaxin-2 (RLX) is a promising insulin-related peptide hormone that protects against renal IRI in rodents, although large animal models are needed before RLX can be tested in a human setting. Methods. In this blinded, randomized, and placebo-controlled experimental study kidneys from 19 donor pigs were retrieved after perfusion with Custodiol® ± RLX (5 or 20 nmol/L) and underwent static cold storage (SCS) for 24 and 48 h, respectively. Subsequently, KT was performed after unilateral right nephrectomy. Study outcomes included markers for kidney function, oxidative stress, lipid peroxidation, and endothelial cell damage. PCR analysis for oxidative stress and apoptosis-related gene panels as well as immunohistochemistry were performed. Results. RLX upregulated SOD2 and NFKB expression to 135% (p = 0.042) and 125% (p = 0.019), respectively, while RIPK1 expression was downregulated to 82% (p = 0.016) of corresponding controls. Further RLX significantly downregulated RIPK1 and MLKL expression and decreased the number of Caspase 3- and MPO-positive cells in grafts after SCS. Conclusions. RLX supplemented Custodiol® significantly decreased IRI via both antioxidant and anti-apoptotic mechanisms. Clinical trials are warranted to implement synthetic human RLX as a novel additive to preservation solutions against IRI.
Highlights
Ischemia/reperfusion injury (IRI) is inevitable after kidney transplantation (KT), impairing short- and long-term outcomes [1]
Immunohistochemistry and graft function representing parameters were similar across the animals treated by 5 or 20 nM RLX (Supplementary File). This large animal KT model investigated whether RLX added to conventional Custodiol® affects a panel of genes involved in oxidative stress and apoptosis/necroptosis as well as graft condition in terms of cell death and inflammation after
RLX upregulates the expression of antioxidant (SOD2) and anti-apoptotic (NFkB) genes in kidney grafts after perfusion and downregulates pro-apoptotic/necroptotic (RIPK; MLKL) genes after Static cold storage (SCS)
Summary
Ischemia/reperfusion injury (IRI) is inevitable after kidney transplantation (KT), impairing short- and long-term outcomes [1]. To overcome the shortage of donor kidneys, the use of extended criteria donor (ECD) grafts is increasing, and these organs are known to be more susceptible to IRI [2,3]. The impact of IRI is an increasing problem, and prevention strategies to better protect grafts are urgently required. The use of pharmacological supplements for organ preservation solutions targeting specific pathways of IRI is a promising strategy to improve KT outcomes. Relaxin-2 (RLX), an insulin-related peptide hormone, displays antifibrotic, antioxidant, anti-inflammatory, and cytoprotective properties [5,6,7,8], it can be considered as a potential substance to reduce IRI. In a rat kidney IRI model, RLX application prior to IR induction resulted in
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