Preventive effect of early introduction of everolimus and reduced-exposure tacrolimus on renal interstitial fibrosis in de novo living-donor renal transplant recipients

  • Hiroaki Ishida
  • Go Ogura
  • Saeko Uehara
  • Shinya Takiguchi
  • Yousuke Nakagawa
  • Naoto Hamano
  • Masahiro Koizumi
  • Takehiko Wada
  • Masafumi Fukagawa
  • Michio NakamuraEmail author
Original article



To improve the long-term outcomes following renal transplantation, prevention of renal-allograft interstitial fibrosis (IF), mainly due to calcineurin inhibitors, is an important therapeutic target. Everolimus (EVR) was reported to have antifibrotic effects. We aimed to investigate the safety, efficacy, and IF of our modified immunosuppressive regimen, which includes early introduction of EVR and reduced-exposure tacrolimus (Tac) (EVR group), and compare it with the standard-exposure tacrolimus-based regimen (Tac group) in de novo living-donor renal recipients.


In this retrospective, single-center cohort study, we compared the 2-year clinical courses between the two groups according to intention to treat. Additionally, in patients in whom biopsies were obtained at 1 h, 3 months, and 12 months post-transplant, we compared IF between the groups using imaging analysis.


Overall, 47 patients were included (EVR group, n = 22; Tac group, n = 25). There were no significant differences in renal function and incidences of rejection and viral infections between the groups at the 2-year post-transplant follow-up. However, pathologic imaging analysis (n = 34) revealed chronological progression of IF in the Tac group during the first year post-transplant and no changes in the EVR group (fibrosis rate at 3 months: 20.8 vs. 13.6%, p < 0.001; at 12 months: 24.7 vs. 14.7%, p < 0.001, respectively).


Our modified immunosuppressive regimen may have an antifibrotic effect on transplanted kidneys without loss of safety and efficacy.


Everolimus Mammalian target of rapamycin inhibitor Tacrolimus Interstitial fibrosis Renal transplantation 



We are grateful to Chisa Okada at the Support Center for Medical Research and Education, Tokai University, for analyzing the images.

Author contributions

HI and MN designed the study. HI analyzed the data. HI, MN, SU, ST, MK, NH, YN, TW, MF, and GO performed the study. HI prepared the manuscript.



Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interest exists.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee at which the studies were conducted (IRB approval number 18R222) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Cosio F, Grande J, Wadei H, Larson T, Griffin M, Stegall M. Predicting subsequent decline in kidney allograft function from early surveillance biopsies. Am J Transplant. 2005;5:2464–72.CrossRefGoogle Scholar
  2. 2.
    Naesens M, Kuypers DR, De Vusser K, et al. Chronic histological damage in early indication biopsies is an independent risk factor for late renal allograft failure. Am J Transplant. 2013;13:86–99.CrossRefGoogle Scholar
  3. 3.
    Shihab FS, Andoh TF, Tanner AM, et al. Role of transforming growth factor-beta 1 in experimental chronic cyclosporine nephropathy. Kidney Int. 1996;49:1141–51.CrossRefGoogle Scholar
  4. 4.
    Alpay N, Ozkok A, Caliskan Y, et al. Influence of conversion from calcineurin inhibitors to everolimus on fibrosis, inflammation, tubular damage and vascular function in renal transplant patients. Clin Exp Nephrol. 2014;18:961–7.CrossRefGoogle Scholar
  5. 5.
    Wang S, Wilkes M, Leof E, Hirschberg R. Noncanonical TGF-beta pathways, mTORC1 and Abl, in renal interstitial fibrogenesis. Am J Physiology Ren Physiology. 2009;298:F142–F149149.CrossRefGoogle Scholar
  6. 6.
    Kurdián M, Herrero-Fresneda I, Lloberas N, et al. Delayed mTOR Inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model. PLoS ONE. 2012;7:e32516.CrossRefGoogle Scholar
  7. 7.
    Rivelli R, Gonçalves R, Leite M, et al. Early withdrawal of calcineurin inhibitor from a sirolimus-based immunosuppression stabilizes fibrosis and the transforming growth factor-β signaling pathway in kidney transplant. Nephrology (Carlton). 2015;20:168–76.CrossRefGoogle Scholar
  8. 8.
    Becker L, Weritz B, Yi X, et al. Evolution of allograft fibrosis and function in kidney transplant recipients: a retrospective analysis of stable patients under CNI and mTORi. Transpl Int. 2015;28:553–64.CrossRefGoogle Scholar
  9. 9.
    Stallone G, Infante B, Schena A, et al. Rapamycin for treatment of chronic allograft nephropathy in renal transplant patients. J Am Soc Nephrol. 2005;16:3755–62.CrossRefGoogle Scholar
  10. 10.
    Witzke O, Sommerer C, Arns W. Everolimus immunosuppression in kidney transplantation: What is the optimal strategy? Transplant Rev. (Orlando). 2016;30:3–12.CrossRefGoogle Scholar
  11. 11.
    Langer R, Hené R, Vitko S, et al. Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation. Transpl Int. 2012;25:592–602.CrossRefGoogle Scholar
  12. 12.
    Tedesco Silva H Jr, Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant. 2010;10:1401–13.CrossRefGoogle Scholar
  13. 13.
    Budde K, Becker T, Arns W, et al. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011;377:837–47.CrossRefGoogle Scholar
  14. 14.
    Holdaas H, Rostaing L, Serón D, et al. Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. Transplantation. 2011;92:410–8.CrossRefGoogle Scholar
  15. 15.
    Nara M, Komatsuda A, Numakura K, et al. Quantification of interstitial fibrosis in renal allografts and clinical correlates of long-term graft function. Am J Nephrol. 2017;46:187–94.CrossRefGoogle Scholar
  16. 16.
    Servais A, Meas-Yedid V, Noel LH, et al. Interstitial fibrosis evolution on early sequential screening renal allograft biopsies using quantitative image analysis. Am J Transplant. 2011;11:1456–63.CrossRefGoogle Scholar
  17. 17.
    Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.CrossRefGoogle Scholar
  18. 18.
    Kanda Y. Investigation of the freely-available easy-to-use software “EZR” (Easy R) for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefGoogle Scholar
  19. 19.
    Vanhove T, Goldschmeding R, Kuypers D. Kidney fibrosis: origins and interventions. Transplantation. 2017;101:713–26.CrossRefGoogle Scholar
  20. 20.
    Schmitt R, Melk A. New insights on molecular mechanisms of renal aging. Am J Transplant. 2012;12:2892–900.CrossRefGoogle Scholar
  21. 21.
    Conway B, Hughes J. Cellular orchestrators of renal fibrosis. QJM. 2012;105:611–5.CrossRefGoogle Scholar
  22. 22.
    Ogawa S, Ishimura T, Miyake H, Fujisawa M. Expression profile of mammalian target of rapamycin-related proteins in graft biopsy specimens: significance for predicting interstitial fibrosis after kidney transplantation. Int J Urol. 2017;24:223–9.CrossRefGoogle Scholar
  23. 23.
    Cosio FG, El Ters M, Cornell LD, Schinstock CA, Stegall MD. Changing kidney allograft histology early posttransplant: prognostic implications of 1-year protocol biopsies. Am J Transplant. 2016;16:194–203.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2019

Authors and Affiliations

  • Hiroaki Ishida
    • 1
  • Go Ogura
    • 3
  • Saeko Uehara
    • 1
  • Shinya Takiguchi
    • 1
  • Yousuke Nakagawa
    • 2
  • Naoto Hamano
    • 2
  • Masahiro Koizumi
    • 2
  • Takehiko Wada
    • 2
  • Masafumi Fukagawa
    • 2
  • Michio Nakamura
    • 1
    Email author
  1. 1.Department of Transplant SurgeryTokai University School of MedicineIseharaJapan
  2. 2.Division of Nephrology, Endocrinology and MetabolismTokai University School of MedicineIseharaJapan
  3. 3.Department of PathologyTokai University School of MedicineIseharaJapan

Personalised recommendations