ABO-Incompatible Transplantation: Less May Be More

Abstract

Many have reported success with ABO-incompatible kidney transplantation using B-cell ablative therapies such as anti-CD20 and splenectomy. However, splenectomy and anti-CD20 is associated with an increased risk of infection. We show how ABO-incompatible kidney transplants can be accomplished with a low risk of antibody-mediated rejection and graft loss using plasmapheresis preconditioning, low-dose intravenous immunoglobulin, and standard maintenance immunosuppression. The mean follow up for our cohort of 53 patients is 2 years. The mean creatinine clearance at 1 and 3 years is 58 mL/min and 63 mL/min, predicting excellent long-term function. Only long-term follow up of these patients will render definitive answers, however, these data demonstrate that ABO-incompatible kidney transplantation increases the donor pool by providing live donor kidneys that function promptly with minimal risk of early loss. This can be accomplished with a modest, brief escalation of immunosuppression and at a lower cost to the health care system than maintaining the patient on dialysis

Blood type incompatibility, once thought to be a formidable barrier to renal transplantation, can be crossed with excellent results and without the need for splenectomy or B-cell ablative therapy that might place patients at increased risk of infection or malignancies. In our cohort of incompatible recipients, splenectomy and anti-CD20 both were associated with a doubling of the risk of infection when compared with matched controls (unpublished data). ABO-incompatible (ABOi) transplants can be accomplished with a low risk of antibody-mediated rejection (AMR) and graft loss using plasmapheresis preconditioning, low-dose intravenous immunoglobulin, and standard maintenance immunosuppression (¹). The mean follow-up for our cohort of 53 patients (Table 1) is still relatively short at 2 years (our unpublished data). The mean creatinine clearance at 1 and 3 years is 58 mL/min and 63 mL/min, respectively, predicting excellent long-term function. The median chronic allograft nephropathy scores at 1 year are 4, which is consistent with other protocol biopsy studies of compatible live donors. Only long-term follow up of these patients will render definitive answers; however, these data demonstrate that ABOi transplantation increases the donor pool by providing live donor kidneys that function promptly with minimal risk of early loss. This can be accomplished with a modest, brief escalation of immunosuppression and at a lower cost to the health care system than maintaining the patient on dialysis (²).

TABLE 1: Patient cohort

The study also outlines the evolution of our desensitization therapy from one that uses heavy immunosuppression including splenectomy and anti-CD20 to a protocol that would be predicted to gain wider acceptance by eliminating potent, costly, and long-lasting anti-B-cell interventions. We perform subgroup analysis showing that there does not appear to be a price to be paid in terms of outcomes by eliminating first splenectomy and then anti-CD20. Patients with a combined positive crossmatch and ABOi and highly sensitized patients with ABOi, HLA identical siblings also have excellent outcomes after desensitization (³). The death-censored graft survival at 1 and 3 years is 100% and 93.4%, respectively. The patient survival rate is 97.6%. The results of this study are dramatic and challenge the existing paradigm that blood type incompatibility is a significant barrier to renal transplantation.

There are currently three possible options available to a patient whose only willing donor is ABOi: waiting on the deceased donor list, kidney paired donation (KPD), or desensitization (⁴). The average waiting time in the United States for an O recipient is 5.2 years (data: UNOS 10/20/06). Patients who receive a transplant rather than remaining on dialysis on average double their life expectancy (⁵). Kidneys from live donors have a predicted half-life that is twice that of a deceased donor organ. Waiting on the deceased donor list when the possibility of a live donor exists is a poor choice in most instances. In KPD, incompatible pairs are matched to produce compatible transplants. Although avoiding the incompatibility completely through KPD is perhaps the best alternative, not every ABOi pair can be matched (⁶). The most common ABOi is an A donor and an O recipient. Because an O recipient can only receive a kidney from an O donor, these pairs need to be matched with positive crossmatch pairs in an unconventional KPD. This also requires that the reciprocal crossmatch with the sensitized patient is negative. KPD simulation experiments have shown that under the very best circumstances, with a large pool and optimized matching algorithm, more than 50% of patients will not find a match (⁷). Additionally, there have only been 145 KPDs performed in the United States since the first took place in 2000 (data: UNOS). Efforts by consortia and regional matching programs have had a very limited impact during the past 6 years.

At the current time, ABOi may be the only transplant option for most patients with blood type-incompatible live donors. The largest barrier to ABOi transplantation has been the perceived requirement for splenectomy (⁸). Results from our group and others show that there is no reduction in graft survival even among patients traditionally thought to be at high risk by eliminating splenectomy and substituting anti-CD20 (^{9, 10}). The use of anti-CD20 in transplantation is recent and efficacy is unproven, although the drug has been widely embraced. We do not know what additional risks are posed by adding this therapy to antibody depletion but, in most circumstances, more immunosuppression has translated into greater risk of complications. We have recently eliminated anti-CD20 from our standard protocol without experiencing any increase in AMR and while maintaining excellent early function. The median follow up is 18 months for this cohort of 24 patients. The 1-year graft survival is 100% with only three episodes of AMR, one requiring salvage splenectomy and the other two easily reversible with additional plasmapheresis. These results demonstrate that with very minimal escalation of immunosuppression over that used in compatible live donor transplantation the blood group barrier can be successfully crossed. This makes ABOi a very attractive option under the current set of clinical realities.

It is important to emphasize that KPD and desensitization are not competitive strategies. Patients are best served by the availability of both modalities. On the basis of the blood type combination and immunologic profile of the incompatible pair, one strategy may be favored over the other. For example, a very high percentage of pairs with blood type combinations A/B or B/A will match in a KPD, and these patients are better served by being triaged to this approach. Blood group O recipients are far less likely to be matched in a KPD pool, especially those with AB donors and would be better served by desensitization. Additionally, the number of ABOi pairs matching in a KPD pool can be increased if sensitized patients with O donors are permitted to match more compatible donors with lower titer crossmatches than their intended donor. We have performed 13 KPDs or domino paired donations that have also included desensitization against low titer positive crossmatches (^{11, 12}). Using this combination of modalities, virtually any patient with an ABOi donor can be successfully transplanted.