Normothermic Machine Perfusion (NMP) Versus Static Cold Storage (SCS) in Human Kidney Transplantation

The first human kidney transplantation (KT) was performed by Murray et al. in 1954 and has evolved as the standard treatment for kidney failure (previously referred to as end-stage renal disease (ESRD). In 2020, approximately 7067 patients were listed for KT in Germany, however only 1342 transplantations could be performed due to organ shortage. The number of patients on the waiting list substantially exceeds the number of donors. Around 390 patients died while waiting for a suitable organ on the waiting list, and another 492 patients dropped out due to morbidity and advancing disease. For increasing donor pool utilization several strategies have been aimed, including living donation, old-for-old KT and transplantation of extended criteria donor (ECD) allografts. While, ECD allografts are associated with a higher incidence of graft related complications and impaired postoperative outcome, novel preservation techniques such as ex-vivo machine perfusion (MP) of the donor allograft have been developed aiming at optimizing the function of marginal organs after transplantation.

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, 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 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.

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.

Hypothermic (HMP) and hypothermic oxygenated MP (HOPE) may be seen as dynamic cold organ preservation based on hypothermia-induced deceleration of metabolism, which aims to combine the positive effects of hypothermia observed in classical cold storage with the positive effects of dynamic preservation. In contrast normothermic perfusion (NMP) mimics physiological circumstances and provides sufficient oxygen and nutrient supply.

End-ischemic HMP with oxygen (HOPE) presents 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, there are no registered randomized controlled clinical trials (RCT), comparing end-ischemic NMP versus SCS in donation after brain death (DBD), the only legal donation circumstance in Germany.

The aim of this study is to investigate the impact of end-ischemic NMP compared to SCS in a multicenter prospective randomized controlled clinical trial (RCT) using ECD kidney allografts from DBD donors.