Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT04122105 |
| Other study ID # |
(H19-02487) |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 1, 2021 |
| Est. completion date |
January 1, 2023 |
Study information
| Verified date |
May 2024 |
| Source |
University of British Columbia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Ischemia-reperfusion (IRI) injuries are common in renal transplantation and cause poor
patient outcomes. Ischemia occurs after the donor's death and reperfusion occurs after kidney
implantation. The donor kidney undergoes warm ischemia (WIT) after blood circulation stops
and cold ischemia (CIT) when subjected to cold storage during transportation. Decreased blood
flow leads to waste product accumulation and cellular damage. During reperfusion, reactive
oxygen radicals and inflammatory processes further damage the kidney. PDE5 inhibitors
increase renal blood flow and could protect the kidney during transplantation. Our study
assesses the utility of giving these drugs perioperatively to reduce the effects of IRI
injury.
Description:
1. Purpose Renal ischemia-reperfusion injuries (IRI) are the result of multifactorial
mechanisms. During ischemia, the kidney is subject to reduced blood flow, oxygen
delivery, and nutrients. This leads to the accumulation of nitrogenous waste products
(i.e. creatinine and blood urea nitrogen) that can lead to cellular damage, depending on
the extent and duration of the ischemia. Moreover, when the kidney is reperfused there
is additional damage caused by reactive oxygen radicals and inflammatory processes.
IRI is a common feature in the presentation of a diverse range of presentations: trauma,
shock, sepsis, renal transplantation, cardiovascular surgery, partial nephrectomy, and
other urologic complications. Moreover, IRI of the kidney specifically can lead to acute
kidney injury (AKI), acute renal failure (ARF), and subsequent chronic renal failure. In
the context of renal transplantation, IRI is associated with primary nonfunction,
delayed graft failure, increased acute rejection, and allograft dysfunction. It has been
postulated that interventions designed at increasing vasodilation during early
reperfusion could reduce the effects of IRI through improving blood flow to the
transplanted kidney.
Phosphodiesterase-5 (PDE5) inhibitors, like sildenafil citrate (Viagra) and tadalafil,
are drugs generally used to treat erectile dysfunction (ED) and pulmonary hypertension.
These drugs prevent the breakdown of nitric oxide (NO) by increasing levels of cyclic
guanosine monophosphate (cGMP). Besides causing smooth muscle relaxation and systemic
vasodilation, NO and cGMP are both believed to help reduce the extent of IRI. NO has
protective vasodilatory effects; while cGMP is an important mediator in the body that
causes neutrophil degranulation, inhibits platelet aggregation, regulates intracellular
calcium levels, and opens mitochondrial K+ATP channels.
A number of different studies have been undertaken that support the use of PDE5
inhibitors as a pretreatment to prevent IRI in kidneys. In particular, sildenafil's
antioxidant, anti-inflammatory, and antiapoptotic properties have been shown to be
renoprotective in some renal injury models. However, the majority of literature is based
from animal studies; there is very little information about the clinical use of PDE5
inhibitors during human kidney transplantation. Previous studies have proven that these
drugs are safe for impotent males with significant comorbidities, including those on
dialysis and those who underwent kidney transplants (>6 months post-op). They have also
proven that sildenafil does not affect immunosuppressive drugs (i.e. tacrolimus and
cyclosporine), despite these drugs sharing a common elimination pathway; Tacrolimus'
pharmacokinetics, trough levels, and half-life are not significantly changed when
administered with sildenafil. However, tacrolimus does change the pharmacokinetics
(increase in Cmax and half-life) of sildenafil when both are administered together.
These studies prove that PDE5 inhibitors are renoprotective, generally well-tolerated,
and do not impact immunosuppressants. However, what they have not shown is the effect of
PDE5 inhibitors administered early in human kidney transplantation and their effect on
the transplanted kidney. Our study will try to amend this by looking at utility of
perioperative administration of sildenafil in early effects on the transplanted
allograft.
2. Hypothesis A.) PDE5 inhibitors given perioperatively will decrease ischemia reperfusion
injury and lead to consequently improved function in the transplanted kidney.
3. Justification In 2018, 133 transplants were performed by the Vancouver General Hospital
(VGH) Kidney Transplant program. 38 of these kidneys were from living donors (LD), while
the remaining 95 were cadaveric donations. This data supports that the majority of renal
transplants are done using kidneys from deceased donors (DD) as opposed to LDs. However,
the quality of these donated organs can vary drastically and DD organs are more likely
to have poorer outcomes relative to LD. This is because the DD kidney undergoes warm
ischemia (WIT) after the blood circulation is stopped and then cold ischemia (CIT) when
subjected to hypothermic conditions meant to preserve the organ. The combined effects of
WIT and CIT inflict cellular damage and may impair renal blood flow to cause primary
renal dysfunction, delayed graft failure, increased acute rejection, and allograft
dysfunction. Increased renal perfusion in this critical phase through vasodilation may
counteract some of these negative effects of procurement and implantation
There is a lot of heterogeneity among DD kidneys due to the exact cause of the donor's
death. Donation after circulatory death (DCD), as opposed to donation after brain death
(DBD), kidney transplants have a higher chance of delayed graft function (DGF). DGF is
defined as needing dialysis in the first week of transplant. This is common in marginal
donor organs such as DCD or extended criteria (ECD) cadaveric transplants and can
predispose to slow graft function or delayed graft function, which themselves are
associated with increased rates of acute rejection and poorer outcomes. Our study aims
to look at both DCD and DBD transplants to determine if PDE5 inhibitors can positively
impact graft function of DD kidneys.
4. Objective A) To measure the utility of perioperative administration of PDE5 inhibitors
in kidney transplant recipients (RTRs)
5. Research Design DRUG CHOICE Sildenafil has the longest safety record of the PDE5
inhibitors. Moreover, it is shown to have a more potent effect in IRI studies. A dose of
50mg twice a day is the standard dose given to patients with Erectile Dysfunction (ED).
METHOD A patient who has given written informed consent will be given a randomly
generated subject ID that is not derived from any aspect of their personally identifying
information, nor details regarding their operation. This subject ID will be stored on a
master list alongside their personal health number to serve as a unique method of
identifying patients.
Patients will randomly be assigned to either the control (no PDE5 inhibitor) or the
intervention (sildenafil) group. The control group will receive standard care. The
intervention group will receive standard care in all capacities with the exception of
sildenafil administration. The first dose (50mg) will be given 1-hour prior to the
surgery. Patients will be given Sildenafil twice daily up to 3 days post-transplant.
Data will be collected and stored on an encrypted, office-only hard drive. Information
on demographics (gender, ethnicity, age, etc.) and postoperative results (kidney
function, all cause 90-day perioperative morbidity and mortality, postoperative
complications, and length of stay in hospital) will be recorded for all patients on an
password protected Excel file.
OUTCOMES Outcomes including intraoperative, postoperative and 90 day followup will be
assessed. Intraoperative: xxxx, xxxx, xxx, xxx. Postoperative: kidney function, all
cause 90-day perioperative outcomes including xxxx, xxx, xxx, xxx. Time zero biopsies
are done as routine and will likewise be taken into account. Kidney Function will be
determined through daily bloodwork while an inpatient, and twice a week for the first 4
weeks, once a week from weeks 5-8, and then every 2 weeks from weeks 9-12. This is the
standard of care follow-up in the Program. All information is normally collected for
transplant patients on this schedule and no extra time or discomfort will be required on
the part of the patient.
6. Statistical Analysis This study will use the Chi square method to analyze categorical
data and the t-test between groups to analyze continuous variable. A P-value < 0.05 will
be considered statistically significant.
For this study, he investigators propose n=100 with 50/50 split between patients undergoing
DCD and DBD transplants and a 1:1 split in the control and experimental arms. Therefore,
there will be 25 patients in each of the following arms: DCD experimental, DCD control, DBD
experimental, and DBD control. The VGH Kidney transplant program completed 133 transplants in
2018. Out of this, 95 were cadaveric transplants. Assuming similar numbers in the future with
50% of the recipients participating, it will take about 2 years to accrue the data needed for
adequate statistical analysis.
