Panel-reactive antibody / cPRA and sensitization

Panel-reactive antibody (PRA) and its modern successor, the calculated panel-reactive antibody (cPRA), are measures of a transplant candidate's degree of sensitization, the breadth of the candidate's preformed antibodies against human leukocyte antigens (HLA).[1][2] The cPRA expresses, as a percentage from 0 to 100, the proportion of the donor population that would be expected to be crossmatch-incompatible for a given candidate on the basis of that candidate's unacceptable antigens.[2][3] A higher cPRA means fewer compatible donors, longer expected waiting time, and higher immunologic risk; for this reason cPRA is built into deceased-donor allocation to give additional priority to highly sensitized candidates.[2][3] Sensitization is assessed as part of the immunologic workup described in Human leukocyte antigen (HLA) and tissue typing and is operationalized through the Crossmatch (CDC, flow, virtual).

Sensitization

A candidate becomes sensitized when prior exposure to foreign HLA stimulates production of anti-HLA antibodies. The three classic sensitizing events are pregnancy (exposure to paternal fetal HLA), blood transfusion, and prior transplantation; ventricular assist devices and certain infections or vaccinations can also contribute.[1][2] Sensitized candidates are harder to match because any donor expressing an HLA antigen to which the candidate has antibody risks a positive crossmatch and antibody-mediated injury.[1][4] Broadly sensitized candidates, conventionally those with a cPRA at or above 80 percent (and especially the 98-100 percent group), face markedly reduced access to compatible organs.[2][3]

From PRA to cPRA

The original PRA was a laboratory measurement: a candidate's serum was tested against a panel of cells from many individuals (or, later, against panels of HLA-coated beads), and the PRA was reported as the percentage of the panel that reacted.[1][5] Because the panel composition, the assay, and the threshold varied between laboratories, the same candidate could receive different PRA values at different centers, undermining the consistency and fairness of allocation.[5]

The calculated PRA replaced this measured approach with a computation. The histocompatibility laboratory determines, from solid-phase single-antigen bead testing, which HLA specificities the candidate has antibody against; the transplant program lists these as unacceptable antigens.[2][5] A calculator then uses HLA antigen and haplotype frequencies derived from a large reference donor population to compute the percentage of donors carrying at least one of those unacceptable antigens, that percentage is the cPRA.[2][5] In the United States the UNOS cPRA calculator was built using HLA-A, -B, -C, -DR, -DQ, and -DP frequencies from a reference set of thousands of actual organ donors, making the value reproducible across centers.[2][5]

The cPRA replaced PRA in U.S. kidney allocation on October 1, 2009, with the stated goals of providing consistency and accountability in reporting sensitization, reducing positive crossmatches and futile organ offers at the top of the list, and improving access for broadly sensitized candidates.[5][6]

cPRA in allocation

Because the cPRA is derived from a candidate's unacceptable antigens, it directly enables the virtual crossmatch: a donor whose HLA type includes none of a candidate's unacceptable antigens is predicted to be crossmatch-compatible, and the allocation system can avoid making offers that would fail.[2][7] In U.S. deceased-donor kidney allocation, candidates receive sliding-scale additional allocation points as cPRA rises, with substantial extra priority for the most sensitized (for example, broad regional or national sharing for candidates at 98, 99, and 100 percent cPRA), specifically to counteract their reduced compatible-donor pool.[3][6] These features have measurably increased transplant rates among highly sensitized candidates since their introduction.[6]

Reducing sensitization and transplanting across it

Several strategies address sensitization rather than waiting for a compatible donor.[4][8]

• Kidney paired donation (paired exchange): an incompatible living donor-recipient pair is matched with one or more other incompatible pairs so each recipient receives a compatible living-donor kidney, which is often the most effective option for a sensitized candidate with a willing but incompatible donor.[8]
• Desensitization: protocols using plasmapheresis, intravenous immunoglobulin (IVIG), and B-cell- or plasma-cell-directed agents (for example, rituximab; in selected programs proteasome inhibitors or complement inhibitors) can lower antibody levels enough to permit transplantation across a positive crossmatch, at the cost of higher antibody-mediated rejection risk and intensive monitoring.[4][8]
• Avoidance through the virtual crossmatch: for many sensitized candidates the most durable solution is accurate unacceptable-antigen listing so the system finds a genuinely compatible donor.[7]

Interpretation and limitations

The cPRA is only as accurate as the unacceptable-antigen list that generates it. Assigning unacceptable antigens involves judgment about which antibody specificities, and at what mean fluorescence intensity threshold on bead assays, are clinically meaningful; listing too many antigens needlessly inflates cPRA and restricts access, while listing too few risks a positive crossmatch.[1][2] Single-antigen bead assays are also subject to technical artifacts (for example, denatured antigen reactivity and the prozone/inhibition effect). For these reasons, antibody assignment and cPRA management are histocompatibility-laboratory and transplant-team decisions, individualized to the candidate.[1][2]

See also

• Human leukocyte antigen (HLA) and tissue typing
• Crossmatch (CDC, flow, virtual)
• Donor-specific antibodies (DSA)
• Transplant rejection
• ABO compatibility and ABO-incompatible transplantation

References

• Justiz Vargas AN, et al. Transplantation Immunology. StatPearls. NBK538218. https://www.ncbi.nlm.nih.gov/books/NBK538218/
• Tambur AR, et al. Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report. Am J Transplant. 2018;18(7):1604-1614. PMID:29603851. https://pubmed.ncbi.nlm.nih.gov/29603851/
• OPTN. Kidney allocation policy (CPRA and priority for sensitized candidates). https://optn.transplant.hrsa.gov/policies-bylaws/policies/
• Acute Transplantation Rejection. StatPearls. NBK535410. https://www.ncbi.nlm.nih.gov/books/NBK535410/
• Cecka JM. Calculated PRA (CPRA): the new measure of sensitization for transplant candidates. Am J Transplant. 2010;10(1):26-29. PMID:20420648. https://pubmed.ncbi.nlm.nih.gov/20420648/
• Cecka JM, Kucheryavaya AY, Reinsmoen NL, Leffell MS. Calculated PRA: initial results show benefits for sensitized patients and a reduction in positive crossmatches. Am J Transplant. 2011;11(4):719-724. PMID:21443677. https://pubmed.ncbi.nlm.nih.gov/21443677/
• Tambur AR, et al. Assessing antibody strength: comparison of MFI, C1q, and titer information. Am J Transplant. 2015;15(9):2421-2430. PMID:25930984.
• Montgomery RA, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med. 2011;365(4):318-326. PMID:21793744. https://pubmed.ncbi.nlm.nih.gov/21793744/