Early CYP3A5 Genotype-Based Adjustment of Tacrolimus Dosage Reduces Risk of De Novo Donor-Specific HLA Antibodies and Rejection among CYP3A5-Expressing Renal Transplant Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. HLA Typing of Recipients and Donors
2.3. HLA Antibody Detection and Specification
2.4. CYP3A5 Genotyping
2.5. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Genotype-Based Adjustment of Calcineurin Inhibitor Dosage Led to Comparable Tacrolimus Trough Levels among CYP3A5 Expressers and Nonexpressers, Whereas the Tacrolimus Dosage Requirement of the Expressers Was Twice as High as That for the Nonexpressers over the 2-Year Follow-Up Period
3.3. Comparable Renal Allograft Outcomes, in Particular Development of Rejection and De Novo DSAs, for CYP3A5 Expressers and Nonexpressers after an Early Genotype-Based Adjustment of Calcineurin Inhibitor Dosage
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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All Patients (n = 160) | CYP3A5 Expressers (n = 33) | Nonexpressers (n = 127) | RR (95%CI) | p Value | |
---|---|---|---|---|---|
Recipient | |||||
Age, median (range) | 52 (19–76) | 49 (23–76) | 52 (19–77) | 0.79 | |
Sex, women, n (%) | 56 (35) | 9 (27) | 47 (37) | 0.74 (0.4–1.3) | 0.3 |
Sex, men, n (%) | 104 (65) | 24 (73) | 80 (63) | 1.16 (0.9–1.4) | 0.3 |
Previous transplants, n (%) | 26 (16) | 8 (24) | 18 (14) | 1.71 (0.8–3.4) | 0.16 |
PRA, n (%) | 8 (5) | 1 (3) | 7 (6) | 0.55 (0.1–3.2) | 0.56 |
Preformed anti-HLA antibodies, n (%) | 67 (42) | 12 (36) | 55 (43) | 0.84 (0.5–1.3) | 0.47 |
Class I, n (%) | 45 (28) | 9 (27) | 36 (28) | 0.96 (0.5–1.7) | 0.9 |
Class II, n (%) | 43 (27) | 6 (18) | 37 (29) | 0.62 (0.3–1.3) | 0.21 |
Class I and II, n (%) | 21 (13) | 3 (9) | 18 (14) | 0.64 (0.2–1.8) | 0.44 |
Cold ischemia time in min, median (range) | 593 (85–10,404) | 566 (103–1094) | 598 (85–1404) | 0.74 | |
Warm ischemia time in min, median (range) | 25 (11–48) | 26 (11–46) | 25 (11–48) | 0.81 | |
Donor | |||||
Deceased donors, n (%) | 128 (80) | 26 (79) | 102 (80) | 0.98 (0.8–1.2) | 0.85 |
Age, median (range) | 56 (16–82) | 58 (30–72) | 55 (16–82) | 0.29 | |
Sex, women, n (%) | 71 (44) | 18 (55) | 53 (42) | 1.31 (0.9–1.8) | 0.19 |
Sex, men, n (%) | 89 (56) | 15 (45) | 74 (58) | 0.78 (0.5–1.1) | 0.19 |
ABO-incompatible transplant, n (%) | 19 (12) | 4 (12) | 15 (12) | 1. 03 (0.4–2.7) | 0.96 |
Immunosuppression at transplant | |||||
Interleukin-2 receptor antagonist, n (%) | 144 (90) | 29 (88) | 115 (91) | 0.97 (0.8–1.1) | 0.65 |
ATG, n (%) | 16 (10) | 3 (9) | 13 (10) | 0.89 (0.3–2.6) | 0.85 |
Tacrolimus extended-release formulation, n (%) | 1 (1) | 0 (0) | 1 (1) | 0 (0–11.4) | 0.61 |
MMF/MPA, n (%) | 160 (100) | 33 (100) | 127 (100) | ||
Steroids, n (%) | 160 (100) | 33 (100) | 127 (100) | ||
HLA mismatches | |||||
MM A/B, n (%) | 133 (83) | 31 (94) | 102 (80) | 1.17 (1.0–1.3) | 0.06 |
HLA class I MM A/B: 1–2, n (%) | 82 (51) | 22 (67) | 60 (47) | 1.41 (1.0–1.9) | 0.05 |
HLA class I MM A/B: 3–4, n (%) | 52 (33) | 10 (30) | 42 (33) | 0.92 (0.5–1.6) | 0.76 |
MM DR, n (%) | 108 (68) | 26 (79) | 82 (65) | 1.22 (0.9–1.5) | 0.12 |
HLA class II MM DR: 1, n (%) | 71 (44) | 16 (48) | 55 (43) | 1.12 (0.7–1.6) | 0.59 |
HLA class II MM DR: 2, n (%) | 37 (23) | 10 (30) | 27 (21) | 1.43 (0.8–2.5) | 0.27 |
Causes of renal failure | |||||
1. Diabetic glomerulosclerosis, n (%) | 16 (10) | 5 (15) | 11 (9) | 1.75 (0.7–4.4) | 0.27 |
2. Chronic glomerulonephritis, n (%) | 8 (5) | 2 (6) | 6 (5) | 1.28 (0.3–5.2) | 0.75 |
3. Nephrosclerosis, n (%) | 26 (16) | 5 (15) | 21 (17) | 0.92 (0.4–2.1) | 0.85 |
4. Polycystic kidney disease, n (%) | 28 (18) | 4 (12) | 24 (19) | 0.64 (0.2–1.6) | 0.36 |
5. Tubulointerstitial nephritis, n (%) | 32 (20) | 7 (21) | 25 (20) | 1.08 (0.5–2.2) | 0.85 |
6. Congenital anomalies, n (%) | 16 (10) | 3 (9) | 13 (10) | 0.89 (0.3–2.6) | 0.85 |
7. Autoimmune diseases, n (%) | 10 (6) | 2 (6) | 8 (6) | 0.96 (0.2–3.7) | 0.96 |
8. Reflux nephropathy/recurrent pyelonephritis, n (%) | 8 (5) | 0 (0) | 8 (6) | 0 (0–1.7) | 0.14 |
9. TMA, n (%) | 3 (2) | 1 (3) | 2 (2) | 1.92 (0.3.11.1) | 0.58 |
10. Other, n (%) | 15 (9) | 4 (12) | 11 (9) | 1.4 (0.5–3.8) | 0.54 |
All Patients (n = 160) | CYP3A5 Expressers (n = 33) | Nonexpressers (n = 127) | RR (95%CI) | p Value | |
---|---|---|---|---|---|
Delayed graft function, n (%) | 33 (21) | 6 (18) | 27 (21) | 0.86 (0.4–1.8) | 0.7 |
Biopsy, n (%) | 73 (46) | 19 (58) | 54 (43) | 1.35 (0.9–1.9) | 0.12 |
>1 biopsy, n (%) | 33 (21) | 9 (27) | 24 (19) | 1.44 (0.7–2.7) | 0.29 |
Rejection, Banff categories 2, 3, and 4, n (%) | 46 (29) | 10 (30) | 36 (28) | 1.07 (0.6–1.8) | 0.82 |
Rejection Banff categories 2 and 4, n (%) | 29 (18) | 8 (24) | 21 (17)) | 1.47 (0.7–2.9) | 0.31 |
ABMR Banff category 2, n (%) | 3 (2) | 2 (6) | 1 (1) | 7.7 (1.0–57.4) | 0.05 |
TCMR Banff categories 3 and 4, n (%) | 44 (28) | 9 (27) | 35 (28) | 0.99 (0.5–1.8) | 0.97 |
TCMR Banff category 4, n (%) | 21 (13) | 4 (12) | 17 (13) | 0.91 (0.3–2.3) | 0.85 |
Transplant failure, n (%) | 5 (3) | 3 (9) | 2 (2) | 5.77 (1.2–27.8) | 0.03 |
eGFR CKD-EPI mL/min/1.73 m2 at 2 years after Tx, median (range) | 54 (12–119) | 58 (12–99) | 54 (112–119) | 0.36 | |
eGFR < 30 mL/min/1.73 m2 at 2 years after Tx, median (range) | 21 (13) | 4 (12) | 17 (13) | 0.91 (0.3–2.3) | 0.85 |
Death, n (%) | 1 (1) | 0 (0) | 1 (1) | 0 (0.14.4) | 0.61 |
De novo anti-HLA antibodies, n (%) | 17 (11) | 4 (12) | 13 (10) | 1.18 (0.4–3.1) | 0.75 |
Class I, n (%) | 8 (5) | 2 (6) | 6 (5) | 1.28 (0.3–5.2) | 0.75 |
Class II, n (%) | 11 (7) | 3 (9) | 8 (6) | 1.44 (0.4–4.6) | 0.57 |
De novo anti-HLA DSAs, n (%) | 7 (4) | 2 (6) | 5 (4) | 1.54 (0.4–6.5) | 0.6 |
Class I, n (%) | 3 (2) | 1 (3) | 2 (2) | 1.92 (0.3–14.1) | 0.58 |
Class II, n (%) | 6 (4) | 2 (6) | 4 (3) | 1.92 (0.4–8.5) | 0.43 |
CNI nephrotoxicity, n (%) | 19 (12) | 5 (15) | 14 (11) | 1.37 (0.5–3.3) | 0.51 |
Follow-up time in years, median (range) | 2 (0.3–2) | 2 (0.3–2) | 2 (0.5–2) | 0.22 |
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Schönfelder, K.; Möhlendick, B.; Eisenberger, U.; Kribben, A.; Siffert, W.; Heinemann, F.M.; Gäckler, A.; Wilde, B.; Friebus-Kardash, J. Early CYP3A5 Genotype-Based Adjustment of Tacrolimus Dosage Reduces Risk of De Novo Donor-Specific HLA Antibodies and Rejection among CYP3A5-Expressing Renal Transplant Patients. Diagnostics 2024, 14, 2202. https://doi.org/10.3390/diagnostics14192202
Schönfelder K, Möhlendick B, Eisenberger U, Kribben A, Siffert W, Heinemann FM, Gäckler A, Wilde B, Friebus-Kardash J. Early CYP3A5 Genotype-Based Adjustment of Tacrolimus Dosage Reduces Risk of De Novo Donor-Specific HLA Antibodies and Rejection among CYP3A5-Expressing Renal Transplant Patients. Diagnostics. 2024; 14(19):2202. https://doi.org/10.3390/diagnostics14192202
Chicago/Turabian StyleSchönfelder, Kristina, Birte Möhlendick, Ute Eisenberger, Andreas Kribben, Winfried Siffert, Falko M. Heinemann, Anja Gäckler, Benjamin Wilde, and Justa Friebus-Kardash. 2024. "Early CYP3A5 Genotype-Based Adjustment of Tacrolimus Dosage Reduces Risk of De Novo Donor-Specific HLA Antibodies and Rejection among CYP3A5-Expressing Renal Transplant Patients" Diagnostics 14, no. 19: 2202. https://doi.org/10.3390/diagnostics14192202