INTRODUCTION — Tissue and blood incompatibility have traditionally been absolute contraindications to transplantation. This was based on the historically poor outcomes when transplantation was attempted across tissue and ABO blood type barriers. In addition, improvement in results using deceased-donor allografts (DDAs) limited enthusiasm for ABO blood group incompatibility (ABOI) transplantation in the United States in the past. However, an extreme lack of available deceased-donor kidneys encouraged investigation into desensitization for ABOI/living-donor allografts (LDAs) in Japan. Data from Japan demonstrating successful long-term results combined with subsequent successful results from ABOI desensitization protocols in the United States and elsewhere have renewed interest in this procedure [1-8].
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. A discussion of the diagnosis and treatment of acute antibody-mediated rejection (ABMR) is presented separately. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)
ABO BLOOD GROUPS AND ANTIGENS — 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 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 (DDA) list is markedly prolonged for patients with blood group B or O [9].
In addition, blood group O individuals tend to have higher isoagglutinin antibody titers to both the A and B antigen as compared with the formation of anti-B by blood group A individuals or anti-A by blood group B individuals. (See "Red blood cell antigens and antibodies", section on 'ABO blood group system'.)
Blood type O recipients have a higher incidence of antibody-mediated rejection (ABMR) following ABOI transplantation [10]. The initial titer of the anti-A or -B isoagglutinin antibody, rather than the antigen targeted (A1, A2, or B), was initially reported to correlate with the risk of ABMR in such cases [4,11-14]. It is not clear whether the titer is as significant in the current era of immunosuppression. The incidence of acute ABMR after ABOI has been reported in the range of 10 to 30 percent.
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 [15]. 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 [15]. Given the lower immunogenic risk of the A2 antigen, donor A2 kidneys can generally be successfully transplanted into recipients with low pretransplant anti-A titers without the use of desensitization [11,12,16-19]. 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 [20,21]. 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 [22]. Acceptance of A2 kidneys is optional for the candidate.
Isoagglutinin antibody titers — It was initially reported that higher baseline isoagglutinin antibody titers predispose to an increased risk of ABMR. It is unclear whether a significantly elevated baseline antibody titer predisposes to a poor long-term outcome, given initial successes through desensitization. Furthermore, although elevated isoagglutinin titers are generally observed during acute ABMR, the positive predictive value of elevated posttransplant titers is poor, with high titers seen in otherwise stable ABOI recipients [23].
There is a marked difference in the reporting of antibody titers among institutions. The classic tube dilution method is most commonly used to report an immunoglobulin M (IgM) isoagglutinin titer and a total isoagglutinin titer. These have commonly been reported in the literature as an IgM and immunoglobulin G (IgG) titer but actually represent IgM and total titer. In addition, given observer variation, the reported result should be considered an approximation. Thus, a titer reported at 1:128 may represent a titer of 1:64 to 1:256.
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 [24].
Most centers also use plasmapheresis or immunoadsorption to maintain an isoagglutinin titer ≤1:16 during the critical two-week period following ABOI transplantation. If fresh frozen plasma (FFP) replacement is required as a result of plasmapheresis treatment, donor blood type or AB donor FFP should be given to avoid the administration of anti-allograft isoagglutinin antibodies. (See 'Monitoring after transplantation' below.)
ABO DESENSITIZATION
Overview of desensitization — The overall goals and purpose of ABO desensitization are to lower the immunogenicity of the incompatibility to allow for successful transplantation with commonly used induction and maintenance immunosuppressive regimens. 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, typically with extracorporeal methods such as plasmapheresis or immunoadsorption (see 'Removal of circulating ABO antibodies' below)
●Immunomodulation of the recipient immune system, typically with intravenous (IV) immune globulins (IVIG) (see 'Immunomodulation' below)
●Depletion of the B cell population responsible for ABO antibody production, most commonly with the anti-CD20 agent rituximab (see 'B cell depletion' below)
Regimens using plasmapheresis and low-dose IVIG alone may be equally effective compared with those involving anti-CD20 therapy or, less commonly, splenectomy [25,26]. In one single-center study, outcomes with initial ABOI protocols involving splenectomy and/or pretransplant rituximab in addition to plasmapheresis and IVIG (32 patients) were compared with their current protocol of plasmapheresis and IVIG alone (28 patients) [26]. Graft survival and rates of antibody-mediated rejection (ABMR) were similar in both groups.
Although long-term follow-up is needed, these reports suggest that attention to the isoagglutinin titer at the time of transplantation and routine posttransplant antibody reduction with either plasmapheresis or immunoadsorption may significantly reduce the risk of ABMR and allow for the elimination of splenectomy and rituximab from the ABOI desensitization protocol.
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 [26-29]. 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".)
Although plasmapheresis and immunoadsorption are commonly employed in ABOI transplantation, there is no high-quality evidence in the form of randomized trials to support their use in this setting. The choice of technique is related to availability, cost, and comfort with the technique. Plasmapheresis and ABOI transplantation are associated with an increased rate of bleeding complications [30].
Immunomodulation — 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 (FcR) to prevent a rebound in anti-A/B antibody titers when the plasma cells have naked receptors and, therefore, are stimulated to make more antibody. IVIG may also have immunoregulatory properties. It should be noted, however, that IVIG products may contain detectable anti-A and anti-B isoagglutinins [27,31], which should be considered if high-dose IVIG is administered.
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. Splenectomy, which was historically used for this purpose [32-35], is no longer used in most countries. However, splenectomy may remain an effective treatment for refractory ABMR [36]. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)
The utility of routine rituximab administration remains uncertain. Rituximab has been reported to allow successful ABOI transplantation when added to a standard protocol in patients otherwise resistant to other desensitization procedures [37]. Despite an absence of detectable splenic B cells after rituximab administration, plasma cells remain as the majority of plasma cells lack CD20 receptors [37,38]. While the intact plasma cells are able to produce isoagglutinin antibodies, the deletion of plasma cell precursors may decrease the risk of ABMR if used in conjunction with other antibody-depleting measures.
In a systematic review of the use of rituximab for desensitization in kidney transplantation, nine studies were identified comparing a rituximab-based with a splenectomy-based protocol for ABOI and found no significant difference overall in patient survival, graft survival, or allograft function, with single studies demonstrating lower isoagglutinin titers and lower rates of ABMR in the rituximab groups [39]. A meta-analysis using patient-level data from observational studies demonstrated a five-year graft survival of 91 percent (95% CI 78.1-93.2) among patients who received rituximab compared with 80.2 percent (95% CI 48.3-92.5) for those who underwent splenectomy prior to transplantation [40]. However, there are no randomized trials that have directly compared rituximab and splenectomy.
The specific dose of rituximab required in this setting is unclear. In a Japanese study, five ABOI kidney transplant recipients received one dose of rituximab (at 10, 15, 35, 150, or 300 mg/m2) 3 to 13 days before transplantation, while one patient did not receive rituximab [41]. B cells were completely eliminated from the circulation within 30 days with every dose except for 10 mg/m2 given once. Single doses of 35 mg/m2 (approximately 100 mg as a single dose) or higher eliminated detectable splenic B cells.
Patient selection — ABOI transplant candidates must meet center-specific, general transplant candidate selection criteria (see "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient") in addition to ABOI-specific criteria. There are no established ABOI-specific selection criteria for recipients. At our institution, patients must satisfy the following criteria:
●The patient must have an initial ABO isoagglutinin titer of ≤1:128. At some transplant centers, an initial titer of ≤1:256 may be acceptable.
●The patient must be willing to undergo ABOI transplantation and all the therapies associated with ABOI transplantation. (See 'ABO-incompatible transplant protocol' below.)
●The patient must not be undergoing concurrent human leukocyte antigen (HLA) desensitization. However, this practice may vary from center to center, and simultaneous HLA incompatible and ABOI transplants are performed at some institutions. (See "Kidney transplantation in adults: HLA desensitization".)
●The patient must have prior authorization from his or her insurance company for all therapies associated with ABOI transplantation.
ABO-incompatible transplant protocol — In patients who will undergo ABOI transplantation, we use a desensitization protocol that begins one month prior to the scheduled transplant surgery and involves the combination of rituximab, plasmapheresis, and IVIG to deplete B cells and reduce circulating anti-A/B antibody levels. Transplantation is performed when the isoagglutinin antibody titer is ≤1:8.
Pretransplant desensitization — Desensitization prior to ABOI transplantation begins one month prior to the scheduled transplant surgery. Our approach is as follows:
●At four weeks prior to the scheduled transplant surgery date, we administer a single dose of rituximab 200 mg. We premedicate for rituximab with IV methylprednisolone 250 mg, acetaminophen 325 mg given orally, and diphenhydramine 25 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 (mycophenolate mofetil [MMF] 500 mg twice daily). We initiate antimicrobial and antiviral prophylaxis with trimethoprim-sulfamethoxazole and acyclovir (both dose adjusted for kidney function), respectively.
●At two weeks prior to the scheduled transplant surgery date, we obtain an isoagglutinin titer and a final crossmatch. Based upon the isoagglutinin titer results, we plan for pretransplant plasmapheresis to achieve a goal isoagglutinin titer of ≤1:8 by the time of transplant surgery, although the goal titer may vary depending upon the transplant center. Thus, if an ABO blood type A recipient is to receive a kidney from an ABO blood type B donor and the anti-B titer is 1:4, then plasmapheresis is not necessary. 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 1:64, it will take three plasmapheresis sessions to achieve a titer of 1:8 (1:64 to 1:32, 1:32 to 1:16, and 1:16 to 1:8).
●We admit patients three to four days prior to the scheduled transplant surgery date, depending upon the isoagglutinin titer and how many plasmapheresis sessions are planned. Once the patient is admitted, we obtain measurements of serum creatinine, electrolytes, a complete blood count, prothrombin time (PT) and international normalized ratio (INR), activated partial thromboplastin time (aPTT), and isoagglutinin titer. We monitor serum creatinine and electrolytes, complete blood count, and isoagglutinin titer on a daily basis while the patient is admitted.
We perform daily plasmapheresis, typically using 1.5 volume exchanges with 5 percent albumin replacement with each plasmapheresis session. If fresh frozen plasma (FFP) is needed for replacement due to an elevated INR, the FFP should be ABO type AB/male to prevent infusion of anti-donor antibodies or donor specific if AB plasma is unavailable.
We give IVIG 10 grams after each plasmapheresis session, except after the final session prior to transplant, to replace immunoglobulins removed with plasmapheresis and to prevent rebound antibody formation. Alternatively, we administer two units of donor blood type or AB-negative blood type plasma. Each unit contains approximately 5 grams of immunoglobulin G (IgG). The use of plasma replacement also acts to replace clotting factors lost with the pheresis procedure. At the last plasmapheresis session prior to transplant, IVIG is administered as 500 mg/kg, rounded to the nearest 10 grams. This is given to correct the preoperative hypogammaglobulinemic state induced by plasmapheresis.
●Upon completion of this desensitization protocol, transplant surgery can be performed.
Induction therapy — The optimal induction therapy in patients receiving a kidney transplant from an ABOI donor is not known. We prefer to use rabbit antithymocyte globulin (rATG)-Thymoglobulin as part of an induction immunosuppressive regimen in these patients. This is discussed in more detail elsewhere:
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 'Pretransplant desensitization' above and "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Initial maintenance immunosuppression in high-risk patients'.)
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
Monitoring after transplantation — Following ABO desensitization and transplantation, patients are monitored using the same approach as that used in recipients of ABO-compatible transplants (see "Kidney transplantation in adults: 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, two to three times per week for the first month posttransplant, weekly for months 2 to 3 posttransplant, and then yearly thereafter. 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, irrespective of the isoagglutinin titer.
Transplant centers vary in the use and timing of protocol renal allograft biopsies. We perform protocol biopsies (unless contraindicated) in all ABOI transplant recipients at 14 days and again at one year posttransplant. 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 renal allograft rejection", section on 'Active (acute) antibody-mediated rejection'.)
Immunologic accommodation — 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 ABMR has been thought to represent ABOI immunologic accommodation [42]. The presence of positive PTC C4d staining in ABOI transplantation has been described by others [4,43-45] and appears to have a different connotation than when seen in the setting of ABMR secondary to HLA incompatibility.
Based upon the findings from one study [5], the authors stated that they no longer recommend initiation of therapy targeting 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 are also likely to be present [4].
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 [46]. At five years, biopsies in ABOI kidneys showed significantly higher rates of C4d deposition, compared with crossmatch-positive kidneys (77.8 versus 18.9 percent), yet death-censored graft survival was superior (79.5 versus 70.7 percent). Additionally, estimated glomerular filtration rate (eGFR) in surviving grafts was superior in ABOI, compared with crossmatch-positive (51.3 versus 44.4 mL/min), and closely resembled 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 [44]. There was no correlation between this finding and histologic evidence of ABMR or graft injury. Although unable to ascertain with certainty given the small sample size in this analysis, positive C4d staining in ABOI allografts may correlate with antibody-mediated graft injury. Whether the early presence of PTC C4d in these protocols impacts long-term graft function remains to be determined.
COMPLICATIONS
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 pheresis procedure [47-50]. An international normalized ratio (INR) of ≤3 is generally acceptable for transplant surgery. In patients who have an INR >3 at the time of surgery, we administer four units of donor-specific ABO-type or AB/male fresh frozen plasma (FFP) to lower the INR to ≤3 prior to the operation. 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 [47,51-53]. The reason for this is unclear, although some have attributed it to the early initiation of mycophenolate [54].
Infection — Compared with non-ABOI recipients, recipients of ABOI kidneys may be at higher risk for infectious complications including pneumonia, urinary tract infections, and/or pyelonephritis, wound infection, and BK nephropathy [28,30,51,55]. 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 (PCP), cytomegalovirus (CMV) infection and disease, and herpes simplex infection (in patients who are at low-CMV risk). In addition, we also administer antifungal prophylaxis, although this practice may vary by transplant center. A detailed discussion of the different prophylactic regimens is presented separately:
●(See "Prophylaxis of infections in solid organ transplantation", section on 'Pneumocystis pneumonia'.)
●(See "Prevention of cytomegalovirus disease in kidney transplant recipients".)
●(See "Prophylaxis of infections in solid organ transplantation", section on 'Antifungal prophylaxis'.)
Malignancy — Despite the use of more intensive induction immunosuppression in ABOI transplantation, 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 [56]. 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 [8]. (See "Malignancy after solid organ transplantation".)
OUTCOMES
Graft and patient 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. 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 [57]. 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.
●ABOI transplantation was associated with a higher risk of sepsis (OR 2.14, 95% CI 1.37-3.33) compared with ABO-compatible transplantation. However, there were no differences in the risks of urinary tract infections, cytomegalovirus (CMV) infection, BK polyomavirus (BKPyV) infection, and Pneumocystis pneumonia between the two groups.
●The risks of surgical revision (OR 1.92, 95% CI 1.65-2.23), bleeding or hematomas (OR 1.76, 95% CI 1.18-2.63), and lymphoceles (OR 2.10, 95% CI 1.41-3.12) were higher among ABOI transplant recipients compared with ABO-compatible transplant recipients.
●There was no difference in the risks of overall, borderline, or T cell-mediated (cellular) rejection between the groups; however, ABOI transplantation was associated with a higher risk of antibody-mediated rejection (ABMR; OR 3.06, 95% CI 1.97-4.75).
Similar findings were described in another meta-analysis of 26 single-center cohort studies that compared graft and patient outcomes among 1346 ABOI kidney transplant recipients and 4943 center-matched ABO-compatible controls [58]. Older studies in which ABOI transplant recipients underwent splenectomy were excluded from the analysis. One-year uncensored graft survival was 96 percent among ABOI transplant recipients compared with 98 percent among ABO-compatible controls (relative risk [RR] 0.97, 95% CI 0.96-0.98). However, among ABOI grafts that survived beyond one year posttransplant, graft survival was comparable with that of ABO-compatible controls. One-year patient survival was lower among ABOI transplant patients (98 versus 99 percent), and more deaths in ABOI transplant recipients were caused by infection compared with ABO-compatible controls (49 versus 13 percent). Biopsy-proven rejection, particularly ABMR (RR 3.9, 95% CI 2.1-7.3), as well as severe nonviral infection and bleeding were more common among ABOI transplant recipients.
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 ABMR [24,59].
Costs of ABO-incompatible transplant — While multicenter studies have established ABOI live-donor kidney transplantation as a clinically effective method to expand access to transplantation commonly used 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 [60]. 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.
KIDNEY PAIRED DONATION — An alternative to ABOI is the use of a kidney paired donation (KPD) program. Willing participants can choose to allow either an ABOI donor in one case to donate his or her kidney to an alternate recipient with an ABO- or human leukocyte antigen (HLA)-incompatible donor through KPD [61-63]. (See "Kidney transplantation in adults: Kidney paired donation".)
This process avoids the need for desensitization and provides a living-donor allograft (LDA) to each recipient. Obviously, both parties 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 programs can help provide allografts to a select number of individuals. In a single-center study, for example, marked success was reported among 22 patients who received 10 paired donations, including two triple exchanges [64]. However, this approach is unlikely to have a significant impact on reducing the waitlist time when the exchange program is confined to an individual transplant center.
Increasing the exchange programs on a national level has expanded the number of suitable donor pairs considerably. This was first shown in a modeling study in which the success of such programs was analyzed using increasing population sizes [65]. In the United States, there are currently three national kidney exchange programs: the United Network for Organ Sharing (UNOS), the National Kidney Registry, and the Alliance for Paired Donation.
The use of donor exchange programs to perform waitlist exchange (wherein the incompatible donor donates to an individual on the waiting list and the incompatible recipient moves to the front of the waitlist), as compared with paired exchange, is somewhat controversial. This process may result in even longer delays for those patients already with the longest wait times, in particular blood group O recipients. Such a strategy may not be acceptable to some patients, particularly those with blood group O [66].
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
●Tissue and blood incompatibility have traditionally been absolute contraindications to transplantation. This was based on the historically poor outcomes when transplantation was attempted across tissue and ABO blood type barriers. However, data from Japan demonstrating successful long-term results of ABO blood group-incompatible (ABOI) kidney transplantation combined with subsequent successful results from ABOI desensitization protocols in the United States and elsewhere have renewed interest in this procedure. (See 'Introduction' above.)
●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 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 (DDA) list is markedly prolonged for patients with blood group B or O. (See 'ABO blood groups and antigens' above.)
●The overall goals and purpose of ABO desensitization are to lower the immunogenicity of the incompatibility to allow for successful transplantation with commonly used induction and maintenance immunosuppressive regimens. Although there is no uniformly accepted ABO desensitization protocol, most commonly used protocols employ a combination of the following strategies (see 'Overview of desensitization' above):
•Removal of circulating ABO antibodies, typically with extracorporeal methods such as plasmapheresis or immunoadsorption (see 'Removal of circulating ABO antibodies' above)
•Immunomodulation of the recipient immune system, typically with intravenous (IV) immune globulins (IVIG) (see 'Immunomodulation' above)
•Depletion of the B cell population responsible for ABO antibody production, most commonly with the anti-CD20 agent rituximab (see 'B cell depletion' above)
●ABOI transplant candidates must meet center-specific, general transplant candidate selection criteria in addition to ABOI-specific criteria. There are no established ABOI-specific selection criteria for recipients. At our institution, patients must satisfy the following criteria (see 'Patient selection' above):
•The patient must have an initial ABO isoagglutinin titer of ≤1:128. At some transplant centers, an initial titer of ≤1:256 may be acceptable.
•The patient must be willing to undergo ABOI transplantation and all the therapies associated with ABOI transplantation.
•The patient must not be undergoing concurrent human leukocyte antigen (HLA) desensitization. However, this practice may vary from center to center, and simultaneous HLA incompatible and ABOI transplants are performed at some institutions.
•The patient must have prior authorization from his or her insurance company for all therapies associated with ABOI transplantation.
●In patients who will undergo ABOI transplantation, we use a desensitization protocol that begins one month prior to the scheduled transplant surgery and involves the combination of rituximab, plasmapheresis, and IVIG to deplete B cells and reduce circulating anti-A/B antibody levels. Transplantation is performed when the isoagglutinin antibody titer is ≤1:8. (See 'ABO-incompatible transplant protocol' above.)
●The optimal induction therapy in patients receiving a kidney transplant from an ABOI donor is not known. We prefer to use rabbit antithymocyte globulin (rATG)-Thymoglobulin as part of an induction immunosuppressive regimen in these patients. This is discussed in more detail elsewhere:
●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 "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Initial maintenance immunosuppression in high-risk patients'.)
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
●Following ABO desensitization and transplantation, patients are monitored using the same approach as that used in recipients of ABO-compatible transplants. In addition, we monitor isoagglutinin titers daily while the patient is in the hospital, two to three times per week for the first month posttransplant, weekly for months 2 to 3 posttransplant, and then yearly thereafter. 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, irrespective of the isoagglutinin titer. We perform protocol biopsies (unless contraindicated) in all ABOI transplant recipients at 14 days and again at one year posttransplant. (See 'Monitoring after transplantation' above.)
●Complications of ABOI transplantation include higher rates of perioperative bleeding and lymphoceles and possibly a higher risk of infectious complications. ABOI recipients do not have an increased risk of malignancy compared with ABO-compatible transplant patients. (See 'Complications' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Christina Klein, MD, who contributed to an earlier version of this topic review.
