Effect of N-acetylcysteine pretreatment of deceased organ donors on renal allograft function: a randomized controlled trial.

Delayed graft function (DGF) remains a complication of kidney transplantation that occurs in 20 to 35% of recipients.1-5 The mechanism of early renal transplant dysfunction remains incompletely understood. Nevertheless, ischemia-reperfusion plays a crucial role, leading to cell deaths, inflammatory response, immunologic activation, tissue fibrosis and impaired renal microcirculation.3-5 Reperfusion is characterized by an exacerbated oxidative stress due to a higher generation of oxygen free radicals.3,6-10 Administration of contrast-medium is practiced in some countries to confirm the diagnosis of brain death before organ procurement. Several factors contribute to consider deceased donors at higher risk for developing contrast-induced acute kidney injury (CI-AKI).11-13 The pathophysiology of this complication has many similarities with the DGF’s one.12-14 Delayed graft function is associated with an increased risk for acute graft rejection, chronic allograft failure and impaired long-term renal function after kidney transplantation.4,15-17 Consequently, many pharmacologic strategies, especially antioxidant molecules, were proposed to limit ischemia-reperfusion renal injuries without real clinical positive effect.3,18-22 Scarce clinical trials have evaluated the impact of various drugs in preventing DGF with conflicting results.23-27 A donor pretreatment with low-dose dopamine reduced the need for dialysis within the first 7 days after kidney transplantation,23 whereas DGF was not reduced with high repeated doses of epoetin25 nor with a unique dose of steroids.24 Thanks to its thiol-group, N-acetylcysteine (NAC) is able to regenerate glutathione stores and scavenges oxygen-free radicals.9,28-31 In addition to its antioxidant properties, NAC reduces ischemia-reperfusion damages by improving renal perfusion and by decreasing cell apoptosis.8,32 Controversy persists whether NAC affects creatinine levels because of modifications in muscular creatinine production.33,34 Thus, the real “protective” effect of NAC on renal function remains questioned. Several recent meta-analysis reported a protective effect of NAC for preventing the development of CI-AKI.35-37 In a randomized controlled trial, Koc et al.38 found that a prophylactic high dose of NAC reduced the occurrence of CI-AKI after coronary procedure. The KDIGO group suggests to administer NAC with an intravenous isotonic crystalloid in patients at risk to prevent CI-AKI.39 The impact of a pretreatment with NAC on kidney graft function has been evaluated in two animal models of kidney transplantation.22,40 N-acetylcysteine did not improve serum creatinine (SCr) levels nor histologic damages 24 hr after transplantation as compared with normal saline infusion.40 Lin et al.22 have shown that SCr and blood urea nitrogen (BUN) were lower at day 3 after renal transplantation. None of these studies assessed the incidence of DGF. Considering its experimental antioxidant properties and vasodilatory effects, NAC might reduce ischemia-reperfusion injuries of kidney grafts. Our goal was therefore to investigate the effectiveness of a donor pretreatment with NAC at reducing the occurrence of DGF after kidney transplantation.