Chilling Donors Not as Good as Machine Perfusion for Kidney Transplant

Therapeutic hypothermia of donors didn’t preserve kidney function as well as machine perfusion of the organ during cold storage, a randomized trial found.

Compared with kidneys pumped with a non-oxygenated, cold dialysate after removal, those obtained from brain-dead organ donors that underwent mild therapeutic hypothermia had significantly higher risk for delayed graft function (adjusted risk ratio [aRR] 1.72, 95% CI 1.35-2.17), according to Claus Niemann, MD, of the University of California San Francisco, and colleagues.

Kidneys from donors cooled to 34-35°C (93-95°F) before explant also had a significantly higher risk of delayed graft function — defined as requiring initiation of dialysis during the first 7 days after transplantation — when compared with kidneys exposed to both hypothermia and machine perfusion (aRR 1.57, 95% CI 1.26-1.96).

While combination therapy wasn’t any worse for donor kidneys than machine perfusion alone, it also wasn’t any better at reducing delayed graft function (aRR 1.09, 95% CI 0.85-1.40), the group reported in the New England Journal of Medicine.

Overall, delayed graft function occurred most often in the hypothermia group (30%), followed by in the combination therapy group (22%), and was least common in the machine perfusion-only group (19%).

One year after transplant, allograft survival was similar across all three groups as a secondary outcome of the trial.

The prospective trial was designed to determine whether hypothermia alone — a less resource-intensive strategy — was noninferior to machine perfusion; but when it was found to actually be inferior, Niemann’s group pulled the plug early.

“Our findings provide additional evidence that machine perfusion protects against delayed graft function as compared with static cold storage, even when the donor was undergoing therapeutic hypothermia,” the researchers said.

In a prior trial conducted by Niemann’s group, transplanted kidneys had a 38% (OR 0.62, 95% CI 0.43-0.92, P=0.02) lower odds of delayed graft function when donors underwent hypothermia (34-35°C) versus normothermia (36.5-37.5°C). A standard period of cold static graft preservation followed explant in both groups.

In an editorial accompanying the new trial findings, Paulo Martins, MD, PhD, of the University of Massachusetts in Worcester, and Winfred Williams, MD, of Massachusetts General Hospital in Boston, cautioned about the lack of a standard practice control group involving pre-procurement donor normothermia and cold static preservation alone, as had been included in the prior trial.

“Therefore, a head-to-head comparison of current-day, standard protocols for procurement and preservation is not possible,” they said.

In the new trial, a total of 910 brain-dead donors and their 1,820 donated kidneys were randomized from six U.S-based organ-procurement organizations for the current trial. All donors were at least age 18 and were hemodynamically stable, receiving low-dose vasopressors and maintained at a mean arterial pressure of more than 60 mm Hg. They also had corrected coagulopathy and electrolyte abnormalities. Kidneys donated after cardiac death, end-stage kidney disease, or a history of dialysis during terminal hospitalization were excluded.

Of the randomized kidneys, 1,349 were transplanted: 359 kidneys in the hypothermia group, 511 in the machine-perfusion group, and 479 in the combination group.

Hypothermia therapy involved reaching a target temperature of 34-35°C in the donor using noninvasive external cooling devices with perfusion of the right kidney; machine perfusion involved normothermia with subsequent ex situ hypothermic, non-oxygenated machine perfusion of both kidneys; and combination therapy involved donor hypothermia and machine perfusion of the left kidney.

Niemann’s group pointed out that 27% of donors assigned to undergo machine perfusion didn’t actually get it, due to either “graft issues or logistic constraints caused by immediate long-distance air transportation needs.” On the other hand, 11% of kidneys assigned to the hypothermia group underwent machine perfusion because of logistic constraints at the transplantation hospital or anticipation of very long cold-ischemia times.

“Future trials should incorporate mechanistic studies and report the procurement interval because these issues have ongoing implications for trial design, transplantation logistics, and outcomes,” the editorialists suggested.

While the ideal time between brain death and organ procurement remains unknown, the editorialists noted that the trial didn’t “carefully control” for the cold-ischemia time between the intervention and control groups — a limitation of the design.