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Efficacy of everolimus with reduced-exposure cyclosporine in de novo kidney transplant patients at increased risk for efficacy events: analysis of a randomized trial

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Abstract

The efficacy of de novo everolimus with reduced-exposure calcineurin inhibitor (CNI) was examined in kidney transplant subpopulations from the A2309 study that were identified to be at increased risk for efficacy events. A2309 was a 24-month, multicenter, open-label trial in which 833 de novo kidney transplant recipients were randomized to everolimus targeting 3–8 or 6–12 ng/ml with reduced-exposure cyclosporine (CsA), or mycophenolic acid (MPA) with standard-exposure CsA, all with basiliximab induction. The composite efficacy endpoint was treated biopsy-proven acute rejection (BPAR), graft loss, death, or loss to follow-up. Cox proportional hazard modeling showed male gender, younger recipient age, black race, delayed graft function, human leukocyte antigen (HLA) mismatch ≥3 and increasing donor age to be significantly predictive for the composite efficacy endpoint at months 12 or 24 post-transplant. CsA exposure was 53–75 % lower, and 46–75 % lower, in patients receiving everolimus 3–8 ng/ml or receiving everolimus 6–12 ng/ml, respectively, versus MPA-treated patients. The incidence of the composite endpoint was similar in all three treatment groups within each subpopulation analyzed. The incidence of treated BPAR was similar with everolimus 3–8 ng/ml or MPA in all subpopulations, but less frequent with everolimus 6–12 ng/ml versus MPA in patients with HLA mismatch ≥3 (p = 0.049). This post hoc analysis of a large, randomized trial suggests that a de novo regimen of everolimus with reduced-exposure CsA maintains immunosuppressive efficacy even in kidney transplant patients at increased risk for efficacy events despite substantial reductions in CsA exposure.

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References

  1. Flechner SM, Kobashigawa J, Klintmalm G (2008) Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin Transplant 22:1–15

    Article  PubMed  Google Scholar 

  2. Sharif A, Shabir S, Chand S, Cockwell P, Ball S, Borrows R (2011) Meta-analysis of calcineurin-inhibitor-sparing regimens in kidney transplantation. J Am Soc Nephrol 22:2107–2118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Ruiz R, Klintmalm GB (2012) Renal-sparing regimens employing new agents. Curr Opin Organ Transplant 17:619–625

    Article  CAS  PubMed  Google Scholar 

  4. Su L, Tam N, Deng R, Chen P, Li H, Wu L (2014) Everolimus-based calcineurin-inhibitor sparing regimens for kidney transplant recipients: a systematic review and meta-analysis. Int Urol Nephrol 46:2035–2044

    Article  CAS  PubMed  Google Scholar 

  5. Gurk-Turner C, Manitpisitkul W, Cooper M (2012) A comprehensive review of everolimus clinical reports: a new mammalian target of rapamycin inhibitor. Transplantation 94:659–668

    Article  CAS  PubMed  Google Scholar 

  6. Zaza G, Granata S, Tomei P, Masola V, Gambaro G, Lupo A (2014) mTOR inhibitors and renal allograft: Yin and Yang. J Nephrol 27:495–506

    Article  PubMed  Google Scholar 

  7. Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U, Kramer S, Fischer W, Gschaidmeier H, Pietruck F, ZEUS Study Investigators (2011) Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet 377:837–847

    Article  CAS  PubMed  Google Scholar 

  8. Mjörnstedt L, Sørensen SS, von Mühlen Zur B, Jespersen B, Hansen JM, Bistrup C, Andersson H, Gustafsson B, Undset LH, Fagertun H, Solbu D, Holdaas H (2012) Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. Am J Transplant 12:2744–2753

    Article  PubMed  Google Scholar 

  9. Budde K, Sommerer C, Rath T, Reinke P, Haller H, Witzke O, Suwelack B, Baeumer D, Sieder C, Porstner M, Arns W (2014) Renal function to 5 years after late conversion of kidney transplant patients to everolimus: a randomized trial. J Nephrol [Epub ahead of print]

  10. Tedesco Silva H Jr, Cibrik D, Johnston T, Lackova E, Mange K, Panis C, Walker R, Wang Z, Zibari G, Kim YS (2010) Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant 10:1401–1413

    Article  PubMed  Google Scholar 

  11. Vitko S, Tedesco H, Eris J, Pascual J, Whelchel J, Magee JC, Campbell S, Civati G, Bourbigot B, Alves Filho G, Leone J, Garcia VD, Rigotti P, Esmeraldo R, Cambi V, Haas T, Jappe A, Bernhardt P, Geissler J, Cretin N (2004) Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 4:626–635

    Article  CAS  PubMed  Google Scholar 

  12. Chan L, Greenstein S, Hardy MA, Hartmann E, Bunnapradist S, Cibrik D, Shaw LM, Munir L, Ulbricht B, Cooper M, CRADUS09 Study Group (2008) Multicenter, randomized study of the use of everolimus with tacrolimus after renal transplantation demonstrates its effectiveness. Transplantation 85:821–826

    Article  CAS  PubMed  Google Scholar 

  13. Albano L, Berthoux F, Moal MC, Rostaing L, Legendre C, Genin R, Toupance O, Moulin B, Merville P, Rerolle JP, Bayle F, Westeel PF, Glotz D, Kossari N, Lefrançois N, Charpentier B, Blanc AS, Di Giambattista F, Dantal J, RAD A2420 Study Group (2009) Incidence of delayed graft function and wound healing complications after deceased-donor kidney transplantation is not affected by de novo everolimus. Transplantation 88:69–76

    Article  CAS  PubMed  Google Scholar 

  14. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 130:461–470

    Article  CAS  PubMed  Google Scholar 

  15. Cibrik D, Silva HT Jr, Vathsala A, Lackova E, Cornu-Artis C, Walker RG, Wang Z, Zibari GB, Shihab F, Kim YS (2013) Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation. Transplantation 95:933–942

    Article  CAS  PubMed  Google Scholar 

  16. Melancon K, Mulgaonkar SP, Delcoro C, Wiland A, McCague K, Shihab FS (2013) Outcomes in ethnic minority renal transplant recipients receiving everolimus versus mycophenolate: comparative risk assessment results from a pooled analysis. Transplantation 96:1073–1081

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Boom H, Mallat MJ, de Fijter JW, Zwinderman AH, Paul LC (2000) Delayed graft function influences renal function, but not survival. Kidney Int 58:859–866

    Article  CAS  PubMed  Google Scholar 

  18. Quiroga I, McShane P, Koo DD, Gray D, Friend PJ, Fuggle S, Darby C (2006) Major effects of delayed graft function and cold ischaemia time on renal allograft survival. Nephrol Dial Transpl 21:1689–1696

    Article  Google Scholar 

  19. Jayaram D, Kommareddi M, Sung RS, Luan FL (2012) Delayed graft function requiring more than one-time dialysis treatment is associated with inferior clinical outcomes. Clin Transplant 26:E536–E543

    Article  PubMed  Google Scholar 

  20. Yarlagadda SG, Coca SG, Formica RN Jr, Poggio ED, Parikh CR (2009) Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant 24:1039–1047

    Article  PubMed  Google Scholar 

  21. Gore JL, Pham PT, Danovitch GM, Wilkinson AH, Rosenthal JT, Lipshutz GS, Singer JS (2006) Obesity and outcome following renal transplantation. Am J Transplant 6:357–363

    Article  CAS  PubMed  Google Scholar 

  22. Cole EH, Johnston O, Rose CL, Gill JS (2008) Impact of acute rejection and new-onset diabetes on long-term transplant graft and patient survival. Clin J Am Soc Nephrol 3:814–821

    Article  PubMed Central  PubMed  Google Scholar 

  23. Dunn TB, Noreen H, Gillingham K, Maurer D, Ozturk OG, Pruett TL, Bray RA, Gebel HM, Matas AJ (2011) Revisiting traditional risk factors for rejection and graft loss after kidney transplantation. Am J Transplant 11:2132–2143

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Fan PY, Ashby VB, Fuller DS, Boulware LE, Kao A, Norman SP, Randall HB, Young C, Kalbfleisch JD, Leichtman AB (2010) Access and outcomes among minority transplant patients, 1999–2008, with a focus on determinants of kidney graft survival. Am J Transplant 10:1090–1107

    Article  PubMed Central  PubMed  Google Scholar 

  25. Ng FL, Holt DW, Chang RWS, Macphee IA (2010) Black renal transplant recipients have poorer long-term graft survival than CYP3A5 expressers from other ethnic groups. Nephrol Dial Transplant 25:628–634

    Article  CAS  PubMed  Google Scholar 

  26. Tullius SG, Tran H, Guleria I, Malek SK, Tilney NL, Milford E (2010) The combination of donor and recipient age is critical in determining host immunoresponsiveness and renal transplant outcome. Ann Surg 252:662–674

    PubMed  Google Scholar 

  27. De Fijter J, Mallat MJ, Doxiadis II, Ringers J, Rosendaal FR, Claas FH, Paul LC (2001) Increased immunogenicity and cause of graft loss of old donor kidneys. J Am Soc Nephrol 12:1538–1546

    PubMed  Google Scholar 

  28. Süsal C, Döhler B, Sadeghi M, Ovens J, Opelz G (2009) HLA antibodies and the occurrence of early adverse events in the modern era of transplantation: a Collaborative Transplant Study report. Transplantation 87:1367–1371

    Article  PubMed  Google Scholar 

  29. Lim WH, Chadban SJ, Clayton P, Budgeon CA, Murray K, Campbell SB, Cohney S, Russ GR, McDonald SP (2012) Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients. Clin Transplant 26:E428–E437

    Article  PubMed  Google Scholar 

  30. Øien CM, Reisaeter AV, Leivestad T, Dekker FW, Line PD, Os I (2007) Living donor kidney transplantation: the effects of donor age and gender on short- and long-term outcomes. Transplantation 83:600–606

    Article  PubMed  Google Scholar 

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Acknowledgments

The study was funded by Novartis Pharma AG, Basel, Switzerland.

Conflicts of interest

Mario Carmellini has no conflicts of interest to declare. Valter Garcia has received travel honoraria and research grants from Novartis, Roche, Libbs and Pfizer, and research grants from Bristol Meyers Squibb and Astellas. Zailong Wang and Marcela Vergara are employees of Novartis Pharma AG. Graeme Russ has served on advisory boards for Novartis and speaker lists for Astellas and Novartis.

Research involving human participiants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee 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.

Author information

Authors and Affiliations

  1. Department of Surgery and Bioengineering, University of Siena, Siena, Italy

    Mario Carmellini

  2. Hospital Don Vicente Scherer, Santa Casa de Misericordia do Porto Alegre, Porto Alegre, Brazil

    Valter Garcia

  3. Novartis Pharma AG, Basel, Switzerland

    Zailong Wang

  4. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    Marcela Vergara

  5. Renal Unit, The Queen Elizabeth Hospital, Woodville, Australia

    Graeme Russ

  6. Centro Trapianti di Rene, Az. Osped Universitaria Senese Ospedale S Maria alle Scotte, U.O.C. Chirugira dei Trpianti-Dip. Chirugria Gen. e Spec, Viale Bracci 1, 53100, Siena, Italy

    Mario Carmellini

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  1. Mario Carmellini
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  2. Valter Garcia
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  3. Zailong Wang
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  4. Marcela Vergara
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Corresponding author

Correspondence to Mario Carmellini.

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Supplementary material 1 (DOC 79 kb)

Study investigators

Argentina: P Novoa, R Schiavelli, L Toselli; Australia: S Campbell, S Chadban, B Hutchinson, J Kanellis, P O’Connell, B Pussell, G Russ, R Walker; Brazil: D Carvalho, V Garcia, L Soares, H Tedesco Silva; Canada: M Walsh; Hong Kong: CS Li; Italy: A Albertazzi, M Carmellini, G Civati, G Colussi, F Schena; Korea: H Duck Jong, SJ Kim, YH Kim, YL Kim, YS Kim, IS Moon; New Zealand: H Pilmore; Slovakia: E Lackova, R Roland; Singapore: T Kee; South Africa: S Naicker; Sweden: G Tufveson; Taiwan: PH Lee; Turkey: E Akin, K Keven, A Uslu; United Kingdom: M Yacoob, H Riad, J Pattison; United States of America: S Abul-Ezz, E Alfrey, K Andreoni, M Aaronson, P Baliga, Y Becker, P Bolin, L Chan, DM Cibrik, M Cooper, A Cotterell, C Foster, C Franklin, S Jensik, TD Johnston, B Kahan, D Katz, D Kim, M Kumar, PC Kuo, J Leone, M Levy, B Marder, B Mistry, S Mulgaonkar, LL Mulloy, T O’Connor, PT Pham, K Rice, V Scantlebury, B Sankari, R Santella, H Shidban, F Shihab, D Slakey, RB Stevens, JR Thistlewaite, JD Welchel, CT Van Buren, N Youssef, C Zayas, G Zibari.

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Carmellini, M., Garcia, V., Wang, Z. et al. Efficacy of everolimus with reduced-exposure cyclosporine in de novo kidney transplant patients at increased risk for efficacy events: analysis of a randomized trial. J Nephrol 28, 633–639 (2015). https://doi.org/10.1007/s40620-015-0180-6

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  • DOI: https://doi.org/10.1007/s40620-015-0180-6

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