{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:25:34Z","timestamp":1786944334350,"version":"build-2736575974"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007560","name":"Chiesi Farmaceutici","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007560","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontierspartnerships.org"],"crossmark-restriction":true},"short-container-title":["Transpl. Int."],"abstract":"<jats:p>Low tacrolimus (Tac) trough concentration-to-dose ratio (C0\/D ratio) identifies kidney transplant patients with high level of Tac metabolization and is associated with poorer outcomes. We hypothesized that fast metabolization is associated with higher maximal Tac blood concentration (Cmax) and that Tac Cmax has a detrimental effect by itself. We retrospectively selected consecutive kidney transplant patients who (i) were treated by Tac, (ii) had systematic pharmacokinetic evaluation at 3- and 12-month posttransplant, and (iii) with a minimal follow-up of 5 years. Association between Tac Cmax\/C0 with traditional transplant outcomes was analysed. 519 patients with a median follow-up of 8 years were included. Fast metabolizers displayed significantly higher median Cmax (20 vs. 17\u00a0ng\/mL p &amp;lt; 0.001). Death-censored graft survival (DCGS) was significantly lower for patients with the highest Cmax\/C0 values (Log rank, p = 0.05). In multivariate cox analysis, higher Cmax\/C0 was independently associated with DCGS (HR = 1.37 [1.01; 1.87], p = 0.043). Our data support the hypothesis that exposure to high Cmax is detrimental and that fast metabolizers exhibit higher Tac Cmax even in situations where Tac C0 is not elevated. Tac formulations prone to mitigate pharmacokinetic peak could thus be particularly beneficial to fast metabolizers and should be evaluated in this indication.<\/jats:p>","DOI":"10.3389\/ti.2026.16212","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:10:14Z","timestamp":1786943414000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of tacrolimus peak concentration on kidney graft outcomes"],"prefix":"10.3389","volume":"39","author":[{"given":"Quentin","family":"Monchal","sequence":"first","affiliation":[{"name":"Centre Hospitalier Universitaire (CHU) de Saint-\u00c9tienne","place":["Saint-Etienne, France"]},{"name":"Universite Jean Monnet Saint-Etienne","place":["Saint-\u00c9tienne, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Claisse","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire (CHU) de Saint-\u00c9tienne","place":["Saint-Etienne, France"]},{"name":"Universite Jean Monnet Saint-Etienne","place":["Saint-\u00c9tienne, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Maillard","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire (CHU) de Saint-\u00c9tienne","place":["Saint-Etienne, France"]},{"name":"Universite Jean Monnet Saint-Etienne","place":["Saint-\u00c9tienne, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Mariat","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire (CHU) de Saint-\u00c9tienne","place":["Saint-Etienne, France"]},{"name":"Universite Jean Monnet Saint-Etienne","place":["Saint-\u00c9tienne, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2562","DOI":"10.1056\/NEJMoa067411","article-title":"Reduced exposure to calcineurin inhibitors in renal transplantation","volume":"357","author":"Ekberg","year":"2007","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"S21-120","DOI":"10.1016\/j.ajt.2023.02.004","article-title":"OPTN\/SRTR 2021 annual data report: Kidney","volume":"23","author":"Lentine","year":"2023","journal-title":"Am J Transpl"},{"key":"B3","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1111\/tri.12155","article-title":"Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF genomics","volume":"26","author":"Israni","year":"2013","journal-title":"Transpl Int"},{"key":"B4","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1399-0012.1997.tb00812.x","article-title":"Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients","volume":"11","author":"Katari","year":"1997","journal-title":"Clin Transpl Juin"},{"key":"B5","doi-asserted-by":"publisher","first-page":"100610","DOI":"10.1016\/j.trre.2021.100610","article-title":"Identifying the association between tacrolimus exposure and toxicity in heart and lung transplant recipients: a systematic review","volume":"35","author":"Braithwaite","year":"2021","journal-title":"Transpl Rev Orlando Fla"},{"key":"B6","doi-asserted-by":"publisher","first-page":"481","DOI":"10.2215\/CJN.04800908","article-title":"Calcineurin inhibitor nephrotoxicity","volume":"4","author":"Naesens","year":"2009","journal-title":"Clin J Am Soc Nephrol CJASN"},{"key":"B7","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3109\/03602532.2016.1151037","article-title":"Clinical determinants of calcineurin inhibitor disposition: a mechanistic review","volume":"48","author":"Vanhove","year":"2016","journal-title":"Drug Metab Rev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1111\/ajt.13935","article-title":"A steady-state head-to-head pharmacokinetic comparison of all FK-506 (Tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two-arm, three-period crossover study","volume":"17","author":"Tremblay","year":"2017","journal-title":"Am J Transplant"},{"key":"B9","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1097\/FTD.0000000000000640","article-title":"Therapeutic drug monitoring of tacrolimus-personalized therapy: second consensus report","volume":"41","author":"Brunet","year":"2019","journal-title":"Ther Drug Monit"},{"key":"B10","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1097\/FTD.0000000000000503","article-title":"Pharmacokinetic therapeutic drug monitoring of advagraf in more than 500 adult renal transplant patients, using an expert system online","volume":"40","author":"Marquet","year":"2018","journal-title":"Ther Drug Monit"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e111128","DOI":"10.1371\/journal.pone.0111128","article-title":"The tacrolimus metabolism rate influences renal function after kidney transplantation","volume":"9","author":"Th\u00f6lking","year":"2014","journal-title":"PLoS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1097\/TP.0000000000002920","article-title":"The TOMATO study (Tacrolimus metabolization in kidney transplantation): impact of the concentration-dose ratio on death-censored graft survival","volume":"104","author":"Jouve","year":"2020","journal-title":"Transplantation"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-021-95201-5","article-title":"Increased renal function decline in fast metabolizers using extended-release tacrolimus after kidney transplantation","volume":"11","author":"Th\u00f6lking","year":"2021","journal-title":"Sci Rep"},{"key":"B14","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3390\/jcm8050587","article-title":"Fast tac metabolizers at risk\u2014it is time for a C\/D ratio calculation","volume":"8","author":"Sch\u00fctte-N\u00fctgen","year":"2019","journal-title":"J Clin Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"32273","DOI":"10.1038\/srep32273","article-title":"Influence of tacrolimus metabolism rate on BKV infection after kidney transplantation","volume":"6","author":"Th\u00f6lking","year":"2016","journal-title":"Sci Rep 30 Ao\u00fbt"},{"key":"B16","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1111\/tri.13356","article-title":"High tacrolimus clearance - a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study","volume":"32","author":"Egeland","year":"2019","journal-title":"Transpl Int"},{"key":"B17","doi-asserted-by":"publisher","first-page":"7","DOI":"10.2217\/pgs-2019-0120","article-title":"CYP3A5*3 and CYP2C8*3 variants influence exposure and clinical outcomes of tacrolimus-based therapy","volume":"21","author":"Genvigir","year":"2020","journal-title":"Pharmacogenomics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1053\/j.ajkd.2017.07.018","article-title":"Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African American kidney transplant recipients","volume":"71","author":"Trofe-Clark","year":"2018","journal-title":"Am J Kidney Dis"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.3390\/jcm8101586","article-title":"A low tacrolimus concentration\/dose ratio increases the risk for the development of acute calcineurin inhibitor-induced nephrotoxicity","volume":"8","author":"Th\u00f6lking","year":"2019","journal-title":"J Clin Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1007\/s12325-018-0855-1","article-title":"Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in de novo Kidney Transplant Recipients: a Randomized, Parallel-Group, Open-Label, Multicenter Study","volume":"36","author":"Kamar","year":"2019","journal-title":"Adv Ther"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.3390\/jcm11051290","article-title":"Improved kidney allograft function after early conversion of fast IR-Tac metabolizers to LCP-tac","volume":"11","author":"Th\u00f6lking","year":"2022","journal-title":"J Clin Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1426","DOI":"10.1093\/CLINCHEM\/42.9.1426","article-title":"Tacrolimus (FK506) metabolite patterns in blood from liver and kidney transplant patients","volume":"42","author":"Gonschior","year":"1996","journal-title":"Clin Chem"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1016\/j.transproceed.2015.12.133","article-title":"Tacrolimus metabolite M-III may have nephrotoxic and myelotoxic effects and increase the incidence of infections in kidney transplant recipients","volume":"48","author":"Zegarska","year":"2016","journal-title":"Transpl Proc."},{"key":"B24","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1016\/s0272-6386(00)70013-8","article-title":"Abbreviated tacrolimus area-under-the-curve monitoring for renal transplant recipients","volume":"35","author":"Wong","year":"2000","journal-title":"Am J Kidney Dis"}],"container-title":["Transplant International"],"original-title":[],"link":[{"URL":"https:\/\/www.frontierspartnerships.org\/articles\/10.3389\/ti.2026.16212\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:10:15Z","timestamp":1786943415000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontierspartnerships.org\/articles\/10.3389\/ti.2026.16212\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":24,"alternative-id":["10.3389\/ti.2026.16212"],"URL":"https:\/\/doi.org\/10.3389\/ti.2026.16212","relation":{},"ISSN":["1432-2277"],"issn-type":[{"value":"1432-2277","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]},"article-number":"16212"}}