{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:23:19Z","timestamp":1787732599579,"version":"build-2784847793"},"reference-count":34,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K12456"],"award-info":[{"award-number":["24K12456"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chronic allograft dysfunction, driven by interstitial fibrosis and tubular atrophy, remains a major cause of long-term renal allograft loss. Everolimus (EVR), a mammalian target of rapamycin (mTOR) inhibitor, may reduce fibrosis through antifibrotic effects and calcineurin inhibitor minimization. This study aimed to evaluate the impact of EVR-involving immunosuppression on renal allograft fibrosis and to identify predictors of fibrotic progression. A total of 104 living-donor kidney transplant recipients transplanted between 2011 and 2017 were retrospectively analyzed (EVR, n = 61; non-EVR, n = 43). Interstitial fibrosis was quantified in protocol biopsies using digital image analysis. Phosphorylation of the mTOR-signaling proteins p70 ribosomal S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1 was assessed using a semiquantitative immunoreactive score. Multivariable regression analyses identified independent predictors of fibrotic progression. Cytomegalovirus infection was less frequent in the EVR group, whereas acute rejection, graft function, and graft survival were comparable between groups. At 1-year posttransplantation, interstitial fibrosis was significantly lower in the EVR group. EVR significantly suppressed p-4EBP1 phosphorylation and effectively modulated the mTOR-signaling pathway. Multivariable analysis identified the absence of EVR therapy as an independent predictor of accelerated fibrosis. EVR-involving immunosuppression attenuated renal interstitial fibrosis, likely through suppression of mTOR-signaling.<\/jats:p>","DOI":"10.3390\/ijms27177634","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:11:15Z","timestamp":1787731875000},"page":"7634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Everolimus-Involving Immunosuppression Attenuates Renal Interstitial Fibrosis Through Modulation of Mammalian Target of Rapamycin-Related Signal Transduction"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7322-4630","authenticated-orcid":false,"given":"Takuro","family":"Saito","sequence":"first","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuru","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"},{"name":"Division of Blood Purification, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan"},{"name":"Center for Kidney Disease and Transplantation, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryohei","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuichiro","family":"Sagehashi","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Aoyama","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuki","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chika","family":"Kajiwara","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Furihata","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Kagaya","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironobu","family":"Yagishita","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9411-2254","authenticated-orcid":false,"given":"Nobuhiro","family":"Fujiyama","sequence":"additional","affiliation":[{"name":"Center for Kidney Disease and Transplantation, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan"},{"name":"Clinical Research Promotion and Support Office, Future Cooperative Research Organization, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4536-3449","authenticated-orcid":false,"given":"Soki","family":"Kashima","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5899-1738","authenticated-orcid":false,"given":"Kazuyuki","family":"Numakura","sequence":"additional","affiliation":[{"name":"Department of Renal and Urologic Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa 078-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2988-1860","authenticated-orcid":false,"given":"Shintaro","family":"Narita","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2148-6129","authenticated-orcid":false,"given":"Masafumi","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7120-2425","authenticated-orcid":false,"given":"Masatomo","family":"Miura","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan"},{"name":"Department of Pharmacokinetics, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonori","family":"Habuchi","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita 010-8543, 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