Transcript Management of sensitized patients in kidney transplantation

Management of
sensitized patients in
kidney transplantation
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
Evolution of HLA Antibody Detection
Cytotoxicity
Enhanced Cytotoxicity
Flow Cytometry
Anti-HLA Antibody
Ly
Ly
Ly
Anti-Human Globulin
Fluorescenated
Anti-Human Globulin
Ly
C1
Ly
Ly
Ly
Membrane Attack
Complex
Membrane Attack
Complex
Dye
Ly
Ly
Dye
Ly
CD19 or
(B cell)
CD3
(T cell)
Flow Cytometer
Bray et al Immunol Res. 29:41, 2004
METHODS FOR ANTIBODY EVALUATION
Antigen Non-Specific
Antigen Specific
Complement-dependent
Cytotoxicity (CDC):
- Direct CDC (Standard CDC)
- Modifications
Washes
Extended Incubation
Anti-human globulin
(AHG-CDC)
DTT / DTE
ELISA
- Yes / No
- PRA % (I & II)
- Specificity (I & II)
Flow Cytometry (cells):
- T cell / B cell
- Pronase
Multi-plex
- Suspension Arrays
- Protein Chips
“FlowPRA”
Flow cytometry using
microparticles (“beads”)
- PRA % (I and II )
- Specificity (I & II)
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
(PRA>10%). ?unreported or unrecognized
pregnancies or transfusions, ?antigenic stimulation
of sperm. ?cross-reacting environmental allergens
Prevalence of Sensitization
•
•
UNOS: 30% of patients on the transplant wait
list have a PRA of > 20%
 New England Organ Bank: 56% with
PRA>50%, 28% with PRA 90-100%.
Accumulation phenomenon: the mean waiting
time for prospective recipients with PRA >
50% is 26.2 months, five times longer than that
for unsensitized recipients with a PRA below
10 percent.
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
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
University of Maryland
Protocol Overview
Anti-CD20
FK 506
MPA
PP/Ig
-10 -9
Steroids
Thymoglobulin
PP/Ig
PP/Ig
-8 -7 -6 -5
PP/Ig
PP/Ig
-4 -3 -2
Tx DSA Testing
-1 0
Time in days
1 2
3
4
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 <5%
Transplantation 2000; 70:1531
Protocol (n = 16)
Contemporaneous (n = 530)
Graft Survival (%)
100
80
60
40
20
0
0
6
12
18
24
Months
30
36
42
48
Mayo Clinic Experience-2006
p < 0.05 IVIG vs. PP groups
AJT 2006, 6:346
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%
Protocols to overcome sensitisation
& blood group incompatibilities

1)
2)
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
Desensitisation for ABOincompatible Tx
 Success
after initial failures attributed to
splenectomy in addition to PP,
azathioprine, ALG and steroids

Ref: Transplant Proc 1987;19: 4538-42
Transplant Proc 1985;17: 138-43
Transplantation 1998;65: 224-8
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
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
Immunomodulation with IVIG:
Desensitization 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 2004;15:3256-62
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
concomittantlyincreasing the risk of graft
loss

Ref: J Am Soc Nephrol 2004;15:3256-62
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 2000;70: 887-95
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
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
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 sucrosecontaining, thrombotic episodes with
hyperosmotic and hemolysis with isoosmolar
products

Ref: Clin J Am Soc Nephrol 2006; 1: 844
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
Conclusions
 High-dose
IVIG/rituximab and PP/lowdose 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
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
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
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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