Version May 2024
INTRODUCTION — Blood type–incompatible kidney transplantation has been attempted since the earliest days of transplantation, but it was quickly learned that without desensitization prior to transplant, ABO incompatibility (ABOI) led to early rejection and allograft loss [1]. Later attempts at crossing the incompatible–blood type barrier relied on antibody reduction therapies including splenectomy, immunoadsorption, and/or plasmapheresis [2]. ABOI transplantation was not considered to be an acceptable method of transplantation until larger experiences, fueled by a shortage of deceased-donor kidneys from Japan, observed that patient and graft survival were comparable to ABO-compatible transplants [3,4]. Although ABOI transplants account for a large percentage of living-donor transplants in other parts of the world [5,6], they are infrequent in the United States and are generally relegated to transplant centers that are equipped with desensitization programs [7]. Nevertheless, because approximately 30 percent of donor and recipient pairs are predicted to be blood type incompatible, ABOI transplantation is a viable option for patients seeking kidney transplantation.
A general overview of ABOI in kidney transplantation and the techniques utilized to treat patients to overcome the ABO antibody barrier are presented in this topic review.
OVERVIEW OF ABO BLOOD GROUP SYSTEM
ABO antigens and antibodies — The ABO blood group consists of four common categories (A, B, AB, and O), with types A and O most frequently found in the United States population. Antigen is expressed on red blood cells, lymphocytes, and platelets, as well as epithelial and endothelial cells. Formation of blood group antibodies, also referred to as isoagglutinins, occurs against those antigens not native to the host. Thus, antibodies to both A and B are found in an individual with blood type O, while an individual with blood type AB has no antibodies to A or B antigens. Given the distribution of blood group antigens in the United States, the waiting time on the deceased-donor allograft list is relatively longer for patients with blood group B or O when compared with A or AB [8].
In addition, individuals with blood type O tend to produce higher anti-A and anti-B isoagglutinin antibody levels than individuals with blood type A or B. Recipients with blood type O have a higher incidence of antibody-mediated rejection (ABMR) following ABOI transplantation [9] although graft survival does not differ among blood types [7].
Blood group A consists of two subtypes, A1 and A2, or more appropriately "non-A1." Approximately 80 percent of individuals in the United States with blood group A express A1 [10]. The antigenic expression of A2 is quantitatively and qualitatively less than that of A1, and the overall immunogenic risk based on antigen expression alone is A1>B>A2 [10]. Given the lower immunogenic risk of the A2 antigen, donor A2 kidneys can generally be successfully transplanted into non-A recipients with low pretransplant anti-A titers without the use of desensitization [11-16]. (See 'Blood type non-A1 (A2) donors' below.)
Isoagglutinin antibody titers — It was initially reported that higher baseline isoagglutinin antibody titers predispose to an increased risk of ABMR although subsequent data indicate the risk of ABMR may be more closely related to the isoagglutinin titer within the first one to two weeks posttransplant [17]. Although elevated isoagglutinin titers are generally observed during acute ABMR, the positive predictive value of elevated posttransplant titers beyond the first few weeks of transplant is poor, with high titers seen in otherwise stable ABOI recipients [17].
Institutions vary in how they measure and report isoagglutinin antibody titers [18,19], making it difficult to compare ABOI protocols and outcomes in the literature. The classic tube dilution method is most commonly used to report an immunoglobulin M (IgM) isoagglutinin titer (saline test) and a total isoagglutinin titer (indirect antiglobulin [Coombs] test), although direct IgG measurements can be made by pretreatment of plasma with dithiothreitol to inactivate IgM. The test should be considered semiquantitative because it depends on visual interpretation of the degree of agglutination and may be subject to interobserver variability. Thus, the reported result should be considered an approximation, and a titer reported at 1:128 could conceivably represent a titer of 1:64 to 1:256.
Other methods include column agglutination technology (gel), which is less time consuming but more costly than the tube dilution method. Titers obtained by the gel and tube dilution methods are generally comparable but can vary up to several standard dilutions from each other [19,20]. Improved assays, such as enzyme-linked immunosorbent assay (ELISA)-based technology, should assist in helping to define and standardize acceptable IgM and IgG isoagglutinin titers at baseline and in the peritransplant period. Although center-specific protocols vary, the total isoagglutinin antibody titer is generally reduced to at least 1:32 (and often to ≤1:8) before proceeding to transplantation as higher titers are associated with acute ABMR posttransplant [21].
TRANSPLANT OPTIONS FOR ABO INCOMPATIBILITY
ABOI transplantation versus kidney paired donation — For kidney transplant candidates who have an ABOI living donor and would like to utilize this donor, options include ABOI transplantation (if offered by the patient's transplant center) and kidney paired donation (KPD).
●ABOI living-donor transplantation requires a period of desensitization of the recipient prior to transplantation. Desensitization lowers anti-A/B antibody titers to a level that permits successful transplantation with commonly used induction and maintenance immunosuppression. (See 'Approach to ABOI transplantation' below and 'Outcomes of ABOI transplantation' below and 'Complications of ABOI transplantation' below.)
●With a KPD program, willing participants can choose to exchange a donor to an alternate recipient with an ABO- or human leukocyte antigen (HLA)-incompatible donor [22-24]. This process avoids the need for desensitization and provides a living-donor allograft to each recipient. Both pairs must be in full agreement and have an understanding of the potential posttransplantation ramifications, as well as make a decision on whether or not the parties should remain anonymous to one another. KPD is discussed in more detail elsewhere. (See "Kidney transplantation in adults: Kidney paired donation".)
Factors that influence the decision to pursue ABOI versus KPD include but are not limited to the following:
●Center experience with incompatible transplantation.
●Recipient preference for their intended donor.
●The possibility that a donor with more favorable characteristics could result from KPD (eg, younger age, fewer medical complexities).
●Recipient blood type and allosensitization (calculated panel reactive antibodies [cPRA]) and their impact on the likelihood and timing of being matched to a donor in a KPD program. Data from both the National Kidney Registry (NKR) and the Alliance for Paired Donation (APD) indicate that highly sensitized patients and/or those with blood type O are less likely to have success with KPD [25-27]. In NKR, 43 percent of patients with blood type O overall remain unmatched within one year of registration [27]. When O blood type is combined with cPRA ≥98 percent, nearly all candidates (90 percent) remain waiting for transplant at one year after registration [26], suggesting that ABOI transplant should be strongly considered for these patients rather than KPD.
●Whether vascular access for plasmapheresis needs to be placed for ABOI desensitization.
●The recipient's ability to tolerate the higher intensity of immunosuppression required for ABOI transplantation.
These are generally complex decisions that involve guidance from the transplant center, but ultimately, the patient should be allowed to decide which option best fits their preference.
Blood type non-A1 (A2) donors — Another option for candidates with blood type B or O is transplantation with a kidney from a blood type non-A1 (A2) donor. Approximately 20 percent of the blood type A population is subtype A2. These donors may come from either living or deceased donors. Donors with this subtype are blood type A, but their red blood cells do not agglutinate with the anti-A1 lectin antiserum used to subtype for A1. For all practical purposes, these donors are considered subtype A2 although there are other non-A1 phenotypes that have weaker antigenic expression than subtypes A1 and A2 [28]. Lectin agglutination accurately subtypes for A1 when strongly reactive and for A2 when nonreactive. Weakly reactive lectin agglutination is typically subtyped as A1 although ABO genotyping indicates that a small percentage of these are indeed A2 [29]. These misclassified donors represent potential missed opportunities for transplantation for blood group incompatible recipients that need to be studied further. (See 'ABO antigens and antibodies' above.)
Antigenic expression of the A carbohydrate antigen N acetylgalactosamine is reduced in the kidney cortex and endothelial surfaces of A2 donor kidneys, thereby making these kidneys inherently less antigenic to recipients with incompatible blood types. The ability to successfully transplant A2 donor kidneys without pretransplant desensitization was recognized early on in the history of ABOI transplantation, in the 1980s [30], and later confirmed by several groups in the 1990s and early 2000s [14,31,32]. Because of the weaker immunogenicity and paucity of expression of A2 in donor kidneys, ABOI transplantation can be performed when pretransplant desensitization is not logistically feasible, such as in deceased-donor kidney transplantation.
Given the longer waiting times of blood type B and O candidates, the allocation of A2 kidneys to select blood group B and O candidates has been studied, demonstrating significantly reduced wait times to transplant with no significant increase in graft loss or death [33,34]. The Organ Procurement and Transplant Network (OPTN) kidney allocation system implemented in 2014 permits allocation of A2 and A2B kidneys to blood group B candidates meeting center-specific criteria including prespecified, low anti-A titers [35]. Acceptance of A2 kidneys is optional for the candidate.
A low baseline anti-A blood group titer is a prerequisite for ABOI transplantation from an A2 donor. It is our opinion that both anti-A IgG and IgM should be low when undergoing incompatible transplantation from an A2 donor, based upon data showing an association between baseline total anti-A (IgM and IgG) titers and rejection [32,36]. Acceptable thresholds for baseline anti-A titers vary across institutions. Most reports describe an anti-A titer of ≤1:8 [13,15,37], although there are reports of successful transplantation with higher titers [14,38].
At our institution, we use a baseline anti-A2 titer of ≤1:16 as our threshold [39] and register all consenting blood type B recipients with an anti-A2 titer ≤1:16 for non-A1 donors. We recheck the anti-A2 titer preoperatively for deceased-donor kidney transplant and proceed if the titer remains ≤1:16. Patients receive the same induction and maintenance immunosuppression as that used for recipients of ABO-compatible transplants. We follow the same monitoring protocol that we use for ABOI transplants. (See "Kidney transplantation in adults: Induction immunosuppressive therapy" and "Kidney transplantation in adults: Maintenance immunosuppressive therapy" and 'Monitoring after transplantation' below.)
APPROACH TO ABOI TRANSPLANTATION — Approaches to ABOI transplantation vary among transplant centers and are usually institution specific. The approach used at our centers is described below.
Patient eligibility — ABOI transplant candidates must meet center-specific general transplant candidate selection criteria in addition to ABOI-specific criteria. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient".)
There are no established ABOI-specific selection criteria for recipients, and criteria vary among transplant centers. At our institution, patients must satisfy the following criteria:
●The patient must have an initial ABO isoagglutinin titer of ≤1:256 for both IgG and IgM using the tube dilution method. Some institutions do not employ criteria for baseline isoagglutinin titer and rely only on the antibody titer achieved after desensitization to determine suitability for ABOI transplantation. Antibody titers vary across institutions, and a given titer at one center may not equate with one obtained from a different program. (See 'Isoagglutinin antibody titers' above.)
●The patient must be willing to undergo ABOI transplantation and all the therapies associated with ABOI transplantation. A low level of anti-human leukocyte antigen (HLA) donor-specific antibodies (DSAs) may also be present in some patients since desensitization and immunosuppressive regimens are similar.
●The patient must have prior authorization from their insurance company for all therapies associated with ABOI transplantation.
Pretransplant ABO desensitization
Overview of desensitization — The overall goals and purpose of ABO desensitization are to lower the anti-A/B antibody titers to a level that is not associated with immediate antibody injury to the allograft and allows successful transplantation with commonly used induction and maintenance immunosuppression.
Although there is no uniformly accepted ABO desensitization protocol, most commonly used protocols employ a combination of the following strategies:
●Removal of circulating ABO antibodies – The reduction of circulating anti-A/B antibody levels to predesignated target titers is a key component of most ABO desensitization protocols. The two most commonly used methods of antibody removal are plasmapheresis and immunoadsorption, with the goal of achieving titers ≤1:8 to 1:32, depending on center practice. The number of treatment sessions is generally determined by the baseline anti-A/B antibody titer [40-43]. Immunoadsorption is not available in the United States but is frequently used in Europe. (See 'Isoagglutinin antibody titers' above and "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
Plasmapheresis is associated with an increased risk of bleeding complications [44]. Bleeding episodes are usually associated with significantly lower values of fibrinogen, platelets, prothrombin time, and hemoglobin levels. Thus, allowing fibrinogen levels to return to the normal range after plasmapheresis or repleting with cryoprecipitate is likely to reduce or prevent risk for bleeding at the time of ABOI transplantation.
●Immunomodulation – Intravenous immune globulin (IVIG) is administered by many transplant centers prior to ABOI transplantation to replace immunoglobulins that are removed with plasmapheresis or immunoadsorption. In addition, IVIG may also block Fc receptors to prevent a rebound in anti-A/B antibody titers when the plasma cells have unbound receptors and, therefore, are stimulated to make more antibody. IVIG may also have immunoregulatory properties and likely reduces circulating IgG when administered in high doses by saturating the Fc neonatal receptor that normally protects IgG from lysosomal degradation [45]. It should be noted, however, that IVIG products may contain detectable anti-A and anti-B isoagglutinins [41,46], which should be considered if high-dose IVIG is administered. In our own practice, we have observed hemolysis in some patients given high-dose IVIG products [47]. This has resulted in IVIG manufacturers adding procedures to remove isoagglutinins from IVIG products that are labeled Iso-low and are associated with lower risk for hemolysis [48].
●B cell depletion – Therapies targeting B cells are used in desensitization protocols because B cells are the precursors for plasma cells that produce the anti-A/B antibodies. Rituximab, a humanized mouse monoclonal antibody that targets CD20 (expressed on the majority of B cells), is the most commonly used agent and has replaced splenectomy, which was a component of the earliest successful ABOI protocols but is associated with greater surgical risks and longer-term morbidity [49-52].
Our approach to desensitization — For patients who will undergo ABOI transplantation, we suggest pretransplant desensitization with the combination of plasmapheresis (or immunoadsorption, where available), IVIG, and rituximab rather than plasmapheresis (or immunoadsorption) and IVIG alone. However, clinical practice varies among transplant centers that perform ABOI transplantation, and protocols also vary geographically. As an example, while plasmapheresis is the preferred antibody removal strategy in the United States, immunoadsorption is more commonly used in Europe.
At our centers, desensitization begins one month prior to the scheduled living-donor transplant surgery. Transplantation is performed when the isoagglutinin antibody titer is ≤1:8.
●At four weeks prior to the scheduled transplant surgery date, we administer a single dose of rituximab 500 mg. The optimal dose of rituximab is unclear, and some centers have reported successful outcomes with lower doses (eg, 100 to 200 mg) [53]. We premedicate for rituximab with intravenous methylprednisolone 125 mg, acetaminophen 650 mg given orally, and diphenhydramine 50 mg given orally.
●At four weeks prior to the scheduled transplant surgery date, we start immunosuppression by administering oral enteric-coated mycophenolate sodium (EC-MPS) 360 mg twice daily (or mycophenolate mofetil [MMF] 500 mg twice daily). (See 'Transplant immunosuppression' below.)
●At two weeks prior to the scheduled transplant surgery date, we initiate plasmapheresis to achieve a goal isoagglutinin titer of ≤1:8, for both IgM (saline) and IgG (Coombs). We perform alternate-day plasmapheresis (usually on Monday, Wednesday, and Friday) for four to five sessions, depending on the initial isoagglutinin titer. Per center protocol, we generally perform plasmapheresis regardless of baseline isoagglutinin titer, even if the titer is already low at baseline. We perform one plasma volume exchange using 5 percent albumin for each plasmapheresis session.
Some centers have reported successful ABOI transplantation without plasmapheresis when the baseline titer is ≤1:16 [43]. However, severe rejections have been seen in patients with acceptable anti-A/B titers at baseline [54].
In general, the titer can be expected to decrease by one dilution with each session of plasmapheresis. This can be used to estimate the number of plasmapheresis sessions necessary to achieve the target titer. As an example, if the starting titer is 1:128, it will take three plasmapheresis sessions to achieve a titer of 1:16 (1:128 to 1:64, 1:64 to 1:32, and 1:32 to 1:16).
●The final plasmapheresis session is generally performed three to four days before the transplant date. We use 5 percent albumin for replacement. However, when plasmapheresis is performed immediately before or after surgery, replacement with blood type AB or donor-specific plasma is preferable to albumin, to minimize bleeding complications while avoiding passive transfer of relevant blood group antibodies.
●Immediately following the final plasmapheresis session, we give IVIG 2 g/kg (maximum dose 140 g). The optimal dose of IVIG is uncertain, and some transplant centers administer a lower dose (500 mg/kg).
●Upon completion of this desensitization protocol, transplant surgery can be performed.
There is no high-quality evidence in the form of randomized trials to guide the optimal approach to ABO desensitization. Evidence in support of our approach comes primarily from several observational studies showing that a combined approach involving antibody removal (either with plasmapheresis or immunoadsorption), immunomodulation with IVIG, and B cell depletion (with splenectomy or rituximab) is associated with successful ABOI transplantation and overall good patient and graft outcomes [40,42,53,55-61] (see 'Patient and graft survival' below). From these collective data, the following points can be highlighted:
●Both plasmapheresis (conventional plasmapheresis or double-filtration plasmapheresis) and immunoadsorption have been shown to effectively reduce anti-A/B antibody titers prior to ABOI transplantation [40,42,53,55-61]. Early studies found that plasmapheresis alone was not sufficient, and the addition of B cell depletion was required for successful transplantation [50,62]. There are no trials directly comparing the efficacy and safety of these antibody removal modalities. One observational study found a higher risk of postoperative bleeding with plasmapheresis compared with immunoadsorption (13 versus 2 percent) [60].
●IVIG has been a widely used component of desensitization strategies although there are no studies directly comparing protocols with or without the use of IVIG. Immunoadsorption-based and DFPP-based protocols without the use of IVIG have been reported, with no apparent adverse effect on outcomes [42,59]. There are no studies comparing different doses of IVIG for ABO desensitization.
●There are no randomized trials directly comparing rituximab and splenectomy. A systematic review comparing a rituximab-based with a splenectomy-based protocol for ABOI found no significant difference overall in patient survival, graft survival, or allograft function, with single studies demonstrating lower isoagglutinin titers and lower rates of antibody-mediated rejection (ABMR) in the rituximab groups [63]. In a meta-analysis using patient-level data from observational studies, five-year graft survival was 91 percent among patients who received rituximab and 80 percent for those who underwent splenectomy prior to transplantation [64].
●The optimal dose of rituximab used for ABOI transplantation is unclear. One small Japanese study found that single doses of 35 mg/m2 (approximately 100 mg as a single dose) or higher eliminated detectable splenic B cells [65]. Excellent long-term outcomes have been reported with rituximab 100 mg [66], 200 mg [67], 500 mg [68], and 375 mg/m2 [5].
●Successful ABOI transplantation has been reported without anti-CD20 therapy [43], but this practice is not universally accepted. Some reports of ABOI transplants without anti-CD20 therapy have employed posttransplant plasmapheresis for at least two weeks to keep the anti-blood group titer ≤1:16 [69]. This approach is both labor and resource intensive, and there is additional concern that the posttransplant anti-blood group antibody titer may not be a reliable predictor for ABMR [70]. In a case report of two patients who underwent ABOI transplant without desensitization, acute kidney injury was observed before increases in antibody titer, and, ultimately, both patients required allograft nephrectomy within two weeks of transplant [54]. In addition, excessive posttransplant plasmapheresis may increase bleeding and infection risk in these patients.
Transplant immunosuppression
●Induction immunosuppression – The optimal induction immunosuppressive therapy for ABOI transplantation is not known. Our approach to induction immunosuppression in ABOI recipients is the same as that for patients undergoing ABO-compatible transplantation, as discussed elsewhere. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Approach to induction therapy'.)
●Maintenance immunosuppression – In recipients of an ABOI kidney transplant, we administer a triple therapy maintenance immunosuppression regimen that includes a calcineurin inhibitor (tacrolimus), an antimetabolite (mycophenolate), and prednisone. This combination is similar to the initial maintenance immunosuppression used in most ABO-compatible kidney transplant recipients, with the exception that mycophenolate is started four weeks before transplant rather than on the day of transplant surgery. (See 'Our approach to desensitization' above and "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
In ABOI recipients, we target higher whole-blood tacrolimus levels compared with ABO-compatible transplant recipients:
•8 to 12 ng/mL for the first month after transplantation
•5 to 10 ng/mL for subsequent months
Infection prophylaxis — In all ABOI recipients, we administer antimicrobial and antiviral prophylaxis with a regimen that is identical to that administered to recipients of an ABO-compatible transplant. This includes prophylaxis against Pneumocystis pneumonia (PJP) and cytomegalovirus (CMV) infection and disease. We also administer antifungal prophylaxis although this practice may vary by transplant center. In addition, at our institution, we require meningococcal vaccination for all patients undergoing desensitization in the event they need complement inhibitor therapy after transplant. We vaccinate against serogroups A, C, W, and Y and against serogroup B.
A detailed discussion of the different prophylactic regimens and vaccinations is presented separately:
●(See "Prophylaxis of infections in solid organ transplantation", section on 'Pneumocystis pneumonia'.)
●(See "Prevention of cytomegalovirus disease in kidney transplant recipients", section on 'Our approach'.)
●(See "Prophylaxis of infections in solid organ transplantation", section on 'Antifungal prophylaxis'.)
●(See "Meningococcal vaccination in children and adults".)
Monitoring after transplantation — Following ABO desensitization and transplantation, patients are monitored using a similar approach as that used in recipients of ABO-compatible transplants. (See "Overview of care of the adult kidney transplant recipient", section on 'Routine follow-up and laboratory monitoring'.)
In addition, we monitor isoagglutinin titers daily while the patient is in the hospital and two times per week for the first month posttransplant. In patients with a posttransplant isoagglutinin titer ≥1:16, a kidney biopsy and/or preemptive plasmapheresis should be performed, particularly if there is evidence of graft dysfunction (eg, delayed/slow graft function or rising serum creatinine). We do not routinely perform protocol plasmapheresis posttransplant.
We do not perform protocol kidney allograft biopsies in our center. Other transplant centers vary in the use and timing of protocol kidney allograft biopsies. The C4d result must be interpreted with other histologic parameters as well as the clinical scenario in order to distinguish immunologic accommodation versus ABMR. (See 'Immunologic accommodation' below and "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection".)
IMMUNOLOGIC ACCOMMODATION — When exposed to a low titer of anti-A/B antibodies, the kidney allograft develops the ability to resist complement-mediated damage approximately two weeks after transplantation. This phenomenon, known as immunologic accommodation, is characterized by the presence of detectable isoagglutinin titers, AB endothelial antigen expression, and positive peritubular capillary (PTC) C4d staining despite the absence of any histologic evidence of antibody-mediated rejection (ABMR) [71]. The presence of positive PTC C4d staining in ABOI transplantation has been described by others [31,72-74] and appears to have a different connotation than when seen in the setting of ABMR secondary to human leukocyte antigen (HLA) incompatibility.
Based upon these findings, we do not initiate treatment for ABMR based upon an isolated finding of positive PTC C4d staining in ABOI transplantation. When graft dysfunction secondary to ABMR is present in the setting of ABOI transplantation, PTC C4d is likely to be positive, but histologic manifestations associated with ABMR (ie, peritubular capillaritis and/or glomerulitis) are also likely to be present [31].
In one study, histologic changes and C4d staining were examined on surveillance biopsies performed one and five years posttransplant in 73 ABOI, 102 crossmatch-positive, and 652 conventional kidney transplants [75]. At five years, biopsies in ABOI kidneys showed significantly higher rates of C4d deposition compared with crossmatch-positive kidneys (78 versus 19 percent), yet death-censored graft survival was superior (80 versus 71 percent). In addition, estimated glomerular filtration rate (eGFR) in surviving grafts was superior in ABOI compared with crossmatch-positive transplants (51 versus 44 mL/min) and closely resembled that of conventional transplants (48.5 mL/min).
Another analysis found that C4d-positive staining was present in 80 percent of protocol ABOI allograft biopsies and in 58 percent of ABOI biopsies performed for graft dysfunction [73]. There was no correlation between this finding and histologic evidence of ABMR or graft injury.
OUTCOMES OF ABOI TRANSPLANTATION
Patient and graft survival — Compared with ABO-compatible transplantation, ABOI kidney transplantation has been associated with lower graft and patient survival within the first three years posttransplant. However, longer-term graft and patient survival rates after ABOI transplantation appear to be comparable to those after ABO-compatible transplantation [76,77]. The best data come from a 2019 meta-analysis of 40 observational studies that compared patient and graft outcomes among 7098 ABOI kidney transplant recipients and 57,965 ABO-compatible recipients [76]. The following findings were reported:
●Compared with ABO-compatible transplantation, ABOI transplantation was associated with a higher risk of mortality at one (odds ratio [OR] 2.17, 95% CI 1.63-2.90), three (OR 1.89, 95% CI 1.46-2.45), and five (OR 1.47, 95% CI 1.08-2.00) years posttransplant but not at eight or more years posttransplant.
●Death-censored graft survival was lower for ABOI transplant recipients than for ABO-compatible transplant recipients at one (OR 2.52, 95% CI 1.80-3.54) and three (OR 1.59, 95% CI 1.15-2.18) years posttransplant but was comparable between the two groups after five years posttransplant.
Outcomes of transplantation across both ABOI and human leukocyte antigen (HLA) barriers are inferior to those of ABOI transplantation, with increased incidence of early and late acute T cell-mediated rejection and antibody-mediated rejection (ABMR) [21,78].
Cost of ABOI transplantation — While multicenter studies have established ABOI live-donor kidney transplantation as a clinically effective method to expand access to transplantation in Japan and Europe, ABOI transplants remain infrequent in the United States due to concerns for high costs of the necessary preconditioning and posttransplant care. In a study examining the United States Renal Data System records for Medicare-insured, live-donor kidney transplant recipients in 2000 to 2012, compared with recipients of ABO-compatible transplants, ABOI recipients experienced modest reductions in three-year patient and graft survival [79]. The average total costs of ABOI transplant hospitalizations were USD $65,080, compared with USD $36,752 and USD $32,039 for A2 incompatible and ABO-compatible transplant hospitalizations, respectively. Adjusted marginal costs of ABOI remained significantly higher during year 1 (USD $25,044), year 2 (USD $10,496), and year 3 (USD $7307) posttransplant. These findings support broader use of ABOI transplantation to expand access to transplantation, particularly for blood group O candidates. While more expensive than ABO-compatible transplantation and associated with modest reductions in outcomes, the increases in total spending are justified by avoiding long-term dialysis and its associated morbidity and costs.
COMPLICATIONS OF ABOI TRANSPLANTATION
Rejection — ABOI transplantation has been associated with a three- to fourfold increased risk of antibody-mediated rejection compared with ABO-compatible transplantation [76,77]. The incidence of active antibody-mediated rejection (ABMR) after ABOI transplantation has been reported in the range of 10 to 30 percent. ABMR most commonly occurs within the first two weeks after ABOI transplantation.
The diagnosis and treatment of ABMR are presented separately. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection" and "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)
Surgical complications — Higher rates of perioperative bleeding have been observed in recipients of ABOI transplants, likely due to the loss of clotting factors due to the plasmapheresis procedure [76,80-83]. Patients who require a perioperative blood transfusion should receive recipient ABO-type leukocyte-depleted packed red blood cells as indicated.
In addition, a higher rate of lymphoceles (19 to 50 percent) has been reported in ABOI transplant recipients, compared with ABO-compatible transplant recipients [57,76,80,84,85]. The reason for this is unclear although some have attributed it to the early initiation of mycophenolate [86].
Infection — Compared with ABO-compatible recipients, recipients of ABOI kidneys may be at higher risk for infectious complications. One meta-analysis found that ABOI transplantation was associated with a higher risk of sepsis (odds ratio [OR] 2.14, 95% CI 1.37-3.33) compared with ABO-compatible transplantation [76]. Individual studies have also reported that recipients of ABOI kidneys may be at higher risk for pneumonia, urinary tract infections or pyelonephritis, wound infection, and BK polyomavirus nephropathy [42,44,84,87].
Malignancy — ABOI recipients do not have an increased risk of malignancy compared with ABO-compatible transplant patients. In a study of 318 ABOI recipients, seven cancers were diagnosed a median of 3.6 years after transplantation [88]. There was no significant difference in cancer risk between ABOI recipients and matched ABO-compatible controls. Similar findings were reported in another multicenter study of 1420 ABOI transplant recipients [89]. (See "Malignancy after solid organ transplantation".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●Transplant options for ABO incompatibility – Approximately 30 percent of donor and recipient pairs are predicted to be blood type incompatible.
•For kidney transplant candidates who have an ABO-incompatible (ABOI) living donor and would like to utilize this donor, options include ABOI transplantation (if offered by the patient's transplant center) and kidney paired donation (KPD). ABOI transplantation requires desensitization prior to transplant to lower the anti-A/B antibody titers to a level that is not associated with immediate antibody injury to the allograft and allows successful transplantation with commonly used induction and maintenance immunosuppressive regimens. (See 'ABOI transplantation versus kidney paired donation' above.)
•Another option for candidates with blood type B or O is transplantation with a kidney from a blood type non-A1 (A2) donor. Because of the weaker immunogenicity and paucity of expression of the A2 antigen in donor kidneys, transplantation can be performed without pretransplant desensitization. In the United States, the kidney allocation system allows allocation of non-A1 (A2) deceased donors to blood type B recipients. (See 'Blood type non-A1 (A2) donors' above.)
●Approach to ABO-incompatible transplantation – Approaches to ABOI transplantation vary among transplant centers. Our approach is as follows:
•Pretransplant desensitization – For patients who will undergo ABOI transplantation, we suggest pretransplant desensitization with the combination of plasmapheresis (or immunoadsorption, where available), intravenous immune globulin (IVIG), and rituximab rather than plasmapheresis (or immunoadsorption) and IVIG alone (Grade 2C). Our protocol is detailed above. (See 'Our approach to desensitization' above.)
•Transplant immunosuppression – Our approach to induction and maintenance immunosuppression in ABOI recipients is similar to that for patients undergoing ABO-compatible transplantation, with the exception that mycophenolate is started four weeks before transplant rather than on the day of transplant surgery. (See 'Transplant immunosuppression' above.)
•Infection prophylaxis – In all ABOI recipients, we administer antimicrobial and antiviral prophylaxis with a regimen that is identical to that administered to recipients of an ABO-compatible transplant. (See 'Infection prophylaxis' above.)
•Posttransplant monitoring – Following transplantation, patients are monitored using a similar approach as that used in recipients of ABO-compatible transplants. In addition, we monitor isoagglutinin titers daily while the patient is in the hospital and two times per week for the first month posttransplant. In patients with a posttransplant isoagglutinin titer ≥1:16, a kidney biopsy and/or preemptive plasmapheresis should be performed, particularly if there is evidence of graft dysfunction. (See 'Monitoring after transplantation' above.)
●Outcomes – Compared with ABO-compatible transplantation, ABOI kidney transplantation has been associated with lower graft and patient survival within the first three years posttransplant. However, longer-term graft and patient survival rates appear to be comparable. (See 'Outcomes of ABOI transplantation' above.)
●Complications – Complications of ABOI transplantation include higher risks of antibody-mediated rejection (ABMR), perioperative bleeding and lymphoceles, and infectious complications. (See 'Complications of ABOI transplantation' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Christina Klein, MD, who contributed to an earlier version of this topic review.
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