VIRTUAL PRA AND CROSSMATCHING Dolly B. Tyan, PhD Cedars-Sinai Medical Center Los Angeles, CA Dolly B. Tyan, PhD UNOS Strategic Planning 10/05

PURPOSE OF PRA TO INFORM THE CLINICIAN/SURGEON OF THE: LIKELIHOOD OF A TRANSPLANT ANTIBODY SPECIFICITY

PRA Panel Reactive Antibody – (%) Relatively uninformative No specificity Population dependent Can vary widely by panel tested

PRA VARIABILITY 50 cell panel A2+ CELLS ON PANEL PRA (%) 5 10 20 25 50

PRA ANALYSIS BY DIFFERING METHODLOGIES POSITIVE NEGATIVE CDC 102 162 AHG-CDC 116 (+13%) 148 ELISA 127 (+10%) 137 FLOW 139 (+10%) 125 Gebel and Bray, Transplantation 69:1370-1374, 2000.

Virtual PRA Calculated PRA value Based on: ABSOLUTE antibody specificity and ACTUAL HLA antigen frequencies in donor population INDEPENDENT of the method Virtual PRA Dolly B. Tyan, PhD UNOS Strategic Planning 10/05

of all donors ever typed NATIONAL PRA Calculate the antigen frequency of all donors ever typed in UNET database

CALCULATED PRA – STANDARDIZED Antibody Specificity PRA (%) A1 21 B8 17 A1 + B8 28 DR3 24 A1 + B8 + DR3 45

Conclusions Results in National PRA Equivalence Virtual PRA antibody detection must: Be Sensitive and HLA-Specific Be able to Predict the final crossmatch Be able to identify ALL unacceptable (avoid) antigens (A-, B-, Cw, DRB1, DQB1, DP??) Requires accurate typing of deceased donors Incorporate Both Class I and Class II specificities Current definition of PRA must change: Need local/national donor pool antigen frequencies Incorporate both Class I and II antigens Results in National PRA Equivalence

PURPOSE OF CROSSMATCH TO INFORM THE CLINICIAN/SURGEON OF THE RISK* FOR: PRESENCE OF DSA (DONOR SPECIFIC ANTIBODIES) HYPERACUTE REJECTION HUMORAL REJECTION * (not contraindication)

CAN WE DO A VIRTUAL CROSSMATCH??? WE ARE DOING IT NOW! (BUT NOT WELL…)

WHAT IS A VIRTUAL CROSSMATCH? Recipient antibodies fully characterized, known, and computerized (i.e., UNOS “unacceptable/avoid” algorithm) Recipients with antibody to donor antigens are eliminated without crossmatch parameters for which antibodies important determined at local level Not a substitute for final crossmatch for remaining potential recipients

FINAL XM WORKLOAD CURRENT PRACTICE Regional trays by ABO blood group (First phase XMs – 100s of samples) Final XMs Negative patients from first phase with highest number of points (may be up to 25) Highly sensitized patients often positive in final XM done by more sensitive technique (e.g., Flow) – i.e., wasted effort

CALCULATED PRA – STANDARDIZED Antibody Specificity PRA (%) A1 21 B8 17 A1 + B8 28 DR3 24 A1 + B8 + DR3 45

VIRTUAL XM PROPOSED PRACTICE No first phase testing Final XMs Incompatible recipients excluded by computer Select top 5 – 10 patients on match run for final XM Highly sensitized patients likely to be transplanted

Crossmatch Comparison First phase XMs 3-4 hrs Final XMs – >25 Repeat CDC Flow Highly sensitized patients eliminated at final – wasted effort First phase XMs 3-4 hrs Final XMs - 5 Repeat CDC Flow Highly sensitized patients transplanted

VIRTUAL CROSSMATCH CHALLENGES Requires complete and accurate knowledge of historical and current antibody specificity/isotype by most sensitive methods Requires real time updating of “unacceptables” in UNET Requires regular screening (not less than quarterly) – More for desensitization protocols

VIRTUAL CROSSMATCH CHALLENGES cont’d Antibody profiles can change over time (e.g., become weaker) Desensitization protocols can cause real time variation in antibody profile May eliminate an eligible recipient depending on local preference (e.g., patient with antibody to 50% of the A2+ cells on panel)

Accelerates organ placement VIRTUAL CROSSMATCH BENEFITS Decreases number of patients needing actual final crossmatch (No regional screen trays) Decreases time required for final crossmatching Minimizes wasted time crossmatching highly sensitized patients with known incompatibilities Decrease in CIT in some regions Accelerates organ placement

CONCLUSIONS VIRTUAL PRA Results in National PRA Equivalence VIRTUAL CROSSMATCH Accelerates organ placement

CAVEAT A variant system is required for patients undergoing desensitization Dolly B. Tyan, PhD UNOS Strategic Planning 10/05