NMP-DBD “first-in-Man” normothermic kidney trial

Screenshot 2023-03-28 at 11.32.42 The common practice of static cold storage (SCS) organ preservation has changed little since the initial introduction of the original University of Wisconsin (UW) organ preservation solution in the late 1980s. Static organ preservation relies on hypothermia to decelerate metabolism and reduce oxygen demand to prolong ischemia tolerance and avoid rapid functional graft impairment, thereby delaying graft damage. While a significant amount of anaerobic metabolism continues at a low rate, depleting cellular adenosine triphosphate (ATP) levels and deregulating ionic homeostasis, the metabolism of the allograft does not cease completely during SCS. In addition, the lack of blood flow-derived shear stress causes a disruption of endogenous nitric-oxide (NO) production and a functional impairment of endothelial cells. Upon reperfusion, the reintroduction of oxygen-rich blood to the ischemic allograft leads to a myriad of molecular events that drive a respiratory-burst with massive reactive oxygen species (ROS) production, mitochondrial oxidative stress and a sterile inflammatory reaction that is pivotal to kidney injury. This cascade of ischemia-reperfusion injury (IRI) ultimately leads to an impaired outcome, especially in the ECD-KT setting. While high-quality grafts are usually less prone to IRI, ECD allografts exhibit an impaired microcirculation and an increased susceptibility to inflammatory and oxidative stress and, as such, poorly tolerate extended periods of cold storage. Current clinical strategies are unable to fulfil the demands presented by the transplantation of ECD allografts. In recent years, MP has been recognized as a promising strategy in the context of ECD kidney transplantation. While SCS only prolongs storage time and limits the damage sustained during the period of cold ischemia, MP can reverse some of these effects. The terms organ “resuscitation” and “reconditioning” have been applied to the sustainment of organ viability and the improvement of graft function through MP before implantation. Currently, two main paradigms prevail in the clinical approach to kidney allograft MP: hypothermic (HMP) and hypothermic oxygenated MP (HOPE) may be seen as dynamic alternatives of the traditional organ preservation based on hypothermia-induced deceleration of metabolism, which aims to combine the positive effects of hypothermia observed in classical cold storage (e.g. technical simplicity, relative safety, decreased metabolism) with the positive effects of dynamic preservation (e.g. controlled sheer stress mediated gene activation, removal of metabolites, transport of oxygen and ATP recharging). In contrast normothermic perfusion (NMP) aims at re-equilibration of cellular metabolism by preserving the organ at physiological temperatures whilst ensuring sufficient oxygen and nutrient supply. In both approaches, the perpetual circulation and moderate shear-stress sustain endothelial functionality. While upfront HMP demonstrated significantly lower incidence of delayed graft function (DGF), primary non-function (PNF), and an improved one-year graft survival, no effect on the incidence of acute rejection, patient survival, hospital stay and long-term graft function was reported. End-ischemic HMP with oxygen (HOPE) presents another MP-approach and is marked by active oxygenation of the perfusate during MP. Even though beneficials effects of HOPE were reported in preclinical studies, no significant impact on DGF, PNF or graft survival after one year in human KT could be demonstrated. In contrast to hypothermic preservation methods, data on NMP in human KT is limited. In fact, only one registered randomized controlled clinical trial (RCT), comparing end-ischemic NMP versus SCS in donation after cardiac death (DCD) is currently recruiting.

The present trial was therefore designed to provide first level-II evidence for NMP in human KT after donation after brain death (DBD), the only legal mode of organ donation in Germany (apart from living donation). In total, 194 human kidney grafts will be randomized to either 4 hours of NMP directly before implantation (intervention group; n = 97) or the current standard of care, SCS (control group; n = 97) prior to transplantation. The primary endpoint will be kidney function after 6 months (6-months eGFR). Secondary endpoints include kidney function after 3 and 12 months, respectively, (3- and 12- months eGFR), incidence of DGF, PNT, surgical complications at 90 days and 1-year, serum creatinine and creatinine reduction ratio, graft- and patient survival, and hospital stay) endpoints are going to be analysed.

NMP-DBD is supported by 1.9 Million Euros national funds of the Federal Ministry of Education and research (BMBF). The study is performed at two major European Liver Transplantation Centers (Charité Universitätsmedizin Berlin, Germany; University Hospital Münster, Germany) and is currently recruiting at 2 sites.
  • NMP-DBD is the first-in-man randomized controlled trial world-wide to investigate the effects of end-ischemic normothermic kidney perfusion (NMP) compared to CCS in a multi-center prospective randomized controlled clinical trial (RCT) using ECD kidney grafts in DBD kidney-transplantation (NCT05031052)
  • NMP-DBD focuses on patients solely receiving ECD- and DBD-allografts, a population we anticipate the best cost/benefit ratio from the utilization of NMP.
  • NMP-DBD focuses on donation after brain death, the most frequent source of ECD-allografts in Europe.
  • Multi-center design, currently 2 centers (Charité Universitätsmedizin Berlin, University Hospital Münster, University Hospital Bonn)
  • Principal Investigator (Charité Universitätsmedizin Berlin): Georg Lurje, M.D.
  • Local Investigator (University Hospital Münster): Andreas Pascher, M.D.
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