Discussion
agonal, thrombosis, ischemic injury, DGF.In liver transplantation, atrributable, ischemia, inflammation, infection, hypotension
THROMBOSIS, GRAFT DYSFUNCTION, CIRCULATORY ARREST, ADVERSE EVENTS, ISCHEMIA, INFLAMMATION, CARDIAC ARREST, COMPLICATION, INFECTION, COMPLICATIONS, VENOUS THROMBOSIS, COLD, COMPLICATIONS
We compared a 1-h period of NMP with conventional SCS for kidney transplantation from DCD donors. The NMP protocol had no effect on the primary endpoint, which was the incidence of DGF, defined as the requirement for dialysis in the first 7 d after transplant. No significant statistical differences were observed in the rates of acute rejection, renal function at 12 months, patient survival or graft survival. Our study also demonstrated that NMP is a safe procedure, as no significant differences were observed in complication rates when compared to SCS, and no adverse events were directly atrributable to NMP.After the introduction of ex vivo NMP for donor kidneys into clinical practiceThere are several possible causes of the high rates of DGF described here and in some of the previous literature. Physiological parameters during the agonal period, defined as the time between withdrawal of treatment and circulatory arrest, are likely to be critical. In the UK, withdrawal of treatment comprises disconnection from the ventilator and stopping inotropes but, in many centers, does not include removal of the endotracheal tube. Continuing support of the airway in this way can prolong the agonal period. Even more importantly, severe and prolonged hypotension during the agonal period and the consequent inadequate organ perfusion causes additional warm ischemic injury and has been shown to be associated with higher DGF rates in DCD kidneysThe high rates of DGF reported here are also related to defining DGF as the requirement for dialysis in the first 7 d after transplant. Although this is the simplest and most widely used definition of DGFThe use of normothermic regional perfusion (NRP), which restores oxygenated blood flow to the abdominal organs in situ after cardiac arrest, has yielded even lower DGF rates of 23–30%Conventional SCS was used as the control arm in this study because it is the standard of care in the UK. Although HMP has been shown to reduce the rate of DGF in DCD kidneys when compared to SCSThere are several possible explanations for the lack of effect of NMP on DGF rates. A 1-h period of NMP may not be long enough to reverse the effects of cold ischemia on renal tubular cells. The rationale for our trial design was based on pilot clinical data suggesting that 1 h of NMP could significantly reduce the rate of DGF in DCD kidneysThere is limited evidence to define the optimal duration of NMP. One experimental study suggested that 1 h of NMP is not as beneficial as more prolonged periods of perfusionThe original intention in our protocol was to deliver a short period of NMP immediately before the kidney was transplanted, but this was not always achieved because of the logistics of preparing patients for transplant surgery. After 1 h of NMP, the kidney was re-flushed with cold preservation solution and placed back on ice for a variable second period of cold storage until removal from ice for implantation. The mean duration of this second cold time was just over 2 h, and, although this may not influence outcome, longer additional cold storage would eventually counteract any beneficial effects of NMP. Post hoc analysis demonstrated that there was no difference in the duration of the second cold ischemic period in NMP kidneys with or without DGF.In liver transplantation, donor livers have been maintained by NMP for the full duration of the preservation periodThe induction of inflammation during NMP is another potential reason for the lack of its effect on the rate of DGF. The red-cell-based perfusate used in the NMP system was designed to create an anti-inflammatory environment without platelets, white cells or complementOur trial has several limitations. It was designed as an open-label study because of the logistics of the NMP technique. Blinding of the surgical team was not possible because NMP was performed in the operating room while the transplant recipient was being prepared for surgery. However, the perfusion teams were not involved in data analysis. We were unable to perform NMP in 14 kidneys (8.2%) randomized to this treatment arm because of concerns over the technical aspects of cannulating the renal arterial system. The alternatives for arterial perfusion are the use of an aortic patch clamp or direct cannulation of the renal artery. The former is more favorable as it allows perfusion of multiple renal arteries without loss of the aortic patch for subsequent anastomosis in the recipientAs NMP requires cannulation of the renal blood vessels, there is potential to cause endothelial damage. There is also a risk of transmitting infection during the period in which the kidney is perfused in an ex vivo organ chamber. In our trial, NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. No significant differences were observed between the groups in terms of recipient safety outcomes. The incidence of renal arterial or venous thrombosis was very low, and there were few complications related to the renal transplant biopsies. Complications associated with kidney transplantation that require hospitalization are common and were categorized into graft dysfunction, infection, related to surgery or immunosuppression based.In conclusion, a 1-h period of NMP after SCS does not reduce the risk of DGF in DCD kidney transplants. Nonetheless, we have demonstrated that this new technology for kidney preservation is feasible, safe and suitable for clinical application. This trial delivers the first, essential step in exploring the broader potential of NMP in kidney transplantation.