Update in Kidney Transplantation-New Protocols

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 a picture. Graphics decompressor QuickTime™ see this 1600 1400 1200 1000 800 600 400 200 0 Year 1991 Peak PRA 0-19% Peak PRA 20-79% 1992 1993 1994 Nearly 30% of the 67,070 patients in the deceased donor waiting list are sensitized Days to Kidney Transplant Preformed anti-HLA antibodies increase the waiting time 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

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