The Benefits of Hypothermic Machine Preservation and Short Cold Ischemia Times in Deceased Donor Kidneys
Transplantation. 2018 Aug;102(8):1344-1350 doi: 10.1097/TP.0000000000002188.
Abstract
BACKGROUND:
Hypothermic machine perfusion (HMP) of deceased donor kidneys is associated with better outcome when compared to static cold storage (CS). Nevertheless, there is little evidence whether kidneys with short cold ischemia time (CIT) also benefit from HMP and whether HMP can safely extend CIT.
METHODS:We analyzed prospectively collected data from the Machine Preservation Trial, an international randomized controlled trial. Seven hundred fifty-two consecutive renal transplants were included: 1 kidney of each of the 376 donors was preserved by HMP, the contralateral organ was preserved by CS.
RESULTS:The mean CIT was 3:05 PM (SD, 4:58 AM). A subgroup analysis was performed, groups were based on CIT duration: 0 to 10 hours, 10 to 15 hours, 15 to 20 hours, or 20 hours or longer. Delayed graft function (DGF) incidence in the subgroup with up to 10 hours CIT was 6.0% (N = 3/50) in the HMP arm and 28.1% (N = 18/64) in the CS arm (univariable P = 0.002; multivariable odds ratio [OR], 0.02; P = 0.007). Cold ischemia time remained an independent risk factor for DGF for machine perfused kidneys recovered from donation after brain death donors (OR, 1.06; 95% confidence interval [CI], 1.017-1.117; P = 0.008), donation after circulatory death donors (OR, 1.13; 95% CI, 1.035-1.233; P = 0.006) and expanded criteria donors (OR, 1.14; 95% CI, 1.057-1.236; P = 0.001).
CONCLUSIONS:In conclusion, HMP resulted in remarkably lower rates of DGF in renal grafts that were transplanted after a short CIT. Also, CIT remained an independent risk factor for DGF in HMP-preserved kidneys.
CET Conclusion
| Reviewer: | Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England. |
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| Conclusion: | This paper describes post hoc additional analyses of data from the European machine perfusion trial published in the NEJM nine years ago. This analysis showed that CIT is an independent risk factor for DGF regardless of the preservation method (HMP or static cold storage). Interestingly and surprisingly, the impact of HMP on DGF was largest in the group with the shortest CIT (p=0.002). There was no significant difference in DGF rates between HMP and static cold storage for kidneys stored between 10 and 20 hours! This is probably due to the lack of power when dividing the numbers down so far. Whether the kidneys were on the pump or cold stored, every additional hour of CIT increased the odds for developing DGF by 8%. |
Expert Review
| Reviewer: | Dr Marc J Clancy, Queen Elizabeth University Hospital, Glasgow, United Kingdom. |
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| Conflicts of Interest: | No |
| Clinical Impact Rating | 2 |
| Review: | This study is a post hoc analysis of a previously published, high quality RCT comparing MCP with SCP [1]. The study attempts to address two areas of controversy: 1. The concept that HMP only benefits marginal kidneys, kidneys sustaining significant ischemic injury and kidneys transplanted after a prolonged cold ischemic period, not therefore kidneys rapidly implanted with short CIT. 2. The concept that CIT has a lesser effect on outcome for kidneys preserved by HMP. The method used is a post-hoc, subgroup analysis of transplants with CIT<10 hrs, 10-15hrs, 15-20hrs and >20 hrs. The data is of the highest standard. Statistical methodology is appropriate however there are multiple methodological limitations attendant to post hoc analysis, particularly the limited power of the small subgroups which are appropriately acknowledged. The DGF definition of "any dialysis requirement in the first week after transplantation" is also problematic as isolated dialysis for hyperkalaemia, acidosis and or fluid overload - with rapid subsequent graft function may be clinically irrelevant. The key novel findings were the following: 1. DGF was significantly reduced in transplants with CIT<10 hrs with no significant differences in longer CIT groups. 2. CIT remained a significant, independent risk factor for DGF in machine-perfused kidneys of all types. The discussion refers to the fact that "general assumptions may be a misconception about the protective effect of HMP. It is thought by many that the duration of cold ischemia time can be relatively safely extended if kidneys are machine perfused" and cites the first finding as essentially a refutation of such a belief. This is to somewhat overstate the findings and misunderstand prevalent views in the field. Units which have applied MCP technology to avoid overnight transplantation and accepted inevitably longer CIT have, in general, done so for reasons of practical necessity within a strained system, fully understanding that additional CIT remained undesirable even under MCP conditions. This paper confirms no significant differences in graft survival at 3 years for any subgroup nor demonstrates any difference between subgroups which actually supports the concept that accepting increased CIT for a machine perfused kidney (up to approx. 22 hrs 30 minutes), in order to avoid an overnight transplant is not unreasonable notwithstanding an increased risk of DGF. The second key finding is important as it confirms the principle that prolonged CIT, even under MCP conditions, leads to cellular injury and DGF but one must conclude given the well established benefit of MCP versus SCP for "all comer" transplants in this data set, that the rate of development of this cellular injury is much slower under MCP conditions and very acceptable (in long term graft survival terms) up to the 22 hrs 30 minute median CIT observed in the >20hrs CIT group. UK uptake of MCP has been limited since the Moers study. In part, this has been due to uncertainties around cost effectiveness. This study on the key trial dataset for the technology makes some interesting observations but in my opinion misjudges prevalent opinions around MCP and supports data like Patel et al [2] that the technology may have been more widely and effectively used over the last decade. [1] Moers C, Pirenne J, Paul A, Ploeg RJ; Machine Preservation Trial Study Group. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med 2012; 366(8): 770-1. [2] Patel K, Nath J, Hodson J, Inston N, Ready A. Outcomes of donation after circulatory death kidneys undergoing hypothermic machine perfusion following static cold storage: A UK population-based cohort study. Am J Transplant 2018; 18(6):1408-1414 |
Methodological quality
| Jadad score | 3 |
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| Allocation concealment | YES |
| Data analysis | PER PROTOCOL |
| Score based on | Moers C, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med. 2009 |
Study Details
| Aims: | To determine whether kidneys with a short ischemia time (CIT) benefit from hypothermic machine perfusion (HMP), and if HMP can safely extend CIT. |
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| Interventions: | This was a post hoc data analysis of the Machine Preservation Trial* data where kidney pairs were randomised and preserved with either HMP or cold storage. A subgroup analysis was performed and the patient cohort was divided into four groups based on the duration of CIT, 0-10 hours, 10-15 hours, 15-20 hours or >20 hours. |
| Participants: | 752 kidneys retrieved from 376 DBD or DCD (Maastricht category III) kidney donors aged ≥ 16 years. |
| Outcomes: | The primary outcomes measured was delayed graft function (DGF). Graft survival, the effect of CIT on the risk of DGF, and the effect of perfusion solution were also measured. |
| Follow Up: | 1 week and 12 months |
Metadata
| Funding: | Industry funding |
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| Publication type: | Randomized Controlled Trial, Randomised Controlled Trial |
| Organ: | Kidney |
| Language: | English |
| MeSH terms: | Adolescent; Adult; Aged; Aged, 80 and over; Cold Ischemia; Delayed Graft Function; Female; Graft Survival; Humans; International Cooperation; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Organ Preservation; Organ Preservation Solutions; Perfusion; Proportional Hazards Models; Prospective Studies; Time Factors; Tissue Donors; Young Adult; AUTHOR EMAIL - J.Kox@Maastrichtuniversity.Nl |