Functional Genetic Variants Affecting Tacrolimus Trough Levels and Side Effects in Chinese Renal Transplantation.

The purpose of this study is to determine whether functional genetic variants can affect tacrolimus dose corrected trough levels and associate with the side effects in Chinese renal transplant recipients.

Study Overview

• Status: Completed
• Conditions: Transplantation

Detailed Description

Tacrolimus is an effective immunosuppressive drug widely used in solid organ transplantation to prevent rejection. It is characterized by a narrow therapeutic range and large inter- and intra- individual variability in its pharmacokinetics. Many factors are associated with the variability. Of these factors, genetic factor play an important role. Full understanding of this mechanism is important for the personalized use of tacrolimus and reducing the risk of side effects.The CYP3A5*3 (A6986G) resulting in a splicing defect and the absence of protein activity, was identified as a functional variant (Kuehl P.2001). The CYP3A4*1G was also reported as a functional variant (Richards-Waugh LL. 2014). In addition, other functional variants will also be identified and analyzed in our project.

Our project has two parts:first, retrospective study, 839 renal transplant recipients using tacrolimus as immunosuppressive drug were recruited from Nanfang Hospital. Fifty-eight SNPs from GWAS, GTEx and promoter region of CYP3A gene were genotyped. The association of 58 SNPs on the dose corrected tacrolimus trough levels and side effects (acute rejection, nephrotoxicity and neurotoxicity) were analyzed. Luciferase reporter gene assay were used to identify the functional variants. Second, in this part, there is another renal transplantation cohort. For this cohort, it was a retrospective cohort. All the patients will be stratified to different groups according to the different genotypes. The side effects (acute rejection, nephrotoxicity and neurotoxicity) will be observed.During the study period, all the therapeutic procedures of the patients are as usual.

This will be the largest cohort of this kind of study in Chinese population. The findings will be useful for the patients to improve the therapeutic efficacy and reduce the side effects.

• Study Type: Observational
• Enrollment (Actual): 1502

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Nanfang Hospital
  • Guangxi
    • Guilin, Guangxi, China, 541002
      • Guilin No.924 Hospital

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

The study population consists of the renal transplant recipients who received tacrolimus as immunosuppressant from Nanfang Hospital and Guilin No.924 Hospital. All the patients are Chinese.

Description

Inclusion Criteria:

Subject has been conducted kidney transplantation. Subject has used tacrolimus as immunosuppressant.

Exclusion Criteria:

Simultaneous liver-kidney transplantation. Patients with age less than 18 years old. Tacrolimus blood concentration monitoring less than 3 times. Failed to extract DNA.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Cohort 1; The retrospective cohort consists of about 839 kidney transplant recipients from Nanfang Hospital. These patients used tacrolimus as immunosuppressive drug for preventing the rejection.The side effects (acute rejection, nephrotoxicity and neurotoxicity) will be recorded.
Cohort 2; The retrospective cohort consists of about 663 kidney transplant recipients from Guilin No. 924 Hospital. These patients used tacrolimus as immunosuppressive drug for preventing the rejection.The side effects (acute rejection, nephrotoxicity and neurotoxicity) will be recorded.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Acute Rejection	We will measure the number of participants with acute rejection during the day 1 to day 61 after transplantation. Kaplan-Meier analyses were performed for acute rejection in participants with different genotypes.	Day 1 to Day 61
Number of Participants With Tacrolimus-related Nephrotoxicities	We will measure the number of participants with tacrolimus-related nephrotoxicities during the day 1 to day 61 after transplantation. Kaplan-Meier analyses were performed for tacrolimus-related nephrotoxicities in participants with different genotypes.	Day1 to Day 61
Number of Participants With Tacrolimus-related Neurotoxicities	We will measure the number of participants with tacrolimus-related neurotoxicities during the day 1 to day 61 after transplantation. Kaplan-Meier analyses were performed for tacrolimus-related neurotoxicities in participants with different genotypes.	Day1 to Day 61

Collaborators and Investigators

• Sponsor: Southern Medical University, China
• Collaborators: Third Affiliated Hospital, Sun Yat-Sen University; 181 Central Hospital of the Chinese PLA

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 1998
• Primary Completion (Actual): July 30, 2019
• Study Completion (Actual): August 1, 2019

Study Registration Dates

• First Submitted: March 8, 2017
• First Submitted That Met QC Criteria: March 13, 2017
• First Posted (Actual): March 20, 2017

Study Record Updates

• Last Update Posted (Actual): November 20, 2019
• Last Update Submitted That Met QC Criteria: October 31, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: tacrolimus; side effects; genetic variants
• Other Study ID Numbers: NFEC-2016-176

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No