Immunosuppression in Transplantation: Balancing Efficacy and Long-Term Outcomes
DOI:
https://doi.org/10.63501/scennn60Keywords:
Immunosuppression, Transplantation, Calcineurin inhibitors, Biologics, Long- term outcomesAbstract
Background: Immunosuppressive therapy is critical for preventing graft rejection in transplant recipients, but long-term use is associated with significant complications, including infections and malignancies.
Objectives: This narrative review evaluates the evolution of immunosuppressive strategies in transplantation, focusing on achieving a balance between efficacy and long-term patient safety.
Methods: We reviewed clinical trials and observational studies from 2012 to 2024, focusing on calcineurin inhibitors, mTOR inhibitors, and novel biologics in renal and liver transplantation.
Results: Modern protocols combining tacrolimus with mycophenolate mofetil have reduced acute rejection rates to below 10%. However, long-term use increases the risk of nephrotoxicity and infections by 25%. Emerging biologics, such as belatacept, show promise in reducing these risks but are limited by high costs and variable efficacy in high-risk patients.
Conclusion: Tailored immunosuppression regimens that minimize toxicity while preventing rejection are essential for improving long-term outcomes. Future research should focus on personalized medicine approaches and the development of cost-effective biologics.
References
1. Halloran PF. Immunosuppressive Drugs for Kidney Transplantation. New England Journal of Medicine [Internet]. 2004 Dec 23 [cited 2025 May 4];351(26):2715–29. Available from: https://pubmed.ncbi.nlm.nih.gov/15616206/
2. Naesens M, Kuypers DRJ, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clinical Journal of the American Society of Nephrology [Internet]. 2009 Feb 1 [cited 2025 May 4];4(2):481–508. Available from: https://pubmed.ncbi.nlm.nih.gov/19218475/
3. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. Chronic Renal Failure after Transplantation of a Nonrenal Organ. New England Journal of Medicine [Internet]. 2003 Sep 4 [cited 2025 May 4];349(10):931–40. Available from: https://pubmed.ncbi.nlm.nih.gov/12954741/
4. Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. New England Journal of Medicine [Internet]. 2016 Jan 28 [cited 2025 May 4];374(4):333–43. Available from: https://pubmed.ncbi.nlm.nih.gov/26816011/
5. Ekberg H, Tedesco-Silva H, Demirbas A, Vítko Š, Nashan B, Gürkan A, et al. Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation. New England Journal of Medicine [Internet]. 2007 Dec 20 [cited 2025 May 4];357(25):2562–75. Available from: https://pubmed.ncbi.nlm.nih.gov/18094377/
6. Leichtman AB. Balancing Efficacy and Toxicity in Kidney-Transplant Immunosuppression. New England Journal of Medicine. 2007 Dec 20;357(25):2625–7.
7. Anglicheau D, Legendre C, Thervet E. Pharmacogenetics in solid organ transplantation: Present knowledge and future perspectives. Transplantation [Internet]. 2004 Aug 15 [cited 2025 May 4];78(3):311–5. Available from: https://pubmed.ncbi.nlm.nih.gov/15316356/
8. Fischer L, Saliba F, Kaiser GM, De Carlis L, Metselaar HJ, De Simone P, et al. Three-year Outcomes in de Novo Liver Transplant Patients Receiving Everolimus with Reduced Tacrolimus: Follow-Up Results from a Randomized, Multicenter Study. Transplantation [Internet]. 2015 Jul 2 [cited 2025 May 4];99(7):1455–62. Available from: https://pubmed.ncbi.nlm.nih.gov/26151607/
9. Ekberg H, Bernasconi C, Tedesco-Silva H, Vítko S, Hugo C, Demirbas A, et al. Calcineurin inhibitor minimization in the symphony study: Observational results 3 years after transplantation. American Journal of Transplantation [Internet]. 2009 Aug [cited 2025 May 4];9(8):1876–85. Available from: https://pubmed.ncbi.nlm.nih.gov/19563339/
10. Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. New England Journal of Medicine [Internet]. 2016 Jan 28 [cited 2025 May 4];374(4):333–43. Available from: https://pubmed.ncbi.nlm.nih.gov/26816011/
11. Rostaing L, Massari P, Garcia VD, Mancilla-Urrea E, Nainan G, Rial MDC, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: A randomized phase II study. Clinical Journal of the American Society of Nephrology [Internet]. 2011 Feb 1 [cited 2025 May 4];6(2):430–9. Available from: https://pubmed.ncbi.nlm.nih.gov/21051752/
12. Silva HT, Cibrik D, Johnston T, Lackova E, Mange K, Panis C, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. American Journal of Transplantation [Internet]. 2010 [cited 2025 May 4];10(6):1401–13. Available from: https://pubmed.ncbi.nlm.nih.gov/20455882/
13. Sharma A, Jain S, Gupta R, Guleria S, Agarwal S, Dinda A. Calcineurin inhibitor toxicity in renal allografts: Morphologic clues from protocol biopsies. Indian J Pathol Microbiol [Internet]. 2010 Oct [cited 2025 May 4];53(4):651–7. Available from: https://pubmed.ncbi.nlm.nih.gov/21045386/
14. de Fijter JW, Holdaas H, Øyen O, Sanders JS, Sundar S, Bemelman FJ, et al. Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial. American Journal of Transplantation [Internet]. 2017 Jul 1 [cited 2025 May 4];17(7):1853–67. Available from: https://pubmed.ncbi.nlm.nih.gov/28027625/
15. Ruggenenti P, Cravedi P, Gotti E, Plati A, Marasà M, Sandrini S, et al. Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial. PLoS Med [Internet]. 2021 Jun 1 [cited 2025 May 4];18(6). Available from: https://pubmed.ncbi.nlm.nih.gov/34166370/
16. Durrbach A, Pestana JM, Pearson T, Vincenti F, Garcia VD, Campistol J, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT Study). American Journal of Transplantation [Internet]. 2010 [cited 2025 May 4];10(3):547–57. Available from: https://pubmed.ncbi.nlm.nih.gov/20415898/
17. Nguyen TT, Pearson RA, Mohamed ME, Schladt DP, Berglund D, Rivers Z, et al. Pharmacogenomics in kidney transplant recipients and potential for integration into practice. J Clin Pharm Ther [Internet]. 2020 Dec 1 [cited 2025 May 4];45(6):1457–65. Available from: https://pubmed.ncbi.nlm.nih.gov/32662547/
18. Rostaing L, Bunnapradist S, Grinyó JM, Ciechanowski K, Denny JE, Silva HT, et al. Novel once-daily extended-release tacrolimus versus twice-daily tacrolimus in de novo kidney transplant recipients: Two-year results of phase 3, double-blind, randomized trial. American Journal of Kidney Diseases [Internet]. 2016 Apr 1 [cited 2025 May 4];67(4):648–59. Available from: https://pubmed.ncbi.nlm.nih.gov/26717860/
19. Fischer L, Saliba F, Kaiser GM, De Carlis L, Metselaar HJ, De Simone P, et al. Three-year Outcomes in de Novo Liver Transplant Patients Receiving Everolimus with Reduced Tacrolimus: Follow-Up Results from a Randomized, Multicenter Study. Transplantation [Internet]. 2015 Jul 2 [cited 2025 May 4];99(7):1455–62. Available from: https://pubmed.ncbi.nlm.nih.gov/26151607/
20. Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. New England Journal of Medicine [Internet]. 2016 Jan 28 [cited 2025 May 4];374(4):333–43. Available from: https://pubmed.ncbi.nlm.nih.gov/26816011/
21. Matas AJ, Smith JM, Skeans MA, Thompson B, Gustafson SK, Schnitzler MA, et al. OPTN/SRTR 2012 Annual Data Report: Kidney. American Journal of Transplantation [Internet]. 2014 [cited 2025 May 4];14(SUPPL. 1):11–44. Available from: https://pubmed.ncbi.nlm.nih.gov/24373166/
22. Sellarés J, De Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, et al. Understanding the causes of kidney transplant failure: The dominant role of antibody-mediated rejection and nonadherence. American Journal of Transplantation [Internet]. 2012 Feb [cited 2025 May 4];12(2):388–99. Available from: https://pubmed.ncbi.nlm.nih.gov/22081892/
23. Eckardt KU, Kasiske BL, Zeier MG. Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. American Journal of Transplantation [Internet]. 2009 Nov [cited 2025 May 4];9:S1–155. Available from: https://pubmed.ncbi.nlm.nih.gov/19845597/
24. Moher D, Liberati A, Tetzlaff J, Altman DG, Antes G, Atkins D, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med [Internet]. 2009 Jul 1 [cited 2025 May 4];6(7). Available from: https://pubmed.ncbi.nlm.nih.gov/19621072/
25. de Jonge H, Kuypers DRJ. Pharmacogenetics in solid organ transplantation: current status and future directions. Transplant Rev [Internet]. 2008 [cited 2025 May 4];22(1):6–20. Available from: https://pubmed.ncbi.nlm.nih.gov/18631854/
26. Budde K, Bunnapradist S, Grinyo JM, Ciechanowski K, Denny JE, Silva HT, et al. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: One-year results of phase III, double-blind, randomized trial. American Journal of Transplantation [Internet]. 2014 Dec 1 [cited 2025 May 4];14(12):2796–806. Available from: https://pubmed.ncbi.nlm.nih.gov/25278376/
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