Deceased Organ Donor Interventions to Protect Kidney Graft Function

BACKGROUND: In the initial Mild Hypothermia Randomized Control Trial (RCT), in collaboration
with the UNOS Region 5 Donor Management Goals (DMG) Workgroup and Web Portal, the research
team was able to conduct a multi-center RCT examining the benefits of mild hypothermia in
donors after neurologic determination of death (DNDDs) on the outcomes of kidney
transplantation. The trial was stopped early by the DSMB due to a significant positive
benefit to kidney transplant recipients, including a 38% reduction in the odds of delayed
graft function (DGF, the primary outcome measure of the trial). The results of this study
have been published in the New England Journal of Medicine (July 2015). This research offers
a zero-cost intervention that can substantially increase transplant success as well as the
pool of potential donors.

To expand upon the success of the hypothermia study, the team is conducting a new RCT to test
whether hypothermia is as effective as machine perfusion (MP) of kidneys from DNDDs. In an
RCT conducted by the Eurotransplant International Foundation in 2009 (Moers et al. NEJM), the
protective effect of MP (OR = 0.57) was similar to that found in the Mild Hypothermia Trial
(OR = 0.62). However, the cost of MP can be very significant for organ procurement
organizations (OPOs) and transplant centers. MP of kidneys from deceased donors has been
increasingly adopted by many centers even though clinical and cost effectiveness studies
remain uncertain in the United States. Between 2012 and 2014, out of 31,798 kidneys available
for transplant, 11,998 (38%) of them were machine perfused. Over the same three-year period,
the number of kidneys pumped annually increased by over 20%. This is an opportune time to
investigate the effectiveness of MP compared to mild hypothermia, as there are enough OPOs
currently using MP that if mild hypothermia was found to be a non-inferior intervention,
there would be considerable cost savings. Similarly, over 60% of kidneys do not receive
machine perfusion and findings that demonstrates a benefit of machine perfusion would likely
lead to rapid increase in use. In addition, DGF still occurs in up to 56% of high-risk
kidneys despite using one of these protective measures and their combined use may be the best
approach moving forward. Either way, a new evidence-based standard will be created that will
significantly affect the way kidney transplants are handled.

METHODS: This will be a pragmatic multi-site randomized controlled trial that bases
enrollment on each OPO/Donation Service Area's current pumping criteria. There will be two
main groups of DNDDs,

1. those that are "pump eligible" based on current practice (this group typically resembles
traditional expanded criteria donors, but is increased in some areas) and

2. those that are lower risk and whose kidneys do not receive MP ("not pump eligible").
Kidneys from donors who are considered"pump eligible" currently receive MP based on
their increased risk for failure. In this trial, "pump eligible" DNDDs will be
randomized to one of three groups

(1) normothermia (36.5-37.5 C) plus MP of both kidneys (standard of practice control group),
(2) mild hypothermia (34-35 C) plus MP of the left kidney only, and (3) mild hypothermia plus
MP of the right kidney only.

In this manner, the same number of kidneys will be randomized to each of the three treatment
strategies (MP alone, mild hypothermia alone, or MP + hypothermia). It is important to note
that kidneys from "pump eligible"/higher risk DNDDs will still receive one form of protection
and possibly two.

In contrast, "not pump eligible" DNDDs will only be randomized to one of two groups: (1)
therapeutic mild hypothermia or (2) normothermia. Being that the Mild Hypothermia Trial was
stopped early for efficacy in the overall DNDD population, there was insufficient statistical
power to confirm a benefit in standard criteria donors (p=0.1 at stoppage). The purpose of
this arm of the trial is to validate the protective effect of hypothermia in a larger sample
size of lower-risk / "not pump eligible" donors.

The following objectives will be addressed by the trial:

Determine the non-inferiority of a hypothermia-only strategy to a standard pump-only strategy
in high risk DNDDs

Evaluate the superiority of a combined hypothermia+MP strategy to both hypothermia or MP
alone in high risk DNDDs

Evaluate the superiority of mild hypothermia versus standard of care normothermia in lower
risk, "not pump eligible" DNDDs

Determine the safety of the hypothermia strategy with respect to the function of
"bystander"organs (e.g., heart, lung)

This protocol has been approved by the UNOS Region 5 Research Committee. In addition, the
following steps have been or will be taken:

A National communication was sent via TransplantPro to allow for a two-week period for public
comment.

Only donors whose families and/or advanced directives (donor registry) have authorized
research will be included in the study.

All organ offers from DNDDs enrolled in the study will include a message in the Donor
Highlights section of DonorNet, a copy of the study summary will be attached to the record,
and allocation/transplantation will occur based on standard practice.

There will not be any interaction between the study team and the transplant recipients and no
additional data will be collected.

Recipient graft function data will be derived from standard UNet forms and obtained from the
OPTN in a de-identified format.

Inclusion Criteria:

- > 18 years of age,

- Brain dead organ donor,

- Authorization for research

Exclusion Criteria:

- DCD Donor

- Coagulopathy, Hemodynamic instability, Electrolyte deficiencies, Pre-existing kidney
disease (per study protocol)