Author: Loren Gragert

Updated CPRA Calculation Released to Production

Loren Gragert Uncategorized

On January 26, 2023, an updated metric for HLA antibody sensitization for the US organ allocation system was released by the United Network for Organ Sharing (UNOS). Under a UNOS contract, our laboratory developed the new reference panel for the calculated panel reactive antibody (CPRA) metric using a dataset of over 2 million high resolution HLA genotypes from the National Marrow Donor Program registry. The CPRA metric is used to determine organ allocation points and priority to ensure equity for highly sensitized transplant candidates who have antibodies against HLA. This updated added the DQA1, DPA1, and DPB1 loci and allowed for allele-specific antibodies to contribute to CPRA. This was the result of an excellent collaboration and data sharing between the stem cell transplant and organ transplant fields.

Please see this page for more information.

Implementation notice: CPRA calculation change

 

ABO-adjusted cPRA – Improving Equity in Kidney Transplantation Among Candidate ABO Blood Groups

Loren Gragert Uncategorized

In collaboration with Dr. James Lan at University of British Columbia, we have developed a new metric for immune sensitization that can be applied to improve equity in organ allocation systems, ABO-adjusted calculated panel reactive antibody (cPRA).

Candidates waiting to receive kidneys who have antibodies against HLA are given increased points and priority in organ allocation. Because their pool of compatible donors is smaller, these patients would otherwise not have an equal chance at getting transplanted. The fewer compatible donors, the more points and priority are needed to ensure equity.

Our innovation is applying James’s idea to treat national antibodies against donor ABO blood group in the same way as antibodies against donor HLA.

Patients who are in blood group B and O have decreased access to transplant, and the frequency of B blood group is double in African Americans versus Whites.

Prioritizing transplant candidates with ABO-adjustment combined with policy changes for organ allocation that would allow for more ABO-compatible transplants will expand access and improve equity.

We have developed a web calculator to demonstrate the concept, providing cPRA with and without ABO-adjustment. https://transplanttoolbox.org/abo_hla_cpra/

Please see find our new publication in American Journal of Transplantation.

ASHI2020 Abstract on HLA Antibody Markup Language (HAML) Integration

Loren Gragert Tools

In collaboration with the histocompatibility laboratory at Emory, we are happy to share a technology demonstration connecting their DPB1 Compatibility Tool with the NMDP Calculated Panel Reactive Antibodies (CPRA) calculator developed by our lab.

HLA nomenclature for the DPB1 locus does not include the concept of serology or allele families in the allele name, making compatibility assessments challenging.

For this demo, we use a HLA Antibody Markup Language (HAML) XML format we developed for the 18th International HLA and Immunogenetics Workshop (IHIW) to populate HLA Class II Single Antigen Bead (SAB) panel data in the DPB1 tool. Based on a fixed MFI threshold,  a subset of DPB1 beads can be automatically assigned positive. This tool allows the user to identify patterns of DPB1 hypervariable region amino acid polymorphisms among beads in the panel. The DPB1 tool then passes a list of unacceptable antigens either as two-field alleles and as DPB1 hypervariable regions if assigned. The DPB1 tool interactively refreshes CPRA values in real time using a web services interface the NMDP CPRA calculator.

The main benefit of the tool is that alleles determined to be electronically incompatible can more easily be listed as unacceptable antigens, and their impact on sensitization can be understood immediately.

From this technology demonstration, we can envision a constellation of web tools and microservices could one day accomplish complex tasks by talking to one another using structured electronic messaging formats for histocompatibility data. Our lab and others plan to continue the development of such tools.

Please find our ePoster #69 at the American Society for Histocompatibility and Immunogenetics (ASHI) 2020 conference to watch a 3-minute walkthrough of this effort.

Try out the web tool at http://dpcompat.hlatools.org/

 

ASHI2020 Workshop on Allocation Disparities

Loren Gragert Conferences/Workshops

Dr. Gragert will be discussing “Population Modeling in Histocompatibility and Equity” at the American Society of Histocompatibility and Immunogenetics (ASHI) 2020 Annual Meeting.

The main topics of the talk be modeling HLA antibody sensitization using the new NMDP CPRA metric and impact of points allocated for donor-recipient HLA matching on equity in the organ allocation system.

Dr. Cathi Murphey from Southwest Immunodiagnostics and Dr. John Gill from University of British Columbia will also be presenting during this session, which will be chaired by Dr. Nicole Valenzuela from UCLA and Dr. Robert Bray from Emory.

Stem cell donor HLA typing improves CPRA in kidney allocation

Loren Gragert Publications

We are proud to announce publication of a new research article in American Journal of Transplantation (AJT)!

The paper validates a new approach to measuring antibody sensitization using a HLA typed reference panel of 6.59 million stem cell donors from National Marrow Donor Program (NMDP). The current United Network for Organ Sharing (UNOS) calculator uses 14,282 deceased donors and does not include two-field alleles or the DQA1 and DPB1 loci. 

The figure shows a key result from validation of a NMDP reference panel for calculated panel reactive antibody (CPRA) calculations. We found to our surprise that in the Caucasian population that HLA haplotype frequencies differed dramatically between the NMDP and current UNOS panel.  We were able to recover expected linkage disequilibrium values in the UNOS dataset by recomputing haplotype frequencies (UNOSRE) using Arlequin EM algorithm. By expanding the UNOS reference panel to 11 years of deceased donors, we achieved higher similarity, indicating that most of the remaining differences with the NMDP dataset are due to sampling error.

Based on this proof of concert, the UNOS Histocompatibility Committee is moving forward with this approach for updating the CPRA calculator based on NMDP data to include all classical HLA loci at high resolution. This will help ensure that highly sensitized patients are treated fairly and equitably in the kidney allocation system. Stay tuned for more news on this!

Kransdorf, E.P., Pando, M.J., Stewart, D., Lindblad, K., Bray, R., Murphey, C., Kaur, N., Patel, J.K., Kim, I., Zhang, X., Maiers, M., Kobashigawa, J.A., Gragert, L. Stem cell donor HLA typing improves CPRA in kidney allocation. American Journal of Transplantation (2020).

https://pubmed.ncbi.nlm.nih.gov/32558252/

 

 

Prototype 11-Locus CPRA Calculator based on NMDP HLA Genotype Frequencies

Loren Gragert Tools

We are happy to announce public availability of a new web tool for measuring HLA antibody sensitization, available as part of our TransplantToolbox.

This calculated panel reactive antibody (CPRA) calculator includes all classical HLA loci and supports any combination of unacceptable antigens represented as IMGT/HLA two-field alleles and UNOS antigens.

The reference panel is based on a large HLA-typed cohort of volunteer donors from National Marrow Donor Program (NMDP). 

Please test out our NMDP CPRA calculator here and provide feedback!

https://www.transplanttoolbox.org/nmdp_cpra/

We also provide a web services interface here for programming integration.

https://www.transplanttoolbox.org/nmdp_cpra/services/