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Experience with Antibody-Mediated Rejection Millie Samaniego, M.D. Associate Professor of Medicine University of Wisconsin and Robert A. Montgomery, M.D.,

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Presentation on theme: "Experience with Antibody-Mediated Rejection Millie Samaniego, M.D. Associate Professor of Medicine University of Wisconsin and Robert A. Montgomery, M.D.,"— Presentation transcript:

1 Experience with Antibody-Mediated Rejection Millie Samaniego, M.D. Associate Professor of Medicine University of Wisconsin and Robert A. Montgomery, M.D., D.Phil. Chief, Division of Transplantation Director, The Johns Hopkins Comprehensive Transplant Center The Johns Hopkins Hospital

2 Characteristic histologic features including: 1) glomerulitis/capillaritis 2) margination of neutrophils in the PTC 3) fibrin thrombi 4) interstitial hemorrhage 5) severe or necrotizing vasculitis Diffuse, linear C4d staining in the PTC Identification of DSA Diagnostic Criteria for Acute AMR Grade 1 Grade 3

3 AMRCellular Accommodation Patterns of Rejection in ABO Incompatible Transplants

4 Therapeutic Options For The Treatment Of AMR Antibody Reduction Plasmapheresis/IA IVIg B-cell Modulation Splenectomy Anti-CD20 Cytoxan Immunomodulation IVIg ATG IL-2R blockers Fk 506, Rapamycin MMF/DSG CAMPATH?

5 Antibody Reduction Therapy High dose IVIG (1-2 gms/kg) Mechanism: Anti-idiotypic networks probably important Many putative immunomodulatory pathways identified Advantages: In vitro test for predicting efficacy Ease of administration? Disadvantages: Non-responders Different techniques required to follow DSA titers Less rapid Ab removal, unproven for high-titer DSA Toxicity & batch-to-batch variability Unproven for ABOi Tx

6 Plasmapheresis/Low Dose IVIg (100 mg/kg) Mechanism: Rapid reduction in anti-HLA or isoagglutinin Ab Induces donor specific unresponsiveness (HLA) or accommodation (ABOI) Advantages: Predictable kinetics of plasmapheresis No evidence of “nonresponders” Able to easily follow DSA levels during/after therapy Disadvantages: DSA may rebound between treatments or if discontinued Treatment may be prolonged and immunosuppressive Expensive and resource intensive Antibody Reduction Therapy

7 B-Cell Modulation Anti-CD20 Mechanism: Rapid ablation of the peripheral B-cell compartment Advantages: Probably reduces precursor cells responsible for clonal expansion during AMR May produce more effective antibody reduction when combined with plasmapheresis or IVIG Well-tolerated, little apparent toxicity Effect on the immune system is temporary (6-months) Disadvantages: Plasma cells persist in the spleen May not, on its own, reduce DSA titers during AMR Immunosuppressive

8 Days from Transplant -19-17-15-12-8-7-6-5-4-3-20+2+3+4+5+6+7+8+9+11+12+13+16+18+19 64 32 16 8 4 88 44 2 44 88 8 22 111 98 85 100 0 20 40 60 80 100 120 0 10 20 30 40 50 60 70 80 90 100 512 128 100 58 0 Tx Anti-CD20 DSA titer PRA PP/ CMVIg PRA DSA titer Case Study: AMR in (+) Cytotoxic XM with High Titer Anti-HLA DSA Cr 6.5 Cr 1.5 Cr 4.4 Cr 2.1 Cr 1.6 CD20=23.7 CD20=0 CD19=0

9 B-cell Modulation Splenectomy Mechanism: Reduces plasma cells, precursor cells, B-cell immune surveillance capabilities Advantages: Can be performed using minimally invasive techniques May produce more effective antibody reduction when combined with plasmapheresis or IVIG Disadvantages: Life-long risk of sepsis from encapsulated bacteria Does not appear on its own to reduce DSA titers Effect on immune system is permanent

10 0 16 32 64 128 256 -28-23-21-18-16-15-14-12-10 -6-4-3-203578101214172125273132 34404245 Day With Respect to Transplant Anti-A Titers (1:X) Serum Creatinine (mg/dL) 4 3 1 2 The Effect of Splenectomy on Anti-Blood Group Ab 512 Tx Splenectomy PP/IVIg

11 Targets of Strategies for Antibody Removal Plasma cells B-cells & Pre B-cells Clonal Expansion Plasmapheresis/IVIG Anti-CD20 Splenectomy

12 Acute De Novo AMR Occurs in 4-6% of transplants (80-100% fail) Risk factors include: + historic XM, history of sensitizing event(s), high risk donor/recipient combination Diagnosis should be made by histology and demonstration of the appearance of DSA Historically suspected only after there is a poor response to anti-lymphocytic agents By definition the current XM is negative

13 PP/CMVIg Treatment Protocol for Acute De Novo AMR 8642Dx of AMR PP/Ig Steroid bolus -OR-  -thymocyte globulin PP/Ig Time Relative to Initiation of Therapy (Days) Plasmapheresis – single plasma volume exchange IVIG – 100mg/kg following each PP treatment (CMV hyperimmune globulin) Heparin D/C FK 506 High Grade:

14 De Novo AMR: Renal Allograft Function 0 5 10 15 Serum Creatinine (mg/dL) NadirRejection 1 Week1 Month Current *** Median Nadir Cr (IQR) Median Cr at AMR (IQR) Median 1 week Cr (IQR) Median 1 month Cr (IQR) Median Current Cr (IQR) 3.3 (2.2 – 7.1) 6.4 (3.2 – 9.3) 4 (2.3 – 7.9) 1.9 (1.5 – 3.0) 1.5 (1.2 – 2.1) * p<0.001 1994-2003: 22 recipients of deceased or live donor kidney transplants with AMR by Bx or DSA treated with PP/IVIg Mean f/u: 5 1/2 years

15 PP/CMVIg Treatment for De Novo AMR Kaplan-Meier Estimate of Graft Survival for recipients who developed de novo AMR and were treated with PP/CMVIg therapy Allograft Survival 10 20 30 40 50 60 70 80 90 100 03657301095 Time (days) Live donorDeceased donor p = NS 10 20 30 40 50 60 70 80 90 100 03657301095 Time (days) Live donorDeceased donor 10 20 30 40 50 60 70 80 90 100 03657301095 Time (days) Live donorDeceased donor p = NS 1-Year: 87.5% 85.8% Live Deceased 3-Year: 87.5% 77.1% 5-Year: Overall 81.1%

16 Bx and DSA Proven De Novo AMR LDDDp n513 Median Days to AMR (Range) 11 (8-253) 9 (7-50) 0.25 Median Months F/U (Range) 13.6 (4-76) 11.2 (3-89) 0.77

17 De Novo Renal Function 0 3 6 9 12 15 Serum Creatinine (mg/dL) LDDD Creatinine at BiopsyCreatinine 1 week Creatinine 1 moCurrent Cr P=NS for comparison between groups at each timepoint

18 De Novo AMR Allograft Survival 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 Survival (%) 061218243036 Time (Months) LiveDeceased

19 POSITIVE CROSSMATCH ABO INCOMPATIBLE # OF PATIENTS 1-YEAR GRAFT SURVIVAL 3-YEAR GRAFT SURVIVAL 86 28 Rejection and Clinical Outcomes Following (+) XM and ABOi Previous Txs 123123 31 12 5 # OF PATIENTS Previous Txs AMR CELLULAR REJECTION 3/28 (11%) 4/28 (14%) 1-YEAR GRAFT SURVIVAL 3-YEAR GRAFT SURVIVAL 89.8% 80.9% AMR CELLULAR REJECTION SUBCLINICAL AMR SUBCLINICAL CELLULAR SUBCLINICAL AMR SUBCLINICAL CELLULAR 0/28 (0%) 7/28 (25%) 92.9%** 92.9% **1 death WNE 1 Noncompliance 7/86 (8%)* 16/86 (19%) 27/86 (31%) 26/86 (30%) 123123 410410 *Bx @ 1, 3, 6, 12 mos

20 (+) XM vs. De Novo AMR De NovoDesensitizedp n1831 Median Days to AMR (Range) 10 (7-253) 20 (2-634) 0.16 Median Months F/U (Range) 12.4 (3-89) 14.1 (0.6-65) 0.76

21 (+) XM vs. De Novo AMR Outcomes 0 3 6 9 12 15 Serum Creatinine (mg/dL) PP/CMVIg DesensitizedDe Novo Rejection Creatinine at BiopsyCreatinine 1 week Creatinine 1 moCurrent Cr P=0.002 P=0.01 P=0.04 P=NS between groups at current timepoint

22 Allograft Survival After AMR (+) XM vs. De Novo 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 Survival (%) 061218243036 Time (Months) (+) XMDeNovo p=NS

23 Kaplan-Meier Estimate of Graft Survival (+) CDC XM @ Time of Tx vs (-) CDC XM +XM @ Tx - XM @ Tx p=NS 1 Year Graft Survival 92.3% 87.2% N= 14N= 32

24 Anti-CD20 Rescue Protocol Inclusion Characteristics Failure to Respond to Plasmapheresis/CMVIg Therapy Study Group Recipients of Deceased or Live Donor Kidneys De novo AMR AMR After Desensitization Poor or Incomplete Clinical Response Persistence of High-Titer DSA Persistence of Histologic Evidence of AMR Initial Histologic Features That Portend Poor Outcome and/or Graft Loss (Grade 2-3 AMR)

25 Renal Function Following Anti-CD20 Rescue BestAMR2 weeks1 monthCurrent 1.8 (1.4 – 2.1) 4.3 (2.5 – 6.5) 3.4 (1.9 – 5.4) 2.1 (1.6 – 3.3) 1.7 (1.1 – 2.6) 0 1 2 3 4 5 6 7 8 9 10 Best CrAMR Cr 2 week Cr1 month Cr Current Cr BestAMR 2 weeks 1 Month Current p=0.0003 p=0.25 p=0.07 p=0.01 17 recipients undergoing  -CD20 rescue therapy for AMR

26 Kaplan-Meier Estimate of Graft Survival for Anti-CD20 Rescue 25 50 75 100 0123456789101112 Months Following Anti-CD20 Treatment % Survival

27 Splenectomy Rescue N4 Median Days to AMR (Range) 4 (2-15) Median Days to Splenectomy Following AMR Dx (Range) 1 (1-4) Median SCr at Biopsy Dx (Range) 3.4 (1.5 – 6.0) Median SCr 1 week (Range) 2.1 (0.8 – 5.8) Median SCr 1 month (Range) 1.5 (0.7 – 2.3) Median Current SCr (Range) 1.3 (1.2 – 2.6) Allograft Survival100% Median Months Followup (Range) 6.9 (2.2 – 11.7)

28 Conventional KPD A B B A # of KPD: 6 (12 patients) Mean PRA: 14 Unconventional KPD A O O A ABOi (+) XM ABOi 6 mos Cr: 1.2 mg/dl AMR: 0% Patient Survival: 100% Graft Survival: 91.7% # of KPD: 5 (13 patients) Mean PRA: 58 6 mos Cr: 1.1 mg/dl AMR: 0% Patient Survival: 100% Graft Survival: 100% Cellular 23% Cellular 8% Paired Donation May Reduce the Incidence of AMR

29 Summary The diagnosis of AMR can now be made with a high level of certainty There are therapeutic interventions for AMR with clinically proven efficacy De novo AMR has a good long-term prognosis when treated with PP or IVIg Results of PP or IVIg treatment for De novo AMR and AMR in the setting of desensitization are comparable A (+) cytotoxic XM at the time of Tx does not predict a worse outcome AMR recalcitrant to PP/IVIg is associated with a lower graft survival rate Results of emergent splenectomy at the time of severe AMR look promising KPD may decrease AMR by lowering immunologic risk

30 De Novo AMR AMR after (+) XM AMR after ABOi PP/IVIg Response Incomplete Response Observe Severe AMR Anti-CD20 Splenectomy Anti-CD20 Algorithm For Approach To AMR

31 Acknowledgements Matt Cooper Lorraine Racusen Mark Haas Karen King Andrea Zachary Susie Lefell Donna Lucas Julie Graziani Renato Vega Chris Sonnenday Dan Warren Chris Simpkins Janet Hiller Jennie Rickard Amie Swardson James Burdick Edward Kraus Hamid Rabb Richard Ugarte Brigitte Reeb Mary Jo Holechek Diane Lepley Dorry Segev Tomasz Kazlowski Johns Hopkins InKTP Columbia Lloyd Ratner Johns Hopkins InKTP


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