Abstract
BackgroundDespite advances in immunosuppressive therapy, kidney graft survival has failed to improve during the last decades. Ischemia/reperfusion injury (IRI) is one of the main pathophysiological mechanisms underlying delayed graft function, which is associated with poor long-term graft survival. Due to organ shortage, the proportion of grafts from expanded criteria donors (ECDs) is ever growing. These grafts may particularly benefit from IRI prevention. In preclinical models, mineralocorticoid receptor antagonists (MRAs) have been shown to efficiently prevent IRI. This study aims to assess the effect of MRA administration in the early phase of kidney transplantation (KT) among recipients of ECD grafts on mid-term graft function.Methods/designThis is a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients on hemodialysis and undergoing a single or a dual KT from an ECD will be eligible for inclusion. We plan to randomize 132 patients. Included patients will be randomized (1:1) to receive either eplerenone 25 mg every 12 h during 4 days (the first dose being administered just prior to KT) or placebo. The primary outcome is graft function at 3 months, assessed by glomerular filtration rate (GFR, in mL/min/1.73m2) measured using iohexol clearance. Secondary outcomes include (1) proportion of patients with either dialysis dependency or a GFR < 30 mL/min/1.73m2 at 3 months, (2) proportion of patients with immediate, slow, or delayed graft function, (3) proteinuria at 3 months, (4) occurrence of hyperkalemia during the first week following KT, (5) length of hospital stay for the KT, and (6) occurrence of biopsy-proven acute rejection in the first 3 months following KT. Estimated GFR, graft, and patient survival will also be collected at 1, 3, and 10 years via the national database of organ recipients.DiscussionImprovement of ECD grafts is a public health priority, since better ECD outcomes could eventually limit organ shortage. MRA administration in the early phase of KT may prevent IRI and subsequently improve mid-term graft function. The trial will also assess the safety of MRA administration in this population, primarily the absence of threatening hyperkalemia.Trial registrationClinicalTrials.gov, NCT02490904. Registered on 1 July 2015.
Highlights
Despite advances in immunosuppressive therapy, kidney graft survival has failed to improve during the last decades
The trial will assess the safety of Mineralocorticoid receptor antagonist (MRA) administration in this population, primarily the absence of threatening hyperkalemia
Context of organ shortage and susceptibility of expanded criteria donor grafts to ischemia/reperfusion lesions The number of patients waiting for kidney transplantation (KT) is increasing at a dramatic pace [22] due to the higher incidence of end-stage renal disease (ESRD) [22] and better access to the waiting list
Summary
Despite advances in immunosuppressive therapy, kidney graft survival has failed to improve during the last decades. Ischemia/reperfusion injury (IRI) is one of the main pathophysiological mechanisms underlying delayed graft function, which is associated with poor long-term graft survival. KT faces organ shortage, leading to a greater use of kidneys from expanded criteria donors (ECDs), which are more susceptible to deleterious ischemia/reperfusion (I/R) lesions [6,7,8]. Preclinical studies in rodents and pigs have demonstrated a beneficial effect of MR antagonists (MRAs) in preventing acute IRI and mid-term GFR following AKI [13,14,15,16,17]. A pilot clinical trial on living-donor renal transplantation [18] demonstrated a beneficial effect of spironolactone on renal oxidative stress when administered to recipients 1 day before and 3 days after KT This trial was not associated with improved short-term renal function, since renal function was already good in the placebo group, as expected in living-donor transplantation. There has yet to be an assessment of the effect of MRA in ECD kidney grafts, which usually experience a much lower GFR than living-donor grafts
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