|Year : 2019 | Volume
| Issue : 2 | Page : 96-103
Immunological barriers in ABO-incompatible kidney transplantation: How to overcome
Sonia Mehrotra, Raj Kumar Sharma
Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||16-Nov-2018|
|Date of Acceptance||10-Jan-2019|
|Date of Web Publication||28-Jun-2019|
Dr. Raj Kumar Sharma
Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Various desensitization strategies are used to overcome immunologic barriers such as anti-human leukocyte antigen-donor-specific antibody (HLA-DSA) and anti-ABO blood group incompatibility. Materials and Methods: Three index cases of ABO-incompatible (ABO-i) kidney transplantation from living-related donors are discussed. Each recipient was evaluated by complement-dependent cytotoxicity crossmatch, flow cytometric crossmatch, lysate-based crossmatch, and single-antigen bead Luminex assay and anti-A, B isoagglutinin titer. The desensitization protocol included 500 mg of rituximab, followed by 2–10 sessions of plasmapheresis with basiliximab/antithymocyte globulin induction. Results: Case 1: A patient received the third transplant as ABO-i transplant, with no anti-HLA-DSA. Anti-ABO antibody titers were immunoglobulin M (IgM)/IgG 1:128/1:256. He had successful desensitization to anti-AB titer of <1:2 (IgM/IgG) with excellent outcome. Case 2: At the time of transplant, a patient had no anti-HLA-DSA. ABO titers were reduced to <1:8 (IgM/IgG) from baseline of IgM/IgG 1:128/1:1024 after desensitization. Posttransplant patient had severe acute graft dysfunction within 1 week, with rebound of anti-B titers to (IgM/IgG) 1:128/1:1024. Graft biopsy showed cortical necrosis resulting in graft loss. Case 3: His first ABO-compatible transplant was lost because of de novo anti-HLA-DSA, which developed within 1 week after transplant. The patient underwent the second ABO-i transplant. He also had anti-HLA-DSA against the second donor. Despite desensitization and anti-ABO titers coming down to <1:8, the patient developed severe acute graft dysfunction within 2 weeks, with rebound of anti-HLA-DSA antibody (titers increased >11000) resulting in graft loss. Conclusions: Careful evaluation of immunological barriers before ABO-i transplantation should be done, especially when both anti-HLA and ABO sensitization are present.
Keywords: ABO-incompatible, antithymocyte globulin, donor-specific antibodies, human leukocyte antigen
|How to cite this article:|
Mehrotra S, Sharma RK. Immunological barriers in ABO-incompatible kidney transplantation: How to overcome. Indian J Transplant 2019;13:96-103
|How to cite this URL:|
Mehrotra S, Sharma RK. Immunological barriers in ABO-incompatible kidney transplantation: How to overcome. Indian J Transplant [serial online] 2019 [cited 2019 Sep 15];13:96-103. Available from: http://www.ijtonline.in/text.asp?2019/13/2/96/261851
| Introduction|| |
Many new techniques to evaluate the immunological barriers such as anti-human leukocyte antigen (HLA) antibodies and ABO antibodies (gel card for ABO titer and solid-phase anti-HLA antibody assays) have improved our ability to regulate the risk of rejection in the presence of such immunological barriers. There have been advancements in therapeutic options to remove and decrease the production of anti-ABO and anti-HLA antibodies for the treatment of acute or chronic antibody-mediated rejection and for reducing the risk of rejection episodes by providing treatments to modulate the immune response before transplantation.,
ABO-incompatible (ABO-i) renal transplantation has the potential to significantly increase the donor pool. ABO-i and positive anti-HLA crossmatch barriers have been considered relative contraindication to transplantation and have a significant risk of hyperacute or acute AMR and graft loss due to the presence of blood group antibodies (isoagglutinins) or anti-HLA antibodies in the recipient.
Anti-HLA antibodies develop after exposure to foreign HLA antigens through blood transfusions, pregnancies, and previous transplants. It has been reported that patients who have antibody against their donor HLA antigens with high strength are at high risk of hyperacute or acute antibody-mediated rejection (ABMR), which can lead to graft loss.
For a recipient of an ABO or HLA incompatible organ, desensitization protocols modulate the immune system (splenectomy and cytotoxic therapies such as rituximab (RTX) and bortezomib decrease the B-cell and plasma cell clones). Physical removal of circulating antibodies is accomplished by plasmapheresis (PP) or double filtration or immunoadsorption. Intravenous immunoglobulin (IVIg) may also directly inhibit the function of circulating antibodies. These desensitization therapies are used for preparing patients for transplantation from donors with ABO and HLA incompatibility. The supplementary immunosuppressive medications such as IVIg modulate through Fc receptor signaling to impair the ability of cells to make antibodies.,,
| Materials and Methods|| |
Three index cases are presented who were evaluated for donor-specific anti-HLA sensitization before they received ABO-i kidney transplantation. Each recipient was evaluated by complement-dependent cytotoxicity (CDC) crossmatch, flow crossmatch, single-antigen bead (SAB) assay, and lysate-based solid-phase crossmatch (SPC) on Luminex platform for sensitization.
Complement-dependent cytotoxicity crossmatch
It is used to detect the donor-specific antibodies directed against the recipient. If the result of the CDC crossmatch is positive, then transplantation with that donor is not advised. CDC detects complement-dependent anti-HLA-specific antibodies. CDC test is based on donor lymphocytotoxicity testing mediated by rabbit complement. It is performed by incubating recipient serum with donor lymphocytes and checking for donor lymphocytotoxicity after adding rabbit complement. Donor T- and B-lymphocytes are added to the recipient serum in the presence of complement. If donor cells are lysed, then CDC is taken as positive, and if there is no lysis, then CDC is considered negative. CDC has a limitation as there is a possibility of complement-fixing antibodies which can cause donor lymphocytotoxicity in the absence of donor-specific anti-HLA antibody. Antibodies are most commonly directed against HLA/major histocompatibility complex Class I and II antigens.,
Flow crossmatch serves as a sensitive crossmatch test for the detection of anti-HLA donor-specific antibody (DSA) against a recipient. A positive flow crossmatch picks up low level of DSA, which may not be clinically relevant. Many laboratories perform both CDC and flow crossmatch assays before transplant, especially in sensitized recipients and second transplants.
A patient's serum samples and donor peripheral blood mononuclear cells are used for T and B flow crossmatching. Fluorescence-labeled anti-CD3 antibody is used to identify T-cells, while anti-CD19 PC5 antibody is used to identify B-cells. Anti-human IgG labeled with fluorescein isothiocyanate (FITC) is used to label T- and B-cells. A total of at least 50,000 events are acquired using flow cytometer, and analysis is performed with calculation of median channel shifts and correlated against negative and positive controls.
The solid-phase assays such as SAB assay, also known as virtual crossmatch, are used to detect anti-HLA antibodies against the donor. In SAB assay, the main advantage is increased sensitivity and specificity of the results.
The detection of Class I or Class II HLA antibodies was done in human serum by Luminex solid-phase assay using the “one-lambda LABScreen PRA Class I (LS1PRA) and PRA Class II (LS2PRA) kits” (http://www.onelambda.com/content/dam/onelambda/en/TDX/Documents/securedocs/docs/Product_Insert/LS-LSCN-PI-EN-00.pdf) which use microbeads coated with purified Class I or Class II HLA antigens and detect antibodies and their specificities against the HLA antigens in each LABScreen panel. PRA Class I or Class II LABScan for analysis of up to 100 bead regions, in a single test. A negative control serum is used to establish the background value for each bead in a test batch. Test serum is incubated with LABScreen beads. Any HLA antibodies present in the test serum bind to the antigens on the beads and then are labeled with R-phycoerythrin (PE)-conjugated goat anti-human IgG. The Luminex detects the fluorescent emission of PE and a dye signature from each bead.
LABScreen PRA Class I or Class II reactivity strength of a test serum to each bead is compared to positive or negative control.
Single-antigen bead (by one lambda) assay
Each bead detects antibody directed against a single-HLA antigen. Median fluorescence intensity (MFI) values of SAB assay semi-quantitatively estimate the intensity of each anti-HLA antibody present and help in detecting various significant anti-HLA antibodies in a recipient. Each microparticle is coated with a single HLA molecule utilizing recombinant technology. Multiplex bead antibody assay systems for anti-HLA antibodies use a solid-phase platform. Panel contains all of the most frequently observed HLA alleles (97 Class I and 91 Class II alleles). Assay beads are mixed with recipient serum. Virtual crossmatch is a SAB assay which is based on donor tissue typing and recipient anti-HLA antibody compatibility. It is also important to keep in mind the limitation of solid-phase assays as the beads could be coated with HLA molecule which could get altered during recombinant processing.
A virtual crossmatch-based DSA monitoring does not require donor material. It is based on old information of HLA typing of donor, to identify the status of HLA antibodies present in recipient against donor HLA antigens. This would need a recipient's fresh serum sample for SAB assay by one-lambda LABScreen single-antigen HLA Class I (LS1A04) and HLA Class II (LS2A01)
Lysate DSA screening done by (LIFECODES DSA by Immucor) uses donor lysate and identifies anti-HLA antibodies for Class I and Class II and their titers but fails to give the HLA specificities. The mixture of the bead was conjugated with monoclonal antibodies which are an identification for HLA Class I and Class II. Control beads are used as a mixture of beads to identify the background in the assay. The beads are mixed with donor lysate and then with recipient serum to identify the DSA target for antibodies in the recipient serum.
To standardize results, laboratories need to identify cutoff (MFI) values for Luminex-based solid-phase tests which would need to be compared with traditional CDC and flow crossmatch results.
Posttransplant DSA monitoring requires a recipient's fresh serum sample.
For lysate-based DSA testing, using LIFECODES DSA kit (www.immucor.com/LIFECODES%20Documents/LC977RUO.14%20-%20LIFECODES%20DSA%20IFU%20RUO.pdf), lysate of donor lymphocytes was used. Donor lymphocyte lysate can be stored at 2°C–8°C for 4 h or can be quickly frozen in small aliquots for single use at −70°C to −80°C for up to 2 years for posttransplant DSA monitoring. This can be done at one point of time.
Gel card method was used to measure anti-ABO titers. IgM ABO antibody titers are done by neutral gel cards on serially diluted patient serum. IgG ABO antibody titers were done using AHG gel cards. Anti-blood group titer of 1:8 was the target for desensitization. The ABO titration was performed before and after every session of PP/IVIg.,
The desensitization protocol for ABO-incompatible transplant at our center includes infusion of 500 mg of RTX (dose – 375/mg/m2) which is administered, 10–12 days before kidney transplant (KT). Two to ten sessions of PP were performed (depending on anti-ABO titer) over 2–14 days before surgery until a recipient's isoagglutinin titer decreased to a level below 1:8. Postoperative PP was only given if the anti-A, B isoagglutinin titer increased above a level of 1:8 (within first 2 weeks of transplant) in association with graft dysfunction or if allograft biopsy was suggestive of ABMR.
All the ABO-i KT patients received induction therapy with either basiliximab (an anti-CD25 monoclonal antibody) (on days 0 and 4) or rabbit anti-thymocyte globulin induction in high-risk patients (given in a total dose of 3–4.5 mg/kg in three doses given on day 0 and then on alternate days posttransplant).
All patients received triple sequential immunosuppression – mycophenolate mofetil (dose: 2 g/day), tacrolimus (dose: 0.05 mg/kg body weight 3.5 mg; given every 12 h to maintain trough levels of 10–12 ng/mL), and steroids were started 10 days before surgery. During the transplant surgery, 500 mg of IV methylprednisolone was given. The patient received RTX (dose – 375/mg/m2) 10 days before the date of transplant. PP up to 11 sessions was performed before surgery to reduce anti-ABO titers to desired targets, followed by IVIg (dose – 100 mg/kg per PP session). We used PP as a method of isoagglutinin removal. In one patient, immunoadsorption was used before transplant. A standard 1.5 plasma volume PP with 5% human albumin (20% human albumin reconstituted in saline) and/or fresh frozen plasma as replacement solution was performed. A minimum of 12-h gap was given after IVIg dose and before the start of the next PP.,,
| Results|| |
A 35-year-old male patient was evaluated for the third KT. The patient had two ABO compatible (ABOc) KTs earlier at private hospitals which were lost due to chronic allograft nephropathy. The patient was evaluated for ABO-i transplant. Various pretransplant clinical and immunological characteristics are shown in [Table 1]. Patient blood group was O positive and donor blood group was B positive. Calculated panel-reactive antibody (cPRA) was 40% positive for Class II and negative for Class I. Donor-specific anti-HLA antibodies were negative. After ABO desensitization, ABO titers became <1:8. Postoperative outcome and characteristics are shown in [Table 2]. The patient had no anti-HLA-DSA and had low baseline ABO titers. He had successful third ABO-i transplant. This was associated with no anti-HLA-DSA using solid-phase assays. The patient also had low baseline anti-ABO titers.
|Table 1: Preoperative comparison between three cases of ABO-incompatible transplantation|
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A 22-year-old male patient underwent ABO-i KT. At the time of transplant, preoperative clinical and immunological characteristic parameters are shown in [Table 1]. His blood group was O positive and donor blood group was B positive. Donor-specific anti-HLA antibodies were negative. However, ABO titers were high at baseline (IgM/IgG) 1:128/1:1024, which became <1:8 after desensitization. Postoperative characteristics and outcomes are shown in [Table 2]. The patient developed acute graft dysfunction within 1 week after transplantation. The patient's anti-B titers increased to above (IgM/IgG) 1:128/1:1024. The patient was started on PP and IVIg. Graft biopsy showed ABMR with cortical necrosis. The patient had persistent hematuria and was passing fleshy material per urethra. Graft nephrectomy was done. Thus, even first ABO-i transplant without any anti-HLA-DSA but high baseline ABO titer failed due to rebound of ABO antibodies after ABO-i transplant.
A 27-year-old male patient previously underwent ABOc KT which failed due to the development of de novo DSA against his donor (MFI Class I and II >14000), as shown in [Figure 1]a. Preoperative parameters are shown in [Table 1]. The second transplant was ABO-i. His blood group was A and donor blood group was AB. At the time of transplant, flow DSA was also positive with multiple anti-HLA antibodies. ABO titers were reduced to <1:4, and anti-HLA-DSA titers were reduced to <2000 MFI with negative CDC crossmatch by PP/IVIg protocol. Postoperative clinical characteristics are shown in [Table 2]. The patient developed acute graft dysfunction within 2 weeks after transplantation. Graft biopsy showed acute ABMR in due to the rebound of anti-HLA antibody (MFI >1000 in Class I and >1,1000 in Class II) [Figure 2]a and [Figure 2]b. There was no rebound of the anti-ABO group antibodies. The patient's HLA-DSA antibody (MFI) titers increased to >11,000 resulting in graft loss. In this case, the patient underwent the first ABOc [Figure 1]a and [Figure 1]b with graft loss due to de novo anti-HLA-DSA. Graft biopsy showed albumin/creatinine ratio + ABMR, C4d + VE in 60% peritubular capillaries (PTCs). ABO blood group incompatibility along with anti-HLA sensitization at the time of the second ABO-i KT in the third case, despite low baseline anti-ABO titer and desensitization, was associated with poor outcome. This was due to the rebound of anti-HLA-DSA resulting in loss of ABO-i transplant despite no rebound of anti-AB titers.
|Figure 1: (a and b) Case III post first kidney transplant single-antigen bead results|
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|Figure 2: (a and b) Case III post second kidney transplant single-antigen bead results|
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| Discussion|| |
Various desensitization strategies have been used to overcome immunologic barriers such as anti-HLA-DSA and ABO blood group incompatibility., However, there are still many problems as the antibody that is responsible for posttransplant acute ABMR in ABO-i transplants could be due to an antibody that was newly synthesized after transplantation (de novo antibody, i.e., anti-ABO histo-blood group antibody or anti-HLA antibody). There could be rebound of anti-HLA-DSA or anti-ABO antibody in high immunological responders (anti-ABO/anti-HLA antibody producers) who are difficult to desensitize.
These cases demonstrate that of the three patients who underwent ABO-i transplantations, only one recipient who despite the third transplant which was ABO-i transplant (Case I) had the best outcome with no episodes of antibody-mediated rejection. This was because his baseline ABO antibody titers were not very high, and after desensitization treatment, target of <1:8 was achieved easily before ABO-i transplant was performed. This patient also had no anti-HLA-DSA. Recipients with high antibody titers at baseline have been reported to be at high risk for antibody-mediated rejection and graft loss.,, Cases II and III show that pretransplant desensitization treatment could reduce anti-ABO blood group antibodies and HLA antibodies to low levels at the time of transplantation. However, there was rebound of anti-HLA antibodies to high levels in the early posttransplant period. This resulted in antibody-mediated rejection and graft loss;,, Chung et al. suggested that KT in patients with combined ABO-i and HLA-i had a similar incidence of acute AMR to that seen in exclusively HLA-sensitized patients, with graft outcome which was inferior to that in ABO-i patients with no anti-HLA sensitization. High baseline titer of anti-A/B antibody alone may not always be a significant predictor for acute AMR. A strong HLA-DSA at baseline in association with ABO incompatibility is a significant risk factor for acute AMR and graft loss in ABO-i transplantation.
Before ABO-i KT, anti-ABO antibody titer should be low. Acceptable titers of anti-ABO antibodies at the time of transplantation after desensitization have varied between 1:4 and 1:32 according to the protocol of different centers.,,,,, The optimal titer should be determined according to the pre- and posttransplant immunosuppressive protocols and centers experience with the testing methods. Clinical significance of an increased anti-ABO antibody titer during the posttransplant period is variable and that there is at times no significant correlation with acute AMR. A high anti ABO antibody titer may be associated with ABMR. But rebound of anti ABO antibodies does not always result in acute AMR after ABO-I transplantation. ABO antibody titers should be monitored for at least 2–3 weeks after ABO-i KT. High posttransplant titers (>1:64) that are associated with graft dysfunction are a high risk for acute AMR and may need to be treated. It is recommended that anti-ABO antibody titer are kept low (1:8–1:16) during the early posttransplant period.,,,,,
Loupy et al. and Amico et al. reported that preformed antibodies correlate with a high incidence of subclinical AMR. There are reports in the literature that pre-transplant anti-HLA-DSA is at times associated with acute vascular and chronic antibody mediated rejection resulting in poorer graft outcomes., Pretransplant anti-HLA-DSA in ABO-i transplant is a risk factor of rejection. Diagnosis of humoral rejection in ABO-i KT is difficult since detection of C4d deposition in the PTCs is almost universal and not related to ABMR in ABO-i transplants. Other reports observed C4d deposition in 80% of protocol biopsy specimens in the absence of allograft dysfunction or other histologic abnormalities suggestive of acute AMR., Racusen and Haas reported that C4d-positive staining in ABO-i transplants suggests graft accommodation. Hyperacute rejection due to ABO histo-blood group antigens generally manifests 2 days after ABO-i transplant. This is the “silent period.” Acute ABMR occurs, especially during the day 2–7 days posttransplant. The incidence decreases after this period. Acute ABMR is rare after 1 month posttransplant (“critical period”). Accommodation gets established after 2 weeks posttransplant in ABO-i transplantation. Once accommodation has been established, acute ABMR does not occur despite the resurgence of antibody (“stable period”). Accommodation is defined as an absence of graft rejection, despite the presence of an incompatible antibody. The initiation and mechanism of the persistence of accommodation is a matter of investigation.
PP and the use of IVIg are the backbones of HLA desensitization therapy. Excellent outcomes have been reported with the addition of RTX (anti-B cell and CD28 antibody). Bortezomib (anti-plasma cell) and eculizumab (complement inhibition) could be good adjuncts for patients who are broadly sensitized with strong, complement-fixing HLA antibodies. Kidney paired donation is an alternative which does not need any desensitization., Toki et al. reported that acute AMR has a significant impact on the long-term outcome, and in ABO-i transplant, preoperative anti-HLA-DSA appears to have a more significant association with poor graft outcomes than anti-blood group antibodies.,
MFIs of SAB assay represent a semi-quantitative estimate of the intensity of each anti-HLA antibodies present. MFI levels help in detecting significant anti-HLA antibodies in various solid-phase assays and show correlation with acute/chronic AMR. HLA Class II DSA, especially HLA-DQ, antibodies are strongly associated with late rejections and resistance to treatment., There is also a strong association between the HLA-DR and HLA-DQ alpha (DQA) and beta (DQB) gene loci. Two HLA-DR mismatches really represent six mismatches due to association with HLA-DQA and HLA-DQB loci. Thus, Class II HLA mismatches between donor and recipient are associated with higher generation of DSAs in posttransplant period.
Lysate DSA screening test (SPC) can be used for detecting DSAs. In a renal transplant patient with only de novo DSA against HLA-DQ antigens resulted in acute antibody-mediated rejection (ABMR), DSA was detected both by SAB assay and lysate-based SPC on Luminex platform. Guillaume et al. suggested that the SPC on Luminex platform can detect Class I antibodies with MFI of 2300 or more and pick up Class II antibodies with MFI of 1,300 or more as in the SAB assay technique. They suggested that SPC assay may not detect HLA-C, HLA-DP, and HLA-DQ antibodies. This is not corroborated by our third case where anti-HLA DQ antibodies were detected by lysate crossmatch also. Billen et al. reported a sensitivity of SPC crossmatch as 89% for Class I and 68% for Class II.
The significance of antibodies detected by various solid-phase assays in relation to posttransplant outcomes requires prospective evaluation. The technique most appropriate to predict the posttransplant outcome is thus far not clear. Our previous study showed association between the development of de novo DSA by lysate-based, SPC Luminex assay and acute rejection episodes. The sensitivity and specificity are important considerations before choosing an assay system for de novo DSA testing after transplant. Our comparison of the SAB assay on Luminex platform and the lysate SPC crossmatch test showed that their interassay variabilities were similar, with similar capture efficiency. However, the SAB assay has shown higher sensitivity and specificity than the lysate-based SPC assay. SPC can be used as a screening test for HLA Class I and HLA Class II using donor lymphocytes.
The UNOS Histocompatibility Committee mooted a proposal of cPRA to bring accountability to PRA reporting and also to take advantage of the new Luminex-based solid-phase assays and technologies. The calculated cPRA is based on unacceptable HLA antigens concept to which the patient has been sensitized and which, if present in a donor, would represent an unacceptable risk for the candidate or the transplant program. The cPRA is computed from HLA antigen frequencies among approximately 12,000 kidney donors in the United States. For example, antibody against a HLA antigen with higher frequency in normal donors would increase cPRA to the same percentage distribution. It thus represents the percentage of actual organ donors that express one or more of those unacceptable HLA antigens. cPRA adds more accountability than previous concept of percentage PRA, By identifying and entering an unacceptable antigen for a prospective recipient, donors expressing that antigen will not be offered for that recipient. The higher the cPRA in a prospective recipient, he or she would get fewer offers of a deceased donor organ.
| Conclusions|| |
Various desensitization strategies have been attempted to overcome immunologic barriers such as anti-HLA-DSA and ABO blood group incompatibility. However, there are still many problems to be resolved as the antibody that is responsible for posttransplant acute ABMR in ABO-i transplants could be due to an antibody that was newly synthesized after transplantation (de novo antibody, i.e., anti-ABO group antibody or HLA antibody). There could be rebound of anti-HLA-DSA or anti-ABO antibody in high anti-ABO antibody producers which are difficult to desensitize.
We should carefully evaluate immunological barriers (anti-HLA-DSA and ABO blood group incompatibility) before performing ABO-i transplantation, especially when there is concomitant anti-HLA sensitization.
With effective desensitization strategy and pre- and posttransplant immunological monitoring, renal transplants are possible in high-risk renal transplant recipients presenting with immunological barriers, i.e., ABO incompatibility and performed or rebound anti-HLA-DSA, which under the current scenario are considered a high risk for successful renal transplantation. Transplant histocompatibility laboratory evaluation is very crucial in such donor-recipient immunological evaluation.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]