What is the issue?
Kidney transplantation is the best treatment for patients with end-stage kidney disease. However, there are not enough donated organs to go around. In addition, whilst a donated kidney is outside of the body it is starved of oxygen, the halting of circulation allows small clots to form, which damages the organ. This damage remains a major barrier to transplantation as it renders many organs unusable and is associated with decreased survival of the kidneys which are transplanted. Traditionally kidneys were kept in ice (termed static cold storage). Machines which drive cold (hypothermic machine perfusion) or warm (normothermic machine perfusion) solutions through donated kidneys aim to decrease the damage done during transport and therefore improve the outcomes for these kidneys.
What did we do?
We performed a rigorous search for studies which compared hypothermic machine perfusion, normothermic machine perfusion and standard static cold storage. Data from included studies could then be combined to allow further analysis. Our primary outcome was rate of delayed graft function (DGF) (the number of patients who needed extra dialysis support in the week following transplant). Our main secondary outcome of interest was one-year kidney survival (the number of transplanted kidneys functioning at one year).
What did we find?
Sixteen studies (2266 participants) comparing hypothermic machine perfusion with static cold storage were included. The use of hypothermic machine perfusion instead of standard static cold storage reduces the risk of DGF by approximately 23%. Two reports performed economic analysis, in the USA and European settings, and both estimated cost savings with the use of hypothermic machine perfusion. Two studies reported hypothermic machine perfusion prolongs the length of time that donated kidneys survive in the recipient, however we were unable to perform an analysis to confirm this. The effect of HMP on other outcomes (incidence of acute rejection, patient survival, hospital stay, long-term kidney function, duration of DGF) remains uncertain.
No completed studies investigating normothermic machine perfusion were identified, but one ongoing study was identified.
Compared with standard static cold storage, hypothermic machine perfusion reduces the rate of DGF in kidneys from deceased donors, and likely results in increased survival of the transplanted kidney and overall cost savings. Studies looking at normothermic machine perfusion are required to assess if this results in superior outcomes.
HMP is superior to SCS in deceased donor kidney transplantation. This is true for both DBD and DCD kidneys, and remains true in the modern era (studies performed in the last decade). As kidneys from DCD donors have a higher overall DGF rate, fewer perfusions are needed to prevent one episode of DGF (7.26 versus 13.60 in DBD kidneys).
Further studies looking solely at the impact of HMP on DGF incidence are not required. Follow-up reports detailing long-term graft survival from participants of the studies already included in this review would be an efficient way to generate further long-term graft survival data.
Economic analysis, based on the results of this review, would help cement HMP as the standard preservation method in deceased donor kidney transplantation.
RCTs investigating (sub)NMP are required.
Kidney transplantation is the optimal treatment for end-stage kidney disease. Retrieval, transport and transplant of kidney grafts causes ischaemia reperfusion injury. The current accepted standard is static cold storage (SCS) whereby the kidney is stored on ice after removal from the donor and then removed from the ice box at the time of implantation. However, technology is now available to perfuse or "pump" the kidney during the transport phase or at the recipient centre. This can be done at a variety of temperatures and using different perfusates. The effectiveness of treatment is manifest clinically as delayed graft function (DGF), whereby the kidney fails to produce urine immediately after transplant.
To compare hypothermic machine perfusion (HMP) and (sub)normothermic machine perfusion (NMP) with standard SCS.
We searched the Cochrane Kidney and Transplant Register of Studies to 18 October 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
All randomised controlled trials (RCTs) and quasi-RCTs comparing HMP/NMP versus SCS for deceased donor kidney transplantation were eligible for inclusion. All donor types were included (donor after circulatory (DCD) and brainstem death (DBD), standard and extended/expanded criteria donors). Both paired and unpaired studies were eligible for inclusion.
The results of the literature search were screened and a standard data extraction form was used to collect data. Both of these steps were performed by two independent authors. Dichotomous outcome results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Continuous scales of measurement were expressed as a mean difference (MD). Random effects models were used for data analysis. The primary outcome was incidence of DGF. Secondary outcomes included: one-year graft survival, incidence of primary non-function (PNF), DGF duration, long term graft survival, economic implications, graft function, patient survival and incidence of acute rejection.
No studies reported on NMP, however one ongoing study was identified.
Sixteen studies (2266 participants) comparing HMP with SCS were included; 15 studies could be meta-analysed. Fourteen studies reported on requirement for dialysis in the first week post-transplant (DGF incidence); there is high-certainty evidence that HMP reduces the risk of DGF when compared to SCS (RR 0.77; 95% CI 0.67 to 0.90; P = 0.0006). HMP reduces the risk of DGF in kidneys from DCD donors (7 studies, 772 participants: RR 0.75; 95% CI 0.64 to 0.87; P = 0.0002; high certainty evidence), as well as kidneys from DBD donors (4 studies, 971 participants: RR 0.78, 95% CI 0.65 to 0.93; P = 0.006; high certainty evidence). The number of perfusions required to prevent one episode of DGF (number needed to treat, NNT) was 7.26 and 13.60 in DCD and DBD kidneys respectively. Studies performed in the last decade all used the LifePort machine and confirmed that HMP reduces the incidence of DGF in the modern era (5 studies, 1355 participants: RR 0.77, 95% CI 0.66 to 0.91; P = 0.002; high certainty evidence). Reports of economic analysis suggest that HMP can lead to cost savings in both the North American and European settings.
Two studies reported HMP also improves graft survival however we were not able to meta-analyse these results. A reduction in incidence of PNF could not be demonstrated. The effect of HMP on our other outcomes (incidence of acute rejection, patient survival, hospital stay, long-term graft function, duration of DGF) remains uncertain.