Management of sensitized patients in kidney transplantation

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• Management of sensitized patients in
  kidney transplantation

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Introduction

• Between 5-10 of patients waiting for a renal
  transplant are classified as highly sensitised
  (Panel Reactive Activity 85 IgG)
• Highly sensitised renal dialysis patients wait
  longer for a suitable crossmatch negative donor
  compared to non-sensitised patients
• Identification of acceptable HLA mismatches
  increases the likelihood of transplantation

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Evolution of HLA Antibody Detection
Cytotoxicity Enhanced
Cytotoxicity Flow Cytometry
Bray et al Immunol Res. 2941, 2004
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METHODS FOR ANTIBODY EVALUATION
Complement-dependent Cytotoxicity (CDC) -
Direct CDC (Standard CDC) -
Modifications Washes Extended Incubation
Anti-human globulin (AHG-CDC) DTT /
DTE Flow Cytometry (cells) - T cell / B
cell - Pronase
ELISA - Yes / No - PRA (I II)
- Specificity (I II) FlowPRA Flow
cytometry using microparticles (beads) -
PRA (I and II ) - Specificity (I
II) Multi-plex - Suspension Arrays -
Protein Chips
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Sources of HLA Sensitization

• Blood transfusion
• Prior transplantation
• Pregnancy
• Others? Among patients receiving their first
  kidney transplant with no known history of blood
  transfusions, approximately 20 of nulliparous
  women and 13 of men were sensitized (PRAgt10).
  ?unreported or unrecognized pregnancies or
  transfusions, ?antigenic stimulation of sperm.
  ?cross-reacting environmental allergens

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Prevalence of Sensitization

• UNOS 30 of patients on the transplant wait list
  have a PRA of gt 20
• New England Organ Bank 56 with PRAgt50, 28
  with PRA 90-100.
• Accumulation phenomenon the mean waiting time
  for prospective recipients with PRA gt 50 is 26.2
  months, five times longer than that for
  unsensitized recipients with a PRA below 10
  percent.

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Why Believe Desensitization Should Succeed?

• Two cases for cadaver transplant
• - Two recipients with known marked sensitization
  presented for transplants two samples for cross
  matching drawn approximately one week apart
  first positive AHG cross match, second negative
• - Transplants done successfully with 10 day T
  cell depletion with OKT3
• Hypothesis with newer anti-T cell depleting
  agents, perhaps Ab depletion will work since only
  need to be cross match negative currently, even
  for just one day

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Pros and Cons of PP/IVIG

• Advantages
• High efficacy
• Somewhat predictable response
• Monitoring DSA possible
• Double-incompatibility possible

• Disadvantages
• Expensive
• Labor intensive
• Only for LD
• Rebound possible
• Adverse effects

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University of Maryland Protocol Overview
Anti-CD20
FK 506 MPA
Steroids Thymoglobulin
Tx
DSA Testing
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
0
1
2
3
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
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Time in days
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UMM Protocol

• Immunosuppression
• MMF 2 g/d, started 3 days prior to 1st PP
• FK506 started on 1st day of PP, target level 15
  ng/ml
• Prednisone 0.25 mg/kg BID with FK506
• Induction with OKT3, 5 mg/d x 10 days with target
  CD3 lt5

Transplantation 2000 701531
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(No Transcript)
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Mayo Clinic Experience-2006
p lt 0.05 IVIG vs. PP groups
AJT 2006, 6346
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Present scenario

• Demand for donor kidneys continues to outpace
  supply
• A ve crossmatch (CMX) indicates presence of DSA
  in the recipient
• Associated with graft-loss in excess of 80

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Protocols to overcome sensitisation blood group
incompatibilities

• 2 regimes
• low-dose IVIG with PP used in live donor
  ABO-incompatible and CMX Tx
• High-dose IVIG in live CMX Tx for highly
  sensitised pts. on deceased donor list

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Desensitisation for ABO-incompatible Tx

• Success after initial failures attributed to
  splenectomy in addition to PP, azathioprine, ALG
  and steroids
• Ref Transplant Proc 198719 4538-42
• Transplant Proc 198517 138-43
• Transplantation 199865 224-8

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Medical splenectomy

• Anti-CD 20 monoclonal antibody now allows
  splenectomy-free protocols
• John Hopkins standard PP/IVIG desensitisation
  protocol plus single-dose anti-CD 20 monoclonal
  antibody on the final pre-transplant day
• Ref Am J Transplant 2004 4 1315-22
• Transplantation 2003 76 730-1

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New more powerful maintenance immunosuppression

• Therapies with B-cell anti-proliferatives
• e.g. MMF. Excellent results now possible without
  B-cell ablative therapies after ABOi
  transplantations
• Ref Am J Transplant 2004 4 561-8
• At Cedars-Sinai employs Rituximab 1 g for 1
  week prior to PP, PP every other day 5 times
  followed by high-dose IVIG

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Immunomodulation with IVIGDesensitization of
highly HLA-sensitized pts.

• Results in reduced allosensitisation
• Reduced ischemia-reperfusion injuries
• Fewer acute rejection episodes
• Higher successful longterm outcomes
• Reductions in anti-HLA antibodies
• Effective in treatment of allograft rejections
• Ref J Am Soc Nephrol 2004153256-62

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NIH IGO 2 Study

• Multi-center, controlled, double blind
• IVIG vs placebo in highly sensitized pts.
• IVIG was superior to placeboin reducing anti-HLA
  antibody levels (p 0.004) and improving rates
  of transplantation without concomittantlyincreasin
  g the risk of graft loss
• Ref J Am Soc Nephrol 2004153256-62

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Low dose IVIG (100 mg/kg) and PP

• Alternative to high-dose IVIG (2 g/kg)
• Limited to live donor tranplantation
• PP removes circulatingDSA while IVIG inhibits the
  function of residual DSA and limits the
  production of alloantibody
• Starting immunosuppression with tacrolimus and
  MMF. Induction on day of transplant with
  daclizumab and steroid bolus
• Ref Transplantation 200070 887-95

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The Mayo Clinic protocol

• Single pre-transplant dose of anti-CD20
• Inclusion of splenectomy
• Use of rabbit anti-human T-cell polyclonal
  antibody (Thymoglobulin) instead of daclizumab
• Suggest more aggressive induction with T-cell
  depleting agents provides better control of
  T-cell alloreactivity
• Ref Am J Transplant 2003 3 1017-23

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IVIG /- Rituximab for desensitization

• For those who do not respond to IVIG alone or
• Who have high-titer anti-HLA antibodies
• IVIG (2 g/kg) followed by 2 weeklydoses of
  Rituximab (1 g). Another IVIG (2 g/kg) dose given
  I week after final Rituximab dose
• Reduces desensitization time from 16 to 4-5 weeks
  reduced costs improved outcomes
• Ref N Engl J Med 2008 359 242-51

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Complication of IVIG therapy

• Highly sensitisedexcipient content patients
  require higher doses of IVIG (1-2 g/kg/dose)
• Higher rates of infusion related complications
• Adverse events could be related to differences in
  various IVIG products
• Some common effects ARF with sucrose-containing,
  thrombotic episodes with hyperosmotic and
  hemolysis with isoosmolar products
• Ref Clin J Am Soc Nephrol 2006 1 844

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Adjunctive therapy

• Splenectomy
• ABOi and CMX renal transplantation is
  associated with a higher rate of AMR
• Accompanied by sudden onset of oliguria or anuria
• These grafts successfully rescued by immediate
  slenectomy and reinitiation of PP/IVIG
• Ref Transplantation 2007 83 99 -100

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Conclusions

• High-dose IVIG/rituximab and PP/low-dose IVIG
  desensitization in highly sensitized pts. are
  safe and viable alternatives to prolonged periods
  of dialysis while awaiting compatible donor organ
• IVIG is critical to all the protocols

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Conclusions contd.

• Desensitization protocols in living donor
  transplantation
• - Accelerate transplantation relative to deceased
  donor wait listing
• - Results approximately equal to ECD DD
  transplants at 5 years
• - Unpredictable rejection most common
  complication
• - Infectious complications remarkably rare
• - Plasmapheresis carries risk in patients with
  cardiovascular disease

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Conclusions contd.

• High Risk Scenarios
• Donor specific antibody (DSA) as consequence of
  renal rejection (versus transfusion)
  particularly early AMR
• Repeat HLA-Ag mismatch in setting of DSA to
  repeat mismatch
• Prior early AMR

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Future Studies

• Clearer epidemiologic data on non-pathologic
  beneficial re-appearance of DSA
• - Is all DSA harmful but with varying pace of
  pathologic injury?
• - Is accommodation present in humans?
• Prospective, multi-center trial with protocol
  biopsy to 5-8 years could answer question
  regarding pathogenic versus beneficial effect of
  DSA re-appearance

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• THANK YOU !