SOT6_ACR and AMR_56 (1).pptx

Solid Organ Transplantati on Rejection in Transplantati on Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Objectives • Review general immunology and recognize the rejection cascade • Understand various types of rejection • Understand the mechanisms of me...

Solid Organ Transplantati on Rejection in Transplantati on Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Objectives • Review general immunology and recognize the rejection cascade • Understand various types of rejection • Understand the mechanisms of medications that can halt or reverse rejection • Recognize the combinations of regimens used in treatment of rejection T-Cells and the Immune Response • Unlike antibodies, which can bind to antigens directly, T cell receptors can only recognize antigens that are bound to certain receptor molecules, called Major Histocompatibility Complex class 1 (MHCI) and class 2 (MHCII). • These MHC molecules are membrane-bound surface receptors on antigenpresenting cells, like dendritic cells and macrophages. •https://www.khanacademy.org/test-prep/mcat/organ-systems/ CD4 and CD8 play a role in T the-immune-system/a/adaptive-immunity https://teachmephysiology.com/immune-system/cells-immunesystem/t-cells/ B-Cells and the Immune Response • When binding of a specific antigen to the surface immunoglobulin receptor of B lymphocytes occurs, the B lymphocyte matures into a plasma cell and produces large quantities of antibody that have the ability to bind to the inciting antigen. • The secreted antibodies may be of five different isotypes (IgG, IgA, IgM, https://medical-dictionary.thefreedictionary.com/neutralizing+antibody IgD, IgE). Hall PD, Pilch N. eChapter 21. Function and Evaluation of the Immune System. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. General Principles of Rejection • Rejection of any transplanted organ is primarily mediated by activation of alloreactive T cells and antigen-presenting cells such as B lymphocytes • Acute allograft rejection is caused primarily by the infiltration of T cells into the allograft, which triggers inflammatory and cytotoxic effects on the graft • Complex interactions between the allograft and cellular cytokines, cell-to-cell interactions, CD4+ and CD8+ T cells, and B cells ultimately lead to chronic rejection and graft loss if adequate immunosuppression is Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Types of Rejection • Hyperacute rejection • Evident within minutes of the transplantation procedure when preformed donor-specific antibodies are present in the recipient at the time of the transplant • Tissue damage can be mediated through antibody-dependent, cell-mediated cytotoxicity, or through activation of the complement cascade • The ischemic damage to the microvasculature rapidly results in tissue necrosis • Uncommon due to screening and crossmatch system Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Types of Acute Rejection • Acute Cellular Rejection (ACR) • Most common in the first few months following transplantation but can occur at any time during the life of the allograft • ACR is mediated by alloreactive T-lymphocytes • Biopsy of the allograft is often used to guide therapy • Antibody Mediated Rejection (AMR) • Characterized by the presence of antibodies directed against donor vascular endothelium • Antibodies activate complement, which creates a membrane attack complex that directly damages the organ Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Types of Rejection • Chronic Rejection • Chronic rejection is a major cause of graft loss • It presents as a slow and indolent form of ACR, in which the involvement of the humoral immune system and antibodies against the vascular endothelium appear to play a role • As a result of the complex interaction of multiple drugs and diseases over time, it is difficult to delineate the true nature of chronic rejection • Unlike acute rejection, chronic rejection is not reversible with any immunosuppressive agents currently available Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Treatment of Acute Rejection • The primary goal of acute rejection therapy is to minimize the intensity of the immune response and prevent irreversible injury to the allograft • The available options include • Increasing the doses of current immunosuppressive drugs • Pulse corticosteroids with subsequent dose taper • Addition of another immunosuppressant indefinitely • Short-term treatment with a polyclonal or monoclonal antibody • The treatment of acute rejection almost always begins with “pulse” corticosteroid therapy for several days (oral or IV) Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Treatment of Acute Rejection • Cytolytic agents are often reserved for those with corticosteroid-resistant rejection, signs of hemodynamic compromise (heart), or more severe rejections • Other innovative forms of therapy for persistent or intractable rejection have been investigated • • • • Low-dose methotrexate Total lymphoid irradiation Plasmapheresis IV immunoglobulin Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Treatment of Acute Cellular Rejection (ACR) Treatme nt of ACR Consider Alternative Therapies Treatment of ACR • Treatment algorithm can be center specific • Optimize Immunosuppression in all cases • Increase CNI dose to target a higher trough level • Increase MMF/MPA/AZA to a higher dose • Add prednisone or increase maintenance dose after pulse dosing • Steroids (while waiting for biopsy results) • Methylprednisolone • 500mg IV x 1 on day 1; 250mg IV x 1 on day 2; 100mg x 1 day 3 and 4 (up to ~ 1 gram) • Begin Prednisone taper over a few weeks to 1 month • May stop here if patient resolves clinically or if biopsy results indicated mild stage of rejection • If refractory/unresponsive to steroids or moderate to severe rejection, then Thymoglobulin 1.5mg/kg IV for 5-7 days Re-start Prophylaxis • Prophylactic agents may be added to minimize adverse effects associated with these intensive immunosuppression regimens (especially if receiving thymoglobulin) • Valganciclovir • Nystatin • Trimethoprim–sulfamethoxazole • H2-receptor antagonists or proton-pump inhibitors • Duration may not be as long as initial prophylactic therapy after transplant Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Treatment of Antibody Mediated Rejection (AMR) Treatment of AMR • The primary aims of therapeutic modalities for AMR are to • Remove existing antibodies • Plasmapheresis • IVIG • Inhibit their re-development • Rituximab • Bortezomib • Eculizumab • The management of AMR is challenging and is associated with poorer outcomes compared with traditional anti-T cell rejection therapy for pure cell-mediated rejection Djamali et al. American Journal of Transplantation 2014; 14: 255–271 Therapies for AMR Plasmapheresis Therapeutic plasma exchange (TPE), also known as plasmapheresis and apheresis, is a procedure in which the plasma in your blood is removed and replaced with another fluid, similar to what happens in kidney dialysis. Removes antibodies in the process. https://www.verywellhealth.com/plasma-exchange-ms-treatment-2440905 Intravenous immunoglobulin - IVIG • Many different effects of IVIG have been demonstrated in vitro, but few studies actually identify the mechanism(s) most important in vivo • Mechanisms of action of IVIG which most likely involve direct competition with autoantibodies include • Neutralization of autoantibodies by antiidiotypes • Inhibition of complement deposition • Increasing catabolism of pathologic antibodies Berger, Melvin et al. “Rapid and reversible responses to IVIG in autoimmune neuromuscular diseases suggest mechanisms of action involving competition with functionally important autoantibodies.” Journal of the peripheral nervous system : JPNS vol. 18,4 (2013): 275- Treatment of AMR - Rituximab • Chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes • Rituximab binds to the CD20 antigen on B lymphocytes leading to cell lysis, possibly through complement-dependent cytotoxicity and/or antibody-dependent cell mediated cytotoxicity • Been used for AMR, suppression of alloantibodies prior to transplantation, and PTLD • Rituximab has been shown to improve graft survival in combination with plasmapheresis and IVIG in patients with AMR Rituxan ® Product Information, Genentech Inc., 2007 Rituximab – Rituxan ® • Significant adverse events (Black Box warnings) • Fatal infusion related reactions – Approximately 80% of fatal infusion reactions occurred in association with the first infusion • Recommended to pre-medicate prior to administration with acetaminophen and diphenhydramine, withhold antihypertensive agents 12 hours prior to rituximab administration, and start with a slow infusion rate for first dose • Tumor Lysis Syndrome in patients with NHL • Severe mucocutaneous reactions, some with fatal outcome, have been reported in association with rituximab treatment • Progressive Multifocal Leukoencephalopathy (PML) - JC virus infection Rituxan ® Product Information, Genentec Inc., 2007 Rituximab – Treatment of Rejection Becker et. al. – Treatment for Refractory Kidney Transplant Rejection Garrett et. al. – Treatment of Cardiac Vascular (B-cell mediated) Rejection • 27 patients diagnosed with biopsy-confirmed rejection, and lack of response to treatment for rejection • 8 patients treated rituximab 375 mg/m2 per week for 4 weeks • Single dose of rituximab 375mg/m2 was added to rejection treatment • In 24 patients serum creatinine decreased from 5.6 +/- 1.0 mg/dL (prior to rituximab) to 0.95 +/- 0.7 mg/dL at Becker et. al. Am J Transplant. 2004; 4(6): 996-1001 discharge • Post-treatment, LVEF returned to baseline (average 53%) with complete resolution of immunofluorescent staining by endomyocardial biopsy • No significant infection or drugrelated complications Garrett et. al. J Heart Lung Transplant. 2005; 24(9): 1337-42 Treatment of AMR Bortezomib • Bortezomib / Velcade® • Bortezomib, a proteasomal inhibitor that is FDA approved for the treatment of multiple myeloma, has been used in the treatment of AMR. • In one series, 20 patients with AMR received four doses of bortezomib 1.3 mg/m2 on days 1, 4, 7, and 11 with plasmapheresis. • Bortezomib was effective in lowering donorspecific antibodies by 50% • Significant side effects, namely diarrhea that leads to dehydration, nausea, edema, vomiting, and infections Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Treatment of AMR Bortezomib • • Rituximab exerts its effects on CD20+ B-cell lines with absence of activity against pro-B cells and plasma cells and questionable activity against memory B cells. Bortezomib targets plasma cells which elaborate the antibodies implicated in donor-specific antibodies and antibody-mediated rejection while the antibodies produced are targeted with intravenous https://www.hindawi.com/journals/jtrans/2010/698594/ Treatment of AMR Eculizumab • Eculizumab / Soliris® • Eculizumab is a humanized monoclonal antibody that targets complement protein C5, inhibiting cleavage into C5a and C5b, and therefore preventing formation of the membrane attack complex (MAC). • It has been used primarily within renal transplantation to treat atypical hemolytic-uremic syndrome (aHUS) and antibody-mediated rejection (AMR) post-transplant • Eculizumab appears to be effective in protecting renal allografts when post-transplant aHUS or AMR occur, although the published cases report relatively short follow-up • All patients should receive vaccination against Neisseria meningitidis prior to receiving eculizumab. Barnett AN et al. The use of eculizumab in renal transplantation. Clin Transplant. Eculizum ab • Overview of the complement activation pathways. • Eculizumab inhibits the cleavage of C5, thus preventing formation of the inflammatory molecules C5a and C5b (which is the initiating component of the membrane attack complex) Barnett AN et al. The use of eculizumab in renal transplantation. Clin Transplant. Treatment of AMR Eculizumab • Retrospective observational study of a consecutive cohort of solitary kidney transplant recipients and had AMR within the first 30 days posttransplant and treated with eculizumab ± plasmapheresis. • Within 1 week of treatment, the median estimated glomerular filtration rate increased from 21 to 34 mL/min (P = 0.001) • Persistent active AMR was only found in 16.7% (2/12) of biopsied patients within 4-6 months • No graft losses occurred • Need larger trials and is limited by its cost Tan EK et al. Use of Eculizumab for Active Antibody-mediated Rejection That Occurs Early Post-kidney Transplantation: A Consecutive Series of 15 Cases. Transplantation. 2019 Nov;103(11):2397-2404. Re-start Prophylaxis • Prophylactic agents may be added to minimize adverse effects associated with these intensive immunosuppression regimens • • • • Valganciclovir Nystatin Trimethoprim–sulfamethoxazole H2-receptor antagonists or proton-pump inhibitors Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Question s • Please contact me at: [email protected] u