Update in Kidney Transplantation: New Protocols
Millie Samaniego, MD Associate Professor of Medicine Section of Nephrology University of Wisconsin School of Medicine and Public Health
Enabling Transplantation In Patients With Prolonged Waiting Time: Overcoming HLA Sensitization
HLA Sensitization: Definition
• The HLA-sensitized state is defined by the presence of antibodies against Class I and/or Class II HLA molecules
• HLA-A, HLA-B, HLA-DR, DQ
• HLA sensitization against an individual or multiple donors:
– Positive donor specific crossmatch
Prevalence of HLA Sensitization in Kidney Transplant Candidates
80000 70000 60000
ESRD Patients
Projected
PRAs
50000 40000 30000 20000 10000 0 1997 1998 1999 2006 2010
0-19% 20-79% 80% or above
Improvement in histocompatibility techniques may account for increase in prevalence
HLA SENSITIZATION: A Barrier To Kidney Transplantation
are needed toand this picture. G rap hics decose ea Q uickTim e™ mpresso r 160 0 140 0 120 0 100 0 800 600 400 200 0
Nearly 30% of the 67,070 patients in the deceased donor waiting list are sensitized
Da ys to Kidney Tran spla nt
Preformed anti-HLA antibodies increase the waiting time
Yea r 199 1 199 2 199 3 199 4 Pe ak P RA 0 -19 % Pe ak P RA 2 0-7 9%
TRANSPLANT EVALUATION: Sensitizing Events
• EXPOSURE TO NON-SELF HLA MOLECULES:
– Previous pregnancies – Previous transplants – Previous blood transfusions – Viral Infections or non-infectious immune stimulation
• CMV infection • Vaccination
Histocompatibility Techniques: Role in Risk Assessment
Sensitivity and Specificity
Solid-phase assays Cell-C’ based assays
NIHCrossmatch
AHG-CDC
ELISA
Flow beads
Luminex®
ABO Incompatible Kidney Transplantation
ABO INCOMPATIBILITY
There is a 35% chance that any 2 individuals will be ABO incompatible:
•1/3 of potential live donors are excluded immediately due to ABO incompatibility
Transplantation Across ABO Incompatibility Barriers
Modalities that Enable Transplantation of Sensitized Kidney Candidates
• Transplantation across a positive donor specific crossmatch
• ABO-incompatible transplantation
• Pair kidney exchange program
Suppression of the T-cell Response
• Induction Therapy:
– Depleting Vs Non-depleting antibodies
• Maintenance immunosuppression
Elimination of Preformed Antibody
• Plasma exchange is the most commonly used modality for rapid elimination of preformed antibody • Length and frequency of plasma exchange depend on:
– Antibody titers – Antibody specificity
IVIg: Inhibition of Circulating Antibody and Complement Activation
• Polyclonal immune globulins derived from pooled human plasma of 50,000100,000 or more screened donors. • >90% intact IgG, F (ab’)2 fragments and traces of IgM and IgA.
Rituximab: B-cell Depletion
• Genetically engineered chimeric murine/human monoclonal antibody
– Variable light- and heavychain regions from murine anti-CD20 antibody IDEC2B8 – Human IgGk constant regions
• First monoclonal antibody to be approved by the FDA for treatment of cancer
University of Wisconsin Desensitization Center
Referring Physicians/Nursing Staff UW Transplant Surgery Division UW Transplant Administration UW Transplant Coordinators UW Department of Pathology UW Transplant Histocompatibility Laboratory and Blood Bank UW Transplant Medicine
UW Desensitization Center
Goals:
1) To enable living donor transplantation across an HLA or ABO antibodies 2) To enable transplantation in patients active on the waiting list with high PRA (>50%) and without a living donor
UW Positive Crossmatch Protocol (Living Donor)
• Protocol:
– Pre- and Post-transplant plasmapheresis – Pre- and Post-transplant IVIg (100 mg/Kg) – Tacrolimus (Prograf®) and MPA (Cellcept® /Myfortic®) 2 weeks before transplantation – IV ATG 1.5 mg/kg and IV steroids preoperatively – Maintenance immunosuppression:
• Tacrolimus+MPA+steroids
UW Positive Crossmatch Protocol (Living Donor)
DSA titer on AHG CDC XM
+Luminex, -AHG
Maximum # of pre-transplant treatments
Maximum # of post- transplant treatments
2 +AHG
2
1:1-1:4 1:8-1:16
3 4
2 3
UW Positive Crossmatch Program (Living Donor)
• Results:
– 21/22 patients
• First patient transplanted on 9/2004
– 60% acute antibody mediated rejection rate – 95% graft survival – 100% patient survival – Excellent functional results
UW Highly Sensitized Protocol (Deceased Donor)
• Eligibility criteria:
– Active on the transplant list – PRA ≥50% for ≥3 mos
• Goal:
– Reduction of PRA≥30% and/or transplantation
• Pre-Transplant Protocol:
– “In vitro” IVIg induced inhibition of PRA
IVIg Modulation of Alloimmune Responses: IVIg Inhibits High-PRA Activity In Vitro S JORDAN
100 80
Panel Reactive Antibodies (%)
100 80 60 40 20 0
100 80 60 40 20 0 0 10 20 0 10 20
Patient Sera 1:2 (IVIG)
60 40 20 0 0 10 20
Untreated Patient Sera
Patient Sera 1:2 (Glycine)
UW Highly Sensitized Protocol (Deceased Donor)
• Pre-Transplant Protocol:
– In vitro IVIg induced inhibition of PRA – IVIg (2g/Kg/month x 6) – Rituximab 375 mg/m2 BSA x 2 – Monitoring of PRA Class I and Class II by Luminex® while on treatment
UW ABO Incompatible Program (Living Donor)
• Protocol:
– Pre- and Post-transplant plasmapheresis – Pre- and Post-transplant IVIg (100 mg/Kg) – Tacrolimus (Prograf®) and MPA (Cellcept® /Myfortic®) 2 weeks before transplantation – IV ATG 1.5 mg/kg and IV steroids preoperatively – Maintenance immunosuppression:
• Tacrolimus+MPA+steroids
UW ABO Incompatible Transplant Protocol (Living Donor)
Isoagglutinin titer (anti-ABO Ab) Maximum # of pre-transplant treatments Maximum # of post- transplant treatments
<1:16 1:32 1:64 1:128
2 3 4 6
2 3 3 3
UW ABO Incompatible Program (Living Donor)
• Results:
– Four patients
• First patient transplanted on 12/2004
– No rejection episodes – 100% patient and graft survival – Excellent functional results
Summary
• Approaches to transplant sensitized patients include elimination of antibodies against the transplant or pair-kidney exchange. • Although desensitization protocols carry a high incidence of rejection, AMR in desensitized patients is responsive to therapy. • Until Pair Kidney Exchange Programs are fully developed
Contact Information
Millie Samaniego, MD
ms1@medicine.wisc.edu