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Antibody-Mediated Rejection in Heart Transplantation Stefanie L. Drahuschak PharmD Candidate Class of 2014 University of Pittsburgh School of Pharmacy Objectives Describe the major differences between hyperacute, acute, and chronic rejection. List the treatment options for antibody-mediated rejection. Apply the concepts of antibody-mediated rejection to a patient case. Patient JL: CC Presented to PUH ED on 1/18/14 with c/o Increasing SOB Abdominal distension Intermittent vomiting after eating Has been worsening over last 3 months Patient JL 58 yo WM s/p OHTx in 6/2009 secondary to ICM No known drug allergies PMHx s/p CABG 4/2009 BiVAD placement 5/2009 Episodic grade 1 cellular rejection, resolved 5/13 Antibody-mediated rejection (class II DSAs) CKD -> ESRD 2/2 AMR tx, on HD T/Th/S T2DM Hypertension Hyperlipidemia Peripheral vascular disease JL: Family and Social Hx Family Hx Family history is listed as non-contributory for this patient Social Hx 20 pack year history, quit 2009 Denies EtOH or illicit drug use Lives with wife and dogs Retired post office employee JL: Home Medications Medication Dosage Frequency Aspirin 81mg Once daily Atorvastatin 40 mg qHS Docusate 100 mg Once daily prn Ergocalciferol 50,000 units Once weekly Furosemide 80 mg Once daily Lantus 10 units qHS Humalog SSI TID AC Magnesium oxide 400 mg Once daily Methadone 5 mg 5 tabs daily prn Metolazone 2.5 mg Once daily Oxycodone 5 mg 2 tabs q6h prn Pantoprazole 40 mg Once daily Miralax 17 g Once daily Bactrim DS 800/160mg 1 tab q MWF Tacrolimus 1 mg 7 mg q 12h JL: Pertinent Findings Upon presentation to PUH ED LE edema Ascites, volume overloaded Elevated BNP (2859) K 6.1, bicarbonate 34 BUN 29, SCr 6.2 Troponin negative LFTs and CBC WNL CXR showed right-sided pleural effusion JL: Inpatient Progression Initial differential: volume overload due to underdialysis Previous RHC (1/13/14): PCWP 33, PA 45, RA 29, RV 32 Underwent HD session TTE (1/21/14) Findings consistent with OHTx, no significant changes from TTE on 9/6/13 Patient d/c’ed 1/24/14 with good allograft function and improved volume status JL: History of Rejection Episodic grade 1 cellular rejection Resolved as of May 2013 Antibody-mediated rejection (class II DSAs) s/p Pulse steroids 4/2013 IVIg, rituximab, and plasmaphoresis 4/2013 Plasmapheresis, IVIg, and carfilzomib 6-7/2013 Review of Rejection Review of Rejection Rejection in any transplanted organ is mediated by activation of T cells and antigen-presenting cells, such as B cells, macrophages, and dendritic cells. Acute rejection is mainly caused by infiltration of T cells into the graft Causing inflammation Chronic rejection is due to interactions between the graft and cellular cytokines, CD4 and CD8 T cells, and B cells Review of Rejection Hyperacute rejection Occurs within minutes of surgery when donor-specific antibodies are present in the recipient Has become uncommon in kidney and heart transplantation due to extensive pre-op screening Treated with supportive care and re-transplantation if possible Review of Rejection Acute rejection Most common in the first few months following transplantation but can occur at any time CD8 cells respond to the HLA class I differences between donor and recipient and CD4 cells respond to HLA class II differences Both CD4 and CD8 can attack the allograft May affect up to 20% of kidney transplant patients ~18% of liver transplantation patients >60% of heart transplantation recipients will experience acute rejection, with 90% occurring within the first 6 months Recurrent episodes lead to chronic rejection Review of Rejection Chronic rejection A major cause of graft loss Occurs more slowly and over time compared with acute rejection Humoral immune system and antibodies against graft both play a role Chronic inflammation and other disease states lead to rejection over time Caused by thickening of the vessel walls and narrowing of their vasculature Results in inadequate blood supply to the graft ischemia death Antibody-Mediated Rejection (AMR) Antibody-Medicated Rejection Also referred to as vascular or humoral rejection Characterized by the presence of antibodies directed against HLA antigens on the donor vasculature – Donor Specific Antibodies (DSAs) Screening for DSAs routinely post-transplantation can help prevent rejection episodes Associated with a significantly worse survival and shown to predispose patients to coronary vasculopathy Less common than cellular rejection and generally occurs in the first 3 months post-transplantation Antibody-Mediated Rejection Associated with an increased fatality rate Increased risk factors for AMR include Female gender, elevated PRA, CMV+, positive crossmatch, and prior sensitization to muromonab (OKT3) To date, there are no FDA-approved immunosuppressive agents for AMR treatment All agents are used off-label Rose, et al. 66% of heart recipients produced anti-HLA lymphocytotoxic antibodies post-transplantation Antibodies were not donor antigen-specific, but their presence correlated with adverse outcomes Graft arteriosclerosis Lower graft survival rate Findings in AMR of Heart J Heart Lung Transplant. 2009;25(2):153-59 Diagnosis – Cardiac Biopsy Standardized Cardiac Biopsy Grading Grade 0R No rejection or inflammation detected Grade 1R (1A or 1B) A=focal infiltrate without necrosis B=diffuse but sparse infiltrate without necrosis Grade 2R One focus only with aggressive infiltration and/or myocyte damage Grade 3R (3A or 3B) A=Multifocal aggressive infiltrates and/or myocyte damage B=Diffuse inflammatory process with necrosis Grade 4R Diffuse aggressive polymorphous ± infiltrate ± edema ± hemorrhage ± vasculitis, with necrosis AMR Diagnosis If features suggestive of AMR seen, diagnosis can be confirmed by either Immunofluorescence microscopy Immunoperoxidase light microscopy using antibodies directed against CD68, CD31, and CD4 Serum should be drawn and tested for DSA HLA Class I and II antibodies and non-HLA antibodies If positive, a positive diagnosis for AMR should be made JL: Diagnosis Patient presented to ED in April 2013 with c/o dyspnea and volume overload x 2 days, severe back spasms Concern for rejection due to history and some noncompliance TTE: overall left ventricular function worse since previous TTE, EF 30-35% RHC: PCWP 21, PA 28, RA 15, RV 15 Elevated pressures volume overload Biopsy showed grade 1R AMR Treatment - Plasmapheresis The removal, treatment, and return of blood plasma from circulation Blood is removed from patient through needle or catheter and plasma and blood are separated via centrifugation or filtration Blood is returned to patient and plasma is treated (antibodies removed) then also returned to patient Offers the quickest short-term answer to removing antibodies from blood, but requires concomitant immunosuppressive therapy AMR Treatment - IVIg IVIg = Intravenous immunoglobulin A blood product containing pooled polyvalent IgG antibodies extracted from plasma of multiple donors (at least 1,000) IVIg suppresses inflammation, which occurs in rejection, by a MOA that is not fully understood Used in combination with rituximab for treatment of AMR and also for desensitization in pre-transplant patients who are highly sensitized AMR Treatment - Rituximab A chimeric anti-CD20 monoclonal antibody An anti-neoplastic agent MOA Binds directly to CD20 that is located on pre-B and mature B cells CD20 regulates an early step in the activation process for cell cycle initiation and differentiation Ultimately mediates B cell lysis AMR Treatment - Rituximab Faguer S, et al. 2 g/kg IVIg on week 0, rituximab on weeks 3 and 4, second dose of IVIg on week 5 Following therapy, PRA levels were reduced significantly (from 77 ± 19% before infusion to 44 ± 30% after second infusion) Transplant was then possible in 16 of the 20 patients 12-month patient and allograft survival rates were 100% and 94%, respectively JL: AMR Treatment April 3-5, 2013 3 days of methylprednisolone 1 gm IV once daily April 13-15, 2013 Plasmapheresis April 15-16, 2013 IVIG 0.5 g/kg x 2 days Premedicated with APAP, diphenhydramine, famotidine, but not well tolerated Did not receive 2nd dose due to elevated creatinine April 19, 2013 Rituximab 675 mg IV once Patient JL May 9, 2013: patient returns to ED with c/o N/V x 1 week with minimal PO tolerance RHC (5/11): RA 18, RV 43/19, PA 43/23 (31) and wedge 25 (elevated pressures) Patient remained in house with intermediate plasmapheresis and IVIg Biopsy on 5/11 revealed grade 0R EF decreased to 25-30% from 55% on admission Biopsy one week prior revealed grade 0R, but notable for strong class II DSAs AMR Refractory Treatment Bortezomib (Velcade®) Proteasome inhibitor, first in its class, approved 2003 Indicated as an antineoplastic agent for multiple myeloma Reversible inhibitor of the 26S proteasome 26S proteasome regulates protein expression and function by degradation of modified proteins (damaged, poorly folded) Prevents peptide generation, which reduces class I MHC expression Negatives: peripheral neuropathy and $$$ To date, no randomized controlled trials have been conducted for AMR treatment Some case reports have been published on the efficacy of bortezomib- based regimens Eckman, et al. First reported use of bortezomib in refractory AMR in cardiac allograft 65 yo woman who developed HF 5 years post-op (biopsy proven CD4+AMR with three DSAs identifed) Treated with a single bortezomib cycle with plasmapheresis prior to each dose Within 2 weeks of treatment, clinical improvement was noted with CD4 resolution on biopsy and improved DSA levels AMR Refractory Treatment Carfilzomib (Kyprolis®) Proteasome inhibitor FDA approved July 20, 2012 Indication: multiple myeloma, relapsed after at least 2 prior therapies MOA Irreversibly binds to active sites of 20S proteasome Even less data available with no clinical trials relating to AMR Dosing: administered IV over 2-10 minutes on two consecutive days each week for three weeks (days 1, 2, 8, 9, 15, 16) followed by a 12-day rest period (28 day cycle) $$$$$$$$$ Patient JL: AMR Treatment June 5, 2013: Plasmaphoresis 1.5 volume IVIg 100 mg/kg Carfilzomab (Kyprolis®) 20 mg/m2 Days 1,2 days 8,9 days 15, 16 JL: Post-Treatment TTE (6/21): LV function had improved from TTE on 5/30/13 EF 45%, markedly improved from 25-30% DSAs negative from 6/19 RHC (6/24): RA 13, wedge 21 - improving Patient was able to be d/c’ed 7/5/13 JL Assessment/Plan 1) Acute HF 2/2 AMR s/p OHTx 6/2009 Underwent plasmaphoresis, IVIG, and carfilzomab Pressors and inotropes weaned Tacrolimus 6 mg q12h (goal 8-10), Myfortic 720 mg BID, Valcyte 450 mg qMN/Th, dapsone 100 mg daily Lasix 80 mg on non-HD days for volume control Patient must closely for s/sx of rejection (fever, unexplained pains, weakness) Biopsies and DSAs should be checked regularly Follow-up Patients who have several episodes of documented AMR should be followed on future biopsies Should be monitored for the production of donor-specific HLA class I and class II antibodies Conclusion AMR is a significant cause of graft loss in transplantation population Can be screened for and potentially prevented with appropriate immunosuppression and monitoring Can be treated with a combination of novel approaches, none of which are FDA approved for their use as AMR treatment Ongoing clinical trials and novel agents give hope for a more treatment options in the future References 1) Dipiro JT, Talbert RL,Yee GC, et al. “Solid-Organ Transplantation”. Pharmacotherapy, Ed. Schonder KS, Johnson HJ. New York, NY: The McGraw-Hill Companies, Inc, 2011. 1537-58. 2) Parham P. “Transplantation of Tissues and Organs”. The Immune System, Ed. New York, NY: Garland Science, Taylor & Francis Group, LLC, 2009. 454-83. 3) Reed EF, Demetris AJ, Hammond E, et al. Acute Antibody-mediated Rejection of Cardiac Transplants. J Heart Lung Transplant. 2006;25(2):153-59. 4) Rose EA, Smith CR, Petrossian GA, et al. Humoral immune responses after cardiac transplantation: correlation with fatal rejection and graft atherosclerosis. Surgery. 1989;106:203-7. 5) Billingham ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: heart rejection study group. J Heart Trans. 1990;9(6):587-93. 6) Mosquera Reboredo JM, Vazquez Martul E. Diagnostic criteria of antibody-mediated rejection in kidney transplants. Nefrologia. 2011;31(4):382-91. 7) Hartung H-P, Mouthon L, Ahmed R, et al. Clinical applications of intravenous immunoglobulins (IVIG) – beyond immunodeficiencies and neurology. Clin Exp Immunol. 2009; 158(1): 23-33. References 8) Faguer S, Kamar N, Guilbeaud-Frugier C, et al. Rituximab therapy for acute humoral rejection after kidney transplantation. Transplantation. 2007;83:1277-80. 9) Sadaka B, Alloway RR, Shields AR, et al. Proteasome inhibitors proteasome inhibition for antibody-mediated allograft rejection. Seminars in Hematology. 2012;49(3):26369. 10) Velcade® [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2012. 11) Kyprolis® [package insert]. San Francisco, CA: Onyx Pharmaceuticals, Inc; 2012. Questions?