Effective Treatment of Antibody-Mediated Rejection and Abrogation by rt3463df

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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., D.Phil.
               Chief, Division of Transplantation
Director, The Johns Hopkins Comprehensive Transplant Center
                 The Johns Hopkins Hospital
    Diagnostic Criteria for Acute AMR

    •Characteristic histologic features including:
Grade 1   1) glomerulitis/capillaritis
          2) margination of neutrophils in the PTC
          3) fibrin thrombi
          4) interstitial hemorrhage
Grade 3   5) severe or necrotizing vasculitis

    •Diffuse, linear C4d staining in the PTC

    •Identification of DSA
  Patterns of Rejection in
ABO Incompatible Transplants
 AMR       Cellular   Accommodation
    Therapeutic Options For The
         Treatment Of AMR
Antibody Reduction   Immunomodulation
•Plasmapheresis/IA    •IVIg

•IVIg                 •ATG

B-cell Modulation     •IL-2R blockers

•Splenectomy          •Fk 506, Rapamycin

•Anti-CD20            •MMF/DSG

•Cytoxan              •CAMPATH?
     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
     Antibody Reduction Therapy
•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
               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
             Case Study: AMR in (+) Cytotoxic XM with
                     High Titer Anti-HLA DSA
                 512                                                  Cr 6.5                                    DSA titer
                                                                                                                                PP/ CMVIg
                                                                                                                PRA
                         128                                                                                                                     100

                 100100                                                        100          Cr 4.4
       120                                      98
                                                                                                                                                 90

                                                                                                                              Cr 2.1
                                                                               Cr 1.5                                                    Cr 1.680
       100
                                                                          85
DSA titer




                                                                                                                                                 70




                                                                                                                                                       PRA
            80
                                                                                                                                                 60


                               64                                                                                                           58
                                                                                                                                                 50
            60

                                                                                                                             CD20=0
                                                                           CD20=23.7            Anti-CD20                    CD19=0
                                                                                                                                                 40


            40                                                                                                                                   30
                                    32    32
                                                                          Tx                                                                     20
            20                                  16                                         16       16 16 16
                                                     8       8 8                     8 8        8                                                10
                                                         4         4 4 2 4     4                                 2 2 1           1      1
             0                                                                                                                              0    0
                   -19     -17      -15   -12   -8 -7 -6 -5 -4 -3 -2 -1   0    +2 +3 +4 +5 +6 +7 +8 +9         +11 +12 +13      +16    +18 +19

                                                             Days from Transplant
               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
The Effect of Splenectomy on Anti-Blood Group Ab
                                                                                                                                                    PP/IVIg

                       512
                       256

                                                                                                                                                4
                                                      Splenectomy
 Anti-A Titers (1:X)




                                                                                                                                                     Serum Creatinine
                                                                                                                                                3




                                                                                                                                                         (mg/dL)
                       128

                                                                                  Tx                                                            2



                       64

                                                                                                                                                1
                       32
                       16
                        0
                             -28 -23 -21 -18 -16-15 -14 -12 -10 -6   -4   -3 -2   -1   0 3   5   7   8 10 12 14 17 21 25 27 31 32 34 40 42 45
                                                                            Day With Respect to Transplant
Targets of Strategies for Antibody Removal


                                      Plasmapheresis/IVIG
                       Plasma cells
                                             Splenectomy
Clonal Expansion
                   B-cells &               Anti-CD20
                   Pre B-cells
         Acute De Novo AMR
•Occurs in 4-6% of transplants (80-100% fail)
•By definition the current XM is negative
•Risk factors include: + historic XM,
history of sensitizing event(s), high risk
donor/recipient combination
•Historically suspected only after there is a poor
response to anti-lymphocytic agents
•Diagnosis should be made by histology and
demonstration of the appearance of DSA
       PP/CMVIg Treatment Protocol
         for Acute De Novo AMR
                           Plasmapheresis – single plasma volume exchange
    Steroid bolus
        -OR-               IVIG – 100mg/kg following each PP treatment
a-thymocyte globulin              (CMV hyperimmune globulin)

       PP/Ig               PP/Ig       PP/Ig          PP/Ig     PP/Ig




       Dx of                2            4              6        8
       AMR
                       Time Relative to Initiation of Therapy
                                      (Days)
              Heparin
High Grade:
              D/C FK 506
De Novo AMR: Renal Allograft Function
                     15                          * p<0.001



                             *               *       *         1994-2003: 22 recipients
                     10
                                                               of deceased or live donor
  Serum Creatinine                                             kidney transplants
      (mg/dL)        5
                                                               with AMR by Bx or DSA
                                                               treated with PP/IVIg
                     0

                                 Nadir             Rejection
                                 1 Week            1 Month
                                 Current
                                                                Mean f/u: 5 1/2 years


    Median                 Median           Median               Median       Median
    Nadir Cr              Cr at AMR        1 week Cr           1 month Cr    Current Cr
     (IQR)                  (IQR)            (IQR)                (IQR)        (IQR)
      3.3                    6.4                4                 1.9           1.5
   (2.2 – 7.1)            (3.2 – 9.3)      (2.3 – 7.9)         (1.5 – 3.0)   (1.2 – 2.1)
PP/CMVIg Treatment for De Novo AMR

 100
  90
 80
                                                             Allograft Survival
 70
 60
                                            p = NS
                                                                    Live    Deceased
 50
                                          p = NS
 40
 30
                                                            1-Year: 87.5%    85.8%
 20
 10
                                                            3-Year: 87.5%    77.1%
       0    365                    730               1095
                   Time (days)
           Live donor
           Live donor            Deceased donor
                                 Deceased donor
                                                            5-Year: Overall 81.1%


Kaplan-Meier Estimate of Graft Survival for recipients who
developed de novo AMR and were treated with PP/CMVIg therapy
Bx and DSA Proven De Novo AMR

                        LD       DD       p
                    n    5       13
   Median Days to AMR    11        9     0.25
              (Range) (8-253)   (7-50)
    Median Months F/U 13.6       11.2    0.77
              (Range) (4-76)    (3-89)
De Novo Renal Function

             15       12
Serum Creatinine (mg/dL)
3      6     0 9




                                      LD                                  DD
                                      Creatinine at Biopsy          Creatinine 1 week
                                      Creatinine 1 mo               Current Cr




                           P=NS for comparison between groups at each timepoint
De Novo AMR Allograft Survival

             100.00
              90.00
              80.00
              70.00
              60.00
  Survival
    (%)       50.00
              40.00
              30.00
              20.00
              10.00
               0.00
                      0   6   12         18         24        30   36
                                   Time (Months)

                              Live                 Deceased
Rejection and Clinical Outcomes Following
             (+) XM and ABOi
       POSITIVE CROSSMATCH                   ABO INCOMPATIBLE


      # OF PATIENTS       86             # OF PATIENTS          28

                    1      31                            1       4
    Previous Txs    2      12           Previous Txs     2       1
                    3       5                            3       0
          AMR         27/86 (31%)            AMR             3/28 (11%)
   CELLULAR REJECTION 26/86 (30%)     CELLULAR REJECTION     4/28 (14%)

    SUBCLINICAL AMR    7/86 (8%)*       SUBCLINICAL AMR    0/28 (0%)
  SUBCLINICAL CELLULAR 16/86 (19%)    SUBCLINICAL CELLULAR 7/28 (25%)

  1-YEAR GRAFT SURVIVAL   89.8%      1-YEAR GRAFT SURVIVAL    92.9%**
  3-YEAR GRAFT SURVIVAL   80.9%      3-YEAR GRAFT SURVIVAL    92.9%

 *Bx @ 1, 3, 6, 12 mos               **1 death WNE
                                      1 Noncompliance
      (+) XM vs. De Novo AMR

                     De Novo   Desensitized    p
                n      18          31
Median Days to AMR      10          20        0.16
           (Range)   (7-253)     (2-634)
 Median Months F/U     12.4        14.1       0.76
           (Range)    (3-89)     (0.6-65)
(+) XM vs. De Novo AMR Outcomes
                                                                  P=0.04




                  15
                                                         P=0.01
                                             P=0.002
      Serum Creatinine (mg/dL)
    3      6      09      12




                                 PP/CMVIg Desensitized                     De Novo Rejection
                                          Creatinine at Biopsy                Creatinine 1 week
                                          Creatinine 1 mo                     Current Cr




                                        P=NS between groups at current timepoint
Allograft Survival After AMR (+) XM
            vs. De Novo
              100.00
               90.00
               80.00
               70.00
               60.00                                         p=NS
   Survival    50.00
     (%)
               40.00
               30.00
               20.00
               10.00
                0.00
                       0   6   12         18        24            30   36
                                    Time (Months)

                               (+) XM                    DeNovo
      Kaplan-Meier Estimate of Graft Survival
      (+) CDC XM @ Time of Tx vs (-) CDC XM



                                                                              1 Year
          100
           90


                                                                           Graft Survival
           80
           70
           60
                                                                p=NS
% Allograft 50
 Survival                                                                 +XM @ Tx - XM @ Tx
            40
           30                                                              N= 14      N= 32
           20
           10                                                              92.3%     87.2%
                 0   30   60   90   120 150 180 210 240 270 300 330 360
                                          Time (Days)
                                     + XM @ Tx          - XM @ Tx
      Anti-CD20 Rescue Protocol
Inclusion Characteristics
•Failure to Respond to Plasmapheresis/CMVIg Therapy
      •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)
•Study Group
      •Recipients of Deceased or Live Donor Kidneys
      •De novo AMR
      •AMR After Desensitization
Renal Function Following Anti-CD20 Rescue
  10
              p=0.0003                   p=0.01
                                    p=0.07
   9
   8                           p=0.25
   7
   6                                                                 17 recipients
   5
                                                                     undergoing a-CD20
   4
   3                                                                 rescue therapy
   2                                                                 for AMR
   1
   0

         Best            AMR     2 weeks 1 Month Current
                           Best Cr              AMR Cr
                           2 week Cr            1 month Cr
                           Current Cr


       Best                AMR                2 weeks         1 month       Current
       1.8               4.3                     3.4             2.1           1.7
   (1.4 – 2.1)       (2.5 – 6.5)             (1.9 – 5.4)     (1.6 – 3.3)   (1.1 – 2.6)
           Kaplan-Meier Estimate of Graft
           Survival for Anti-CD20 Rescue
             100



             75

   %
Survival     50



             25




                   0   1   2    3    4    5    6    7    8    9       10   11   12
                               Months Following Anti-CD20 Treatment
   Splenectomy Rescue
                                            N         4

                        Median Days to AMR            4
                                   (Range)         (2-15)
Median Days to Splenectomy Following AMR Dx           1
                                     (Range)        (1-4)
                     Median SCr at Biopsy Dx         3.4
                                     (Range)     (1.5 – 6.0)
                          Median SCr 1 week          2.1
                                    (Range)      (0.8 – 5.8)
                         Median SCr 1 month          1.5
                                    (Range)      (0.7 – 2.3)
                         Median Current SCr          1.3
                                   (Range)       (1.2 – 2.6)
                            Allograft Survival     100%

                     Median Months Followup          6.9
                                    (Range)      (2.2 – 11.7)
Paired Donation May Reduce the Incidence of AMR
   Conventional KPD             Unconventional KPD
   A         B ABOi                A         O ABOi
   B         A ABOi               O          A (+) XM


    # of KPD: 6 (12 patients)   # of KPD: 5 (13 patients)

    Mean PRA: 14                Mean PRA: 58

    6 mos Cr: 1.2 mg/dl         6 mos Cr: 1.1 mg/dl
    AMR: 0% Cellular 8%         AMR: 0%     Cellular 23%
    Patient Survival: 100%      Patient Survival: 100%
    Graft Survival: 91.7%       Graft Survival: 100%
                               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
     Algorithm For Approach To AMR

 De Novo AMR       AMR after (+) XM    AMR after ABOi




                          PP/IVIg


     Severe AMR           Response    Incomplete Response




Anti-CD20   Splenectomy    Observe        Anti-CD20
              Acknowledgements
Johns Hopkins InKTP     Johns Hopkins InKTP
  Matt Cooper              Janet Hiller
  Lorraine Racusen         Jennie Rickard
  Mark Haas                Amie Swardson
  Karen King               James Burdick
  Andrea Zachary           Edward Kraus
  Susie Lefell             Hamid Rabb
                           Richard Ugarte
  Donna Lucas
                           Brigitte Reeb
  Julie Graziani
                           Mary Jo Holechek
  Renato Vega
                           Diane Lepley
  Chris Sonnenday          Dorry Segev
  Dan Warren               Tomasz Kazlowski
  Chris Simpkins


                           Columbia
                            Lloyd Ratner

								
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