{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T03:47:40Z","timestamp":1794368860987,"version":"4.9.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec>\n            <jats:title>Background.<\/jats:title>\n            <jats:p>The single-nucleotide polymorphism <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> rs776746 is related to a reduction in the metabolizing activity of the <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> enzyme. People carrying at least one copy of the wild-type allele, defined as <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> expressers, exhibit higher clearance and lower trough concentrations of tacrolimus than homozygous nonexpressers, and this difference may affect alloimmunization and allograft function.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods.<\/jats:title>\n            <jats:p>We retrospectively studied 400 kidney transplant recipients treated with a tacrolimus-based immunosuppression regimen to detect <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> genotype, de novo formation of HLA antibodies and donor-specific antibodies (DSAs), and clinical outcome up to 5 y after transplant.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results.<\/jats:title>\n            <jats:p>We found that 69 (17%) of the 400 patients were <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> expressers. During the first 3 y after transplant, <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> expressers tended to have lower tacrolimus trough levels than nonexpressers, although their tacrolimus dosage was as much as 80% higher. De novo DSAs were found more frequently in <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> expressers than in nonexpressers (13\/69 [19%] versus 33\/331 [10%], <jats:italic toggle=\"yes\">P<\/jats:italic> = 0.02). De novo DSA-free survival rates (<jats:italic toggle=\"yes\">P<\/jats:italic> = 0.02) were significantly lower for expressers than for nonexpressers. <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> genotype had no effect on allograft failure, but <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> expressers exhibited a significantly higher frequency of antibody-mediated rejection. <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> expresser status was an independent risk factor for the development of de novo DSAs (relative risk, 2.34, <jats:italic toggle=\"yes\">P<\/jats:italic> = 0.01).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions.<\/jats:title>\n            <jats:p>Early detection of <jats:italic toggle=\"yes\">CYP3A5<\/jats:italic> expressers, enabling genotype-based dose adjustment of tacrolimus immediately after renal transplant, may be a useful strategy for reducing the risk of de novo DSA production and antibody-mediated rejection.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/tp.0000000000003871","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T18:30:58Z","timestamp":1625509858000},"page":"1031-1042","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":12,"title":["Development of De Novo Donor-specific HLA Antibodies and AMR in Renal Transplant Patients Depends on CYP3A5 Genotype"],"prefix":"10.1097","volume":"106","author":[{"given":"Justa","family":"Friebus-Kardash","sequence":"first","affiliation":[{"name":"Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ejona","family":"Nela","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birte","family":"M\u00f6hlendick","sequence":"additional","affiliation":[{"name":"Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kribben","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"Siffert","sequence":"additional","affiliation":[{"name":"Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Falko Markus","family":"Heinemann","sequence":"additional","affiliation":[{"name":"Institute for Transfusion Medicine, Transplantation Diagnostics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Eisenberger","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"R1-20250604","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1517\/14656566.9.4.635","article-title":"The role of tacrolimus in renal transplantation.","volume":"9","author":"Bowman","year":"2008","journal-title":"Expert Opin Pharmacother"},{"key":"R2-20250604","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.2165\/11593890-000000000-00000","article-title":"Once- versus twice-daily tacrolimus: are the formulations truly equivalent?","volume":"71","author":"Barraclough","year":"2011","journal-title":"Drugs"},{"key":"R3-20250604","doi-asserted-by":"crossref","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":"R4-20250604","doi-asserted-by":"crossref","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":"R5-20250604","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/phar.2300","article-title":"Tacrolimus concentration-to-dose ratios in kidney transplant recipients and relationship to clinical outcomes.","volume":"39","author":"Bartlett","year":"2019","journal-title":"Pharmacotherapy"},{"key":"R6-20250604","doi-asserted-by":"crossref","first-page":"e273","DOI":"10.1097\/TP.0000000000001796","article-title":"High tacrolimus clearance is a risk factor for acute rejection in the early phase after renal transplantation.","volume":"101","author":"Egeland","year":"2017","journal-title":"Transplantation"},{"key":"R7-20250604","doi-asserted-by":"crossref","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":"R8-20250604","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.trre.2015.01.002","article-title":"Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management.","volume":"29","author":"Shuker","year":"2015","journal-title":"Transplant Rev (Orlando)"},{"key":"R9-20250604","first-page":"23","article-title":"CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment.","volume":"11","author":"Chen","year":"2018","journal-title":"Pharmgenomics Pers Med"},{"key":"R10-20250604","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1097\/TP.0b013e318200e991","article-title":"Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium.","volume":"91","author":"Jacobson","year":"2011","journal-title":"Transplantation"},{"key":"R11-20250604","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1126\/science.286.5439.487","article-title":"Pharmacogenomics: translating functional genomics into rational therapeutics.","volume":"286","author":"Evans","year":"1999","journal-title":"Science"},{"key":"R12-20250604","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1124\/dmd.30.10.1108","article-title":"Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA.","volume":"30","author":"Koch","year":"2002","journal-title":"Drug Metab Dispos"},{"key":"R13-20250604","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1097\/00008571-200112000-00005","article-title":"The genetic determinants of the CYP3A5 polymorphism.","volume":"11","author":"Hustert","year":"2001","journal-title":"Pharmacogenetics"},{"key":"R14-20250604","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s40262-013-0120-3","article-title":"The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation.","volume":"53","author":"Hesselink","year":"2014","journal-title":"Clin Pharmacokinet"},{"key":"R15-20250604","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ijpharm.2013.05.033","article-title":"From gut to kidney: transporting and metabolizing calcineurin-inhibitors in solid organ transplantation.","volume":"452","author":"Knops","year":"2013","journal-title":"Int J Pharm"},{"key":"R16-20250604","doi-asserted-by":"crossref","first-page":"513","DOI":"10.2174\/1389200219666180129151948","article-title":"Pharmacokinetics, pharmacodynamics and pharmacogenetics of tacrolimus in kidney transplantation.","volume":"19","author":"Yu","year":"2018","journal-title":"Curr Drug Metab"},{"key":"R17-20250604","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1111\/bcp.12076","article-title":"A published pharmacogenetic algorithm was poorly predictive of tacrolimus clearance in an independent cohort of renal transplant recipients.","volume":"76","author":"Boughton","year":"2013","journal-title":"Br J Clin Pharmacol"},{"key":"R18-20250604","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1111\/j.1600-6143.2004.00435.x","article-title":"The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation.","volume":"4","author":"MacPhee","year":"2004","journal-title":"Am J Transplant"},{"key":"R19-20250604","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1097\/FPC.0b013e3283557c74","article-title":"The effect of CYP3A5 6986A>G and ABCB1 3435C>T on tacrolimus dose-adjusted trough levels and acute rejection rates in renal transplant patients: a systematic review and meta-analysis.","volume":"22","author":"Terrazzino","year":"2012","journal-title":"Pharmacogenet Genomics"},{"key":"R20-20250604","doi-asserted-by":"crossref","first-page":"3046","DOI":"10.1093\/ndt\/gfr253","article-title":"CYP3A5 and ABCB1 polymorphisms in donor and recipient: impact on Tacrolimus dose requirements and clinical outcome after renal transplantation.","volume":"26","author":"Glowacki","year":"2011","journal-title":"Nephrol Dial Transplant"},{"key":"R21-20250604","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/j.1432-2277.2012.01446.x","article-title":"Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation.","volume":"25","author":"Gervasini","year":"2012","journal-title":"Transpl Int"},{"key":"R22-20250604","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s00228-015-1990-0","article-title":"Impact of CYP3A5 polymorphism on trough concentrations and outcomes of tacrolimus minimization during the early period after kidney transplantation.","volume":"72","author":"Yaowakulpatana","year":"2016","journal-title":"Eur J Clin Pharmacol"},{"key":"R23-20250604","doi-asserted-by":"crossref","first-page":"165","DOI":"10.2217\/pgs-2016-0146","article-title":"Clinical impact of the CYP3A5 6986A>G allelic variant on kidney transplantation outcomes.","volume":"18","author":"Flahault","year":"2017","journal-title":"Pharmacogenomics"},{"key":"R24-20250604","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/tpj.2014.38","article-title":"Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies.","volume":"15","author":"Rojas","year":"2015","journal-title":"Pharmacogenomics J"},{"key":"R25-20250604","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1097\/TP.0000000000002366","article-title":"A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology.","volume":"102","author":"Roufosse","year":"2018","journal-title":"Transplantation"},{"key":"R26-20250604","doi-asserted-by":"crossref","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","article-title":"A new equation to estimate glomerular filtration rate.","volume":"150","author":"Levey","year":"2009","journal-title":"Ann Intern Med"},{"key":"R27-20250604","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1159\/000228834","article-title":"HLA genotyping and antibody characterization using the Luminex\u2122 multiplex technology.","volume":"36","author":"Heinemann","year":"2009","journal-title":"Transfus Med Hemother"},{"key":"R29-20250604","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1093\/ndt\/gfw462","article-title":"Unacceptable human leucocyte antigens for organ offers in the era of organ shortage: influence on waiting time before kidney transplantation.","volume":"32","author":"Ziemann","year":"2017","journal-title":"Nephrol Dial Transplant"},{"key":"R30-20250604","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/TP.0b013e31827a19cc","article-title":"Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation.","volume":"95","author":"Tait","year":"2013","journal-title":"Transplantation"},{"key":"R31-20250604","doi-asserted-by":"crossref","first-page":"105881","DOI":"10.1016\/j.intimp.2019.105881","article-title":"Association of immunosuppressive agents and cytomegalovirus infection with de novo donor-specific antibody development within 1 year after renal transplantation.","volume":"76","author":"Fujiyama","year":"2019","journal-title":"Int Immunopharmacol"},{"key":"R32-20250604","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1002\/cpt.1618","article-title":"Intrapatient variability of tacrolimus exposure in solid organ transplantation: a novel marker for clinical outcome.","volume":"107","author":"Kuypers","year":"2020","journal-title":"Clin Pharmacol Ther"},{"key":"R33-20250604","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/S1734-1140(10)70378-9","article-title":"Frequencies and roles of CYP3A5, CYP3A4 and ABCB1 single nucleotide polymorphisms in Italian teenagers after kidney transplantation.","volume":"62","author":"Turolo","year":"2010","journal-title":"Pharmacol Rep"},{"key":"R34-20250604","doi-asserted-by":"crossref","first-page":"179","DOI":"10.2217\/pgs.13.199","article-title":"CYP3A5 and CYP3A4, but not ABCB1 polymorphisms affect tacrolimus dose-adjusted trough concentrations in kidney transplant recipients.","volume":"15","author":"Kurzawski","year":"2014","journal-title":"Pharmacogenomics"},{"key":"R35-20250604","doi-asserted-by":"crossref","first-page":"e13424","DOI":"10.1111\/ctr.13424","article-title":"Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype: effects on acute rejection and graft failure in European American and African American kidney transplant recipients.","volume":"32","author":"Seibert","year":"2018","journal-title":"Clin Transplant"},{"issue":"suppl 2","key":"R36-20250604","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/tan.13665","article-title":"Relevance of donor-specific antibody monitoring after kidney transplantation: findings from the Collaborative Transplant Study and the Heidelberg Transplant Center.","volume":"94","author":"S\u00fcsal","year":"2019","journal-title":"HLA"},{"key":"R37-20250604","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1097\/TP.0000000000001040","article-title":"Within-Patient variability in tacrolimus blood levels predicts kidney graft loss and Donor-Specific antibody development.","volume":"100","author":"Rodrigo","year":"2016","journal-title":"Transplantation"},{"key":"R38-20250604","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.3748\/wjg.v24.i16.1795","article-title":"High tacrolimus intra-patient variability is associated with graft rejection, and de novo donor-specific antibodies occurrence after liver transplantation.","volume":"24","author":"Del Bello","year":"2018","journal-title":"World J Gastroenterol"},{"key":"R39-20250604","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s00467-019-04377-6","article-title":"Tacrolimus variability is associated with de novo donor-specific antibody development in pediatric renal transplant recipients.","volume":"35","author":"Solomon","year":"2020","journal-title":"Pediatr Nephrol"},{"key":"R40-20250604","doi-asserted-by":"crossref","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":"R41-20250604","first-page":"414","article-title":"Association between CYP3A5 genetic polymorphisms with tacrolimus dose requirement and allograft outcomes in Iranian kidney transplant recipients.","volume":"13","author":"Ghafari","year":"2019","journal-title":"Iran J Kidney Dis"},{"key":"R42-20250604","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/s41397-019-0144-7","article-title":"CYP3A5 gene polymorphisms and their impact on dosage and trough concentration of tacrolimus among kidney transplant patients: a systematic review and meta-analysis.","volume":"20","author":"Khan","year":"2020","journal-title":"Pharmacogenomics J"},{"key":"R43-20250604","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1111\/tri.13605","article-title":"Early postoperative calculation of the tacrolimus concentration-to-dose ratio does not predict outcomes after kidney transplantation.","volume":"33","author":"Bartmann","year":"2020","journal-title":"Transpl Int"},{"key":"R44-20250604","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1111\/j.1742-7843.2008.00327.x","article-title":"Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients.","volume":"103","author":"Quteineh","year":"2008","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"R45-20250604","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s00210-009-0415-y","article-title":"Impact of CYP3A5 and CYP3A4 gene polymorphisms on dose requirement of calcineurin inhibitors, cyclosporine and tacrolimus, in renal allograft recipients of North India.","volume":"380","author":"Singh","year":"2009","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"R46-20250604","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1097\/FTD.0b013e3181e06818","article-title":"Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients.","volume":"32","author":"Kuypers","year":"2010","journal-title":"Ther Drug Monit"},{"key":"R47-20250604","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/FPC.0000000000000296","article-title":"The combination of CYP3A4*22 and CYP3A5*3 single-nucleotide polymorphisms determines tacrolimus dose requirement after kidney transplantation.","volume":"27","author":"Lloberas","year":"2017","journal-title":"Pharmacogenet Genomics"},{"key":"R48-20250604","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.transproceed.2013.11.023","article-title":"Influence of cytochrome P450 3A5 polymorphisms on viral infection incidence in kidney transplant patients treated with tacrolimus.","volume":"46","author":"Hattori","year":"2014","journal-title":"Transplant Proc"},{"key":"R49-20250604","doi-asserted-by":"crossref","first-page":"349","DOI":"10.12659\/AOT.883974","article-title":"Combination assays for evaluation of immune function and CYP3A5 genotype to identify the risk of infectious complications and mortality in living donor liver transplant patients.","volume":"18","author":"Mizuno","year":"2013","journal-title":"Ann Transplant"}],"container-title":["Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/TP.0000000000003871","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T19:08:13Z","timestamp":1749064093000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/TP.0000000000003871"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,1]]},"references-count":48,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022]]}},"URL":"https:\/\/doi.org\/10.1097\/tp.0000000000003871","relation":{},"ISSN":["0041-1337"],"issn-type":[{"value":"0041-1337","type":"print"}],"subject":[],"published":{"date-parts":[[2021,7,1]]}}}