A 49-year-old CKD 5 lady highly sensitized due to pregnancy and blood transfusion. Her cRF (Calculated reaction frequency is also called calculated panel reacting antibodies (cPRA) is 97%.
- What is the cRF and its significance?
- What is the difference between PRA (Panel Reacting Antibodies) and cPRA?
- How would you transplant this patient?
What is the cRF and its significance?
The calculated CPRA is based upon un acceptable HLA antigens to which the recipient has been sensitized and which, if present in a donor , wound represent an unacceptable risk for the candidate or the transplant program . The un acceptable antigens can be identified by the presence of HLA antibodies in the sera of transplant recipients.
What is the difference between PRA (Panel Reacting Antibodies) and cP RA?
PRA is testing patient plasma (antibodies) against lymphocytes obtained from 100 persons donor pool same population .
CPRA is testing patient plasma (antibodies) against lymphocytes from standard 10000 donor pool from same population and ethnicity.
Results of test for PRA giving percentage of reactivity.
Result of CPRA giving unaccepted antigens according to reference MFI .
How would you transplant this patient?
The immunosuppressant protocol for this patient depend on the cross matching .
If cross match is positive ,consider desensitization, in addition to induction using ATG and maintenance triple TAC.
If cross match is negative ,consider induction and maintenance triple TAC.
DSA monitoring and protocol biopsy should be considered in both groups .
Reference
1) Cecka JM. Calculated ORA (cPRA): The new measure of sensitization for transplant candidates. Am J Transplant 2010;10:26-29.
2) Cecka JM, Kucheryavaya AY, reinsmoen NL, et al. Calculated PRA: initial results show benefits for sensitized patients and a reduction in positive crossmatches. Am J Transplant 2011;11:719-724.
3) Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Eng J Med 2008;359:242
A panel-reactive antibody (PRA) is a group of antibodies in the serum that are reactive against specific antigens in a panel of test cells or purified HLA antigens from cells.
It is an immunologic test routinely performed on the blood of people awaiting organ transplantation.
In this test recipient serum are exposed to cells of donor population and estimation risk of acute rejection. The PRA score is expressed as a percentage between 0% and 100%.
It represents the proportion of the population to which the person being tested will react via pre-existing antibodies against human cell surface antigens, which include human leukocyte antigen |HLA] and other polymorphic antigen systems. A PRA score greater than 6 is in danger, and over 20 requires a desensitization process, but its intensity varies. These antibodies target the surface antigens of target cells, such as HLAs.
In other words, it is a test of the degree of alloimmunity in a graft recipient and thus a test that quantifies the risk of transplant rejection. Each population has a different demographic prevalence of particular antigens, so the PRA test panel constituents differ from country to country.
A traditional PRA test is performed using a panel of lymphocytes from potential donor population. Since late 1990s, a purified HLA antigen panel has been used to replace a cell panel for the PRA test, based on the assumption that HLA is the major target antigen system of alloantibody reaction. However, the non-HLA antibody effect on the PRA test has been ignored
The cPRA estimates the percentage of donors with whom a particular recipient would be incompatible. In other words, it would give you an idea of the percentage of offered kidneys your body would likely reject at the time of transplantation. The cPRA is used in the allocation of kidney and pancreas transplants
Calculated panel reactive antibody (CPRA) values are based on the HLA antigens that are listed as unacceptable for renal transplant candidates. The unacceptable HLA antigens can be identified by the presence of HLA antibodies in the sera of transplant recipients .
Extensive efforts have been made to identify treatment regimes to reduce PRA in sensitized transplant candidates. In certain circumstances, plasma exchange, intravenous immunoglobulin, rituximab and other “antibody-directed” immune therapies may be employed, but this is an area in which active investigation continues.
Tinckam KJ, Liwski R, Pochinco D et al. cPRA increases with DQA, DPA, and DPB unacceptable antigens in the Canadian cPRA calculator. Am J Transplant 2015; 15: 3194–3201.
The c PRA is computed from HLA antigen frequencies among approximately 12,000 kidney donors in US between 2003 and 2005 representing percentage of actual organ donors that express one or more of unacceptable HLA antigens.
c PRA enables us to calculate possibility that the recipient and donor would be incompatible to each other.
A panel-reactive antibody (PRA) is a group of antibodies in a test serum that are reactive against several known specific antigens in a panel of purified HLA antigens from cells.
Difference between PRA (Panel Reacting Antibodies) and c PRA:
Unlike PRA, the c PRA provides a meaningful estimate of possibility of transplantation for most patients, as it is calculated from unacceptable HLA antigens that will preclude offers from predictably XM incompatible donors.
(Calculated PRA (CPRA): The New Measure of Sensitization for Transplant Candidates
This patient could be transplanted according to her crossmatch :
If her crossmatch( CDC & FC) is positive beside his 97% c PRA, desensitization method is very crucial. In case of negative XM,no need for desensitization .
References 1- up todate medicine , kidney transplantaion in adults: HLA desensitization accessed 2021. .
2-Highly Sensitized Patients Are Well Served by Receiving a Compatible Organ Offer Based on Acceptable Mismatches,Front. Immunol., 25 June 2021 | https://doi.org/10.3389/fimmu.2021.687254.
The level of sensitization called reaction frequency ( cPRA ) calculated by finding the percentage of blood group identical , HLA incompatible donor in the donor pool
sensitization is major barrier for renal transplantation the higher patient PRA the more likely to have positive cross match
PRA : measures the antibody specificities in an individual serum sample against a panel of HLA antigens
PRA more than 10%defined sensitized and more than 85%
by desensitization treatment : removal of antibodies from the donor immediately before the transplant with immunoglobulin and rituximab
Bortezomib
plasma exchange and low dose IV immunoglobulin
By desensitizing the patient. Desensitization therapy aims to clear or reduce the levels of circulating antibodies, thus creating a window of oppurtunity for the recipient to receive the transplant while the recipient has a negative cross match. There are several ways of desensitizing the patient
A protocol uses low dose IVIG with plasma exchange. Another protocol uses high dose IVIG in multiple uses, and this has been shown todesensitize HLA-sensitized patients on the deceased waiting donor list
REFERENCES
Kim Irene K et al. Transplantation in highly HLA-sensitized patients: challenges and solutions.
Heidt S et al. Highly Sensitized Patients areWell served by receiving a compatible organ Based onaceptable Mismatches. Front. Immunol., 25 June 2021
It is classified as a high risk transplantation due to the presence of preformed donor specific antibodies. The donor specific antibodies could be complement fixing or non complement fixing, so a traditional CDC cross match and Flow cytometry cross match is essential before renal transplantation.
If the patient is on dialysis, she needs 6monthly monitoring of cPRA. if the patient is high on the list 2 doses of Inj Rituximab 375mg/m2 2 weeks apart and plasmaphresis 1.5 times plasma volume is done, anticipating a possible cadaver kidney in the near future.
At the time of transplant with a living donor:
+ve CDC cross match – reject
-ve CDC cross match and MCS in Flow cytometry is <250 and DSA MFI < 1000 – proceed even if it is a mismatched antigen donor
-ve CDC cross match and MCS in flow cytometry is >250 – reject as the DSA is expected to be higher than 5000
-ve CDC cross match, MCS flow cytometry <250, DSA MFI > 1000 – 5000 – Transplant with induction agent ALG/ATG, high dose triple immunosuppression, Inj Rituximab 375mg/m2 given 2 doses 1 dose every week 2 weeks before transplant, 2 sessions of plasma exchange during transplant and immediate post transplant monitoring of DSA in day 3,5 and every week for 1 month. Some centers use IVIG 2gm/kg for 5 doses 1 week before transplant instead of plasma exchange
-ve CDC cross match, MCS flow cytometry <250, DSA MFI > 5000 – transplant can be proceeded only after desensitization and repeat DSA MFI <5000 . Desensitization can be done with 2 doses of Inj Rituximab 375mg/m2 given 2 weeks before transplant, plasmaphresis 1.5l plasma removal with FFP replacement every alternate day, triple immunosuppression 2 weeks before transplant. If MFI <5000 can proceed with Inj ALG/ATG induction and high dose immunosuppresion and weekly monitoring of post transplant DSA for 1 month and monthly monitoring of DSA for 6 months.
CPRA is computerised process represents the un accepted antigens in doners among 120000 donors which not suitable for our recipient
It’s significant.. it is the most accurate tool to give positive cross match or not .
PRA.. it measures patient serum reactions against lymphocytes from about 100 donors 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.
How to transplantation?
This patient must be desensitized by ivig and retuximab .
Calculated reaction frequency is the percentage of donors in the donor pool that the patient HLA is incompatible with them.
PRA is a test used to assess the patient sensitization pre transplantation, using cross match based on cytotoxicity method, by mixing the recipient serum with the lymphocytes of the candidate donors and estimating the percentage of the positive reactions.
Calculated PRA is more accurate than PRA. It uses solid phase antibody testing to detect the unacceptable HLA antigens and the percentage of donors that the patient has antibodies against their unacceptable HLA antigens.
Patients with high cPRA have lower opportunity to find a compatible donor, so there some ways to decrease the PRA titre like plasmapheresis and IVIG.
The MFI in patients with positive PRA should be less than 5000 in class I and less than 3000 in class II.
PRA has been used as a diagnostic marker of sensitization before kidney transplantation. Sensitization is related to preformed anti-HLA antibodies and shows risk of hyperacute or accelerated ABMR rejection in transplants. A transplant candidate with 80% PRA indicates 80% likelihood of positive crossmatch against a regional donor pool and was considered sensitized. However with introduction of more sensitive tests (solid-phase antibody tests) the number of sensitized candidates in waiting list are increased. So UNOS committee decided to use unacceptable antigens for class I and class II HLA. CPRA is calculated by computer program in patient’s geographic region. By determination of donor’s HLA before transplantation, sensitized candidates with high CPRA with negative virtual crossmatch have priority to others.
Yes, but kidney transplantation in sensitized patients is challenging. The best option when available, is receiving transplant from a zero HLA-mismatched living donor. Otherwise unacceptable antigens are registered in a computer program and perform deceased donors HLA typing and based of a virtual crossmatch patient will be considered for transplantation. Sensitization protocol consisting plasmapheresis and IVIG for several sessions and Rituximab or even Bortezomib if indicated.
●●●CALCULATED REACTION FRQUENCY:
The level of sensitisation (called reaction frequency [RF]) for a patient is calculated by finding the percentage of blood group identical, HLA incompatible donors in the donor pool.
●☆●SIGNIFICANCE :
If the patient’s serum reacts with 50 % of a panel of sera that is representative of the donor pool, then half of donors would be expected to give a positive cross match and be unacceptable.
HLA antibodies therefore represent a serious obstacle to successful transplantation.
Pre-transplant identification of preformed HLA antibodies is essential in order to predict whether a potential donor will be HLA compatible and to avoid unnecessary consideration of an inappropriate donor.
●●●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 exapmle We 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
●●●C- PRA
The cPRA estimates the percentage of donors with whom a particular recipient would be incompatible.
In other words, it would give you an idea of the percentage of offered kidneys your body would likely reject at the time of transplantation.
The system will calculate the CPRA using the unacceptable values that have been entered for a candidate.
The cPRA is used in the allocation of kidney and pancreas transplants.
Like PRA, CPRA is a tool for characterizing and monitoring sensitization.
Unlike PRA, the CPRA provides a *meaningful estimate* of transplantability for most patients, because it is calculated from unacceptable HLA antigens that will preclude offers from predictably crossmatch incompatible donors.
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.
●●●HOW I WOULD TRANSPLANT THE PTN ?
I would transplant the patient
BY CALCULATING THE C-PRA in addition to –> the CRF where the unacceptable antigens have been put in consideration.
May be i can find a donar from the remaining 3 % where a possible mismatch is out of reach.
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.
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(possible mismatches) for candidates increases the efficiency of organ allocation by screening off incompatible donors.
REFERENCE:
_https://www.kidney.org/atoz/content/Antibodies-and-Transplantation
_https://optn.transplant.hrsa.gov/resources/allocation-calculators/about-cpra
●●●Risk factors for HLA sensitization include prior transplantation, blood product transfusion, pregnancy, and ☆ ventricular assist device use☆ . Of these risk factors, the strongest is a history of prior transplantation
24. Velez M, Johnson MR. Management of allosensitized cardiac transplant candidates. Transplantation Reviews. 2009;23(4):235–247. [PMC free article] [PubMed] [Google Scholar] [Ref list]
25. Pirim I, Soyoz M, Ayna TK, et al. De Novo Produced Anti-Human Leukocyte Antigen Antibodies Relation to Alloimmunity in Patients with Chronic Renal Failure. Genetic testing and molecular biomarkers. 2015. [PubMed] [Google Scholar] [Ref list]
* A panel-reactive antibody (PRA)
a group of antibodies in a test serum that are reactive against any of several known specific antigens in a panel of test cells or purified HLA antigens from cells. It is an immunologic test routinely performed by clinical laboratories on the blood of people awaiting organ transplantation. In this test recipient cells are exposed to panel of cells of donor population and estimation risk of acute rejection. The PRA score is expressed as a percentage between 0% and 100%. It represents the proportion of the population to which the person being tested will react via pre-existing antibodies against human cell surface antigens, which include human leukocyte antigen [HLA] and other polymorphic antigen systems. A PRA score greater than 6 is in danger, and over 20 requires a desensitization process, but its intensity varies. These antibodies target the surface antigens of target cells, such as HLAs. In other words, it is a test of the degree of alloimmunity in a graft recipient and thus a test that quantifies the risk of transplant rejection. Each population has a different demographic prevalence of particular antigens, so the PRA test panel constituents differ from country to country.
***Calculated panel reactive antibody (CPRA) values are based on the HLA antigens that are listed as unacceptable for renal transplant candidates. The unacceptable HLA antigens can be identified by the presence of HLA antibodies in the serums of transplant recipients
***Multiple desensitization protocols have been reported, combining plasmapheresis with drugs targeting antibodies, B cells or plasma cells, or newer agents targeting complement or cytokines. The intent of desensitization is to reduce the titer and/or the pathogenicity of DSA sufficiently to prevent hyperacute rejection and permit transplantation . A US multicenter study demonstrated a substantial survival benefit for patients undergoing desensitization and transplant as compared with patients who did not undergo transplantation and remained on the waiting list . A similar study in the UK, however, showed that survival with desensitization was comparable with those remaining on dialysis awaiting an HLA-compatible organ . Contributing to this outcome variation is the differential survival of the comparator groups who remained on dialysis; the decision to offer desensitization to a patient must therefore be weighed in the context of their unique dialysis mortality. No clearly superior desensitization protocol has been identified to date and the success is strongly influenced by the initial antibody amount .
***References :
1 Tinckam KJ, Liwski R, Pochinco D et al. cPRA increases with DQA, DPA, and DPB unacceptable antigens in the Canadian cPRA calculator. Am J Transplant 2015; 15: 3194–3201.
2 Orandi BJ, Garonzik-Wang JM, Massie AB et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transplant 2014; 14: ‘ 14: 1573–1580.
3 Sethi S, Choi J, Toyoda M et al. Desensitization: overcoming the immunologic barriers to transplantation. J Immunol Res 2017; 2017: 6804678.
4 Orandi BJ, Luo X, Massie AB et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med 2016; 374: 940.
5 Manook M, Koeser L, Ahmed Z et al. Post-listing survival for highly sensitised patients on the UK kidney transplant waiting list: a matched cohort analysis. Lancet 2017; 389: 727-734.
Dear All
Well done
I acknowledge your replies.
PRA is out of the window and not performed in most of countries. Single Antigen Beads (SAB) is the way forward to calculate the cPRA
Calculated Panel Reactive Antibody (c-PRA):
is a virtual cross-match based on a database of real kidney donors (12,000 pools).
c-PRA test specifies and gives the strength of DSA.
It is done to test for the presence of the donor’s HLA antigen (unaccepted Ag) against which the recipient has formed antibodies, (this means the recipient is sensitized to these Ag). It is done using solid-phase immunoassays (SPI). calculating class, I and II together.
If it is positive (DSA present) and the recipient is excluded for that donor. This recipient will have a high chance to get a negative cross-match donor.
Panel Reactive Antibody (PRA)
is a screening tool to test the patient reactivity to the donor’s HLA antigens. It estimates the probability of getting a negative crossmatch. Done by mixing patient’s serum with the pool of lymphocytes obtained from general population blood donors. It tests for HLA class I and class II separately.
For our patient
She is highly sensitized and will not be offered the available DD, she will wait for a negative crossmatch.
If she has LD, I will do the crossmatch then decide if she will need desensitization. AS may get OOO crossmatch
Desensitization can be done by IV Ig, Rituximab, plasmapheresis
Difference between PRA cPRA
PRA is testing patient plasma (antibodies) against lymphocytes obtained from 100 persons donor pool same population….not standard
cPRA is testing patient plasma (antibodies) against lymphocytes from standard 10000 donor pool from same population and ethnicity
Results
PRA giving percentage of reactivity
CPRA giving unaccepted antigens according to reference MFI which may different from center to another but it reflect the real percentage of possible donors
How i would transplantat this donor
I have 4 tools every single one has its point of strength
CDC DTT cross match
Flow cytometry crossmatch…MCS
Virtual cross match…MFI
RIS…..17
Possibilities
negative CDC cx
Negative flow cx
Virtual cross match NO DSA
acceptthis donor even we have 6/6mismatch
Or
Negative CDC cx
Positive flow cytometry crossmatch ….look to MCS if more than 250…this patient will have for sure strong DSA and RIS more than 17 and i will reject the donor
If flow cytometry crossmatch postive below 250 look to RIS below 17…..do desensitization then depleting induction and heavy immunosuppressant medication
Reference
1) Cecka JM. Calculated ORA (cPRA): The new measure of sensitization for transplant candidates. Am J Transplant 2010;10:26-29.
2) Cecka JM, Kucheryavaya AY, reinsmoen NL, et al. Calculated PRA: initial results show benefits for sensitized patients and a reduction in positive crossmatches. Am J Transplant 2011;11:719-724.
3) Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Eng J Med 2008;359:242
Excellent Ramy
This is the way of academic writing. Well done
PRA is the main routine measure or test that used to assess the degree of recipient sensitisation and it’s affected by blood transfusion, pregnancy and previous transplantation ,it’s associated with less immune transplant reactivity to the transplanted kidney in case of negative DSA .
CPRA used to estimate or calculate unacceptable HLA Ag that will help to predicte incompatible cross match.
For this patient she needs desensitization protocol with plasmapheresis (usually 4 sessions ) followed by IVIG with ATG induction pre transplant also proper choose of donor with negative DSA this will help to increase chance of graft survival and decrease post op. complications.
C PRA is a refined PRA form used to detect the percentage of the unacceptable HLA Ags present in the potential donors and it depends on the frequencies of HLA antigens within a particular donor population.
It differs from PRA in that it takes into account the HLA Ag frequency in certain population so its more accurate than PRA in expressing the degree of patient sensitization .(1)
As the patient is highly sensitized , desensitization protocols are needed to decrease Ab level and modulate immune response through
1- Removal of preformed anti-HLA antibodies
a. Plasmapheresis ;non specific removal of immunoglobulins
b. Immunoadsorption : can remave specific immunoglobulins.
c. IdeS (immunoglobulin G-degrading enzyme of Streptococcus pyogenes).
2. Depleting the antibody-producing cells
a. Naïve and memory B cells: rituximab (anti-CD20)
b. Plasma cells: bortezomib
3. Inhibiting antibody and complement-system cascade
a. IVIg
b. Complement inhibitors as Eculizumab (C5a inhibitor) and C1 inhibitor
4. Inhibiting cytokines production through IVIg or Tocilizumab (anti–IL-6 receptor blocker).(2)
The commonly used desensitization protocols with demonstrated clinical efficacy are
A- Pretransplantation
1- Plasmapheresis (between 5-10 sessions depending on level os DSA ) or immunoadsorption and high-dose IVIg (2 g/kg IVIg monthly infusions til either the crossmatch is negative or a total of four doses are administered). .
2- Plasmapheresis (or immunoadsorption and low-dose IVIg (100 mg/kg after each PP session for 5 sessions ).
B- Post transplantations : vary between centers . some centers consider between two to five sessions PP depending on level of DSA , other test for DSA 1 St if –ve no further PP is performed
1- Shen, S. W., Chang, C. K., Gao, Y. S., Hsu, P. J., Cheng, S. C., Liu, F. Y., & Lo, S. C. (2017). Establishment of calculated panel reactive antibody and its potential benefits in improving the kidney allocation strategy in Taiwan. Journal of the Formosan Medical Association = Taiwan yi zhi, 116(12), 956–963. https://doi.org/10.1016/j.jfma.2017.09.008
2- Marfo, K., Lu, A., Ling, M., & Akalin, E. (2011). Desensitization protocols and their outcome. Clinical Journal of the American Society of Nephrology, 6(4), 922-936.
As you mentioned, I liked the word (Refined) and significantly how it depends on the population. Thank you
cRF mean determine the frequency of incompatible donor HLA phenotype based on the unacceptable class 1 and 11 antigens that have been listed for each candidate, it reflect the probability of incompatible donor ,so if the patient had a high cPRA that mean the chance to get donor is low.
The PRA is a real time screening for the patient antibodies towards specific donor that done by luminex and if it positive they did the specifications for donor specific antibodies.
I would transplant this patient after doing quantitation of the antibodies (MFI) if it less than 8000 and not DSA , I will do desensitization by plasmapheresis.
Panel Reactive Antibody (PRA) is a test for identifying a candidate’s serum antibody against a panel of lymphocytes from normal individuals who are representative of the local pool. Percent PRA provides an estimate of how often the patient would have a positive cross match against local pool donors. This test was the first measure of sensitization. Crossmatch tests have become more precise and more sensitive over time. CDC assay was the first method for HLA antibodies screening.
CPRA determines the frequency of incompatible donor HLA phenotypes based on unacceptable class I and class II HLA that have been listed for each candidate. HLA-A, -B, C, -DR, and DQ of actual deceased kidney donors from that national donor pool were used to calculate the antigen frequency and the CPRA reflects the true probability of an incompatible donor based on unacceptable antigens that have listed for a patient.
A CPRA of 97% means that 97% of deceased donors will express at least one incompatible HLA antigen, so finding a deceased donor who is HLA compatible with candidates is very difficult.
Recent allocation system by accounting for CPRA and virtual crossmatch, giving top priority to the high sensitized patients in the waiting list, utilizing desensitization protocols for sensitized candidates, kidney paired donation and finding living donor are solutions which have been offered for transplantation for broadly sensitized patients.
In this scenario, if she has a potential living donor, she can proceed to a crossmatch against her donor, and if negative, can be transplanted. But if the living donor is an HLA incompatible donor, the patient can go to a deceased donor waiting list or receive a living donor organ through desensitization, or go to a KPD program. Performing desensitization depend on CDC cross match, flowcytometric crossmatch, median channel shift, relative intensity score (assigned base on MFI). Desensitization protocols consist of IVIG, rituximab and plasmapheresis.
If a deceased donor transplantation is the only choice for her, she should be monitored periodically and evaluated for alteration in her antibodies and receive a top priority in the waiting list as well. Also, crossmatch have to be performed before transplantation.
Like PRA, CPRA is a tool for characterizing and monitoring sensitization. Unlike PRA, the CPRA provides a meaningful estimate of transplant ability for most patients, because it is calculated from unacceptable HLA antigens that will preclude offers from predictably crossmatch incompatible donors.
CPRA provides a more accurate estimate of sensitization because it includes both class I and class II HLA specificities in the calculation, a major departure from traditional PRA, where class I and class II specificities are measured separately. Even B-cell panels, which express both class I, and class II antigens are generally constructed to cover the class II HLA antigens and are not representative of HLA distributions in the general population
this patient needs to do cross match to see if she needs desinsitization
Thank you, Michael
From where does the term calculated emerge? Why it’s more meaningful?
CPRA
calculated from HLA antigens frequencies among 12,000 kidney donors
represent percentage of actual donors who express one or more of unacceptable HLA antigens to which the recipient has been sensitized
used to determine the immunosuppression regimen as highly sensitized patients receive depleting antibody induction and more intense maintenance immunosuppression
PRA assessment is important for immune risk stratification
mixing patient serum against panel of lymphocytes representing local donor pool
it is percentage of donor to which candidate has reactive antibodies
It assess the degree of recipient sensitization but don’t consider donor specificity
if she has a living donor with both negative complement dependent cytotoxicity (CDC) & flow cytometric crossmatch (FCXM) can proceed to transplantation
if not, desensitization using regimens that decrease preformed antibodies
the goal of therapy is to reduce the antibody level so the FCXM is negative or low
plasmapheresis, IV immunoglobulins, Rituximab, Bortezomib can be used for desensitization
DSA should be closely monitored as low level DSA have injurious long-term effect on the graft
Thank you All for your contribution. I’m glad to see cPRA and FCXM in your response. Feel free to add more contributions and press “Complete”.
cPRA and its significance
-implemented by UNNOS in Dec 2007
-to solve the variability in PRA reporting that developed over the time by using different call panels and diff test for HLA antibodies
-calculated by determining the probabilities of incompatible donor HLA phenotypes based on unacceptable class 1 and 2 HLA antigens that has been listed
-shows the true frequencies of an incompatible donor based on unacceptable antigens that has been listed for the patient
-cPRA -80% means 80 percent of deceased donor kidneys will have at least one unacceptable antigens and make the patient not suitable for transplant
-different centres have different threshold for unacceptable antigens
-interpretation of the test before transplantation might not be as easy or straight forward. So, it requires comparing more than one test platforms to assure the weak reactions are similar among the tests.
differences between PRA and cPRA
PRA
– The value depends upon the panel composition and the technique used for antibody detection.
-composition of the antigen panel varies with the use of different commercially available kits or locally procured cell panels. it often do not represent the potential donor population
-variability arises from the use of tests with differing sensitivity in detecting HLA antibodies.
cPRA
-entering unacceptable antigens of patient in a calculator will automatically determine a CPRA value
-add additions or deletions to the patient’s unacceptable list, the value will automatically recalculate
-will provide consistency in listing since each center will determine the CPRA values in the same way.
How would you transplant this patient?
-our hope is to find a donor with both a negative CDC and FCXM, which can be difficult in her case
-next method is Highly sensitized candidates with living donors have option of paired donor exchange that have more favorable crossmatch results
-if not consider ABO incompatible donor pairs – increase the pool size -the ABOI KT is much easier than HLA incompatibility
cPRA
The computed CPRA is based on the patient’s sensitization to undesirable HLA antigens that, if present in a donor, would represent a unacceptably high risk for the transplant program or recipient. HLA antigens are used to calculate the CPRA which were present among the approximately 12,000 kidney donors between 2003 and 2005 in the United States in a variety of frequencies.It reflects the proportion of actual organ donors who have one or more of the HLA antigens that are considered undesirable.
PRA
Test that could identify sensitized patients and estimate their likelihood of finding
a crossmatch-compatible donor using a panel of normal blood donors as representative of the potential local organ donor pool. PRA is simply the percentage of this pool of donors to which a patient had reactive antibodies. A patient with 80% PRA would be crossmatch incompatible with 80% of donors.
A high traditional PRA number indicated a high likelihood of a positive crossmatch, but because CPRA is based on undesirable antigens, offers from those donors having those antigens will be rejected and less likely for a positive cross match.
How would you transplant this patient?
CDC XM – , FCXM –
Transplant
CDC XM +, FCXM +
Avoid transplant
CDC XM -,FCXM +
1) DSA CLASS 1 AND 2
Absent- accept for transplant with thymoglobulin induction.
Present –
MFI <1000- transplant with thymoglobulin induction
MFI 1000-10000 – plasmapheresis + low dose ivig + ATG(Target MFI<1000 or FCXM negative with MFI,1500)
MFI >10000- Avoid transplant .
HLA Desensitization Based on Results of the Luminex Technique in
Kidney Transplant – A Single‑center Experience-S.B. Bansal,A. Gade, S. Sinha,
A. Mahapatra,P. Jha, S.K. Sethi.
Dear All
What are the conditions where desensitisation of this case is not required?
Negative cross match ,no desentization requried.
-our hope is to find a donor with both a negative CDC and FCXM, which can be difficult in her case
-next condition is highly sensitized candidates with living donors have option of paired donor exchange that have more favorable crossmatch results
Calculated reaction frequency or Calculated PRA , represent % of having unacceptable antigens , its prepared from 12000 actual donors ,
It’s done using luminex technology which allows more specific detection of antibodies
It represe amore accurate measure for sensitization of a patient.
PRA is ameasure of degree of sensitization And is done by testing recipient serum with panel of lymphocytes from normal population , with PRA 80% means that the patient with have antibodies against 80% of the population
Highly sensitized patient would be further assessed for presence of DSA, their intensity should be detected ( MFI ) , their ability to fix complement ( C1q )
And if any of these detected , we would go for a desensitization protocol which most commonly consisted of plasma exchange, IVIG +- retuximab
Dear All
What are the conditions where desensitisation of this case is not required?
If virtual Cross match is negative she doesn’t need desensitization .
But I think with cPRA 97% , she is still considered high risk , she needs induction therapy with ATG / thymoglobulin, with frequent monitoring of DSAs after transplantation
If she has a compatible donor and negative cross match,no need for desensitization
PRA% as an indication for patient sensitization has been replaced widely in UK by NHS Blood and Transplant (NHSBT-ODT) with a high cRF. The purpose of such test is to define the recipient immune profile caused by a prior HLA exposure and the obtained results are expressed as percentage. Accordingly, patients with a cRF>85% are considered as highly sensitised.
Patients with high PRA are not precluded from transplantation. Nonetheless, highly sensitized patients are more prone to hyper-acute rejections with early graft loss, therefore and depending on cross-match results; several desensitisation protocols have been implemented (if the cross match with their potential donor turn to be positive), most of those based on either high dose intravenous immunoglobulin’s (IVIG) or a plasmaexchange (PE)/Immunoadsorption (IA) with low dose IVIG.
Rituximab were included lately in most protocols to inhibit antibodies synthesis. The combinations of rituximab, PE and IVIGs had eased the access of sensitised patients to transplant list and improved graft survival. On the other hand, bortezomib were utilised as a part of desensitisation protocols, though the results are indefinite.
Alternatively, eculizumab (anti-C5 monoclonal antibody) were used to decrease injuries induced by DSA-complement activation. Desensitisation protocols aim to attain a negative crossmatch. Though the majority of these protocols can decreases HLA antibodies to a level can permit transplantation, yet the results on the long term remains uncertain.
KDIGO clinical practice guidelines in 2009 had necessities aggressive immunosuppressive administration in patients with considerably high rejection risk, including those with: high PRA. For those patients, the 2009 guidelines suggested to use the lymphocyte-depleting agents, which are potent immunosuppressive for patients at high immunologic risk.
References:
1. BTS & BSHI (2016) BTS guidelines for the detection and characterisation of clinically relevant antibodies in allotransplantation. Available at: http://www.bshi.org.uk and http://www.bts.org.uk
2. Goes N, Chandraker A (2000) Human leukocyte antigen matching in renal transplantation: An update. Curr Opin Nephrol Hypertens 9: 683-687.
3. Hajeer AH (2006) Panel Reactive Antibody test (PRA) in renal transplantation. SJKD 17: 1-4
4. Braya RA, Nolena J, Larsenb C, Pearson T, Newell KA, et al. (2006) Transplanting the highly sensitized patient:The emory algorithm. Am J Transplant 6: 2307-2315.
5. Marfo K, Lu A, Ling M, Akalin E (2011) Desensitization protocols and their outcome. Clin J Am Soc Nephrol 6: 922-936
1- A 49-year-old CKD 5 lady highly sensitized due to pregnancy and blood transfusion. Her cRF (Calculated reaction frequency is also called calculated panel reacting antibodies (cPRA) is 97%.
c-RF is the abbreviation of calculated reaction frequency in the UK which is equal to cPRA (calculated Panel reactive antibodies).
It represents the donors who have unacceptable antigens to which the proposed donor is sensitized.
PRA (Panel Reactive Antibody)is a measure to test the probability of finding a compatible donor for a transplant recipient.
The patient serum is added to a panel of lymphocytes from normal blood donors among the general population, positive cross match will happen if the patient has antibodies against the donor lymphocytes. The result is calculated and the value is obtained as a percent form
PRA measures class I and class II antibodies separately.
PRA results can vary based on laboratory and time of testing.
cPRA (calculated PRA)is a refined version of PRA.
It is a computer system where we have a database of donor pool lymphocytes coming from a large pool of actual kidney donors, the laboratories are expected to enter specific unacceptable antigens for the prospective recipient.
It points to the percentage of donors being declined because of unacceptable antigens.
This lady needs desensitization.
Desensitization protocol for LD transplant: Injection Rituximab (day 0, day 14) + High dose IVIG (day 28, day 42), aim for negative cross match then proceed for transplantation.
Desensitization protocol for DD transplant:
Plasma exchange (every other day for total 5 sessions) , followed by IVIG and Rituximab one week later.
Dear All
What are the conditions where desensitisation of this case is not required?
Dear All
What are the conditions where desensitisation of this case is not required?
Panel reacting antibodies (PRA) is testing patient, s serum against a panel of lymphocytes from normal individuals representative of the local donor pool. It is the first measure for sensitization. A high percentage of PRA means is difficult to find a suitable donor.
cPRA is the estimated percentage of donors with whom a particular recipient would be incompatible. It would give you an idea of the percentage of the offered kidney that rejects by the recipient body at the time of transplantation. It is based on class I and II HLA antigens that are listed as unacceptable for the patient.it reflects the probability of an incompatible donor based on unacceptable antigens that have been listed for the patient. It refines the form of PRA. In October 2009,cPRA officials replaced traditional PRA as assessment of patient sensitization 1
This sensitized patient with CPRA 97% needs cross matching. If the cross-match is negative no need for desensitization, but if the cross-match is positive he needs desensitization.
Desensitization had 2 approaches based on the use of IV immunoglobulin:
First approach
1. IV immunoglobulin
2. plasmapharesis
3.Rituximab or Bortezumab
Second approach :
1.IV immunoglobulin
2.plasmapharesis2
References:
1.Cecka JM. Calculated PRA (CPRA): the new measure of sensitization for transplant candidates. Am J Transplant 2010; 10: 26.
2. Danovitch G.M handbook of kidney transplantation sixth edition.
Dear All
What are the conditions where desensitisation of this case is not required?
If crossmatch is negative.
If crossmatching is negatives.
PRA and cPRA is a measure for sensitization of a person to the donor pool. PRA is measured by mixing the recipient serum with lymphocytes from donor pool( usually less than 100 person). The cPRA is calculated by comparing the unacceptable HLA antigens with the HLA data of donor pool ( thousands of people). so cPRA is more representative of the actual donor pool.
High cPRA ( which also means high level of sensitization ) reduce the chance of finding a compatible donor , which leads to increasing the time on waiting list.
Regarding transplantation of this lady with cPRA >97% :
If she had compatible living donor(negative FCXM , negative CDC), we can proceed with transplantation.
If she incompatible living donor ( positive FCXM, negative CDC) , paired exchange donation with compatible donor is the best option. but if compatible pair not founded , we can do desensitization (using IVIG, plasmapheresis , rituximab, bortezomib,…etc) then to proceed to transplantation if desensitization succeeded.
If she didn’t had a living donor , deceased compatible donor is her only chance. if the expected time on the waiting list is to long , we can do desensitization to increase her chance to find a compatible donor.
Reference :
Douglas S. Keithcorresponding author and Gayle M. Vranic Approach to the Highly Sensitized Kidney Transplant Candidate Clin J Am Soc Nephrol. 2016 Apr 7; 11(4): 684–693.
In this patient’s case a compatible living donor is always the best option. However, for most highly sensitized candidates this scenario is unlikely. For candidates with an incompatible donor, paired donor exchange can improve the prospects of finding a compatible living.
Desensitization of a living donor/recipient pair with low levels of incompatibility is another reasonable approach. But for pairs with high levels of pathologic HLA antibodies, outcomes after desensitization for the patient and allograft are less optimal. Determining the degree of sensitization by calculated panel-reactive antibody (cPRA) is critical in counselling the highly sensitized patient on expected wait times to deceased-donor transplant .For the candidate without a living donor and with a low probability of finding a deceased-donor match, desensitization on the waiting list can be considered.
Dear All
What are the conditions where desensitisation of this case is not required?
negative cross match
PRA is a way for assessing of the extent of sensitization to HLA antigens.
calculated PRA which differ from PRA that it got much larger pool of 10,000 to 120,000 of the a area , Determine the strength of DSA using MFI ,Flow cytometry bead assay is used .
Desensitization will not eliminate anti-HLA antibodies but will decrease there MFI.
virtual cross match if present in this case , the donor will be rejected
cross matching by CDC and DTT and flow cytometry for the decision of desensitization to go for it or only treat the patient as a high risk for induction
Desensitization protocol for living donor transplant: Rituximab + High dose IVIG
Rituximab 375 mg/m2 and after 2 weeks, followed by high dose IVIG 2 gram per kg and then rituximab after a month and a month and a half or
Plasmapheresis alternate day for 5 sessions, followed by IVIG 2 gram per Kg and Injection Rituximab 375-500 mg/m2 one week later.
transplant can be proceeded with if CDC cross match is negative and Flow cytometry cross match is either negative, or positive with MCS (Mean Channel Shift) <250.
Induction using ATG
Maintenance triple therapy
-steroids
-MMF
-Tacrolimus
DSA follow up closely
References:
Cecka JM, Kucheryavaya AY, reinsmoen NL, et al. Calculated PRA: initial results show benefits for sensitized patients and a reduction in positive crossmatches. Am J Transplant 2011;11:719-724.
Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Eng J Med 2008;359:242.
Thanks, Dr Moahmed
Will you do virtual crossmatch in this case?
i will do a virtual cross match by luminex anyway .
another opinion is if the cross match is -ve then no need for the virtual cross match , but the question: there may be DSAs with-ve flow cytometry for example right ?
in this case we will do DSAs any way .
but someone may ask why will you do it when your target of having -ve cross match is already achieved ? my answer : may be these DSAs will cause something in the future .
what do you think Prof. ?
ON 2007 UNOS IMPLENTED cPRA, WHICH DETERMINES THE FREQUENCY OF INCOMPATIBLE DONOR HLA PHENOTYPES BASED ON UNNACCPTEABLE CLASS 1,2 HLA ANTIGENS THAT HAVE BEEN LISTED FOR EACH CANDIDTAE , SINCE HLA-A, B,C -DR AND DQ SUBTYPES OF ACTUAL DECESD KIDNEY DONORS WERE USED TO COMPUTE ANTIGEN FREQUENCIES, THE c-PRA RFLECTS THE TRUE PROBALITY OF INCOMAPTIBLE DONOR BASED ON UNACCEPTATBLE ANTIGENS THAT HAVE BEEN LISTED FOR A PTIENT.
Calculated PRA use wider pool than PRA.
PRA is calculated by cross match based on cytotoxicity method, while calculated PRA is based on solid phase antibody testing.
this lady is unlikely to find a decased donor, very low chances due to very hih cPRA and also desntization protocol will not add much very costly and and also alot of comaplictions during desentiztion process,
i will advise her to bring a living related donor first degree realtive ( brother sister, son , daughter). cross match will be hopefuly negative .
PRA
Panel reactive antibodies (PRAs) have been used to measure the relative degree of sensitization in renal allograft recipients.
PRA levels represent the percentage of likely cross-match incompatible donors, and are determined by testing recipient sera against cells from a panel of HLA-typed donors or solubilized HLA antigens attached to a solid phase.
The panels should be representative of the local pools of potential organ donors. However, the results of PRA testing can be highly variable and inconsistent depending on the panel composition and the techniques used for HLA antibody detection [1].
the use of recombinant single antigens (SA) in the Luminex assay makes it possible to detect HLA-specific antibodies with greater sensitivity and accuracy.
CPRA
Calculated panel reactive antibody (CPRA) values are based on the HLA antigens that are listed as unacceptable for renal transplant candidates. The unacceptable HLA antigens can be identified by the presence of HLA antibodies in the sera of transplant recipients [2].
This assessment can predict crossmatch-positive donor kidneys (as a virtual crossmatch) and has increased the efficiency of organ allocation.
the Korean Network for Organ Sharing (KONOS) does not administer the PRA or CPRA, and only uses crossmatch results to measure sensitization for the renal allocation system.
The application of the cPRA and acceptable mismatch can benefit highly sensitized patients and reduce positive lymphocyte cytotoxicity crossmatch.
for highly sensitized patient negative crossmatch and absence of DSAs is more important than PRA and with 000 mismatch we don’t need desensitization
1 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;11:719–724. [PubMed] [Google Scholar]
2. Cecka JM. Calculated PRA (CPRA): the new measure of sensitization for transplant candidates. Am J Transplant. 2010;10:26–29.
As many colleagues stated, PRA is reported by a test done with 100 samples as discussed in the previous week. on the contrary, the cPRA is computed using computerized software to measure these considering antibodies not acceptable to the recipient. one of the main differences in that they use more than 1200 (not 100). this patient is very highly sensitized and should be managed according to this in two sides:
1- biological approach: choosing another donor or exchange program etc.
2- pharmacological approach: high dose IVIG and or plasmaphereses, may be adding rituximab, bortezomib, or alemtuzumab etc. (** this be according to crossmatch , luminex, etc)
What is the most critical factor that determines PRA? Is it all the same?
Why is it calculated PRA or RF? Does this make any difference?
may be the previous transplant is the critical one
cPRA has much more pool of donors than PRA
The fundamental factor determining the chance of having a suitable donor is the population we are testing, i.e., the Panel, which is not the same across world regions and ethnicities.
What is the most critical factor that determines PRA? Is it all the same?
The RRA test depends on testing the patient serum against a blot of 100 potential donors, so it will give different results based upon the different panels prepared from different donors (lack of standardization) (1).
Why is it calculated PRA or RF? Does this make any difference?
The cPRA matches the unacceptable class I and class II HLA antigens that have been
identified for a specific candidate against 10,000 actual deceased kidney donors, so it is more informative and standardized compared to conventional PRA (1). Nevertheless, A cPRA based on a national donor pool may not always reflect the HLA antigen distribution of a local donor population. different regions may differ in racial and ethnic composition, but these variations generally do not result in substantially different cPRAs.
Another factor that may cause differences in cPRA is the threshold of unacceptable anti HLA antibodies accepted by the transplant centre as illustrated in figure 1 (1).
A conservative centre that wishes to avoid donors with HLA antigens to which a patient has DSA might select a threshold of 1,000 MFI as unacceptable, in which case the patient would have 100% cPRA. Another centre, willing to accept more donor offers and perhaps a shorter wait for their patient at the expense of increased risk of ABMR might set a threshold of 8,000 MFI and base their decision to transplant on the result of the final crossmatch test. With the higher threshold, the CPRA is 79%/
file:///C:/Users/drahm/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png
References:
1) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
Kidney transplantation of highly sensitized patients remain a challenge and the presence of numerous performed anti-HLA antibodies make it difficult to find a compatible donor.
The way to measure this sensitization level was traditionally the Panel Reactive antibody which is both a test and a result.
It is done by testing the patient sera against a panel of HLA-typed donor cells (lymphocytes) obtained from a panel of about 100 blood donors that represent the make up for donors from this area. The PRA % is the number of reactions within this panel. So if a patient reacts in 80 out of 100 samples, he has PRA of 80%, so he has to wait a long time until a compatible donor is available population being previously exposed to non-self-antigens from previous blood transfusion , pregnancy or previous transplantation.
The refined cPRA was introduced in 2007 to estimate the percentage of donors with whom a particular recipient would be incompatible (Calculates specific unacceptable HLA class I and II antigens from the wide donor database), so it will give an idea about the percent of offered kidneys the recipient would likely to reject at the time of transplantation. Currently ,there redly on line calculators to calculate CPRA
patients with high cPRA levels get priority (30% of waiting list patients in USA) for transplantation by different organ allocation systems(Eurotranplant, united network for organ sharing, Canadian transplant registry) by giving them higher points because of their limited ability to have suitable donor
Patient with ≥ 30% are considered sensitized, and should be assessed for desensitization. Patients with cPRA ≥80 % are considered highly sensitized
This lady is highly sensitized because of previous pregnancy and blood transfusion However, desensitization decision depends on the cross match result (CDC & flow cytometry) if positive beside high cPRA(97%), desensitization is necessary. If her cross match is negative, then no need for desensitization .
For desensitization use (plasma exchange +IV IgG +Rituximab) intensive induction therapy with ATG ,intensive maintenance therapy (steroids, MMF, Tacrolimus) with monitoring of DSA
Heidt S., Hassnoot G, Vander Lindan-van M., et al. Highly Sensitized Patients Are Well Served by Receiving a Compatible Organ Offer Based on Acceptable Mismatches. Fron Immun. 2021;12:1-7.
Gebel HM, Kasiske BL, Gustafson SK, et al. Allocating Deceased Donor Kidneys to Candidates with High Panel-Reactive Antibodies. Clin J Am Soc Nephrol 2016; 11:505.
Orandi BJ, Garonzik-Wang JM, Massie AB, et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transplant 2014; 14:1573.
Dear All
Assume this patient received an offer (000 mismatch) with negative crossmatch. Will you do desensitisation?
Desensitization is done to achieve a negative cross match.So if the patient has 000 mismatch,no Desensitization is required
With 000 mismatches and negative crossmatch i think won’t do desensitization for the patient and and i will do follow up of DSAs
negative cross match needs no desensitization protocol, but of course will follow DSAs
Ithink no need as aim of desensitisations to achieve 000 missmatch.
calculated reaction frequency:
The level of sensitisation (called reaction frequency [RF]) for a patient is calculated by finding the percentage of blood group identical, HLA-incompatible donors in the donor pool: i.e. if the patient’s serum reacts with 50 % of a panel of sera that is representative of the donor pool, then half of the donors would be unsuitable for donation.
Like PRA, CPRA is a tool for characterizing and monitoring sensitization. Unlike PRA, the CPRA provides a meaningful estimate of transplantability for most patients, because it is calculated from unacceptable HLA antigens that will preclude offers from predictably crossmatch incompatible donors.
If the cross-match(CDC or flow cytometry with MCS>250) is positive;
For desensitization using (PP +IV IgG+RITUXIMAB) until crossmatch is negative then proceed for transplantation within one week.
Sethi S, Choi J, Toyoda M, et al. Desensitization: Overcoming the Immunologic Barriers to Transplantation. J Immunol Res 2017; 2017:6804678.
PRA means non specific donor AB and its significance due to mean that patient is highly sensitive or sensitized against any foreign antigens
panel reactive antibodies (PRA) aiming to estimate the percentage of possible donors with whom a patient will have a positive crossmatch
Calculated PRA represent the actual donor have AG that will sestize recipient
I’ll do desensitization first to decrease this cPRA to be lower than 60 or40%
Use
Retuximab
Start low dose immunosuppressant before transplant
&plasma pharesis before &after procedure
Thanks, Wael for your effort
I disagree with desensitisation. It is guided by the crossmatch results rather than the absolute degree of sensitisation. This patient might get 000 mismatched kidney. Will you do desensitization?
Please read my replies to above
C PRA is a refined PRA form used to detect the percentage of the unacceptable HLA Ags present in the potential donors and it depends on the frequencies of HLA antigens within a particular donor population.
It differs from PRA in that it takes into account the HLA Ag frequency in certain population so its more accurate than PRA in expressing the degree of patient sensitization .(1)
As the patient is highly sensitized , desensitization protocols are needed to decrease Ab level and modulate immune response through
1- Removal of preformed anti-HLA antibodies
a. Plasmapheresis ;non specific removal of immunoglobulins
b. Immunoadsorption : can remave specific immunoglobulins.
c. IdeS (immunoglobulin G-degrading enzyme of Streptococcus pyogenes).
2. Depleting the antibody-producing cells
a. Naïve and memory B cells: rituximab (anti-CD20)
b. Plasma cells: bortezomib
3. Inhibiting antibody and complement-system cascade
a. IVIg
b. Complement inhibitors as Eculizumab (C5a inhibitor) and C1 inhibitor
4. Inhibiting cytokines production through IVIg or Tocilizumab (anti–IL-6 receptor blocker).(2)
The commonly used desensitization protocols with demonstrated clinical efficacy are
A- Pretransplantation
1- Plasmapheresis (between 5-10 sessions depending on level os DSA ) or immunoadsorption and high-dose IVIg (2 g/kg IVIg monthly infusions til either the crossmatch is negative or a total of four doses are administered). .
2- Plasmapheresis (or immunoadsorption and low-dose IVIg (100 mg/kg after each PP session for 5 sessions ).
B- Post transplantations : vary between centers . some centers consider between two to five sessions PP depending on level of DSA , other test for DSA 1 St if –ve no further PP is performed
1- Shen, S. W., Chang, C. K., Gao, Y. S., Hsu, P. J., Cheng, S. C., Liu, F. Y., & Lo, S. C. (2017). Establishment of calculated panel reactive antibody and its potential benefits in improving the kidney allocation strategy in Taiwan. Journal of the Formosan Medical Association = Taiwan yi zhi, 116(12), 956–963. https://doi.org/10.1016/j.jfma.2017.09.008
2- Marfo, K., Lu, A., Ling, M., & Akalin, E. (2011). Desensitization protocols and their outcome. Clinical Journal of the American Society of Nephrology, 6(4), 922-936.
1- cRF is equal to CPRA but the former term is used in UK. it is a measure of sensitization of a recepient to possible donors. if cRF is high, it means high sensitization and less chance of successful transplantation.
2- PRA is calculated as a percentage of reactive anti-bodies to a panel of donors. e.g if PRA is 40 %, it means that this recepient has sensitive antibodies to 40 % of that pool of donors. class I and II HLA specificities are measured separately. calculated PRA is based on an unacceptable HLA antigens that were computed from HLA antigen frequencies in 12,000 kidney donors. it provides more accurate estimate of sensitization as it include both class I and II HLA specificities.
3- this pt. can be transplanted by :
a- transfer to specific centres specialiesed in managing these condtions.
b- pretransplant removal of these antibodies by plasmapharesis and monoclonal antibodies.
c- intensive induction therapy including lymphocyte depleting antibodies.
d- intensive maintenance immnuosuppression with more frequent FU.
Thanks, Ibrahim for your excellent answer and your wonderful effort.
I may disagree with you regarding pretransplant removal of these antibodies by plasmapheresis and monoclonal antibodies if the PRA is more than 40%.
PRA should be interpreted with care. We use cPRA as you alluded to above.
Desensitisation is based on the crossmatch. If negative, no need for desensitization. The principle of desensitization is to achieve a negative crossmatch. If the crossmatch is positive, this may need sensitisation and DSA monitoring.
Historically sensitization was identified as panel reactive antibodies which assessed the recipients degree of sensitization to the donors HLA antigens and thereby the risk of acute rejection after transplantation.
Since 2007 UNOS discarded the use of PRA and mandated the use of cPRA/Crf which provides more accountable method of evaluation of sensitization. Cpra is calculated based on solid phase assay used to screen for antibodies. So the known frequency of HLA antigens among donors in addition to the results of SAB assay are calculated and represented in c-PRA.
Approximately30 percent of patients who are waiting for a donor kidney are considered sensitized.
So in this particular patient who is highly sensitized due to pregnancy and blood transfusion with c-PRA of 97%, this means that the patient has antibodies directed toward different loci of donor HLA antigens. But still she has a chance of 3% to have a full matched donor kidney, or a lower c-PRA with incomplete mismatch.
The decision on desensitization depends on the result of crossmatch, primarily by flow cytometric assay because positive complement dependent cytotoxic crossmatch is considered absolute indication to transplantation. However positive results from flow cytometry cross based or virtual crossmatch may not preclude moving forward with transplantation.
If this patient has positive flow cytometry/CDC cross match, she has a significant burden of DSA and high risk of hyperacute rejection.
With negative CDC crossmatch and positive flow cytometry cross match, she is at moderate burden of DSA, and desensitization protocol should be used prior to transplantation.
If both flow cytometry and CDC crossmatches are negative then lowest burden of DSA and desensitization is not indicated.
PRA is a tool for assessment of the degree of sensitization to HLA antigens, thereby the likehood of getting a graft, assessed by using recipient serum and determine the reactivity to cells obtained from a pool of volunteers with HLA phenotypes that represent donors using cell based cytotoxic assays (CDC).
In 2007 PRA is replaced by calculated PRA which differ from PRA in the following :
1- Donor pool contains 10,000 samples compared to 50 samples in PRA
2- Flow cytometry beed assay is used to determine preformed DSA, patient serum is tested against HLA antigens attached to solid beeds , usually multibe- antigen FCM beed assay is done to screen for DSA, if positive single antigen beed assay (luminex)-SAB is performed to detect specific HLA antigens to which patient has antibodies.
3- Take in account the frequency of occurrence of these HLA antigens in a particular region, the difference between PRA and cPRA that patient may has antibodies against a lot of HLA antigens but if these have lower or rare frequency the cPRA may not be high, so cPRA provide higher accuracy.
4- Determine the strength of DSA usin MFI
– Antigens of MFI of < 5000 are week antigens and take 2 points in relative intensity score (RIS)
– Antigens of MFI of 5000-10000 are moderately strong antigens and take 5 points in RIS
– Antigens of MFI of > 10000 are strong antigens and take 10 points in RIS
– Antigens of MFI of >15000 are unacceptable antigens, this mean if there is DSA to this antigen there will be very high probability of ABMR and graft failure, thus this donor should be excluded.
Patient with ≥ 30% are considered sensitized, and should be assessed for desensitization.
Patients with cPRA ≥80 % are considered highly sensitized this mean that the likehood of finding donor is extremely low without desensitization. (1)
So our patient likehood of finding a donor is extremely low so desensitization may be the only way to find a donor, desensitization will not eliminate anti-HLA antibodies but will decrease there MFI.
A- If there is available potential living donor for this lady :
Do virtual cross match to determine unacceptable antigens (if present exclude this donor) according to cPRA result, CDC and FCM :
1- if CDC cross match positive exclude this donor (2)
2- if CDC negative but flow cross match positive determine the strength of DSA
⦁ if MCS> 250 exclude this donor
⦁ if MCS 250 or less and RIS 17 or more exclude this donor
⦁ If MCS 250 or less and RIS 17 or less perform desensitization with IVIG+ rituximab then repeat cross match if acceptable proceed as a high risk patient
3- if CDC, FCM negative proceed in transplantation as a high risk patient
The recommended regimen for desensitization is :
Start with 2 doses of Rituximab 375mg/m2 (2 weeks apart) then 2 weeks later give 2 doses of high dose of IVIG 2 gm/m2 (2 weeks apart).
Premedication with methyleprednisolone 40 mg, diphenhydramine 50 mg, paracetamol 1 gm when giving rituximab and IVIG
After completing desensitization repeat CDC, FCM if acceptable (CDC negative, FCM negative) proceed to transplant surgery within 1 week of negative crossmatch. (3)
B- If there is no potential living donor
Patient is put in waiting list for deceased donor.
In all sensitized patients with cPRA ≥ 30%, If an offer is expected to be within 1 year (according to cPRA) start desensitization as before.
If surgery done within 6 m ok , If not start plasma exchange 1.5 volume exchange every other day for 5 sessions, single high dose IVIG is given after the last session, 1 w later single dose of rituximab is given, this desensitization protocol can be repeated every 6 m till transplant surgery
In all accepted patients suggested protocol :
1- Induction using ATG in all patients except if there is 6 HLA antigen mismatch ( HLA incompatible donor) in this case it is recommended to use alemtuzumab 30 mg sc at the day of transplant + additional dose of high dose IVIG is given at the time of transplant and within 7-14 days after surgery+ rituximab dose given within 7-14 days after surgery if not given within last 6 m+ solumedrol.
2- Maintenance triple therapy
-Corticosteroids
-Mycophenolate mophetil
-Tacrolimus with trough 7-10 first month and 3-7 thereafter
3- Monitoring patient for DSA every month for first 3 months then every 3 m till 1 y post transplant then yearly
REFERANCES
1- Gebel HM, Kasiske BL, Gustafson SK, et al. Allocating Deceased Donor Kidneys to Candidates with High Panel-Reactive Antibodies. Clin J Am Soc Nephrol 2016; 11:505.
2-Orandi BJ, Garonzik-Wang JM, Massie AB, et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transplant 2014; 14:1573.
3- Vo AA, Peng A, Toyoda M, et al. Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation. Transplantation 2010; 89:1095.
Thanks Sherif
Well done
Dear All
Please remember that the donor pool contains 10,000 to 12,0000 samples in cPRA compared to 50 samples in PRA
cPRA or cRF :
The cPRA is computed from HLA antigen frequencies among approximately 12,000 kidney donors in the United States between 2003 and 2005 and thus represents the percentage of actual organ donors that express one or more of those unacceptable HLA antigens.
It’s significance: by cPRA, it means we can calculate the likelihood that the recipient and donor would be incompatible.
A panel-reactive antibody (PRA) is a group of antibodies in a test serum that are reactive against any of several known specific antigens in a panel of test cells or purified HLA antigens from cells.
Difference between PRA (Panel Reacting Antibodies) and cPRA:
Unlike PRA, the cPRA provides a meaningful estimate of transplantability for most patients, because it is calculated from unacceptable HLA antigens that will preclude offers from predictably crossmatch incompatible donors.
(Calculated PRA (CPRA): The New Measure of Sensitization for Transplant Candidates
J. M. Cecka
First published: 17 December 2009 https://doi.org/10.1111/j.1600-6143.2009.02927.x)
I would transplant this patient according to her crossmatch :
If her crossmatch( CDC & flow cytometry) is positive beside his 97% cPRA, desensitization method is very crucial. If her crossmatch is negative, then no need for desensitization .
Excellent Assafi
Well done
If negative, no need for desensitization. The principle of desensitization is to achieve a negative crossmatch. If the crossmatch is positive, this may need sensitisation and DSA monitoring.
CPRA is a method used measure patient sensitization & classified transplant recipients in multiple transplantation allocation systems. UNOS used a CPRA to measure HLA-A, HLA-B, HLA-C & HLA-DQ frequencies of > 12000 donors who are included in the OPTN.
Virtual cross-match depend on CPRA by using unacceptable Ag so increase allocation for patients with sensitization
Traditional PRA is used to measure either HLA class I &/or classIIAg & expressed as percentage.
Desensitization aimed to removed already performed antibodies &/ or decrease antibodies production & antibody action. Tis done by plasma exchange, IVIG, rituximab, bortizomab, eculizumab & splenectomy ( not longer used).
Desensitization permit for sensitized patients to have a chance for transplantation which may be not feasible without desensitization. But it still carry high risk of post transplant complication as acute rejection that may reach ~70%. Although this high risk, desensitized patients had survival benefit compared to patients on dialysis programs.
References:
PRA is the measure of sensitization to predict the probability to find a compatible donor for kidney transplantation
Is done by using a panel of normal blood-donors as representative of the potential local organ donor pool and patient’s serum,the percentage of this pool of donors to which a patient had reactive Abs is called PRA.
A patient with 80% PRA would be crossmatch incompatible with 80%of donors.
Because of lacking organized guidelines for labs to indicate which PRA should be used ,many Labs chose the highest PRA value among their test platforms
CPRA is based upon unacceptable HLA Ags to which the patients has been sensitized and which,if present in a donor, mean unacceptable risk for the candidate or transplant program.
CPRA represent the percentage of actual organ donors that express one or more of these unacceptable HLA Ags and it is computed from HLA Ags frequencies among 12,000 kidney donors.
The percentage of the people from general population carring that unacceptable Ag is the CPRA of that patient
CPRA provides a more accurate estimate of sensitization because it include both class l and class lol HLA specificities in the calculation which is a major shift from the traditional PRA where class l and class lol specificities are measured separately.
In traditional PRA, a high value mean a high probability of a positive crossmatch.
While in CPRA, a high value should mean a high probability of a negative crossmatch.
In order to do transplantation for highly sensitized patients we must do one of these two options:
1- either choose the the donor toward whom the patients has negative crossmatch.
or
2-Desensitization by one or more of the following:
A-immunomodulation of the recipients by IVIG and plasmapheresis.
B-removal of circulatory HLA Abs by plasmapheresis , immunoadsorption
C-depletion of B-cells by Rituximab
D-complement inhibitors by Eculizumab.
Reference:
issues in kidney disease series-transplantation 2021 by Bhamidipati V.R Murphy & Stephen Z. Fadem
What is the cRF and its significance?
cRF (calculated reaction frequency) or cPRA (calculated Panel reactive antibodies) is based on the HLA antigens to which the prospective recipient has been sensitized (hence called unacceptable antigens) and represents the actual organ donors who have one or more of these unacceptable antigens.
So, if a patient has cPRA of 97%, it means that 97% of the donors have at least on unacceptable antigen.
The significance of cPRA is that donors with unacceptable antigens will not be offered to the patient. So a patient with high cPRA has higher chances to get an offer of a kidney with a negative cross match. (1)
What is the difference between PRA (Panel Reacting Antibodies) and cPRA?
PRA (Panel Reactive Antibody) is a measure to test the probability of finding a compatible donor for a transplant recipient. The process involves cross-matching of the patient’s serum with a panel consisting of lymphocytes from normal blood donors amongst the general population. This result can be calculated and a value can be obtained in percent form. So if a patient has antibodies against 65% of the donor lymphocytes (hence cross-match positive), the PRA comes as 65%. High PRA indicates high chance of a positive cross match. PRA measures clas I and class II antibodies separately. PRA results can vary based on laboratory and time of testing.
cPRA (calculated PRA) is a refined version of PRA as here the donor pool of lymphocytes comes from a large pool of actual kidney donors, hence represents the true picture vis a vis cross-match incompatibility. The assessment for sensitization is more accurate with cPRA as it involves both class I and class II HLA specificities in the final calculation. For cPRA, the laboratories are expected to enter specific unacceptable antigens for the prospective recipient in the computer system. So, cPRA points towards the percentage of prospective donors being declined due to presence of one or more unacceptable antigens. The overall effect of cPRA is that there is a higher chance of getting a negative cross-match organ for the patient. cPRA values do not vary as they are based on a uniform database. (2)
How would you transplant this patient?
This is a highly sensitized patient and desensitization should be done in the patient.
Desensitization protocol for living donor transplant: Injection Rituximab + High dose IVIG
Injection Rituximab 375 mg/m2 on day 0 and day 14, followed by high dose IVIG 2 gram per kg) on days 28 and 42. (3)
Post desensitization, transplant can be proceeded with if CD cross match is negative and Flow cytometry cross match is either negative, or positive with MCS (Mean Channel Shift) <250
In case of deceased donor, if the patient does not receive an offer in 6 months, desensitization needs to be repeated with a protocol involving Plasmapheresis (1.5 plasma volume each) alternate day for 5 sessions, followed by IVIG 2 gram per Kg and Injection Rituximab 375 mg/m2 one week later.
References:
1) Cecka JM. Calculated ORA (cPRA): The new measure of sensitization for transplant candidates. Am J Transplant 2010;10:26-29.
2) Cecka JM, Kucheryavaya AY, reinsmoen NL, et al. Calculated PRA: initial results show benefits for sensitized patients and a reduction in positive crossmatches. Am J Transplant 2011;11:719-724.
3) Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Eng J Med 2008;359:242.
Excellent response.
cPRA: Percentage of donors whose HLA antigens are not expected to be suitable for transplant candidates. This is the probability that the patient will give a positive cross-comparison result. (sensitivity measure).
PRA : It measures antibodies to a person in the blood. The PRA score is expressed as a percentage between 0 and 99%, indicating the likelihood of having antibodies to a particular donor in the blood.
Comparison of PRA and CPRA.
PRA:
– Separately Measure Class I and Class II Antibodies
– Indicator of non-specific reactivity between the recipient and a possible donor sample.
– Positive crossmatch with a donor offer is more likely when PRA is high.
– PRA changes based on the laboratory and the period of testing.
CPRA:
– ClassI and classII are counted together.
– Calculates certain antigens that are undesirable in a large donor database.
– Even with a high CPRA, there is a high probability of a negative cross-match after an organ is offered.
– There are no differences because it is dependent on an uniform database.
For transplantation for this patient :
There is multiple desensitization programs depend on
– Use an innovative protocol that combines IVIG therapy with Rituxan. With this technique, approximately 97% of highly sensitive patients can be successfully desensitized.
– A minimum or high plasmapheresis sessions associated with Intravenous immunoglobulin. Use IVIG therapy to desensitize transplant patients. Treatment lowers antibody levels and blocks the ability to attack the transplanted organ.
– The main challenges are cost and complexity, which may not be feasible even in resource-heavy environments
References:
– Desensitization Protocol in Highly Sensitized Renal Transplant Patients .
Available at : https://www.oatext.com/pdf/TiT-7-195.pdf
– Comparison of PRA with CPRA. Available at : https://scholars.direct/Articles/transplant-surgery/jts-1-002-table3.html
– Chan, Y.P., Wong, M.W., Tang, L.W., Guo, M., Yang, W., Ip, P., Li, P.K., Leung, C.B., Chau, K.F., Lam, J.C. and Yeung, N.K., 2017. A simplified method of calculating cPRA for kidney allocation application in Hong Kong: a retrospective study. Transplant International, 30(12), pp.1234-1242.Available at : https://pubmed.ncbi.nlm.nih.gov/28777478/
Dear All
Will you do desensitisation based on cPRA of 97% regardless of the crossmatch results, bear in mind the crossmatch may be negative if this patient received 000 mismatched kidney?
It the CPRA is 97% and the crossmatch was negative No need for desensitization
Eurotransplant Acceptable Mismatch(AM) program goal was to increase the chance of high sensitized patients to have transplantation . this program add acceptable Ag of HLA recipient , this will expand HLA type based on which allocation take place with mandatory exportation of compatible kidney to AM patient. So the recipient can be transplanted with standard immunosuppressant regime with out desensitization. This program had better outcome & lower cost.
Yes if the patient had compatible donor , she can precede to transplantation with out desensitization.
Ban/Asmaa
Well done
If negative, no need for desensitization. The principle of desensitization is to achieve a negative crossmatch. If the crossmatch is positive, this may need sensitisation and DSA monitoring.
no need for desensitization in this case since the main rule of desensitization is negative cross match
Prof. Ahmed, thank you.
based on cPRA of 97% , Extremely sensitized patients can be transplanted from a negative cross-match donor with out the need of desensitization
Sherif/Rania
Well done
If negative, no need for desensitization. The principle of desensitization is to achieve a negative crossmatch. If the crossmatch is positive, this may need sensitisation and DSA monitoring.
Highly sensetized recipient has 2 problems
First, the low likehood of obtaining a graft without desensitization.
Second, high propability of developing post transplant DSA so immunosuppression should be aggressive.
No need to desensitize , because you have already negative cross-match
cPRA
The HLA sensitization status is traditionally evaluated by the panel-reactive antibody (PRA) assay. However, this assay is method dependent and does not consider the ethnic differences in HLA frequencies
. A calculated PRA (cPRA), based on a population’s HLA frequency and patients’ unacceptable antigens (UAs), correctly estimates the percentage of donors suitable for candidates.
The terms “calculated HLA antibody reaction frequency” (cRF) and “calculated panel reactive antibod- ies” (cPRA) are used synonymously to describe the level of allosensitization, where 0% cRF is nonsensitized, 50% cRF is antibody incompatible with half of a random donor pool, and 90% cRF would be antibody incompatible with 9 out of 10 random donors
The Organ Procurement and Transplantation Network (OPTN), operated by the United Network for Organ Sharing (UNOS), USA, has introduced the calculated PRA (cPRA) since December 2007 to provide a more uniform and accountable method for assessing sensitization to HLAs.
The cPRA is based on the HLA phenotype frequencies of each ethnic group and types of HLA antibodies present in a patient’s serum.
renal transplant candidates with a higher cPRA value would have lower opportunities to find a matched donor. Therefore, the cPRA is a more reliable indicator of the HLA sensitization status than is the classical PRA.(1)
Transplantation of highly sensitized patients
According to 2020 data from the Organ Procurement and Transplantation Network (OPTN), approximately 12 percent of patients on the DDA waiting list are highly presensitized to HLA (defined as ≥80 percent calculated panel reactive antibody [CPRA])
Patients with a willing but HLA-incompatible donor may wait for a deceased-donor organ or receive a living-donor organ through desensitization, kidney paired donation (KPD), or a combination of both. The choice between desensitization or KPD for an individual recipient depends upon the likelihood of finding a suitable match through KPD and the chances of successful desensitization.
The degree of human leukocyte antigen (HLA) sensitization of a potential transplant recipient is first determined at the time of initial transplant evaluation by testing patient sera against solubilized HLA antigens attached to solid beads.
At first perform a multiple-antigen flow cytometry bead assay to screen for the presence of anti-HLA antibodies; if positive, a single-antigen bead assay (Luminex) is performed to identify the specific HLA antigens to which the patient has antibodies.
antigens with a mean fluorescence intensity (MFI) of ≥15,000 are designated as “unacceptable antigens” and entered into UNet, the computer system operated by the United Network for Organ Sharing (UNOS).
If an unacceptable antigen for a specific patient is listed in UNet, kidneys from donors with that antigen will not be offered to the patient.
It should be noted that MFI levels can vary by approximately 20 to 25 percent between HLA labs and that MFI threshold levels used to designate an unacceptable antigen are not standardized across transplant centers.
A calculated panel reactive antibody (CPRA) is computed based upon the patient’s unacceptable antigens; this number reflects both the breadth and depth of the patient’s sensitization. All patients evaluated at our center who have a CPRA ≥30 percent or who are seeking a retransplant are considered to be sensitized and potentially qualify for desensitization. (2)
Reference
1-Shen SW,Chang CK ,etal. Establishment of calculated panel reactiveantibody and its potential benefits inimproving the kidney allocation strategyin Taiwan. Journal of the Formosan Medical Association (2017) 116, 956-963.
2- Up to date Jan 08, 2021.
PRA basically tell us the chance of recipient getting kidney from the pools of donors kidneys. it determine the translatability. For example if PRA = 97% it mean in every 100 kidneys available , the recipient will be eligible for only 3 kidneys. the concept is the same like CDCXM ,only here we are testing recipient serum against multiple donor lymphocytes. In USA ,according to UNOS they allocates some points to those on waiting list and the higher the PRA you have , the more points you get which can you to up in the list. cPRA is the same concept ,but more specific door pools. Higher PRA indicates high immunological risk due to HLA to the presence of HLA antibodies against donor antigens( unacceptable antigens) and sometimes we do accept this risk specially if you a situation of high risk of death if remain on dialysis. There is different desensitization programs based on plasmapheresis( the numbers of sessions can be very depending on the antibody titre) , rituximab, IVIG but the main challenges are the cost, difficulty, and may not be feasible even in high resource setting. some data also confirmed that remaining on dialysis may be the same if you went through desensitization in terms outcome
cPRA: the percentage of donors expected to have HLA antigens that are unacceptable for a transplant candidate. It is the probability for a patient to give a positive cross-match.( measurement of sensitization). it requires large number of samples(Euro transplant’s cPRA calculation is based on HLA phenotype of 6 870 deceased renal donors).1
PRA: is calculated by testing patient’s serum against a panel of donor lymphocytes,it is the percentage of positive cross-match over total number of donor tested.1
to transplant a highly sensitized patient 2 ways are present:
1st selection of donor toward whom the patient has negative cross match
2nd desensitization through a combination of one or more of the following strategies:
1.immunomodulation of the recipient immune system:
a. IVIG either high or low dose in combination with plasmapheresis
b. Tocilizumab larger RCT needed to determine its efficacy in desensitization.
2. removal of circulating anti-HLA ab:
a. plasmapheresis
b. immunoadsorption
c. IgG endopeptidase
3. depletion of B-Cells:
a. Rituximab ( anti CD20 ab)
b. Bortezomib ( proteasome inhibitor)
complement inhibitors:
a. Eculizumab C5 inhibitor
b. C1 esterase inhibitor ( Berinert).2
references:
Thanks, Huda for your excellent input. Will you do desensitisation based on cPRA of 97% regardless of the crossmatch results, bear in mind the crossmatch may be negative if this patient received 000 mismatched kidney?
thanks prof Ahmed
highly sensitized patients can be transplanted with negative cross-match donor without the need for desensitization,
Excellent Huda, well done
If negative, no need for desensitization. The principle of desensitization is to achieve a negative crossmatch. If the crossmatch is positive, this may need sensitisation and DSA monitoring.
Thanks
Well ,
I’ve seen in practice, if you allowed me sir
Highly sensitized patient with PRA 97% , I would do a virtual cross match , check if there where DSAs , will check their MFIs , their ability to fix complement , then if all negative then we could check for non HLA antibodies
Many patients with negatively cross match, have DSAs
What do you think sir
Or is the idea that 000 mismatch would lead to no DSAs , then what about non HLA antibody assessment ?
Calculated reaction frequency (CRF) is the estimation of % of donors that are expected to be HLA incompatable with a certain recipient .
This pool is annualy updated to reflect any HLA types changing within the donor population.
· PRA
-Indicator of general non-specific reactivity between recipient and potential sample of donors
-Measures class-I and class-II antibodies separately
-High PRA indicates high probability of positive crossmatch with a donor offer
-Variation in PRA based on laboratory and time of testing
· CPAR
-Calculates specific unacceptable antigens in the wide donor database
-Class-I and class-II both calculated together
-Even with a high CPRA, high probability of a negative crossmatch once the organ is offered
-No variation as it is based on a uniform database
For transplantation for this patient :
The combination of Pretransplant Plasma pharesis , low-dose IVIG with or without rituximab may prove effective as a desensitization regimen ,also possibly the recent complement inhibitor eculizumab, anti-CD20 obintuzumab, or IgG cleaving enzyme imlifidase can be used (1)
Another option for highly sensitized patients is transplantation with a crossmatch negative donor without any added intervention.
The Eurotransplant Acceptable Mismatch (AM) program was initiated more than 30 years ago to increase the possibility of transplantation for highly sensitized patients ,by allocating deceased donor kidneys on the basis of a match with the recipient’s own HLA antigens in combination with predefined acceptable antigens. Acceptable antigens are those HLA antigens towards which the patients has never formed antibodies, as determined by extensive laboratory testing, thereby creating an ‘extended’ HLA type on the basis of which allocation takes place, in combination with mandatory shipment of compatible donor organs to the AM patient (2)
1- Sethi S, Choi J, Toyoda M, Vo A, Peng A, Jordan SC. Desensitization: Overcoming the Immunologic Barriers to Transplantation. J Immunol Res (2017) 2017:6804678. doi: 10.1155/2017/6804678
2-Heidt S , Haasnoot GW , et al , Highly Sensitized Patients Are Well Served by Receiving a Compatible Organ Offer Based on Acceptable Mismatch. Front. Immunol., 25 June 2021es.