Transplant Library

Abstract

BACKGROUND:

Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death.

METHODS:

This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO2), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intention-to-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed.

FINDINGS:

Between March 15, 2015, and April 11, 2017, 197 kidney pairs were randomised with 106 pairs transplanted into eligible recipients. 23 kidney pairs were excluded from the primary analysis because of kidney failure or patient death. Mean eGFR at 12 months was 50·5 mL/min per 1·73 m2 (SD 19·3) in the HMPO2 group versus 46·7 mL/min per 1·73m2 (17·1) in HMP (mean difference 3·7 mL/min per 1·73m2, 95% CI -1·0 to 8·4; p=0·12). Fewer severe complications (Clavien-Dindo grade IIIb or more) were reported in the HMPO2 group (46 of 417, 11%, 95% CI 8% to 14%) than in the HMP group (76 of 474, 16%, 13% to 20%; p=0·032). Graft failure was lower with HMPO2 (three [3%] of 106) compared with HMP (11 [10%] of 106; hazard ratio 0·27, 95% CI 0·07 to 0·95; p=0·028).

INTERPRETATION:

HMPO2 of kidneys donated after circulatory death is safe and reduces post-transplant complications (grade IIIb or more). The 12-month difference in eGFR between the HMPO2 and HMP groups was not significant when both kidneys from the same donor were still functioning 1-year post-transplant, but potential beneficial effects of HMPO2 were suggested by analysis of secondary outcomes.

FUNDING:

European Commission 7th Framework Programme.

CET Conclusion

Reviewer:	Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:	The well-designed, multicentre, double-blind, randomised controlled trial compared oxygenated hypothermic machine perfusion (HMP) with standard (non-oxygenated) HMP in kidney pairs from DCD donors aged 50 and over with sites in Belgium, The Netherlands and United Kingdom. Kidneys from each pair were randomised according to a computer-generated sequence. Blinding was ensured by using empty dummy oxygen bottles in the standard HMP arm and all health care professionals and transplant recipients were blinded to the allocation. The sample size calculation showed that 81 pairs were needed to provide 90% power to show an 8 ml/min/1.73m² difference in the primary outcome estimated GFR. The primary analysis, based on intention-to-treat and ony including only kidney pairs for which both grafts were functioning at 12 months, showed no significant difference in eGFR. A sensitivity analysis that accounted for failed grafts and patient death showed a significantly higher eGFR in the oxygenated group. Graft failure was significantly lower in the oxygenated HMP group as was the number of biopsy-proven rejection episodes. The authors conclude that oxygenated HMP has the potential to improve clinical outcomes and reduce health-care costs.

Reviewer:

Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford

Conclusion:

The well-designed, multicentre, double-blind, randomised controlled trial compared oxygenated hypothermic machine perfusion (HMP) with standard (non-oxygenated) HMP in kidney pairs from DCD donors aged 50 and over with sites in Belgium, The Netherlands and United Kingdom. Kidneys from each pair were randomised according to a computer-generated sequence. Blinding was ensured by using empty dummy oxygen bottles in the standard HMP arm and all health care professionals and transplant recipients were blinded to the allocation. The sample size calculation showed that 81 pairs were needed to provide 90% power to show an 8 ml/min/1.73m² difference in the primary outcome estimated GFR. The primary analysis, based on intention-to-treat and ony including only kidney pairs for which both grafts were functioning at 12 months, showed no significant difference in eGFR. A sensitivity analysis that accounted for failed grafts and patient death showed a significantly higher eGFR in the oxygenated group. Graft failure was significantly lower in the oxygenated HMP group as was the number of biopsy-proven rejection episodes. The authors conclude that oxygenated HMP has the potential to improve clinical outcomes and reduce health-care costs.

Expert Review

Reviewer:	Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review:	The publication of this recent paper revisits the addition of oxygen to hypothermic machine perfusion (HMP). The trial was conducted across 19 European transplant centres in three countries (Belgium, the Netherlands and the United Kingdom). The trial was of a robust design, with double‐blinding, effective randomization and intention‐to‐treat analysis. In order to maximize the potential benefit, only donors over the age of 50 from Donation after Circulatory Death were included, and initially, they were analysed in paired fashion, one being allocated to receive oxygen and the other without. Possibly because of this analysis method, there was not significant evidence of improved GFR at 12 months after transplantation; kidney pairs where one kidney was lost or not transplanted could not be included in this analysis. However, graft failure at 12 months was significantly higher in the group without oxygen (10% vs. 3%) and severe complications were also significantly higher (11% vs. 8%). When including in the analysis kidneys from pairs where one kidney failed, GFR at 12 months was also significantly better for the group receiving oxygen. One standout, and unexpected result, was the significant reduction in acute rejection seen in the oxygenated group as well (14% vs. 26%). It is speculated that this may be related to the improved GFR at 12 months. This study demonstrates potential important clinical benefits of oxygenated HMP over standard HMP in this study cohort. The device used for perfusion was the Kidney Assist Transporter (Organ Assist BV, Groningen, the Netherlands), and no changes to perfusion settings were made once started. Machine perfusion was not possible in only 5% of kidneys retrieved and deemed suitable for transplantation at that point. The process of oxygenated perfusion is therefore straightforward and suitable for the majority of kidneys. Perfusion was maintained from retrieval to implantation, which may prove to be a logistical challenge for some centres or programmes, when transport of the machine has to be considered. The median cold ischaemic time was 10–11 h. It is unclear whether the potential benefit would be present with a shorter period of oxygenated perfusion after a period of either static cold storage or nonoxygenated cold perfusion. However, the addition of supplemental oxygen to HMP can be a simple process with the right equipment, is safe, feasible for many kidneys and may have significant clinical benefits.

Reviewer:

Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford

Review:

The publication of this recent paper revisits the addition of oxygen to hypothermic machine perfusion (HMP). The trial was conducted across 19 European transplant centres in three countries (Belgium, the Netherlands and the United Kingdom). The trial was of a robust design, with double‐blinding, effective randomization and intention‐to‐treat analysis. In order to maximize the potential benefit, only donors over the age of 50 from Donation after Circulatory Death were included, and initially, they were analysed in paired fashion, one being allocated to receive oxygen and the other without. Possibly because of this analysis method, there was not significant evidence of improved GFR at 12 months after transplantation; kidney pairs where one kidney was lost or not transplanted could not be included in this analysis. However, graft failure at 12 months was significantly higher in the group without oxygen (10% vs. 3%) and severe complications were also significantly higher (11% vs. 8%). When including in the analysis kidneys from pairs where one kidney failed, GFR at 12 months was also significantly better for the group receiving oxygen. One standout, and unexpected result, was the significant reduction in acute rejection seen in the oxygenated group as well (14% vs. 26%). It is speculated that this may be related to the improved GFR at 12 months. This study demonstrates potential important clinical benefits of oxygenated HMP over standard HMP in this study cohort. The device used for perfusion was the Kidney Assist Transporter (Organ Assist BV, Groningen, the Netherlands), and no changes to perfusion settings were made once started. Machine perfusion was not possible in only 5% of kidneys retrieved and deemed suitable for transplantation at that point. The process of oxygenated perfusion is therefore straightforward and suitable for the majority of kidneys. Perfusion was maintained from retrieval to implantation, which may prove to be a logistical challenge for some centres or programmes, when transport of the machine has to be considered. The median cold ischaemic time was 10–11 h. It is unclear whether the potential benefit would be present with a shorter period of oxygenated perfusion after a period of either static cold storage or nonoxygenated cold perfusion. However, the addition of supplemental oxygen to HMP can be a simple process with the right equipment, is safe, feasible for many kidneys and may have significant clinical benefits.

Methodological quality

Jadad score	5
Allocation concealment	YES
Data analysis	STRICT INTENTION TO TREAT
Research notes	The primary data analyses was intention to treat.

Study Details

Aims:	This study aimed to determine if supplemental oxygen during hypothermic machine perfusion (HMP) led to improvements in the outcome of kidneys donated following circulatory death.
Interventions:	One kidney from each donor was randomised to either oxygenated hypothermic machine perfusion (HMPO2) or HMP without oxygenation.
Participants:	197 kidney pairs were randomised.
Outcomes:	The primary endpoint was the estimated glomerular filtration rate (eGFR) at 12 months post-transplant. The secondary endpoints included patient survival and graft survival up at 12 months, primary non function, delayed graft function, renal function according to CKD-EPI and MDRD equations, acute rejection and safety outcomes.
Follow Up:	12 months

Metadata

Funding:	Non-industry funding
Publication type:	Randomized Controlled Trial, Randomised Controlled Trial
Trial registration:	ISRCTN - 32967929
Organ:	Kidney
Language:	English
Author email:	ina.jochmans@uzleuven.be
MeSH terms:	Cold Temperature; Double-Blind Method; Europe; Female; Glomerular Filtration Rate; Humans; Kidney Transplantation; Male; Middle Aged; Organ Preservation; Oxygen; Perfusion; Tissue Survival; Tissue and Organ Harvesting; S88TT14065 (Oxygen)

Transplant Evidence Alert

Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial