Kidney transplantation in highly sensitized patient is challenging, in spite of advancement in desensitization and pre-transplant therapy. Living kidney transplant is less common among highly sensitized patients especially with accumulating barriers and increasing degrees of sensitization.
This article reviewed the merits and demerits of the alternatives to transplantation in highly sensitized patients , KPD and desensitization therapy.
The probability of finding a donor is getting less with increasing sensitization. It depends on:
· The degree of incompatibility the program or the transplant center is tending to coincide and follow.
· The degree of sensitization (cPRA).
· The size of the donor pool.
Kidney paired donation can be one of :
· Small and single center with internal exchange.
· Large and multiple centers with national exchange.
UNOS/OPTN data analysis regarding KPD among 2 groups of patients followed from 2016 for 1 year ( 262patients with cPRA 99%,528 patients with cPRA 100%):
· The performed living TX was as follows: 13/262(5.0%) and 13/528(2.5%).
· Only 16/26 of these living rTX were performed after KPD.
· The rate of living rTX among KTRs with cPRA<80% was 27% and 14% of these living donations were promoted after KPD.
Despite the revision and development of kidney allocation system to increase the donors pool for highly sensitized patients, still there’s a difficulty in finding a suitable donor for those with high cPRA. These observations suggested the likelihood of performing incompatible rTX to shorten the stay in the waiting list and to avoid the downside of remaining on dialysis.
HLAi-rTX is a relevant option for highly sensitized patients without a suitable donor, provided that the post-transplant mortality and graft loss were noticed with positive XM(FCXM or CDCXM) 1, while the outcome is similar in the presence of a negative crossmatch in those with DSA alone and those with HLA compatibility. Orandi et al 2in a multicenter data analysis found that the living incompatible rTX had a higher survival rate in comparison to those remained on the waiting list or received deceased donation. The survival rate was higher regardless the degree of incompatibility including among patients with DSA and negative XM, those with positive FCXM and CDCXM. Overall, it’s better to undergo kidney transplantation, whatever the degree of incompatibility than remaining on dialysis.
Reference
1. Orandi BJ, Garonzik-Wang JM, Massie AB, Zachary AA, Montgomery JR, Van Arendonk KJ, et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transplant. 2014;14:1573–80.
2. Orandi BJ, Luo X, Massie AB, Garonzik-Wang JM, Lonze BE, Ahmed R, et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med. 2016;374:940–50.
amiri elaf
2 years ago
# Please summarise this article
# Introduction
*Highly sensitized patients had limited chance for renal transplantation, due to ineffective therapies for desensitization; increase the incidence of rejection rates, poor graft survival and more costly. *Options available for highly sensitized patients with an incompatible living donor are paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant.
*This study showed the advantage and disadvantage of paired kidney exchange and desensitization and provides recommendations for patients and providers on the approach to the highly sensitized patient with an incompatible living donor.
# HLA Sensitization and the Probability of Kidney Transplantation
*The first step in counseling a highly sensitized patient is to assess the possibility of finding a suitable donor.
*The probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors.
*With this equation, it is estimated that a patient with a cPRA >99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; and so on.
*For transplant centers that only consider compatible transplants, these figures give a quantifiable approximation of the possibility of finding a suitable donor, either through paired kidney exchange or waiting for a deceased donor.
*The probability of finding a donor also depends on the size of the donor pool. The kidney exchange donor pool can range from small, single-center internal exchanges to large multi-center national exchange programs.
*Given the exponential relationship between cPRA and the number of match runs required to find a compatible donor, achieving living donor transplantation becomes exceedingly unlikely as the cPRA increases above 99%.
# Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
*One of the main role of the revised KAS was to elevate the access to reduce donor kidney transplantation for highly sensitized patients.
*Sensitized recpients receive waitlist points according to a sliding-scale beginning at cPRA 20%.
The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA > 98%, also candidates with cPRA > 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys.
*The KAS has advancing the access to deceased donor kidney transplantation across the spectrum of allosensitization overall, but the allocation policy changes have not improved the most highly sensitized.
# Outcomes Associated with HLA-Incompatible Kidney Transplantation
Study showed that the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
*Recent data indicate that there is little center-level variability in patient and graft survival outcomes associated with HLA-incompatible living donor kidney transplantation, suggesting that center-specific factors, such as volume of incompatible transplants or type of desensitization protocol employed, have minimal impact on outcomes.
*Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatiblekidney transplantation the best choice.
# Role of Kidney Paired Donation
*It gives a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor
*Sensitized candidates, many are unsuccessful in finding a donor through paired exchange. Data from the NKR indicates that approximately 35–40% of all candidates remain unmatched within a year.
* The percentage of unmatched candidates is higher for those with blood type O (43%) or who are highly sensitized (cPRA 97%; 58%). For those who have the combination of both O blood type and cPRA 98%, only approximately 10% successfully find a donor within 1 year.
# Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
The following considerations should be recognized:
*Assess the Feasibility of Desensitization by performing Luminex single antigen
testing to identify DSA and perform a CDC and flow cytometry crossmatch.
*Desensitization for a positive CDC crossmatch not recommended.
*Not proceed with transplant with a flow cytometry crossmatch median channel shift > 250
or a DSA relative intensity score (RIS) 17.
*The RIS is a risk score that accounts for the binding strength of DSA and assigns
10 points for each DSA in the strong-binding range (MFI) 10,000, 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI 17 is associated with a positive predictive value of 91% for ABMD.
# Assess Alternatives to HLA-Incompatible Kidney Transplantation Paired Kidney Exchange
The kidney paired donation may be recommended for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization and to discuss all details with both recipient and donor.
# Deceased Donor Transplantation
Study showed that 58% of deceased donor transplants performed among candidates with cPRA >99% were in the presence of DSA. Centers that are unwilling to perform an HLA-incompatible transplant should refer these patients to a center that is experienced with desensitization.
Theepa Mariamutu
2 years ago
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates
The choice of transplant for sensitised patients was restricted due to lack of effectiveness of desensitisation therapies, higher rejection rate, and poor graft outcomes.
Many centres still reluctant to do HLAi transplantation although there is improvement in desensitisation protocols and better outcome compared to remaining dialysis. This results in many highly sensitised patients continue waiting for a compatible donor.
HLA sensitization and the probability of kidney transplantation:
First step in counselling a highly sensitized candidate is to assess the likelihood of finding a matched donor through the following equation:
probability of finding an acceptable match= 1-(cPRA)n, n= no of potential donors.
The transplant centres that only does compatible transplants, these estimates provide a quantifiable approximation of the likelihood of finding a suitable donor either through PKD or waiting for a deceased donor. The probability of finding a donor also depends on the size of the donor pool.
Assessing the probability of deceased donor kidney transplantation in the kidney allocation system era:
US KAS was revised in 2014 to provide easy access to deceased donor kidney transplantation. The sensitised patients receive waitlist points according to a sliding scale which begins at cPRA 20%. Number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA more than or equal to 98%. In addition, candidates with cPRA more or equal to 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys.
The changes in KAS resulted in an increase in the number of transplants for highly sensitised patients. Not only that, it also improved access to DCD.
Such changes in the KAS did not improve transplantation rates for high-risk candidates with cPRA>99.95%, and this resulted in candidates should be advised to undergo HLAi transplantation.
Outcomes associated with HLA-incompatible kidney transplantation:
Graft outcome is the main consideration in HLAi transplants or highly sensitised Transplants. The effect of HLAi transplant on graft and patient survival is only evident when the crossmatch is positive. Meanwhile, the presence of a negative crossmatch, the risk of graft loss or death was comparable between transplants performed with DSA alone and those that were HLA compatible.
The desensitisation protocols vary from centre to another, non-prospective, randomised studies comparing those protocols. So, there is variability in patient and graft cervical outcomes associated with HLAi LRRT centre level variability. It suggests that centre specific factors according to volume of incompatibility transplants or type of desensitisation protocol used and have minimal impact on outcomes.
Role of kidney paired donation:
PKD is the platform for those patients with an incompatible donor to find more better matched donors. However, many sensitised candidates fail to find a compatible donor through PKD.
National kidney registries (NKR) and alliance for paired donation (APD) showed that for highly sensitised candidates, PKD should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one. Desensitization should be considered as an adjunct to paired exchange for difficult to match patients.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor:
Assess the Feasibility of Desensitization
Luminex single antigen testing done to identify DSA and a CDC and flow cytometry crossmatch to assess the suitability of desensitisation.
The Tx is not recommend desensitising a positive CDC crossmatch.
Do not proceed with transplant with a flow cytometry crossmatch median channel shift (MCS) > 250 or a DSA relative intensity score (RIS) ≥ 17.
Participation in a paired kidney exchange program if HLA-incompatible transplantation is predicted to be of high risk.
The RIS is a risk score those accounts for the binding strength of DSA and is calculated as follows:
10 points for each DSA in the strong-binding range (MFI ≥ 10,000).
5 points for each moderate-intensity DSA (MFI 5000 to 9999).
2 points for each weak DSA (MFI < 5000).
A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
Assess Alternatives to HLA-Incompatible Kidney Transplantation Paired Kidney Exchange
PKD may be considered for patients with an incompatible donor although it is predicted that the transplant is feasible with desensitization. It is important to counsel regarding all the potential benefits and harm of the process with the candidate although patient’s blood group and cPRA, could limit the possibility of finding an acceptable donor.
Deceased Donor Transplantation
LRRT is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option for better life. But high cPRA is a limiting factor for this option. Desensitization may be considered to achieve successful transplantation
ahmed saleeh
2 years ago
The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant.
Probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization.
A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find acompatible donor .
cleardiscussionofthe risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation when the likelihood of finding a compatible donor is prohibitively low.
Akram Abdullah
2 years ago
Aims of the study is to review the treatment options for highly sensitized kidney transplant candidates & provide recommendations.
Highly sensitized kidney transplantation is challenging, historically it was not feasible because of limited ineffective therapy , poor graft outcomes , nowadays there are many options for those patients, either to go for paired exchange program, desensitization or cadaveric kidney transplant.
Transplantation in highly sensitized candidates is better than waitlisted.
The first step in counselling the patient is to find a suitable donor .if not available , assess the probability of deceased donor KTX by kidney allocation system , which depends on c PRA patient more than 80% get more points to get the donor, but in case of cPRA >99% the advice to consider incompatible transplantation.
The outcomes associated with HLA-Incompatible Kidney Transplantation, higher degrees of crossmatch incompatibility being associated with increasing risk of patient & graft outcomes.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
Initial step is to assess the amenability of desensitization
to a potential living donor by performing SAB, DSA FCXM
we do not proceed with transplant
with a FCXM median channel shift > 250
or a DSA relative intensity score (RIS) ≥ 17.
Assess Alternatives to HLA-Incompatible Kidney
Transplantation
Paired Kidney Exchange
kidney paired donation may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization.
MICHAEL Farag
3 years ago
Introduction
Despite the advent of newer protocols for desensitization and favorable outcomes compared to remaining on dialysis, many centers remain reluctant to perform HLA-incompatible kidney transplants. Desensitization regimens can be resource intensive, costly, and require clinical, immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful implementation.
This review addressed the pros and cons of paired kidney exchange and desensitization and provides recommendations.
HLA Sensitization and the Probability of Kidney Transplantation
Probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors, the probability of finding a donor also depends on the size
of the donor pool. If participation in a paired kidney exchange program is being considered, the number of potential donors available for exchange should be evaluated.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
Although the revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates.
Closer examination of transplantation rates by unrounded cPRA reveals that
candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die. These observations suggest that patients in the highest cPRA categories should be advised to consider incompatible transplantation. Although compatible transplantation remains a remote possibility for patients with cPRA ≥ 99.95%, the likelihood of finding a compatible donor is low, and, at a minimum, an extended waiting time is expected.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
Graft outcome is an important consideration when choosing between transplant options for highly sensitized candidates.
It is important to recognize that HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility,
such as DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch. The distinction is relevant, as outcomes differ according to the degree of incompatibility.
Role of Kidney Paired Donation
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange, but they should recognize that this approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor -Assess the Feasibility of Desensitization
Our initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch
Each center has criteria to assess for feasibility of desensitization and in this article the criteria as follow:
we do not recommend desensitization for a positive CDC crossmatch, we do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17. The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) ≥ 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000). A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
If HLA-incompatible transplantation is predicted to be prohibitively high risk based on these criteria, we recommend participation in a paired kidney exchange program.
–Assess Alternatives to HLA-Incompatible Kidney Transplantation
– Paired Kidney Exchange
kidney paired donation may be a consideration for patients with an incompatible
donor even if it is predicted that the transplant is feasible with desensitization. A recommendation to participate in kidney paired donation should include a detailed discussion with both recipient and donor about the expectations of participation, the likelihood of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis leveraged against the risks of desensitization and HLA-incompatible transplantation, and a time limit for participation before determining the futility of kidney exchange.
In our opinion, paired kidney exchange should not be offered to all patients with an
incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with
desensitization
-Deceased Donor Transplantation
Conclusion
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization. Although participation in a kidney paired donation program offers the possibility of finding a compatible
or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O. A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find
a compatible donor.
kumar avijeet
3 years ago
So in a nutshell it is very difficult to get a tx for highly sensitized patient, which he/she gets through desensitization/kpd/deceased donation tx.So deciding between the above methods is really nailbitting.
In HLAi tx all method CDC,FCXM,Single bead assay to be done, if CDC postive or FCXM positive with with mcs >250 or DSA with RIS (relative intensity score)>17, then patient should not be put on desensitization and look for other methods like KPD and KPD with desensitization or deceased donation as in above situation graft and patient outcome is very poor.
Those with lower incompatibility may be considered for desensitization because which is better than waiting on deceased donor list or hd.
Now for highly sensitized patient in deceased donation higher points are given through KAS, which increases tx.
Ahmed Omran
3 years ago
Highly sensitized patients have 2 options; either to receive transplant from living incompatible donor ; directly or through paired exchange program or a deceased donor. When possibility of HLA compatible donor is very low, desensitization before HLA incompatible transplant is an option.
The possibility of finding an acceptable donor relies on the size of the donor pool and the thresholds for incompatibility in a given transplant program. With increasing c PRA value, the number of match runs required to have a 95% chance of finding an acceptable donor increase exponentially (9 runs for a c PRA of 70%, 59 runs for a c PRA of 95% and 30000 runs for a c PRA of 99.99%). The probability of finding a deceased donor has increased post-2014 due to implementation of newer kidney allocation system (KAS), which gives highest priority to c PRA ≥98%, so led to 5 times increase in transplants of patients with c PRA ≥99%. However, with newer KAS era, the patients with c PRA ≥99.95% are still not able to get a transplant.
Based on these data, HLA incompatible transplant should be considered for such highly sensitized patients. It was found that HLA incompatible transplant in patients with negative crossmatch has no effect on mortality and graft loss, with poorer outcomes only with a positive cross match, worse with degree of crossmatch incompatibility. The number of transplants and type of desensitization protocols did not have any effect on the graft outcomes. There is survival advantage comparing results of incompatible transplant to remaining on dialysis.
A large proportion of these highly sensitized patients are not able to have donor through kidney paired donation (KPD) programs, especially blood group O or c PRA ≥97%. It was found that transplant rates of 60-65% at one year So, a KPD program can be used to find a more acceptable donor.
The approach towards highly sensitized patient with a living donor includes getting a CDC, FCXM and Luminex bead assay. A positive CDC crossmatch or FCXM with median channel shift (MCS) > 250 or a DSA relative intensity score (RIS) ≥17 should not be taken up for desensitization and be listed in a KPD program, due to high probability of AMR. Otherwise, with discussion of pros and cons of remaining on waitlist vs having incompatible donor kidney after desensitization, incompatible living donor transplant can be proceeded for. Also, deceased donor following desensitization can be carried out, especially with cPRA ≥99.95% after adjusting MFI cut-offs of unacceptable antigens to bring down the c PRA to <99.95%.
Making early decision is needed considering remaining on waitlist or getting an incompatible transplant ;living or deceased, after assessing the probability of having compatible donor, the crossmatch results and the MFI levels.
MOHAMED Elnafadi
3 years ago
in past kidney tranx for sesetized patients was unlikely and has no promising outcome due to ineffective therapies for desensitization, high rejection rates, and poor graft survival,also Desensitization regimens can be resource intensive,costly,and require clinical,immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful tranx.
he most intensely sensitized candidates tend to be transplanted mainly through deceased donation. This is undoubtedly related to the challenges of finding a compatible donor through the living donor pool.
increasing cPRA always carry the risk of not having a kidney donor , the aim of kidey allocation system is to increase the access of highly sensitized patients to deceased donor kidney transplant.
Outcomes Associated with HLA-Incompatible Kidney Transplantation range from mild with low-level DSA and negative crossmatch to a higher degree of incompatibility with positive crossmatch.
kidney paired donation can give agood solution for those highly sensetized patients by having asuitably matched donor through paired kidney exchange.
Deceased Donor Transplantation cosidered ahope for highly sensetized patients not suitable for living donor tranx.
all of the previous solutions whether paired kidney exchange or deceased kidney donation require having desensitization as a necessary component for successful transplanx.
Mohamed Essmat
3 years ago
High degree of sensitization makes living donor transplantation more hard As the cPRA increases above 99%, the possibility of receiving a living donor graft becomes unlikely. The revision of kidney allocation system (KAS) aimed to increase the access of highly sensitized patients to deceased donor kidney transplant. It resulted in five-fold increase in number of transplantation in highly sensitized patients with cPRA >99%. However, highly sensitized patients with cPRA :99.95% remain unlikely to receive transplantation. The outcome of transplantation varies according to the degree of compatibility It ranges from mild incompatibility (low level DSA with negative crossmatch) to high level incompatibility (DSA with positive FCXM or CDCXM) Patients with DSA but negative cross-match have same risk of graft loss and mortality as HLA compatible transplants. Studies showed that the outcome of kidney transplantation (regardless the type of donor) is better than remaining on dialysis waiting for more preferable donor. Kidney paired donation provides patients with incompatible donor to find more suitably matched donor. However, many highly sensitized patients fail to find donor. Desensitization is not recommended in case of positive CDCXM In case of positive FCXM with median channel shift>250 or DSA RIS>/=17, it is not recommended to proceed with transplantation. These criteria predict high risk incompatible transplant which is better to be avoided. KPD should be considered despite feasibility of incompatible transplant as incompatible transplant is associated with increased risk of graft loss and mortality compared to compatible transplants. Patients with broad HLA sensitization, if living donor transplantation is not feasible, deceased donor transplant will be an option. If there is a low probability of finding compatible donor, desensitization should be considered. Conclusion: Desensitization may be considered in highly sensitized patients who have a living donor. Combination of both KPD and desensitization is more beneficial If there is a low probability of finding donor, desensitization and incompatible transplants should be considered .
Jamila Elamouri
3 years ago
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates
Transplant highly sensitized patients still have favourable outcomes when compared with those remaining on dialysis. Nevertheless, many transplant centres are reluctant to perform HLA-incompatible kidney transplants.
Like other transplant candidates, highly sensitized candidates can receive transplants from either living or deceased donors. However, living donor transplantation is progressively less common and the main option for them is a deceased donors.
A highly sensitized candidate with an incompatible living donor can participate in the KPD program, to increase the chance to find a more compatible donor. Or wait for a deceased donor, or proceed with a direct donation with an incompatible live donor. HLA Sensitization and the Probability of Kidney Transplantation: The first step in counselling a highly sensitized candidate is to assess the likelihood of finding a suitable donor who differs from one program to another according to their thresholds for incompatibility. Probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors It is estimated that a patient with c PRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor, which increases to 600 match runs for a candidate with c PRA 99.5%. In centres that perform incompatible transplants, the number of the match runs estimated to find a suitable donors is less. The probability to find a donor also depends on the size of the donor pool. The kidney exchange donor pool can range from small to large multi-centre international programs.
Assessing the Probability of Deceased DonorKidney Transplantation in the KidneyAllocation System (KAS) Era
Even with KAS that has been revised in 2014 in UK, the probability to transplant highly sensitized candidate with c PRA ≥ 99.95% remain low and these patients are more likely to be removed from the waitlist or die. These patients should be advised to consider incompatible transplantation.
Outcomes Associated with HLA-IncompatibleKidney Transplantation
The outcomes differ according to the degree of incompatibility. Which range from mild with low-level DSA and negative crossmatch to a higher degree of incompatibility with positive crossmatch.
Multi-centre study revealed that the risk of HLA incompatibility on post-transplant mortality andgraft loss was only observed in the presence of a positivecrossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increased risk of bothoutcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone or those that were HLA-compatible. Many studies reveal that it is generally better to undergo kidney transplantation from any donor type rather than remain on dialysis in an attempt to wait for a more preferable donor.
Role of Kidney Paired Donation
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange. But this approach yields only small number of highly sensitized patients get successful donor.
Approach to the Highly Sensitized Candidatewith an Incompatible Living Donor
According to the authors, the initial step is to assess the ability of desensitization to a potential living donor by performing Luminex single antigen test and perform a CDC and flow cytometry crossmatch.
The authors do not recommend the following:
1- desensitization for a positive CDC crossmatch, although successful transplantation can be in this setting.
2- To proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA RIS ≥ 17.
RIS is the binding strength of the DSA, it is assigned as the following:
DSA with MFI ≥ 10,000 given 10 points
DSA with MFI ≥ 5000 – 9999 given 5 points
DSA with MFI < 5000 given 2 points
Resistant index score (RIS) ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
If by using these criteria the probability of the transplantation is a seriously high risk, it should be prohibited.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
1- Paired kidney donation
2- Deceased donor Conclusion:
The authorsrecommend a clear discussion of the risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation when the likelihood of finding a compatible donor is prohibitively low.
Zahid Nabi
3 years ago
Historically, transplant options for highly sensitized kidney transplant candidates were limited due to ineffective therapies for desensitization, high rejection rates, and poor graft survival.This article has again tried to devise a scheme to transplant this pool of highly sensitized patients.
The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor trans- plant.
Transplant programs vary in their thresholds for incompatibility, and as such, the likelihood of finding a suitable donor may differ from one program to another.
The fact that having a cPRA of 99% makes it almost impossible to find a living donor even if recipient is part of KPD programme. UNOS data showed that only 2.5% of such recipients got a living donation.
The revised 2014 KAS in USA helped to find more donors for cPRA upto 99% but for those with CPRA 99.5% or above still were unable to find a suitable matched donor.This means that patients in this CPRA category should be advised to consider incompatible transplant.
The outcome of such transplants differ according to the degree of incompatibility.
According to study by Orlando BJ and colleagues risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compat- ible.
The choices for a highly sensitized patients are few they might have to decide at some stage to accept incompatible donor or to forgo.The hope lies in the fact that a multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario .
First step is to assess the feasibility of desensitization.
Identify DSA. Binding strength of DSA is also important which is interpreted by RIS score. The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) ≥ 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI 250. In such cases participation in paired kidney exchange programs is advised.
Wee Leng Gan
3 years ago
Management options for HLA incompatible living donor kidney to highly sensitized kidney transplant recipients.
HLA incompatible kidney transplantation remain a challenged due to expensive desensitization regimens. Improper desensitization protocol lead to high rejection rate and graft failure. This journal addressed the rational of paired kidney exchange and desensitization among HLA incompatible kidney transplant recipients.
In paired kidney exchange program the kidney exchange pool is highly dependent on the setting of transplantation center. Furthermore, achieving living donor transplantation is challenging if c PRA increases more than 99%. The probability of finding an acceptable match = 1- (cPRA)n.
According to 2014 KAS, sensitized candidates receive waitlist points base on sliding-scale beginning at cPRA 20%. This resulted in exponential increase in the number of kidney transplantation performed in highly sensitized recipients with cPRA more than 99%. Unfortunately, recipients with cPRA more than 99.95% still having low transplantation rate which ultimately succumbed to their underlying morbidity. Compatible transplantation is the only hope for those with cPRA more than 99.95%. But, in real world experience, the probability to get compatible donor is low with exhausted waiting time.
The outcome of HLA incompatible kidney transplant is greatly dependent on the severity of the incompatibility. In mild incompatibility, low DSA is associated with negative crossmatch. On the other hand, high incompatibility is associated with high DSA in flow cytometry or complement-dependent cytotoxicity crossmatch. High HLA incompatibility is associated with renal graft rejection, graft failure and mortality.
There are no concrete evidence to support the transplant outcome for different desensitization protocol from various transplant centers. Recent data support that following desensitization protocol at respective centers, HLA incompatible living kidney transplant has better survival rate compare to decease kidney transplant or remain at waiting list.
Paired kidney exchange may find a more suitably matched donor for HLA incompatible recipients unfortunately the successful rate is low especially blood group O. For highly sensitized kidney transplant recipients, kidney paired donation should be used as a tool to search for suitable donor, but not necessarily a HLA compatible one. Desensitization is adjunct to paired kidney exchange for HLA incompatible living kidney transplant.
The initial step for HLA incompatible living donor kidney transplant is to assess the amenability of desensitization by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch. However, desensitization is not recommended for positive CDC crossmatch. Proceed with paired kidney exchange program if flow cytometry crossmatch median channel shift more than 250 or a DSA relative intensity score more than 17. Desensitization is essential for successful HLA incompatible deceased donor transplantation if the cPRA is more than 99.95%.
In summary, combined approach which consisting of both desensitization and kidney paired donation is essential in dealing with HLA incompatible living donor kidney transplantation base on risks and benefits.
Mohamed Essmat
3 years ago
High degree of sensitization makes living donor transplantation more hard As the cPRA increases above 99%, the possibility of receiving a living donor graft becomes unlikely. The revision of kidney allocation system (KAS) aimed to increase the access of highly sensitized patients to deceased donor kidney transplant. It resulted in five-fold increase in number of transplantation in highly sensitized patients with cPRA >99%. However, highly sensitized patients with cPRA :99.95% remain unlikely to receive transplantation. The outcome of transplantation varies according to the degree of compatibility It ranges from mild incompatibility (low level DSA with negative crossmatch) to high level incompatibility (DSA with positive FCXM or CDCXM) Patients with DSA but negative cross-match have same risk of graft loss and mortality as HLA compatible transplants. Studies showed that the outcome of kidney transplantation (regardless the type of donor) is better than remaining on dialysis waiting for more preferable donor. Kidney paired donation provides patients with incompatible donor to find more suitably matched donor. However, many highly sensitized patients fail to find donor. Desensitization is not recommended in case of positive CDCXM In case of positive FCXM with median channel shift>250 or DSA RIS>/=17, it is not recommended to proceed with transplantation. These criteria predict high risk incompatible transplant which is better to be avoided. KPD should be considered despite feasibility of incompatible transplant as incompatible transplant is associated with increased risk of graft loss and mortality compared to compatible transplants. Patients with broad HLA sensitization, if living donor transplantation is not feasible, deceased donor transplant will be an option. If there is a low probability of finding compatible donor, desensitization should be considered. Conclusion: Desensitization should be considered in highly sensitized patients who have a living donor. Combination of both KPD and desensitization is more beneficial If there is a low probability of finding donor, desensitization and incompatible transplants should be considered .
Wael Jebur
3 years ago
The options for highly sensitized patients:
1) Life donor transplantation: it’s quite difficult to find HLA matching donor when cPRA is 99%.
However, paired kidney donation PKD program can facilitate the transplantation significantly. Nevertheless, highly sensitized patients might not be matching any donor and continue on hemodialysis or removed from the waiting list.
2) Cadaveric kidney transplantation:
The Kidney Allocation System KAS: Prioritizes the transplantation for highly sensitized patients by giving them 4 points, according to HLA matching..the draw back, is that ,there might not be matching donor when cPRA is 98-100%.
One strategy is to extend to regional and national registry ,which has similarly improved the percentage of highly sensitized patients who got there transplanted kidney.
3) HLA Incompatible HLAi transplantation;
For life donor transplantation. Desensitization protocol can be combined with PKD to further facilitate the selection of less immunogenic donor.
DSAs are assessed by Luminex assay.
Recommendation against desensitization in the following situation:
1) Positive CDC.
2) flow cytometry cross match with median channel shift of >250.
3) DSA Relative intensity score RIS of more than 17:
RIS is a risk score that account for the DSA binding strength ,and assigned 10 points for each DSA of MFI of 10000 or more, and 5 for DSAs score of 5000 -9999 MFI. And 2 for each DSAs strength of <5000.
RIS of more than 17 is associated with a positive predictive value of 91% for AMR.
In high risk HLAi transplantation (as per criteria set earlier), PKD program is recommended.
The disadvantage of remaining on dialysis has to be leveraged against the risks of HLAi transplantation and desensitization programs.
It has been shown ,that ,after amendment of KAS, 54% of deceased donor allograft recipients have DSAs when cPRA is more than 99%.
Balaji Kirushnan
3 years ago
Transplanting across a positive cross match remains a challenge.
Highly sensitized patients who are waiting in the deceased donor program list have increased chance of mortality and morbidity when compared to transplantation with donor after desensitization. In other words, transplantation even if HLA incompatible should be attempted after desensitization as there is enough evidence to show that graft and patient expectancy is the same for HLA incompatible renal transplant as compared to deceased donor recipient.
Transplant programs vary in their threshold for allocating kidneys. The relationship between finding a compatible donor for those with cPRA is expressed as
Probability of finding a compatible donor = 1- (cPRA)n , where n is the number of donors in the population. With the above equation it is clear that many match runs are needed to identify a compatible donor. For eg. 3000 match runs for a patient with cPRA of 99.9%. According to the UNOS only 5% of the cPRA 0f 99.9% have received compatible donors as of the year 2016.
The probability of kidney allocation in the current kidney allocation system needs to be discussed. It depends on the number of donor in the population available. The more the population and donors willing to donate the organs, the better would be the transplant outcome. Prior to 2014 KAS, those candidates with cPRA >80% were given 4 more points in the kidney waitlist. But this did not improve the chance of allocation for those patients with cPRA of 99 and 99.5% patients as still their probability of getting a matched kidney donor still remained <10%. So after 2016, the KAS was revised and an exponential sliding scale allocation system of points were given starting from cPRA>20%. This resulted in improvement in kidney allocation for those with very high cPRA>99%.
Paired kidney donation is an alternative to those who are unable to find a suitable donor in KAS with high cPRA. In many centers only 50% were able to receive a suitable kidney donor through paired kidney donation. Paired kidney donation becomes a problem when the blood group is O positive and those with cPRA>90%, the success rate of transplant at the end of 1 year is less than 10%.
The first step in assessment of transplant in a highly sensitized patient is to know the degree of sensitization. CDC, Flowcytometry and SAB Luminex assay need to be done. The CDC positive cross match recipients will never benefit from desensitization. In FCXM we determine the Median channel shift. If MCS >250 is a relative contraindication for transplant. DSA SAB MFI >5000 is also a contraindication for desensitization. The Relative Intensity Scoring (RIS) is calculated for the binding strength of DSA. RIS score of 10 for each DSA MFI>5000, RIS of 5 for each MFI DSA between 1000-5000, RIS score of 2 for weak DSA MFI <1000. The total RIS >17% is associated with highest risk of transplant and it is contraindicated even for desensitization.
Centers who do not routinely do desensitization should refer the patients to places were routine desensitization is done and transplant is feasible. Paired kidney exchange should not be offered as a blanket treatment to those with high PRA as still the rates of kidney allocation for blood group O and cPRA >90% is low. A combined desensitization protocol with paired kidney exchange could help these patients.
Ahmed Abd El Razek
3 years ago
This summary highlights important recommendations for the highly sensitized patient with an incompatible living donor in order to avoid lengthy dialysis with considering that the difficulty of finding a biologically compatible donor, the degree of HLA-incompatibility and their associated outcomes in comparison to compatible transplantation. Introduction Transplant challenges for highly sensitized renal recipients are limited due to ineffective therapies for desensitization, high rejection rates, poor graft survival keeping in mind the cost and urgent need for clinical, immunology, and nursing expertise along with blood bank and plasmapheresis capabilities for successful implementation. HLA Sensitization and the Probability of Kidney Transplantation
First step in counseling a highly sensitized renal transplant candidate is to assess find a suitable donor. The relationship between calculated panel reactive antibodies (c PRA) and the probability of finding a compatible donor is expressed as: Probability of finding an acceptable match = 1- (c PRA )n, where n = the number of potential donors . So finding a donor to a tx recipient of c PRA 99% is somehow impossible . Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era KAS target was to increase access to deceased donor kidney transplantation for highly sensitized candidates. Even though KAS has improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates. These observations suggest that patients in the highest c PRA categories should be advised to consider incompatible transplantation. Outcomes Associated with HLA-Incompatible Kidney Transplantation Outcomes differ according to the degree of incompatibility.it ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative cross match, to higher levels of incompatibility, such as DSA in the presence of a positive flow cytometry or Complement-dependent cytotoxicity (CDC) cross match. A large multi-center study involving 22 transplant centers performing HLA-incompatible kidney transplantation compared patient and graft survival outcomes among living donor kidney transplant recipients with varying degrees of HLA-incompatibility found that post-transplant mortality and graft loss was only noted in the existence of a positive cross match. While in the presence of a negative cross match, the risk of graft loss or death was equal to transplants performed with DSA alone and those that were HLA-compatible. The most common desensitization protocols, depend on high-dose IVIG with or without rituximab versus low-dose IVIG in conjunction with plasmapheresis. Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients. Reflecting that it is better to go for kidney transplantation from a donor of any type rather than remain on dialysis in a trial to wait for a more suitable donor. Role of Kidney Paired Donation In a single-center study of 22 living donor kidney transplants facilitated because of a DSA against the intended living donor, only 10/22 (45%) were able to be achieved with a compatible donor after kidney paired donation. The 12 DSA-positive transplants had donors with lower expected immunological risk than their previously intended donors. Especially after considering that data from the NKR (National Kidney Registry) claims that approximately 35–40% of all candidates remain unmatched within a year with higher values for those with blood type O (43%) or being highly sensitized (c PRA 97%; 58%) of waiting time reached to 671 days. So, kidney paired donation should be viewed as a solution for finding a more suitable donor, but not necessarily a compatible one with the option of desensitization when needed. Assess the Feasibilityof Desensitization According to Luminex single antigen testing to identify DSA , CDC , flow cytometry cross match and mean fluorescence intensity (MFI) decision of desensitization is designed. Assess Alternatives to HLA-Incompatible Kidney Transplantation A recommendation to participate in kidney paired donation program should include a detailed discussion with both partners about the expectations of participation, the probability of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis against the risks of desensitization and HLA-incompatible transplantation, and a time limit for participation before determining the benefit of kidney exchange. Deceased Donor Transplantation Desensitization should be considered as a necessary component for successful transplantation. After revised KAS implementation program, Houp et al. reported that 58% of deceased donor transplants performed among candidates with c PRA 99% were in the presence of DSA. Conclusions Highly sensitized kidney transplant patients who areready to have a living donor should be considered for desensitization. kidney paired donation program offers the possibility of finding a more suitably matched donor. Therefore, a combined approach consisting of both desensitization and kidney paired donation seems to be more successful.
Hamdy Hegazy
3 years ago
Rationalizing incompatible living donor renal transplantation for highly sensitized candidates.
Highly sensitized renal transplant candidates face a limited option of treatment because:
1- Ineffective desensitization therapies.
2- High rates of rejection.
3- Poor graft survival.
Many centers remain reluctant to perform HLA incompatible renal transplantation.
Highly sensitized kidney transplant candidates tend to receive deceased donation more than living donation.
Options for highly sensitized renal transplant candidates include:
1- Paired kidney exchange program.
2- Direct donation with an incompatible living donor.
3- Waiting for a deceased donor transplant program.
The probability of finding an acceptable matched donor = 1- (cPRA)n
Where n= number of potential donors.
Data from UNOS 2016, after 1 year follow up, revealed the following:
13/262 (5%) in recipients with c-PRA>99%.
13/528 (2.5%) in recipients with 100% were from a living donor.
Only 16 of theses 26 recipients had living donors via paired kidney donation.
Mild HLA incompatibility means low level of DSA and negative crossmatch.
High HLA incompatibility means high level of DSA and positive crossmatch detected by flowcytometry or CDC which is usually associated with patient mortality and graft loss.
There are different desensitization practices between transplant centers. There is no study to compare desensitization protocols.
Desensitization protocols include either:
1- High Dose IVIG +/- Rituxmab.
2- Low dose IVIG+ Plasmapheresis.
Role of kidney paired donation:
Data from 9 years of KPD from National Kidney Registry revealed the following:
239/2037 (11.7%) required desensitization because crossmatch incompatibility (222) or ABO incompatibility (17).
35-40% of all candidates remain unmatched within a year.
Only 10% of blood group O candidates with c-PRA>98% found a donor.
Waiting time to transplant for blood group O with c-PRA>95% was reported 671 days.
Approach to highly sensitized candidates with an incompatible living donor:
1- Assess feasibility of desensitization by Luminex SAB or flowcytometry or CDC (to identify DSA).
2- It is not recommended to do desensitization for a positive CDC crossmatch.
3- It is not recommended to proceed for Tx when flowcytometry medium channel shift>250 or DSA RIS >17.
4- Paired kidney exchange should not be offered to all patients with an incompatible donor especially if the patient’s c-PRA and blood type predict a low likelihood of finding a match through PKE and the flowcytometry crossmatch indicates a high likelihood of successful transplant with desensitization.
5- Deceased donor transplantation.
Naglaa Abdalla
3 years ago
Highly sensitized patients have limited options for kidney transplant due to:
1- Ineffective therapies for desensitization.
2- High rejection rates.
3- Poor graft survival.
It is very important to assess the likelihood of finding a suitable donor.
The probability of finding a suitable match =1 – (cPRA) where n is = the number of potential donors.
It was found that for a patient with cPRA of 99% may need up to 300 match runs to find a compatible donor, but this increases up to 600 match runs for a patient with cPRA of 99.5%. Another important factor is the size of donor pool.
Kidney Allocation System (KAS) was revised in 2014 to increase access to deceased donor kidney transplant for highly sensitized patients : these patients receive wait list points according to sliding scale beginning at cPRA 20% so the number of point increase exponentially with cPRA and the priority was for those with cPRA ≥ 98%. For patients with cPRA >99% have a longer donor pool through regional and national sharing of deceased kidney donors.
But this revised KAS did not help the most sensitized patient with cPRA ≥ 99.95% and are more likely to be removed from the list or die. They should be advised for incompatible transplant. Outcomes Associated with HLA –Incompatible kidney transplantation
A large multicenter union of 22 transplant centers that perform HLA – incompatible kidney transplant compared patients and graft survival outcomes among living donor kidney transplant recipients with varying degrees of HLA incompatibility, found that the risk of HLA- incompatibility on post-transplant mortality and graft loss was only observed in the presence of positive crossmatch and as the more severe of this , the risk become higher for both. But if there is negative crossmatch the risk for both outcomes very similar between transplants performed with DSA alone and those with compatible HLA.
A prospective randomized trails comparing the most common desensitization protocols :high dose IVIG with or without Rituximab versus low dose IVIG in conjunction with plasmapheresis is needed.
A multi-center data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched control who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients so it is a best choice. Role of Kidney Paired Donation:
Paired kidney exchange may provide a more suitable donor for highly sensitized patients. In a single center report of 22 living donor kidney transplant (have DSA against the intended living donor) only 10/229(45%) were transplanted with a compatible donor after kidney paired donation.
In a comprehensive summary of experience of 9 years of kidney paired donation through the National Kidney Registry (NKR) 239/2037 (11.7%) of all transplants done required desensitization because of crossmatch incompatibility (222/239) or ABO incompatibility (17/239) .
Data from NKR indicates that 35 – 40% of all patients remain unmatched within a year. This percentage is higher is for those with blood group type O (43%) or highly sensitized (cPRA ≥97%, 58%).
Those with combined of both blood group O and cPRA ≥98% only 10% find a donor within 1 year. Same was found in the Alliance of Paired Donation(APD). A approach to the Highly Sensitized Candidates with an Incompatible Living Donor:
1- Assess the feasibility of desensitization
a. Identify DSA by doing luminex single antigen test.
b. Do CDC and flow-cytometry crossmatch.
2- Assess alternatives to HLA incompatible kidney transplant;
a. Paired kidney exchange: the authors recommended a detailed discussion with both thr recipient and donor about the expectations, the possibilities of finding a compatible or more suitable matched donor. The disadvantages of remaining on dialysis versus the risk of desensitization and HLA incompatible transplant and limitation of time.
b. Deceased donor transplant:
Identify a suitable donor by knowing the exponential relationship between cPRA and the number of potential donors.
Desensitization for highly sensitized patients.
After revision of KAS implementation, Houp. etal (single center experience) reported that 58% of deceased donor transplants performed among patients with cPRA ≥ 99% were in the presence of DSA.
Radwa Ellisy
3 years ago
Desensitization although is expensive, costly, and need more expertise, it opened a way for the highly sensitized patient and allow them to receive living donor rather than being on dialysis waiting for a deceased offer
Treatment options for highly sensitized patients include
· Receiving deceased donor
· Waiting for a compatible living donor which is extremely rare
· HLA incompatible tx
· Paired exchange
The probability of sensitized patient for transplantation,
1- Determining the probability of a sensitized patient finding a matched donor
– Essential for counseling the sensitized patient
– Equals: (1- cPRA) and estimates the potential donor
– It estimates the expected no of match run for a recipient to find a suitable donor by a percent 95%. However, it differs according to the center’s policy accepting sensitized patients or not
2- according to the donor pool
The probability of a deceased donor
In the united states, the revised KAS 2014 gave a greater chance for those with a cPRA> 98 by increasing their points exponentially with the cPRA values. However, those with cPRA 9.95% don’t benefit even after the prioritization with
*Definitions for sensitization level: @Low level: DSA with low levels, a negative crossmatch @High levels of incompatibility: DSA with positive flow cytometry or CDC crossmatch.
– In a multicenter consortium, Poor patient survival and graft survival was noted with positive crossmatch and correlated with the degree of incompatibility.
– Whereas patient survival, and graft survival didn’t show a significant difference in patients with DSA only and those with HLA incompatible
– HLA incompatible transplantation is the best option for patients with living donors who failed or without an available paired exchange program, alternatively being on the waiting list for deceased donor carries a worse outcome
· Paired exchange
– 35-40% of recipients are expected to fail to find suitable donors by one year Approach to the highly sensitized patients include:
a. Assess the feasibility of desensitization:
Tests: single antigen bead, CDC, and flow cytometry
Don’t proceed if : positive CDC XM, flow cytometry XM with MCS > 250 or a DSA (RIS) ≥ 17
For those: paired exchange
If failed: waiting for a deceased donor with prioritization according to cPRA
For cPRA >99.95 desensitization done to bring their cPRA below 99.95
Abdulrahman Ishag
3 years ago
The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant.
HLA Sensitization and the Probabilityof Kidney Transplantation;
The probability of finding a donor also depends on the size of the donor pool. The relationship between calculated panel reactive antibodies (cPRA) and the probability of finding a compatible donor is expressed as: Probability of finding an acceptable match = 1- (cPRA)n ,where n = the number of potential donors .With this equation, it is estimated that a patient with a cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a cPRA 99.5% and 3000 match runs for a candidate with cPRA 99.9%.
Assessing the Probability of Deceased Donor Kidney Transplantation
in the Kidney Allocation System (KAS) Era;
Historical data prior to KAS revision indicates that ;
1-The percentage of deceased donor kidney transplants performed among recipients with cPRA 80–97% was proportionally similar to their representation on the wait list .
2-kidney recipients with a cPRA ≥ 98% received disproportionately fewer transplants than expected given their representation on the wait list .
A revision of the US Kidney Allocation System (KAS) was implemented on December 4, 2014. One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates.
Allocation policy changes in 2014 KAS;
1-Sensitized candidates receive wait list points according to a sliding-scale beginning at cPRA 20%.
2-The number of wait list points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥ 98% .
3-Candidates with cPRA ≥ 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys.
Although the revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates. Candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die .
Outcomes Associated with HLA-Incompatible Kidney Transplantation;
1- The risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive cross match, with progressively higher degrees of cross match incompatibility being associated with increasing risk of both outcomes.
2- The approaches have been employed to demonstrate the survival advantage of transplantation over dialysis for a wide range of subpopulations , underscoring the message that it is generally better to undergo kidney transplantation from a donor of any type rather than remain on dialysis in an attempt to wait for a more preferable donor.
Role of Kidney Paired Donation;
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange, but they should recognize that this approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor.
Although living donor transplantation can be facilitated for some highly sensitized candidates, many are unsuccessful in finding a donor through paired exchange.
The percentage of unmatched candidates is higher for those with blood type O (43%) or who are highly sensitized (cPRA ≥ 97%; 58%) . For those who have the combination of both O blood type and cPRA ≥ 98% in NKR, only approximately 10% successfully find a donor within 1 year .
Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation to finding a compatible donor may be unrealistic.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor;
To summarize, our approach takes into account the following considerations:
1-Assess the Feasibility of Desensitization.
2- Assess Alternatives to HLA-Incompatible Kidney Transplantation
Assess the Feasibility of Desensitization;
1-The initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch.
2- Not to recommend desensitization for a positive CDC crossmatch, although successful transplantation can be achieved in selected cases in this setting .
3- Not to proceed with transplant with a flow cytometory cross match median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17.
4- The RIS is a risk score that accounts for the binding strength of DSA and assigns;
-10 points for each DSA in the strong-binding range (MFI) ≥ 10,000
-5 points for each moderate-intensity DSA (MFI 5000 to 9999)
-2 points for each weak DSA (MFI < 5000).
A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection .
Assess Alternatives to HLA-Incompatible Kidney Transplantation;
Paired kidney exchange should not be offered to all patients with an incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry cross match indicates a high likelihood of successful transplantation with desensitization.
Deceased Donor Transplantation;
Unfortunately, living donor transplantation is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option. A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor , and MFI thresholds for defining an antigen as unacceptable should be adjusted to bring the cPRA down to at least < 99.95%. Therefore, desensitization should be considered as a necessary component for successful transplantation.
Conclusions;
1-Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization.
2- Although participation in a kidney paired donation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O.
3-A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find a compatible donor.
Hinda Hassan
3 years ago
Highly sensitized patients who have no compatible living donor can depend on paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant.The 95%probability of finding a compatible donor equal 1- (cPRA)n, where n = the number of potential donors. this equation estimate that a patient with a cPRA 99% requires approximately 300 match runs and the patient with cPRA 99.9% 600 requires 3000 match runs. So, living donation is difficult in this population even with paired exchange programs as they need a large pool of donors. The US Kidney Allocation System (KAS) increased access to deceased donor kidney transplantation for highly sensitized patients but it did little to increase access to transplant for those with cPRA more than 98%. A recent revised system provides waitlist points according to a sliding-scale beginning at cPRA 20% and increase with increased cPRA. The highest allocation priority was given to those with cPRA more than 98%. Again highly sensitized patents did not receive benefit from these changes. So, highly sensitized patents, more than 99.95%, are advised to consider incompatible transplantation. The graft outcomes differ according to the degree of incompatibility as it can ranges from mild incompatibility with negative cross match to severe incompatibility with a positive cross match. Mortality and graft were associated with the degrees of cross match incompatibility. Despite this, it was noted that the 8-year survival was more in patients who received an incompatible living donor transplant when compare to those remained on the waiting list or received a deceased donor transplant. Paired kidney exchange is another option for highly sensitized candidates but the difficulty of finding a living donor in a definite time is still being there. NKR data showed that in the presense of both O blood type and cPRA more than 98% in NKR, the success of finding a donor within 1 year is only 10%. Alliance for Paired Donation (APD) data showed only 25% of patients with cPRA> 95% were transplanted through paired donation compared to 23% with cPRA >95% through a deceased donor over 6 years period. The waiting time for those with both blood group O and cPRA >95% was 671 days. To overcome this, the kidney paired donation should focus on finding a more suitable donor than finding a compatible donor. The protocol of the authors for highly sensitized candidate with an incompatible living donor includes: 1-Assess the feasibility of desensitization to a potential living donor by doing CDC and flow cytometry crossmatch. They do not recommend desensitization for a positive CDC cross match. They do not transplant those with with a FCXM median channel shift > 250 or a DSA relative intensity score (RIS) >17 as it is associated with a positive predictive value of 91% for AMR. “The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) > 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000).” 2- Paired Kidney Exchange after a detailed discussion with both recipient and donor about the expectations of participation, the possibility of finding a more suitable donor, the risk of remaining on dialysis , the risks of desensitization ,the risk of HLA-incompatible transplantation and a time limit for participation before determining the futility of kidney exchange. Paired kidney exchange in the author protocol should not be offered to all patients with an incompatible donor, especially if the patient has a low likelihood of finding a match or he can have a chance of successful desensitization. 3- Deceased donor transplantation with consideration of the relation between cPRA and the number of potential donors according to the equation. Patients with a cPRA >99.95% are highly unlikely to be offered a deceased donor. MFI thresholds are adjusted to bring the cPRA down to at least < 99.95%to increases the likelihood of incompatible donor offers.
CARLOS TADEU LEONIDIO
3 years ago
Please summarise this article
Despite the advent of newer protocols for desensitization and favorable outcomes compared to remaining on dialysis, many centers remain reluctant to perform HLA-incompatible kidney transplants. Desensitization regimens can be resource intensive, costly, and require clinical, immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful implementation. The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant. There is lack of consensus and guidelines to inform transplant programs and candidates on how to choose between these options.
HLA Sensitization and the Probability of Kidney Transplantation
Transplant programs vary in their thresholds for incompatibility, and as such, the likelihood of finding a suitable donor may differ from one program to another. The relationship between calculated panel reactive antibodies (cPRA) and the probability of finding a compatible donor is expressed as: Probability of finding an acceptable match = 1- (cPRA)n , where n = the number of potential donos. With this equation, it is estimated that a patient with a cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a cPRA 99.5% and 3000 match runs for a candidate with cPRA 99.9%
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
A revision of the US Kidney Allocation System (KAS) was implemented on December 4, 2014. One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates. Prior to the 2014 KAS revision, candidates with a cPRA ≥ 80% were awarded four waitlist points toward allocation. This policy benefited those with cPRA 80–97%, for whom the probability of finding a compatible donor are generally favorable, but did little to improve access to transplant for those with cPRA ≥ 98%.
Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%. The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥ 98%. Additionally, candidates with cPRA ≥ 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys. These allocation policy changes resulted in dramatic early increases in the number of transplants performed in highly sensitized candidates with cPRA ≥ 99% .
Outcomes Associated with HLA-Incompatible Kidney Transplantation
Graft outcome is an important consideration when choosing between transplant options for highly sensitized candidates. It is important to recognize that HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility, such as DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch. The distinction is relevant, as outcomes differ according to the degree of incompatibility.
A large multi-center consortium involving 22 transplant centers that perform HLA-incompatible kidney transplantation compared patient and graft survival outcomes among living donor kidney transplant recipients with varying degrees of HLA-incompatibility. Notable from this study is that the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
Role of Kidney Paired Donation
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange, but they should recognize that this approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor. Although living donor transplantation can be facilitated for some highly sensitized candidates, many are unsuccessful in finding a donor through paired exchange. Data of Alliance for Paired Donation (APD), in over a 6-year period, only 25% of patients with cPRA ≥ 95% were transplanted from a living donor through paired donation; in comparison, a similar percentage of APD registered patients with cPRA ≥ 95% found a deceased donor during the same time period (23%).
Thus, the data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one. Providers should set realistic expectations for candidates who enter into the paired exchange process and must recognize which patients are unlikely to receive a transplant without desensitization.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
Assess the Feasibility of Desensitization
Our initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch. In our program, we do not recommend desensitization for a positive CDC crossmatch, although successful transplantation can be achieved in selected cases in this setting. Additionally, we do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17.
If HLA-incompatible transplantation is predicted to be prohibitively high risk based on these criteria, we recommend participation in a paired kidney exchange program.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
Recognizing that positive cross-match kidney transplants are associated with an increased risk of graft loss and mortality compared to compatible transplantation, kidney paired donation may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization. In our opinion, paired kidney exchange should not be offered to all patients with an incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
Deceased Donor Transplantation
Unfortunately, living donor transplantation is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option. In these cases, the provider must recognize the exponential relationship between cPRA and the number of potential donors that are required in order to identify a suitable donor. Therefore, desensitization should be considered as a necessary component for successful transplantation. In their early single-center experience after revised KAS implementation.
CONCLUSION
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization. Although participation in a kidney paired donation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O. A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find a compatible donor.
Mohamed Ghanem
3 years ago
Introduction :
There was a lack of kidney transplantation of highly sensitized patients due to high rejection rates, poor graft outcomes, and high cost of desensitization strategies.
Options were waiting matched living donor from paired kidney donation or deceased kidney allograft or transplantation with an incompatible living donor. HLA Sensitization and the Probability of Kidney Transplantation:
Finding compatible donors depends on cPRA
as the probability of finding matched donor =1-cPRA
Patients with cPRA of 99 % must have 300 cross-match of different donors to have a chance of 95 % to find a matched donor
Also, the probability of finding a donor depends on the size of the donor pool make PKD a chance of making a large pool of donors available
Kidney Allocation System (KAS) :
KAS has a role in transplantation of highly sensitized CKD , as made priority to the patients with high c PRA for available deceased donor
However patients with cPRA >98 % received donors less than expected
Points of priority increase with the number of cPRA of sensitized CKD Outcomes Associated with HLA-Incompatible Kidney Transplantation:
Degree of incompatibility differ from mild degree with the low level of DSA with negative cross-match , to moderate degree with only positive flow crossmatch to a high degree with positive CDC crossmatch
the outcome was worse in patients with incompatible HLA with positive crossmatch
however, patients with incompatible HLA with negative crossmatch didn’t differ from patients transplanted with compatible HLA in graft loss and death.
Survival of highly sensitized patients transplanted with incompatible HLA was better than patients who continued on dialysis waiting for matched HLA donors.
Survival was better with negative crossmatch > positive flow cytometry crossmatch >positive CDC crossmatch. Role of Kidney Paired Donation:
Highly sensitized patients may find a compatible donor through paired kidney exchange however many were unsuccessful.
With higher patients with blood group O, c PRA >97% and For those who have the combination of both O blood type and cPRA 98% ( 43%,58 %, 90 % ) respectively failed to find a suitable donor within first year on the waiting list for PKD.
Desensitization in combination with PKD may help highly sensitized patients to find compatible donors earlier.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor :
First PRA by Luminex single antigen, flowcytometry crossmatch, and CDC cross-match:
And transplantation is not to be done if positive CDC cross-match or positive flow cytometry cross-match with median channel shift > 250 or presence of DSA with RIS > 17
Conclusions :
Finding the matched donor for highly sensitized patients is difficult so combining of PKD and desensitization may help to find suitable donors earlier.
however, HLA Incompatible transplantation may be another way to shorten the time of waiting for these patients.
Mahmud Islam
3 years ago
Transplanting sensitized patients is undesirable in many centers may be due to lack of capabilities. Although transplanting these patients is better than remaining on dialysis cost is a challenge. options for such patients are involved in paired kidney donation programs, waiting on the list, or being transplanted with an incompatible one.
The authors suggested trying to find a suitable donor through this may differ from one program to another.
The kidney allocation system (KAS) does not offer a big chance for sensitized patients with very high PRA%, so it may be eligible to consider incompatible donors.
The outcome of compatibility is better for sure. some studies showed that incompatible donor donation may be better than deceased donor transplantation.
we have one of three options:
1- incompatible donation
2- paired kidney exchange
3- deceased donor transplantation.
Highly sensitized patşents who ave donor that is incompatible should be evaluated for desensitization. It is difficult to have paired kidney in case of very high PRA and being of blood group O for example
After evaluation of probable risks, desensitization should be considered as option
Batool Butt
3 years ago
Highly sensitized transplant recipient always have difficulty in finding a suitable living donor and usually are maintained for long time in the waiting list for a deceased donor.
The probability of finding a suitable donor with negative crossmatch can be calculated using this formula 1- (cPRA)n, where n is the number of available donors
It was found that in patients with a cPRA of 99% only 1 from 300 donor offer will be suitable for transplantation with a negative crossmatch which increases to 3000 match runs for a candidate with cPRA 99.9%.
Following are the options for a Highly sensitized transplant candidate who don’t have a suitable living donor:
1- Keeping the patient on hemodialysis ,though it is associated with higher mortality,
2- Try to find compatible living kidney donor
3- Wait for compatible deceased donor
4- Desensitization to render incompatible donor possible for transplantation Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
In 2014 KAS revision , allocation policy changes resulted in dramatic early increases in the number of transplants performed in highly sensitized candidates with cPRA => 99% . Patients in the highest cPRA categories should be advised to consider incompatible transplantation.Sensitized transplant recipient take waitlist priority points according to his/her cPRA which starts from cPRA of 20% and increase gradually till reaching to patients with cPRA ≥ 98. Outcomes Associated with HLA-Incompatible Kidney Transplantation
Graft outcome is an important consideration in HLAi transplants. A study showed that the effect of HLAi transplant on graft and patient survival is only evident when the crossmatch is positive, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA compatible Role of kidney paired donation:
Patients with an incompatible donor may find a more suitable donor through KPD, but many sensitized candidates fail to find a compatible donor throughout this method.
Kidney paired donation will help us finding a more suitable donor for highly sensitized patients, but not necessarily a compatible one. Desensitization should be considered as an adjunct to paired exchange for difficult to match patients Approach to the Highly Sensitized Candidate with an Incompatible Living Donor: Assess the Feasibility of Desensitization
By performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch.Desensitization is not recommended for a positive CDC crossmatch, flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17.If high-risk HLA-incompatible transplantation, then patient should be enrolled in paired kidney donation program. The RIS is a risk score that accounts for the binding strength of DSA and is calculated as follows:10 points for each DSA in the strong-binding range (MFI ≥ 10,000), 5 points for each moderate-intensity DSA (MFI 5000 to 9999), 2 points for each weak DSA (MFI < 5000).
A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection. Assess Alternatives to HLA-Incompatible Kidney Transplantation Paired Kidney Exchange
PKE should be considered despite the feasibility of incompatible transplant as incompatible transplant is associated with an increased risk of graft loss and mortality compared to compatible transplants. Detailed counseling is required to understand the pro and cons of this program.
. Deceased Donor Transplantation
A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor and MFI thresholds for unacceptability should be adjusted to bring the cPRA down to at least < 99.95%. CONCLUSION:
Highly HLA sensitized kidney transplant patients who have a living donor should be considered for desensitization.
A combined approach consisting of both desensitization and kidney paired donation will generally be more successful
Mohamed Mohamed
3 years ago
I. Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates Please summarise this article Treatment options for highly sensitized recipients: 1. Paired kidney exchange: – Poor chances of finding a suitable donor, especially for those with PRA=>99 – Variable kidney exchange donor pool size. 2. Desensitization with HLA-incompatible transplantation: HLA-i transplantation is an appropriate option for many highly sensitized recipients. Drawbacks of desensitization include: – Ineffective available regimens – Rejection rates are high – Graft survival is poor – Costly & resource demanding – Inter-institutional variability in thresholds for incompatability. This will reflect the chance of finding a suitable donor 3. Deceased donor transplant: Revised KAS 2014 aimed to increase access of highly sensitized patients to donors pool; however this did little to improve access to transplant for those with cPRA=> 98%. There is no consensus to inform transplant programs & candidates on how to choose between these options. Therefore many highly sensitized patients continue waiting for a compatible donor that may never come. HLA sensitization & the probability of kidney transplantation: 1st step is to assess the likelihood of finding a suitable donor. Thresholds for incompatibility, & thus the likelihood of finding a suitable donor, vary between centers. The probability of finding a compatible donor is: 1- (cPRA)n, where n = the number of potential donors. So a patient with cPRA 99% needs about 300 match runs to get a 95% chance of finding a compatible donor. The number of match runs needed to find a suitable donor is less for centers performing incompatible transplants.
The probability of finding a donor also depends on the size of the donor pool. A revised KAS on December 4, 2014 aimed to increase access to deceased donor kidney transplantation for highly sensitized candidates. This policy benefited those with cPRA 80–97%, for whom the probability of finding a compatible donor are generally favorable, but did little to improve access to transplant for those with cPRA >98%.
Studies show that the risk of HLA incompatibility on post-transplant mortality & graft loss was only observed in the presence of a positive XM; the higher the degrees of XM incompatibility the higher the risk of both outcomes. In the presence of a negative XM, the risk of both outcomes was similar between transplants performed with DSA alone & those that were HLA-compatible. No prospective trials comparing the most common desensitization protocols, including high-dose IVIG +/- rituximab versus low-dose IVIG in conjunction with PP. There is little center to center variability in patient & graft survival outcomes associated with HLA-i living donor transplantation. Data showed higher 8 years survival rates for incompatible living donor transplant compared to matched controls who remained on the waiting list or received a deceased donor transplant. The higher survival rate was seen irrespective to the degree of incompatibility. Patients in the highest cPRA groups should be advised to consider incompatible transplantation. Role of Kidney Paired Donation This approach gives a compatible donor only a fraction of time & many highly sensitized patients may not succeed to find any donor. NKR data indicates that 35–40% of all candidates remain unmatched within a year. The % unmatched candidates is higher for those with blood type O or cPRA > 97% 58%). In those who have both O blood type & cPRA > 98%, only 10% successfully find a donor within 1 year. Data show that for highly sensitized patients, KPD should be considered as a means for finding a more suitable donor, rather than a compatible one. Approach to the highly sensitized candidate with an incompatible living donor The following should be considered: Assess suitability of desensitization to a potential living donor by Luminex SAB to identify DSA & perform a CDC & FCM-XM flow. Desensitization for a +ve CDC XM is not recommended. Not to proceed with transplant if a FCM-XM MCS > 250 or a DSA relative intensity score (RIS) >17. RIS (10 points for each DSA with MFI >10,000], 5 points for each DSA with MFI 5000 -9999), & 2 points for each weak DSA(MFI < 5000). A RIS >17 is associated with a positive predictive value of 91% for AMR. If RIS >17 participation in a paired kidney exchange program is recommended. KPD may be a considered for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization. Counsel both recipient & donor about the expectations, cons & pros of participation in KPD program. KPD paired should not be offered to all incompatible patients, especially if the cPRA & ABO type predict a low likelihood of finding a match. Deceased donor transplantation May be the only hope for those in whom living donor transplantation is not possible due the breadth of HLA sensitization. There is an exponential relationship between cPRA & the number of potential donors that are required in order to find a suitable donor: – A cPRA >99.95% is highly unlikely to find an offer. – MFI thresholds for unacceptable antigens should be adjusted to bring the cPRA down to at least < 99.95%; however this increases the likelihood of incompatible donor offers. So desensitization is a necessary component for successful transplantation. Conclusions Desensitization should be considered for highly sensitized patients who have a living donor. KPD may offer the possibility of finding a compatible or more suitably matched donor. The most broadly sensitized patients, especially those who are blood type O, may benefit from combining both desensitization & KPD. Patients should be clearly counseled regarding risks & benefits of treatment options & early consideration of desensitization & HLA-i transplantation when the likelihood of finding a compatible donor is extremely low.
Weam Elnazer
3 years ago
Candidates who have been exposed to high levels of sensitivity are more likely to be transplanted mostly through the skin.
contribution from a deceased person.
Options accessible to the highly sensitive applicant who has a living donor who is incompatible with him or her
include:
Participation in a kidney exchange program with a matched donor.
Donation through a live donor who is incompatible with the recipient.
Waiting for a dead donor transplant to become available.
In order to inform transplant programs and candidates, there is a paucity of consensus and recommendations.
about how to make a decision amongst these alternatives.
The Relationship Between HLA Sensitization and the Chances of Receiving a Kidney Transplant
The first step in advising a highly sensitive kidney transplant candidate is to determine the applicant’s level of sensitivity.
A highly sensitive kidney transplant candidate’s chances of finding a compatible donor are the first step in the process of advising them, and this might vary from one program to another.
The probability of discovering a suitable match is given by 1- (cPRA)n, where n is the number of possible donors available.
This equation predicts that patients with high cPRA will require additional match runs in order to boost their chances of finding a matching donor, according to the researchers.
As an example, these estimates give a measurable approximation of the chance of obtaining a suitable donor through paired kidney exchange or waiting for a dead donor in the case of transplant facilities that only consider compatible transplants.
As previously stated, the likelihood of finding a donor is also influenced by the size of the donor pool, which is increased by participation in a matched kidney exchange program.
As the cPRA rises beyond 99 per cent, it is becoming increasingly difficult to achieve living donor transplantation.
Considering the Possibility of Deceased Donor Kidney Transplantation in the Kidney Transplantation Study
The Key Allocation System (KAS) was established in the following year.
One of the primary objectives of the amended KAS was to expand access to deceased donor kidney transplantation for applicants who were highly sensitized to the procedure.
The updated KAS has significantly increased access to deceased donor kidney transplantation throughout the spectrum of allo-sensitization on the whole, but the modifications in allocation policy have not been beneficial to the most highly sensitized applicants, according to the findings.
The risks and advantages of current therapeutic alternatives must be clearly discussed, and early consideration should be given to desensitization and HLA-incompatible kidney transplantation when the chance of obtaining a compatible donor is minimal.
Huda Al-Taee
3 years ago
Introduction:
Historically, transplant options for sensitized patients were limited due to ineffective desensitization therapies, high rejection rate, and poor graft outcomes.
Despite improvement in desensitization protocols and the favourable outcome compared to dialysis, still many centers are reluctant to do HLAi transplantation. Many highly sensitized patients continue waiting for a compatible donor that may never come.
HLA sensitization and the probability of kidney transplantation:
The first step in counselling a highly sensitized candidate is to assess the likelihood of finding a compatible donor through the following equation:
probability of finding an acceptable match= 1-(cPRA)n
n= no of potential donors.
For transplant centers that only consider compatible transplants, these estimates provide a quantifiable approximation of the likelihood of finding a suitable donor either through PKD or waiting for a deceased donor. The probability of finding a donor also depends on the size of the donor pool.
Assessing the probability of deceased donor kidney transplantation in the kidney allocation system era:
The US KAS was revised in 2014 to increase access to deceased donor kidney transplantation. So sensitized patients receive waitlist points according to a sliding scale beginning at cPRA 20%. the number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA more than or equal to 98%. In addition, candidates with cPRA> or equal to 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys.
The changes in allocation systems resulted in a dramatic increase in the number of transplants for highly sensitized patients, also improved access to deceased donors.
Unfortunately, these changes in the KAS did not improve transplantation rates for candidates with cPRA>99.95%, so these candidates should be advised to undergo HLAi transplantation.
Outcomes associated with HLA-incompatible kidney transplantation:
Graft outcome is an important consideration in HLAi transplants. A study showed that the effect of HLAi transplant on graft and patient survival is only evident when the crossmatch is positive, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA compatible.
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on a waiting list or received a deceased donor transplant indicated that survival is highest for incompatible living donor recipients, making incompatible transplantation is the best option for this scenario.
Role of kidney paired donation:
Patients with an incompatible donor may find a more suitable donor through KPD, but many sensitized candidates fail to find a compatible donor throughout this method.
The data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one. Desensitization should be considered as an adjunct to paired exchange for difficult to match patients.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor:
Assess the Feasibility of Desensitization
This is done by performing Luminex single antigen testing to identify DSA and a CDC and flow cytometry crossmatch.
Rationale:
not recommend desensitizing a positive CDC crossmatch.
do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17.
participation in a paired kidney exchange program if HLA-incompatible transplantation is predicted to be of high risk.
The RIS is a risk score that accounts for the binding strength of DSA and is calculated as follows:
10 points for each DSA in the strong-binding range (MFI ≥ 10,000).
5 points for each moderate-intensity DSA (MFI 5000 to 9999).
2 points for each weak DSA (MFI < 5000).
A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
KPD may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization. It is important to discuss all the potential benefits and disadvantages of the process with the candidate keeping in mind the patient’s blood group and cPRA which could limit the possibility of finding an acceptable donor.
Deceased Donor Transplantation
Unfortunately, living donor transplantation is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option. Still, high cPRA is a limiting factor for this option. Desensitization may be considered to achieve successful transplantation.
Nasrin Esfandiar
3 years ago
· Highly sensitized candidates for TX are challenging due to anti-bodies against a lot of HLA antigens that makes finding a suitable donor difficult. A large population of donor is needed to find a suitable kidney for these patients. So finding a compatible living donor is not practical in most cases.
To solve this problem, paired kidney exchange programs, desensitization or deceased donor TX are other options.
At this article TX of the highly sensitized patients with an incompatible living donor is approached.
Probability of finding a suitable donor with acceptable match = 1- (CPRA) n
n= number of potential donors. For example, for CPRA 99%, near 300 match is needed for 95% chance of finding a compatible donor. So, number of matched is depended on degree of incompatibility which is accepted by a program.
On the other hand, its probability depends on the size of the donor pool. Paired kidney exchange program can range from single-center to large multi-central exchange programs.
In previous kidney allocation system (KAS), sensitized patients with CPRA ≥80% were awarded four points when were in waiting list. But in new KAS program, points –scale begins at cPRA≥ 20% and with increasing cPRA up to 98%, number of points is increased and patients with CPRA ≥ 99 are drawn from a larger regional and national sharing system, which resulted in 5- fold higher chance for TX among patients. But candidates with a cPRA ≥ 99.95% have low chance to receive a compatible TX and are considering in compatible TX. In a large study, risk of post-transplant mortality or graft failure was increased in the presence of positive XM.
· Desensitization protocol include:
IVIG with plasmapheresis with or without rituximab.
· The highest survival was related to those who received an incompatible living donor TX vs those who remained on waiting list.
· Paired kidney exchange (PKE) is another option for those with an incompatible donor in some cases who are lucky. But about 35-40 % of all candidates can’t receive a matched kidney within one year. Especially with blood type O or CPRA ≥97% with average 671 days waiting time. So, desensitization should be considered in these cases. To approach to these patients, first should perform luminex –SAB to identify DSA and then do a CDC and flow cytometry XM. Desensitization is not done for positive CDC XM or positive flow- XM with median channel shift >250 or DSA R1S ≥ 17 R1S. RIS assigns 10 points for MFI≥10000, 5 points for MFI 5000 to 9999 and 2 point for MFI <5000.
· If the risk is high, participation in a PKE program is recommended.
In patients with a CPRA ≥ 99.95 % finding a deceased donor is unlikely and desensitization is a required component for TX in these patients. So a combined approach (both PKE and desensitization) is more successful.
Highly sensitized patients are more commonly transplanted through deceased donation due to difficulties in finding a compatible living donor.
High degree of HLA sensitization makes living donor transplantation less common. HLA sensitization and probability of kidney transplantation:
The probability of finding suitable donor to highly sensitized patients varies according to degree of incompatibility a program is accepting, size of the donor pool, number of potential donors in kidney exchange program.
As the cPRA increases above 99%, the possibility of having living donor transplantation becomes unlikely. Assessing the probability of deceased donor kidney transplant in kidney allocation system (KAS) era: The revision of KAS aimed to increase the access of highly sensitized patients to deceased donor kidney transplant.
It includes increase of the waitlist points exponentially with increased cPRA with giving high priority to patients with cPRA>/= 98% also patients with cPRA>/=99% draw from larger donor pool through regional and national sharing of deceased donor kidneys.
It resulted in five-fold increase in number of transplantation in highly sensitized patients with cPRA >99%.
However, highly sensitized patients with cPRA>/=99.95% remain unlikely to receive transplantation. Outcome associated with HLA incompatible kidney transplant:
The outcome of transplantation varies according to the degree of compatibility
It ranges from mild incompatibility (low level DSA with negative crossmatch) to high level incompatibility (DSA with positive FCXM or CDCXM)
A large multicenter study showed that HLA incompatibility in presence of positive crossmatch is associated with increased risk of graft loss and death and the degree of crossmatch incompatibility is associated with increased risk of poor outcome.
Patients with DSA but negative crossmatch have same risk of graft loss and mortality as HLA compatible transplants.
A multicenter study showed that patient survival over 8 years was higher in incompatible living donor transplant than in patients who remained on dialysis or received deceased donor transplant.
Studies showed that the outcome of kidney transplantation (regardless the type of donor) is better than remaining on dialysis waiting for more preferable donor. Role of kidney paired donation (KPD):
Kidney paired donation provides patients with incompatible donor to find more suitably matched donor. However, many highly sensitized patients fail to find donor.
A comprehensive summary of KPD in 9 years showed that 11.7% of transplants required desensitization because of crossmatch and/or ABO incompatibility.
35-40% of all candidates remained unmatched for one year.
KPD provides highly sensitized patients with a more suitable donor and not necessarily a compatible donor and some patients are unlikely to find a donor without desensitization. Approach to the highly sensitized candidates with incompatible living donor: Assess the feasibility of desensitization:
Desensitization is not recommended in case of positive CDCXM
In case of positive FCXM with median channel shift>250 or DSA RIS>/=17, it is not recommended to proceed with transplantation.
These criteria predict high risk incompatible transplant which is better to be avoided. Assess alternatives to HLA incompatible kidney transplant:
KPD should be considered despite feasibility of incompatible transplant as incompatible transplant is associated with increased risk of graft loss and mortality compared to compatible transplants.
Before participation in KPD, several considerations should be determined as possibility of finding compatible donor, disadvantages of remaining on dialysis compared to risk of desensitization and incompatible transplant and time limit for participation while waiting for suitable donor.
Patients with broad HLA sensitization, if living donor transplantation is not feasible, deceased donor transplant will be an option.
If there is a low probability of finding compatible donor, desensitization should be considered. Conclusion:
Desensitization should be considered in highly sensitized patients who have a living donor.
KPD provides more suitable or compatible donor but is not successful in broadly sensitized patients.
Combination of both KPD and desensitization is more beneficial
If there is a low probability of finding donor, desensitization and incompatible transplants should be considered early.
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
Non compatible transplantion is very risky , which may lead to immediate graft loss due to hyepracute rejection or AMBR or cAMBR.
These kind of transplantion uses very aggresive immunosupreesion protocols and pre transplant desentization reigmen which is very costly and not avilable in any center.
Patients with cPRA more than 95% only have three options for transplantion, incomatible living transplantion,paired kidney donation if feasible in their country, waiting for cadaeveric comaptible offers.
Regardless of these obstacles ,it is still an option for patients which are highly senstized with sky high cPRA .
A simple equatin is designed for the probabilty of thess patinets to find such donor which is (acceptable match =1-(cPRA)n,where n means the number of potential donors .
In 2014 KAS revised their criteria for listing the patients on cadaver list,they give the priority for the patients with skyhigh cPRA >98%.
Descion of incompatible kidney transplantion is center dependent ,after counselling the patient about the pros and cons , and the avilabilty of highly qualified transplant nephrologist who can handle such kind of transplantion balancing with good resources in the hospital .
Mihir Kumar
3 years ago
Any form of kidney transplantation -living compatible,noncompatible or deceased kidney transplantation gives better survival compared to remaining on Dialysis. Kidney transplanation should be 1st choice even in highly sensitized ckd5 patients ,because they offer better patient survival and quality of life compared to those remain on dialysis. As cPRA increases ,probablity of finding a suitable match decreases .For cPRA Above 99% percent ,it is very difficult to find a match .
For these highly sensized patients, there are 3 options which we can offer to them,each having own merits and demerits
1.Kidney pair donation- Paired kidney exchange is probably the best option for incompatible transplant, but many highly sensitized candidate failed to get a donor through KPD. 35–40% of all candidates remain unmatched within a year . Those who have O blood group and highly sensitized cPRA >97% often fails to find a match via KPD. It is a attractive option available to those who are less senstized.Now a days many centers using some form of desensitazion for highly sensitized patients to make them less sensitized and then Placing them in KPD program ,so that they can be matched .
2.Deceased donor transplantation- The new deceased-donor kidney allocation rules for candidates with a cPRA 98% have significantly improved organ availability for highly sensitized candidates. For mild to moderately sensitized candidates , especially for common blood types, finding acceptable deceased donors is usually possible without large increases in waiting time. But for highly sensitized patients ,It is very difficult to find a match through deceased donation program.
3.Live donation after desensitazion–Any form of living donation be it comaptible or non compatible ,gives better graft and patient survival compared to deceased donation. HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility, such as DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch.Risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
Feasibility of Desensitization-
Most center do not recommend desensitization for a positive CDC crossmatch, although positive crossmatch is not a absolute containdication to desensitazion. Successful transplantation can be achieved in selected cases in this setting . Additionally, many center do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17. A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection. In addition cost of these desensitazion is high and many poor patient cant afford this cost.
Asmaa Khudhur
3 years ago
HLA Sensitization and the Probability of Kidney Transplantation
Probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors
With this equation, it is estimated that a patient with a
cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a cPRA 99.5% and 3000 match runs for a candidate with cPRA 99.9%.
The probability of finding a donor also depends on the size of the donor pool.
The kidney exchange donor pool can range from small, single-center internal exchanges to large multi-center national exchange programs.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates.
Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%. The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥ 98% .
These allocation policy changes resulted in dramatic early increases in the number of transplants performed in highly sensitized candidates with cPRA ≥ 99% that have since stabilized at rates that are approximately 5-fold higher than that observed before the 2014 KAS revision.
Role of Kidney Paired Donation
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange, but they should recognize that this approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor.
the data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation to finding a compatible donor may be unrealistic.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor:
This approach takes into account the following considerations:
Assess the Feasibility of Desensitization
initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch.
In this program, they do not recommend desensitization for a positive CDC crossmatch, although successful transplantation can be achieved in selected cases in this setting .Additionally, they do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17.
The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) ≥ 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000). A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection .
If HLA-incompatible transplantation is predicted to be pro- hibitively high risk based on these criteria, they recommend participation in a paired kidney exchange program.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
kidney paired donation may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization.
A recommendation to participate in kidney paired donation should include a detailed discussion with both recipient and donor about the expectations of participation, the likelihood of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis leveraged against the risks of desensitization and HLA-incompatible transplantation, and a time limit for participation before determining the futility of kidney exchange.
They suggest paired kidney exchange should not be offered to all patients with an incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
Deceased Donor Transplantation:
Unfortunately, living donor transplantation is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option.
A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor
and MFI thresholds for defining an antigen as unacceptable should be adjusted to bring the cPRA down to at least < 99.95%.
Conclusions
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization.
Although participation in a kidney paired do- nation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O.
A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find a compatible donor.
Recommendation:
They recommend clear discussion of the risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation when the likelihood of finding a compatible donor is prohibitively low.
Alaa eddin salamah
3 years ago
Journal club I
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates
The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant
This review addressed the pros and cons of paired kidney exchange and desensitization and provides recommendations for patients and providers on the approach to the highly sensitized patient with an incompatible living donor.
HLA Sensitization and the Probability of Kidney Transplantation
Probability of finding an acceptable match = 1- (cPRA)n,
where n = the number of potential donors
This probability depends on:
1- The degree of incompatibility a program is willing to accept.
2- The probability of finding a donor also depends on the size of the donor pool.
Assessing the Probability of Deceased Donor
Kidney Transplantation in the Kidney Allocation System (KAS) Era
One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%.
The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA >= 98% candidates with cPRA >= 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys.
These allocation policy changes resulted in dramatic early increases in the number of transplants performed in highly sensitized candidates with cPRA >= 99% that have since stabilized at rates that are approximately 5-fold higher than that observed before the 2014 KAS revision
Outcomes Associated with HLA-Incompatible Kidney Transplantation
It is important to recognize that HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility, such as DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch.
A multi-center study found that the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes.
Howeve, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario
Role of Kidney Paired Donation
Data from the NKR indicates that approximately 35–40% of all candidates remain unmatched within a year the data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one
Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation to finding a compatible donor may be unrealistic.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
Assess the Feasibility of Desensitization
This a proposed approach by the study
we do not recommend desensitization for a positive CDC crossmatch, although successful transplantation can be achieved in selected cases in this setting, we do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) => 17.
The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) >= 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000). A RIS >= 17 is associated with a positive predictive value of 91% for antibody-mediated rejection
Assess Alternatives to HLA-Incompatible Kidney Transplantation
If HLA-incompatible transplantation is predicted to be prohibitively high risk based on these criteria, we recommend participation in a paired kidney exchange program or Deceased Donor Transplantation
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization. Although participation in a kidney paired donation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O. A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find a compatible donor.
Drtalib Salman
3 years ago
2 message I learn from this article:
1- Highly sensitize patient c PRA from 80 to 95 percent and previously we thought it is difficult to find compatible donor , now it is easy and possible to find donor with good allocation system or paired kidney donation programs .
2- For highly sensitized patient we may found suitable donor but not compatible so we need to do desensitization protocol but unfortunately there is no randomized study to compare different regimen ,so it is different from Centre to Centre.
Drtalib Salman
3 years ago
Please summarise this article
Despite the advent of newer protocols for desensitization and favorable outcomes compared to remaining on dialysis, many centers remain reluctant to perform HLA-incompatible kidney transplants,
The options available to the highly sensitized candidate with an incompatible living donor include :
1-a paired kidney exchange program,
2-direct donation with an incompatible live donor.
3- waiting for a deceased donor transplant.
Probability of finding an acceptable match = 1- (c PRA)n , where n = the number of potential donors ,with this equation, it is estimated that a patient with a c PRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a c PRA 99.5% and 3000 match runs for a candidate with c PRA 99.9%.
Prior to the 2014 KAS revision, candidates with a c PRA ≥ 80% were awarded four waitlist points toward allocation. This policy benefited those with c PRA 80–97%, for whom the probability of finding a compatible donor are generally favorable, but did little to improve access to transplant for those with c PRA ≥ 98% .
candidates with a c PRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die .
A large multi-center consortium involving 22 transplant centers that perform HLA-incompatible kidney transplantation compared patient and graft survival outcomes among living donor kidney transplant recipients with varying degrees of HLA-incompatibility, the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes.
There are no prospective, randomized trials comparing the most common desensitization protocols, including high-dose IVIG with or without rituximab versus low-dose IVIG in conjunction with plasmapheres.
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario.
The percentage of unmatched candidates is higher for those with blood type O or who are highly sensitized (c PRA ≥ 97%) . for those who have the combination of both O blood type and c PRA ≥ 98% in NKR, only approximately 10% successfully find a donor within 1 year.
The data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) ≥ 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000). A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
Options for highly sensitized patients are very limited and they include ;
1.Paired kidney exchange program 2.Direct donation with an incompatible live donor 3.Waiting for a deceased donor transplant
It is not clear how select between these options resulting in large numbers of highly sensitized patients continue to wait for a compatible that may not come
This study looked at the pros & cons of paired kidney exchange and desensitization and advise on how to deal with highly sensitized patients
HLA Sensitization and the probability of kidney transplantation ;
The chance or probability of having a suitable donor for highly sensitized patient = 1 – (cPRA)n ,where n is is the number of potential donor [1]
Example ; cPRA = 99% requires ~ 300 match runs to get 95% chance of finding a suitable or compatible donor. cPRA = 99.9 requires ~ 3000 match runs to get 95% chance of finding a compatible donor. This depend on the size of the donor pool
Living kidney transplant may not be possible if cPRA > 99%
Assessing the probability of Deceased Donor Kidney Transplantation in the Kidney Allocation system(KAS)Era
The objective of the revised KAS was to improve access to deceased donor kidney transplantation for highly sensitized patients[4]
The number of allocating points is proportional to cPRA & the policy directed the highest allocation points to patients with cPRA >=98%
Highly sensitized cPRA > 99% are now 5 fold higher rate transplantation than before adoption of the new KAS[5,6]
Those with cPRA >99.95 did not benefited from the news KAS and many of them either removed from the wait list or die[2,6]
Outcomes Associated with HLA-Incompatible Kidney Transplantation
HLA-incompatability may be mild ; low level of DSAs + negative XM or severe incompatible ; DSAs + positive FCXM or CDCXM
The risk of mortality & graft loss was only seen in the presence of positive cross-match[7]
In the presence of negative cross-match outcomes was similar to those with HLA-compatible transplantation[7]
Multi-center studies demonstrated that higher survival rate among HLA-incompatible living donor compared with to matched controls who remained on waiting list or received a deceased donor transplant[9]. This higher survival was independent to the degree of incompatibility e.g. low DSA + NEG XM or DSA + POS FCXM or CDCXM
Role of Kidney Paired Donation
Candidates with incompatible donor may get a more suitably matched donor through paired kidney exchange.
Some patients required desensitization due to HLA/ABO-incompatibilty[14]
Many HLA-incompatible patient did not succeed to find compatible donor in KPD pools . 35 -40% remain un-matched for one year particularly those with blood group type O and having cPRA >=97%
Waiting time to transplant blood type O having cPRA >=97% was reported to be 671 days
Desensitization must be combined with PKD for difficult to match recipients.
Approach to the highly Sensitized Candidate with an Incompatible donor 1.Assess the feasibility of Desensitization; DSA, FCXM,& CDCXM ;
No desensitization if CDCXM +ve (some centers allowed this to proceed) [19]
No desensitization if FCXM median channel shift > 250 or DSA relative intensity(binding strength of the antibody) score > 17 ; if MFI > 10,000= 10 points, MFI =5000-9999= 5 points, MFI < 5000 = 2 points
A RIS >= 17 has PPV of 91% for AMR
2.Assess Alternatives to HLA-incompatible Kidney Transplantation
Paired Kidney Exchange ; This should be considered even if desensitization is required
Deceased Donor Transplantation ; Houp et al. reported that 58% of deceased donor transplants performed among patients with cPRA >=99%[22]
Conclusion
Desensitization may be considered in highly sensitized patients
PKD facilitate transplant in highly sensitized groups but this can be very difficult for those with blood type O & cPRA>=97
Patients should be educated,counseled well about the risk and the benefit of all of the available options
Shereen Yousef
3 years ago
• highly sensitized patients have limited chances of having compatible donor, they also have higher rejection rates, and poor graft survival.
•options available to the highly sensitized candidate with an incompatible living donor include:
-paired kidney exchange program.
-direct donation with an incompatible live donor.
-deceased donor transplant.
This review address the pros and cons of paired kidney exchange and desensitization and provides recommendations to help highly sensitized recipients and avoid long waiting time on dialysis.
• HLA Sensitization and the Probability of Kidney Transplantation
-each transplant programs have its own thresholds for incompatibility,so the chance of having a suitable donor may differ from one program to another.
– Probability of finding an acceptable match = 1-(cPRA)n , where n = the number of potential donors.
The higher the cPRA the higher number of match runs needed to find compatible donor.
The probability of finding a donor also depends on the size of the donor pool.
More participation in paired kidney exchange program increase the donor pool and increase the chance of finding more matched doner.
•Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era:
revision of the US Kidney Allocation System (KAS) was implemented on December 4, 2014. One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates
Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%. The number of waitlist points increases exponentially with cPRA with highest allocation priority to candidates with cPRA 98%.
But still patients with highest cPRA are advised to consider incompatible transplantation.
•Outcomes Associated with HLA-Incompatible Kidney Transplantation:
Long term graft survival is affected by degree of mismatch ,DSA level and results of crossmatch,
A large multi-center consortium involving 22 transplant centers that perform HLA-incompatible kidney transplantation found that
the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch and in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
*Desensitization protocols are diffrent between centres and no prospective, randomized trials comparing the outcomes of these protocols
*HLA-incompatible transplantation is less preferable to compatible transplantation,
this is only relevant for patients for whom both options are available.
Generally transplantation even from incompatible donor is much better than dialysis.
•Role of Kidney Paired Donation
kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
Desensitization should be considered as an adjunct to paired exchange for highly sensitized candidates .
•Approach to Highly Sensitized Candidate with an Incompatible Living Donor:
*Assess the feasibility of desensitization.
Authors mentioned that in their programme they do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) 17, as it will be high risk transplantation so they recommend participation in a paired kidney exchange
*Assess alternatives to HLA-incompatible kidney transplantation by:
-kidney paired donation may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization
Although In this review they recommended that paired kidney exchange should not be offered to all patients with an
incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
-Deceased Donor Transplantation ;the provider must recognize the exponential relationship between cPRA and the number of potential donors
that are required in order to identify a suitable donor.
-experienced centres with desensitization should manage HLA incompatibile transplantation.
saja Mohammed
3 years ago
Summary Introduction
Kidney transplantations of highly sensitized candidates hindered by many challenges including the difficulty to allocate compatible donor especially for group O and B , with long waiting risk on dialysis , also the available alternative treatment options like desensitization associated with many limitation include risk of intensive immunosuppression , allograft rejection , opportunistic infection , malignancy , in addition to the cost and logistics with resources like need of expertise in transplant immunology ,hematology and plasmapheresis
This article reviews the current available treatment options and give recommendation based on the expertise opinion from local centers keeping in mind till date there is no standardization of desensitization protocols and each center use their own available resources
Sources of the donors for highly sensitized recipients including:
1-Living HLA incompatible donor.
2-paired kidney exchange program (local center, multicenter, national base)
2- kidney allocation system (KAS) such program of allocation prioritizes the access to DD in sensitized recipients with CPRA > 80-97%.
3- combination of both KPD and desensitization
HLA Sensitization and the Probability of Kidney Transplantation
Assessing the degree of sensitization can be done by either CPRA by percentage usually the higher the CPRA % the more difficult to find match donors for example those with CPRA > 99, they need large pool of 300 donors in order to get matched donor
many observational studies from different centers addressing the graft survival outcomes in highly sensitized patients whom underwent HLA incompatible donor kidney transplantation, they found 8 years survival was highest in incompatible living donor group compared to control group (9). So this encourage to go for transplantation from any type of donor rather than stay on long wait list and dye on dialysis.
Kidney paired donation program:
Such program will allow the access for better matched donors over time but again in highly sensitized patients especially with group O with CPRA≥ 97% may need to wait for many years to get suitable donor, as per NKR only around 10% got matched donor with one year. and from other registry only 25% of patients with CPRA>95% got matched DD in 6 years waiting list so in such types of patients should consider the combination of KPD and desensitization which is more realistic approach.
Desensitization protocol for incompatible living donor transplantation to be performed after DSA level by Luminex SAB with relative intensity score (RIS)<17 and FXCM preferred with MFI < 250.
RIS ≥17 is associated with positive predictive value of 91% for AMR (20).
Avoid desensitization for positive CDCXM , or FCXM with MFI≥ 250 or DSA RIS≥ 17.
Conclusion:
individualized the decision for early access to combined KPD and desensitization protocol over PKD alone or DD alone
proper counselling and address the risk and benefits of the available treatment options
Mohammed Sobair
3 years ago
Highly sensitized candidates can receive transplants from either living or deceased
donor.
The most intensely sensitized candidates tend to be transplanted mainly through
deceased donation.
Options available to the highly sensitized candidate with an incompatible living donor
include:
Participation in a paired kidney exchange program.
Direct donation with an incompatible live donor.
Waiting for a deceased donor transplant.
There is lack of consensus and guidelines to inform transplant programs and candidates
on how to choose between these options.
HLA Sensitization and the Probability of Kidney Transplantation:
First step in counseling a highly sensitized kidney transplant candidate is to assess the
likelihood of finding a suitable donor.
Probability of finding an acceptable match = 1- (cPRA) n, where n = the number of
potential donors.
The number of match runs estimated to find a suitable donor is less for centers that
perform incompatible transplants.
Given the exponential relationship between cPRA and the number of match runs
required to find a compatible donor, it is not surprising that achieving living donor
transplantation becomes exceedingly unlikely as the cPRA increases above 99%
. Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney
Allocation System (KAS)Era:
One of the principal goals of the revised KAS was to increase access to deceased donor
kidney transplantation for highly sensitized candidates.
This policy benefited those with cPRA 80–97%, for whom the probability of finding a
compatible donor are generally favorable, but did little to improve access to transplant
for those with cPRA ≥ 98%.
Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-
scale beginning at cPRA 20%. The number of waitlist points increases exponentially with
cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥
98%.
cPRA ≥ 99% draw from a larger donor pool through regional and national sharing of
deceased donor kidneys. These allocation policy changes resulted in dramatic early
increases in the number of transplants performed in highly sensitized candidates with
cPRA ≥ 99% that have since stabilized at rates that are approximately 5-fold higher than that observed before the 2014 KAS revision.
Changes have not benefited the most highly sensitized candidate.
Candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant
despite the priority afforded by the KAS and are more likely to be removed from the
waitlist or die.
Observations suggest that patients in the highest cPRA categories should be advised to
consider incompatible transplantation. Although compatible transplantation remains a
remote possibility for patients with cPRA ≥ 99.95%, the likelihood of finding a compatible
donor is low, and, at a minimum, an extended waiting time is expected.
Outcomes Associated with HLA-Incompatible Kidney Transplantation:
Outcomes differ according to the degree of incompatibility.
Mild incompatibility: low level DSA associated with a negative crossmatch,
High levels of incompatibility, such as DSA in the presence of a positive FC or CDC
crossmatch.
A large multi-center consortium study from this study, the risk of HLA incompatibility on
post-transplant mortality and graft loss was only observed in the presence of a positive
crossmatch, with progressively higher degrees of crossmatch incompatibility being
associated with increasing risk of both outcomes.
However, the presence of a negative crossmatch, the risk of graft loss or death was
similar between transplants performed with DSA alone and those that were HLA-
compatible.
Multicenter data comparing survival over 8 years among patients who received an
incompatible living donor transplant to matched controls who remained on the waiting list
or received a deceased donor transplant indicates that survival is highest for
incompatible living donor recipients, making incompatible Kidney transplantation the best
choice for a broadly sensitized patient with an incompatible living donor who is
amenable to desensitization.
The higher survival rate was seen regardless of the degree of incompatibility, including
among patients with DSA and a negative crossmatch, those with a positive flow
cytometry crossmatch, and those with a positive CDC cross match.
Underscoring the message: it is generally better to undergo kidney transplantation
from a donor of any type rather than remain on dialysis in an attempt to wait for a more
preferable donor.
Role of Kidney Paired Donation:
Incompatible donor may find a more suitably matched donor through KPD.
Yields a compatible donor only a fraction of the time, and many highly sensitized
candidates are unsuccessful in finding any donor.
Kidney paired donation should be viewed as a mechanism for finding a more suitable
donor, but not necessarily a compatible one.
Desensitization should be considered as an adjunct to paired exchange for difficult-to-
match patients.
Assess the Feasibility of Desensitization:
Do not proceed with transplant PATIENT with:
Positive CDC.
Flow cytometry crossmatch median channel shift > 250 .
DSA relative intensity score (RIS) ≥ 17.
If HLA-incompatible transplantation is predicted to be prohibitively high risk based on
these criteria, we recommend participation in a paired kidney exchange program.
Assess Alternatives to HLA-Incompatible Kidney Transplantation Paired Kidney
Exchange:
Kidney paired donation:
May be a consideration for patients with an incompatible donor even if it is predicted
that the transplant is feasible with desensitization.
A recommendation to participate in kidney paired donation should include a detailed
discussion with both recipient and donor about :
The expectations of participation.
The likelihood of finding a compatible or more suitably matched donor.
The disadvantages of remaining on dialysis leveraged against the risks of
desensitization and HLA-incompatible transplantation.
Time limit for participation before determining the futility of kidney exchange
n our opinion, paired kidney exchange should not be offered to all patients with an
incompatible donor, especially if the patient’s cPRA and blood type predict a low
likelihood of finding a match through paired exchange and the flow cytometry crossmatch
indicates a high likelihood of successful transplantation.
Conclusions:
Highly HLA sensitized kidney transplant patients who are have a living donor
should be considered for desensitization.
A combined approach consisting of both desensitization and kidney paired donation will
generally be more successful.
We recommend clear discussion of the risks and benefits of available treatment options
and early consideration of desensitization and HLA-incompatible kidney transplantation
when the likelihood of finding a compatible donor is prohibitively low.
Mohamad Habli
3 years ago
Treatment options for highly sensitized candidates include PKE, desensitization with HLA-incompatible transplantation, or waiting for a DKD.
Desensitization regimens are expensive, limited to highly equipped center with advance immunology and PEX, and need nursing expertise and blood bank for successful implementation.
In this summary I will address the key points of the provided article. HLA Sensitization and the Probability of Kidney Transplantation
Transplant programs vary from center to another in their definitions and thresholds for incompatibility and sensitization. Because, for one center with good experience in transplanting sensitized patients and well developed desensitization protocols, highly sensitized pts could find donor match much rapidly than centers with limited experience.
The probability of finding a suitable donor depends on the cPRA and number of donor pool.
Probability of finding an acceptable match = 1- (cPRA)n ,with this equation, it is estimated that a patient with a cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor. The probability of finding a donor also depends on the number of donors, whether the paired kidney exchange program is local or national, where higher number of donor are included. Assessing the Probability of DDK Transplantation in the Kidney Allocation System
US Kidney Allocation System was implemented in 2014 to increase access to DDK for highly sensitized candidates. However, retrospectively analysis showed that DDK performed among recipients with cPRA 80–97% was proportionally similar to their representation on the waitlist, and recipients with cPRA were excluded.
Although KAS has greatly improved access to DDK in sensitized recipients, overall, the allocation policy changes have not benefited the most highly sensitized candidates with c-PRA >99%. Outcomes Associated with HLA-Incompatible Kidney Transplantation
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a DDK transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario. Role of Kidney Paired Donation
Paired kidney exchange is best option for incompatible donor but many highly sensitized candidate are not successful find any donor. In a comprehensive summary of the experience from the first 9 years of kidney paired donation through the NKR, 11.7% of all transplants required desensitization because of crossmatch-incompatibility or ABO-incompatibility.
Data from the NKR indicate that approximately 33-40% of all candidate remain unmatched for a year and higher percentage in blood group O and highly sensitized cPRA 97% .
That’s why, desensitization should be considered as adjuvant to kidney paired exchange program for difficult to match patients. Assess the Feasibility of Desensitization
Desensitization should be excluded in the followings group of candidate:
1) Positive CDC crossmatch
2) Positive flowcytometry crossmatch >250 or a DSA relative intensity score (RIS)> or equal 17
3) MFI> or equal 10,000
If HLA incompatible TX is predicted to be prohibited high risk based on these criteria: recommended to share in paired kidney exchanged program.
Conclusions
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization. Although participation in a kidney paired donation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates
Tahani Ashmaig
3 years ago
☆Rationalizing Incompatible Living Donor
Kidney Transplantation for Highly Sensitized Candidates
☆☆☆☆☆☆☆☆
▪︎This review addressed the pros and cons of paired kidney exchange and desensitization and provides recommendations for patients and providers on the approach to the highly sensitized patient with an incompatible living donor.
☆HLA Sensitization and the Probability of Kidney Transplantation:
________________________
▪︎ The likelihood of finding a suitable donor is the first step in counseling a highly sensitized kidney transplant candidate and this may differ from one program to another.
▪︎The Probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors.
– With this equation, it is estimated that patients with high cPRA require more match runs to increase the chance of finding a compatible donor,
▪︎ For transplant centers that only consider compatible transplants, these estimates provide a quantifiable approximation of the likelihood of finding a suitable donor, either through paired kidney exchange or waiting for a deceased donor.
▪︎The probability of finding a donor also depends on the size of the donor pool which increases by participation in a paired kidney exchange program.
▪︎ Achieving living donor transplantation is unlikely as the cPRA increases above 99%.
☆Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney
Allocation System (KAS) Era:
____________________________
▪︎ One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates.
▪︎Although the revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates.
▪︎ Candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die.
▪︎ Patients in the highest cPRA categories should be advised to consider incompatible transplantation.
☆Outcomes Associated with HLA-Incompatible Kidney Transplantation:
_____________________________________
▪︎ The distinction of HLA incompatibility (mild or higher) must be relevant, as outcomes differ according to the degree of incompatibility.
▪︎ There is little center-level variability in patient and graft survival outcomes associated with HLA-incompatible living donor kidney transplantation.
▪︎ HLA-incompatible transplantation is less preferable to compatible transplantation,
this is only relevant for patients for whom both options are available.
▪︎Making incompatible kidney transplantation is the best choice for the common scenario of: ( a broadly sensitized patient with an incompatible living donor who is amenable to desensitization).
▪︎The above patient may attempt to find a more suitable donor through paired kidney exchange, but if this is not possible, must decide whether to attempt an incompatible transplant or forgo the donor with the expectation of finding a more suitably matched deceased donor from the kidney waitlist.
▪︎ It is generally better to undergo kidney transplantation from a donor of any type rather than remain on dialysis.
☆Role of Kidney Paired Donation:
___________________________________
▪︎ This approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor.
▪︎ The percentage of unmatched candidates is higher for those with blood type O and thighly sensitized (cPRA ≥ 97%).
▪︎ For highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
▪︎Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients .
☆Approach to Highly Sensitized Candidate with an Incompatible Living Donor:
______________________
The following considerations are imp:
1) Assess the feasibility of desensitization.
2) Assess alternatives to HLA-incompatible kidney transplantation by:
2.1) Paired kidney exchange (should not be offered to all patients with an
incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
2.2) Deceased Donor Transplantation (the provider must recognize the exponential relationship between cPRA and the number of potential donors
that are required in order to identify a suitable donor.
▪︎Centers that are unwilling to perform an HLA-incompatible transplant should refer these patients to a center that is experienced with desensitization.
☆Conclusions:
_________________
▪︎ Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization.
▪︎Participation in a kidney paired donation program is rarely successful for the
most broadly sensitized candidates
▪︎A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find
a compatible donor.
☆This study recomended that:
________________________________
▪︎When the likelihood of finding a compatible donor is low there must be a clear discussion of the risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation
fakhriya Alalawi
3 years ago
Desensitization regimens can be resource-intensive, costly, and require clinical, immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful implementation. This review aims to provide recommendations for the highly sensitized patient with an incompatible living donor.
The options available to the highly sensitized candidate with an incompatible living donor include:
· Participation in a paired kidney exchange program,
· Direct donation with an incompatible live donor, or
· Waiting for a deceased donor transplant. The probability of finding a compatible donor depends on the size of the donor pool.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
Although the revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates. Candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die. Hence, it will advisable for patients with cPRA ≥ 99.95%, to consider incompatible transplantation. Outcomes Associated with HLA-Incompatible Kidney Transplantation
HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consistingof low-level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility, such as DSA in the presence of positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch. The distinction is relevant, as outcomes differ according to the degree of incompatibility.
A large multi-centre consortium involving 22 transplant centres that perform HLA-incompatible kidney transplantation with varying degrees of HLA-incompatibility, observedthat the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increased risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario.The higher survival rate was seen regardless of the degree of incompatibility, including among patients with DSA and a negative crossmatch, those with a positive flow cytometry crossmatch, and those with a positive CDC crossmatch.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
Kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation of finding a compatible donor may be unrealistic.
A recommendation to participate in kidney paired donation should include a detailed discussion with both recipient and donor about the expectations of participation, the likelihood of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis leveraged against the risks of desensitization and HLA-incompatible transplantation, and a time limit for participation before determining the futility of kidney exchange.
Paired kidney exchange should not be offered to all patients with an incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
Deceased Donor Transplantation
A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor, and MFI thresholds for defining an antigen as unacceptable should be adjusted to bring the cPRA down to at least < 99.95%. In doing so, however, it must be recognized that this increases the likelihood of incompatible donor offers. Therefore, desensitization should be considered a necessary component for successful transplantation.
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates
This article discusses the pro and cons of paired kidney exchange and desensitization and gives recommendations. Treatment options in highly sensitized patient are limited due to poor graft survival , higher rejection rates and poor therapeutic options. With newer protocols , renal transplantation in highly sensitized patients offer better outcome as compared to those on dialysis . Renal transplantation in highly sensitized patients requires more cost ,resources and new therapeutic modalities like Plasmaphresis. Their options include both living and deceased donors , however finding suitable living donor is very less likely and they have to resort to deceased donors. Such patients on long waiting list can enrol in paired kidney exchange programme , direct donation from incompatible living donor or wait a donation from deceased donor.
HLA Sensitization and the Probability of Kidney Transplantation- The probability of finding suitable donor can calculated using the formula-
Probability of finding an acceptable match
1- (cPRA)n n = the number of potential donors.
Finding deceased donor in Kidney allocation system- KAS
KAS can be regional, national or international and patients on waiting list will take priority points as per their cPRA . CPRA can range from 20 -98%.
Transplantation with desensitization protocols
The goal of desensitisation is to remove DSA from recipient circulation and can improve graft survival in recipients with cPRA >80%. The options will include Plasmaphresis, IVIG and Rituximab In this study, those patients with positive CDC did not undergo transplantation. Thos ewith positive FXCM and Channel shift more that 250 and relative intensitive score more than 17 did not progress to transplantation . cPRA >99.995 will hardly receive organ from deceased donor and will need desensitization protocol at some stage.
The short term outcome may be better but long term outcome may not be good due to rejection , infection and complications of immunosuppression. Ideally it should be avoided wherever it is possible due to complications and cost . So it should be limited to those with no suitable living donor and are on top of waiting list.
Kidney Pair Donation
This process involves kidney exchange between living donor and recipient pair due to HLA or ABO incompatibility thus providing opportunity to have a better matched transplant. Those with cPRA >98% or blood group O have only 10% probability of finding living donor in one year. KPD will try to find most suitable non compatible donor. Detailed counselling is required to understand the pro and cons of this programme .
Conclusions
Highly sensitised who can find suitable living donor should be considered for desnsitization
Kidney paired donation can find suitable matched donor , especially those with blood group O
Combined approach of desensitization and paired kidney donation will be more successful than paired exchange alone in finding a living donor
Patients should be counselled about risk and benefits of available options and early consideration of desensitization and HLA incompatible transplant when chances of finding a compatible donor are low
mai shawky
3 years ago
· The best option for transplant is matched donor. However, sometimes we need to transplant those with positive cross match and had been long waiting time to have better QOL than on dialysis.
· The probability to find a suitable donor can be calculated by formula:
1- (cPRA)n, when n is the number of available donors, it was found that in patients with a cPRA of 99% only 1 from 300 donor offer will be suitable for transplantation with a negative crossmatch.
· Different options for those with high cPRA (highly sensitized):
o Continue on hemodialysis with poor QOL and higher mortality than non compatible transplantation.
o Use paired kidney donation (PKD)to find more suitable donor (so difficult especially for those with long waiting time, more exposure to sensitizing events).
o Use deceased donor who is more suitable by virtual cross match which has improved due to improvement of the kidney allocation system (KAS).
o Use of aggressive desensitization protocols to remove antibodies and render them transplantable.
Value of KAS
Use either local or even national system for organ allocation to increase pool of available organs and facilitate better matching.
Application of concept of priority to those who are highly sensitized with higher cPRA can help them to find suitable donor.
However, it does not help those with c PRA > 98 % and will require long waiting time also.
Desensitization protocols
It means removal of preformed DSA which can lead to hyper acute rejection with immediate graft loss.
This can be done by Plasmapheresis, IVIG, and Rituximab
It can be used for highly sensitized recipients (C PRA > 80% and positive cross match). However, those with detectable DSA and negative cross match an have similar graft outcome to non sensitized.
However it has many drawbacks:
Higher risk of infection (BK and CMV) and malignancy (especially skin cancer).
Also higher cost and economic burden due to additional immunosuppressive for desensitization and treatment of expected subsequent relapses.
So it should be limited highly sensitized (cPRA ≥ 99.95% ) and cannot find a deceased donor offer on KAS waiting list and has been waiting for long unacceptable time.
Desensitization is indicated in patients with only positive FXM due to DSA provided that MCS< 250 and RIS <17 if MCS > 250 or RIS > 17 this donor should be excluded
Paired kidney donation (PKD)
It means exchange of kidneys between donor- recipient couples due to ABO or HLA incompatibility, so allow recipients to receive a better-matched kidney.
It is only applied in living kidney transplant (as no time in deceased one to be applied).
For those with cPRA ≥ 98% and blood group O, the probability to find compatible donor is only 10% within 1 year, so the aim here is to find the most suitable not compatible donor to reduce waiting time.
Amit Sharma
3 years ago
Please summarise this article
Highly sensitized patients can receive a transplant from either a living incompatible donor (either directly or through a paired exchange program) or a deceased donor. As the chances of finding an HLA compatible donor are very low, desensitization followed by an HLA incompatible transplant is an option worth considering in such patients.
The chances of finding an acceptable donor depends on the size of the donor pool as well as the thresholds taken for incompatibility in a particular transplant program. As the cPRA value increases, the number of match runs required to have a 95% chance of finding an acceptable donor increase exponentially (9 runs for a cPRA of 70%, 59 runs for a cPRA of 95% and 30000 runs for a cPRA of 99.99%). So, it is very important to assess the probability of finding a living donor for such patients. The probability of finding a deceased donor has increased post-2014 due to implementation of newer kidney allocation system (KAS), which gives highest priority to cPRA ≥98%, and hence led to 5 times increase in transplants of patients with cPRA ≥99%. Even in newer KAS era, the patients with cPRA ≥99.95% have not been able to get a transplant.
In this background, an HLA incompatible transplant should be considered for such highly sensitized patients. It has been shown that HLA incompatible transplant in patients with negative crossmatch has no effect on post-transplant mortality and graft loss, with poorer results only with a positive cross match, worsening with the degree of crossmatch incompatibility. The number of transplants and type of desensitization protocols used in the transplant program did not have any effect on the graft outcomes. Comparing the results of an incompatible transplant to remaining on dialysis, there is a survival advantage.
A large proportion of these highly sensitized patients are not able to get a donor through kidney paired donation (KPD) programs, especially blood group O or cPRA ≥97%. Studies have shown transplant rates of 60-65% at one year (10% for O group and cPRA ≥98%). So, a KPD program can be utilized to find a more acceptable donor, rather than a compatible donor.
The approach towards highly sensitized patient with a living donor includes getting a CDC, flow cytometry crossmatch and Luminex bead assay. A positive CDC crossmatch or a flow cytometry cross match with median channel shift (MCS) > 250 or a DSA relative intensity score (RIS) ≥17 should not be taken up for desensitization and be listed in a KPD program, due to high probability of antibody-mediated rejection. In other patients, after discussing the pros and cons of remaining on waitlist versus getting an incompatible donor kidney after desensitization, the incompatible living donor transplant can be proceeded with. Even a deceased donor after desensitization can be carried out, especially in patients with cPRA ≥99.95% after adjusting the MFI cut-offs of unacceptable antigens to bring down the cPRA to <99.95%.
So, early decision regarding remaining on waitlist or getting an incompatible transplant (living or deceased) should be taken after assessing the probability of receiving a compatible donor, the crossmatch results and the MFI levels of the antibodies.
Doaa Elwasly
3 years ago
The choices for highly sensitized candidate with an incompatible living donor are
either participation in a paired kidney exchange program,
or direct donation with an incompatible live donor,
or waiting for a deceased donor transplant. HLA Sensitization and the Probability of Kidney Transplantation
The possibility of getting a suitable donor may differ from one program to another.
The Probability of finding an acceptable match = 1- (cPRA)n , where n = the number of potential donors
For centers that only proceed with compatible transplants, these estimates provide a quantifiable approximation of the likelihood of finding a suitable donor while for centers that perform incompatible transplants, the number of match runs estimated to find a suitable donor is less depending on the degree of incompatibility a program accepts.
The probability of finding a suitable match also depends on the size of the donor pool available either from a single center or multicenter national one. Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
It was done inorder to increase possibility of finding a deceased donor kidney transplantation for highly sensitized candidates.
This was useful for cases with cPRA 80–97%, for whom the possibility of finding a compatible donor are generally favorable, but didnot improve access to donors for caseswith cPRA ≥ 98%.
The waitlist points increases exponentially with cPRA and it gives the highest priority to candidates with cPRA ≥ 98%.
The candidates with cPRA ≥ 99% draw from a larger donor pool.
Patients in the highest cPRA categories should consider incompatible transplantation. Although compatible transplantation remains difficult for them ,the possibility of finding a compatible donor is low, and prolonged waiting time is expected. Outcomes Associated with HLA-Incompatible Kidney Transplantation
A study was done demonstrated that the risk of HLA incompatibility on post-transplant mortality and graft loss was associated with the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of mortality and graft loss.
It was mentioned that the volume of incompatible transplants or type of desensitization protocol employed, have little effect on outcomes.
A multicenter data comparing survival over 8 years among recipients with incompatible living donor transplant to matched controls whom was kept on the waiting list or received a deceased donor transplant revealing that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for such cases. Role of Kidney Paired Donation
Although living donor transplantation is made easier for some highly sensitized candidates, others fail to find a suitable donor through paired exchange.
For highly sensitized candidates, kidney paired donation is a way for finding a more suitable donor, not necessarily a compatible one as desensitization is an adjunct to paired exchange for difficult-to-match cases. Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
It includes Assess the Feasibility of Desensitization
Done by doing Luminex single antigen testing and a CDC and flow cytometry crossmatch.
In their program desensitization for a positive CDC crossmatch is not advisable , although it can work with some cases .
Also they do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17 which is highly associated with antibody medicated rejection.
High risk cases based on these criteria, are enrolled in a paired kidney exchange program. Assess Alternatives to HLA-Incompatible Kidney Transplantation
Which is either Paired kidney exchange
It is done through a detailed discussion with recipient and donor about the expectations of participation, the possibility of finding a suitable donor, the disadvantages of remaining on dialysis compared to the risks of desensitization and HLA-incompatible transplantation. Deceased donor transplantation
In some cases due to HLA sensitization , living donor transplantation is not possible for them keeping a deceased donor their only choice.
Desensitization is necessary for successful transplantation in patient with a cPRA ≥ 99.95% and MFI threshold is manged to keep cPRA < 99.95% Conclusion
A combined approach of both desensitization and kidney paired donation will be more successful for highly HLA sensitized kidney transplant patients who are having a living donor
-Transplant options for highly sensitized kidney transplant candidates were limited due to ineffective therapies for desensitization, high rejection rates, and poor graft survival.
– Highly sensitized patients can receive transplants from either living or deceased donors, but mainly from a deceased donor.
-The first step in counseling a highly sensitized kidney transplant candidate is to assess the likelihood of finding a suitable donor.
-The relationship between calculated panel reactive antibodies (cPRA) and the probability of finding a compatible donor is expressed as:
Probability of finding an acceptable match = 1- (cPRA)n,
where n = the number of potential donors.
-For eg, it is estimated that a patient with a cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a cPRA 99.5% and 3000 match runs for a candidate with cPRA 99.9%.
-For transplant centers that only consider compatible transplants, these estimates provide a quantifiable approximation of the likelihood of finding a suitable donor, either through paired kidney exchange or waiting for a deceased donor.
-The number of the match runs estimated to find a suitable donor is less for centers that perform incompatible transplants, with fewer match runs required depending on the degree of incompatibility a program is willing to accept.
-A revision of the US Kidney Allocation System (KAS) was implemented on December 4, 2014.
-The principal goals of the revised KAS was to increase access to deceased donor
kidney transplantation for highly sensitized candidates.
– KAS benefited those with cPRA 80–97% .
-Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%.
-These allocation policy changes resulted in early increases in the number of transplants performed in highly sensitized candidates with cPRA ≥ 99% that has since stabilized at rates that are approximately 5-fold higher than that observed before the 2014 KAS revision.
-The revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, but the allocation policy changes have not benefited the most highly sensitized candidates.
-Patients with a cPRA ≥99.95%remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die .
-The patients in the highest cPRA categories should be advised to consider incompatible transplantation. Outcomes Associated with HLA-Incompatible Kidney Transplantation
-A large multi-center consortium involving 22 transplant centers that perform HLA-incompatible kidney transplantation compared patient and graft survival outcomes among living donor kidney transplant recipients with varying degrees of
HLA-incompatibility , showed:
1-The risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with an increasing risk of both outcomes.
2-In the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
3-Desensitization practices varied across transplant centers in this study.
-Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients.
4- It is better to undergo kidney transplantation from a donor of any type rather than remain on dialysis in an attempt to wait for a more preferable donor. Role of Kidney Paired Donation
-Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange.
– In a comprehensive summary of the experience from the first 9 years of kidney
paired donation through the National Kidney Registry (NKR), 239/2037 (11.7%) of all transplants facilitated required desensitization because of crossmatch-incompatibility or ABO-incompatibility .
– Data from the NKR indicates that approximately 35–40% of all candidates remain unmatched within a year.
-The data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
-Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation of finding a compatible donor may be unrealistic. Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
The approach takes into account the following considerations: Assess the Feasibility of Desensitization
-Initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch.
-It does not recommend desensitization for a positive CDC crossmatch and does not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ˃ 17.
-If HLA-incompatible transplantation is predicted to be prohibitively
high risk based on these criteria, it recommend participation in a paired kidney exchange program. Assess Alternatives to HLA-Incompatible Kidney Transplantation Paired Kidney Exchange
-Kidney paired donation may be a consideration for patients with an incompatible
donor even if it is predicted that the transplant is feasible with desensitization. Deceased Donor Transplantation
-A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor , and MFI thresholds for defining an antigen as unacceptable should be adjusted to
bring the cPRA down to at least < 99.95%.
– Desensitization should be considered as a necessary component for successful transplantation.
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates. Introduction:
Transplantation is still the best modality for end stage renal disease patients related to morbidity and mortality rates and specially from point of quality of life.
Highly sensitized candidates for transplantation is challenging for us till now as those patients are between two difficult options, each one is more difficult than the other , the first is to find the compatible living donor that may never come or incompatible that need desensitization protocols which also costly, and require clinical, immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful implementation.
The second option is waiting for a deceased donor transplant or continuing on PD/HD with lower quality of life.
This review addressed the upsides and downsides of paired kidney exchange and desensitization and provides recommendation for patients and providers on the approach to the highly sensitized patient with an incompatible living donor. HLA Sensitization and the Probability of Kidney Transplantation:
The best option for those patients to find suitable compatible living donor which has a good graft survival.
The relationship between calculated panel reactive antibodies (cPRA) and the probability of finding a compatible donor is expressed as: Probability of finding an acceptable match = 1- (cPRA)n, which differ from system to another.
e.g. patient with (Cpra) is 99 needs 300 match runs to have a 95% chance of finding a compatible donor.
You can increase possibility of finding compatible donors either through paired kidney exchange (which depends on the size of donor pool) or waiting for a deceased donor.
Some center going for incompatible transplantation depending on the degree of incompatibility a program is willing to accept. Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates.
The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥ 98%, but candidates with a cPRA ≥ 99.95% still not benefited from the system with high waiting time or die, so the patients in the highest cPRA categories should be advised to consider incompatible transplantation. Outcomes Associated with HLA-Incompatible Kidney Transplantation
HLA incompatibility divided to:
-Mild incompatibility (low level donor-specific antibodies (DSA) associated with a negative cross match).
-Higher incompatibility (s DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) cross -match) which has poor patient and graft outcome than the mild incompatible group.
Comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients which is considered by Multicenter data.
So better to go for kidney transplantation from a donor of any type rather than remain on dialysis in an attempt to wait for a more preferable donor. Role of Kidney Paired Donation
Paired kidney exchange is allowing highly sensitized recipients to find suitable compatible donor but still those who have the combination of both O blood type and cPRA ≥ 98% in NKR, only approximately 10% successfully find a donor within 1 year ,so the concept of paired kidney donation system should be changed to find a more suitable donor, but not necessarily a compatible one. Approach to the Highly Sensitized Candidate with an Incompatible Living Donor: Assess the Feasibility of Desensitization:
In their program, they do not recommend desensitization for a positive CDC cross-match and they do not proceed with transplant with a flow cytometry cross-match median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17 because associated with a positive predictive value of 91% for antibody-mediated rejection.
The RIS is a risk score that accounts for the binding strength of DSA.
10 points for each DSA (MFI) ≥ 10,000).
5 points for each DSA (MFI 5000 to 9999).
2 points for each weak DSA (MFI < 5000). Assess Alternatives to HLA-Incompatible Kidney Transplantation:
Paired Kidney Exchange:
Increase the likelihood of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis outweighed against the risks of desensitization and HLA-incompatible transplantation.
But if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange, can replace the paired kidney donation by transplantation with desensitization.
Deceased Donor Transplantation:
In some highly sensitized patients due to due to the breadth of HLA sensitization, deceased donor transplantation remains their only option. Conclusions:
In highly sensitized patients with low chance to find compatible living donor should participate in paired kidney donation with desensitization, We recommend clear discussion of the risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation or Deceased Donor Transplantation as the last resort.
Kidney transplantation in highly sensitized patient is challenging, in spite of advancement in desensitization and pre-transplant therapy. Living kidney transplant is less common among highly sensitized patients especially with accumulating barriers and increasing degrees of sensitization.
This article reviewed the merits and demerits of the alternatives to transplantation in highly sensitized patients , KPD and desensitization therapy.
The probability of finding a donor is getting less with increasing sensitization. It depends on:
· The degree of incompatibility the program or the transplant center is tending to coincide and follow.
· The degree of sensitization (cPRA).
· The size of the donor pool.
Kidney paired donation can be one of :
· Small and single center with internal exchange.
· Large and multiple centers with national exchange.
UNOS/OPTN data analysis regarding KPD among 2 groups of patients followed from 2016 for 1 year ( 262patients with cPRA 99%,528 patients with cPRA 100%):
· The performed living TX was as follows: 13/262(5.0%) and 13/528(2.5%).
· Only 16/26 of these living rTX were performed after KPD.
· The rate of living rTX among KTRs with cPRA<80% was 27% and 14% of these living donations were promoted after KPD.
Despite the revision and development of kidney allocation system to increase the donors pool for highly sensitized patients, still there’s a difficulty in finding a suitable donor for those with high cPRA. These observations suggested the likelihood of performing incompatible rTX to shorten the stay in the waiting list and to avoid the downside of remaining on dialysis.
HLAi-rTX is a relevant option for highly sensitized patients without a suitable donor, provided that the post-transplant mortality and graft loss were noticed with positive XM(FCXM or CDCXM) 1, while the outcome is similar in the presence of a negative crossmatch in those with DSA alone and those with HLA compatibility. Orandi et al 2 in a multicenter data analysis found that the living incompatible rTX had a higher survival rate in comparison to those remained on the waiting list or received deceased donation. The survival rate was higher regardless the degree of incompatibility including among patients with DSA and negative XM, those with positive FCXM and CDCXM. Overall, it’s better to undergo kidney transplantation, whatever the degree of incompatibility than remaining on dialysis.
Reference
1. Orandi BJ, Garonzik-Wang JM, Massie AB, Zachary AA, Montgomery JR, Van Arendonk KJ, et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transplant. 2014;14:1573–80.
2. Orandi BJ, Luo X, Massie AB, Garonzik-Wang JM, Lonze BE, Ahmed R, et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med. 2016;374:940–50.
# Please summarise this article
# Introduction
*Highly sensitized patients had limited chance for renal transplantation, due to ineffective therapies for desensitization; increase the incidence of rejection rates, poor graft survival and more costly. *Options available for highly sensitized patients with an incompatible living donor are paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant.
*This study showed the advantage and disadvantage of paired kidney exchange and desensitization and provides recommendations for patients and providers on the approach to the highly sensitized patient with an incompatible living donor.
# HLA Sensitization and the Probability of Kidney Transplantation
*The first step in counseling a highly sensitized patient is to assess the possibility of finding a suitable donor.
*The probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors.
*With this equation, it is estimated that a patient with a cPRA >99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; and so on.
*For transplant centers that only consider compatible transplants, these figures give a quantifiable approximation of the possibility of finding a suitable donor, either through paired kidney exchange or waiting for a deceased donor.
*The probability of finding a donor also depends on the size of the donor pool. The kidney exchange donor pool can range from small, single-center internal exchanges to large multi-center national exchange programs.
*Given the exponential relationship between cPRA and the number of match runs required to find a compatible donor, achieving living donor transplantation becomes exceedingly unlikely as the cPRA increases above 99%.
# Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
*One of the main role of the revised KAS was to elevate the access to reduce donor kidney transplantation for highly sensitized patients.
*Sensitized recpients receive waitlist points according to a sliding-scale beginning at cPRA 20%.
The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA > 98%, also candidates with cPRA > 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys.
*The KAS has advancing the access to deceased donor kidney transplantation across the spectrum of allosensitization overall, but the allocation policy changes have not improved the most highly sensitized.
# Outcomes Associated with HLA-Incompatible Kidney Transplantation
Study showed that the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
*Recent data indicate that there is little center-level variability in patient and graft survival outcomes associated with HLA-incompatible living donor kidney transplantation, suggesting that center-specific factors, such as volume of incompatible transplants or type of desensitization protocol employed, have minimal impact on outcomes.
*Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatiblekidney transplantation the best choice.
# Role of Kidney Paired Donation
*It gives a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor
*Sensitized candidates, many are unsuccessful in finding a donor through paired exchange. Data from the NKR indicates that approximately 35–40% of all candidates remain unmatched within a year.
* The percentage of unmatched candidates is higher for those with blood type O (43%) or who are highly sensitized (cPRA 97%; 58%). For those who have the combination of both O blood type and cPRA 98%, only approximately 10% successfully find a donor within 1 year.
# Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
The following considerations should be recognized:
*Assess the Feasibility of Desensitization by performing Luminex single antigen
testing to identify DSA and perform a CDC and flow cytometry crossmatch.
*Desensitization for a positive CDC crossmatch not recommended.
*Not proceed with transplant with a flow cytometry crossmatch median channel shift > 250
or a DSA relative intensity score (RIS) 17.
*The RIS is a risk score that accounts for the binding strength of DSA and assigns
10 points for each DSA in the strong-binding range (MFI) 10,000, 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI 17 is associated with a positive predictive value of 91% for ABMD.
# Assess Alternatives to HLA-Incompatible Kidney Transplantation Paired Kidney Exchange
The kidney paired donation may be recommended for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization and to discuss all details with both recipient and donor.
# Deceased Donor Transplantation
Study showed that 58% of deceased donor transplants performed among candidates with cPRA >99% were in the presence of DSA. Centers that are unwilling to perform an HLA-incompatible transplant should refer these patients to a center that is experienced with desensitization.
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates
The choice of transplant for sensitised patients was restricted due to lack of effectiveness of desensitisation therapies, higher rejection rate, and poor graft outcomes.
Many centres still reluctant to do HLAi transplantation although there is improvement in desensitisation protocols and better outcome compared to remaining dialysis. This results in many highly sensitised patients continue waiting for a compatible donor.
HLA sensitization and the probability of kidney transplantation:
Assessing the probability of deceased donor kidney transplantation in the kidney allocation system era:
Outcomes associated with HLA-incompatible kidney transplantation:
Role of kidney paired donation:
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor:
Assess the Feasibility of Desensitization
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
PKD may be considered for patients with an incompatible donor although it is predicted that the transplant is feasible with desensitization. It is important to counsel regarding all the potential benefits and harm of the process with the candidate although patient’s blood group and cPRA, could limit the possibility of finding an acceptable donor.
Deceased Donor Transplantation
LRRT is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option for better life. But high cPRA is a limiting factor for this option. Desensitization may be considered to achieve successful transplantation
The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant.
Probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization.
A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find acompatible donor .
cleardiscussionofthe risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation when the likelihood of finding a compatible donor is prohibitively low.
Aims of the study is to review the treatment options for highly sensitized kidney transplant candidates & provide recommendations.
Highly sensitized kidney transplantation is challenging, historically it was not feasible because of limited ineffective therapy , poor graft outcomes , nowadays there are many options for those patients, either to go for paired exchange program, desensitization or cadaveric kidney transplant.
Transplantation in highly sensitized candidates is better than waitlisted.
The first step in counselling the patient is to find a suitable donor .if not available , assess the probability of deceased donor KTX by kidney allocation system , which depends on c PRA patient more than 80% get more points to get the donor, but in case of cPRA >99% the advice to consider incompatible transplantation.
The outcomes associated with HLA-Incompatible Kidney Transplantation, higher degrees of crossmatch incompatibility being associated with increasing risk of patient & graft outcomes.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
Initial step is to assess the amenability of desensitization
to a potential living donor by performing SAB, DSA FCXM
we do not proceed with transplant
with a FCXM median channel shift > 250
or a DSA relative intensity score (RIS) ≥ 17.
Assess Alternatives to HLA-Incompatible Kidney
Transplantation
Paired Kidney Exchange
kidney paired donation may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization.
Introduction
Despite the advent of newer protocols for desensitization and favorable outcomes compared to remaining on dialysis, many centers remain reluctant to perform HLA-incompatible kidney transplants. Desensitization regimens can be resource intensive, costly, and require clinical, immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful implementation.
This review addressed the pros and cons of paired kidney exchange and desensitization and provides recommendations.
HLA Sensitization and the Probability of Kidney Transplantation
Probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors, the probability of finding a donor also depends on the size
of the donor pool. If participation in a paired kidney exchange program is being considered, the number of potential donors available for exchange should be evaluated.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
Although the revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates.
Closer examination of transplantation rates by unrounded cPRA reveals that
candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die. These observations suggest that patients in the highest cPRA categories should be advised to consider incompatible transplantation. Although compatible transplantation remains a remote possibility for patients with cPRA ≥ 99.95%, the likelihood of finding a compatible donor is low, and, at a minimum, an extended waiting time is expected.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
Graft outcome is an important consideration when choosing between transplant options for highly sensitized candidates.
It is important to recognize that HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility,
such as DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch. The distinction is relevant, as outcomes differ according to the degree of incompatibility.
Role of Kidney Paired Donation
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange, but they should recognize that this approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
-Assess the Feasibility of Desensitization
Our initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch
Each center has criteria to assess for feasibility of desensitization and in this article the criteria as follow:
we do not recommend desensitization for a positive CDC crossmatch, we do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17. The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) ≥ 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000). A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
If HLA-incompatible transplantation is predicted to be prohibitively high risk based on these criteria, we recommend participation in a paired kidney exchange program.
–Assess Alternatives to HLA-Incompatible Kidney Transplantation
– Paired Kidney Exchange
kidney paired donation may be a consideration for patients with an incompatible
donor even if it is predicted that the transplant is feasible with desensitization. A recommendation to participate in kidney paired donation should include a detailed discussion with both recipient and donor about the expectations of participation, the likelihood of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis leveraged against the risks of desensitization and HLA-incompatible transplantation, and a time limit for participation before determining the futility of kidney exchange.
In our opinion, paired kidney exchange should not be offered to all patients with an
incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with
desensitization
-Deceased Donor Transplantation
Conclusion
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization. Although participation in a kidney paired donation program offers the possibility of finding a compatible
or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O. A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find
a compatible donor.
So in a nutshell it is very difficult to get a tx for highly sensitized patient, which he/she gets through desensitization/kpd/deceased donation tx.So deciding between the above methods is really nailbitting.
In HLAi tx all method CDC,FCXM,Single bead assay to be done, if CDC postive or FCXM positive with with mcs >250 or DSA with RIS (relative intensity score)>17, then patient should not be put on desensitization and look for other methods like KPD and KPD with desensitization or deceased donation as in above situation graft and patient outcome is very poor.
Those with lower incompatibility may be considered for desensitization because which is better than waiting on deceased donor list or hd.
Now for highly sensitized patient in deceased donation higher points are given through KAS, which increases tx.
Highly sensitized patients have 2 options; either to receive transplant from living incompatible donor ; directly or through paired exchange program or a deceased donor. When possibility of HLA compatible donor is very low, desensitization before HLA incompatible transplant is an option.
The possibility of finding an acceptable donor relies on the size of the donor pool and the thresholds for incompatibility in a given transplant program. With increasing c PRA value, the number of match runs required to have a 95% chance of finding an acceptable donor increase exponentially (9 runs for a c PRA of 70%, 59 runs for a c PRA of 95% and 30000 runs for a c PRA of 99.99%). The probability of finding a deceased donor has increased post-2014 due to implementation of newer kidney allocation system (KAS), which gives highest priority to c PRA ≥98%, so led to 5 times increase in transplants of patients with c PRA ≥99%. However, with newer KAS era, the patients with c PRA ≥99.95% are still not able to get a transplant.
Based on these data, HLA incompatible transplant should be considered for such highly sensitized patients. It was found that HLA incompatible transplant in patients with negative crossmatch has no effect on mortality and graft loss, with poorer outcomes only with a positive cross match, worse with degree of crossmatch incompatibility. The number of transplants and type of desensitization protocols did not have any effect on the graft outcomes. There is survival advantage comparing results of incompatible transplant to remaining on dialysis.
A large proportion of these highly sensitized patients are not able to have donor through kidney paired donation (KPD) programs, especially blood group O or c PRA ≥97%. It was found that transplant rates of 60-65% at one year So, a KPD program can be used to find a more acceptable donor.
The approach towards highly sensitized patient with a living donor includes getting a CDC, FCXM and Luminex bead assay. A positive CDC crossmatch or FCXM with median channel shift (MCS) > 250 or a DSA relative intensity score (RIS) ≥17 should not be taken up for desensitization and be listed in a KPD program, due to high probability of AMR. Otherwise, with discussion of pros and cons of remaining on waitlist vs having incompatible donor kidney after desensitization, incompatible living donor transplant can be proceeded for. Also, deceased donor following desensitization can be carried out, especially with cPRA ≥99.95% after adjusting MFI cut-offs of unacceptable antigens to bring down the c PRA to <99.95%.
Making early decision is needed considering remaining on waitlist or getting an incompatible transplant ;living or deceased, after assessing the probability of having compatible donor, the crossmatch results and the MFI levels.
in past kidney tranx for sesetized patients was unlikely and has no promising outcome due to ineffective therapies for desensitization, high rejection rates, and poor graft survival,also Desensitization regimens can be resource intensive,costly,and require clinical,immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful tranx.
he most intensely sensitized candidates tend to be transplanted mainly through deceased donation. This is undoubtedly related to the challenges of finding a compatible donor through the living donor pool.
increasing cPRA always carry the risk of not having a kidney donor , the aim of kidey allocation system is to increase the access of highly sensitized patients to deceased donor kidney transplant.
Outcomes Associated with HLA-Incompatible Kidney Transplantation range from mild with low-level DSA and negative crossmatch to a higher degree of incompatibility with positive crossmatch.
kidney paired donation can give agood solution for those highly sensetized patients by having asuitably matched donor through paired kidney exchange.
Deceased Donor Transplantation cosidered ahope for highly sensetized patients not suitable for living donor tranx.
all of the previous solutions whether paired kidney exchange or deceased kidney donation require having desensitization as a necessary component for successful transplanx.
High degree of sensitization makes living donor transplantation more hard
As the cPRA increases above 99%, the possibility of receiving a living donor graft becomes unlikely.
The revision of kidney allocation system (KAS) aimed to increase the access of highly sensitized patients to deceased donor kidney transplant.
It resulted in five-fold increase in number of transplantation in highly sensitized patients with cPRA >99%.
However, highly sensitized patients with cPRA :99.95% remain unlikely to receive transplantation.
The outcome of transplantation varies according to the degree of compatibility
It ranges from mild incompatibility (low level DSA with negative crossmatch) to high level incompatibility (DSA with positive FCXM or CDCXM)
Patients with DSA but negative cross-match have same risk of graft loss and mortality as HLA compatible transplants.
Studies showed that the outcome of kidney transplantation (regardless the type of donor) is better than remaining on dialysis waiting for more preferable donor.
Kidney paired donation provides patients with incompatible donor to find more suitably matched donor. However, many highly sensitized patients fail to find donor.
Desensitization is not recommended in case of positive CDCXM
In case of positive FCXM with median channel shift>250 or DSA RIS>/=17, it is not recommended to proceed with transplantation.
These criteria predict high risk incompatible transplant which is better to be avoided.
KPD should be considered despite feasibility of incompatible transplant as incompatible transplant is associated with increased risk of graft loss and mortality compared to compatible transplants.
Patients with broad HLA sensitization, if living donor transplantation is not feasible, deceased donor transplant will be an option.
If there is a low probability of finding compatible donor, desensitization should be considered.
Conclusion:
Desensitization may be considered in highly sensitized patients who have a living donor.
Combination of both KPD and desensitization is more beneficial
If there is a low probability of finding donor, desensitization and incompatible transplants should be considered .
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates
Transplant highly sensitized patients still have favourable outcomes when compared with those remaining on dialysis. Nevertheless, many transplant centres are reluctant to perform HLA-incompatible kidney transplants.
Like other transplant candidates, highly sensitized candidates can receive transplants from either living or deceased donors. However, living donor transplantation is progressively less common and the main option for them is a deceased donors.
A highly sensitized candidate with an incompatible living donor can participate in the KPD program, to increase the chance to find a more compatible donor. Or wait for a deceased donor, or proceed with a direct donation with an incompatible live donor.
HLA Sensitization and the Probability of Kidney Transplantation:
The first step in counselling a highly sensitized candidate is to assess the likelihood of finding a suitable donor who differs from one program to another according to their thresholds for incompatibility.
Probability of finding an acceptable match = 1- (cPRA)n,
where n = the number of potential donors
It is estimated that a patient with c PRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor, which increases to 600 match runs for a candidate with c PRA 99.5%.
In centres that perform incompatible transplants, the number of the match runs estimated to find a suitable donors is less.
The probability to find a donor also depends on the size of the donor pool. The kidney exchange donor pool can range from small to large multi-centre international programs.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
Even with KAS that has been revised in 2014 in UK, the probability to transplant highly sensitized candidate with c PRA ≥ 99.95% remain low and these patients are more likely to be removed from the waitlist or die. These patients should be advised to consider incompatible transplantation.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
The outcomes differ according to the degree of incompatibility. Which range from mild with low-level DSA and negative crossmatch to a higher degree of incompatibility with positive crossmatch.
Multi-centre study revealed that the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch
incompatibility being associated with increased risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone or those that were HLA-compatible. Many studies reveal that it is generally better to undergo kidney transplantation from any donor type rather than remain on dialysis in an attempt to wait for a more preferable donor.
Role of Kidney Paired Donation
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange. But this approach yields only small number of highly sensitized patients get successful donor.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
According to the authors, the initial step is to assess the ability of desensitization to a potential living donor by performing Luminex single antigen test and perform a CDC and flow cytometry crossmatch.
The authors do not recommend the following:
1- desensitization for a positive CDC crossmatch, although successful transplantation can be in this setting.
2- To proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA RIS ≥ 17.
RIS is the binding strength of the DSA, it is assigned as the following:
DSA with MFI ≥ 10,000 given 10 points
DSA with MFI ≥ 5000 – 9999 given 5 points
DSA with MFI < 5000 given 2 points
Resistant index score (RIS) ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
If by using these criteria the probability of the transplantation is a seriously high risk, it should be prohibited.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
1- Paired kidney donation
2- Deceased donor
Conclusion:
The authors recommend a clear discussion of the risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation when the likelihood of finding a compatible donor is prohibitively low.
Historically, transplant options for highly sensitized kidney transplant candidates were limited due to ineffective therapies for desensitization, high rejection rates, and poor graft survival.This article has again tried to devise a scheme to transplant this pool of highly sensitized patients.
The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor trans- plant.
Transplant programs vary in their thresholds for incompatibility, and as such, the likelihood of finding a suitable donor may differ from one program to another.
The fact that having a cPRA of 99% makes it almost impossible to find a living donor even if recipient is part of KPD programme. UNOS data showed that only 2.5% of such recipients got a living donation.
The revised 2014 KAS in USA helped to find more donors for cPRA upto 99% but for those with CPRA 99.5% or above still were unable to find a suitable matched donor.This means that patients in this CPRA category should be advised to consider incompatible transplant.
The outcome of such transplants differ according to the degree of incompatibility.
According to study by Orlando BJ and colleagues risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compat- ible.
The choices for a highly sensitized patients are few they might have to decide at some stage to accept incompatible donor or to forgo.The hope lies in the fact that a multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario .
First step is to assess the feasibility of desensitization.
Identify DSA. Binding strength of DSA is also important which is interpreted by RIS score. The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) ≥ 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI 250. In such cases participation in paired kidney exchange programs is advised.
Management options for HLA incompatible living donor kidney to highly sensitized kidney transplant recipients.
HLA incompatible kidney transplantation remain a challenged due to expensive desensitization regimens. Improper desensitization protocol lead to high rejection rate and graft failure. This journal addressed the rational of paired kidney exchange and desensitization among HLA incompatible kidney transplant recipients.
In paired kidney exchange program the kidney exchange pool is highly dependent on the setting of transplantation center. Furthermore, achieving living donor transplantation is challenging if c PRA increases more than 99%. The probability of finding an acceptable match = 1- (cPRA)n.
According to 2014 KAS, sensitized candidates receive waitlist points base on sliding-scale beginning at cPRA 20%. This resulted in exponential increase in the number of kidney transplantation performed in highly sensitized recipients with cPRA more than 99%. Unfortunately, recipients with cPRA more than 99.95% still having low transplantation rate which ultimately succumbed to their underlying morbidity. Compatible transplantation is the only hope for those with cPRA more than 99.95%. But, in real world experience, the probability to get compatible donor is low with exhausted waiting time.
The outcome of HLA incompatible kidney transplant is greatly dependent on the severity of the incompatibility. In mild incompatibility, low DSA is associated with negative crossmatch. On the other hand, high incompatibility is associated with high DSA in flow cytometry or complement-dependent cytotoxicity crossmatch. High HLA incompatibility is associated with renal graft rejection, graft failure and mortality.
There are no concrete evidence to support the transplant outcome for different desensitization protocol from various transplant centers. Recent data support that following desensitization protocol at respective centers, HLA incompatible living kidney transplant has better survival rate compare to decease kidney transplant or remain at waiting list.
Paired kidney exchange may find a more suitably matched donor for HLA incompatible recipients unfortunately the successful rate is low especially blood group O. For highly sensitized kidney transplant recipients, kidney paired donation should be used as a tool to search for suitable donor, but not necessarily a HLA compatible one. Desensitization is adjunct to paired kidney exchange for HLA incompatible living kidney transplant.
The initial step for HLA incompatible living donor kidney transplant is to assess the amenability of desensitization by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch. However, desensitization is not recommended for positive CDC crossmatch. Proceed with paired kidney exchange program if flow cytometry crossmatch median channel shift more than 250 or a DSA relative intensity score more than 17. Desensitization is essential for successful HLA incompatible deceased donor transplantation if the cPRA is more than 99.95%.
In summary, combined approach which consisting of both desensitization and kidney paired donation is essential in dealing with HLA incompatible living donor kidney transplantation base on risks and benefits.
High degree of sensitization makes living donor transplantation more hard
As the cPRA increases above 99%, the possibility of receiving a living donor graft becomes unlikely.
The revision of kidney allocation system (KAS) aimed to increase the access of highly sensitized patients to deceased donor kidney transplant.
It resulted in five-fold increase in number of transplantation in highly sensitized patients with cPRA >99%.
However, highly sensitized patients with cPRA :99.95% remain unlikely to receive transplantation.
The outcome of transplantation varies according to the degree of compatibility
It ranges from mild incompatibility (low level DSA with negative crossmatch) to high level incompatibility (DSA with positive FCXM or CDCXM)
Patients with DSA but negative cross-match have same risk of graft loss and mortality as HLA compatible transplants.
Studies showed that the outcome of kidney transplantation (regardless the type of donor) is better than remaining on dialysis waiting for more preferable donor.
Kidney paired donation provides patients with incompatible donor to find more suitably matched donor. However, many highly sensitized patients fail to find donor.
Desensitization is not recommended in case of positive CDCXM
In case of positive FCXM with median channel shift>250 or DSA RIS>/=17, it is not recommended to proceed with transplantation.
These criteria predict high risk incompatible transplant which is better to be avoided.
KPD should be considered despite feasibility of incompatible transplant as incompatible transplant is associated with increased risk of graft loss and mortality compared to compatible transplants.
Patients with broad HLA sensitization, if living donor transplantation is not feasible, deceased donor transplant will be an option.
If there is a low probability of finding compatible donor, desensitization should be considered.
Conclusion:
Desensitization should be considered in highly sensitized patients who have a living donor.
Combination of both KPD and desensitization is more beneficial
If there is a low probability of finding donor, desensitization and incompatible transplants should be considered .
The options for highly sensitized patients:
1) Life donor transplantation: it’s quite difficult to find HLA matching donor when cPRA is 99%.
However, paired kidney donation PKD program can facilitate the transplantation significantly. Nevertheless, highly sensitized patients might not be matching any donor and continue on hemodialysis or removed from the waiting list.
2) Cadaveric kidney transplantation:
The Kidney Allocation System KAS: Prioritizes the transplantation for highly sensitized patients by giving them 4 points, according to HLA matching..the draw back, is that ,there might not be matching donor when cPRA is 98-100%.
One strategy is to extend to regional and national registry ,which has similarly improved the percentage of highly sensitized patients who got there transplanted kidney.
3) HLA Incompatible HLAi transplantation;
For life donor transplantation. Desensitization protocol can be combined with PKD to further facilitate the selection of less immunogenic donor.
DSAs are assessed by Luminex assay.
Recommendation against desensitization in the following situation:
1) Positive CDC.
2) flow cytometry cross match with median channel shift of >250.
3) DSA Relative intensity score RIS of more than 17:
RIS is a risk score that account for the DSA binding strength ,and assigned 10 points for each DSA of MFI of 10000 or more, and 5 for DSAs score of 5000 -9999 MFI. And 2 for each DSAs strength of <5000.
RIS of more than 17 is associated with a positive predictive value of 91% for AMR.
In high risk HLAi transplantation (as per criteria set earlier), PKD program is recommended.
The disadvantage of remaining on dialysis has to be leveraged against the risks of HLAi transplantation and desensitization programs.
It has been shown ,that ,after amendment of KAS, 54% of deceased donor allograft recipients have DSAs when cPRA is more than 99%.
Transplanting across a positive cross match remains a challenge.
Highly sensitized patients who are waiting in the deceased donor program list have increased chance of mortality and morbidity when compared to transplantation with donor after desensitization. In other words, transplantation even if HLA incompatible should be attempted after desensitization as there is enough evidence to show that graft and patient expectancy is the same for HLA incompatible renal transplant as compared to deceased donor recipient.
Transplant programs vary in their threshold for allocating kidneys. The relationship between finding a compatible donor for those with cPRA is expressed as
Probability of finding a compatible donor = 1- (cPRA)n , where n is the number of donors in the population. With the above equation it is clear that many match runs are needed to identify a compatible donor. For eg. 3000 match runs for a patient with cPRA of 99.9%. According to the UNOS only 5% of the cPRA 0f 99.9% have received compatible donors as of the year 2016.
The probability of kidney allocation in the current kidney allocation system needs to be discussed. It depends on the number of donor in the population available. The more the population and donors willing to donate the organs, the better would be the transplant outcome. Prior to 2014 KAS, those candidates with cPRA >80% were given 4 more points in the kidney waitlist. But this did not improve the chance of allocation for those patients with cPRA of 99 and 99.5% patients as still their probability of getting a matched kidney donor still remained <10%. So after 2016, the KAS was revised and an exponential sliding scale allocation system of points were given starting from cPRA>20%. This resulted in improvement in kidney allocation for those with very high cPRA>99%.
Paired kidney donation is an alternative to those who are unable to find a suitable donor in KAS with high cPRA. In many centers only 50% were able to receive a suitable kidney donor through paired kidney donation. Paired kidney donation becomes a problem when the blood group is O positive and those with cPRA>90%, the success rate of transplant at the end of 1 year is less than 10%.
The first step in assessment of transplant in a highly sensitized patient is to know the degree of sensitization. CDC, Flowcytometry and SAB Luminex assay need to be done. The CDC positive cross match recipients will never benefit from desensitization. In FCXM we determine the Median channel shift. If MCS >250 is a relative contraindication for transplant. DSA SAB MFI >5000 is also a contraindication for desensitization. The Relative Intensity Scoring (RIS) is calculated for the binding strength of DSA. RIS score of 10 for each DSA MFI>5000, RIS of 5 for each MFI DSA between 1000-5000, RIS score of 2 for weak DSA MFI <1000. The total RIS >17% is associated with highest risk of transplant and it is contraindicated even for desensitization.
Centers who do not routinely do desensitization should refer the patients to places were routine desensitization is done and transplant is feasible. Paired kidney exchange should not be offered as a blanket treatment to those with high PRA as still the rates of kidney allocation for blood group O and cPRA >90% is low. A combined desensitization protocol with paired kidney exchange could help these patients.
This summary highlights important recommendations for the highly sensitized patient with an incompatible living donor in order to avoid lengthy dialysis with considering that the difficulty of finding a biologically compatible donor, the degree of HLA-incompatibility and their associated outcomes in comparison to compatible transplantation.
Introduction
Transplant challenges for highly sensitized renal recipients are limited due to ineffective therapies for desensitization, high rejection rates, poor graft survival keeping in mind the cost and urgent need for clinical, immunology, and nursing expertise along with blood bank and plasmapheresis capabilities for successful implementation.
HLA Sensitization and the Probability of Kidney Transplantation
First step in counseling a highly sensitized renal transplant candidate is to assess find a suitable donor.
The relationship between calculated panel reactive antibodies (c PRA) and the probability of finding a compatible donor is expressed as:
Probability of finding an acceptable match = 1- (c PRA )n, where n = the number of potential donors .
So finding a donor to a tx recipient of c PRA 99% is somehow impossible
. Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
KAS target was to increase access to deceased donor kidney transplantation for highly sensitized candidates. Even though KAS has improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates.
These observations suggest that patients in the highest c PRA categories should be advised to consider incompatible transplantation.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
Outcomes differ according to the degree of incompatibility.it ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative cross match, to higher levels of incompatibility, such as DSA in the presence of a positive flow cytometry or
Complement-dependent cytotoxicity (CDC) cross match.
A large multi-center study involving 22 transplant centers performing HLA-incompatible kidney transplantation compared patient and graft survival outcomes among living donor kidney transplant recipients with varying degrees of HLA-incompatibility found that post-transplant mortality and graft loss was only noted in the existence of a positive cross match. While in the presence of a negative cross match, the risk of graft loss or death was equal to transplants performed with DSA alone and those that were HLA-compatible.
The most common desensitization protocols, depend on high-dose IVIG with or without rituximab versus low-dose IVIG in conjunction with plasmapheresis.
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients. Reflecting that it is better to go for kidney transplantation from a donor of any type rather than remain on dialysis in a trial to wait for a more suitable donor.
Role of Kidney Paired Donation
In a single-center study of 22 living donor kidney transplants facilitated because of a DSA against the intended living donor, only 10/22 (45%) were able to be achieved with a compatible donor after kidney paired donation.
The 12 DSA-positive transplants had donors with lower expected immunological risk than their previously intended donors. Especially after considering that data from the NKR (National Kidney Registry) claims that approximately 35–40% of all candidates remain unmatched within a year with higher values for those with blood type O (43%) or being highly sensitized (c PRA 97%; 58%) of waiting time reached to 671 days.
So, kidney paired donation should be viewed as a solution for finding a more suitable donor, but not necessarily a compatible one with the option of desensitization when needed.
Assess the Feasibility of Desensitization
According to Luminex single antigen testing to identify DSA , CDC , flow cytometry cross match and mean fluorescence intensity (MFI) decision of desensitization is designed.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
A recommendation to participate in kidney paired donation program should include a detailed discussion with both partners about the expectations of participation, the probability of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis against the risks of desensitization and HLA-incompatible transplantation, and a time limit for participation before determining the benefit of kidney exchange.
Deceased Donor Transplantation
Desensitization should be considered as a necessary component for successful transplantation.
After revised KAS implementation program, Houp et al. reported that 58% of deceased donor transplants performed among candidates with c PRA 99% were in the presence of DSA.
Conclusions
Highly sensitized kidney transplant patients who areready to have a living donor should be considered for desensitization. kidney paired donation program offers the possibility of finding a more suitably matched donor. Therefore, a combined approach consisting of both desensitization and kidney paired donation seems to be
more successful.
Rationalizing incompatible living donor renal transplantation for highly sensitized candidates.
Highly sensitized renal transplant candidates face a limited option of treatment because:
1- Ineffective desensitization therapies.
2- High rates of rejection.
3- Poor graft survival.
Many centers remain reluctant to perform HLA incompatible renal transplantation.
Highly sensitized kidney transplant candidates tend to receive deceased donation more than living donation.
Options for highly sensitized renal transplant candidates include:
1- Paired kidney exchange program.
2- Direct donation with an incompatible living donor.
3- Waiting for a deceased donor transplant program.
The probability of finding an acceptable matched donor = 1- (cPRA)n
Where n= number of potential donors.
Data from UNOS 2016, after 1 year follow up, revealed the following:
13/262 (5%) in recipients with c-PRA>99%.
13/528 (2.5%) in recipients with 100% were from a living donor.
Only 16 of theses 26 recipients had living donors via paired kidney donation.
Mild HLA incompatibility means low level of DSA and negative crossmatch.
High HLA incompatibility means high level of DSA and positive crossmatch detected by flowcytometry or CDC which is usually associated with patient mortality and graft loss.
There are different desensitization practices between transplant centers. There is no study to compare desensitization protocols.
Desensitization protocols include either:
1- High Dose IVIG +/- Rituxmab.
2- Low dose IVIG+ Plasmapheresis.
Role of kidney paired donation:
Data from 9 years of KPD from National Kidney Registry revealed the following:
239/2037 (11.7%) required desensitization because crossmatch incompatibility (222) or ABO incompatibility (17).
35-40% of all candidates remain unmatched within a year.
Only 10% of blood group O candidates with c-PRA>98% found a donor.
Waiting time to transplant for blood group O with c-PRA>95% was reported 671 days.
Approach to highly sensitized candidates with an incompatible living donor:
1- Assess feasibility of desensitization by Luminex SAB or flowcytometry or CDC (to identify DSA).
2- It is not recommended to do desensitization for a positive CDC crossmatch.
3- It is not recommended to proceed for Tx when flowcytometry medium channel shift>250 or DSA RIS >17.
4- Paired kidney exchange should not be offered to all patients with an incompatible donor especially if the patient’s c-PRA and blood type predict a low likelihood of finding a match through PKE and the flowcytometry crossmatch indicates a high likelihood of successful transplant with desensitization.
5- Deceased donor transplantation.
Highly sensitized patients have limited options for kidney transplant due to:
1- Ineffective therapies for desensitization.
2- High rejection rates.
3- Poor graft survival.
It is very important to assess the likelihood of finding a suitable donor.
The probability of finding a suitable match =1 – (cPRA) where n is = the number of potential donors.
It was found that for a patient with cPRA of 99% may need up to 300 match runs to find a compatible donor, but this increases up to 600 match runs for a patient with cPRA of 99.5%. Another important factor is the size of donor pool.
Kidney Allocation System (KAS) was revised in 2014 to increase access to deceased donor kidney transplant for highly sensitized patients : these patients receive wait list points according to sliding scale beginning at cPRA 20% so the number of point increase exponentially with cPRA and the priority was for those with cPRA ≥ 98%. For patients with cPRA >99% have a longer donor pool through regional and national sharing of deceased kidney donors.
But this revised KAS did not help the most sensitized patient with cPRA ≥ 99.95% and are more likely to be removed from the list or die. They should be advised for incompatible transplant.
Outcomes Associated with HLA –Incompatible kidney transplantation
A large multicenter union of 22 transplant centers that perform HLA – incompatible kidney transplant compared patients and graft survival outcomes among living donor kidney transplant recipients with varying degrees of HLA incompatibility, found that the risk of HLA- incompatibility on post-transplant mortality and graft loss was only observed in the presence of positive crossmatch and as the more severe of this , the risk become higher for both. But if there is negative crossmatch the risk for both outcomes very similar between transplants performed with DSA alone and those with compatible HLA.
A prospective randomized trails comparing the most common desensitization protocols :high dose IVIG with or without Rituximab versus low dose IVIG in conjunction with plasmapheresis is needed.
A multi-center data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched control who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients so it is a best choice.
Role of Kidney Paired Donation:
Paired kidney exchange may provide a more suitable donor for highly sensitized patients. In a single center report of 22 living donor kidney transplant (have DSA against the intended living donor) only 10/229(45%) were transplanted with a compatible donor after kidney paired donation.
In a comprehensive summary of experience of 9 years of kidney paired donation through the National Kidney Registry (NKR) 239/2037 (11.7%) of all transplants done required desensitization because of crossmatch incompatibility (222/239) or ABO incompatibility (17/239) .
Data from NKR indicates that 35 – 40% of all patients remain unmatched within a year. This percentage is higher is for those with blood group type O (43%) or highly sensitized (cPRA ≥97%, 58%).
Those with combined of both blood group O and cPRA ≥98% only 10% find a donor within 1 year. Same was found in the Alliance of Paired Donation(APD).
A approach to the Highly Sensitized Candidates with an Incompatible Living Donor:
1- Assess the feasibility of desensitization
a. Identify DSA by doing luminex single antigen test.
b. Do CDC and flow-cytometry crossmatch.
2- Assess alternatives to HLA incompatible kidney transplant;
a. Paired kidney exchange: the authors recommended a detailed discussion with both thr recipient and donor about the expectations, the possibilities of finding a compatible or more suitable matched donor. The disadvantages of remaining on dialysis versus the risk of desensitization and HLA incompatible transplant and limitation of time.
b. Deceased donor transplant:
Identify a suitable donor by knowing the exponential relationship between cPRA and the number of potential donors.
Desensitization for highly sensitized patients.
After revision of KAS implementation, Houp. etal (single center experience) reported that 58% of deceased donor transplants performed among patients with cPRA ≥ 99% were in the presence of DSA.
Desensitization although is expensive, costly, and need more expertise, it opened a way for the highly sensitized patient and allow them to receive living donor rather than being on dialysis waiting for a deceased offer
Treatment options for highly sensitized patients include
· Receiving deceased donor
· Waiting for a compatible living donor which is extremely rare
· HLA incompatible tx
· Paired exchange
The probability of sensitized patient for transplantation,
1- Determining the probability of a sensitized patient finding a matched donor
– Essential for counseling the sensitized patient
– Equals: (1- cPRA) and estimates the potential donor
– It estimates the expected no of match run for a recipient to find a suitable donor by a percent 95%. However, it differs according to the center’s policy accepting sensitized patients or not
2- according to the donor pool
The probability of a deceased donor
In the united states, the revised KAS 2014 gave a greater chance for those with a cPRA> 98 by increasing their points exponentially with the cPRA values. However, those with cPRA 9.95% don’t benefit even after the prioritization with
*Definitions for sensitization level:
@Low level: DSA with low levels, a negative crossmatch
@High levels of incompatibility: DSA with positive flow cytometry or CDC crossmatch.
– In a multicenter consortium, Poor patient survival and graft survival was noted with positive crossmatch and correlated with the degree of incompatibility.
– Whereas patient survival, and graft survival didn’t show a significant difference in patients with DSA only and those with HLA incompatible
– HLA incompatible transplantation is the best option for patients with living donors who failed or without an available paired exchange program, alternatively being on the waiting list for deceased donor carries a worse outcome
· Paired exchange
– 35-40% of recipients are expected to fail to find suitable donors by one year
Approach to the highly sensitized patients include:
a. Assess the feasibility of desensitization:
Tests: single antigen bead, CDC, and flow cytometry
Don’t proceed if : positive CDC XM, flow cytometry XM with MCS > 250 or a DSA (RIS) ≥ 17
For those: paired exchange
If failed: waiting for a deceased donor with prioritization according to cPRA
For cPRA >99.95 desensitization done to bring their cPRA below 99.95
The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant.
HLA Sensitization and the Probabilityof Kidney Transplantation;
The probability of finding a donor also depends on the size of the donor pool. The relationship between calculated panel reactive antibodies (cPRA) and the probability of finding a compatible donor is expressed as: Probability of finding an acceptable match = 1- (cPRA)n ,where n = the number of potential donors .With this equation, it is estimated that a patient with a cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a cPRA 99.5% and 3000 match runs for a candidate with cPRA 99.9%.
Assessing the Probability of Deceased Donor Kidney Transplantation
in the Kidney Allocation System (KAS) Era;
Historical data prior to KAS revision indicates that ;
1-The percentage of deceased donor kidney transplants performed among recipients with cPRA 80–97% was proportionally similar to their representation on the wait list .
2-kidney recipients with a cPRA ≥ 98% received disproportionately fewer transplants than expected given their representation on the wait list .
A revision of the US Kidney Allocation System (KAS) was implemented on December 4, 2014. One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates.
Allocation policy changes in 2014 KAS;
1-Sensitized candidates receive wait list points according to a sliding-scale beginning at cPRA 20%.
2-The number of wait list points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥ 98% .
3-Candidates with cPRA ≥ 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys.
Although the revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates. Candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die .
Outcomes Associated with HLA-Incompatible Kidney Transplantation;
1- The risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive cross match, with progressively higher degrees of cross match incompatibility being associated with increasing risk of both outcomes.
2- The approaches have been employed to demonstrate the survival advantage of transplantation over dialysis for a wide range of subpopulations , underscoring the message that it is generally better to undergo kidney transplantation from a donor of any type rather than remain on dialysis in an attempt to wait for a more preferable donor.
Role of Kidney Paired Donation;
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange, but they should recognize that this approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor.
Although living donor transplantation can be facilitated for some highly sensitized candidates, many are unsuccessful in finding a donor through paired exchange.
The percentage of unmatched candidates is higher for those with blood type O (43%) or who are highly sensitized (cPRA ≥ 97%; 58%) . For those who have the combination of both O blood type and cPRA ≥ 98% in NKR, only approximately 10% successfully find a donor within 1 year .
Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation to finding a compatible donor may be unrealistic.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor;
To summarize, our approach takes into account the following considerations:
1-Assess the Feasibility of Desensitization.
2- Assess Alternatives to HLA-Incompatible Kidney Transplantation
Assess the Feasibility of Desensitization;
1-The initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch.
2- Not to recommend desensitization for a positive CDC crossmatch, although successful transplantation can be achieved in selected cases in this setting .
3- Not to proceed with transplant with a flow cytometory cross match median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17.
4- The RIS is a risk score that accounts for the binding strength of DSA and assigns;
-10 points for each DSA in the strong-binding range (MFI) ≥ 10,000
-5 points for each moderate-intensity DSA (MFI 5000 to 9999)
-2 points for each weak DSA (MFI < 5000).
A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection .
Assess Alternatives to HLA-Incompatible Kidney Transplantation;
1-Paired Kidney Exchange;
2-Deceased Donor Transplantation;
Paired Kidney Exchange;
Paired kidney exchange should not be offered to all patients with an incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry cross match indicates a high likelihood of successful transplantation with desensitization.
Deceased Donor Transplantation;
Unfortunately, living donor transplantation is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option. A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor , and MFI thresholds for defining an antigen as unacceptable should be adjusted to bring the cPRA down to at least < 99.95%. Therefore, desensitization should be considered as a necessary component for successful transplantation.
Conclusions;
1-Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization.
2- Although participation in a kidney paired donation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O.
3-A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find a compatible donor.
Highly sensitized patients who have no compatible living donor can depend on paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant.The 95%probability of finding a compatible donor equal 1- (cPRA)n, where n = the number of potential donors. this equation estimate that a patient with a cPRA 99% requires approximately 300 match runs and the patient with cPRA 99.9% 600 requires 3000 match runs. So, living donation is difficult in this population even with paired exchange programs as they need a large pool of donors.
The US Kidney Allocation System (KAS) increased access to deceased donor kidney transplantation for highly sensitized patients but it did little to increase access to transplant for those with cPRA more than 98%. A recent revised system provides waitlist points according to a sliding-scale beginning at cPRA 20% and increase with increased cPRA. The highest allocation priority was given to those with cPRA more than 98%. Again highly sensitized patents did not receive benefit from these changes. So, highly sensitized patents, more than 99.95%, are advised to consider incompatible transplantation. The graft outcomes differ according to the degree of incompatibility as it can ranges from mild incompatibility with negative cross match to severe incompatibility with a positive cross match. Mortality and graft were associated with the degrees of cross match incompatibility. Despite this, it was noted that the 8-year survival was more in patients who received an incompatible living donor transplant when compare to those remained on the waiting list or received a deceased donor transplant.
Paired kidney exchange is another option for highly sensitized candidates but the difficulty of finding a living donor in a definite time is still being there. NKR data showed that in the presense of both O blood type and cPRA more than 98% in NKR, the success of finding a donor within 1 year is only 10%. Alliance for Paired Donation (APD) data showed only 25% of patients with cPRA> 95% were transplanted through paired donation compared to 23% with cPRA >95% through a deceased donor over 6 years period. The waiting time for those with both blood group O and cPRA >95% was
671 days. To overcome this, the kidney paired donation should focus on finding a more suitable donor than finding a compatible donor.
The protocol of the authors for highly sensitized candidate with an incompatible living donor includes:
1-Assess the feasibility of desensitization to a potential living donor by doing CDC and flow cytometry crossmatch. They do not recommend desensitization for a positive CDC cross match. They
do not transplant those with with a FCXM median channel shift > 250 or a DSA relative intensity score (RIS) >17 as it is associated with a positive predictive value of 91% for AMR.
“The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) > 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000).”
2- Paired Kidney Exchange after a detailed discussion with both recipient and donor about the expectations of participation, the possibility of finding a more suitable donor, the risk of remaining on dialysis , the risks of desensitization ,the risk of HLA-incompatible transplantation and a time limit for participation before determining the futility of kidney exchange. Paired kidney exchange in the author protocol should not be offered to all patients with an incompatible donor, especially if the patient has a low likelihood of finding a match or he can have a chance of successful desensitization.
3- Deceased donor transplantation with consideration of the relation between cPRA and the number of potential donors according to the equation. Patients with a cPRA >99.95% are highly unlikely to be
offered a deceased donor. MFI thresholds are adjusted to bring the cPRA down to at least < 99.95%to
increases the likelihood of incompatible donor offers.
Despite the advent of newer protocols for desensitization and favorable outcomes compared to remaining on dialysis, many centers remain reluctant to perform HLA-incompatible kidney transplants. Desensitization regimens can be resource intensive, costly, and require clinical, immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful implementation. The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant. There is lack of consensus and guidelines to inform transplant programs and candidates on how to choose between these options.
HLA Sensitization and the Probability of Kidney Transplantation
Transplant programs vary in their thresholds for incompatibility, and as such, the likelihood of finding a suitable donor may differ from one program to another. The relationship between calculated panel reactive antibodies (cPRA) and the probability of finding a compatible donor is expressed as: Probability of finding an acceptable match = 1- (cPRA)n , where n = the number of potential donos. With this equation, it is estimated that a patient with a cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a cPRA 99.5% and 3000 match runs for a candidate with cPRA 99.9%
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
A revision of the US Kidney Allocation System (KAS) was implemented on December 4, 2014. One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates. Prior to the 2014 KAS revision, candidates with a cPRA ≥ 80% were awarded four waitlist points toward allocation. This policy benefited those with cPRA 80–97%, for whom the probability of finding a compatible donor are generally favorable, but did little to improve access to transplant for those with cPRA ≥ 98%.
Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%. The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥ 98%. Additionally, candidates with cPRA ≥ 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys. These allocation policy changes resulted in dramatic early increases in the number of transplants performed in highly sensitized candidates with cPRA ≥ 99% .
Outcomes Associated with HLA-Incompatible Kidney Transplantation
Graft outcome is an important consideration when choosing between transplant options for highly sensitized candidates. It is important to recognize that HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility, such as DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch. The distinction is relevant, as outcomes differ according to the degree of incompatibility.
A large multi-center consortium involving 22 transplant centers that perform HLA-incompatible kidney transplantation compared patient and graft survival outcomes among living donor kidney transplant recipients with varying degrees of HLA-incompatibility. Notable from this study is that the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
Role of Kidney Paired Donation
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange, but they should recognize that this approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor. Although living donor transplantation can be facilitated for some highly sensitized candidates, many are unsuccessful in finding a donor through paired exchange. Data of Alliance for Paired Donation (APD), in over a 6-year period, only 25% of patients with cPRA ≥ 95% were transplanted from a living donor through paired donation; in comparison, a similar percentage of APD registered patients with cPRA ≥ 95% found a deceased donor during the same time period (23%).
Thus, the data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one. Providers should set realistic expectations for candidates who enter into the paired exchange process and must recognize which patients are unlikely to receive a transplant without desensitization.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
Assess the Feasibility of Desensitization
Our initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch. In our program, we do not recommend desensitization for a positive CDC crossmatch, although successful transplantation can be achieved in selected cases in this setting. Additionally, we do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17.
If HLA-incompatible transplantation is predicted to be prohibitively high risk based on these criteria, we recommend participation in a paired kidney exchange program.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
Recognizing that positive cross-match kidney transplants are associated with an increased risk of graft loss and mortality compared to compatible transplantation, kidney paired donation may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization. In our opinion, paired kidney exchange should not be offered to all patients with an incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
Deceased Donor Transplantation
Unfortunately, living donor transplantation is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option. In these cases, the provider must recognize the exponential relationship between cPRA and the number of potential donors that are required in order to identify a suitable donor. Therefore, desensitization should be considered as a necessary component for successful transplantation. In their early single-center experience after revised KAS implementation.
CONCLUSION
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization. Although participation in a kidney paired donation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O. A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find a compatible donor.
Introduction :
There was a lack of kidney transplantation of highly sensitized patients due to high rejection rates, poor graft outcomes, and high cost of desensitization strategies.
Options were waiting matched living donor from paired kidney donation or deceased kidney allograft or transplantation with an incompatible living donor.
HLA Sensitization and the Probability of Kidney Transplantation:
Finding compatible donors depends on cPRA
as the probability of finding matched donor =1-cPRA
Patients with cPRA of 99 % must have 300 cross-match of different donors to have a chance of 95 % to find a matched donor
Also, the probability of finding a donor depends on the size of the donor pool make PKD a chance of making a large pool of donors available
Kidney Allocation System (KAS) :
KAS has a role in transplantation of highly sensitized CKD , as made priority to the patients with high c PRA for available deceased donor
However patients with cPRA >98 % received donors less than expected
Points of priority increase with the number of cPRA of sensitized CKD
Outcomes Associated with HLA-Incompatible Kidney Transplantation:
Degree of incompatibility differ from mild degree with the low level of DSA with negative cross-match , to moderate degree with only positive flow crossmatch to a high degree with positive CDC crossmatch
the outcome was worse in patients with incompatible HLA with positive crossmatch
however, patients with incompatible HLA with negative crossmatch didn’t differ from patients transplanted with compatible HLA in graft loss and death.
Survival of highly sensitized patients transplanted with incompatible HLA was better than patients who continued on dialysis waiting for matched HLA donors.
Survival was better with negative crossmatch > positive flow cytometry crossmatch >positive CDC crossmatch.
Role of Kidney Paired Donation:
Highly sensitized patients may find a compatible donor through paired kidney exchange however many were unsuccessful.
With higher patients with blood group O, c PRA >97% and For those who have the combination of both O blood type and cPRA
98% ( 43%,58 %, 90 % ) respectively failed to find a suitable donor within first year on the waiting list for PKD.
Desensitization in combination with PKD may help highly sensitized patients to find compatible donors earlier.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor :
First PRA by Luminex single antigen, flowcytometry crossmatch, and CDC cross-match:
And transplantation is not to be done if positive CDC cross-match or positive flow cytometry cross-match with median channel shift > 250 or presence of DSA with RIS > 17
Conclusions :
Finding the matched donor for highly sensitized patients is difficult so combining of PKD and desensitization may help to find suitable donors earlier.
however, HLA Incompatible transplantation may be another way to shorten the time of waiting for these patients.
Transplanting sensitized patients is undesirable in many centers may be due to lack of capabilities. Although transplanting these patients is better than remaining on dialysis cost is a challenge. options for such patients are involved in paired kidney donation programs, waiting on the list, or being transplanted with an incompatible one.
The authors suggested trying to find a suitable donor through this may differ from one program to another.
The kidney allocation system (KAS) does not offer a big chance for sensitized patients with very high PRA%, so it may be eligible to consider incompatible donors.
The outcome of compatibility is better for sure. some studies showed that incompatible donor donation may be better than deceased donor transplantation.
we have one of three options:
1- incompatible donation
2- paired kidney exchange
3- deceased donor transplantation.
Highly sensitized patşents who ave donor that is incompatible should be evaluated for desensitization. It is difficult to have paired kidney in case of very high PRA and being of blood group O for example
After evaluation of probable risks, desensitization should be considered as option
Highly sensitized transplant recipient always have difficulty in finding a suitable living donor and usually are maintained for long time in the waiting list for a deceased donor.
The probability of finding a suitable donor with negative crossmatch can be calculated using this formula 1- (cPRA)n, where n is the number of available donors
It was found that in patients with a cPRA of 99% only 1 from 300 donor offer will be suitable for transplantation with a negative crossmatch which increases to 3000 match runs for a candidate with cPRA 99.9%.
Following are the options for a Highly sensitized transplant candidate who don’t have a suitable living donor:
1- Keeping the patient on hemodialysis ,though it is associated with higher mortality,
2- Try to find compatible living kidney donor
3- Wait for compatible deceased donor
4- Desensitization to render incompatible donor possible for transplantation
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
In 2014 KAS revision , allocation policy changes resulted in dramatic early increases in the number of transplants performed in highly sensitized candidates with cPRA => 99% . Patients in the highest cPRA categories should be advised to consider incompatible transplantation.Sensitized transplant recipient take waitlist priority points according to his/her cPRA which starts from cPRA of 20% and increase gradually till reaching to patients with cPRA ≥ 98.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
Graft outcome is an important consideration in HLAi transplants. A study showed that the effect of HLAi transplant on graft and patient survival is only evident when the crossmatch is positive, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA compatible
Role of kidney paired donation:
Patients with an incompatible donor may find a more suitable donor through KPD, but many sensitized candidates fail to find a compatible donor throughout this method.
Kidney paired donation will help us finding a more suitable donor for highly sensitized patients, but not necessarily a compatible one. Desensitization should be considered as an adjunct to paired exchange for difficult to match patients
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor:
Assess the Feasibility of Desensitization
By performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch.Desensitization is not recommended for a positive CDC crossmatch, flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17.If high-risk HLA-incompatible transplantation, then patient should be enrolled in paired kidney donation program. The RIS is a risk score that accounts for the binding strength of DSA and is calculated as follows:10 points for each DSA in the strong-binding range (MFI ≥ 10,000), 5 points for each moderate-intensity DSA (MFI 5000 to 9999), 2 points for each weak DSA (MFI < 5000).
A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
PKE should be considered despite the feasibility of incompatible transplant as incompatible transplant is associated with an increased risk of graft loss and mortality compared to compatible transplants. Detailed counseling is required to understand the pro and cons of this program.
.
Deceased Donor Transplantation
A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor and MFI thresholds for unacceptability should be adjusted to bring the cPRA down to at least < 99.95%.
CONCLUSION:
Highly HLA sensitized kidney transplant patients who have a living donor should be considered for desensitization.
A combined approach consisting of both desensitization and kidney paired donation will generally be more successful
I. Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates
Please summarise this article
Treatment options for highly sensitized recipients:
1. Paired kidney exchange:
– Poor chances of finding a suitable donor, especially for those with PRA=>99
– Variable kidney exchange donor pool size.
2. Desensitization with HLA-incompatible transplantation:
HLA-i transplantation is an appropriate option for many highly sensitized recipients.
Drawbacks of desensitization include:
– Ineffective available regimens
– Rejection rates are high
– Graft survival is poor
– Costly & resource demanding
– Inter-institutional variability in thresholds for incompatability. This will reflect the chance of finding a suitable donor
3. Deceased donor transplant:
Revised KAS 2014 aimed to increase access of highly sensitized patients to donors pool; however this did little to improve access to transplant for those with
cPRA=> 98%.
There is no consensus to inform transplant programs & candidates on how to choose between these options.
Therefore many highly sensitized patients continue waiting for a compatible donor that may never come.
HLA sensitization & the probability of kidney transplantation:
1st step is to assess the likelihood of finding a suitable donor.
Thresholds for incompatibility, & thus the likelihood of finding a suitable donor, vary between centers.
The probability of finding a compatible donor is:
1- (cPRA)n, where n = the number of potential donors.
So a patient with cPRA 99% needs about 300 match runs to get a 95% chance of finding a compatible donor.
The number of match runs needed to find a suitable donor is less for centers performing incompatible transplants.
The probability of finding a donor also depends on the size of the donor pool.
A revised KAS on December 4, 2014 aimed to increase access to deceased donor kidney transplantation for highly sensitized candidates.
This policy benefited those with cPRA 80–97%, for whom the probability of finding a compatible donor are generally favorable, but did little to improve access to transplant for those with cPRA >98%.
Studies show that the risk of HLA incompatibility on post-transplant mortality & graft loss was only observed in the presence of a positive XM; the higher the degrees of XM incompatibility the higher the risk of both outcomes.
In the presence of a negative XM, the risk of both outcomes was similar between transplants performed with DSA alone & those that were HLA-compatible.
No prospective trials comparing the most common desensitization protocols, including high-dose IVIG +/- rituximab versus low-dose IVIG in conjunction with PP.
There is little center to center variability in patient & graft survival outcomes associated with HLA-i living donor transplantation.
Data showed higher 8 years survival rates for incompatible living donor transplant compared to matched controls who remained on the waiting list or received a deceased donor transplant.
The higher survival rate was seen irrespective to the degree of incompatibility.
Patients in the highest cPRA groups should be advised to consider incompatible transplantation.
Role of Kidney Paired Donation
This approach gives a compatible donor only a fraction of time & many highly sensitized patients may not succeed to find any donor.
NKR data indicates that 35–40% of all candidates remain unmatched within a year. The % unmatched candidates is higher for those with blood type O or cPRA > 97% 58%). In those who have both O blood type & cPRA > 98%, only 10% successfully find a donor within 1 year.
Data show that for highly sensitized patients, KPD should be considered as a means for finding a more suitable donor, rather than a compatible one.
Approach to the highly sensitized candidate with an incompatible living donor
The following should be considered:
Assess suitability of desensitization to a potential living donor by Luminex SAB to identify DSA & perform a CDC & FCM-XM flow.
Desensitization for a +ve CDC XM is not recommended.
Not to proceed with transplant if a FCM-XM MCS > 250
or a DSA relative intensity score (RIS) >17.
RIS (10 points for each DSA with MFI >10,000], 5 points for each DSA with MFI 5000 -9999), & 2 points for each weak DSA(MFI < 5000). A RIS >17 is associated with a positive predictive value of 91% for AMR.
If RIS >17 participation in a paired kidney exchange program is recommended.
KPD may be a considered for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization.
Counsel both recipient & donor about the expectations, cons & pros of participation in KPD program.
KPD paired should not be offered to all incompatible patients, especially if the cPRA & ABO type predict a low likelihood of finding a match.
Deceased donor transplantation
May be the only hope for those in whom living donor transplantation is not possible due the breadth of HLA sensitization.
There is an exponential relationship between cPRA & the number of potential donors that are required in order to find a suitable donor:
– A cPRA >99.95% is highly unlikely to find an offer.
– MFI thresholds for unacceptable antigens should be adjusted to bring the cPRA down to at least < 99.95%; however this increases the likelihood of incompatible donor offers. So desensitization is a necessary component for successful
transplantation.
Conclusions
Desensitization should be considered for highly sensitized patients who have a living donor.
KPD may offer the possibility of finding a compatible or more suitably matched donor.
The most broadly sensitized patients, especially those who are blood type O, may benefit from combining both desensitization & KPD.
Patients should be clearly counseled regarding risks & benefits of treatment options & early consideration of desensitization & HLA-i transplantation when the likelihood of finding a compatible donor is extremely low.
Candidates who have been exposed to high levels of sensitivity are more likely to be transplanted mostly through the skin.
contribution from a deceased person.
Options accessible to the highly sensitive applicant who has a living donor who is incompatible with him or her
include:
Participation in a kidney exchange program with a matched donor.
Donation through a live donor who is incompatible with the recipient.
Waiting for a dead donor transplant to become available.
In order to inform transplant programs and candidates, there is a paucity of consensus and recommendations.
about how to make a decision amongst these alternatives.
The Relationship Between HLA Sensitization and the Chances of Receiving a Kidney Transplant
The first step in advising a highly sensitive kidney transplant candidate is to determine the applicant’s level of sensitivity.
A highly sensitive kidney transplant candidate’s chances of finding a compatible donor are the first step in the process of advising them, and this might vary from one program to another.
The probability of discovering a suitable match is given by 1- (cPRA)n, where n is the number of possible donors available.
This equation predicts that patients with high cPRA will require additional match runs in order to boost their chances of finding a matching donor, according to the researchers.
As an example, these estimates give a measurable approximation of the chance of obtaining a suitable donor through paired kidney exchange or waiting for a dead donor in the case of transplant facilities that only consider compatible transplants.
As previously stated, the likelihood of finding a donor is also influenced by the size of the donor pool, which is increased by participation in a matched kidney exchange program.
As the cPRA rises beyond 99 per cent, it is becoming increasingly difficult to achieve living donor transplantation.
Considering the Possibility of Deceased Donor Kidney Transplantation in the Kidney Transplantation Study
The Key Allocation System (KAS) was established in the following year.
One of the primary objectives of the amended KAS was to expand access to deceased donor kidney transplantation for applicants who were highly sensitized to the procedure.
The updated KAS has significantly increased access to deceased donor kidney transplantation throughout the spectrum of allo-sensitization on the whole, but the modifications in allocation policy have not been beneficial to the most highly sensitized applicants, according to the findings.
The risks and advantages of current therapeutic alternatives must be clearly discussed, and early consideration should be given to desensitization and HLA-incompatible kidney transplantation when the chance of obtaining a compatible donor is minimal.
Introduction:
Historically, transplant options for sensitized patients were limited due to ineffective desensitization therapies, high rejection rate, and poor graft outcomes.
Despite improvement in desensitization protocols and the favourable outcome compared to dialysis, still many centers are reluctant to do HLAi transplantation. Many highly sensitized patients continue waiting for a compatible donor that may never come.
HLA sensitization and the probability of kidney transplantation:
The first step in counselling a highly sensitized candidate is to assess the likelihood of finding a compatible donor through the following equation:
probability of finding an acceptable match= 1-(cPRA)n
n= no of potential donors.
For transplant centers that only consider compatible transplants, these estimates provide a quantifiable approximation of the likelihood of finding a suitable donor either through PKD or waiting for a deceased donor. The probability of finding a donor also depends on the size of the donor pool.
Assessing the probability of deceased donor kidney transplantation in the kidney allocation system era:
The US KAS was revised in 2014 to increase access to deceased donor kidney transplantation. So sensitized patients receive waitlist points according to a sliding scale beginning at cPRA 20%. the number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA more than or equal to 98%. In addition, candidates with cPRA> or equal to 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys.
The changes in allocation systems resulted in a dramatic increase in the number of transplants for highly sensitized patients, also improved access to deceased donors.
Unfortunately, these changes in the KAS did not improve transplantation rates for candidates with cPRA>99.95%, so these candidates should be advised to undergo HLAi transplantation.
Outcomes associated with HLA-incompatible kidney transplantation:
Graft outcome is an important consideration in HLAi transplants. A study showed that the effect of HLAi transplant on graft and patient survival is only evident when the crossmatch is positive, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA compatible.
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on a waiting list or received a deceased donor transplant indicated that survival is highest for incompatible living donor recipients, making incompatible transplantation is the best option for this scenario.
Role of kidney paired donation:
Patients with an incompatible donor may find a more suitable donor through KPD, but many sensitized candidates fail to find a compatible donor throughout this method.
The data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one. Desensitization should be considered as an adjunct to paired exchange for difficult to match patients.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor:
Assess the Feasibility of Desensitization
This is done by performing Luminex single antigen testing to identify DSA and a CDC and flow cytometry crossmatch.
Rationale:
The RIS is a risk score that accounts for the binding strength of DSA and is calculated as follows:
10 points for each DSA in the strong-binding range (MFI ≥ 10,000).
5 points for each moderate-intensity DSA (MFI 5000 to 9999).
2 points for each weak DSA (MFI < 5000).
A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
KPD may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization. It is important to discuss all the potential benefits and disadvantages of the process with the candidate keeping in mind the patient’s blood group and cPRA which could limit the possibility of finding an acceptable donor.
Deceased Donor Transplantation
Unfortunately, living donor transplantation is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option. Still, high cPRA is a limiting factor for this option. Desensitization may be considered to achieve successful transplantation.
· Highly sensitized candidates for TX are challenging due to anti-bodies against a lot of HLA antigens that makes finding a suitable donor difficult. A large population of donor is needed to find a suitable kidney for these patients. So finding a compatible living donor is not practical in most cases.
To solve this problem, paired kidney exchange programs, desensitization or deceased donor TX are other options.
At this article TX of the highly sensitized patients with an incompatible living donor is approached.
Probability of finding a suitable donor with acceptable match = 1- (CPRA) n
n= number of potential donors. For example, for CPRA 99%, near 300 match is needed for 95% chance of finding a compatible donor. So, number of matched is depended on degree of incompatibility which is accepted by a program.
On the other hand, its probability depends on the size of the donor pool. Paired kidney exchange program can range from single-center to large multi-central exchange programs.
In previous kidney allocation system (KAS), sensitized patients with CPRA ≥80% were awarded four points when were in waiting list. But in new KAS program, points –scale begins at cPRA≥ 20% and with increasing cPRA up to 98%, number of points is increased and patients with CPRA ≥ 99 are drawn from a larger regional and national sharing system, which resulted in 5- fold higher chance for TX among patients. But candidates with a cPRA ≥ 99.95% have low chance to receive a compatible TX and are considering in compatible TX. In a large study, risk of post-transplant mortality or graft failure was increased in the presence of positive XM.
· Desensitization protocol include:
IVIG with plasmapheresis with or without rituximab.
· The highest survival was related to those who received an incompatible living donor TX vs those who remained on waiting list.
· Paired kidney exchange (PKE) is another option for those with an incompatible donor in some cases who are lucky. But about 35-40 % of all candidates can’t receive a matched kidney within one year. Especially with blood type O or CPRA ≥97% with average 671 days waiting time. So, desensitization should be considered in these cases. To approach to these patients, first should perform luminex –SAB to identify DSA and then do a CDC and flow cytometry XM. Desensitization is not done for positive CDC XM or positive flow- XM with median channel shift >250 or DSA R1S ≥ 17 R1S. RIS assigns 10 points for MFI≥10000, 5 points for MFI 5000 to 9999 and 2 point for MFI <5000.
· If the risk is high, participation in a PKE program is recommended.
In patients with a CPRA ≥ 99.95 % finding a deceased donor is unlikely and desensitization is a required component for TX in these patients. So a combined approach (both PKE and desensitization) is more successful.
Thanks Nesrine
Highly sensitized patients are more commonly transplanted through deceased donation due to difficulties in finding a compatible living donor.
High degree of HLA sensitization makes living donor transplantation less common.
HLA sensitization and probability of kidney transplantation:
The probability of finding suitable donor to highly sensitized patients varies according to degree of incompatibility a program is accepting, size of the donor pool, number of potential donors in kidney exchange program.
As the cPRA increases above 99%, the possibility of having living donor transplantation becomes unlikely.
Assessing the probability of deceased donor kidney transplant in kidney allocation system (KAS) era:
The revision of KAS aimed to increase the access of highly sensitized patients to deceased donor kidney transplant.
It includes increase of the waitlist points exponentially with increased cPRA with giving high priority to patients with cPRA>/= 98% also patients with cPRA>/=99% draw from larger donor pool through regional and national sharing of deceased donor kidneys.
It resulted in five-fold increase in number of transplantation in highly sensitized patients with cPRA >99%.
However, highly sensitized patients with cPRA>/=99.95% remain unlikely to receive transplantation.
Outcome associated with HLA incompatible kidney transplant:
The outcome of transplantation varies according to the degree of compatibility
It ranges from mild incompatibility (low level DSA with negative crossmatch) to high level incompatibility (DSA with positive FCXM or CDCXM)
A large multicenter study showed that HLA incompatibility in presence of positive crossmatch is associated with increased risk of graft loss and death and the degree of crossmatch incompatibility is associated with increased risk of poor outcome.
Patients with DSA but negative crossmatch have same risk of graft loss and mortality as HLA compatible transplants.
A multicenter study showed that patient survival over 8 years was higher in incompatible living donor transplant than in patients who remained on dialysis or received deceased donor transplant.
Studies showed that the outcome of kidney transplantation (regardless the type of donor) is better than remaining on dialysis waiting for more preferable donor.
Role of kidney paired donation (KPD):
Kidney paired donation provides patients with incompatible donor to find more suitably matched donor. However, many highly sensitized patients fail to find donor.
A comprehensive summary of KPD in 9 years showed that 11.7% of transplants required desensitization because of crossmatch and/or ABO incompatibility.
35-40% of all candidates remained unmatched for one year.
KPD provides highly sensitized patients with a more suitable donor and not necessarily a compatible donor and some patients are unlikely to find a donor without desensitization.
Approach to the highly sensitized candidates with incompatible living donor:
Assess the feasibility of desensitization:
Desensitization is not recommended in case of positive CDCXM
In case of positive FCXM with median channel shift>250 or DSA RIS>/=17, it is not recommended to proceed with transplantation.
These criteria predict high risk incompatible transplant which is better to be avoided.
Assess alternatives to HLA incompatible kidney transplant:
KPD should be considered despite feasibility of incompatible transplant as incompatible transplant is associated with increased risk of graft loss and mortality compared to compatible transplants.
Before participation in KPD, several considerations should be determined as possibility of finding compatible donor, disadvantages of remaining on dialysis compared to risk of desensitization and incompatible transplant and time limit for participation while waiting for suitable donor.
Patients with broad HLA sensitization, if living donor transplantation is not feasible, deceased donor transplant will be an option.
If there is a low probability of finding compatible donor, desensitization should be considered.
Conclusion:
Desensitization should be considered in highly sensitized patients who have a living donor.
KPD provides more suitable or compatible donor but is not successful in broadly sensitized patients.
Combination of both KPD and desensitization is more beneficial
If there is a low probability of finding donor, desensitization and incompatible transplants should be considered early.
Any form of kidney transplantation -living compatible,noncompatible or deceased kidney transplantation gives better survival compared to remaining on Dialysis. Kidney transplanation should be 1st choice even in highly sensitized ckd5 patients ,because they offer better patient survival and quality of life compared to those remain on dialysis. As cPRA increases ,probablity of finding a suitable match decreases .For cPRA Above 99% percent ,it is very difficult to find a match .
For these highly sensized patients, there are 3 options which we can offer to them,each having own merits and demerits
1.Kidney pair donation- Paired kidney exchange is probably the best option for incompatible transplant, but many highly sensitized candidate failed to get a donor through KPD. 35–40% of all candidates remain unmatched within a year . Those who have O blood group and highly sensitized cPRA >97% often fails to find a match via KPD. It is a attractive option available to those who are less senstized.Now a days many centers using some form of desensitazion for highly sensitized patients to make them less sensitized and then Placing them in KPD program ,so that they can be matched .
2.Deceased donor transplantation- The new deceased-donor kidney allocation rules for candidates with a cPRA 98% have significantly improved organ availability for highly sensitized candidates. For mild to moderately sensitized candidates , especially for common blood types, finding acceptable deceased donors is usually possible without large increases in waiting time. But for highly sensitized patients ,It is very difficult to find a match through deceased donation program.
3.Live donation after desensitazion–Any form of living donation be it comaptible or non compatible ,gives better graft and patient survival compared to deceased donation. HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility, such as DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch.Risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
Feasibility of Desensitization-
Most center do not recommend desensitization for a positive CDC crossmatch, although positive crossmatch is not a absolute containdication to desensitazion. Successful transplantation can be achieved in selected cases in this setting . Additionally, many center do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17. A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection. In addition cost of these desensitazion is high and many poor patient cant afford this cost.
HLA Sensitization and the Probability of Kidney Transplantation
Probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors
With this equation, it is estimated that a patient with a
cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a cPRA 99.5% and 3000 match runs for a candidate with cPRA 99.9%.
The probability of finding a donor also depends on the size of the donor pool.
The kidney exchange donor pool can range from small, single-center internal exchanges to large multi-center national exchange programs.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates.
Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%. The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥ 98% .
These allocation policy changes resulted in dramatic early increases in the number of transplants performed in highly sensitized candidates with cPRA ≥ 99% that have since stabilized at rates that are approximately 5-fold higher than that observed before the 2014 KAS revision.
Role of Kidney Paired Donation
Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange, but they should recognize that this approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor.
the data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation to finding a compatible donor may be unrealistic.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor:
This approach takes into account the following considerations:
Assess the Feasibility of Desensitization
initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch.
In this program, they do not recommend desensitization for a positive CDC crossmatch, although successful transplantation can be achieved in selected cases in this setting .Additionally, they do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17.
The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) ≥ 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000). A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection .
If HLA-incompatible transplantation is predicted to be pro- hibitively high risk based on these criteria, they recommend participation in a paired kidney exchange program.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
kidney paired donation may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization.
A recommendation to participate in kidney paired donation should include a detailed discussion with both recipient and donor about the expectations of participation, the likelihood of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis leveraged against the risks of desensitization and HLA-incompatible transplantation, and a time limit for participation before determining the futility of kidney exchange.
They suggest paired kidney exchange should not be offered to all patients with an incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
Deceased Donor Transplantation:
Unfortunately, living donor transplantation is not feasible for some patients due to the breadth of HLA sensitization, and deceased donor transplantation remains their only option.
A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor
and MFI thresholds for defining an antigen as unacceptable should be adjusted to bring the cPRA down to at least < 99.95%.
Conclusions
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization.
Although participation in a kidney paired do- nation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O.
A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find a compatible donor.
Recommendation:
They recommend clear discussion of the risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation when the likelihood of finding a compatible donor is prohibitively low.
Journal club I
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates
The options available to the highly sensitized candidate with an incompatible living donor include participation in a paired kidney exchange program, direct donation with an incompatible live donor, or waiting for a deceased donor transplant
This review addressed the pros and cons of paired kidney exchange and desensitization and provides recommendations for patients and providers on the approach to the highly sensitized patient with an incompatible living donor.
HLA Sensitization and the Probability of Kidney Transplantation
Probability of finding an acceptable match = 1- (cPRA)n,
where n = the number of potential donors
This probability depends on:
1- The degree of incompatibility a program is willing to accept.
2- The probability of finding a donor also depends on the size of the donor pool.
Assessing the Probability of Deceased Donor
Kidney Transplantation in the Kidney Allocation System (KAS) Era
One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%.
The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA >= 98% candidates with cPRA >= 99% draw from a larger donor pool through regional and national sharing of deceased donor kidneys.
These allocation policy changes resulted in dramatic early increases in the number of transplants performed in highly sensitized candidates with cPRA >= 99% that have since stabilized at rates that are approximately 5-fold higher than that observed before the 2014 KAS revision
Outcomes Associated with HLA-Incompatible Kidney Transplantation
It is important to recognize that HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consisting of low level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility, such as DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch.
A multi-center study found that the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes.
Howeve, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario
Role of Kidney Paired Donation
Data from the NKR indicates that approximately 35–40% of all candidates remain unmatched within a year the data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one
Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation to finding a compatible donor may be unrealistic.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
Assess the Feasibility of Desensitization
This a proposed approach by the study
we do not recommend desensitization for a positive CDC crossmatch, although successful transplantation can be achieved in selected cases in this setting, we do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) => 17.
The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) >= 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000). A RIS >= 17 is associated with a positive predictive value of 91% for antibody-mediated rejection
Assess Alternatives to HLA-Incompatible Kidney Transplantation
If HLA-incompatible transplantation is predicted to be prohibitively high risk based on these criteria, we recommend participation in a paired kidney exchange program or Deceased Donor Transplantation
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization. Although participation in a kidney paired donation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates, especially for those who are blood type O. A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find a compatible donor.
2 message I learn from this article:
1- Highly sensitize patient c PRA from 80 to 95 percent and previously we thought it is difficult to find compatible donor , now it is easy and possible to find donor with good allocation system or paired kidney donation programs .
2- For highly sensitized patient we may found suitable donor but not compatible so we need to do desensitization protocol but unfortunately there is no randomized study to compare different regimen ,so it is different from Centre to Centre.
Please summarise this article
Despite the advent of newer protocols for desensitization and favorable outcomes compared to remaining on dialysis, many centers remain reluctant to perform HLA-incompatible kidney transplants,
The options available to the highly sensitized candidate with an incompatible living donor include :
1-a paired kidney exchange program,
2-direct donation with an incompatible live donor.
3- waiting for a deceased donor transplant.
Probability of finding an acceptable match = 1- (c PRA)n , where n = the number of potential donors ,with this equation, it is estimated that a patient with a c PRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a c PRA 99.5% and 3000 match runs for a candidate with c PRA 99.9%.
Prior to the 2014 KAS revision, candidates with a c PRA ≥ 80% were awarded four waitlist points toward allocation. This policy benefited those with c PRA 80–97%, for whom the probability of finding a compatible donor are generally favorable, but did little to improve access to transplant for those with c PRA ≥ 98% .
candidates with a c PRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die .
A large multi-center consortium involving 22 transplant centers that perform HLA-incompatible kidney transplantation compared patient and graft survival outcomes among living donor kidney transplant recipients with varying degrees of HLA-incompatibility, the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of both outcomes.
There are no prospective, randomized trials comparing the most common desensitization protocols, including high-dose IVIG with or without rituximab versus low-dose IVIG in conjunction with plasmapheres.
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario.
The percentage of unmatched candidates is higher for those with blood type O or who are highly sensitized (c PRA ≥ 97%) . for those who have the combination of both O blood type and c PRA ≥ 98% in NKR, only approximately 10% successfully find a donor within 1 year.
The data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
The RIS is a risk score that accounts for the binding strength of DSA and assigns 10 points for each DSA in the strong-binding range [mean fluorescence intensity (MFI) ≥ 10,000], 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI < 5000). A RIS ≥ 17 is associated with a positive predictive value of 91% for antibody-mediated rejection.
Introduction ;
1.Paired kidney exchange program
2.Direct donation with an incompatible live donor
3.Waiting for a deceased donor transplant
HLA Sensitization and the probability of kidney transplantation ;
Assessing the probability of Deceased Donor Kidney Transplantation in the Kidney Allocation system(KAS)Era
Outcomes Associated with HLA-Incompatible Kidney Transplantation
Role of Kidney Paired Donation
Approach to the highly Sensitized Candidate with an Incompatible donor
1.Assess the feasibility of Desensitization; DSA, FCXM,& CDCXM ;
2.Assess Alternatives to HLA-incompatible Kidney Transplantation
Conclusion
• highly sensitized patients have limited chances of having compatible donor, they also have higher rejection rates, and poor graft survival.
•options available to the highly sensitized candidate with an incompatible living donor include:
-paired kidney exchange program.
-direct donation with an incompatible live donor.
-deceased donor transplant.
This review address the pros and cons of paired kidney exchange and desensitization and provides recommendations to help highly sensitized recipients and avoid long waiting time on dialysis.
• HLA Sensitization and the Probability of Kidney Transplantation
-each transplant programs have its own thresholds for incompatibility,so the chance of having a suitable donor may differ from one program to another.
– Probability of finding an acceptable match = 1-(cPRA)n , where n = the number of potential donors.
The higher the cPRA the higher number of match runs needed to find compatible donor.
The probability of finding a donor also depends on the size of the donor pool.
More participation in paired kidney exchange program increase the donor pool and increase the chance of finding more matched doner.
•Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era:
revision of the US Kidney Allocation System (KAS) was implemented on December 4, 2014. One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates
Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%. The number of waitlist points increases exponentially with cPRA with highest allocation priority to candidates with cPRA 98%.
But still patients with highest cPRA are advised to consider incompatible transplantation.
•Outcomes Associated with HLA-Incompatible Kidney Transplantation:
Long term graft survival is affected by degree of mismatch ,DSA level and results of crossmatch,
A large multi-center consortium involving 22 transplant centers that perform HLA-incompatible kidney transplantation found that
the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch and in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
*Desensitization protocols are diffrent between centres and no prospective, randomized trials comparing the outcomes of these protocols
*HLA-incompatible transplantation is less preferable to compatible transplantation,
this is only relevant for patients for whom both options are available.
Generally transplantation even from incompatible donor is much better than dialysis.
•Role of Kidney Paired Donation
kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
Desensitization should be considered as an adjunct to paired exchange for highly sensitized candidates .
•Approach to Highly Sensitized Candidate with an Incompatible Living Donor:
*Assess the feasibility of desensitization.
Authors mentioned that in their programme they do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) 17, as it will be high risk transplantation so they recommend participation in a paired kidney exchange
*Assess alternatives to HLA-incompatible kidney transplantation by:
-kidney paired donation may be a consideration for patients with an incompatible donor even if it is predicted that the transplant is feasible with desensitization
Although In this review they recommended that paired kidney exchange should not be offered to all patients with an
incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
-Deceased Donor Transplantation ;the provider must recognize the exponential relationship between cPRA and the number of potential donors
that are required in order to identify a suitable donor.
-experienced centres with desensitization should manage HLA incompatibile transplantation.
Summary
Introduction
Kidney transplantations of highly sensitized candidates hindered by many challenges including the difficulty to allocate compatible donor especially for group O and B , with long waiting risk on dialysis , also the available alternative treatment options like desensitization associated with many limitation include risk of intensive immunosuppression , allograft rejection , opportunistic infection , malignancy , in addition to the cost and logistics with resources like need of expertise in transplant immunology ,hematology and plasmapheresis
This article reviews the current available treatment options and give recommendation based on the expertise opinion from local centers keeping in mind till date there is no standardization of desensitization protocols and each center use their own available resources
Sources of the donors for highly sensitized recipients including:
1-Living HLA incompatible donor.
2-paired kidney exchange program (local center, multicenter, national base)
2- kidney allocation system (KAS) such program of allocation prioritizes the access to DD in sensitized recipients with CPRA > 80-97%.
3- combination of both KPD and desensitization
HLA Sensitization and the Probability of Kidney Transplantation
Assessing the degree of sensitization can be done by either CPRA by percentage usually the higher the CPRA % the more difficult to find match donors for example those with CPRA > 99, they need large pool of 300 donors in order to get matched donor
many observational studies from different centers addressing the graft survival outcomes in highly sensitized patients whom underwent HLA incompatible donor kidney transplantation, they found 8 years survival was highest in incompatible living donor group compared to control group (9). So this encourage to go for transplantation from any type of donor rather than stay on long wait list and dye on dialysis.
Kidney paired donation program:
Such program will allow the access for better matched donors over time but again in highly sensitized patients especially with group O with CPRA≥ 97% may need to wait for many years to get suitable donor, as per NKR only around 10% got matched donor with one year. and from other registry only 25% of patients with CPRA>95% got matched DD in 6 years waiting list so in such types of patients should consider the combination of KPD and desensitization which is more realistic approach.
Desensitization protocol for incompatible living donor transplantation to be performed after DSA level by Luminex SAB with relative intensity score (RIS)<17 and FXCM preferred with MFI < 250.
RIS ≥17 is associated with positive predictive value of 91% for AMR (20).
Avoid desensitization for positive CDCXM , or FCXM with MFI≥ 250 or DSA RIS≥ 17.
Conclusion:
individualized the decision for early access to combined KPD and desensitization protocol over PKD alone or DD alone
proper counselling and address the risk and benefits of the available treatment options
Highly sensitized candidates can receive transplants from either living or deceased
donor.
The most intensely sensitized candidates tend to be transplanted mainly through
deceased donation.
Options available to the highly sensitized candidate with an incompatible living donor
include:
Participation in a paired kidney exchange program.
Direct donation with an incompatible live donor.
Waiting for a deceased donor transplant.
There is lack of consensus and guidelines to inform transplant programs and candidates
on how to choose between these options.
HLA Sensitization and the Probability of Kidney Transplantation:
First step in counseling a highly sensitized kidney transplant candidate is to assess the
likelihood of finding a suitable donor.
Probability of finding an acceptable match = 1- (cPRA) n, where n = the number of
potential donors.
The number of match runs estimated to find a suitable donor is less for centers that
perform incompatible transplants.
Given the exponential relationship between cPRA and the number of match runs
required to find a compatible donor, it is not surprising that achieving living donor
transplantation becomes exceedingly unlikely as the cPRA increases above 99%
.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney
Allocation System (KAS) Era:
One of the principal goals of the revised KAS was to increase access to deceased donor
kidney transplantation for highly sensitized candidates.
This policy benefited those with cPRA 80–97%, for whom the probability of finding a
compatible donor are generally favorable, but did little to improve access to transplant
for those with cPRA ≥ 98%.
Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-
scale beginning at cPRA 20%. The number of waitlist points increases exponentially with
cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥
98%.
cPRA ≥ 99% draw from a larger donor pool through regional and national sharing of
deceased donor kidneys. These allocation policy changes resulted in dramatic early
increases in the number of transplants performed in highly sensitized candidates with
cPRA ≥ 99% that have since stabilized at rates that are approximately 5-fold higher than that observed before the 2014 KAS revision.
Changes have not benefited the most highly sensitized candidate.
Candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant
despite the priority afforded by the KAS and are more likely to be removed from the
waitlist or die.
Observations suggest that patients in the highest cPRA categories should be advised to
consider incompatible transplantation. Although compatible transplantation remains a
remote possibility for patients with cPRA ≥ 99.95%, the likelihood of finding a compatible
donor is low, and, at a minimum, an extended waiting time is expected.
Outcomes Associated with HLA-Incompatible Kidney Transplantation:
Outcomes differ according to the degree of incompatibility.
Mild incompatibility: low level DSA associated with a negative crossmatch,
High levels of incompatibility, such as DSA in the presence of a positive FC or CDC
crossmatch.
A large multi-center consortium study from this study, the risk of HLA incompatibility on
post-transplant mortality and graft loss was only observed in the presence of a positive
crossmatch, with progressively higher degrees of crossmatch incompatibility being
associated with increasing risk of both outcomes.
However, the presence of a negative crossmatch, the risk of graft loss or death was
similar between transplants performed with DSA alone and those that were HLA-
compatible.
Multicenter data comparing survival over 8 years among patients who received an
incompatible living donor transplant to matched controls who remained on the waiting list
or received a deceased donor transplant indicates that survival is highest for
incompatible living donor recipients, making incompatible Kidney transplantation the best
choice for a broadly sensitized patient with an incompatible living donor who is
amenable to desensitization.
The higher survival rate was seen regardless of the degree of incompatibility, including
among patients with DSA and a negative crossmatch, those with a positive flow
cytometry crossmatch, and those with a positive CDC cross match.
Underscoring the message: it is generally better to undergo kidney transplantation
from a donor of any type rather than remain on dialysis in an attempt to wait for a more
preferable donor.
Role of Kidney Paired Donation:
Incompatible donor may find a more suitably matched donor through KPD.
Yields a compatible donor only a fraction of the time, and many highly sensitized
candidates are unsuccessful in finding any donor.
Kidney paired donation should be viewed as a mechanism for finding a more suitable
donor, but not necessarily a compatible one.
Desensitization should be considered as an adjunct to paired exchange for difficult-to-
match patients.
Assess the Feasibility of Desensitization:
Do not proceed with transplant PATIENT with:
Positive CDC.
Flow cytometry crossmatch median channel shift > 250 .
DSA relative intensity score (RIS) ≥ 17.
If HLA-incompatible transplantation is predicted to be prohibitively high risk based on
these criteria, we recommend participation in a paired kidney exchange program.
Assess Alternatives to HLA-Incompatible Kidney Transplantation Paired Kidney
Exchange:
Kidney paired donation:
May be a consideration for patients with an incompatible donor even if it is predicted
that the transplant is feasible with desensitization.
A recommendation to participate in kidney paired donation should include a detailed
discussion with both recipient and donor about :
The expectations of participation.
The likelihood of finding a compatible or more suitably matched donor.
The disadvantages of remaining on dialysis leveraged against the risks of
desensitization and HLA-incompatible transplantation.
Time limit for participation before determining the futility of kidney exchange
n our opinion, paired kidney exchange should not be offered to all patients with an
incompatible donor, especially if the patient’s cPRA and blood type predict a low
likelihood of finding a match through paired exchange and the flow cytometry crossmatch
indicates a high likelihood of successful transplantation.
Conclusions:
Highly HLA sensitized kidney transplant patients who are have a living donor
should be considered for desensitization.
A combined approach consisting of both desensitization and kidney paired donation will
generally be more successful.
We recommend clear discussion of the risks and benefits of available treatment options
and early consideration of desensitization and HLA-incompatible kidney transplantation
when the likelihood of finding a compatible donor is prohibitively low.
Treatment options for highly sensitized candidates include PKE, desensitization with HLA-incompatible transplantation, or waiting for a DKD.
Desensitization regimens are expensive, limited to highly equipped center with advance immunology and PEX, and need nursing expertise and blood bank for successful implementation.
In this summary I will address the key points of the provided article.
HLA Sensitization and the Probability of Kidney Transplantation
Transplant programs vary from center to another in their definitions and thresholds for incompatibility and sensitization. Because, for one center with good experience in transplanting sensitized patients and well developed desensitization protocols, highly sensitized pts could find donor match much rapidly than centers with limited experience.
The probability of finding a suitable donor depends on the cPRA and number of donor pool.
Probability of finding an acceptable match = 1- (cPRA)n ,with this equation, it is estimated that a patient with a cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor. The probability of finding a donor also depends on the number of donors, whether the paired kidney exchange program is local or national, where higher number of donor are included.
Assessing the Probability of DDK Transplantation in the Kidney Allocation System
US Kidney Allocation System was implemented in 2014 to increase access to DDK for highly sensitized candidates. However, retrospectively analysis showed that DDK performed among recipients with cPRA 80–97% was proportionally similar to their representation on the waitlist, and recipients with cPRA were excluded.
Although KAS has greatly improved access to DDK in sensitized recipients, overall, the allocation policy changes have not benefited the most highly sensitized candidates with c-PRA >99%.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a DDK transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario.
Role of Kidney Paired Donation
Paired kidney exchange is best option for incompatible donor but many highly sensitized candidate are not successful find any donor. In a comprehensive summary of the experience from the first 9 years of kidney paired donation through the NKR, 11.7% of all transplants required desensitization because of crossmatch-incompatibility or ABO-incompatibility.
Data from the NKR indicate that approximately 33-40% of all candidate remain unmatched for a year and higher percentage in blood group O and highly sensitized cPRA 97% .
That’s why, desensitization should be considered as adjuvant to kidney paired exchange program for difficult to match patients.
Assess the Feasibility of Desensitization
Desensitization should be excluded in the followings group of candidate:
1) Positive CDC crossmatch
2) Positive flowcytometry crossmatch >250 or a DSA relative intensity score (RIS)> or equal 17
3) MFI> or equal 10,000
If HLA incompatible TX is predicted to be prohibited high risk based on these criteria: recommended to share in paired kidney exchanged program.
Conclusions
Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization. Although participation in a kidney paired donation program offers the possibility of finding a compatible or more suitably matched donor, it is rarely successful for the most broadly sensitized candidates
☆Rationalizing Incompatible Living Donor
Kidney Transplantation for Highly Sensitized Candidates
☆☆☆☆☆☆☆☆
▪︎This review addressed the pros and cons of paired kidney exchange and desensitization and provides recommendations for patients and providers on the approach to the highly sensitized patient with an incompatible living donor.
☆HLA Sensitization and the Probability of Kidney Transplantation:
________________________
▪︎ The likelihood of finding a suitable donor is the first step in counseling a highly sensitized kidney transplant candidate and this may differ from one program to another.
▪︎The Probability of finding an acceptable match = 1- (cPRA)n, where n = the number of potential donors.
– With this equation, it is estimated that patients with high cPRA require more match runs to increase the chance of finding a compatible donor,
▪︎ For transplant centers that only consider compatible transplants, these estimates provide a quantifiable approximation of the likelihood of finding a suitable donor, either through paired kidney exchange or waiting for a deceased donor.
▪︎The probability of finding a donor also depends on the size of the donor pool which increases by participation in a paired kidney exchange program.
▪︎ Achieving living donor transplantation is unlikely as the cPRA increases above 99%.
☆Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney
Allocation System (KAS) Era:
____________________________
▪︎ One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates.
▪︎Although the revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates.
▪︎ Candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die.
▪︎ Patients in the highest cPRA categories should be advised to consider incompatible transplantation.
☆Outcomes Associated with HLA-Incompatible Kidney Transplantation:
_____________________________________
▪︎ The distinction of HLA incompatibility (mild or higher) must be relevant, as outcomes differ according to the degree of incompatibility.
▪︎ There is little center-level variability in patient and graft survival outcomes associated with HLA-incompatible living donor kidney transplantation.
▪︎ HLA-incompatible transplantation is less preferable to compatible transplantation,
this is only relevant for patients for whom both options are available.
▪︎Making incompatible kidney transplantation is the best choice for the common scenario of: ( a broadly sensitized patient with an incompatible living donor who is amenable to desensitization).
▪︎The above patient may attempt to find a more suitable donor through paired kidney exchange, but if this is not possible, must decide whether to attempt an incompatible transplant or forgo the donor with the expectation of finding a more suitably matched deceased donor from the kidney waitlist.
▪︎ It is generally better to undergo kidney transplantation from a donor of any type rather than remain on dialysis.
☆Role of Kidney Paired Donation:
___________________________________
▪︎ This approach yields a compatible donor only a fraction of the time, and many highly sensitized candidates are unsuccessful in finding any donor.
▪︎ The percentage of unmatched candidates is higher for those with blood type O and thighly sensitized (cPRA ≥ 97%).
▪︎ For highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
▪︎Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients .
☆Approach to Highly Sensitized Candidate with an Incompatible Living Donor:
______________________
The following considerations are imp:
1) Assess the feasibility of desensitization.
2) Assess alternatives to HLA-incompatible kidney transplantation by:
2.1) Paired kidney exchange (should not be offered to all patients with an
incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
2.2) Deceased Donor Transplantation (the provider must recognize the exponential relationship between cPRA and the number of potential donors
that are required in order to identify a suitable donor.
▪︎Centers that are unwilling to perform an HLA-incompatible transplant should refer these patients to a center that is experienced with desensitization.
☆Conclusions:
_________________
▪︎ Highly HLA sensitized kidney transplant patients who are fortunate to have a living donor should be considered for desensitization.
▪︎Participation in a kidney paired donation program is rarely successful for the
most broadly sensitized candidates
▪︎A combined approach consisting of both desensitization and kidney paired donation will generally be more successful than relying on paired exchange alone to find
a compatible donor.
☆This study recomended that:
________________________________
▪︎When the likelihood of finding a compatible donor is low there must be a clear discussion of the risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation
Desensitization regimens can be resource-intensive, costly, and require clinical, immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful implementation. This review aims to provide recommendations for the highly sensitized patient with an incompatible living donor.
The options available to the highly sensitized candidate with an incompatible living donor include:
· Participation in a paired kidney exchange program,
· Direct donation with an incompatible live donor, or
· Waiting for a deceased donor transplant. The probability of finding a compatible donor depends on the size of the donor pool.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
Although the revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, the allocation policy changes have not benefited the most highly sensitized candidates. Candidates with a cPRA ≥ 99.95% remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die. Hence, it will advisable for patients with cPRA ≥ 99.95%, to consider incompatible transplantation.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
HLA incompatibility comprises a spectrum that ranges from mild incompatibility, consisting of low-level donor-specific antibodies (DSA) associated with a negative crossmatch, to higher levels of incompatibility, such as DSA in the presence of positive flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch. The distinction is relevant, as outcomes differ according to the degree of incompatibility.
A large multi-centre consortium involving 22 transplant centres that perform HLA-incompatible kidney transplantation with varying degrees of HLA-incompatibility, observed that the risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increased risk of both outcomes. However, in the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for this scenario. The higher survival rate was seen regardless of the degree of incompatibility, including among patients with DSA and a negative crossmatch, those with a positive flow cytometry crossmatch, and those with a positive CDC crossmatch.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
Kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one. Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation of finding a compatible donor may be unrealistic.
A recommendation to participate in kidney paired donation should include a detailed discussion with both recipient and donor about the expectations of participation, the likelihood of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis leveraged against the risks of desensitization and HLA-incompatible transplantation, and a time limit for participation before determining the futility of kidney exchange.
Paired kidney exchange should not be offered to all patients with an incompatible donor, especially if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange and the flow cytometry crossmatch indicates a high likelihood of successful transplantation with desensitization.
Deceased Donor Transplantation
A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor, and MFI thresholds for defining an antigen as unacceptable should be adjusted to bring the cPRA down to at least < 99.95%. In doing so, however, it must be recognized that this increases the likelihood of incompatible donor offers. Therefore, desensitization should be considered a necessary component for successful transplantation.
Thanks Fakhriya
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates
This article discusses the pro and cons of paired kidney exchange and desensitization and gives recommendations. Treatment options in highly sensitized patient are limited due to poor graft survival , higher rejection rates and poor therapeutic options. With newer protocols , renal transplantation in highly sensitized patients offer better outcome as compared to those on dialysis . Renal transplantation in highly sensitized patients requires more cost ,resources and new therapeutic modalities like Plasmaphresis. Their options include both living and deceased donors , however finding suitable living donor is very less likely and they have to resort to deceased donors. Such patients on long waiting list can enrol in paired kidney exchange programme , direct donation from incompatible living donor or wait a donation from deceased donor.
HLA Sensitization and the Probability of Kidney Transplantation- The probability of finding suitable donor can calculated using the formula-
Probability of finding an acceptable match
1- (cPRA)n n = the number of potential donors.
Finding deceased donor in Kidney allocation system- KAS
KAS can be regional, national or international and patients on waiting list will take priority points as per their cPRA . CPRA can range from 20 -98%.
Transplantation with desensitization protocols
The goal of desensitisation is to remove DSA from recipient circulation and can improve graft survival in recipients with cPRA >80%. The options will include Plasmaphresis, IVIG and Rituximab In this study, those patients with positive CDC did not undergo transplantation. Thos ewith positive FXCM and Channel shift more that 250 and relative intensitive score more than 17 did not progress to transplantation . cPRA >99.995 will hardly receive organ from deceased donor and will need desensitization protocol at some stage.
The short term outcome may be better but long term outcome may not be good due to rejection , infection and complications of immunosuppression. Ideally it should be avoided wherever it is possible due to complications and cost . So it should be limited to those with no suitable living donor and are on top of waiting list.
Kidney Pair Donation
This process involves kidney exchange between living donor and recipient pair due to HLA or ABO incompatibility thus providing opportunity to have a better matched transplant. Those with cPRA >98% or blood group O have only 10% probability of finding living donor in one year. KPD will try to find most suitable non compatible donor. Detailed counselling is required to understand the pro and cons of this programme .
Conclusions
Highly sensitised who can find suitable living donor should be considered for desnsitization
Kidney paired donation can find suitable matched donor , especially those with blood group O
Combined approach of desensitization and paired kidney donation will be more successful than paired exchange alone in finding a living donor
Patients should be counselled about risk and benefits of available options and early consideration of desensitization and HLA incompatible transplant when chances of finding a compatible donor are low
· The best option for transplant is matched donor. However, sometimes we need to transplant those with positive cross match and had been long waiting time to have better QOL than on dialysis.
· The probability to find a suitable donor can be calculated by formula:
1- (cPRA)n, when n is the number of available donors, it was found that in patients with a cPRA of 99% only 1 from 300 donor offer will be suitable for transplantation with a negative crossmatch.
· Different options for those with high cPRA (highly sensitized):
o Continue on hemodialysis with poor QOL and higher mortality than non compatible transplantation.
o Use paired kidney donation (PKD)to find more suitable donor (so difficult especially for those with long waiting time, more exposure to sensitizing events).
o Use deceased donor who is more suitable by virtual cross match which has improved due to improvement of the kidney allocation system (KAS).
o Use of aggressive desensitization protocols to remove antibodies and render them transplantable.
Value of KAS
Desensitization protocols
Paired kidney donation (PKD)
For those with cPRA ≥ 98% and blood group O, the probability to find compatible donor is only 10% within 1 year, so the aim here is to find the most suitable not compatible donor to reduce waiting time.
Highly sensitized patients can receive a transplant from either a living incompatible donor (either directly or through a paired exchange program) or a deceased donor. As the chances of finding an HLA compatible donor are very low, desensitization followed by an HLA incompatible transplant is an option worth considering in such patients.
The chances of finding an acceptable donor depends on the size of the donor pool as well as the thresholds taken for incompatibility in a particular transplant program. As the cPRA value increases, the number of match runs required to have a 95% chance of finding an acceptable donor increase exponentially (9 runs for a cPRA of 70%, 59 runs for a cPRA of 95% and 30000 runs for a cPRA of 99.99%). So, it is very important to assess the probability of finding a living donor for such patients. The probability of finding a deceased donor has increased post-2014 due to implementation of newer kidney allocation system (KAS), which gives highest priority to cPRA ≥98%, and hence led to 5 times increase in transplants of patients with cPRA ≥99%. Even in newer KAS era, the patients with cPRA ≥99.95% have not been able to get a transplant.
In this background, an HLA incompatible transplant should be considered for such highly sensitized patients. It has been shown that HLA incompatible transplant in patients with negative crossmatch has no effect on post-transplant mortality and graft loss, with poorer results only with a positive cross match, worsening with the degree of crossmatch incompatibility. The number of transplants and type of desensitization protocols used in the transplant program did not have any effect on the graft outcomes. Comparing the results of an incompatible transplant to remaining on dialysis, there is a survival advantage.
A large proportion of these highly sensitized patients are not able to get a donor through kidney paired donation (KPD) programs, especially blood group O or cPRA ≥97%. Studies have shown transplant rates of 60-65% at one year (10% for O group and cPRA ≥98%). So, a KPD program can be utilized to find a more acceptable donor, rather than a compatible donor.
The approach towards highly sensitized patient with a living donor includes getting a CDC, flow cytometry crossmatch and Luminex bead assay. A positive CDC crossmatch or a flow cytometry cross match with median channel shift (MCS) > 250 or a DSA relative intensity score (RIS) ≥17 should not be taken up for desensitization and be listed in a KPD program, due to high probability of antibody-mediated rejection. In other patients, after discussing the pros and cons of remaining on waitlist versus getting an incompatible donor kidney after desensitization, the incompatible living donor transplant can be proceeded with. Even a deceased donor after desensitization can be carried out, especially in patients with cPRA ≥99.95% after adjusting the MFI cut-offs of unacceptable antigens to bring down the cPRA to <99.95%.
So, early decision regarding remaining on waitlist or getting an incompatible transplant (living or deceased) should be taken after assessing the probability of receiving a compatible donor, the crossmatch results and the MFI levels of the antibodies.
The choices for highly sensitized candidate with an incompatible living donor are
either participation in a paired kidney exchange program,
or direct donation with an incompatible live donor,
or waiting for a deceased donor transplant.
HLA Sensitization and the Probability of Kidney Transplantation
The possibility of getting a suitable donor may differ from one program to another.
The Probability of finding an acceptable match = 1- (cPRA)n , where n = the number of potential donors
For centers that only proceed with compatible transplants, these estimates provide a quantifiable approximation of the likelihood of finding a suitable donor while for centers that perform incompatible transplants, the number of match runs estimated to find a suitable donor is less depending on the degree of incompatibility a program accepts.
The probability of finding a suitable match also depends on the size of the donor pool available either from a single center or multicenter national one.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
It was done inorder to increase possibility of finding a deceased donor kidney transplantation for highly sensitized candidates.
This was useful for cases with cPRA 80–97%, for whom the possibility of finding a compatible donor are generally favorable, but didnot improve access to donors for caseswith cPRA ≥ 98%.
The waitlist points increases exponentially with cPRA and it gives the highest priority to candidates with cPRA ≥ 98%.
The candidates with cPRA ≥ 99% draw from a larger donor pool.
Patients in the highest cPRA categories should consider incompatible transplantation. Although compatible transplantation remains difficult for them ,the possibility of finding a compatible donor is low, and prolonged waiting time is expected.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
A study was done demonstrated that the risk of HLA incompatibility on post-transplant mortality and graft loss was associated with the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with increasing risk of mortality and graft loss.
It was mentioned that the volume of incompatible transplants or type of desensitization protocol employed, have little effect on outcomes.
A multicenter data comparing survival over 8 years among recipients with incompatible living donor transplant to matched controls whom was kept on the waiting list or received a deceased donor transplant revealing that survival is highest for incompatible living donor recipients, making incompatible kidney transplantation the best choice for such cases.
Role of Kidney Paired Donation
Although living donor transplantation is made easier for some highly sensitized candidates, others fail to find a suitable donor through paired exchange.
For highly sensitized candidates, kidney paired donation is a way for finding a more suitable donor, not necessarily a compatible one as desensitization is an adjunct to paired exchange for difficult-to-match cases.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
It includes
Assess the Feasibility of Desensitization
Done by doing Luminex single antigen testing and a CDC and flow cytometry crossmatch.
In their program desensitization for a positive CDC crossmatch is not advisable , although it can work with some cases .
Also they do not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17 which is highly associated with antibody medicated rejection.
High risk cases based on these criteria, are enrolled in a paired kidney exchange program.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Which is either
Paired kidney exchange
It is done through a detailed discussion with recipient and donor about the expectations of participation, the possibility of finding a suitable donor, the disadvantages of remaining on dialysis compared to the risks of desensitization and HLA-incompatible transplantation.
Deceased donor transplantation
In some cases due to HLA sensitization , living donor transplantation is not possible for them keeping a deceased donor their only choice.
Desensitization is necessary for successful transplantation in patient with a cPRA ≥ 99.95% and MFI threshold is manged to keep cPRA < 99.95%
Conclusion
A combined approach of both desensitization and kidney paired donation will be more successful for highly HLA sensitized kidney transplant patients who are having a living donor
Thanks
-Transplant options for highly sensitized kidney transplant candidates were limited due to ineffective therapies for desensitization, high rejection rates, and poor graft survival.
– Highly sensitized patients can receive transplants from either living or deceased donors, but mainly from a deceased donor.
-The first step in counseling a highly sensitized kidney transplant candidate is to assess the likelihood of finding a suitable donor.
-The relationship between calculated panel reactive antibodies (cPRA) and the probability of finding a compatible donor is expressed as:
Probability of finding an acceptable match = 1- (cPRA)n,
where n = the number of potential donors.
-For eg, it is estimated that a patient with a cPRA 99% requires approximately 300 match runs to have a 95% chance of finding a compatible donor; the estimate increases to 600 match runs for a candidate with a cPRA 99.5% and 3000 match runs for a candidate with cPRA 99.9%.
-For transplant centers that only consider compatible transplants, these estimates provide a quantifiable approximation of the likelihood of finding a suitable donor, either through paired kidney exchange or waiting for a deceased donor.
-The number of the match runs estimated to find a suitable donor is less for centers that perform incompatible transplants, with fewer match runs required depending on the degree of incompatibility a program is willing to accept.
-A revision of the US Kidney Allocation System (KAS) was implemented on December 4, 2014.
-The principal goals of the revised KAS was to increase access to deceased donor
kidney transplantation for highly sensitized candidates.
– KAS benefited those with cPRA 80–97% .
-Under the 2014 KAS, sensitized candidates receive waitlist points according to a sliding-scale beginning at cPRA 20%.
-These allocation policy changes resulted in early increases in the number of transplants performed in highly sensitized candidates with cPRA ≥ 99% that has since stabilized at rates that are approximately 5-fold higher than that observed before the 2014 KAS revision.
-The revised KAS has greatly improved access to deceased donor kidney transplantation across the spectrum of allosensitization overall, but the allocation policy changes have not benefited the most highly sensitized candidates.
-Patients with a cPRA ≥99.95%remain exceedingly unlikely to receive a transplant despite the priority afforded by the KAS and are more likely to be removed from the waitlist or die .
-The patients in the highest cPRA categories should be advised to consider incompatible transplantation.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
-A large multi-center consortium involving 22 transplant centers that perform HLA-incompatible kidney transplantation compared patient and graft survival outcomes among living donor kidney transplant recipients with varying degrees of
HLA-incompatibility , showed:
1-The risk of HLA incompatibility on post-transplant mortality and graft loss was only observed in the presence of a positive crossmatch, with progressively higher degrees of crossmatch incompatibility being associated with an increasing risk of both outcomes.
2-In the presence of a negative crossmatch, the risk of graft loss or death was similar between transplants performed with DSA alone and those that were HLA-compatible.
3-Desensitization practices varied across transplant centers in this study.
-Multicenter data comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients.
4- It is better to undergo kidney transplantation from a donor of any type rather than remain on dialysis in an attempt to wait for a more preferable donor.
Role of Kidney Paired Donation
-Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange.
– In a comprehensive summary of the experience from the first 9 years of kidney
paired donation through the National Kidney Registry (NKR), 239/2037 (11.7%) of all transplants facilitated required desensitization because of crossmatch-incompatibility or ABO-incompatibility .
– Data from the NKR indicates that approximately 35–40% of all candidates remain unmatched within a year.
-The data indicate that for highly sensitized candidates, kidney paired donation should be viewed as a mechanism for finding a more suitable donor, but not necessarily a compatible one.
-Desensitization should be considered as an adjunct to paired exchange for difficult-to-match patients and limiting one’s expectation of finding a compatible donor may be unrealistic.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor
The approach takes into account the following considerations:
Assess the Feasibility of Desensitization
-Initial step is to assess the amenability of desensitization to a potential living donor by performing Luminex single antigen testing to identify DSA and perform a CDC and flow cytometry crossmatch.
-It does not recommend desensitization for a positive CDC crossmatch and does not proceed with transplant with a flow cytometry crossmatch median channel shift > 250 or a DSA relative intensity score (RIS) ˃ 17.
-If HLA-incompatible transplantation is predicted to be prohibitively
high risk based on these criteria, it recommend participation in a paired kidney exchange program.
Assess Alternatives to HLA-Incompatible Kidney Transplantation
Paired Kidney Exchange
-Kidney paired donation may be a consideration for patients with an incompatible
donor even if it is predicted that the transplant is feasible with desensitization.
Deceased Donor Transplantation
-A patient with a cPRA ≥ 99.95% is highly unlikely to be offered a deceased donor , and MFI thresholds for defining an antigen as unacceptable should be adjusted to
bring the cPRA down to at least < 99.95%.
– Desensitization should be considered as a necessary component for successful transplantation.
Thanks
Rationalizing Incompatible Living Donor Kidney Transplantation for Highly Sensitized Candidates.
Introduction:
Transplantation is still the best modality for end stage renal disease patients related to morbidity and mortality rates and specially from point of quality of life.
Highly sensitized candidates for transplantation is challenging for us till now as those patients are between two difficult options, each one is more difficult than the other , the first is to find the compatible living donor that may never come or incompatible that need desensitization protocols which also costly, and require clinical, immunology, and nursing expertise and blood bank and plasmapheresis capabilities for successful implementation.
The second option is waiting for a deceased donor transplant or continuing on PD/HD with lower quality of life.
This review addressed the upsides and downsides of paired kidney exchange and desensitization and provides recommendation for patients and providers on the approach to the highly sensitized patient with an incompatible living donor.
HLA Sensitization and the Probability of Kidney Transplantation:
The best option for those patients to find suitable compatible living donor which has a good graft survival.
The relationship between calculated panel reactive antibodies (cPRA) and the probability of finding a compatible donor is expressed as: Probability of finding an acceptable match = 1- (cPRA)n, which differ from system to another.
e.g. patient with (Cpra) is 99 needs 300 match runs to have a 95% chance of finding a compatible donor.
You can increase possibility of finding compatible donors either through paired kidney exchange (which depends on the size of donor pool) or waiting for a deceased donor.
Some center going for incompatible transplantation depending on the degree of incompatibility a program is willing to accept.
Assessing the Probability of Deceased Donor Kidney Transplantation in the Kidney Allocation System (KAS) Era
One of the principal goals of the revised KAS was to increase access to deceased donor kidney transplantation for highly sensitized candidates.
The number of waitlist points increases exponentially with cPRA and the policy awards the highest allocation priority to candidates with cPRA ≥ 98%, but candidates with a cPRA ≥ 99.95% still not benefited from the system with high waiting time or die, so the patients in the highest cPRA categories should be advised to consider incompatible transplantation.
Outcomes Associated with HLA-Incompatible Kidney Transplantation
HLA incompatibility divided to:
-Mild incompatibility (low level donor-specific antibodies (DSA) associated with a negative cross match).
-Higher incompatibility (s DSA in the presence of a positive flow cytometry or complement-dependent cytotoxicity (CDC) cross -match) which has poor patient and graft outcome than the mild incompatible group.
Comparing survival over 8 years among patients who received an incompatible living donor transplant to matched controls who remained on the waiting list or received a deceased donor transplant indicates that survival is highest for incompatible living donor recipients which is considered by Multicenter data.
So better to go for kidney transplantation from a donor of any type rather than remain on dialysis in an attempt to wait for a more preferable donor.
Role of Kidney Paired Donation
Paired kidney exchange is allowing highly sensitized recipients to find suitable compatible donor but still those who have the combination of both O blood type and cPRA ≥ 98% in NKR, only approximately 10% successfully find a donor within 1 year ,so the concept of paired kidney donation system should be changed to find a more suitable donor, but not necessarily a compatible one.
Approach to the Highly Sensitized Candidate with an Incompatible Living Donor:
Assess the Feasibility of Desensitization:
In their program, they do not recommend desensitization for a positive CDC cross-match and they do not proceed with transplant with a flow cytometry cross-match median channel shift > 250 or a DSA relative intensity score (RIS) ≥ 17 because associated with a positive predictive value of 91% for antibody-mediated rejection.
The RIS is a risk score that accounts for the binding strength of DSA.
10 points for each DSA (MFI) ≥ 10,000).
5 points for each DSA (MFI 5000 to 9999).
2 points for each weak DSA (MFI < 5000).
Assess Alternatives to HLA-Incompatible Kidney Transplantation:
Paired Kidney Exchange:
Increase the likelihood of finding a compatible or more suitably matched donor, the disadvantages of remaining on dialysis outweighed against the risks of desensitization and HLA-incompatible transplantation.
But if the patient’s cPRA and blood type predict a low likelihood of finding a match through paired exchange, can replace the paired kidney donation by transplantation with desensitization.
Deceased Donor Transplantation:
In some highly sensitized patients due to due to the breadth of HLA sensitization, deceased donor transplantation remains their only option.
Conclusions:
In highly sensitized patients with low chance to find compatible living donor should participate in paired kidney donation with desensitization, We recommend clear discussion of the risks and benefits of available treatment options and early consideration of desensitization and HLA-incompatible kidney transplantation or Deceased Donor Transplantation as the last resort.
Thanks