PROlonged ex-vivo normothermic machine PERfusion for kidney regeneration

Kidney transplantation is the most effective and cost-efficient treatment for
patients with end stage renal disease (ESRD). While outcomes of transplantation
have improved, leading to a higher demand in transplantation, the availability
of high-quality donor organs has stagnated. In response to this widening
disparity between the number of donor organs available for transplantation and
number of patients on the waiting list, there has been an increase in the use
of kidneys from older and higher risk donors. To date, more and more deceased
donor kidneys procured from older donors with co-morbidities i.e. extended
criteria donors (ECD) and donors after circulatory death (DCD) are being
transplanted. These kidneys are known to have an inferior graft function and
survival.

To date, the choice to accept or decline a donor kidney for transplantation is
currently based on a number of clinically available criteria, however, the
influence of a combination of risk factors is not clear-cut and clinicians are
in need of more accurate criteria whether to decline or accept the organ. The
discard rate of organs from these higher risk donors is probably unnecessarily
high, while other kidneys that are currently deemed suitable may never function
in the recipient (primary non-function).

Normothermic machine perfusion (NMP) as ex-situ machine perfusion preservation
is a promising graft protective strategy that is increasingly being utilized
and is the subject of ongoing research and evolving clinical trials. NMP
entails perfusing the kidney with warmed, oxygenated red blood cell (RBC) based
perfusate to simulate physiological conditions. Advances in organ preservation
have the potential to enable treatment of donor organs with therapeutic
interventions that would otherwise be unsuitable for transplantation, thereby
increasing organ utilization and the donor pool, reducing the waiting list for
transplantation.

In this study, we propose the use of prolonged (>1 hour) NMP (PNMP) which has
the added advantage of creating a window for ex-vivo regeneration of marginal
donor organs, and to better test graft viability. The most pronounced effect of
PNMP can be expected in these marginal kidneys, which will have acquired
considerable damage before PNMP is started.

For clinical transplantation, no PNMP preservation method has yet been
implemented. In our pre-clinical study using the PROPER protocol in both
participating centers (LUMC and UMCG) we successfully have perfused a total of
24 donor kidneys, deemed untransplantable, for a minimum of 6 hours. In this
process we adapted a previously tested protocol of 1-hour NMP to the perfusate
that optimally allowed prolonged NMP (dubbed the PROPER protocol). An hourly
analysis of standardized parameters of function, damage and repair was
performed showing no extra injury.
In conclusion, in the preliminary phase of the PROPER study we have gained
expertise in PNMP, optimised the protocol and have established the necessary
logistics to proceed to and initiate the clinical phase of PROPER.

The primary aim of this present clinical study is to determine the safety of
PNMP for up to 6 hours in kidneys from DCD donors. Moreover, we will
investigate whether PNMP allows better assessment and transplantability of DCD
kidneys grafts and indeed offers a better platform for reconditioning and
regeneration.

Primary Objective: To test clinical safety of PNMP up to 6 hours as a modality
to assess viability and evaluate initiation of tissue repair ex-situ in donor
kidneys prior to transplantation.

Secondary Objective(s): To monitor standard and novel renal function parameters
whilst the graft is normothermically perfused in order to help identify a set
of markers predictive for organ performance.

The PROPER study is designed as a clinical safety study. It will be conducted
in two transplant centres, LUMC and UMCG, where we developed the optimal
conditions for PNMP in discarded human donor kidneys in a pre-clinical setting.
The NMP procedures will take place in a dedicated room in the operating
theatre, i.e. the Organ Preservation and Regeneration (OPR) room, under sterile
conditions performed by a surgeon and the local investigator. Following
hypothermic machine perfusion (HMP) during the transportation of the donor
kidney, which is standard practice in the Netherlands, a total of n=18
(eighteen) donor kidneys will be subjected to PNMP prior to transplantation.

A cohort of n=6 (six) DCD kidneys will be subjected to 1 (one) hour of NMP and
subsequently transplanted. Once this has been successfully achieved, the 1
(one) hour NMP period will be expanded to 3 (three) hours (PNMP3) and an
additional n=6 (six) kidneys will be transplanted. Following a successful
evaluation of outcomes following PNMP3 an additional n=6 (six) kidneys will be
subjected to n=6 (six) hours of PNMP (PNMP6).

From a safety perspective, prior to proceeding from NMP1 to PNMP3, we will
determine that no SUSARs have occurred and at least similar secondary outcomes
will be met 1 month post transplantation to those expected from kidney
transplants with similar donor and recipient characteristics, based on
historical matched cohorts.
Similarly, the step up from PNMP3 to PNMP6 will need to meet at least similar
results as the comparable historical cohort.

In this study, the use of prolonged (1-6 hours) NMP (PNMP) of donor kidneys
will be tested which has the added advantage of creating a timeframe for
ex-situ regeneration of marginal donor organs, and allows better assessment of
graft viability.

In this study, we propose to use prolonged normothermic machine perfusion as a
novel technique that entails pumping the kidney with warmed, oxygenated
perfusate based on RBCs to closely simulate normal physiological conditions.
The potential risks and burden to the patients in this study are minimal.

The minimal potential risks and burden for patients in this trial are related
to the procedures which are performed merely for this trial: (prolonged) NMP
itself and the additional biopsy that is collected.

For the (P)NMP itself, Hosgood et al. have shown that 1-hour NMP can be
performed in a safe manner. We expect similar or better outcomes. However, NMP
is performed using a machine, which could display technical failure during
perfusion. If a technical failure occurs, an alarm goes off and the kidney can
be removed immediately from the machine by the standby surgeon within a sterile
environment. It will be immediately flushed with UW cold storage solution to
4ºC as is the case in static cold storage as per standard care. We regard the
risk of NMP to be minimal.

Another factor is timing of the transplant. Theoretically, the start of the
transplant surgery can be delayed with a minimum of 1 hour and a maximum of 6
hours by participation in this study. However, although we strive to limit cold
ischemia time, it is quite common that kidney transplants are delayed for a
couple of hours for logistical reasons. We therefore expect that the regular
interval needed for logistics (at theatre or when there is a need for dialysis
before transplantation) will take place simultaneously with the PNMP, and
application of the PROPER protocol will not contribute to significant delay for
the transplantation.