Frontiers in immunology · 2026
Timing matters: tacrolimus intra-patient variability within the initial seven months forecasts de novo DSA and subsequent rejection in a Chinese kidney transplant cohort.
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Wang Xuebin, You Jia, Sun Hong, Wu Dan, Liu Hongxia, Zhu Yan, Chen Lizhi, Fu Jiazhao, Zhao Wenyu, Sui Mingxing
Аннотация
BACKGROUND: High intra-patient variability (IPV) in tacrolimus exposure is a known risk factor for poor long-term kidney transplant outcomes. However, significant heterogeneity exists regarding the optimal post-transplant period for its assessment. This study aimed to identify the earliest predictive time window for tacrolimus IPV and to evaluate its association with de novo donor-specific antibody (dnDSA) development and rejection, while also examining the impact of CYP3A5*3 and CYP3A4*1G polymorphisms on IPV.
METHODS: In a single-center retrospective study (2016-2021) of Chinese kidney transplant recipients, tacrolimus IPV (coefficient of variation) was calculated across consecutive intervals from transplantation to month 24, using all available whole blood drug trough concentration measurements within each window. The primary analysis assessed the association between time-window-specific IPV and the cumulative 7-year incidence of dnDSA, antibody-mediated rejection (ABMR), and T-cell-mediated rejection (TCMR). The influence of dnDSA on rejection and of genetic polymorphisms on IPV was also analyzed.
RESULTS: A total of 446 kidney transplant recipients were included in the analysis. The cumulative incidences of dnDSA and overall rejection were 16.37% (73/446) and 17.04% (76/446), respectively, comprising ABMR (n=49, 64.47%), TCMR (n=21, 27.63%), and mixed ABMR + TCMR (n=6, 7.89%). Tacrolimus IPV calculated over the first 7 postoperative months emerged as the earliest significant predictor for dnDSA development (P = 0.0048). IPV from month 13 onward significantly correlated with overall rejection risk (P = 0.014). No association was found between CYP3A5*3 or CYP3A4*1G polymorphisms and IPV. Furthermore, dnDSA-positive patients had significantly higher risks of overall rejection (34.25% vs. 10.99%, P = 0.022) and ABMR (26.03% vs. 8.04%, P = 0.0049) compared to dnDSA-negative patients.
CONCLUSION: Tacrolimus IPV during the initial 7 post-transplant months serves as the earliest predictive window for dnDSA, a key risk factor for subsequent ABMR. These findings advocate for a dual strategy integrating early IPV-guided tacrolimus monitoring and systematic dnDSA surveillance to improve long-term graft outcomes.
METHODS: In a single-center retrospective study (2016-2021) of Chinese kidney transplant recipients, tacrolimus IPV (coefficient of variation) was calculated across consecutive intervals from transplantation to month 24, using all available whole blood drug trough concentration measurements within each window. The primary analysis assessed the association between time-window-specific IPV and the cumulative 7-year incidence of dnDSA, antibody-mediated rejection (ABMR), and T-cell-mediated rejection (TCMR). The influence of dnDSA on rejection and of genetic polymorphisms on IPV was also analyzed.
RESULTS: A total of 446 kidney transplant recipients were included in the analysis. The cumulative incidences of dnDSA and overall rejection were 16.37% (73/446) and 17.04% (76/446), respectively, comprising ABMR (n=49, 64.47%), TCMR (n=21, 27.63%), and mixed ABMR + TCMR (n=6, 7.89%). Tacrolimus IPV calculated over the first 7 postoperative months emerged as the earliest significant predictor for dnDSA development (P = 0.0048). IPV from month 13 onward significantly correlated with overall rejection risk (P = 0.014). No association was found between CYP3A5*3 or CYP3A4*1G polymorphisms and IPV. Furthermore, dnDSA-positive patients had significantly higher risks of overall rejection (34.25% vs. 10.99%, P = 0.022) and ABMR (26.03% vs. 8.04%, P = 0.0049) compared to dnDSA-negative patients.
CONCLUSION: Tacrolimus IPV during the initial 7 post-transplant months serves as the earliest predictive window for dnDSA, a key risk factor for subsequent ABMR. These findings advocate for a dual strategy integrating early IPV-guided tacrolimus monitoring and systematic dnDSA surveillance to improve long-term graft outcomes.