What Can the Developing World (and Others) Learn From the Indian Experience in Crossing the ABO Blood Group Barrier in Kidney Transplantation.

Due to the organ shortage, several programs, predominately in Japan and the United States, including Mayo Clinic, developed protocols to cross the ABO blood group barrier.1-3 These protocols aimed to reduce pretransplant isohemagglutinin titers to avoid acute or hyperacute antibody-mediated rejection with careful posttransplant monitoring to detect, and intervene on, rebounding levels. Isohemagglutinin removal is achieved either by plasma exchange (PLEX) or immunoadsorption (IA). Intense immunosuppression to avoid rebound of isohemagglutinins included both T-cell and B-cell depletion, splenectomy, and initiating maintenance immunosuppression pretransplant.2,4 With ABO incompatible (ABOi) transplants, the risks above and beyond compatible (ABOc) transplants lie in the interventions needed to lower isohemagglutinins levels (PLEX or IA), augmented immunosuppression, and acute antibody-mediated rejection. Fortunately, unlike anti–HLA antibodies, the long-term survival of ABOi kidney transplants that escape the early period does not seem to be compromised by the ongoing presence of isohemagglutinins and visible C4d staining—a poorly understood process termed accommodation. The outcomes of ABOi have evolved over time.5-7 Compared with remaining on the waitlist, they appear to provide a survival advantage. Compared with ABOc transplants, the findings are varied. Some studies show similar outcomes, whereas others show higher risks of infections and worse patient survival. Consistent, however, are the increased cost and the peritransplant risks. With wider adoption of Kidney Paired Exchange (KPD), the default in many programs, including ours, is to avoid ABOi transplants. A possible exception is an ABOi but with well-matched HLA donors for highly sensitized recipients. The lower antigenicity of A2 kidneys has also been leveraged in the kidney allocation system in the United States to address the disproportionately long waiting times for blood group B recipients. Programs and patients can accept an A2 to B allocation if they are willing and meet center-specific criteria. In this issue, Kute et al8 present the Indian experience with ABOi transplants. The authors brought together 25 centers (2 public and 23 private) to compile retrospective data pertaining to 1759 ABOi and 33 157 ABOc transplants performed between 2011 and 2022. As expected in a retrospective study with no prior study protocol, the authors found a wide variation in practice among centers and in some instances within one center. Most patients underwent isohemagglutinin removal via PLEX, but a small subset received IA therapy (8%). This was due to location, practice, and financial attributes. There was a wide variation in isohemoagglutinins titers at baseline and at time of transplant, but a large proportion was ≤1:512 to be considered for desensitization and <1:16 at the time of transplant. The variability was attributed to center expertise and comfort level. Over time the use of rituximab diminished, driven by a desire to reduce immunosuppression and risk of infection, noting no added benefit, and cost. The authors did not find a relationship between titers and graft outcome. They did notice a change during the pandemic with a higher risk of graft loss prepandemic but higher risk of rejection during the pandemic. The former due to the learning curve and the latter was attributed to logistic difficulties of follow-up and obtaining immunosuppression during the pandemic surges. Noteworthy is that 505 (29%) ABOi transplants were performed during the pandemic. Overall, the commonest cause of graft loss was due to patient death, most commonly infectious, but the authors deemed infections comparable to the usual seen in developing nations. It should be noted that 19 patients developed severe coronavirus disease with 11 (58%) succumbing. There was no observed difference in patient or graft survival between ABOc and ABOi transplants. Of note is that this was based on univariate analyses and the ABOc group had a higher proportion of retransplants, sensitized patients (11% versus 2%), and obstructive uropathy, among other differences that preclude a definitive conclusion. Patients lost to follow-up within 30 d of transplant were excluded from the study, which could have disproportionately censored ABOi graft losses. The data do not show the number of subjects who may have been turned down for ABOi transplants or who may not have reached the desired pretransplant titers. One public center in the study performed 484 of 848 KPD transplants (57%) indicating the potential opportunity for greater adoption of KPD among centers. The study authors are commended for bringing together so many centers in this collaboration. They have shown the breadth and depth of ABOi transplantation in a large, diverse nation with challenges that exist in many parts of the world. The data do not provide sufficient actionable items that would help centers develop their own ABOi protocols given the marked variation of practices, not subtyping blood group A in most cases, possible recall bias, and lack of baseline registry data. Although the A2 is rarer in the Indian population,9,10 without subtyping blood group A donors, some A to B or A to O transplants could be A2 (none A1) that would have a markedly reduced reactivity. Using higher titers at time of transplant would be concerning given the lack of standardization and benchmarking of testing even with the same techniques. Although only 2 patients, A1 to A2B and A1B to A2B would be considered ABOc by many centers and would be expected to have the same outcome as ABOc transplants. With these limitations, it is not possible to define the best practice. We see from this experience, the benefit of having national registries that collect data systematically and consistently such as the Australia and New Zealand Dialysis and Transplant Registry and the United Network for Organ Sharing. Expanding KPD programs and developing national KPD networks would help increase access to compatible transplants, reduce costs, and avoid the need for desensitization procedures with their attendant risks. Including parameters such as avoiding preformed HLA antibodies, prior HLA exposure, cytomegalovirus or Epstein-Barr virus mismatch, size, and age mismatch, may provide a benefit for blood group compatible pairs to participate. Would there still be a role for ABOi transplants? Yes, but it would be better to avoid when possible.