Renal transplant across an ABO barrier

A 24 year-old ESRD patient secondary to IgA nephropathy has been on HD for almost one year. His mother is a potential donor for living related kidney transplant. The condition seemed perfect—zero mismatch on HLA, no PRA, no DSA—except for ABO-incompatibility. Type O in the recipient and type A in the donor.

What are ABO antigens, and where are they expressed?
 ABO antigens, discovered by Karl Landsteiner in 1901, are glycoprotein antigens, expressed not only on the surface of red blood cells, but also on endothelial cells, and epithelial cells.

Why is ABO incompatibility a relative contraindication to transplantation? 
As noted above, ABO antigens are expressed on the donor kidney, and can be a target of antibody-mediated rejection. The first ABO-incompatible kidney transplant (ABOi KT) was performed in mid 1950s and ended up with hyperacute rejection (HAR). Therefore, this procedure was considered as a contraindication until recently. The concept of depleting anti-AB Abs was introduced in early 1980s, leading to successful ABOi KT by Alexandre et al., followed by great effort in Japan to improve outcomes, where ABOi KT now consists of 30% of living donor KT. Nowadays, ABOi KT is becoming a reasonable option in the US as well.

What is the usual immunosuppressive protocol to transplant these patients? Are ABO antibody titers important for determining the feasibility of transplant? 
Unfortunately, there are no randomized controlled trials for the pre-transplant conditioning regimens for ABOi KT. However, the basic idea of overcoming ABO-incompatibility is decreasing the circulating ABO antibodies via combination of (1) antibody depletion (e.g. plasmaphresis) (2) IVIG, (3) Rituximab or splenectomy. Pre-transplant ABO antibody titers should be taken into consideration, which generally should be 1:16 or lower, although the number is exclusively based on empirical evidence. Interestingly, there may be no correlation with baseline antibody titers and graft survivals. For maintenance immunosuppressive regimen, therapy, there is no need for higher intensity of immunosuppression compared to ABO compatible KT.

What are the potential complications?
Initially, HAR was the largest concern for ABOi KT, but is not major concern with the use of current desensitization protocols . Antibody-mediated hemolysis and delayed antibody-mediated rejection are potential complications. Therefore, post-transplant monitoring of AB antibody titers is usually recommended. Of note, however, in the setting of ABOi KT, peritubular capillary C4d deposition alone is not diagnostic as this can be observed even in 80% of fully functioning grafts, called “accommodation”, the mechanism of which is not fully understood.

How good are the long-term outcomes of transplants crossing an ABO barrier? 
Reports showed long-term graft survival of ABO-incompatible renal transplants are the same as those of ABO-matched transplants. One report from Japan showed that the overall patient survival rate was 97% for the first year and 95%, 93% and 90% for 3, 5 and 9 years after surgery, respectively. The 1-year graft survival rate was 93%, and that for 3, 5 and 9 years was 89%, 84%, and 72%, respectively. Of note, Montgomery et al.  reported no difference in long-term patient survival but suggested more graft loss in the first 14 days after transplantation.

Going back to our case, the patient went through plasmapheresis and two doses of rituximab injections (150 mg/m2, on POD #-14 and -1) as a pre-conditioning regimen. This was followed by a successful ABOi KT using Basiliximab as induction therapy, FK/MMF/Prednisone as maintenance regimen with excellent graft function months after transplant.

Naoka Murakami
Leonardo V. Riella