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

• ClinicalTrials.gov Identifier: NCT00857844
• Recruitment Status: Completed
• First Posted: March 9, 2009
• Last Update Posted: May 3, 2013
• Sponsor: Northwestern University
• Collaborator: Northwestern Memorial Hospital
• Information provided by (Responsible Party): Lorenzo Gallon, Northwestern University

Study Description

Brief Summary:

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.

Condition or disease
Complication of Transplanted Liver

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 Design

• Study Type: Observational
• Actual Enrollment: 207 participants
• Observational Model: Cohort
• Time Perspective: Cross-Sectional
• Official Title: Genetic Predisposition of Chronic Nephrotoxicity From Calcineurin Inhibitors in Liver Transplant Recipients, Potential Correlation With Urinary Biomarkers
• Study Start Date: July 2007
• Actual Primary Completion Date: October 2008
• Actual Study Completion Date: May 2012

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

1. 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).

Secondary Outcome Measures :

1. 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)
2. Organ transplant tolerance in subjects who are currently using immunosuppressant medications. [ Time Frame: One additional blood draw - follow-up time point ]
   Blood draw (18cc).

Biospecimen Retention:   Samples With DNA

• Urine 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.
• An additional 18mls of blood will be collected. This blood will be used to study organ transplant tolerance in subjects who are currently using immunosuppressant medications.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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:

Criteria

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

Contacts and Locations

Locations

United States, Illinois

Northwestern Memorial Hospital

Chicago, Illinois, United States, 60611

Sponsors and Collaborators

Northwestern University

Northwestern Memorial Hospital

Investigators

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

More Information

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• Responsible Party: Lorenzo Gallon, Associate Professor, Northwestern University
• ClinicalTrials.gov Identifier: NCT00857844
• Other Study ID Numbers: STU8309 0773-018
• First Posted: March 9, 2009
• Last Update Posted: May 3, 2013
• Last Verified: May 2013

Keywords provided by Lorenzo Gallon, Northwestern University:

Chronic Nephrotoxicity; Kidney dysfunction post liver transplant; Urinary biomarkers of chronic nephrotoxicity from CI

Additional relevant MeSH terms:

Disease Susceptibility; Genetic Predisposition to Disease; Disease Attributes; Pathologic Processes