Clinical significance of intra-patient tacrolimus variability and tacrolimus exposure in older kidney transplant recipients

Background: Low tacrolimus exposure and high intra-patient variability (IPV) are associated with increased risks of de novo donor-specific antibodies (DSA) and graft failure. However, the clinical significance of these factors in older kidney transplant recipients,who may exhibit reduced alloimmune responses, remains unclear.
Methods: This retrospective cohort study included adult kidney transplant recipients (≥18 years) from 2006 to June 2023, stratified into four groups based on 1-year tacrolimus trough levels and IPV: 1) low tacrolimus(<4ng/ml) /low IPV(<30%), 2) high tacrolimus (≥4ng/ml)/low IPV(<30%), 3) low tacrolimus(<4ng/ml) /high IPV(≥30%), and 4) high tacrolimus (≥4ng/ml)/ high IPV(≥30%). Primary outcomes included death-censored graft survival (DCGF) and secondary endpoints such as patient survival, biopsy-proven rejection, renal function, and de novo DSA development. Median follow-up was 92 months.
Results: Among 1,951 eligible recipients, the impact of tacrolimus exposure and IPV on graft survival differed by age group (P=0.007). In recipients under 60 years, the low IPV/high tacrolimus group showed the best graft survival, while the high IPV/high tacrolimus group had the worst outcomes. Conversely, in recipients over 60 years, the low tacrolimus/ low IPV group demonstrated the highest graft survival, whereas the low tacrolimus/ high IPV group exhibited the poorest outcomes. Cox regression confirmed high IPV as a significant risk factor for DCGF in older recipients, regardless of tacrolimus levels. Differences in patient survival among tacrolimus/IPV groups were not statistically significant (P=0.221).
Conclusion: This study highlights age-specific differences in the clinical significance of tacrolimus exposure and IPV. Reducing IPV and careful optimization of tacrolimus exposure for older kidney transplant recipients are critical to improving graft outcomes. These findings underscore the need for tailored immunosuppressive strategies in this population.