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

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00857844
• Other study ID #: STU8309 0773-018
• Status: Completed
• Phase: N/A
• First received: March 6, 2009
• Last updated: May 1, 2013
• Start date: July 2007
• Est. completion date: May 2012

Study information

• Verified date: May 2013
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 207
• Est. completion date: May 2012
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Observational Model: Cohort, Time Perspective: Cross-Sectional

Related Conditions & MeSH terms

• Complication of Transplanted Liver
• Disease Susceptibility
• Genetic Predisposition to Disease

Locations

Country	Name	City	State
United States	Northwestern Memorial Hospital	Chicago	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
Northwestern University	Northwestern Memorial Hospital

Country where clinical trial is conducted

United States, 

References & Publications (37)

Amer H, Lieske J, Grande J, Stegall M, Larson T. Urinary TGF-beta1 predicts progressive renal allograft fibrosis on one year protocol biopsies. Abstract, ASN, 2006. San Diego

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Inoue I, Nakajima T, Williams CS, Quackenbush J, Puryear R, Powers M, Cheng T, Ludwig EH, Sharma AM, Hata A, Jeunemaitre X, Lalouel JM. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest. 1997 Apr 1;99(7):1786-97. — View Citation

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Vleming LJ, van der Pijl JW, Lemkes HH, Westendorp RG, Maassen JA, Daha MR, van Es LA, van Kooten C. The DD genotype of the ACE gene polymorphism is associated with progression of diabetic nephropathy to end stage renal failure in IDDM. Clin Nephrol. 1999 Mar;51(3):133-40. — View Citation

Yamamoto T, Nakagawa T, Suzuki H, Ohashi N, Fukasawa H, Fujigaki Y, Kato A, Nakamura Y, Suzuki F, Hishida A. Urinary angiotensinogen as a marker of intrarenal angiotensin II activity associated with deterioration of renal function in patients with chronic kidney disease. J Am Soc Nephrol. 2007 May;18(5):1558-65. Epub 2007 Apr 4. — View Citation

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* Note: There are 37 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Blood draw (20cc) and urine collection (80cc).	At time of enrollment	No
Secondary	The study will also evaluate if specific demographic characteristics are associated with an increased risk of nephrotoxic damage from CI.	Blood draw (20cc)	At time of enrollment	No
Secondary	Organ transplant tolerance in subjects who are currently using immunosuppressant medications.	Blood draw (18cc).	One additional blood draw - follow-up time point	No