OrganOx (United Kingdom)

Abstract Background The storage lesion is a multifactorial degradation effect seen in units of banked blood, and results in an increase in the time-constant of oxygen-unloading from red cells (tau). We have previously shown the relevance of this effect in observational data from a recent clinical trial of prolonged normothermic kidney perfusion as a preservation technique ahead of transplantation. We sought direct confirmatory evidence for diffusion-limited oxygen release by stored red cells (RBCs) during normothermic kidney perfusion in a precisely controlled experimental setting. Methods A novel twinned-circuit kidney perfusion system using common, recirculated dialysis was developed, achieving physical separation of RBCs of two conditions whilst allowing non-cellular components of the perfusate to equilibrate throughout. Using human kidneys unsuitable for transplantation, perfusion was alternated between stored and rejuvenated RBCs (treated with PIPA solution) originating from the same donation, to manipulate oxygen-unloading whilst holding all non-RBC parameters constant, without interrupting blood flow. Results Tau improved with PIPA treatment (1.6 to 1.1s). Rejuvenated oxygen-unloading kinetics reversibly and significantly improved the kidney’s oxygen diffusion capacity and increased cortical oxygen tension by 60%. This supported observations from our clinical trial, where increased tau was strongly associated with restricted renal oxygen consumption. Conclusions We have confirmed that oxygen delivery to tissues can become diffusion-limited during normothermic perfusion with stored blood. This effect is reversible by treatment with PIPA solution. This has important implications for ex-vivo normothermic organ perfusion, and potentially for other scenarios such as major hemorrhage, elective surgery with high blood product utilisation, and paediatric transfusion.

To compare conventional low-temperature storage of transplant donor livers [static cold storage (SCS)] with storage of the organs at physiological body temperature [normothermic machine perfusion (NMP)]. The high success rate of liver transplantation is constrained by the shortage of transplantable organs (eg, waiting list mortality >20% in many centers). NMP maintains the liver in a functioning state to improve preservation quality and enable testing of the organ before transplantation. This is of greatest potential value with organs from brain-dead donor organs (DBD) with risk factors (age and comorbidities), and those from donors declared dead by cardiovascular criteria (donation after circulatory death). Three hundred eighty-three donor organs were randomized by 15 US liver transplant centers to undergo NMP (n = 192) or SCS (n = 191). Two hundred sixty-six donor livers proceeded to transplantation (NMP: n = 136; SCS: n = 130). The primary endpoint of the study was "early allograft dysfunction" (EAD), a marker of early posttransplant liver injury and function. The difference in the incidence of EAD did not achieve significance, with 20.6% (NMP) versus 23.7% (SCS). Using exploratory, "as-treated" rather than "intent-to-treat," subgroup analyses, there was a greater effect size in donation after circulatory death donor livers (22.8% NMP vs 44.6% SCS) and in organs in the highest risk quartile by donor risk (19.2% NMP vs 33.3% SCS). The incidence of acute cardiovascular decompensation at organ reperfusion, "postreperfusion syndrome," as a secondary outcome was reduced in the NMP arm (5.9% vs 14.6%). NMP did not lower EAD, perhaps related to the inclusion of lower-risk liver donors, as higher-risk donor livers seemed to benefit more. The technology is safe in standard organ recovery and seems to have the greatest benefit for marginal donors.

ABSTRACTA central dogma in physiology is that oxygen release at tissues is not diffusion-limited because gas exchange at capillaries is rapid. This assertion has influenced clinical care, which focuses on optimising oxygen delivery through improving blood flow and oxygen content, rather than oxygen unloading from red blood cells (RBCs). Since storage of blood causes profound changes that slow oxygen release from RBCs, transfusions could compromise tissue respiration. We investigated this in transplant human kidneys normothermically perfused with stored blood. During perfusions, renal respiration was measured from blood gases and RBCs were analysed for oxygen-unloading kinetics. Respiratory rate did not correlate significantly with the standard definition of oxygen delivery based on blood flow and oxygen content. However, a strong correlation was obtained after introducing a factor describing oxygen release from RBCs. Oxygen release to tissues can become diffusion-limited with transfused blood, and therefore the kinetic quality of RBCs should be considered.

There is a limited access to liver transplantation, however, many organs are discarded based on subjective assessment only. Here we report the VITTAL clinical trial (ClinicalTrials.gov number NCT02740608) outcomes, using normothermic machine perfusion (NMP) to objectively assess livers discarded by all UK centres meeting specific high-risk criteria. Thirty-one livers were enroled and assessed by viability criteria based on the lactate clearance to levels ≤2.5 mmol/L within 4 h. The viability was achieved by 22 (71%) organs, that were transplanted after a median preservation time of 18 h, with 100% 90-day survival. During the median follow up of 542 days, 4 (18%) patients developed biliary strictures requiring re-transplantation. This trial demonstrates that viability testing with NMP is feasible and in this study enabled successful transplantation of 71% of discarded livers, with 100% 90-day patient and graft survival; it does not seem to prevent non-anastomotic biliary strictures in livers donated after circulatory death with prolonged warm ischaemia.