**6. Blood type incompletable (ABOi) renal transplantation**

Blood type or ABO incompatibility (ABOi) poses another barrier to SOT. Earlier attempts to cross the ABO barrier without desensitization failed [65]. It was an absolute contraindication for transplantation due to the higher risk of ABMR and graft failure. However, the shortage of deceased organ availability (especially in Japan) fueled the re-exploration of this avenue. Moreover, approximately one-third of the living donors have ABOi with their potential recipients. ABOi renal transplants are performed globally thanks to desensitization. The outcomes of ABOi renal transplants are comparable to ABO-compatible transplants [66].

Blood group antigens are present on red blood cells, platelets, lymphocytes, endothelial cells, and epithelial cells. Human blood is classified into four blood groups, i.e., A, B, AB and O. Blood group antibodies called isohemagglutinins, are formed against non-self-blood group antigens. For example, an individual with blood group A will have antibodies against B antigens, while a person with blood group O will have antibodies to both A and B antigens.

Blood group O donors can donate to any blood group. In contrast, blood group AB recipients can receive grafts from all blood group types without desensitization. The blood type frequencies in the population vary; however, blood groups A and O are the most common. Renal transplant candidates with blood groups O and B wait longer on the waiting list for compatible donors. In the context of ABOi transplantation, both IgM and IgG isohemagglutinins are clinically relevant.

It is also important to note that individuals with the blood group O produce higher Isohemagglutinins levels than those with blood type A or B. Therefore, the risk of ABMR is higher with blood type O after ABOi transplantation.

Blood type A consists of two sub-groups: A1 and non-A1. A1 type occurs in 80% of the population, while non-A1 is observed in 20% of the US population. The non-A1 type carries low immunologic risk due to lower antigenic expression.

The measurement and reporting of ABO isohemagglutinin vary from center to center [67]. Isohemagglutinins titers are measured by the dilution method. Interpretation of this method is observer-dependent, and the outcomes are semiquantitative. For example, the actual value of isohemagglutinins titer 1:8 could range between 1:4 and 1:32. Some centers use column agglutination technology, but it is expensive.

#### **6.1 Desensitization in ABOi renal transplantation**

The purpose of ABO desensitization is to reduce pre-transplant anti-A/B isohemagglutinins, reducing the risk of ABMR, and allowing successful transplantation. ABO desensitization therapy is commenced well before the transplant surgery. It is offered presently in the living donor set up only. However, sporadic cases of deceased donor ABOi renal transplants are reported [68, 69]. There is a lack of consensus about a standard ABOi desensitization protocol. Therefore, protocols are center specific. However, like HLAi transplantation, most centers use the following treatments in various combinations,

• Aphaeresis—The risk of acute ABMR is high in patients with higher pretransplant isoagglutinin titers [70]. Apheresis reduces the circulating anti-A/B isohemagglutinins to a predetermined titer. Most protocols consider isohemagglutinins titers (IgG and IgM) ≤ 1:8 safe for transplantation. Some centers

perform transplantation with isohemagglutinins titers up to 1:32 [71]. Most centers decline candidates for transplantation with baseline isohemagglutinins titers ≥1:256 for both IgM and IgG using the tube dilution method. One PE session (1.5 plasma volume) reduces isohemagglutinins titer by one dilution. The baseline isohemagglutinins titers help in calculating the dose and frequency of apheresis.


ABO desensitization therapy is commenced before the scheduled surgery date; however, the time and sequence of desensitization therapy varies according to the center.

In our center, a single rituximab dose (500 mg IV) is administered with premedications 2 weeks before surgery. PE is initiated 1 week before the operation. Each exchange is followed by a 100 mg/kg IVIG replacement. Three doses of ATG (1.5 mg/ kg/day) are administered at induction. Patients are maintained on a triple maintenance regimen. A/B isohemagglutinins titers are checked daily for 2 weeks. After a fortnight, the allograft develops immunologic accommodation to low levels of A/B isohemagglutinins and resists complement-mediated damage. Additional PE and renal biopsy are considered with rising isohemagglutinins titers and serum creatinine levels within the first two weeks. Some units commence desensitization and maintenance immunosuppression simultaneously a month before the scheduled surgery. PE has not been considered in some centers if A/B isohemagglutinins titers are ≤1:16 [73], but higher rejection rates are reported with this practice.

There is a lack of high-quality evidence to guide optimal desensitization protocol for ABOi renal transplantation; however, non-randomized studies data show the efficacy of the combination therapies described above. Plasma exchange and immunoadsorption effectively remove isohemagglutinins [74]. Although IVIG is used in most ABOi desensitization protocols, this practice has not been trialed in randomized studies. Moreover, the optimal dose of IVIG is also not clearly defined. Rituximab and splenectomy are not directly studied. A systematic review showed similar graft and patient survival comparing splenectomy-based and rituximab-based protocols [75]. Some researchers have reported successful ABOi renal transplantation without using rituximab; however, they employed daily plasmapheresis for at least 2 weeks to keep isohemagglutinins titers ≤1:16 [76].

#### **6.2 Outcomes and cost of ABOi renal transplantation**

The risk of complications is high in the first few years after ABOi renal transplantation. A meta-analysis reported higher mortality in the first 3 years after an ABOi transplant vs. ABO compatible renal transplant [77]. However, this difference fails to exist at 8 years or more. Similarly, death-censored graft survival was low in ABOi vs. ABO compatible transplants, but this difference equalizes after 5 years. Furthermore, the risk of surgical complications, rejection, infections, and malignancy is higher in ABOi compared to ABO-compatible transplants.

The outcomes of ABOi and HLAi transplants are inferior to compatible transplants. However, desensitization is justified in selected patients due to long waiting time, high mortality on dialysis and low access to compatible donors.

ABOi renal transplantation bears a higher monetary cost. The average total cost of hospitalization was \$65,080 for ABOi vs. \$32,039 for compatible transplants [78]. However, the benefits of ABOi transplants outweigh its higher cost in the long run. Due to suboptimal outcomes, efforts should be made to avoid ABO incompatible transplantation; however, if it is not possible, ABOi transplantation with desensitization is an alternative.
