Infections after kidney transplantation: A comparison of mTOR-Is and CNIs as basic immunosuppressants. A systematic review and meta-analysis.
calcineurin inhibitor
infection
mTOR inhibitor
renal transplantation
Journal
Transplant infectious disease : an official journal of the Transplantation Society
ISSN: 1399-3062
Titre abrégé: Transpl Infect Dis
Pays: Denmark
ID NLM: 100883688
Informations de publication
Date de publication:
Jun 2020
Jun 2020
Historique:
received:
30
09
2019
revised:
24
01
2020
accepted:
16
02
2020
pubmed:
20
2
2020
medline:
4
2
2021
entrez:
20
2
2020
Statut:
ppublish
Résumé
Side effects of the immunosuppressive therapy after solid organ transplantation are well known. Recently, significant benefits were shown for mTOR-Is with respect to certain viral infections in comparison with CNIs. However, reported total incidences of infections under mTOR-Is vs CNIs are usually not different. This raises the question to additional differences between these immunosuppressants regarding development and incidence of infections. The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 954 trials screened of which 19 could be included (9861 pts.). The 1-year incidence of infections, patient and graft survival were assessed in meta-analyses. Meta-analysis on 1-year incidence of infections showed a significant benefit of an mTOR-I based therapy when combined with a CNI vs CNI-based therapy alone (OR 0.76). There was no difference between mTOR-I w/o CNI and CNI therapy (OR 0.97). For pneumonia, a significant disadvantage was seen only for mTOR-I monotherapy compared to CNI's (OR 2.09). The incidence of CMV infections was significantly reduced under mTOR-I therapy (combination with CNI: OR 0.30; mTOR w/o CNI: OR: 0.46). There was no significant difference between mTOR-I and CNI therapy with respect to patient survival (mTOR-I w/o CNI vs CNI: OR 1.22; mTOR-I with CNI vs CNI: OR 0.86). Graft survival was negatively affected by mTOR-I monotherapy (OR 1.52) but not when combined with a CNI (OR 0.97). Following renal transplantation the incidence of infections is lower when mTOR-Is are combined with a CNI compared to a standard CNI therapy. Pneumonia occurs more often under mTOR-I w/o CNI.
Sections du résumé
BACKGROUND
BACKGROUND
Side effects of the immunosuppressive therapy after solid organ transplantation are well known. Recently, significant benefits were shown for mTOR-Is with respect to certain viral infections in comparison with CNIs. However, reported total incidences of infections under mTOR-Is vs CNIs are usually not different. This raises the question to additional differences between these immunosuppressants regarding development and incidence of infections.
METHODS
METHODS
The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 954 trials screened of which 19 could be included (9861 pts.). The 1-year incidence of infections, patient and graft survival were assessed in meta-analyses.
RESULTS
RESULTS
Meta-analysis on 1-year incidence of infections showed a significant benefit of an mTOR-I based therapy when combined with a CNI vs CNI-based therapy alone (OR 0.76). There was no difference between mTOR-I w/o CNI and CNI therapy (OR 0.97). For pneumonia, a significant disadvantage was seen only for mTOR-I monotherapy compared to CNI's (OR 2.09). The incidence of CMV infections was significantly reduced under mTOR-I therapy (combination with CNI: OR 0.30; mTOR w/o CNI: OR: 0.46). There was no significant difference between mTOR-I and CNI therapy with respect to patient survival (mTOR-I w/o CNI vs CNI: OR 1.22; mTOR-I with CNI vs CNI: OR 0.86). Graft survival was negatively affected by mTOR-I monotherapy (OR 1.52) but not when combined with a CNI (OR 0.97).
CONCLUSION
CONCLUSIONS
Following renal transplantation the incidence of infections is lower when mTOR-Is are combined with a CNI compared to a standard CNI therapy. Pneumonia occurs more often under mTOR-I w/o CNI.
Substances chimiques
Calcineurin Inhibitors
0
Immunosuppressive Agents
0
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Comparative Study
Journal Article
Meta-Analysis
Systematic Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13267Subventions
Organisme : Pfizer GmbH
Informations de copyright
© 2020 The Authors. Transplant Infectious Disease published by Wiley Periodicals, Inc.
Références
Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357:2601-2614.
Fishman JA. Practice ASTIDCo: introduction: infection in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S3-S6.
Fishman JA, Issa NC. Infection in organ transplantation: risk factors and evolving patterns of infection. Infect Dis Clin North Am. 2010;24:273-283.
Weikert BC, Blumberg EA. Viral infection after renal transplantation: surveillance and management. Clin J Am Soc Nephrol. 2008;3(Suppl 2):S76-S86.
Andrassy J, Hoffmann VS, Rentsch M, et al. Is cytomegalovirus prophylaxis dispensable in patients receiving an mTOR inhibitor-based immunosuppression? A systematic review and meta-analysis. Transplantation. 2012;94:1208-1217.
Jouve T, Rostaing L, Malvezzi P. Place of mTOR inhibitors in management of BKV infection after kidney transplantation. J Nephropathol. 2016;5:1-7.
Suwelack B, Malyar V, Koch M, Sester M, Sommerer C. The influence of immunosuppressive agents on BK virus risk following kidney transplantation, and implications for choice of regimen. Transplant Rev (Orlando). 2012;26:201-211.
Siddiqui AS, Zimmerman JL. Everolimus associated interstitial pneumonitis in a liver transplant patient. Respir Med Case Rep. 2016;19:15-17.
Badve SV, Pascoe EM, Burke M, et al. Mammalian target of rapamycin inhibitors and clinical outcomes in adult kidney transplant recipients. Clin J Am Soc Nephrol. 2016;11:1845-1855.
Cravedi P, Ruggenenti P, Remuzzi G. Sirolimus for calcineurin inhibitors in organ transplantation: contra. Kidney Int. 2010;78:1068-1074.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-634.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539-1558.
Viechtbauer W. Bias and efficiency of meta-analytic variance estimators in the random-effects model. J Educ Behav Stat. 2005;30:261-293.
Doug Altman DA, Bender R, Bunce C, et al.Chapter 16: Special topics in statistics. Cochrane Handbook for Systematic Reviews of Interventions Version 510 (updated March 2011). The Cochrane Collaboration. Edited by Julian PT Higgins JJDaDGAobotCSMG. 2011.
Pengel LH, Barcena L, Morris PJ. The quality of reporting of randomized controlled trials in solid organ transplantation. Transplant Int. 2009;22:377-384.
Martin-Gandul C, Mueller NJ, Pascual M, Manuel O. The impact of infection on chronic allograft dysfunction and allograft survival after solid organ transplantation. Am J Transplant. 2015;15:3024-3040.
Chelala L, Kovacs CS, Taege AJ, Hanouneh IA. Common infectious complications of liver transplant. Cleve Clin J Med. 2015;82:773-784.
Kuppahally S, Al-Khaldi A, Weisshaar D, et al. Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients. Am J Transplant. 2006;6:986-992.
Dean PG, Lund WJ, Larson TS, et al. Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus. Transplantation. 2004;77:1555-1561.
Zuckermann A, Barten MJ. Surgical wound complications after heart transplantation. Transplant Int. 2011;24:627-636.
Frascaroli G, Varani S, Blankenhorn N, et al. Human cytomegalovirus paralyzes macrophage motility through down-regulation of chemokine receptors, reorganization of the cytoskeleton, and release of macrophage migration inhibitory factor. J Immunol. 2009;182:477-488.
Moorman NJ, Shenk T. Rapamycin-resistant mTORC1 kinase activity is required for herpesvirus replication. J Virol. 2010;84:5260-5269.
Araki K, Turner AP, Shaffer VO, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460:108-112.
Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation. 2009;87:1019-1026.
Wali RK, Drachenberg C, Hirsch HH, et al. BK virus-associated nephropathy in renal allograft recipients: rescue therapy by sirolimus-based immunosuppression. Transplantation. 2004;78:1069-1073.
Mallat SG, Tanios BY, Itani HS, et al. CMV and BKPyV infections in renal transplant recipients receiving an mTOR inhibitor-based regimen versus a CNI-based regimen: a systematic review and meta-analysis of randomized, controlled trials. Clin J Am Soc Nephrol. 2017;12:1321-1336.
Nashan B. Maximizing the clinical outcome with mTOR inhibitors in the renal transplant recipient: defining the role of calcineurin inhibitors. Transplant Int. 2004;17:279-285.
de Jonge H, Naesens M, Kuypers DR. New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation. Ther Drug Monit. 2009;31:416-435.
Saemann MD, Haidinger M, Hecking M, Horl WH, Weichhart T. The multifunctional role of mTOR in innate immunity: implications for transplant immunity. Am J Transplant. 2009;9:2655-2661.
Weichhart T, Haidinger M, Katholnig K, et al. Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells. Blood. 2011;117(16):4273-4283.
Dizdar OS, Ersoy A, Akalin H. Pneumonia after kidney transplant: incidence, risk factors, and mortality. Exp Clin Transplant. 2014;12:205-211.
Duran I, Goebell PJ, Papazisis K, et al. Drug-induced pneumonitis in cancer patients treated with mTOR inhibitors: management and insights into possible mechanisms. Expert Opin Drug Saf. 2014;13:361-372.
Baas MC, Struijk GH, Moes DJ, et al. Interstitial pneumonitis caused by everolimus: a case-cohort study in renal transplant recipients. Transplant Int. 2014;27:428-436.
Haynes R, Baigent C, Harden P, et al. Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol. Transplant Res. 2013;2:7.
Sousa SR, Galante NZ, Barbosa DA, Pestana JO. Incidence of infectious complications and their risk factors in the first year after renal transplantation. J Bras Nefrol. 2010;32:75-82.
Xie X, Jiang Y, Lai X, Xiang S, Shou Z, Chen J. mTOR inhibitor versus mycophenolic acid as the primary immunosuppression regime combined with calcineurin inhibitor for kidney transplant recipients: a meta-analysis. BMC Nephrol. 2015;16:91.
Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D, Thymoglobulin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355:1967-1977.
Hellemans R, Hazzan M, Durand D, et al. Daclizumab versus rabbit antithymocyte globulin in high-risk renal transplants: five-year follow-up of a randomized study. Am J Transplant. 2015;15:1923-1932.
Pilch NA, Taber DJ, Moussa O, et al. Prospective randomized controlled trial of rabbit antithymocyte globulin compared with IL-2 receptor antagonist induction therapy in kidney transplantation. Ann Surg. 2014;259:888-893.
Buchler M, Caillard S, Barbier S, et al. Sirolimus versus cyclosporine in kidney recipients receiving thymoglobulin, mycophenolate mofetil and a 6-month course of steroids. Am J Transplant. 2007;7:2522-2531.
Ekberg H, Tedesco-Silva H, Demirbas A, et al. Study EL-S: reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357:2562-2575.
Flechner SM, Glyda M, Cockfield S, et al. The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant. 2011;11:1633-1644.
Silva HT Jr, Felipe CR, Garcia VD, et al. Planned randomized conversion from tacrolimus to sirolimus-based immunosuppressive regimen in de novo kidney transplant recipients. Am J Transplant. 2013;13:3155-3163.
Wolf S, Hoffmann VS, Habicht A, et al. Effects of mTOR-Is on malignancy and survival following renal transplantation: a systematic review and meta-analysis of randomized trials with a minimum follow-up of 24 months. PLoS ONE. 2018;13:e0194975.
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;377:837-847.
Lehner F, Budde K, Zeier M, et al. Efficacy and safety of conversion from cyclosporine to everolimus in living-donor kidney transplant recipients: an analysis from the ZEUS study. Transplant Int. 2014;27:1192-1204.
Pascual J, Berger SP, Witzke O, et al. Everolimus with reduced calcineurin inhibitor exposure in renal transplantation. J Am Soc Nephrol. 2018;29:1979-1991.
Santos AH Jr, Casey MJ, Xuerong W, Womer KL. Association of baseline viral serology and sirolimus regimens with kidney transplant outcomes: a 14-year registry-based cohort study in the United States. Transplantation. 2017;101:377-386.
Knoll GA, Kokolo MB, Mallick R, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ. 2014;349:g6679.