Transplantation
Conditions
Keywords
tacrolimus, genetic variants, side effects
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.
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.
Interventions
None listed
Sponsors
Third Affiliated Hospital, Sun Yat-Sen University
181 Central Hospital of the Chinese PLA
Southern Medical University, China
Study design
Observational model
COHORT
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 839 |
| 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. | 663 |
| Total | 1,502 |
Baseline characteristics
| Characteristic | Cohort 1 | Total | Cohort 2 |
|---|---|---|---|
| Age, Continuous | 41.3 years STANDARD_DEVIATION 11.6 | 41.1 years STANDARD_DEVIATION 11.2 | 40.8 years STANDARD_DEVIATION 10.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 839 Participants | 1502 Participants | 663 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 839 participants | 1502 participants | 663 participants |
| Sex: Female, Male Female | 263 Participants | 452 Participants | 189 Participants |
| Sex: Female, Male Male | 576 Participants | 1050 Participants | 474 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 819 | 0 / 631 |
| other Total, other adverse events | 0 / 819 | 0 / 631 |
| serious Total, serious adverse events | 256 / 819 | 37 / 631 |
Outcome results
Primary
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.
Time frame: Day 1 to Day 61
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Acute Rejection | 256 participants |
| Cohort 2 | Number of Participants With Acute Rejection | 37 participants |
Primary
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.
Time frame: Day1 to Day 61
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Tacrolimus-related Nephrotoxicities | 26 participants |
| Cohort 2 | Number of Participants With Tacrolimus-related Nephrotoxicities | 2 participants |
Primary
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.
Time frame: Day1 to Day 61
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Tacrolimus-related Neurotoxicities | 10 participants |
| Cohort 2 | Number of Participants With Tacrolimus-related Neurotoxicities | 1 participants |