Functional Genetic Variants Affecting Tacrolimus Trough Levels and Side Effects in Chinese Renal Transplantation.
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
|
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 CYP3A53 (A6986G) resulting in a splicing defect and the absence of protein activity, was identified as a functional variant (Kuehl P.2001). The CYP3A41G 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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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. |
Outcome Measures
Primary Outcome Measures
- Number of Participants With Acute Rejection [Day 1 to Day 61]
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.
- Number of Participants With Tacrolimus-related Nephrotoxicities [Day1 to Day 61]
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.
- Number of Participants With Tacrolimus-related Neurotoxicities [Day1 to Day 61]
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.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Nanfang Hospital | Guangzhou | Guangdong | China | 510515 |
| 2 | Guilin No.924 Hospital | Guilin | Guangxi | China | 541002 |
Sponsors and Collaborators
- Southern Medical University, China
- Third Affiliated Hospital, Sun Yat-Sen University
- 181 Central Hospital of the Chinese PLA
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.- NFEC-2016-176
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Cohort 1 | Cohort 2 |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Period Title: Overall Study | ||
| STARTED | 839 | 663 |
| COMPLETED | 819 | 631 |
| NOT COMPLETED | 20 | 32 |
Baseline Characteristics
| Arm/Group Title | Cohort 1 | Cohort 2 | Total |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | Total of all reporting groups |
| Overall Participants | 839 | 663 | 1502 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
41.3
(11.6)
|
40.8
(10.6)
|
41.1
(11.2)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
263
31.3%
|
189
28.5%
|
452
30.1%
|
| Male |
576
68.7%
|
474
71.5%
|
1050
69.9%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
839
100%
|
663
100%
|
1502
100%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
| White |
0
0%
|
0
0%
|
0
0%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| China |
839
100%
|
663
100%
|
1502
100%
|
Outcome Measures
| Title | Number of Participants With Acute Rejection |
|---|---|
| Description | 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. |
| Time Frame | Day 1 to Day 61 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cohort 1 | Cohort 2 |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 819 | 631 |
| Number [participants] |
256
30.5%
|
37
5.6%
|
| Title | Number of Participants With Tacrolimus-related Nephrotoxicities |
|---|---|
| Description | 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. |
| Time Frame | Day1 to Day 61 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cohort 1 | Cohort 2 |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 819 | 631 |
| Number [participants] |
26
3.1%
|
2
0.3%
|
| Title | Number of Participants With Tacrolimus-related Neurotoxicities |
|---|---|
| Description | 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. |
| Time Frame | Day1 to Day 61 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cohort 1 | Cohort 2 |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 819 | 631 |
| Number [participants] |
10
1.2%
|
1
0.2%
|
Adverse Events
| Time Frame | Transplant recipients were followed for 61 days after transplantation to monitor side effects (acute rejection, nephrotoxicity and neurotoxicity). | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | All the participants are at risk for All-Cause Mortality. | |||
| Arm/Group Title | Cohort 1 | Cohort 2 | ||
| Arm/Group Description | 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. | 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. | ||
All Cause Mortality |
||||
| Cohort 1 | Cohort 2 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/819 (0%) | 0/631 (0%) | ||
Serious Adverse Events |
||||
| Cohort 1 | Cohort 2 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 256/819 (31.3%) | 37/631 (5.9%) | ||
| Renal and urinary disorders | ||||
| Acute rejection | 256/819 (31.3%) | 256 | 37/631 (5.9%) | 37 |
Other (Not Including Serious) Adverse Events |
||||
| Cohort 1 | Cohort 2 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/819 (0%) | 0/631 (0%) | ||
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Liang Li |
|---|---|
| Organization | Southern Medical University |
| Phone | 86 20 61648510 |
| liliang@smu.edu.cn |
- NFEC-2016-176