Oxygenated Versus Standard Cold Perfusion Preservation in Kidney Transplantation (COMPARE): A Randomized, Double-blind, Paired, Phase 3 Trial
Jochmans I, Brat A, Davies L, et al. Lancet. 2020;396:1653–1662.
Maximizing the pool of available organs is a priority for the transplantation community. Ex vivo organ perfusion has been the focus of significant research to minimize allograft damage between retrieval and implantation, the fundamental principle being mechanical maintenance of perfusate flow through the organ vasculature to reduce ischemia.1 However, the optimal physiologic composition of the perfusate and its delivery parameters remain debated. To this end, the recently published phase 3 randomized, double-blind COMPARE study brings the potential benefits of supplemental oxygen into focus.2 Here, the investigators assessed hypothermic machine perfusion (HMP) with standard perfusate (Belzer Machine Perfusion Solution) delivered at a pulsatile pressure of 25 mm Hg to HMP with the same solution actively oxygenated to a supraphysiological partial oxygen tension of 600 mg Hg through administering 100% O2 at 100 mL/min (HMPO2).
The study randomized 197 kidney pairs from circulatory death donors aged over 50. As the authors discuss, recruitment was restricted to this donor demographic as a key strength of ex vivo perfusion is to “rescue” organs that historically were unsuitable for transplant. Of the 197 recruited donor pairs, ultimately 114 were excluded (91 following randomization and 23 during or after follow-up for various donor- or recipient-related issues). The primary endpoint was estimated glomerular filtration rate at 12 months following transplantation. The authors performed an intention to treat analysis of 83 kidney pairs demonstrating neither a difference in eGFR nor a difference in patient mortality. However, secondary analyses revealed a reduced incidence of acute rejection with the use of supplemental oxygen. Of the 106 protocol biopsies in each arm, there was histopathological evidence of acute rejection in 27 (26%) in the HMP arm, compared with 15 (14%) in the HMPO2 arm. The study additionally observed a lower incidence of graft failure at 12 months in the HMPO2 arm (n = 3) compared with the HMP arm (n = 11) with fewer serious side effects.
This study demonstrates the safety of perfusate oxygenated to supraphysiological levels for short-term ex vivo maintenance of kidneys from DCD donors, and more broadly contributes with data describing the role of HMP. While not captured by this 12-month study, episodes of early acute rejection are known to impact medium- and long-term graft outcomes,3 and the lower proportion of biopsy-proven rejection in the HMPO2 arm is therefore intriguing. Equally on a mechanistic level, it is clear that ischemia and reperfusion drive a vigorous predominantly innate inflammatory response,4 and strategies to mitigate this clinically are important to develop. While detailed data on immunosuppression, sensitization, and independent biopsies are missing, this clinical trial demonstrates a fascinating effect of oxygenation on outcomes and alloimmunity. Future mechanistic studies will need to test if those effects are donor-age dependent and specifically linked to prolonged warm ischemic times in DCD donors.
Obesity Induces Gut Microbiota Alterations and Augments Acute Graft-versus-host Disease After Allogeneic Stem Cell Transplantation
Khuat LT, Le CT, Pai C-CS, et al. Sci Transl Med. 2020;12:eaay7713.
With the worldwide incidence of obesity increasing, delineating dietary effects in specific transplantation settings is of clear importance.5 In this study,6 Khaut et al made an important contribution to understanding the effect of diet and obesity on acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT).
Using established acute and chronic GVHD mouse models, the authors investigated the impact of diet-induced obesity, achieved by feeding C57BL/6 or BALB/c mice a high-fat diet (HFD) for 4 to 6 months. In the acute GVHD model, major MHC-mismatched donor BALB/c bone marrow and T cells were infused into C57BL/6 mice. When recipient mice had been on a HFD before infusion, they died rapidly from acute CD4+ lymphocyte-mediated GVHD characterized by severe gastrointestinal inflammation and increased production of proinflammatory cytokines. In comparison, mice following a low-fat diet developed acute GVHD much less rapidly. In the chronic GVHD model, the effect of obesity was even more striking. Here, MHC-matched but minor histocompatibility antigen mismatched B10.D2 donor bone marrow and splenocytes were infused into BALB/c recipients. As expected, nonobese control mice developed nonlethal cutaneous fibrosis. However, all the HFD mice succumbed rapidly to GVHD closely resembling observations in the acute MHC-mismatched GVHD model.
The authors then went on to investigate the mechanisms behind the increased obesity-induced mortality in both acute and chronic GVHD models. Gastrointestinal acute GVHD was associated with increased translocation across the GI tract membrane, serum endotoxin, and programmed GI epithelial cell death. Using 16S ribosomal PCR amplification and next-generation sequencing, they observed restricted microbial diversity in HFD mice. Intriguingly, considering that the acute GVHD was associated with restricted microbial diversity, the authors also observed that 2 weeks of ampicillin, vancomycin, and neomycin before alloHSCT reduced mortality by approximately 50%.
The authors next investigated whether similar effects from obesity were also of relevance in human cohorts. They stratified a previously published cohort of 37 patients receiving unrelated donor alloHSCT by BMI, demonstrating transplant-related mortality approximately 5 times higher in patients with BMI >30 kg/m2. In addition, using a separate cohort of 10 patients undergoing unrelated or related mismatched alloHSCT, they demonstrated significantly increased levels of ST2, a serum biomarker of acute GVHD, in patients with BMI >30 kg/m2. Finally, they observed that mortality in the 11 patients with BMI >30 kg/m2 and elevated ST2 was 64% at 12 months, compared with a 19% mortality in the remaining 26 patients.
Thus, the study provides evidence for the deleterious effects of obesity when patients undergo alloHSCT, an observation of clear clinical and scientific relevance. While it is uncertain whether the substantial benefit of antibiotic prophylaxis seen here is clinically translatable, the study nevertheless lends support to further metabolomic investigation in this patient group. More broadly, it reinforces the principle of pretreatment optimization and targeted lifestyle intervention improving outcomes.
1. Nasralla D, Coussios CC, Mergental H, et al.; Consortium for Organ Preservation in Europe. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018; 557:50–56
2. Jochmans I, Brat A, Davies L, et al.; COMPARE Trial Collaboration and Consortium for Organ Preservation in Europe (COPE). Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial. Lancet. 2020; 396:1653–1662
3. Clayton PA, McDonald SP, Russ GR, et al. Long-term outcomes after acute rejection in kidney transplant recipients: an ANZDATA analysis. J Am Soc Nephrol. 2019; 30:1697–1707
4. Zhao H, Alam A, Soo AP, et al. Ischemia-reperfusion injury reduces long term renal graft survival: mechanism and beyond. Ebiomedicine. 2018; 28:31–42
5. Swinburn BA, Kraak VI, Allender S, et al. The global syndemic of obesity, undernutrition, and climate change: the lancet commission report. Lancet. 2019; 393:791–846
6. Khuat LT, Le CT, Pai C-CS, et al. Obesity induces gut microbiota alterations and augments acute graft-versus-host disease after allogeneic stem cell transplantation. Sci Transl Med. 2020; 12:eaay7713