|Year : 2023 | Volume
| Issue : 2 | Page : 45-52
Transplanting highly sensitized patients: Is it still a reasonable option?
Mohamed Habli1, Dawlat Belal2, Ajay Sharma3, Ahmed Halawa4
1 Department of Internal Medicine, Nephrology Division, Kingdom Hospital and Consulting Clinics, Riyadh, Saudi Arabia; World Kidney Academy, Cairo University, Cairo, Egypt
2 World Kidney Academy, Cairo University, Cairo, Egypt; Kasr El-Ainy School of Medicine, Cairo University, Cairo, Egypt
3 World Kidney Academy, Cairo University, Cairo, Egypt; Royal Liverpool University Hospital, Liverpool, UK
4 World Kidney Academy, Cairo University, Cairo, Egypt; World Kidney Academy, Sheffield Teaching Hospital, Sheffield, UK
|Date of Submission||12-Nov-2022|
|Date of Acceptance||03-Mar-2023|
|Date of Web Publication||03-Apr-2023|
Dr. Ahmed Halawa
World Kidney Academy Sheffield Teaching Hospital
Source of Support: None, Conflict of Interest: None
Immunological barrier posed by preformed antibodies against donor’s human leukocyte antigen (HLA) antigens compounds the situation of global shortage of kidney donors. Pretransplantation sensitization carries a high risk of acute rejection and allograft loss. Therefore, there is a need for careful evaluation of potential recipients, based on HLA typing, HLA match, and comprehensive screening of antibodies (is conceptual). Sensitization events include previous transplantations, blood transfusions, or pregnancies. Despite advances in molecular techniques and solid-phase assays used to identify at-risk patients, kidney transplantation continues to be challenging in patients with calculated panel reactive antibodies greater than 85%. The development of desensitization protocols has been used to overcome acute rejection risk; however, the associated further increase in the risk of infection and malignancy is of significant concern owing to enhanced immunosuppression. The introduction of rituximab, bortezomib, plasmapheresis, and intravenous immunoglobulins has improved the success rate of desensitization protocols. On the contrary, paired (pooled) exchange kidney program has been instrumental in widening access to allografts to highly sensitized patients by offering lesser HLA mismatches. Moreover, desensitization protocols are rather expensive, leading to a high economic burden in the pretransplantation and posttransplantation period. This review aims to discuss the scientific basis and practical issues of managing highly sensitized patients.
Keywords: desensitization, highly sensitized, kidney transplantation, paired exchange program, positive cross-match
|How to cite this article:|
Habli M, Belal D, Sharma A, Halawa A. Transplanting highly sensitized patients: Is it still a reasonable option?. J Egypt Soc Nephrol Transplant 2023;23:45-52
|How to cite this URL:|
Habli M, Belal D, Sharma A, Halawa A. Transplanting highly sensitized patients: Is it still a reasonable option?. J Egypt Soc Nephrol Transplant [serial online] 2023 [cited 2023 Jun 8];23:45-52. Available from: http://www.jesnt.eg.net/text.asp?2023/23/2/45/372070
| Introduction|| |
Renal transplantation is the optimal therapy for end-stage renal disease by improving quality of life and reducing the mortality risk ,,,.
To keep a fine balance between immunological loss of allograft and overimmunosuppression, kidney transplantation has been traditionally offered to patients with low to moderate immunological status . Implementation of expanded criteria donor has increased the options for patients who remain on the waiting list for many years owing to sensitization against human leukocyte antigen (HLA) kidney [6,7], or those with blood group B or O [7,8]. Sensitization toward HLA occurs through previous blood transfusion, previous transplantations, and pregnancies ([Figure 1]).
Sensitization is defined as the presence of anti-HLA antibodies  or high isoagglutinin titers in the potential recipient’s serum . Patients are considered highly sensitized if the calculated panel reactive antibodies (cPRA) is greater than 80–85%. The presence of such antibodies, if not appropriately managed, will probably lead to hyperacute or acute antibody-mediated rejection (ABMR) and subsequent early allograft failure ,,,. Within Euro-transplant, 20% of patients waiting for kidney offer are sensitized and 5% are highly sensitized . As per 2020 data from the organ procurement and transplantation network, 12% of patients on the waiting list are highly sensitized .
The foremost challenge is that only 15% of highly sensitized transplant recipients with cPRA greater than equal to 98% have a chance of getting a compatible donor. The recipients with blood group O are the most difficult to transplant. Moreover, highly sensitized recipients with a negative virtual cross-match might have a positive wet cross-match.
The degree of HLA sensitization of a potential transplant candidate is defined during the initial assessment in the pretransplant period. The flow cytometry technique identifies the presence of anti-HLA antibodies, whereas solid-phase assay as a single antigen bead (SAB) precisely recognizes the specificity of HLA antigens against which the patient has preformed antibodies . Patients with a rare HLA phenotype are disadvantaged from getting kidney offer in an acceptable time frame . A collaboration with other transplant centers would expand the possibility of being transplanted.
Advances in desensitization protocols over the last two decades have been shown to overcome immunological barriers, resulting in successful transplantation . Desensitization therapies aim to increase the chance of successful kidney transplantation in highly sensitized patients and prevent ABMR after transplantation.
It is well established, based on scientific evidence, that the mortality rate is lower with kidney transplantation as compared with dialysis waitlisted matched controls ,,,,.
Orandi et al.  reported good long-term allograft survival after highly sensitized patients transplanted through the acceptable mismatch program, which was comparable to nonsensitized patients transplanted through regular allocation. Krishnan et al.  demonstrated acceptable outcomes in terms of short-term and long-term allograft and patient survival, after HLA-incompatible transplantation, which were comparable to deceased donor transplantation.
Despite advances in immunosuppression and new strategies for desensitization, many centers are still unwilling to proceed with transplantation in HLA-incompatible status owing to increased morbidity of immunosuppression and financial costs.
When a directed donation is not possible, an alternative option is to enter kidney program (KPD) . Patients with an incompatible donor may find a more suitably matched donor through paired kidney exchange, but many highly sensitized candidates are unsuccessful in finding any donor . Transplant outcomes for patients transplanted through KPD are comparable to those of nonsensitized patients [29,30].
Immunosuppressive therapies that have been used in desensitization include rituximab, intravenous immunoglobulins (IVIG), plasmapheresis, complement factors inhibitors, interleukin-6 receptor blocker, and others . This review aims to discuss the scientific basis and practical issues of managing highly sensitized patients.
Approaches to highly sensitized patients
Highly sensitized patients are mainly transplanted with kidneys from deceased donors . Several approaches to the highly sensitized potential recipients include living donation from an incompatible donor preceded by desensitization, waiting for a kidney from deceased donor , with or without desensitization, and Kidney paired donation.
Positive complement-dependent cytotoxicity (CDC) cross-match is considered, historically and conceptually, an absolute contraindication for transplantation. Many centers in the United States have performed living renal transplantation after desensitization therapy for CDC positive cross-match; however, the results are rather discouraging as up to 40% of patients faced allograft loss after 5 years of transplantation . In conclusion, transplanting against positive CDC should not be performed.
On the contrary, for patients who have a positive FCXM - Flowcytometry crossmatch and a negative CDC cross-match, the approach is based on the median channel shift, which reflects the strength of the antibodies detected in the flow cross-match test. If the median channel shift is below 250, and the relative intensity score of the potential recipient is below 17, desensitization is warranted. When relative intensity score is more than 17, desensitization should not be attempted .
Desensitization in highly sensitized patients and outcomes
Desensitization increases the chances of a highly sensitized patient getting a kidney offer from a living or deceased donor, by reducing hyperacute ABMR after transplantation .
Desensitization protocols include the combination of different strategies: 
- (1) Removal of circulating anti-HLA antibodies, using extracorporeal techniques such as plasmapheresis.
- (2) B-cell depletion blocks the production of anti-HLA antibodies.
- (3) Immunomodulation of the recipient’s immune system,
There is an appreciable variance in desensitization protocols, based on the availability of drugs, local clinical experience, and preference. Desensitization strategies, in most transplant centers, are achieved using a combination of plasmapheresis, IVIG, rituximab, and other drugs.
Plasmapheresis is an effective procedure used to remove circulating antibodies. However, reequilibrium between the intravascular and extravascular compartments that follows the treatment session limits its efficacy [36, 38, 39]. Plasmapheresis is associated with coagulation disturbances, thrombocytopenia, along with electrolyte adverse events, in particular, hypocalcemia.
IVIG is used as an immunomodulatory agent that contributes to immune response modulation through inhibition of T-cell and B-cell proliferation, apoptosis of B cells, and inhibition of cytokine release [40,41].
Rituximab, an anti-CD20 monoclonal antibody, originally used for the treatment of B-cell lymphomas, is an essential component of desensitization protocols. Rituximab causes the elimination of B cells via CDC and apoptosis. Rituximab use is effective in depleting not only mature B cells but also immature cells because of the broad expression of CD 20 in these cells ,,.
Desensitization protocol combinations and timing depend upon whether the donor is a living or deceased donor kidney. In patients who qualify for desensitization, pretransplant desensitization is performed using high-dose IVIG and rituximab in addition to plasmapheresis.
Bortezomib, a potent proteasome inhibitor, has been used as part of desensitization protocols to eliminate mature plasma cells responsible for antibody production ,,. Diwan and colleagues and Kute and colleagues have demonstrated the efficacy of bortezomib, in combination with plasmapheresis and IVIG. In contrast, one study reported that the use of bortezomib was associated with frequent adverse effects with only a modest decline in anti-HLA antibodies .
Eculizumab is a monoclonal antibody that blocks complement protein C5, inhibiting cleavage to C5a and C5b, and thus preventing cell lysis. Eculizumab has been used in small studies for HLA desensitization, but data from these studies are limited [49,50]. Bentall et al.  and Cornell and colleagues demonstrated that the addition of eculizumab to conventional desensitization protocols showed no additional effect.
Imlifidase or IdeS, an investigational drug, has been evaluated as desensitization therapy in highly sensitized candidates in two independent American and Swedish studies. The use of imlifidase was promising in highly sensitized patients, but further studies are needed to evaluate the long-term outcomes [51,52]. [Table 1] summarizes the mechanism of action of different immunosuppressive agents used commonly in desensitization protocols.
|Table 1: Commonly used desensitization therapy and its mechanism of action|
Click here to view
It remains unclear which combination of immunosuppressive drugs is optimal regarding a sustained reduction in antibodies with a low risk of infections and malignancies.
Outcomes of pretransplant desensitization therapy
A study by Vo et al.  evaluated highly sensitized kidney transplant candidates who received IVIG plus rituximab as a desensitization therapy, before kidney transplantation from either a living or deceased donor.
In another follow-up study by Vo et al.  that included highly sensitized patients receiving the same desensitization protocol, PRA levels were reduced in 75% of patients, and FCXM became negative, allowing renal transplantation in all patients.
A Korean study evaluated the outcomes of transplanting high immunologic risk patients who underwent kidney transplantation following desensitization therapy from 2012 to 2018. In this study, Lim and colleagues demonstrated no significant difference in acute rejection-free survival, graft survival, and patient survival between the living donor control groups and incompatible kidney transplantation groups. However, the incidence of ABMR was higher in HLAi transplanted group .
Another national cohort study by the Korean Organ Transplantation Registry Study Group assessed clinical outcomes of ABOi and HLAi transplantation. In this cohort, Ko and colleagues evaluated graft and patient survival in four different groups, including the control and HLAi groups. After a mean follow-up of 3 years, they found no difference in graft survival among the four groups. However, the incidence of biopsy-proven acute rejection was higher in the HLAi and ABOi+HLAi groups .
In a small single-center French study by Rostaing and colleagues, incompatible living kidney transplantation preceded by desensitization therapy was found to be a suitable option for broadly immunized candidates. In a mean follow-up of 19 months, patient survival was 100%, whereas allograft survival was 91.6% .
In another retrospective study by Pandey and colleagues, 200 incompatible kidney transplants performed against HLA and ABO blood group compatibility were evaluated. Of 200 patients, 154 were HLAi transplantation, whereas the remaining were either ABOi or HLAi+ABOi. Observations of this study are consistent with the results of other studies, in which renal and patient survival were comparable to patients who received compatible kidney matches. Pandey et al.  reported a higher ABMR rate in the first year in dual incompatible transplantation (HLAi as well as ABOi), followed by HLAi transplantation, with the lowest incidence in the compatible transplantation group.
Following desensitization protocol administration, in cases of a potential living donor, T-cell and B-cell CDC and FCXM are performed after pronase digestion to avoid false-positive tests owing to rituximab treatment. If both B-cell and T-cell cross-match results are negative, the kidney transplantation team can proceed with the surgery within 1 week. In patients awaiting deceased kidney donors, desensitization is performed using a similar protocol in candidates awaiting living kidney donors. However, when the desensitization protocol is completed, Luminex single antigen bead (SAB) is conducted every month to follow-up on anti-HLA antibodies and their MFI. In addition, their latest serum is preserved for cross-match testing.
When a direct living kidney donor is not feasible or applicable, engagement in KPD is proposed. KPD is greatly beneficial in countries or centers where living kidney donation is the primary source of kidney grafts and/or a deceased donor program is not established. Since 1991, when KPD was performed in South Korea, many counties have started to develop their kidney-paired exchange registries [59,60].
Dutch National Living Donor was first established. Other countries such as the UK, United States, Australia, and Canada have lately developed their national registries. KPD has grown from a simple exchange between two incompatible pairs ([Figure 2]) to a more complex exchange between many pairs ([Figure 3]).
|Figure 3: Chains of transplantation with NDD and bridge donor. NDD, nondirected donor.|
Click here to view
Because of the shortage of organs for patients with end-stage kidney disease awaiting kidney transplantation, getting a kidney offer for highly sensitized patients is more challenging.
To overcome this difficulty, kidney exchange programs endeavor to prioritize highly sensitized recipients with cPRA greater than 95% in the donor pool. Despite advances in exchange kidney donation, only a small percentage of highly sensitized patients are being transplanted, especially with blood group O [27,61]. In this particular group of patients, expanding the O-donor pool could be a successful strategy to overcome the blood group barrier. Using a nondirected donor is another strategy to overcome sensitization status and blood group barrier, in which a nondirected donor starts a donation chain to one recipient, whereas the last donor in this exchange chain donates his (or her) kidney to a waitlisted patient or becomes a bridge donor who can be used to start another exchange chain (refer to [Figure 2]) . Other option is to initiate donation chain with a deceased donor to shorten the waiting time to transplantation by all the exchange chain members .
Outcomes of the kidney program
In one study by Flechner and colleagues, 2037 kidney transplantations through KPD were analyzed for renal graft outcomes at 1, 3, and 5 years. At 1 and 3 years, it was reported that graft survival was comparable to non-KPD living kidney donation, whereas after 5 years of follow-up, patients engaged in the KPD program had a higher graft survival rate .
A study from Canada assessed the efficacy of the national Canadian KPD program that involved 240 kidney transplantations from 2008 to 2013, including 24 highly sensitized patients with cPRA greater than 97%. In the follow-up of 1 year, Cole et al.  reported patient and graft outcomes of 99 and 96%, respectively.
Allen et al.  also reported graft and patient outcomes of the Australian KPD program in a retrospective study. In this study, the graft and patient outcomes at 1 year were 97 and 98%, respectively.
Overall, KPD programs have shown efficacy, facilitating the transplantation of highly immunized patients. However, with the development of this complex kidney exchange donation program in some centers, transplanting highly sensitized patients continues to be difficult, with a match rate of at most 15% .
Are different strategies complementary or contradictory?
A combination of desensitization therapy and KPD will increase the opportunities for broadly immunized patients to match potential donors with lower immunological risk and better graft survival. The combination strategy was considered by many transplantation centers worldwide [28, 61, 67]. Yabu and colleagues and Blumberg and colleagues have demonstrated in their studies that highly sensitized patients who got engaged in donor exchange programs following desensitization therapy have a better chance of finding an adequate donor from kidney-paired donation pool with a shorter time being on the waiting list and with excellent graft and patient survival rate after 2 years of transplantation.
In addition to desensitization strategies and exchange programs, national and international allocation systems across Europe and North America have been updated to improve the allocation of organs to the most highly sensitized patients with cPRA greater than 98%. As broadly immunized patients have a higher mortality rate because they have to wait much longer on the waiting list, kidney allocation systems have prioritized the distribution of deceased donor kidneys to this subset of patients [68,69]. Massie and colleagues reported a 10-fold rise in transplantation of patients with cPRA of 100% as a result of updated kidney allocation system.
Development and availability of desensitization protocols, advanced kidney exchange donation program, and updated kidney allocation system are critical points in approaching highly sensitized patients. When all these measures are combined, highly sensitized patients can get acceptable kidney transplantation in a shorter time with satisfactory renal and survival outcomes.
Increased morbidity and financial cost of desensitization, is it worth it?
Although HLA-incompatible kidney transplantation has been established as an effective treatment for highly sensitized patients, pretransplant desensitization treatment, transplantation surgery, and posttransplant care carry a high economic burden. Incompatible transplantation requires a well-equipped transplant center, availability of drugs for desensitization protocols and acute rejection treatment, standardized protocols for diagnosis and management of complications related to kidney transplantation, highly qualified laboratory, services, and multidisciplinary medical and surgical teams. Compared with nonsensitized recipients, broadly immunized patients require more extended hospitalization stay, more intravenous drug administration, and more frequent graft biopsies and treatment for more frequent acute rejections. It is worth emphasizing as previously mentioned that transplantation in patients with initial positive CDC cross-match is highly expensive and is associated with unacceptable outcomes.
A National Cohort Analysis published in 2017 for kidney transplantation performed between 2002 and 2011 reported an increased cost of kidney transplantation in sensitized patients at 26% higher for positive FCXM but negative CDC and 39% higher for positive CDC . Economic analysis by Axelrod et al.  revealed that transplantations of ABOi or HLAi living donors were more expensive than HLA-compatible transplantation by 50 and 10% more costly than maintenance dialysis. Al-Jedai and colleagues also reported the expenses of transplanting highly sensitized patients in comparison with staying on hemodialysis. In this analysis, they showed that administration of desensitization protocols to highly sensitized patients is costly but is associated with cost savings in the long term when compared with maintenance hemodialysis .
In conclusion, kidney transplantation remains the best option despite the tremendous expense of the optimal treatment of highly sensitized patients. Kidney transplantation preceded by desensitization is a cost-effective treatment for patients with broad sensitization. Living or deceased kidney donation through KPD is cost-saving and effective in approaching these patients. Increased awareness about kidney transplantation and organ donation is an essential step. Desensitization in combination with KPD and kidney allocation system offers hope to highly sensitized patients on the waiting list for renal transplantation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]