Genetic Predisposition-Chronic Nephrotoxicity From CI-Liver Transplant Recipients-Potential Correlation-Urinary Biomarkers

May 1, 2013 updated by: Lorenzo Gallon, Northwestern University

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 Overview

Status

Completed

Conditions

Detailed Description

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.

Study Type

Observational

Enrollment (Actual)

207

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern Memorial Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

This study will be conducted in liver transplant recipients. We are planning to collect data and genotyping in 650 liver transplant recipients. Patients who satisfy the following inclusion/exclusion criteria will be eligible for the study:

Description

Inclusion Criteria:

  • Informed consent
  • Males and females > 18 years old
  • Liver transplant recipients who have received a liver transplant at least 6 months ago
  • Liver transplant recipients receiving a maintenance immunosuppression.

Exclusion Criteria:

  • Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope and possible consequences of the study
  • Pre-existing known kidney disease before liver transplantation
  • Multi-organ transplant

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Group 1
Normal GFR (>90ml/min/1.73m2). Stage I CKD
Group 2
GFR between 30-59ml/min/1.73m2. Stage III CKD
Group 3
GFR between 15-29ml/min/1.72m2. Stage IV CKD

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To investigate, in liver transplant patients, the role of urinary biomarkers as indirect indices of chronic nephrotoxicity from CI and associate, where possible, urinary biomarkers to genomic variants of the angiotensin converting
Time Frame: At time of enrollment
Blood draw (20cc) and urine collection (80cc).
At time of enrollment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The study will also evaluate if specific demographic characteristics are associated with an increased risk of nephrotoxic damage from CI.
Time Frame: At time of enrollment
Blood draw (20cc)
At time of enrollment
Organ transplant tolerance in subjects who are currently using immunosuppressant medications.
Time Frame: One additional blood draw - follow-up time point
Blood draw (18cc).
One additional blood draw - follow-up time point

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Northwestern University

Collaborators

Northwestern Memorial Hospital

Investigators

  • Principal Investigator: Lorenzo Gallon, M.D., Northwestern University, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2007

Primary Completion (Actual)

October 1, 2008

Study Completion (Actual)

May 1, 2012

Study Registration Dates

First Submitted

March 6, 2009

First Submitted That Met QC Criteria

March 6, 2009

First Posted (Estimate)

March 9, 2009

Study Record Updates

Last Update Posted (Estimate)

May 3, 2013

Last Update Submitted That Met QC Criteria

May 1, 2013

Last Verified

May 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STU8309 0773-018

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Complication of Transplanted Liver

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Latvia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe