{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:51:02Z","timestamp":1787028662896,"version":"build-2736575974"},"reference-count":24,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Asan Institute for Life Sciences","award":["2020IT0011"],"award-info":[{"award-number":["2020IT0011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Combining calcineurin inhibitors (CNIs) with mTOR inhibitors has been explored to reduce CNI exposure. However, the safety of this early conversion approach remains uncertain, and the optimal therapeutic targets for tacrolimus and sirolimus trough concentrations in patients have not been clearly established. Method: In this retrospective multicenter cohort, we analyzed 8027 kidney transplant recipients and compared a standard group (tacrolimus + MMF) with an early conversion group (MMF to sirolimus within 3 months post-transplant). To address group-size and baseline imbalances\u2014including differences in age, induction therapy, and diabetes\u2014we performed 4:1 propensity score matching, yielding a cohort of 1180 patients. The primary endpoint was biopsy-proven acute rejection between 3 and 12 months post-transplant. Results: The early conversion group had a higher acute rejection rate (7.6%) than the standard group (2.9%; p = 0.001). Stepwise threshold analysis suggested a combined tacrolimus\u2013sirolimus exposure (Tacro\u2013Siro Csum) of 11.6 ng\/mL as the level associated with the lowest rejection risk, whereas levels &lt; 8.5 ng\/mL were substantially higher risk. Patients with Tacro\u2013Siro Csum &lt; 8.5 ng\/mL showed a higher rejection rate even when CNI trough levels were adequate (p = 0.031). Tacro\u2013Siro Csum showed the strongest inverse correlation with rejection (r = \u22120.33), underscoring its utility as a composite indicator. Conclusions: In early sirolimus conversion, the combined trough level of tacrolimus and sirolimus is more important than either drug alone. To reduce the risk of acute rejection, it is crucial to maintain this combined concentration at a therapeutic level.<\/jats:p>","DOI":"10.3390\/jcm14217808","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T19:30:27Z","timestamp":1762198227000},"page":"7808","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tacrolimus\u2013Sirolimus Combined Exposure and Acute Rejection in Kidney Transplant Recipients Undergoing Early Conversion to Sirolimus: A Multicenter Retrospective Cohort Threshold Analysis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9245-5066","authenticated-orcid":false,"given":"Byunghyun","family":"Choi","sequence":"first","affiliation":[{"name":"Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Busan 43241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngmin","family":"Ko","sequence":"additional","affiliation":[{"name":"Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Myung","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Eun","family":"Kwon","sequence":"additional","affiliation":[{"name":"Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung","family":"Shin","sequence":"additional","affiliation":[{"name":"Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo Hee","family":"Jung","sequence":"additional","affiliation":[{"name":"Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5018-5304","authenticated-orcid":false,"given":"Hyunwook","family":"Kwon","sequence":"additional","affiliation":[{"name":"Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1097\/01.tp.0000188300.26762.74","article-title":"Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus\/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation: Results of the Atlas study","volume":"80","author":"Vitko","year":"2005","journal-title":"Transplantation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1053\/j.ackd.2019.08.006","article-title":"The Many Faces of Calcineurin Inhibitor Toxicity-What the FK?","volume":"27","author":"Farouk","year":"2020","journal-title":"Adv. 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