abo incompatible transplantation: to b or not to b

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American Journal of Transplantation 2004; 4: 1011–1012 Blackwell Munksgaard Copyright C Blackwell Munksgaard 2004 doi: 10.1111/j.1600-6143.2004.00496.x Editorial ABO Incompatible Transplantation: To B or not to B Robert A. Montgomery Department of Surgery, Johns Hopkins University, Baltimore, MD, USA Corresponding author: Robert A. Montgomery, [email protected] ABO antibodies (isoagglutinins) represent a formidable bar- rier to optimizing live donation and organ distribution. Blood group antigens are expressed on the endothelium of solid organs, and transplantation across a blood group barrier can result in hyperacute or acute antibody-mediated rejection (AMR). Based on blood group distributions in the United States, there is a 36% probability that any two individuals in the population will be ABO incompatible (ABOi), result- ing in the exclusion of up to one third of willing live donors. The use of ABOi kidneys dates back to the earliest days of renal transplantation. Dismal results, enhanced availability of kidneys from deceased donors, and a better organ shar- ing infrastructure pre-empted further development of ABOi transplantation in the West. However, in Japan where cul- tural beliefs have limited utilization of deceased donors, ABOi renal transplantation flourished during the 1990s. The article by Takahashi et al. (1) reports the outcomes of 441 ABOi kidney transplants performed at 55 centers across Japan and shows no significant difference in graft survival when compared with historic recipients of ABO- compatible living donor organs. This is a landmark study representing the largest series of ABOi kidney transplants with the longest follow up to date. The results are the en- dorsement that the field of transplantation has been wait- ing for and a further expansion of the practice of ABOi trans- plantation now seems inevitable. While these results are very promising, many questions remain unanswered and there is a bewildering lack of standardization of protocol and reporting (titers, rescue treatments, biopsies) among the Japanese centers. Splenectomy: Something’s Rotten in Denmark The requirement for splenectomy in ABOi transplantation originated from an article by Alexandre and colleagues in which all patients in whom splenectomy was avoided as part of the preconditioning regimen lost their grafts to AMR (2). The unsavory nature of splenectomy among the im- munosuppressed continues to be a major limiting factor to the wider acceptance of ABOi transplantation. In the Takahashi et al. series 98% of the patients underwent splenectomy and thus the question of the utility of splenec- tomy has not been addressed. Splenectomy reduces early graft loss from AMR but does not appear to affect graft survival after the first 3 months. We (3) and others (4) have begun using the B-cell ablative monoclonal antibody, anti- CD20, in place of splenectomy with excellent results in re- cipients of A 2 , B, and A 1 kidneys. The theoretical advantage of this strategy is that the B-cell compartment is allowed to reconstitute with intact splenic function after the period when the risk of AMR is greatest, minimizing the life-long risk of infection. A 2 Advantage?: A 2 Brute Blood group A has two subtypes, A 1 and A 2 . In Japan the A 2 subtype is very rare, whereas in the United States about 20% of blood group A has the A 2 phenotype. The expres- sion of A antigen is both qualitatively and quantitatively re- duced in A 2 individuals (B is intermediate). For this reason the A 2 donor has been considered preferable. However, there are recent data that bring into question the prima facie superiority of the A 2 donor and suggest that initial isoagglutinin titers might be more predictive of outcome than donor subtype (5). Shimmura et al. reported an AMR rate of 71% and poor results when the starting A isoagglu- tinin titer was 128 (6). The protocol used in Japan does not include post-transplant plasmapheresis treatments and this may be responsible for their early graft losses from AMR. We have performed five ABOi transplants using A 1 kidneys with initial recipient titers 128 (range 128–1024) without AMR by continuing plasmapheresis after the trans- plant and maintaining isoagglutinin titers <16 during the first 2 weeks post-transplant. Accommodation: A Rose Is A Rose We have observed that preconditioning for a positive cross- match durably suppresses donor-specific antibody while third-party antibodies persist (tolerance) (7). Conversely, isoagglutinins remain detectable in the circulation after an ABOi transplant without evidence of injury to the graft (ac- commodation). The mechanism of accommodation in the ABOi setting is unknown. One-year protocol biopsies of ABOi grafts show diffuse C4d staining, raising the pos- sibility of a down-stream inhibitor of complement in the 1011

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American Journal of Transplantation 2004; 4: 1011–1012Blackwell Munksgaard

Copyright C© Blackwell Munksgaard 2004

doi: 10.1111/j.1600-6143.2004.00496.x

Editorial

ABO Incompatible Transplantation: To B or not to B

Robert A. Montgomery∗

Department of Surgery, Johns Hopkins University,Baltimore, MD, USA∗Corresponding author: Robert A. Montgomery,[email protected]

ABO antibodies (isoagglutinins) represent a formidable bar-rier to optimizing live donation and organ distribution. Bloodgroup antigens are expressed on the endothelium of solidorgans, and transplantation across a blood group barrier canresult in hyperacute or acute antibody-mediated rejection(AMR). Based on blood group distributions in the UnitedStates, there is a 36% probability that any two individualsin the population will be ABO incompatible (ABOi), result-ing in the exclusion of up to one third of willing live donors.

The use of ABOi kidneys dates back to the earliest days ofrenal transplantation. Dismal results, enhanced availabilityof kidneys from deceased donors, and a better organ shar-ing infrastructure pre-empted further development of ABOitransplantation in the West. However, in Japan where cul-tural beliefs have limited utilization of deceased donors,ABOi renal transplantation flourished during the 1990s.The article by Takahashi et al. (1) reports the outcomesof 441 ABOi kidney transplants performed at 55 centersacross Japan and shows no significant difference in graftsurvival when compared with historic recipients of ABO-compatible living donor organs. This is a landmark studyrepresenting the largest series of ABOi kidney transplantswith the longest follow up to date. The results are the en-dorsement that the field of transplantation has been wait-ing for and a further expansion of the practice of ABOi trans-plantation now seems inevitable. While these results arevery promising, many questions remain unanswered andthere is a bewildering lack of standardization of protocoland reporting (titers, rescue treatments, biopsies) amongthe Japanese centers.

Splenectomy: Something’s Rottenin Denmark

The requirement for splenectomy in ABOi transplantationoriginated from an article by Alexandre and colleagues inwhich all patients in whom splenectomy was avoided aspart of the preconditioning regimen lost their grafts to AMR(2). The unsavory nature of splenectomy among the im-

munosuppressed continues to be a major limiting factorto the wider acceptance of ABOi transplantation. In theTakahashi et al. series 98% of the patients underwentsplenectomy and thus the question of the utility of splenec-tomy has not been addressed. Splenectomy reduces earlygraft loss from AMR but does not appear to affect graftsurvival after the first 3 months. We (3) and others (4) havebegun using the B-cell ablative monoclonal antibody, anti-CD20, in place of splenectomy with excellent results in re-cipients of A2, B, and A1 kidneys. The theoretical advantageof this strategy is that the B-cell compartment is allowedto reconstitute with intact splenic function after the periodwhen the risk of AMR is greatest, minimizing the life-longrisk of infection.

A2 Advantage?: A2 Brute

Blood group A has two subtypes, A1 and A2. In Japan theA2 subtype is very rare, whereas in the United States about20% of blood group A has the A2 phenotype. The expres-sion of A antigen is both qualitatively and quantitatively re-duced in A2 individuals (B is intermediate). For this reasonthe A2 donor has been considered preferable. However,there are recent data that bring into question the primafacie superiority of the A2 donor and suggest that initialisoagglutinin titers might be more predictive of outcomethan donor subtype (5). Shimmura et al. reported an AMRrate of 71% and poor results when the starting A isoagglu-tinin titer was ≥128 (6). The protocol used in Japan doesnot include post-transplant plasmapheresis treatments andthis may be responsible for their early graft losses fromAMR. We have performed five ABOi transplants using A1

kidneys with initial recipient titers ≥ 128 (range 128–1024)without AMR by continuing plasmapheresis after the trans-plant and maintaining isoagglutinin titers <16 during thefirst 2 weeks post-transplant.

Accommodation: A Rose Is A Rose

We have observed that preconditioning for a positive cross-match durably suppresses donor-specific antibody whilethird-party antibodies persist (tolerance) (7). Conversely,isoagglutinins remain detectable in the circulation after anABOi transplant without evidence of injury to the graft (ac-commodation). The mechanism of accommodation in theABOi setting is unknown. One-year protocol biopsies ofABOi grafts show diffuse C4d staining, raising the pos-sibility of a down-stream inhibitor of complement in the

1011

Montgomery

Donor Recipient

O A

A O ABOi

(+) XM

Figure 1: Computer-matching ABOi and positive crossmatch

(+ XM) living donor/recipient pairs entered into a national

repository database could produce many more compatible

transplants and reduce reliance on costly desensitization

protocols.

accommodated kidney. We have stained biopsy samplesfor blood group antigen and have not observed a reductionin A or B antigen expression, however, these antigens canbe released into the plasma bound to glycoproteins andplatelets and could serve as decoys for isoagglutinins.

Paired Kidney Exchange: Double, DoubleToil and Trouble

While logistically and ethically challenging, paired kidneyexchange schemes may offer the best, lower cost alterna-tive to preconditioning protocols for ABOi patients. One op-tion is to assign elevated recipient status on the deceaseddonor list for contributing a live donor kidney to an organbank. However, this has the effect of disadvantaging Opatients on the waiting list. We favor live donor paired kid-ney exchanges as they provide the highest quality organsand do not impact on the deceased donor list. Implementa-tion of a national database of incompatible donor/recipientpairs would allow highly sensitized and ABOi patients to

receive live donor, crossmatch-negative, ABO-compatibleorgans in conventional and unconventional (Figure 1)exchanges.

All’s well that ends well

ABOi renal transplantation and the paired kidney exchangeare two innovative approaches for ameliorating the currentcrisis in organ availability. It is time for the transplant com-munity to come together and remove the remaining ad-ministrative, logistical, and financial barriers to wider appli-cation of these techniques.

References

1. Takahashi K, Saito K, Takahara S et al. Excellent long-term outcomeof ABO-incompatible living donor kidney transplantation in Japan.Am J Transplant 2004; 4: 1089–1096.

2. Alexandre GP, Squifflet JP, De Bruyere M et al. Splenectomy as aprerequisite for successful human ABO-incompatible renal trans-plantation. Transplant Proc 1985; 17: 138–143.

3. Sonnenday CJ, Warren DS, Cooper M et al. Plasmapheresis, CMVhyperimmune globulin, and anti-CD20 allow ABO-incompatible re-nal transplantation without splenectomy. Am J Transplant 2004,in press.

4. Tyden G, Kumlien G, Fehrman I. Successful ABO-incompatible kid-ney transplantations without splenectomy using antigen-specificimmunoadsorption and rituximab. Transplantation 2003; 76: 730–731.

5. Gloor JM, Lager DJ, Moore SB et al. ABO-incompatible kidneytransplantation using both A2 and non-A2 living donors. Transplan-tation 2003; 75: 971–977.

6. Shimmura H, Tanabe K, Ishikawa N, Tokumoto T, Takahashi K,Toma H. Role of anti-A/B antibody titers in results of ABO-incompatible kidney transplantation. Transplantation 2000; 70:1331–1335.

7. Zachary AA, Montgomery RA, Ratner LE et al. Specific and durableelimination of antibody to donor HLA antigens in renal-transplantpatients. Transplantation 2003; 76: 1519–1525.

1012 American Journal of Transplantation 2004; 4: 1011–1012