The aim of the current study is two-folded. The primary aim is to assess the impact of NMP on the incidence of PNF/DGF. Secondly, we investigate the association between microcirculation and oxyhaemoglobin during NMP as measured with the MoorO2Flo…
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
- Renal and urinary tract therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The incidence of DGF/PNF.
Secondary outcome
Clinical objectives:
To evaluate the impact of NMP on the following graft outcomes:
• The overall incidence of DGF.
• The incidence of DGF, excluding dialysis sessions for hyperkalaemia or volume
overload.
• Duration of DGF, which is defined as the time between transplant and the last
dialysis session.
• Total number of post-transplant dialysis sessions (measured up to 3 months
post-transplantation)
• The incidence of PNF.
• Estimated Glomerular Filtration Rate (eGFR) trajectory in the first year
after transplant calculated with the Chronic Kidney Disease Epidemiology
collaboration (CKD-EPI) formula.
• eGFR at 1 year, 3 years and 5 years calculated with the CKD-EPI formula.
• Biopsy-proven acute rejection within the first year post-transplant.
• Graft survival up to 5 years.
• Patient survival up to 5 years.
• Length of hospital stay, calculated from transplantation date until the date
of discharge.
• The incidence and severity of (serious) adverse events graded according to
the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0)
• Postoperative complications, graded according to the Clavien-Dindo
classification
Measures of microcirculation and pathophysiological processes:
• To evaluate the association between microcirculation/oxyhaemoglobin
concentration during NMP and immediate kidney function (no DGF/PNF).
• To evaluate the association between microcirculation/oxyhaemoglobin
concentration during NMP and other important graft outcomes:
• DGF duration
• Biopsy-proven acute rejection within the 1st year post-transplant
• Estimated Glomerular Filtration Rate trajectory in the first year
post-transplant
• Graft survival up to 5 years
• To investigate differences in gene expression profile of the donor kidney
during the course of NMP (measured in biopsies taken during NMP hourly), and
differences in gene expression profile in NMP compared to HMP.
• To investigate the quantity of donor-derived cell-free DNA after
transplantation as a marker of ischemia-reperfusion injury (measured in
recipient blood on day 1-6 after transplant).
• To evaluate differences in perfusate sodium/urine sodium ratio during the
course of NMP (measured in perfusate and urine produced during NMP)
• To investigate the production of renine, EPO and vitamin D during the course
of NMP (measured in perfusate during NMP).
• To investigate differences in oxygen consumption during the course of NMP
(measured in perfusate during NMP)
• To evaluate differences in renal histology at start and end of NMP (measured
in biopsies taken during NMP), and differences in renal histology in NMP
compared to HMP.
• To evaluate the quantity of extracellular vesicles during the course of NMP
(measured in perfusate)
Background summary
The major challenge in kidney transplantation is the shortage of suitable donor
kidneys. One way to enlarge the kidney donor pool is by using Extended Criteria
Donor (ECD) grafts. However, these grafts have a 70% increased chance of graft
failure, possibly because these grafts are more sensitive to
ischemia-reperfusion injury(2). Because of the increased use of ECD kidneys,
therapies to improve quality of these kidneys are of utmost importance. Dynamic
preservation techniques have been introduced as being superior to static cold
storage (SCS). A randomized controlled trial already showed the benefit of
hypothermic machine perfusion (HMP) over SCS, which led to a protocol change in
2016(3). During HMP, the kidney is not metabolically active which means that
the injury process persists. For more severely damaged kidneys, such as ECD
kidneys, active repair may be needed to optimize the kidney before
transplantation. Therefore, normothermic machine perfusion (NMP) has regained
interest as a better preservation method for these kidneys.
NMP allows donor organs to be perfused with warm, oxygenated red blood cells in
the absence of the immune components normally present in blood, including
complement and neutrophils, with the aim of reversing the deleterious effects
of warm and cold ischemia.
The first clinical study about NMP of the Cambridge group showed a significant
decrease in DGF/PNF after NMP, which is a surrogate marker for long-term graft
survival(4, 5). The second study was carried out in Erasmus Medical Center
(POSEIDON study, MEC 2017-503) and also showed a difference in the incidence of
DGF and PNF (NMP group: 36%, controls: 63%, manuscript submitted), which was
not statistically significant. Currently, an RCT is carried out in the UK to
investigate the use of additional NMP against static cold storage only(6).
However, it is still unknown whether NMP has additional value to HMP alone.
During NMP, viability and function of the donor kidney can be assessed. So far,
clinical assessment of viability is performed through visual inspection,
measurement of flow and resistance, urine production, perfusate injury markers
and blood gas analysis. However, these methods only provide a general overview
of the flow through the kidney without taken into account potential localized,
suboptimal perfused areas(7). There is no method of constant real-time feedback
on the perfusion of the donor kidney yet. The MoorO2Flo may be a device that
can be useful for this purpose. This device is a non-contact,
near-infrared-based imaging system with high temporal and spatial resolution,
providing an index of blood flow and oxyhaemoglobin concentration over large
surface areas. It allows continuous, quantitative assessment of
microcirculatory perfusion, perfusion heterogeneity and relative tissue
oxyhaemoglobin concentration. It has shown to be feasible to identify ischemic
areas on gastric tube reconstructions following esophagectomy(8). However, the
MoorO2Flo has not been validated for NMP yet and it is unknown whether
differences in microcirculation and oxyhaemoglobin concentration or homogeneity
correlate with post-transplant kidney function.
Study objective
The aim of the current study is two-folded. The primary aim is to assess the
impact of NMP on the incidence of PNF/DGF. Secondly, we investigate the
association between microcirculation and oxyhaemoglobin during NMP as measured
with the MoorO2Flo and immediate kidney function (no DGF or primary non
function (PNF)).
Study design
Open-label, single-center, prospective randomized clinical trial
Intervention
The intervention for the donor kidney is 2 hours of normothermic, end-ischemic
machine perfusion.
Study burden and risks
Because of the normothermic oxygenated nature of the perfusion, failure of the
process leads to warm ischemia. In our pilot study (POSEIDON study, MEC
2017-503), no failures of the NMP procedure were observed and no primary
nonfunction occurred. This shows the safety of the NMP procedure. If a failure
would occur, a highly trained transplant surgeon is present at all time during
the perfusion to switch to cold storage immediately if needed. Therefore, extra
risk of the NMP procedure is deemed small. Renal biopsies are obtained during
machine perfusion hourly. These biopsies have been shown in previous studies in
our institution (INEX study, POSEIDON study) to possess no risk to the patient.
Renal biopsies will also be obtained in the control group. One biopsy will be
obtained during benching, and one biopsy will be obtained during
transplantation after ureter anastomosis. All blood sampling will be combined
with routine lab work. The amount of blood samples taken from the patient is 15
ml daily on day 1-6 after transplantation during hospitalization. NB: Blood
sampling will only occur in a subset of 45 of the included patients. No extra
hospital visits are needed. The most important benefit from participation is
the prospect of a better functioning graft post-transplant.
Dr Molewaterplein 40
Rotterdam 3015 GD
NL
Dr Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
Kidney related:
In order to be eligible to participate in this study, the donor kidney must
meet the following criteria:
- Donation after Circulatory Death (DCD) type III/IV/V (Maastricht criteria) OR
- Donation after Brain Death (DBD) donor kidney IF the kidney meets ECD
criteria:
o Donor >=60, OR
o Donor 50-59 years with 2 of the following risk factors: history of high blood
pressure, creatinine greater than or equal to 1.5 mg/dl (133 umol/l), death
resulting from stroke.
Recipient related:
- Adult (>=18 years old) recipients.
- Mentally competent recipients.
- Recipients who receive renal replacement therapy at the moment of
transplantation.
- Recipients who provided written informed consent.
Exclusion criteria
- Multi-organ transplant recipients (such as combined liver/kidney).
- Receiving a donor kidney preserved on static cold storage.
- Receiving a donor kidney that is explanted after normothermic regional
perfusion.
- DCD type I and II (Maastricht criteria).
- Dual kidney transplantation
- The patient receives another immunosuppression regime than standard-of-care
(which is induction with basiliximab followed by triple therapy with
tacrolimus, mycofenolate mofetil and prednisone)
Design
Recruitment
Medical products/devices used
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In other registers
| Register | ID |
|---|---|
| CCMO | NL73213.078.20 |