Background
Patients and methods
Base line, clinical and transplantation related data
Single nucleotide polymorphism (SNP) genotyping
Statistical analysis
Results
Age at transplantation (years) | Mean ± SD | 9.3 ± 2.9 | |
---|---|---|---|
Post-transplant follow-up duration (months) | median (IQR) | 60 (36–93) | |
Original kidney disease | CAKUT | N (%) | 42 (50.6%) |
NONE CAKUT | N (%) | 41 (49.4%) | |
Family history of any kidney disease | N (%) | 6 (7.2%) | |
Patients required hemodialysis before transplantation | N (%) | 79 (95.2%) | |
Pre-epmptive kidney transplantation | N (%) | 4 (4.8%) | |
Hemodialysis duration (months) | median (IQR) | 12 (1–60) | |
Native nephrectomy | No | N (%) | 43 (51.8%) |
Unilateral | N (%) | 12 (14.5%) | |
Bilateral | N (%) | 28 (33.7%) | |
Cause of nephrectomy | Heavy proteinuria | N (%) | 17 (42.5%) |
Large polycystic kidney | N (%) | 2 (5%) | |
Pyelonephritic kidney | N (%) | 6 (15%) | |
Marked hydronephrosis | N (%) | 15 (37.5%) | |
Anthropometric measures at enrollment in the study | Weight (Kg) | Mean ± SD | 37 ± 11.9 |
Height (m) | Mean ± SD | 1.36 ± 0.17 | |
BMI (kg/m2) | Mean ± SD | 19.4 ± 4.5 | |
*CMV risk stratification | Low risk | N (%) | 8 (9.6%) |
Intermediate | N (%) | 70 (84.3%) | |
High risk | N (%) | 5 (6%) | |
Donor/recipient HLA mismatch | 4/6 | N (%) | 3 (3.6%) |
3/6 | N (%) | 50 (60.2%) | |
2/6 | N (%) | 25 (30.1%) | |
1/6 | N (%) | 3 (3.6%) | |
0/6 | N (%) | 2 (2.4%) | |
Antibody induction therapy | Basiliximab | N (%) | 43 (51.8%) |
ATG | N (%) | 40 (48.2%) | |
Preemptive PEX | N (%) | 15 (18.1%) | |
Maintenance IS other than TAC | MMF | N (%) | 82 (98.8%) |
Azathioprine | N (%) | 1 (1.2%) |
All KTRs (n = 83) | AR group (n = 36) | None AR group (n = 47) | Controls (n = 80) | AR vs. None AR | AR vs. Controls | None AR vs. Controls | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
N (%) | N (%) | N (%) | N (%) | OR (95% CI) | P value | OR (95% CI) | P value | OR (95% CI) | P value | |||
C3435T
|
Genotype
|
TT
| 22 (26.5) | 3 (8.3) | 19 (40.4) | 24 (30) |
Reference
| - |
Reference
| - |
Reference
| - |
CT
| 35 (42.2) | 20 (55.6) | 15 (31.9) | 40 (50) | 3.58 (1.64–7.80) |
0.001
| 2.20 (1.08–4.46) |
0.028
| 0.63 (0.37–1.06) | 0.082 | ||
CC
| 26 (31.3) | 13 (36.1) | 13 (27.7) | 16 (20) | 2.99 (1.32–6.75) |
0.008
| 2.98 (91.37–6.46) |
0.006
| 1.02 (0.56–1.83) | 0.957 | ||
Allele
|
T
| 79 (47.6) | 26 (36.1) | 53 (56.4) | 88 (55) |
Reference
|
-
|
Reference
|
-
|
Reference
| - | |
C
| 87 (52.4) | 46 (63.9) | 41 (43.6) | 72(45) | 1.67 (1.13–2.46) |
0.010
| 1.59 (1.13–2.24) |
0.008
| 0.97 (0.70–1.32) | 0.83 | ||
G2677T
|
Genotype
|
GG
| 23 (27.7 | 5 (13.9) | 18 (38.3) | 39 (48.8) |
Reference
| - |
Reference
| - |
Reference
| - |
GT
| 37 (44.6 | 19 (52.8) | 18 (38.3) | 28 (35) | 2.259 (1.12–4.555) |
0.023
| 2.625 (1.43–4.817) |
0.002
| 1.226 (0.743–2.021) | 0.425 | ||
TT
| 23 (27.7) | 12 (33.3) | 11 (23.4) | 13 (16.3) | 2.306 (1.069–4.975) |
0.033
| 3.181 (1.592–6.356) |
0.001
| 1.455 (0.793–2.668) | 0.226 | ||
Allele
|
G
| 83 (50) | 29 (40.3) | 54 (57.4) | 106 (66.3) |
Reference
| - |
Reference
| - |
Reference
| - | |
T
| 83 (50) | 43 (59.7) | 40 (42.6) | 54 (33.8) | 1.541 (1.047–2.268) |
0.028
| 1.91 (1.353–2.697) |
< 0.001
| 1.261 (0.911–1.744) | 0.162 |
Variable | AR (n = 36) | None AR (n = 47) | OR (95% CI) | P value |
---|---|---|---|---|
N (%) | N (%) | |||
TT
3435
GG
2677
| 3 (8.3%) | 10 (21.3%) |
Reference
| |
CC
3435
GT
2677
| 8 (22.2%) | 6 (12.8%) | 2.500 (0.918–6.806) | 0.073 |
CC
3435
TT
2677
| 5 (13.9%) | 6 (12.8%) | 1.863 (0.647–5.363) | 0.249 |
CT
3435
GG
2677
| 2 (5.6%) | 7 (14.9%) | 0.972 (0.298–3.172) | 0.962 |
CT
3435
GT
2677
| 11 (30.6%) | 6 (12.8%) | 3.046 (1.155–8.033) |
0.024
|
CT
3435
TT
2677
| 7 (19.4%) | 2 (4.3%) | 4.486 (1.375–14.639) |
0.013
|
CC
3435
GG
2677
| 0 (0%) | 1 (2.1%) | - | 1 |
TT
3435
GT
2677
| 0 (0%) | 6 (12.8%) | - | 1 |
TT
3435
TT
2677
| 0 (0%) | 3 (6.4%) | - | 1 |
C3435T genotypes | G2677T genotypes | |||||||
---|---|---|---|---|---|---|---|---|
Variables | CC (n = 26) | CT (n = 35) | TT (n = 22) | P value | GG (n = 23) | GT (n = 37) | TT (n = 23) | P value |
Median (IQR) | Median (IQR) | |||||||
Trough level (ng/ml)
| ||||||||
1st month
| 7.9 (5.8-9) | 7.3 (6-9.5) | 7.8 (7-9.3) | 0.9 | 7.6 (4.3–9.9) | 7.9 (2.5-8) | 7.6 (2.5–8.3) | 0.896 |
2nd month
| 8 (6.3–9.4) | 9.8 (7.2–10) | 9.8 (7–11) | 0.7 | 9.9 (5.2–10.3) | 9.5 (5.2–10.3) | 9.7 (6–10) | 0.530 |
3rd month
| 8 (6.7–9.6) | 8.5 (6.7–10.2) | 9.2 (8.5–10.5) | 0.083 | 9.2 (4.5–9.5) | 9 (4.5–10) | 7.5 (4.5-9) |
0.012
|
4th month
| 7.2 (6-9.7) | 9.3 (7.2–10.3) | 9 (8–10) | 0.2 | 9.3 (4.4–10) | 8.3 (4.2–9.6) | 7.7 (5.1–8.7) | 0.081 |
5th month
| 7.4 (5–10) | 8.4 (5-10.2) | 8.2 (5-9.8) | 0.2 | 8.4 (5-9.5) | 8.3 (5-9.7) | 7 (5-8.4) | 0.135 |
6th month
| 6.6 (6-8.5) | 7.4 (4.7–9.6) | 7 (4.7–9.1) | 0.1 | 7.4 (4.4-9) | 7.2 (2.5-8) | 6 (4.5–7.9) | 0.850 |
Mean trough level of 1st 6 months (ng/ml)
| 8 (5.9–9.3) | 8.5 (6.1–9.9) | 8.65 (6.7–9.95) | 0.154 | 9.18 (4.6–9.9) | 8.51 (6.43–9.5) | 7.98 (6.21–8.5) |
0.043
|
TAC dose (mg/kg/day)
| ||||||||
1st month
| 0.3 (0.2–0.3) | 0.18 (0.15–0.2) | 0.16 (0.14–0.18) |
< 0.001
| 0.17 (0.08–0.23) | 0.18 (0.1–0.26) | 0.27 (0.14–0.3) |
< 0.001
|
2nd month
| 0.27 (0.2–0.3) | 0.18 (0.15–0.19) | 0.18 (0.15–0.19) |
< 0.001
| 0.17 (0.04–0.25) | 0.18 (0.13–0.26) | 0.26 (0.13–0.29) |
< 0.001
|
3rd month
| 0.28 (0.2–0.31) | 0.18 (0.15–0.2) | 0.15 (0.13–0.19) |
< 0.001
| 0.15 (0.04–0.23) | 0.18 (0.11–0.25) | 0.28 (0.13–0.3) |
< 0.001
|
4th month
| 0.29 (0.18–0.3) | 0.16 (0.13–0.24) | 0.12 (0.08–0.16) |
< 0.001
| 0.13 (0.04–0.21) | 0.16 (0.07–0.2) | 0.29 (0.12–0.3) |
< 0.001
|
5th month
| 0.24 (0.17–0.3) | 0.17 (0.13–0.19) | 0.1 (0.06–0.17) |
< 0.001
| 0.14 (0.05–0.22) | 0.17 (0.06–0.21) | 0.23 (0.1–0.26) |
< 0.001
|
6th month
| 0.23 (0.18–0.3) | 0.17 (0.13–0.23) | 0.13 (0.08–0.15) |
0.001
| 0.13 (0.07–0.2) | 0.18 (0.04–0.22) | 0.23 (0.1–0.25) |
0.003
|
Mean TAC dose (mg/kg/day)
| 0.27 (0.2–0.32) | 0.17 (0.15–0.2) | 0.14 (0.12–0.19) |
< 0.001
| 0.15 (0.055–0.22) | 0.17 (0.115–0.23) | 0.27 (0.12–0.28) |
< 0.001
|
C/D ratio (ng/ml/mg/kg/day)
| ||||||||
1st month
| 25 (17.6–51.2) | 49.5 (31.1–64.6) | 54.3 (38.1–66.7) |
0.002
| 51.18 (23.33–100.5) | 40 (8.33–62.86) | 35 (8.33–62.5) |
0.024
|
2nd month
| 25.5 (23.8–50) | 55.6 (43.9–72) | 55 (35.6–71.4) |
< 0.001
| 64.71 (18.67-80) | 50 (20.83–77.22) | 25.53 (9.43–79.23) |
0.001
|
3rd month
| 26.9 (21.4–37.2) | 45 (32.5–90) | 65.4 (50.7-105.6) |
< 0.001
| 65.38 (29.63-90) | 40.63 (14.43–66.3) | 26.92 (14.43–57.4) |
< 0.001
|
4th month
| 27.1 (20.7–42.5) | 49 (38-66.3) | 72.7 (54.7–150) |
< 0.001
| 66.25 (20.38–70.5) | 42.86 (8.95–67.5) | 27.08 (8.95–47.67) |
< 0.001
|
5th month
| 30.4 (21.8–41) | 41.2 (33.3–78.8) | 69.2 (57.9-101.7) |
< 0.001
| 60 (28-96.67) | 41.18 (10.38–76.6) | 25.16 (10.38–65.4) |
< 0.001
|
6th month
| 30 (21.4–42.9) | 43 (30.7–58.8) | 58.8 (38.3–91) |
0.001
| 56.3 (28.7–86.9) | 42.9 (13.8–77.5) | 26.7 (13.1–60.6) |
0.002
|
Mean C/D ratio in 1st six months
| 30.2 (22.4–38.5) | 47.3 (38.5–74) | 68.1 (49.9-106.3) |
< 0.001
| 68.1 (26.6–90) | 47.3 (13–83) | 29.2 (13-75.2) |
< 0.001
|
Variables | N (%) | |||
---|---|---|---|---|
C3435T | CC (N = 26) | CT (N = 35) | TT (N = 22) | P value |
Nephrotoxicity
| 5 (19.2%) | 10 (28.6%) | 5 (22.7%) | 0.690 |
Neurotoxicity
| 1 (3.8%) | 1 (2.9%) | 5 (22.7%) | 0.670 |
NODAT
| 0 (0%) | 1 (2.9%) | 0 (0%) | 0.500 |
Dyslipidemia
| 1 (3.8%) | 2 (5.7%) | 1 (4.5%) | 0.943 |
hirsutism
| 0 (0%) | 1 (2.9%) | 0 (0%) | 0.500 |
G2677T
|
GG (N = 19)
|
GT (N = 44)
|
TT (N = 20)
|
P value
|
Nephrotoxicity
| 9 (39.1%) | 8 (21.6%) | 3 (13.0%) | 0.105 |
Neurotoxicity
| 0 (0%) | 1 (2.7%) | 1 (4.3%) | 0.622 |
NODAT
| 1 (4.3%) | 0 (0%) | 0 (0%) | 0.554 |
Dyslipidemia
| 1 (4.3%) | 2 (5.4%) | 1 (4.3%) | 0.975 |
hirsutism
| 1 (4.3%) | 0 (0%) | 0 (0%) | 0.554 |
Variables | AR group N = 36 | Non-AR N = 47 | OR (95% CI) |
P
Value
| ||
---|---|---|---|---|---|---|
Age at transplant
|
Mean ± SD
| 9.4 (3.2%) | 10 ± 2.8 | 0.953(0.819–1.109) | 0.535 | |
Sex
|
Male
|
N (%)
| 30 (83.3%) | 35 (74.5%) |
Reference
| - |
Female
|
N (%)
| 6 (16.7%) | 12 (25.5%) | 0.552(0.183–1.66) | 0.290 | |
Original kidney disease
|
NONE CAKUT
|
N (%)
| 17 (47.2%) | 24 (51.1%) |
Reference
| - |
CAKUT
|
N (%)
| 19 (52.8%) | 23 (48.9%) | 1.101 (0.640–1.893) | 0.744 | |
Dialysis before Tx
|
No
|
N (%)
| 2 (5.6%) | 2 (4.3%) |
Reference
| - |
Yes
|
N (%)
| 34 (94.4%) | 45 (95.7%) | 1.324(0.177–9.877) | 0.785 | |
Dialysis duration (months)
|
Median, IQR
| 12 (2–60) | 12 (1–60) | 0.979(0.936–1.025) | 0.366 | |
Donor/recipient HLA mismatch
|
4/6
|
N (%)
| 0 | 3 (6.4) |
Reference
| - |
3/6
|
N (%)
| 22 (61.1) | 28 (59.6) | - | 0.1 | |
2/6
|
N (%)
| 12 (33.3) | 13 (27.7) | - | 0.1 | |
1/6
|
N (%)
| 2 (5.6) | 1 (2.1) | - | 0.1 | |
0/6
|
N (%)
| 0 | 2 (4.3) | - | - | |
CMV risk stratification*
|
Low risk
|
N (%)
| 5 (13.9%) | 3 (6.4%) |
Reference
| - |
Intermediate
|
N (%)
| 30 (83.3%) | 40 (85.1%) | 0.607(0.239–1.543) | 0.295 | |
High risk
|
N (%)
| 1 (2.8%) | 4 (8.5%) | 0.313(0.068–1.452) | 0.138 | |
Antibody induction
|
Basiliximab
|
N (%)
| 15 (41.7%) | 28 (59.6%) |
Reference
| - |
ATG
|
N (%)
| 21 (58.3%) | 19 (40.4%) | 1.57(0.909–2.714) | 0.106 | |
Preemptive PEX
|
NO
|
N (%)
| 32 (88.9%) | 36 (76.6%) |
Reference
| - |
Yes
|
N (%)
| 4 (11.1%) | 11 (23.4%) | 0.577(0.275–1.215) | 0.148 | |
Maintenance IS other than TAC
|
MMF
|
N (%)
| 36 (100%) | 46 (97.9%) | - | 0.379 |
Azathioprine
|
N (%)
| 0 (0%) | 1 (2.1%) |
Discussion
MDR1 C3435T | |||||||||
---|---|---|---|---|---|---|---|---|---|
First author/ Reference | Country | Control number | CC | CT | TT | C | T | HW p | FST vs. current |
Korkor et al.; [current]
|
Egypt
| 80 | 16 | 40 | 24 | 0.450 | 0.550 | 0.928 | - |
[49]. |
Jordan
| 116 | 24 | 60 | 32 | 0.466 | 0.534 | 0.671 | < 0.001 |
[49]. |
Sudan
| 131 | 69 | 55 | 7 | 0.737 | 0.263 | 0.348 | 0.045 |
[50]. |
Morocco
| 100 | 39 | 51 | 10 | 0.645 | 0.355 | 0.256 | 0.038 |
[51]. |
Bahrain
| 184 | 64 | 84 | 36 | 0.576 | 0.424 | 0.376 | 0.016 |
[52]. |
Iran
| 200 | 40 | 105 | 55 | 0.463 | 0.538 | 0.429 | < 0.001 |
[53]. |
Turkey
| 150 | 30 | 80 | 40 | 0.467 | 0.533 | 0.382 | < 0.001 |
[54]. |
Egypt
| 200 | 68 | 103 | 29 | 0.598 | 0.403 | 0.317 | 0.022 |
[8]. |
France
| 81 | 29 | 34 | 18 | 0.568 | 0.432 | 0.193 | 0.014 |
[14]. |
Germany
| 188 | 53 | 90 | 45 | 0.521 | 0.479 | 0.576 | 0.005 |
MDR1 G2677T
| |||||||||
First author/ Reference
|
Country
|
Control number
|
GG
|
GT
|
TT
|
G
|
T
|
HW p
| FSTvs.
current
|
Korkor et al.; [current]
|
Egypt
| 80 | 39 | 28 | 13 | 0.663 | 0.338 | 0.052 | - |
[33]. |
Iran
| 120 | 78 | 25 | 0 | 0.879 | 0.121 | 0.161 | 0.066 |
[55]. |
China
| 200 | 35 | 75 | 42 | 0.477 | 0.523 | 0.892 | 0.035 |
[56]. |
Brazil
| 106 | 42 | 42 | 19 | 0.612 | 0.388 | 0.151 | 0.003 |
[57]. |
England
| 285 | 94 | 135 | 42 | 0.596 | 0.404 | 0.571 | 0.005 |
[58]. |
Korea
| 632 | 120 | 214 | 103 | 0.519 | 0.481 | 0.690 | 0.021 |
[59]. |
Scotland
| 370 | 102 | 174 | 94 | 0.511 | 0.489 | 0.256 | 0.024 |