Renal protection against ischaemia-reperfusion in transplantation

The gap between the supply of kidneys for transplantation and the demand of
recipients is growing steadily in the Netherlands. Between 1998 and 2008, the
total number of kidney transplants has not changed significantly, despite the
fact that in recent years over 50% of the patients received a kidney transplant
from a living donor. Patients waiting on the transplant list endure reduced
quality of life and increased death rates, not to mention the economic burden
of renal replacement therapy (dialysis). Therefore, new approaches to maximise
the benefit of each transplanted kidney are needed, so that each patient gets
extra years of benefit. One influence on kidney function after transplantation
is damage that occurs when the kidney is removed from the donor and loses its
blood supply. This is known as ischaemic injury. Reconnecting the kidney to the
recipient's circuation reduces ischaemic injury but triggers a second phase of
injury, known as reperfusion injury. Therefore tissue damage is a combination
of injury that occurs during ischaemia and reperfusion, known as
ischaemia*reperfuson (IR) injury. The degree of IR injury determines the speed
of recovery of kidney function in the short term and influences long term
success of the transplant. Reduction in IR injury has potential to improve the
outcome of kidney (and other organ) transplantation. This trial will determine
whether remote ischaemic preconditioning (RIPC), an intervention that we have
shown to reduce human IR injury, improves renal function after living*donor
kidney transplantation.
Remote ischaemic preconditioning: Over thirty studies in animals have shown
that if the blood flow to an organ is transiently cut off, this stimulates a
protective reflex. This phenomenon of remote ischaemic preconditioning (RIPC)
makes many different organs resistant to the damage caused by low blood flow,
including the heart, lung, liver, skin and skeletal muscle. Our research group
has extended these animal observations to humans and has shown that transient
reductions in blood flow to the arm or leg reduces experimental IR injury in
healthy subjects and patients. Three small scale clinical trials have shown
that RIPC protects the heart in children and adults undergoing heart surgery,
and the kidneys in patients undergoing abdominal surgery. We have recently
completed a pilot study showing that RIPC protects the kidney in living*donor
kidney transplantation in children. The focus of this clinical trial is to
extend these observations in a kidney transplantation trial of adequate size to
measure if RIPC has protective effects that are sufficiently large to benefit
patients.

The intervention that we will test in this trial is remote ischaemic
preconditioning. Remote ischaemic preconditioning is a protective reflex that
is induced by repeatedly obstructing the blood supply to the arm over a 40
minute period. We have shown this procedure reduces kidney injury in a small
pilot study and now plan to do trial of sufficient size to establish the actual
clinical benefit with precision.

Primary objective:
To determine if remote ischaemic preconditioning improves renal function (GFR
measured by iohexol clearance) 12 months after transplantation

Secondary objective(s):
To determine the effect on
1. Rate of fall in creatinine in the first 72 hours after transplantation
2. Inflammatory response to surgery in the first 5 days after transplantation
3. Protein expression in kidney parenchyma samples using histochemistry
4. Protein activation and expression in renal vasculature using immunoblotting
5. Kidney fibrosis 6 months after transplantation
6. Alloreactivity of T cells in the first 18 months after transplantation
7. Patient outcomes 2-5 years after transplantation using renal registry data

Double*blind, randomised, placebo-controlled
Patients (and their donors) will be will be randomised as pair to one of 4
groups:
1. sham RIPC to act as a control group
2. early phase RIPC
3. late phase RIPC
4. Dual RIPC (early and late phase RIPC)

Patients (donors and recipients) will be randomised to four groups: control
(sham RIPC), early RIPC, late RIPC and dual RIPC. Active treatment will consist
of four 5*minute inflations of a blood pressure cuff on the upper arm to 40
mmHg above systolic blood pressure. The inflations will be separated by
5*minute periods when the blood pressure cuff will be deflated. To activate
late phase RIPC, the inflations will occur 24 hours before surgery. Placebo
treatment (sham RIPC) will consist of four 5*minute inflations of a blood
pressure cuff on the upper arm to 40 mmHg (and below systolic blood pressure).

1. Standard procedures for kidney transplantation will be followed in each of
the centres involved in this study. This includes preoperative care,
anaesthetic and surgical procedures, postoperative care and follow up
thereafter.
2. The main additional procedure is the remote ischaemic preconditioning
intervention. This is a benign procedure, consisting of 4 periods of inflation
of a blood pressure cuff to 40 mmHg above blood pressure, each lasting for 5
minutes. Each inflation will be followed by a 5 minute period when the cuff is
deflated. During the inflation of the cuff, blood flow will be cut off to the
arm for 5 minutes. This will not cause any damage though there is a risk of arm
discomfort. Some research subjects will undergo the preconditioning cuff
inflation on two occasions, the first 24 hours before surgery and the second
immediately before surgery. The kidney donor and recipient will undergo
preconditioning cuff inflations. A placebo group will be included who will
undergo a sham inflation of the cuff; this will be dome by inflating the cuff
to a pressur of 40 mmHg and well below usual blood pressure so as not ti impede
blood flow into the arm.
3. Volunteers will undergo blood and urine sampling in the first 5 days after
surgery. Most of these will be as part of routine clinical care but some will
be for research purposes
4. Therefore the main ethical issues will be the discomfort of the cuff
inflations, preserving patient confidentiality and the inconvenience to the
patients of extra blood and urine sampling. To address these issues, subjects
can withdraw from the study if they do not tolerate any discomfort or
inconvenience. Standard approaches to maintain patient confidentiality will be
adopted whilst at the same time collecting the minimum patient*identifiable
data that is needed to address the research question.
5. Tissue samples that are surplus to requirements will be collected for
analyses. We will ask that these be gifted for research purposes.
6. Informed consent will be obtained from all research subjects.
7. The study will be randomised, placebo*controlled and double blind so
limiting the effect of bias. The organisational issues that arise will be dealt
with by the recruitment of staff to run the study at each of the sites.
8. There are no commercial conflicts of interest. The study is funded by the
NIHR and the MRC.