Optimal tacrolimus trough levels and allograft outcomes in kidney transplant recipients: insights from a multicenter real-world study in South Korea
Ahram Han1, Sangil Min2, Ae Jeong Jo3, Young Hoon Kim4, Kyu Ha Huh5, Jae Berm Park6, Sun Cheol Park7, Joongyub Lee8, Mohamed Soliman9
1Department of Kidney and Pancreas Transplantation, Seoul National University, Seoul, Korea
2Department of Kidney and Pancreas Transplantation, Seoul National University Hospital, Seoul, Korea
3Department of Information Statistics, Andong National University, Andong, Korea
4Department of Kidney and Pancreas Transplantation, Asan Medical Center, University of Ulsan, Seoul, Korea
5Division of Transplant Surgery, Department of Surgery, Severance Hospital, Yonsei University, Seoul, Korea
6Division of Transplant Surgery, Department of Surgery, Samsung Medical Center, Seoul, Korea
7Division of Transplant Surgery, Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
8Department of Preventive Medicine, Seoul National University, Seoul, Korea
9Department of Medical Affairs, Astellas Pharma Singapore Pte Ltd, Singapore
Correspondence to: Sangil Min
E-mail: surgeonmsi@gmail.com
Background: The optimal tacrolimus trough levels after kidney transplantation (KT) and its impact on allograft outcomes remains uncertain. Evidence regarding the association with long-term outcomes is limited. Our study aimed to evaluate the relationship between time-varying periodic mean tacrolimus trough levels and composite allograft outcomes in KT recipients across five transplant centers in South Korea.
Methods: Data from 10,329 patients who underwent KT during 2005–2020 was retrieved from the institutional clinical data warehouse. Two-month periodic mean was derived from outpatient tacrolimus trough levels for 2–12 months posttransplant and categorized into seven ranges. The inverse probability of treatment weighting method with stabilized weights was utilized to assess the relationship between time-varying tacrolimus levels and the 1-year composite outcome (biopsy-proven acute rejection, renal dysfunction, de novo donor-specific antibodies (dnDSA), and death-censored graft failure). We also analyzed the association between the 1-year periodic mean from 2–6 years posttransplant and the 6-year outcomes.
Results: The overall incidence of the composite allograft outcome at 2–12 months and 2–6 years posttransplant was 11.2% and 23.1%. With 8 ng/mL as reference, tacrolimus levels below 3 ng/mL and 3–3.9 ng/mL were associated with a higher likelihood of developing the 1-year composite allograft outcome, while 4–4.9 ng/mL showed higher hazards of dnDSA development and graft failure. Conversely, 5–5.9 ng/mL, 6–6.9 ng/mL, and 7–7.9 ng/mL groups had lower risks of developing the composite allograft outcome. For the 2–6 year outcome, trough levels 5–5.9 ng/mL and 6–6.9 ng/mL showed benefit over 8 ng/mL (adjusted hazard ratio [aHR] 0.68, 95% confidence interval [CI] 0.53–0.87, P=0.0024; and HR 0.65, 95% CI 0.50–0.85, P=0.0012)
Conclusions: This real-world multicenter study in South Korea provides important insights into the association between tacrolimus trough levels and allograft outcomes in KT recipients. The findings suggest that maintaining a target trough level of 5–7.9 ng/mL during 2–12 months posttransplant, and 5–6.9 ng/mL during 2–6 years posttransplant, is associated with better allograft outcomes.