Clinical trial NCT05031052: Normothermic Machine Perfusion (NMP) Versus Static Cold Storage (SCS) in Human Kidney Transplantation
Official title: Normothermic Machine Perfusion (NMP) Compared to Static Cold Storage (SCS) in Donation After Brain Death (DBD) Kidney Transplantation; a Prospective Multicenter Randomized Controlled Trial (NMP-DBD)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Kidney Transplant; Complications
Kidney Failure
Graft Dysfunction
Keywords: ex-vivo machine perfusion
normothermic machine perfusion
kidney transplantation
extended criteria donation
donation after brain death
NMP
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
First posted: 2021-09-01
Enrollment: 194
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter prospective randomized controlled trial
Primary purpose: TREATMENT

Brief summary: Due to organ shortage in kidney transplantation (KT) several strategies have been implemented in an attempt to increase donor pool utilization, including transplantation of extended criteria donor (ECD) allografts. While the transplantation of ECD organs saves patients from waiting-list dropout, these pre-damaged organs exhibit an increased susceptibility to further injury during organ storage and transplantation. Static cold storage (SCS) involves the transportation of procured donor kidneys on ice and has remained the gold standard for organ preservation for decades. SCS relies on hypothermia to reduce cellular metabolism and oxygen demand while achieving a prolonged preservation time of organs. Upon reperfusion, the reintroduction of oxygen to the ischemic kidney leads to a respiratory burst with massive production of mitochondrial reactive oxygen species and subsequent sterile inflammation of the entire organ. This ischemia-reperfusion injury (IRI) is a central predictor of graft and patient survival. Current clinical preservation strategies are unable to meet the challenges of ECD allograft transplantation and there is a great demand to optimize preservation techniques for such high risk ECD allografts.

Currently, two main paradigms prevail in the clinical approach to kidney allograft machine perfusion (MP) in regard to optimized preservation techniques: while end-ischemic 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 could not proof a beneficial effect on delayed graft function or primary graft failure, the impact of normothermic perfusion (NMP) on ECD kidney allografts is still missing. NMP aims at re-equilibration of cellular metabolism by preserving the organ at physiological temperatures whilst ensuring sufficient oxygen and nutrient supply. The present trial was therefore designed to provide first level-II evidence for NMP in human KT after donation after brain death (DBD). In total, 194 human kidney grafts will be randomized to either 4 hours of NMP directly before implantation (intervention group; n = 97) or to 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, incidence of delayed graft function (DGF), primary non-function (PNF) and surgical complications assessed by the comprehensive complication index (CCI).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent
* Patients 18 years or older
* Patients suffering from end-stage kidney disease / kidney failure
* Listed for kidney transplantation
* Receiving ECD-allograft

Exclusion Criteria:

* Recipients of living donor kidney transplants
* Previous kidney transplantation
* Combined transplantations (liver-kidney, kidney-pancreas, etc.)
* Participation in other kidney related trials
* Exposure to an investigational drug within 30 days prior to inclusion
* Unwilling or unable to follow the procedures outlined in the protocol
* Mentally or legally incapacitated

Primary outcomes:
measure: Kidney function
timeFrame: After 6 months postoperatively
Secondary outcomes:
measure: Kidney function
timeFrame: After 3- and 12 months postoperatively
measure: Delayed graft function
timeFrame: First 7 postoperative days
measure: Functional delayed graft function
timeFrame: First 7 postoperative days
measure: Creatinine change ratio
timeFrame: Day 2 and day 5 postoperatively
measure: Primary non function (PNF)
timeFrame: After 3 months postoperatively
measure: Incidence and severity of postoperative complications
timeFrame: 90-days and 1-year postoperatively
measure: Hospitalization
timeFrame: Follow-up duration of 1-year
measure: Cost analysis
timeFrame: Follow-up duration of 1-year
measure: Recipient- and graft survival
timeFrame: Follow-up duration of 1-year
measure: Acute rejection incidence
timeFrame: Follow-up duration of 1-year
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité Universitaetsmedizin Berlin, Campus Mitte | Campus Virchow-Klinikum
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover (MHH), Department of Surgery and Transplantation
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg, Department of Surgery and Transplantation
city: Munich
country: Germany
facility: Ludwig-Maximilian's University, Campus Grosshadern, Department of General, Visceral, and Transplant Surgery
Study officials:
References: