Complication of Transplanted Liver Clinical Trial
Official title:
Genetic Predisposition of Chronic Nephrotoxicity From Calcineurin Inhibitors in Liver Transplant Recipients, Potential Correlation With Urinary Biomarkers
The purpose of this study is to determine the relationship between genomic variants of
components of the renin-angiotensin system and the development of kidney problems due to
Calcineurin-inhibitors post liver transplant.Also the investigator will evaluate the
relationship between chronic renal failure post liver transplant and the risk of death. A
sample of blood and urine wil be examined to see how the patient's genes are arranged in
order to determine the difference in genes between people which may explain who will develop
chronic renal failure after having received a liver transplant.
The results may help us classify patients according to their risk and allow us to target
their treatment to their individual need. In addition, it may ultimately lead to treatments
that slows or prevents the development of chronic rejection.
Study Design:
This study will be a cross-sectional investigation of liver transplant recipients who
received a liver transplant and have at least 6 months of follow-up. This study will be
conducted at Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation and
Northwestern University.
Patients who underwent liver transplantation and have at least 6 months of follow-up
receiving a maintenance immunosuppression (which consists of calcineurin inhibitors (CI),
cyclosporine (CsA), or tacrolimus (Tac)) during the entire post-transplant follow-up period
will be included in the analysis.
For each patient, the following information will be collected:
- Date of transplantation, age, gender, race, causes of liver failure, past medical
history including incidence of hypertension, diabetes mellitus, post-operative
complications, post-operative infections, number of acute liver rejection episodes,
death, CsA and Tac trough levels at different time points post-transplant and sCr
levels before liver transplant, at 1, 6, 12, 24 months, and yearly post-transplant.
- GFR (Glomerular Filtration Rate) with MDRD equation before liver transplant, at 1, 6,
12, 24 months, and yearly post-transplant.
- In the attempt to rule out all patients with pre-existing CRF before liver transplant,
only the patients with sCr<1.0mg/dL before liver transplant will be included in our
analysis.
Genotyping:
- DNA will be extracted using blood buffy coat from liver transplant recipients.
- Determination of ACE genotypes will be performed by using polymerase chain reaction
sequence-specific primers (PCR-SSP) and polymerase chain reaction restriction fragment
length polymorphism (PCR-RFLP).
- Based on GRF calculation by MDRD equation liver transplant patients will be categorized
into three groups based on NKF staging of chronic kidney disease:
Group I->normal GFR (>90ml/min/1.73m2). Stage I CKD Group II->GFR between
30-59ml/min/1.73m2. Stage III CKD Group III->GFR between 15-29ml/min/1.72m2. Stage IV CKD
- Urine (80cc) will be collected from all patients in the 3 groups and analyzed for
biomarkers of interstitial fibrosis and proximal tubule injury. Specific biomarkers
that will be tested are: urinary TGF-beta1, kidney injury molecule-1 and
angiotensinogen. Urinary biomarkers will be normalized to creatinine and analyzed using
an ELISA assay.
- Blood (20cc)will be taken at one visit.
- An additional blood draw (18cc) will be requested from all subjects. This blood will be
used to study organ transplant tolerance in subjects who are currently using
immunosuppressant medications.
Statistical Plan-Statistical tests to be performed:
Once liver transplant patients are genotyped and urine samples are collected we will
compared the development of CKD post liver transplant for associations with urinary
biomarkers and polymorphisms of the ACE gene. Two sample t tests will be used to compare
differences in continuous variables between liver patients with different degree of CKD; chi
square tests will be used to compare differences in discrete variables. Multivariable
logistic regression analysis will be also performed to identify the combination of clinical
variable and gene polymorphisms that are significantly associated with the development of
post liver transplant renal dysfunction.
This study will enable us to learn and evaluate potential genetic predisposition for the
development of renal dysfunction after exposure to CI. If our hypothesis is correct, testing
of the component of the RAS genotypes may help identify patients at risk for CI
nephrotoxicity and help in the pre-selection of liver transplant candidates in whom the use
of CI as primary immunosuppression should be avoided.
Furthermore, the data generated from this study might serve as a strong basis for a
prospective NIH-founded project to look at the role of agents that block the
renin-angiotensin system for the prevention of CI-induced chronic nephrotoxicity.
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Observational Model: Cohort, Time Perspective: Cross-Sectional
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