Drugs used in kidney transplantation 2.pptx

Drugs used in kidney transplant

1. Drugs used in kidney Transplantation, their mechanism of action and common adverse effects Presenter: Dr. Ram Chandra Patel DM Resident Department of Nephrology IGIMS, Patna Seminar Presentation

2. Content Introduction Classification of Immunosuppressive Therapies Timeline of immunosuppressive therapies Stages of T-cell activation: targets of ISA Induction agents Maintenance immunosuppressive drugs Other immunosuppressive drugs used in kidney transplantation. Conclusion.

3. Introduction The central issue in organ transplantation remains suppression of allograft rejection. Development of immunosuppressive drugs is the key to successful allograft function. Immunosuppressive agents are used for induction, maintenance, and reversal of established rejection.

4. Classification of Immunosuppressive Therapies 1) Glucocorticoids 2) Small-molecule drugs Calcineurin inhibitors : Cyclophilin-binding drugs: cyclosporine FKBP12-binding drugs: tacrolimus Target-of-rapamycin inhibitors: sirolimus, everolimus Inhibitors of nucleotide synthesis Purine synthesis (IMPDH) inhibitors : Mycophenolate mofetil, Enteric-coated mycophenolic acid Antimetabolites: azathioprine

5. Classification of Immunosuppressive Therapies contd. 3) Protein drugs Depleting antibodies (against T cells, B cells, or both) Polyclonal antibody: horse or rabbit antithymocyte globulin Mouse monoclonal anti-CD3 antibody (muromonab-CD3) Humanized monoclonal anti-CD52 antibody (alemtuzumab) B-cell–depleting monoclonal anti-CD20 antibody (rituximab) Nondepleting antibodies and fusion proteins Humanized or chimeric monoclonal anti-CD25 antibody (daclizumab, basiliximab ) Fusion protein with natural binding properties: CTLA-4–Ig ( Belatacept ) Intravenous immune globulin

6. Stages of T-cell activation: targets of ISA (source- Brenner & Rector’s The kidney 11 th edition)

7. INDUCTION IMMUNOSUPPRESSIVE AGENTS

8. Polyclonal T-cell depleting antibodies MC used in clinical practice : rabbit antithymocyte globulin ( rATG Thymoglobulin, Genzyme). Two other existing preparations rATG -Fresenius ( Jurkat T-cells) equine ATG (ATGAM). Antirabbit (or antiequine ) antibodies : decreased activity and serum sickness upon re-exposure. Hardinger KL. Rabbit antithymocyte globulin induction therapy in adult renal transplantation. Pharmacotherapy. 2006;26(12):1771–1783.

9. Polyclonal antibodies contd. Antibodies at higher concentrations : TCR, CD2,CD3, CD5, CD6, CD8, CD11A, CD49, and ꟕ2 microglobulin . Mechanism of T-cell depletion Peripheral blood : complement-dependent cell lysis. Spleen and axillary lymph nodes : apoptosis and phagocytosis Mueller TF. Mechanisms of action of thymoglobulin. Transplantation. 2007;84(11S):S5–S10

10. Polyclonal antibodies contd. Another important mechanism of action of ATG : modulation . Antigen–antibody complex is internalized : pathway remains inhibited for up to 4 weeks. Downmodulation affects molecules that regulate T-cell activation Molecules involved in leukocyte– endothelial interactions. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21(7):1387–1394.

11. Polyclonal antibodies contd. Induction and proliferation of Treg cells. ATG used as an induction agent prevents acute rejection, increases the risk of CMV infection, thrombocytopenia, and leukopenia. The impact of ATG on death, graft survival, and malignancy are unclear. ATG is also used as a treatment for acute rejection. Hill P, Cross NB, Barnett AN, et al. Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst Rev. 2017;(1):CD004759.

12. MOA of immunosuppressive agents viewed as a function of inhibiting T-cell activation

13. Monoclonal T-cell depleting antibody Muromonab-CD3 ( Orthoclone OKT3) : mouse anti-human MAB against the T-cell receptor-associated CD3 antigen first approved for clinical use in 1985. Apoptosis and rapid depletion of T cells from the circulation. Transient antibody-induced T-cell activation and cytokine surge. T-cell number and function : return to normal limits one week after the completion of the treatment.

14. Monoclonal T-cell depleting antibody contd. Cytokine release syndrome – first infusion mild, self-limited flu-like illness; severe life-threatening reactions, such as serious cardiovascular and CNS manifestations, have been reported. Non-cardiac pulmonary edema Anti-mouse neutralizing antibody Use of OKT3 decreased considerably following the emergence of alternative immunosuppressive agents, such as ATG and IL-2 blockers. OKT3 was the first monoclonal antibody to be approved by the U.S. FDA.

15. Anti-IL-2R antibodies Two agents : 1) Daclizumab ( humanized MAB) 2) Basiliximab ( chimeric MAB) Nondepleting, chimeric, MAB targeted against CD25, or IL-2R. Basiliximab is currently the only agent in the anti-IL-2R class. Binding to the α subunit of IL-2R : inhibits IL-2–induced lymphocyte proliferation. Yeung MY, Gabardi S, Sayegh MH. Use of polyclonal/monoclonal antibody therapies in transplantation. Expert Opin Biol Ther. 2017;17(3):339–352

16. Anti-IL-2R antibodies contd. Basiliximab induction : T-cell suppression for 4 to 6 weeks. Indicated in the prevention, but not the treatment, of rejection. Less effective in prevention of acute rejection compared to ATG and alemtuzumab Regimen of the treatment : 2 infusions of 20 mg; First, at the time of transplantation, Second, 3 to 4 days posttransplantation Amlot PL, Rawlings E, Fernando ON, et al. Prolonged action of a chimeric interleukin-2 receptor (CD25) monoclonal antibody used in cadaveric renal transplantation. Transplantation. 1995;60(7): 748–756

17. Anti-CD52 antibody Alemtuzumab ( Campath ) : humanized, rat monoclonal IgG1 antibody directed against CD52. CD52 : expressed on both B and T cells and on NK cells, monocytes, macrophages, and DCs. Involved in T-cell costimulation , migration, and adhesion, and may also induce T-reg cells. van der Zwan M, Baan CC, van Gelder T, et al. Review of the clinical pharmacokinetics and pharmacodynamics of alemtuzumab and its use in kidney transplantation. Clin Pharmacokinet. 2017.

18. Anti-CD52 antibody contd. As an induction agent, the efficacy of alemtuzumab is similar to that of ATG. Increased risk of formation of de novo DSA compared with basiliximab or ATG. Treatment for acute TCMR in patients with steroid-resistant rejection. Side-effects: Neutropenia and anemia Auto-immune disease LaMattina JC, Mezrich JD, Hofmann RM, et al. Alemtuzumab as compared to alternative contemporary induction regimens. Transpl Int. 2012;25(5):518–526

19. Anti-CD20 antibodies Rituximab (Rituxan) : chimeric anti-CD20 cytolytic monoclonal antibody. Initially used for the treatment of post-transplant lymphoproliferative disease. Interferes with the humoral allo -response. Part of an induction regimen for selected immunologically high risk patients. van den Hoogen MW, Kamburova EG, Baas MC, et al. Rituximab as induction therapy after renal transplantation: a randomized, double-blind, placebo-controlled study of efficacy and safety. Am J Transplant. 2015;15:407–416.

20. Anti-CD20 antibodies contd. Element in many pretransplant desensitization protocols. Treatment of recurrent or de novo posttransplant glomerular diseases . Infusion-related side effects Obintuzumab : next generation anti-CD20 antibody Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008;359:242–251

21. Intravenous Immunoglobulin (IVIg) Part of both HLA- or ABO incompatible-desensitization protocols, Induction in patients with pre-formed DSA Treatment of ABMR Mechanism of action neutralization of circulating (anti-HLA) antibody, inhibition of complement modulation of B-cell and antigen presenting cell function, cytokine inhibition. Jordan SC, Toyoda M, Kahwaji J, et al. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011;11:196–202.

22. Intravenous Immunoglobulin (IVIg) contd. Treatment of posttransplant viral infections BK virus parvovirus. Side effects infusion reaction, headache (common and troublesome), aseptic meningitis, hemolysis (especially in patients who are blood group A) Thrombosis (rare)

23. MAINTENANCE IMMUNOSUPPRESSIVE AGENTS

24. Calcineurin inhibitors Calcineurin : Calcium dependent serine/threonine phosphatase dephosphorylates the transcription factor, nuclear factor of activated T- cells (NFAT). After dephosphorylation, NFAT translocates to the nucleus. This complex regulates gene transcription, including the gene for IL-2.

25. Differences between tacrolimus and cyclosporine Cyclosporine Tacrolimus (FK506) Constituent & MOA Small cyclic peptide of fungal origin Binds to a family of cytoplasmic molecules termed cyclophilins. Macrolide antibiotic produced by fungi Binds to a family cytosolic proteins, the FK binding protein. Formulations Oil based ( Sandimmune ), Microemulsion ( Neoral ), Water-based microemulsion ( Gengraf ) 2 extended-release formulations ( Astagraf and Envarsus ) Ekberg H, Bernasconi C, Tedesco-Silva H, et al. Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation. Am J Transplant. 2009;9(8):1876–1885.

26. Adverse effects of CNIs

27. Mycophenolic acid (MPA) Fermention product of penicillium brevicompactum fungi Mycophenolate mofetil (MMF) : a prodrug Inhibits the proliferation of human T and B cells. Main mechanism of action: inhibition of inosine-5’- monophosphate dehydrogenase (IMPDH) limits the rate of guanosine nucleotide synthesis. Zmonarski SC, Boratynska M, Madziarska K, et al. Mycophenolate mofetil severely depresses antibody response to CMV infection in early posttransplant period. Transplant Proc. 2003;35(6):2205–2206

28. MPA contd. Decrease antibody responses to multiple alloantigens including CMV and equine proteins found in ATGAM preparations. Suppress DSA production. Suppresses autoantibody production through early inhibition of B cell proliferation and differentation . other mechanisms of action in context of organ transplant: Suppress the maturation of DCs and inhibit their capacity to present antigens.

29. MPA contd. Reduce the recruitment of monocytes into sites of graft rejection and inflammation. MPA has superior efficacy in preventing acute rejection episodes and death-censored graft loss when compared with azathioprine. Mycophenolate sodium ( Myfortic ) : enteric-coated slow-release formulation of MPA Wagner M, Earley AK, Webster AC, et al. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev. 2015;(12):CD007746.

30. Azathioprine Purine analog; enzymatically converted in vivo to 6-mercaptopurine and other derivatives. After metabolic conversion, it has multiple activities, incorporation into DNA and RNA resulting in cell death inhibition of purine nucleotide synthesis T-cell apoptosis. Decreases the number of migratory mononuclear and granulocytic cells. Inhibits proliferation of promyelocytes in the bone marrow.

31. Azathioprine Contd. Substituted for MMF in female transplant recipients who are planning to conceive. Side effects: leukopenia, thrombocytopenia, hepatotoxicity, and an increased risk of neoplasia. Pancreatitis(rare but serious side effect). Wagner M, Earley AK, Webster AC, et al. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev. 2015;(12):CD007746.

32. MAMMALIAN TARGET OF RAPAMYCIN INHIBITORS Rapamycin, or sirolimus macrolide antibiotic Blocks T-cell proliferation during the late G1 phase of the cell cycle and before the S phase. After binding to intracellular FK-binding proteins, rapamycin forms an effector complex that inhibits mTOR. mTOR inhibition prevents phosphorylation of the p70 S6 kinase, which reduces the translation of mRNAs.

33. MAMMALIAN TARGET OF RAPAMYCIN INHIBITORS Contd. Inhibition of the enzymatic activity of the cdk2-cyclin E complex, a regulator of G1/S transition. Benefit in patients at high risk of cancer and those who are intolerant to calcineurin inhibitors. Everolimus : derived from Sirolimus and has a shorter half-life Approved for prophylaxis against rejection in kidney transplant Side effects: dyslipidemia, peripheral edema, cytopenia, acne, proteinuria, and oral ulcers. Knoll GA, Kokolo MB, Mallick R, et al. Effect of sirolimus on malig_x0002_nancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ. 2014;349:g6679 .

34. Corticosteroids Modulate the immune response by regulating gene expression. Bind to the steroid receptor in cytosol. Complex migrates to the nucleus and binds regulatory regions of DNA called glucocorticoid response elements . Regulate the transcription of many genes, including IL-1, IL-2, IFN-γ, TNF-α, and IL-6. Haller MC, Royuela A, Nagler EV, et al. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev. 2016;(8):CD005632.

35. Belatacept Fusion protein composed of an Fc fragment of human IgG1 linked to an extracellular domain of cytotoxic T lymphocyte antigen-4 (CTLA-4). After binding with B7-1 and B7-2 on the surface of APCs, CD28 provides a costimulatory signal. CD80 and CD86 also bind with CTLA-4, inducing a negative regulatory effect on T-cell activation.

36. Belatacept Contd. First intravenous maintenance immunosuppressive. Use of belatacept (versus cyclosporine) in combination with MMF, prednisone, and basiliximab induction : higher graft function 1 year posttransplantation . Cases of PTLD in transplant recipients who were EBV-seronegative before transplantation. Conversion from calcineurin inhibitors to belatacept : Improvement in graft function up to 3 years after conversion. Kumar D, LeCorchick S, Gupta G. Belatacept as an alternative to calcineurin inhibitors in patients with solid organ transplants. Front Med (Lausanne). 2017;4:60

37. OTHER IMMUNOSUPPRESSIVE AGENTS USED IN THE FIELD OF KIDNEY TRANSPLANTATION

38. Bortezomib Reversible inhibitor of the 26S proteasome, a multicatalytic enzyme complex . Accumulation of misfolded proteins within the endoplasmic reticulum, leading to apoptosis. Plasma cells are particularly sensitive to proteasome inhibition. Alexander T, Sarfert R, Klotsche J, et al. The proteasome inhibitiorbortezomib depletes plasma cells and ameliorates clinical manifesta_x0002_tions of refractory systemic lupus erythematosus. Ann Rheum Dis. 2015;74(7):1474–1478.

39. Bortezomib contd. Desensitization protocols that also included rituximab and IVIg. Beneficial effect limited to ABMR episodes occurring in the early posttransplant period. Impact of bortezomib on late ABMR is currently being investigated. Walsh RC, Brailey P, Girnita A, et al. Early and late acute antibodymediated rejection differ immunologically and in response to proteasome inhibition. Transplantation. 2011;91(11):1218–1226.

40. Eculizumab Humanized monoclonal antibody Prevents the cleavage of complement C5a component, inhibiting the formation of the MAC . Prevents the recurrence of atypical HUS, and has reversed acute ABMR. Meningococcal vaccination is recommended at least 2 weeks before administering the first dose. Legendre CM, Campistol JM, Feldkamp T, et al. Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis. Transpl Int. 2017.

41. Tocilizumab Humanized monoclonal antibody directed at the soluble and membrane forms of IL-6R. Innate immune cells release IL-6 after recognizing PAMPs or DAMPs. IL-6 stimulates B cells, promotes antibody synthesis and Tfh cell populations Induces proinflammatory Th17 cell differentiation at the expense of Treg-cell induction Kang S, Tanaka T, Kishimoto T. Therapeutic uses of anti-interleukin-6 receptor antibody. Int Immunol. 2015;27(1):21–29.

42. Tocilizumab contd. FDA-approved for the treatment of severe RA and juvenile arthritis. Desensitization protocols, as well as for the treatment of chronic ABMR. Jordan SC, Choi J, Kim I, et al. Interleukin-6, a cytokine critical to mediation of inflammation, autoimmunity and allograft rejection: therapeutic implications of IL-6 receptor blockade. Transplantation. 2017;101(1):32–44

43. Drugs Side effects Corticosteroids Glucose intolerance, hypertension, hyperlipidemia, osteoporosis, osteonecrosis, myopathy, cosmetic defects; growth suppression in children Cyclosporine Nephrotoxicity (acute and chronic), hyperlipidemia, hypertension, glucose intolerance, cosmetic defects Tacrolimus Broadly similar to cyclosporine; diabetes mellitus more common; hypertension, hyperlipidemia, and cosmetic defects less common Azathioprine Bone marrow suppression; rarely pancreatitis, hepatitis Mycophenolate mofetil (MMF) Bone marrow suppression, gastrointestinal upset; invasive. CMV disease more common than with azathioprine Sirolimus Bone marrow suppression, proteinuria, mouth ulcers, hyperlipidemia, interstitial pneumonitis; edema; enhanced nephrotoxicity of cyclosporine/tacrolimus Belatacept PTLD in EBV seronegative, reactivation of TB

44. Conclusion Most immunosuppressive agents either deplete lymphocytes or act at the level of, or downstream from, one or more of the three T-cell immune activation signals. Immunosuppression remains a double-edged sword for kidney transplant patients. Although current immunosuppressive regimen has yielded excellent results in terms of acute rejection prevention and increased short-term graft survival, the risk of infection and cancer remain problematic.

45. Thank you