Introduction
Kidney transplantation is the best treatment for kidney failure, offering better survival and quality of life than dialysis. However, donor organ availability remains a challenge. In deceased donor transplantation, organs undergo ischemia-reperfusion injury due to storage between retrieval and transplant. Static cold storage (SCS) is the simplest method to slow this damage but has limitations.
Machine perfusion, which circulates preservation fluid through the organ, offers advantages such as reduced injury, improved organ viability assessment, and potential for extended storage. Perfusion methods differ by temperature (hypothermic, normothermic, subnormothermic), oxygen delivery, timing, and location (ex situ, NRP).
A Cochrane Review compared various machine perfusion methods with each other and with SCS, including all donor types and study designs. Meta-analyses were conducted using random-effects models and indirect comparisons where needed. Evidence quality was assessed using the GRADE approach.
Findings
Twenty-two studies (4,007 participants) were included. The risk of bias was generally low across all studies and bias domains. The majority of the evidence compared nonoxygenated hypothermic machine perfusion (HMP) with standard static cold storage (19 studies). The remaining 3 studies compared the following: (1) normothermic machine perfusion versus static cold storage, (2) nonoxygenated HMP versus oxygenated HMP, and (3) oxygenated HMP versus static cold storage.
Nonoxygenated HMP versus static cold storage
Nonoxygenated hypothermic machine perfusion (HMP) significantly reduced the rate of delayed graft function (DGF) compared to static cold storage (SCS), particularly when applied continuously from donor hospital to transplant center. This benefit was consistent across both donation after circulatory death (DCD) and brainstem death (DBD) donors, with no difference in treatment effect between them. Due to a higher baseline risk in DCD kidneys, fewer perfusions were needed to prevent one case of DGF. The effectiveness of HMP remained evident even in studies conducted after 2008 and in cases with short cold ischemia times. However, DGF as an outcome measure has limitations, as it may not always reflect graft quality or long-term success.
More meaningful outcomes like graft survival showed stronger advantages for continuous nonoxygenated HMP over SCS. Meta-analyses revealed improved 1-year graft survival and long-term graft outcomes with HMP, but these effects were not observed when HMP was not applied continuously. While the impact of HMP on other clinical outcomes such as primary nonfunction, rejection, or patient survival remains uncertain, economic analyses suggest that HMP is either cost-saving or cost-effective in various healthcare settings. Given its long-term benefits in graft survival, the true economic value of HMP may be even greater than current estimates suggest.
Oxygenated HMP
One study investigated continuous oxygenated HMP versus nonoxygenated HMP (low risk of bias in all domains). This study used a “dummy” oxygen cylinder and is therefore the only included study that could be double-blind. The simple addition of oxygen during continuous HMP leads to additional benefits over nonoxygenated HMP in DCD donors (>50 years). This included further improvements in graft survival, improved 1-year kidney function, and reduced acute rejection. It is important to note that the control group in this trial is nonoxygenated HMP, which is itself superior to static cold storage.
One large study, which was deemed low risk of bias in all domains, investigated end-ischemic oxygenated HMP versus static cold storage in extended-criteria DBD kidneys. They found that end-ischemic oxygenated HMP (median machine perfusion time 4.6 hours) demonstrated no benefit compared to static cold storage. This further reinforces the importance of timing of kidney perfusion.
Normothermic machine perfusion
A single study investigated normothermic machine perfusion versus static cold storage (low risk of bias in all domains). One hour of end-ischemic normothermic machine perfusion did not improve delayed graft function, graft survival, or 1-year kidney function compared with static cold storage alone. An indirect comparison revealed that continuous nonoxygenated HMP (the most studied intervention) was associated with improved graft survival compared with end-ischemic normothermic machine perfusion (indirect HR, 0.31; 95% CI, 0.11-0.92; P = 0.03).
No studies investigated NRP or included any donors undergoing NRP. There is, however, growing evidence from retrospective studies that NRP appears to improve post-transplant kidney outcomes.
Conclusion
Continuous nonoxygenated hypothermic machine perfusion (HMP) is clearly superior to static cold storage in deceased donor kidney transplantation. It significantly reduces delayed graft function, enhances graft survival, and proves cost-effective across donor types (DBD and DCD), cold ischemia times (short and long), and remains effective in the modern clinical setting. In older DCD donors (>50 years), adding oxygen to continuous HMP offers further improvements in graft survival, kidney function, and reduces acute rejection rates compared to nonoxygenated HMP.
The timing and duration of HMP are critical factors—continuous application shows clear advantages, while short-duration end-ischemic HMP (around 4.6 hours) does not offer similar benefits, particularly in DBD donors. End-ischemic normothermic machine perfusion (1 hour) also fails to outperform static cold storage and is inferior to continuous HMP in graft survival outcomes. Future research is focusing on advanced techniques like subnormothermic acellular perfusion and combinations with normothermic regional perfusion, aiming to optimize organ preservation and explore therapeutic delivery during perfusion.
References
1. R.A. Wolfe, V.B. Ashby, E.L. Milford, et al.
Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant
N Engl J Med, 341 (23) (1999), pp. 1725-1730
2. G.J. Nieuwenhuijs-Moeke, S.E. Pischke, S.P. Berger, et al.
Ischemia and reperfusion injury in kidney transplantation: relevant mechanisms in injury and repair
J Clin Med, 9 (1) (2020), p. 253
3. C.H. Wilson, N.R. Brook, D. Talbot
Preservation solutions for solid organ transplantation
Mini Rev Med Chem, 6 (10) (2006), pp. 1081-1090
4. M.I. Bellini, J. Yiu, M. Nozdrin, V. Papalois
The effect of preservation temperature on liver, kidney, and pancreas tissue ATP in animal and preclinical human models
J Clin Med, 8 (9) (2019), p. 1421
5. C. Moers, J.M. Smits, M.H.J. Maathuis, et al.
Machine perfusion or cold storage in deceased-donor kidney transplantation
N Engl J Med, 360 (1) (2009), pp. 7-19
6. S.A. Hosgood, C.J. Callaghan, C.H. Wilson, et al.
Normothermic machine perfusion versus static cold storage in donation after circulatory death kidney transplantation: a randomized controlled trial
Nat Med, 29 (6) (2023), pp. 1511-1519
7. M.J.A. de Haan, M.E. Jacobs, F.M.R. Witjas, et al.
A cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys
Nat Commun, 15 (1) (2024), p. 3818
8. I. Jochmans, A. Brat, L. Davies, et al.
Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial
Lancet, 396 (10263) (2020), pp. 1653-1662
9. S.J. Tingle, E.R. Thompson, R.S. Figueiredo, et al.
Normothermic and hypothermic machine perfusion preservation versus static cold storage for deceased donor kidney transplantation
Cochrane Database Syst Rev, 7 (7) (2024), Article CD011671
10. G.C. Oniscu, J. Mehew, A.J. Butler, et al.
Improved organ utilization and better transplant outcomes with in situ normothermic regional perfusion in controlled donation after circulatory death
Transplantation, 107 (2) (2023), pp. 438-448
