Cold Perfusion Cuts Liver Transplant Complications

Compared with conventional static cold storage, hypothermic oxygenated machine perfusion resulted in a lower risk of non-anastomotic biliary strictures 6 months after liver transplants were received from donors after circulatory death (DCD), a multicenter randomized study found.

The primary endpoint in the Dual Hypothermic Oxygenated Perfusion of DCD Liver Grafts in Preventing Biliary Complications After Transplantation (DHOPE-DCD) trial, symptomatic non-anastomotic biliary strictures, occurred in just 6% of the experimental machine-perfusion group versus 18% in the standard-storage control group, translating to a risk ratio of 0.36 (95% CI 0.14-0.94, P=0.03).

“The lower incidence of this type of cholangiopathy was both statistically and clinically significant,” wrote Robert J. Porte, MD, of University Medical Center Groningen in the Netherlands, and colleagues in the New England Journal of Medicine.

Such strictures – resulting from incomplete recovery from biliary ischemia reperfusion injury and causing fibrotic narrowing of the bile duct lumen and bile flow obstruction – remain a major concern in DCD liver grafts, the authors noted.

Study details

The trial was conducted at six transplant facilities in the Netherlands, Belgium, and the U.K., during 2016-2020.

Investigators randomized 78 adult patients to receive a machine-perfused liver and 78 to receive a liver preserved in standard static cold storage. Median age of liver donors was similar across arms at 52 in the intervention group and 49 in the control group. Men accounted for 67% and 65% of donors in the two arms, respectively, and donors in both arms had a mean body mass index of 25.

In other comparative endpoints:

• Post-reperfusion syndrome occurred in 12% of the intervention group versus 27% of the control group (RR 0.43, 95% CI 0.20-0.91)
• Early allograft dysfunction occurred in 26% of the machine-perfused livers versus 40% of control livers (RR 0.61, 95% CI 0.39-0.96)
• The cumulative number of treatments for non-anastomotic biliary strictures was lower by a factor of nearly 4 after machine perfusion
• Incident adverse events were similar in both groups at 644 and 694, respectively, with nine and 16 graft rejections in the two arms, respectively, and 131 versus 162 infections
• Two control patients required retransplantation within 6 months owing to severe cholangiopathy

Machine perfusion did not, however, appear to improve overall patient or graft survival.

This technology has been proposed as an alternative to conventional organ preservation that may reduce ischemia reperfusion injury. Compared with other dynamic preservation methods such as normothermic machine perfusion, this technique offers an advantage in that in the event of malfunction the organ is still kept cool. “This situation differs from normothermic machine perfusion, in which device or operator errors result in warm ischemia and may lead to organ loss,” the investigators wrote.

An accompanying editorial outlined a bright future for machine perfusion, which could potentially improve the function of organs obtained from deceased donors and allow better assessment of the viability of organs of uncertain quality, thereby significantly expanding the pool of livers available for transplant.

“Moreover, this technology will almost certainly yield exciting new applications such as ex vivo defatting of steatotic livers, the induction of liver regeneration ex vivo, and the modification of organs by means of gene editing to improve post-transplantation outcomes,” wrote editorialists Winfred W. Williams, MD, a deputy editor of the NEJM, and James F. Markmann, MD, PhD, of Massachusetts General Hospital and Harvard Medical School in Boston.

They noted that both normothermic and hypothermic perfusion have their own proponents.

DHOPE-DCD’s results bode well for improving patient outcomes, the editorialists said: avoiding costly retransplantations and increasing organ supply if some of the currently discarded DCD organs could be safely transplanted. It remains to be determined, however, if DHOPE can discriminate organ quality as well as perfusion at physiologic temperatures, they cautioned. “Such a discrimination could be critical for determining whether warm or cold perfusion will gain broad acceptance, since the greatest benefit would be to decrease the current discard rate of 3000 livers,” they wrote.

Two randomized U.S. trials of normothermic perfusion (OCS LIVER PROTECT and WPO1 – Normothermic Liver Preservation) may help answer that question — both were recently completed but results have not been reported, the editorialists noted.