Learn more about CPRA
What is PRA?
PRA stands for Panel Reactive Antibodies. In order to determine whether or not a patient already has any specific HLA antibodies, a lab specialist will test a patient's blood (serum) against lymphocytes (white blood cells) obtained from a panel of about 100 blood donors. These 100 donors represent the potential HLA makeup for a donor from that area. Percent PRA (%PRA) is the number of reactions within that panel. If a candidate's serum does not react with any of the donor samples, the candidate is not sensitized and has a PRA of 0. If a candidate's serum reacts in 80 out of 100 samples, the patient has a PRA of 80%. Theoretically, that means that if a donor becomes available from that donor pool, the recipient would experience acute rejection 8 out of 10 times. That patient might have to wait a very long time until a compatible donor becomes available. This is why the kidney allocation algorithm gives patients with a PRA of 80% or higher, 4 additional points.
Why do we need to refine PRA?
There's a problem with PRA. We might know that a patient will have a reaction 80% of the time, but we don't know what they are reacting to. However, technology has advanced to the point that in most cases the specificity of an antibody produced by a patient can be identified. For example, a patient could develop antibodies to A2 and A24. In this case A2 and A24 may be considered unacceptable antigens (mismatches) for this patient. If the patient were transplanted with a kidney that had A2 and/or A24, it could be rejected hyperacutely. Transplant centers enter these unacceptable antigens for their candidates. That way a potential donor with the unacceptable antigen will not even be considered for that candidate. Entering unacceptable antigens for candidates increases the efficiency of organ allocation by screening off incompatible donors.
What is CPRA?
We also know the number of times A2 and A24 appear in our national donor pool. This means we can calculate the likelihood that the recipient and donor would be incompatible. This would be known as the CPRA or the Calculated Panel Reactive Antibodies. The system will calculate the CPRA using the unacceptable values that have been entered for a candidate. To determine the CPRA value, the computer system will use an established formula and HLA frequencies derived from the HLA types found in more than 12,000 donors.
When a transplant coordinator enters the unacceptable antigens for a patient, the CPRA calculator automatically calculates the CPRA value. Whenever a transplant coordinator updates a patient's unacceptable antigens, the system will automatically recalculate the value. Candidates with a CPRA value of 80% or higher will receive points in the kidney allocation formula.
Antibody: A protein molecule produced by the immune system in response to a foreign body, such as virus or a transplanted organ.
HLA stands for Human Leukocyte Antigen. HLA antigens are substances, usually a protein, found on the surface of our cells that stimulate the production of antibodies. These antigens are referred to with a letter and a number such as A2 or B23.
Each person's HLA make-up is unique. You inherit it from your parents. If something foreign is introduced into your body, your immune system recognizes the foreign intruder and mounts an antibody attack against it. In the case of an organ transplant, the body will recognize the HLA antigens on the transplanted organ as not being the same as its own, and form specific antibodies against those particular HLA antigens.
HLA is important in organ transplantation for two main reasons:
First, a body may reject any transplanted organ (eg, kidney, pancreas, heart, lung, liver, and intestine) because the recipient's immune system recognizes the organ as foreign and initiates a rejection response (this can be in the form of antibody production) which could eventually destroy the organ. Patients receive anti-rejection drugs after a transplant to prevent antibodies from forming.
Second, because of previous medical events, some patients have already developed antibodies to specific HLA antigens. For example, if a candidate has developed a specific antibody to the HLA antigen A2, that person is said to be "sensitized" to the A2 antigen. If a donor organ that displayed the A2 antigen were placed in that candidate, there may be an immediate rejection response (a hyperacute response) which would lead to the rejection of the transplanted organ.
Now for the good news.
It is not easy to become sensitized to human HLA antigens. Most people waiting for a transplant (around 80%) are not sensitized. Patients can become sensitized to HLA antigens because of:
- Pregnancies. About 30-50% of women with three or more pregnancies will develop HLA antibodies. In some women the antibodies could be present for just a short time (weeks to months), while in others they may persist for many years.
- Blood transfusions. About 50% of patients who receive multiple transfusions will develop antibodies. Today, most patients who require blood transfusions receive filtered blood, which decreases the chances for a patient to become sensitized.
- Previous transplant. About 90% of patients develop HLA antibodies within two weeks of a failed graft. However, by the time the patient is relisted (some will have "lost" their antibodies.
- Viral/bacterial infections. There are some reports that patients with virus infections develop HLA antibodies, although this is relatively rare.
Patients with preformed antibodies against donor HLA antigens may experience hyperacute or accelerated acute antibody-mediated rejection. You can determine the presence of HLA specific antibodies by testing patient sera against cells from a panel of HLA typed donors or against solubilized HLA antigens attached to solid supports. The results have historically been used to estimate the panel reactive antibodies (PRA) or percentage of likely cross-match incompatible donors. Nearly a third of the OPTN renal transplant wait list is sensitized patients with a PRA of 10% or more. These candidates wait significantly longer than non-sensitized patients do and once transplanted suffer a greater risk of graft loss from rejection. Recognizing these disadvantages, the current renal allocation system awards sensitized patients with PRAs > 80 an additional 4 points to increase their access to potentially compatible donors. The Histocompatibility Committee began examining the PRA listing practices in 2004 in response to concern raised by the Kidney and Pancreas Transplantation Committee over the variability of PRA results. The committee identified several problems with the existing system, which include both the definition of PRA and the way professionals apply it.
Using current methods, the degree of sensitization represented by PRA is highly variable and inconsistent. The value of PRA depends both upon the panel composition and the technique used for antibody detection. The composition of the antigen panel varies considerably with the use of different commercially available kits or locally procured cell panels which often do not represent the potential donor population. Additional variability arises from the use of tests with differing sensitivity in detecting HLA antibodies. Depending upon the assay method, the amount of antibody detected also can vary significantly. Detection methods range from the relatively insensitive complement dependent cytotoxicity tests to highly sensitive solid phase immunoassays. Because of these variables, PRA does not provide a realistic measure of how difficult it will be to find a compatible donor. PRA is also not a consistent means for comparing the relative degrees of sensitization among patients on the renal wait list.
Applying PRA in Allocation
There are several problems with the application of PRA in renal allocation. The cutoff value for PRA points is arbitrarily set at 80, but patients with lower levels of sensitization who are also disadvantaged receive no extra allocation benefit . Moreover, centers can choose to use either a peak or current PRA to determine whether the patient is eligible for extra PRA points. As of 12/31/04, among the 64,335 kidney registrations on the wait list, 44.3% of transplant centers use the current PRA to determine PRA points, while 55.7% use the peak serum PRA (1). Using assays with different levels of sensitivity to detect antibodies also contributes to the wide range in the proportion of highly sensitized patients among transplant centers. The Histocompatibility committee determined that 10% of centers (25/ 249) had a high proportion of their wait list composed of candidates with PRAs >80. These proportions ranged from nearly twice to 4.2 times the national proportion of highly sensitized candidates, which is 7.9% (1). The use of more sensitive antibody assays can be an issue, if a crossmatch technique with the same level of sensitivity is not used, since more donors will be crossmatch compatible than the PRA would indicate.
In addition to the problems with PRA definition, the listing of unacceptable antigens for sensitized patients is inadequate. The transplant community began entering unacceptable antigens to help facilitate renal allocation. This approach eliminated patients from consideration with donors who possessed one or more HLA antigens to which the patient was known to be sensitized. The Histocompatibility Committee's review of the kidney registrations on 12/31/04 demonstrated substantial disparity in the listing of PRA and unacceptable antigens. Only 59.6% of patients with PRA > 80 had at least one unacceptable antigen listed and only 44.2% of those with PRAs from 20-79, had an unacceptable antigen listed. Twenty-one percent (54/249) of centers did not list unacceptable antigens in any PRA category and 31.7 percent (79/249) did not list unacceptable antigens for their highly sensitized patients (PRA>80). In the past, when the cytotoxicity assay was the sole means for defining HLA antibodies, it was often difficult to identify all the antibodies that a highly sensitized patient might have. The development of solid phase immunoassays that use solubilized HLA antigens as targets have greatly increased the ability to detect and identify HLA specific antibodies (2-4). Additionally, as shown in Table 1, these methods show excellent correlation with predicted positive crossmatch outcome (5). When no unacceptable antigens are listed for highly sensitized patients, crossmatches may be performed for patients with known HLA specific antibodies that could have been avoided. Given the scarcity of deceased donor organs and the impact of prolonged ischemia time on graft outcome, these predictably positive crossmatches should be eliminated to improve the allocation process.
When you enter unacceptable antigens for a patient, the calculator will automatically determine a CPRA value. If you add any additions or deletions to the patient's unacceptable list, the value will automatically recalculate. The OPTN/UNOS Histocompatibility subcommittee derived and validated the necessary HLA frequencies for this calculation. The calculated frequency of incompatible donors will provide consistency in listing since each center will determine the CPRA values in the same way.
Establishing criteria for listing unacceptable antigens
Centers will determine their own criteria for unacceptable antigens, which may include other factors, such as repeat mismatches. These criteria should reflect what is considered as a contraindication for transplantation for each candidate. For example, some centers may not want to list antigens for which their patient only has very low levels of antibody and who would be crossmatch compatible by their protocols with a donor having those antigens. However, not listing some unacceptable antigens will also reduce a candidate's eligibility for the extra points awarded when the CPRA is 80 or greater. It is important to note that the intent of awarding the extra points is to move patients who will only be compatible with 20% or less of donors to the top of the match list when a suitable donor becomes available. If center protocols permit acceptance of donors when there may be low levels of sensitization, those candidates will have access to a larger proportion of donors and should not, therefore, receive the extra CPRA points.
The algorithm is a more representative measure of sensitization, not only because of the use of more accurate HLA frequencies, but also because it accounts for sensitization to both HLA class I and II antigens. The calculated frequency also has been shown to give increased benefit to racial/ ethnic minority candidates who are sensitized to HLA antigens that are relatively common in the deceased donor population (9).
- Cherikh W. Variability of PRA levels and reporting of unacceptable antigens among transplant centers. Report to the Histocompatibility Committee on January 26, 2006 of an analysis of OPTN/UNOS data.
- Cecka JM, Zhang Q, Reed EF. Preformed cytotoxic antibodies in potential allograft recipients: recent data. Hum Immunol. 2005;4:343-9.
- Leffell MS, Montgomery RM, Zachary AA. The Changing Role of Antibody Testing for Transplantation. In: Clinical Transplants 2005 ( Cecka M and Terasakin PI, eds). 2006. UCLA.
- Gebel HM, Bray RA, Nickerson P. Pre-transplant assessment of donor-reactive, HLA-specific antibodies in renal transplantation: contraindication vs. risk. Am J Transplant. 2003;12:1488-500.
- Cherikh WS, Baker T, Nelson K, Land G, Leffell M, Nikaein A. Broader geographic sharing through accurate prediction of crossmatch results. Abstract # 868. World Transplant Congress 2006. Blackwell Publishing, Malden, MA, page 360.
- Zachary AA and Braun WE. Calculation of a predictive value for transplantation. Transplantation 1985;39:316-8.
- Zachary AA and Steinberg AG. Statistical Analysis and Applications of HLA Population Data. In, NR Rose, EC de Marcario, JD Folds, HC Lane, and RM Nakamura, Eds., Manual of Clinical Laboratory Immunology, 5th Edition, Washington, DC, ASM Press, 1997:132-40.
- Leffell MS, Cherikh W S, Land GA, Zachary AA. Improved definition of HLA frequencies among minorities: applicability to estimates of transplant compatibility. Abstract #2135. World Transplant Congress 2006. Blackwell Publishing, Malden, MA, page 773-774.
- Leffell MS, Kaplan I, Zachary AA. The probability of a positive crossmatch is a more accurate measure of sensitization and benefits minorities. Abstract # 766. World Transplant Congress 2006. Blackwell Publishing, Malden, MA, page 325.