ECD Kidneys Preserved with Oxygenated End-Hypothermic Machine Perfusion

The preferred standard form of treatment for end-stage kidney disease is kidney transplantation. Facing the increasing demand for kidney transplants and to shorten waiting times for patients on the transplant waitlist, the majority of transplant centers accept kidneys that have been retrieved from expanded criteria donors (ECDs), including older and higher-risk donors with multiple comorbidities.

The ECD program also results in increased rates of complications such as primary nonfunction or delayed graft function and, ultimately, reductions in long-term graft survival. Nevertheless, according to Peri Husen, MD, and colleagues, despite the increased risk for graft survival, the use of higher-risk kidneys is associated with significant survival benefit for recipients compared with patients remaining on maintenance dialysis.

There are two methods of preservation of donor kidneys: (1) static cold storage (SCS), where the kidney is flushed with a preservation solution at time of procurement and submerged in cold preservation solution and kept on ice until transplant; and (2) hypothermic machine perfusion (HMP) where the donor kidney is perfused with a cold machine perfusion using a device. Previous studies have suggested an association between continuous HMP of the donor kidney starting immediately after organ procurement until implantation in the recipient and reduced risk of delayed graft function and improved kidney graft survival in the first year following transplant.

A recent single-center study using SCS followed by a short-term preimplantation period of HMP (end-HMP), suggested a reduction in risk for delayed graft function in ECD kidneys. However, there are no clinical trial data providing evidence  of a potential benefit. Dr. Husen et al. conducted a prospective, randomized, multicenter trial designed to compare the effect of end-HMP after SCS versus SCS alone on 1-year graft survival in ECD donor kidneys from donors who were brain dead. Results of the trial were reported online in JAMA Surgery [doi:10.1001/jamasurg.2021.0949].

The primary end point in the intention-to-treat analysis was 1-year graft survival. Secondary end points were delayed graft function, primary nonfunction, acute rejection, estimated glomerular filtration rate (eGFR), and patient survival. Using an online randomization tool, eligible kidneys were randomly assigned to either standard SCS or the combination of SCS with subsequent oxygenated HMP (end-HMPo2) after arrival at the recipient center.

Of the 305 randomized kidneys, 53 were subsequently excluded. The two trial arms had similar discard and withdrawal rates, resulting in 127 end-HMPo2 and 135 SCS kidneys available for primary and secondary outcome analysis. Because machine perfusion was found to be impossible, 14 kidneys in the end-HMPo2 group were cold stored, and six kidneys received machine perfusion for >2 hours for logistical reasons. All of the organs were included in the end-HMPo2 arm on an intention-to-treat basis.

In both the SCS and the end-HMPo2 arm, donor and recipient characteristics were well balanced. The calculated kidney donor risk index and the kidney donor profile index were comparable in the two treatment arms.

Median cold ischemia time, defined as the total preservation time, was 13.2 hours in the end-HMPo2 group and 12.9 hours in the SCS group. In the end-HMPo2 arm, median SCS time prior to placement on the perfusion device was 7.97 hours, followed by a median of 4.67 hours of hypothermic oxygenate machine perfusion.

In the end-HMPo2 group, 92.1% (117/127) of kidney grafts were functioning at 1 year post-transplant, compared with 93.3% (126/135) in the SCS group. Both groups were similar in death-censored graft survival at 1 year post-transplant. Graft losses were due to immunological reasons (n=3), viral or bacterial infection (n=3), arterial or venous thrombosis and complications (n=5), or other reasons (n=8).

At all assessed time points, eGFR was similar in both groups and showed a steady increase over time until the 1 year timepoint. The rates of delayed graft function were numerically lower in the end-HMPo2 group than in the SCS group (30 [23.6%] vs 38 [28.1%]); the difference did not reach statistical significance. Results of analysis of functional delayed graft function were similar, with lower rates in the end-HMPo2 group than in the SCS group (76 [59.8%] vs 93 [68.9%]). The rates of primary nonfunction were the same in both groups.

The rates of patient death were higher in the end-HMPo2 group than in the SCS group (9 [7.1%] vs 2 [1.5%}. Over the course of the 12 months following transplantation, the causes of death were myocardial infarction (n=5), wound infection and subsequent sepsis (n=3), multiorgan failure (n=1), unintentional cerebrovascular injury (n=1), and malignant neoplasms (n=1). With the exception of one patient, the patients in the end-HMPo2 group who did not survive died with a functioning graft.

There were no significant differences in the two groups in rates of biopsy-proven acute rejection. Rates of patients with at least one reported adverse event were similar between the two groups, as was the incidence of at least one serious adverse event. None of the serious adverse events were attributable to the storage method.

Results of further exploratory analysis demonstrated that when stratifying for graft failure according to study group and the incidence of delayed graft function, once delayed graft function occurred, graft survival was nearly identical between kidneys that were either cold stored or machine perfused.

In citing limitations to the study, the researchers noted that the baseline assumption of 80.2% 1-year graft survival in ECD kidneys has been exceeded by far in the study’s control group, and the study being statistically underpowered due to the current improved graft survival rates compared with the clinical trial data used for the statistical analysis plan.

In conclusion, the researchers said, “Reconditioning of higher-risk ECD kidneys from donors after brain death using short-term oxygenated HMP immediately prior to transplant after a period of SCS does not lead to improved graft survival or graft function when compared with simple SCS alone.”

Takeaway Points

  1. Researchers explored whether short-term reconditioning of kidney grafts using oxygenated hypothermic machine perfusion after static cold storage would improve 1-year graft survival in kidneys from expanded criteria donors.
  2. The randomized trial results demonstrated that 1-year survival was similar between kidneys that remained on static cold storage and those that were machine perfused following static cold storage.
  3. There was also no difference between the two groups in secondary outcomes including delayed graft function, primary nonfunction, acute rejection, estimated glomerular filtration rate, and patient survival.