| Abstract|| |
Some patients with end-stage renal disease do not have suitable living related donors due to ABO incompatibility. Crossing the ABO barrier has long been considered an absolute contraindication to kidney transplantation. Although transplantation using A 2 kidneys has been performed in a few centers over the past two decades with variable success, the presence of blood group antigens can cause immediate or early graft loss due to preformed antibody-mediated hyperacute rejection. Over the past few years, novel protocols designed to reduce anti-donor antibodies have allowed successful transplantation across the ABO barrier. This requires careful preoperative conditioning, which will be described in this article.
Keywords: Renal transplant, Blood group, ABO barrier.
|How to cite this article:|
Alkhunaizi AM. Renal Transplantation across the ABO Barrier. Saudi J Kidney Dis Transpl 2006;17:311-5
| Introduction|| |
With the severe shortage of cadaver donors, the waiting time for kidney transplantation in the Kingdom of Saudi Arabia (KSA) has become very long. Some patients with endstage renal disease do not have suitable living related donors due to ABO incompatibility. While some elect to undergo living unrelated renal transplantation performed outside the KSA, the majority are never transplanted. Crossing the ABO barrier has long been considered an absolute contraindication to kidney transplantation. The presence of blood group antigens can cause immediate or early graft loss due to preformed antibody-mediated hyperacute rejection. 
Over the past few years, novel protocols designed to reduce anti-donor antibodies have allowed successful transplantation across the ABO barrier. In particular, allocation of kidneys from blood group A 2 donors to recipients of blood groups O and B may expand the donor pool and shorten the waiting time for kidney transplantation. Among Caucasians with blood group A, the A 2 subtype is present in 20%.  As opposed to A 1 , A 2 is a weaker antigen, and does not induce an agglutination reaction when exposed to anti-A1 reagents.  In addition, patients with blood group A 2 have lower total amounts of A antigens and do not express the other subtypes (i.e., A 3 and A 4 ) in the kidney. 
| ABO Incompatible Renal Transplantation|| |
Transplantation across the ABO barrier has been performed in the past with little success. Hume et al  reported in 1955 a series of 10 patients who underwent ABO incompatible renal transplantation. Eight allografts were lost within the first few post-operative days. In the early 1960s, Starzl et al reported the outcome in three recipients of ABO incompatible renal allografts.  However, among those three patients, one recipient had blood group AB and received a blood group A kidney from his wife; the second patient had blood group O and received a blood group A kidney. There were no subtypes identified for blood group A. The third patient had blood group A and received a blood group B kidney from his sister. Among the three cases, only the third one may have been a true ABO incompatible kidney transplant. Blood group A in the second patient may have been A 2 , which has a favorable outcome. 
Due to the lack of cadaveric organs in Japan, some investigators have performed renal transplantation using living related kidneys with ABO incompatibility. Takahashi et al  reported 44 cases of ABO incompatible living related kidneys. Quintuple drug therapy was combined with plasmapheresis (PP) and immunoadsorption prior to transplantation. Splenectomy was performed on all recipients at the time of transplantation. Among those cases, one patient had a hyperacute rejection, 3 patients had accelerated rejection, and multiple acute rejection episodes were encountered in 15 cases. In 1995, the same group published an update of their experience with ABO incompatible renal transplantation, showing graft and patient survivals equal to those of ABO compatible organs.  However, at a later follow-up, they reported poorer long-term graft survival as compared to recipients of ABO compatible kidneys.  In a more recent analysis, Takahshi's group reported the outcome of 441 cases of ABO incompatible living related renal transplants. The 9-year patient and graft survival rates were 84% and 59% respectively.  The Mayo clinic group recently published their experience with 35 cases of ABO incompatible renal transplantation, showing a one-year graft survival of 88%. , This group also performed splenectomies as part of the pretransplant conditioning protocol. In other countries, the experience with ABO incompatible renal transplantation has been rather limited with variable outcomes. ,,, In most of those cited reports, splenectomy was performed at the time of transplantation as a way to further modify antibody formation.
| Transplantation Using A2 Kidneys|| |
Transplantation using A 2 kidneys has been performed in a few centers over the past two decades with variable success. In the early 1980's, Brynger et al reported 14 cases of renal transplantation from A 2 donors into O recipients. , In that group, three allografts were lost in the early postoperative period. One allograft was lost secondary to acute irreversible rejection, and the remaining two had nonimmunologic failures. Mendez et al  reported success in a small series of renal transplants using A 2 kidneys into O, B, and A 2 B recipients. Similarly, Nelson et al from the Midwest Organ Bank reported their early experience transplanting A 2 kidneys into O and B patients. , In their series, there was a correlation between pretransplant anti-A titers and allograft loss. Recipients with low preoperative anti-A titers did well, while those with titers > 1:8 did poorly and had a high incidence of early allograft loss. No PP or immunoadsorption was performed. They recommended a titer of <1:8 as a prerequisite for using A 2 kidneys in non A recipients. In a more recent analysis from the Midwest Transplant Network, Bryan et al reported on the outcome of 56 blood group B recipients who received A 2 or A 2 B kidneys from 1994-2003.  There was a trend toward increased acute rejection in A 2 and A 2 B to B transplants; however, the actuarial 7-year death censored graft survival was 72% for B recipients regardless of donor type. Schnuelle et al published a pooled analysis of 108 cases of transplantation of A 2 and A 2 B kidneys into O and B recipients.  In this analysis, the graft survival was only 68% at one year, and 73% when patients who died with a functioning graft were censored. Among those patients, only 7 (6.5%) underwent plasmapheresis (PP) prior to transplantation, and 2 of these underwent splenectomy.
We have previously reported the outcome of A2 allocation to O and B recipients at Oregon Health Sciences University (OHSU). , Nineteen patients were transplanted from 1991 to 2000. The median pretransplant IgM/IgG and IgG anti-A1 titers were 1:16 and 1:2, respectively. Those with anti A 1 titers > 1:8 underwent PP. None of the patients developed side effects related to PP. No patient underwent splenectomy. The patients were followed up for 6-120 months with a median followup of 44 months. All of the patients but two underwent induction with the anti-biological antibodies OKT3 (12 patients), thymoglobulin (4 patients), or basiliximab (1 patient). Eighteen patients were assigned to a maintenance therapy of calcineurin inhibitor (CNI)-based triple therapy with either cyclosporine A or FK506. One patient (HLA identical) did not receive CNIs. The patients received either azathiprine (8 patients) or mycophenolate mofetil (11 patients) in addition to prednisone. One patient with IgM/IgG and IgG anti-A 1 titers of 1:64 and 1:16 respectively did not receive PP and lost her allograft within 36 hours because of hyperacute rejection. Six of the 12 recipients of the deceased donor organs developed delayed graft function and required dialysis. Five of these recipients developed at least one acute rejection episode. None of the living donor recipients developed acute cellular rejection. Rebound increase of anti-A1 titers was observed in 9 patients. No rejection episodes were encountered in those who had no rebound increase of their titers. Among those who had rebound increase of their titers, acute rejection was observed in 6 patients (67%). The mean serum creatinine level was 1.7 ± 0.48 mg/dl at 3 and 12 months, and 1.4 mg/dl at 3 years post transplant. Actuarial one-year graft survival was 93%, and patient survival was 100%. This is comparable to the graft and patient survival of all other patients transplanted at OHSU over the same period of time. In a non-published analysis, we have observed that long-term graft and patient survival for the study group was not different from that of the control group. The superior outcome in our series may be attributed to the utilization of PP for patients with high isoagglutinine titers. The difference in outcome between our data and the other studies strongly indicates that PP is a very important key to success of A allocation to O and B recipients. Nevertheless, one should carefully evaluate patients, and only those with low titers should be considered candidates for A 2 allocation. Although PP is assumed to lower the risk of hyperacute rejection, it by no means prevents rejection. Loss of an allograft secondary to hyperacute or accelerated rejection is a disastrous outcome, especially in the setting of living donation.
Up to 8% of A 2 persons may have anti-A 1 alloantibodies in their sera.  It may be logical for donors and recipients with blood group A to undergo sub-typing. Those potential recipients who are identified to be A 2 should be tested for the presence of anti-A 1 alloantibodies, and those with a positive reaction should preferably receive A 2 or O kidneys.
In conclusion, transplantation across the ABO barrier can be safely performed with careful preoperative conditioning. In particular, transplantation using kidneys from A 2 donors is successful in patients with low anti-A titers. Those with elevated titers should undergo perioperative plasmapheresis. Splenectomy is not necessary in these cases. A very careful evaluation of candidates is mandatory as there is a risk of encountering hyperacute or accelerated rejection.
| References|| |
|1.||Paul LC, Baldwin WM 3 rd . Humoral rejection mechanisms and ABO incompatibility in renal transplantation. Transplant Proc 1987;19:4463-7. |
|2.||Branch DR, Dzik WH, Judd WH: ABO, H and P blood groups and structurally related antigens. In: Walker RH, ed. Technical manual, 11th edition.Bethesda: American Association of Blood Banks. 1993;203. |
|3.||Bariety J, Oriol R, Hinglais N, et al. Distribution of blood group antigen A in normal and pathologic human kidneys. Kidney Int 1980;17:820-6. |
|4.||Hume DM, Merrill JP, Miller BF, Thorn GW. Experiences with renal homotransplantation in the human: report of nine cases. J Clin Invest 1955;34:327-82. [PUBMED] [FULLTEXT]|
|5.||Starzl TE, Marchioro TL, Holmes JH, et al. Renal homografts in patients with major donor-recipient blood group incompatibilities. Surgery 1964;55:195-200. [PUBMED] |
|6.||Alkhunaizi AM, de Mattos AM, Barry JM, Bennett WM, Norman DJ. Renal transplantation across the ABO barrier using A2 kidneys. Transplantation 1999; 67:1319-24. [PUBMED] [FULLTEXT]|
|7.||Takahashi K, Yagisawa T, Sonda K, et al. ABO-incompatible kidney transplantation in a single-center trial. Transplant Proc 1993;25:271-3. [PUBMED] |
|8.||Tanabe K, Takahashi K, Sonda K, et al. ABO-incompatible living kidney donor transplantation: results and immunological aspects. Transplant Proc 1995;27:1020-3. [PUBMED] |
|9.||Tanabe K, Takahashi K, Sonda K, et al. Long-term results of ABO-incompatible living kidney transplantation: a singlecenter experience. Transplantation 1998;65: 224-8. [PUBMED] [FULLTEXT]|
|10.||Takahashi K, Saito K, Takahara S, et al. Excellent long-term outcome of ABOincompatible living donor kidney transplantation in Japan. Am J Transplant 2004; 4:1089-96. [PUBMED] [FULLTEXT]|
|11.||Gloor JM, Lager DJ, Moore SB, et al. ABO-incompatible kidney transplantation using both A2 and non-A2 living donors. Transplantation 2003;75:971-7. [PUBMED] [FULLTEXT]|
|12.||Stegall MD, Dean PG, Gloor JM. ABOincompatible kidney transplantation. Transplantation 2004;78:635-40. |
|13.||Alexandre GP, Squifflet JP, De Bruyere M, et al. Present experiences in a series of 26 ABO-incompatible living donor renal allografts. Transplant Proc 1987;19:4538-42. |
|14.||Bannett AD, McAlack RF, Raja R, Baquero A, Morris M. Experiences with known ABO-mismatched renal transplants. Transplant Proc 1987;19:4543-6. |
|15.||Aswad S, Mendez R, Mendez RG, et al. Crossing the ABO blood barrier in renal transplantation. Transplant Proc 1993;25: 267-70. [PUBMED] |
|16.||Haberal M, Gulay H, Sert S, Altunkan S, Bilgin N. ABO-incompatible living related donor criteria. Transplant Proc 1990;22:345. |
|17.||Brynger H, Rydberg L, Samuelsson B, Sandberg L. Experience with 14 renal transplants with kidneys from blood group A (subgroup A2) to O recipients. Transplant Proc 1984;16:1175-6. [PUBMED] |
|18.||Brynger H, Rydberg L, Samuelsson B, Blohme I, Lindholm A, Sandberg L. Renal transplantation across a blood group barrier-'A2' kidneys to 'O' recipients. Proc Eur Dial Transplant Assoc 1983;19:427-31. |
|19.||Mendez R, Sakhrani L, Chaballout A, Mendez RG. ABO incompatible transplants involving A2 donors. Transplant Proc 1991;23:1738-41. [PUBMED] |
|20.||Nelson PW, Helling TS, Shield CF, Beck M, Bryan CF. Current experience with renal transplantation across the ABO barrier. Am J Surgery 1992;164:541-4. |
|21.||Nelson PW, Landreneau MD, Luger AM, et al. Ten-year experience in transplantation of A2 kidneys into B and O recipients. Transplantation 1998;65:256-60. [PUBMED] [FULLTEXT]|
|22.||Bryan CF, Winklhofer FT, Murillo D, et al. Improving access to kidney transplantation without decreasing graft survival: long-term outcomes of blood group A2/A2B deceased donor kidneys in B recipients. Transplantation 2005;80:75-80. [PUBMED] [FULLTEXT]|
|23.||Schnuelle P, van der Woude FJ. Should A2 kidneys be transplanted into B or O recipients? Lancet 1998;351:1675-6. [PUBMED] |
|24.||Norman DJ, Prather JC, Alkhunaizi AM, deMattos AM, Golconda M, Barry JM. Use of A(2) kidneys for B and O kidney transplant recipients: report of a series of patients transplanted at a single center spanning a decade. Transplant Proc 2001;33:3327-30. [PUBMED] [FULLTEXT]|
Ahmed M Alkhunaizi
Saudi Aramco, PO Box 10955, Dhahran 31311