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Complication of Transplanted LiverNCT00857844

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

An observational study of Complication of Transplanted Liver, run by Northwestern University at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Complication of Transplanted Liver
Type of treatment
Injection or infusion
How many people
207 participants
Where
1 siteUnited States
Study dates
Jul 2007to May 2012
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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:

Who may be able to join

  • 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.

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Northwestern Memorial Hospital

    Chicago, Illinois, 60611

Other trials in United States

About this study

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.

Read the 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.

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

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT00857844
Study groupRoleWhat they receive
Group 1Normal GFR (>90ml/min/1.73m2). Stage I CKD
Group 2GFR between 30-59ml/min/1.73m2. Stage III CKD
Group 3GFR between 15-29ml/min/1.72m2. Stage IV CKD

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Blood draw (20cc) and urine collection (80cc).

    Measured: At time of enrollment

Secondary outcomes (2)
  1. The study will also evaluate if specific demographic characteristics are associated with an increased risk of nephrotoxic damage from CI.

    Blood draw (20cc)

    Measured: At time of enrollment

  2. Organ transplant tolerance in subjects who are currently using immunosuppressant medications.

    Blood draw (18cc).

    Measured: One additional blood draw - follow-up time point

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Mar 2009 (estimated)
  2. Study startJul 2007
  3. Primary completionOct 2008
  4. Study completionMay 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Cross-sectional
Enrolment
207 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00857844
Sponsor's protocol ID
STU8309 0773-018
Status last verified
May 2013
First submitted
6 Mar 2009
Last updated
3 May 2013
Results posted
No
Data monitoring committee
No

Publications

  • Bennett WM. Insights into chronic cyclosporine nephrotoxicity. Int J Clin Pharmacol Ther. 1996 Nov;34(11):515-9.

    PubMed 8937936
  • Bennett WM, DeMattos A, Meyer MM, Andoh T, Barry JM. Chronic cyclosporine nephropathy: the Achilles' heel of immunosuppressive therapy. Kidney Int. 1996 Oct;50(4):1089-100. doi: 10.1038/ki.1996.415. No abstract available.

    PubMed 8887265
  • Myers BD. Cyclosporine nephrotoxicity. Kidney Int. 1986 Dec;30(6):964-74. doi: 10.1038/ki.1986.280. No abstract available.

    PubMed 3546916
  • Puschett JB, Greenberg A, Holley J, McCauley J. The spectrum of ciclosporin nephrotoxicity. Am J Nephrol. 1990;10(4):296-309. doi: 10.1159/000168123. No abstract available.

    PubMed 2240057
  • Young EW, Ellis CN, Messana JM, Johnson KJ, Leichtman AB, Mihatsch MJ, Hamilton TA, Groisser DS, Fradin MS, Voorhees JJ. A prospective study of renal structure and function in psoriasis patients treated with cyclosporin. Kidney Int. 1994 Oct;46(4):1216-22. doi: 10.1038/ki.1994.387.

    PubMed 7861719
  • Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosporine-associated chronic nephropathy. N Engl J Med. 1984 Sep 13;311(11):699-705. doi: 10.1056/NEJM198409133111103.

    PubMed 6382005
  • Goldstein DJ, Zuech N, Sehgal V, Weinberg AD, Drusin R, Cohen D. Cyclosporine-associated end-stage nephropathy after cardiac transplantation: incidence and progression. Transplantation. 1997 Mar 15;63(5):664-8. doi: 10.1097/00007890-199703150-00009.

    PubMed 9075835
  • Hornberger J, Best J, Geppert J, McClellan M. Risks and costs of end-stage renal disease after heart transplantation. Transplantation. 1998 Dec 27;66(12):1763-70. doi: 10.1097/00007890-199812270-00034.

    PubMed 9884274
  • Fisher NC, Nightingale PG, Gunson BK, Lipkin GW, Neuberger JM. Chronic renal failure following liver transplantation: a retrospective analysis. Transplantation. 1998 Jul 15;66(1):59-66. doi: 10.1097/00007890-199807150-00010.

    PubMed 9679823
  • Gonwa TA, Mai ML, Melton LB, Hays SR, Goldstein RM, Levy MF, Klintmalm GB. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation. 2001 Dec 27;72(12):1934-9. doi: 10.1097/00007890-200112270-00012.

    PubMed 11773892
  • Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003 Sep 4;349(10):931-40. doi: 10.1056/NEJMoa021744.

    PubMed 12954741
  • Mervaala E, Lassila M, Vaskonen T, Krogerus L, Lahteenmaki T, Vapaatalo H, Karppanen H. Effects of ACE inhibition on cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on a high-sodium diet. Blood Press. 1999;8(1):49-56. doi: 10.1080/080370599438392.

    PubMed 10412883
  • Perico N, Benigni A, Bosco E, Rossini M, Orisio S, Ghilardi F, Piccinelli A, Remuzzi G. Acute cyclosporine A nephrotoxicity in rats: which role for renin-angiotensin system and glomerular prostaglandins? Clin Nephrol. 1986;25 Suppl 1:S83-8.

    PubMed 3519031
  • Shihab FS, Bennett WM, Tanner AM, Andoh TF. Angiotensin II blockade decreases TGF-beta1 and matrix proteins in cyclosporine nephropathy. Kidney Int. 1997 Sep;52(3):660-73. doi: 10.1038/ki.1997.380.

    PubMed 9291185
  • Pichler RH, Franceschini N, Young BA, Hugo C, Andoh TF, Burdmann EA, Shankland SJ, Alpers CE, Bennett WM, Couser WG, et al. Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin. J Am Soc Nephrol. 1995 Oct;6(4):1186-96. doi: 10.1681/ASN.V641186.

    PubMed 8589285

Questions about this trial

What is this clinical trial studying?

An observational study of Complication of Transplanted Liver, run by Northwestern University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 May 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00857844, which also lists 37 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2013.

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