NDT Advance Access originally published online on September 27, 2006
Nephrology Dialysis Transplantation 2007 22(1):25-27; doi:10.1093/ndt/gfl557
© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
ABO-incompatible transplantation—a safe way to perform renal transplantation?
Jörg Beimler and
Martin Zeier
Department of Nephrology, University of Heidelberg, Heidelberg, Germany
Correspondence and offprint requests to: Jörg Beimler, Nierenzentrum Heidelberg, Department of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany. Email: beimler{at}gmx.de
Keywords: ABO-incompatible renal transplantation; desensitization; immunoadsorption; living kidney donation; plasmapheresis; rituximab
The shortage of donor organs, especially in renal transplantation, leads to an increasing discrepancy between the number of end-stage renal disease patients on waiting lists and the number of available deceased donor kidneys. Expansion of the donor pool can be achieved by increasing the numbers of living kidney transplantation and by overcoming the immunological barriers of ABO-incompatibility and HLA-sensitization. Despite a substantial increase in the number of patients, receiving living kidney transplant, otherwise suitable donors have to be rejected due to pre-existing human leuocyte antigen antibodies or ABO-incompatibility. Isoagglutinins (ABO-antibodies) represent a major barrier in optimizing living kidney donation and organ distribution. As blood group antigens are expressed by the endothelium of solid organs including the kidney, transplantation across the blood group barrier can result in hyperacute antibody-mediated allograft rejection. Depending on blood group distributions in different populations, as much as 30–35% of potential living donors have to be excluded from living donation due to ABO-incompatibility. ABO-incompatible transplantation was already performed as early as in the 1970s, but due to hyperacute rejection, results were discouraging. In 1987, Alexandre et al. [1] published a first series of 26 ABO-incompatible kidney transplantations using splenectomy and an immunosuppressive regimen with steroids, cyclosporine, azathioprine, antithymocyte globulin and donor-specific platelet transfusions. Due to a severe shortage of available deceased donor organs, most ABO-incompatible kidney transplantations have taken place in Japan. Recently published data demonstrated an excellent long-term outcome of ABO-incompatible living donor kidney patients in Japan [2]. Similar successful short-term results have been shown for protocols developed in Europe and the United States. Results from Japan, the United States and Europe are promising, but a lot of questions remain unanswered and there is a lack of standardization among the different protocols. Different approaches to performing successful ABO-incompatible kidney transplantation have been used in different countries over the last decade.
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The European way
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The recent availability of specific anti-A or anti-B immunoadsorption
columns (Glycosorb®) and the use of anti-CD2O monoclonal
antibody (rituximab) in different immunosuppressive regimens
resulted in the introduction of ABO-incompatible renal transplantation
as a routine procedure in different European countries, mainly
in Sweden and Germany, including our centre. The first series
of ABO-incompatible renal transplantation without splenectomy,
using antigen-specific immunoadsorption and rituximab, was published
by the Stockholm group of Tyden
et al. [
3,
4]. In 21 patients
successfully treated with this protocol, the immunosuppressive
regimen consisted of one dose of rituximab (375 mg/m
2) given
2–4 weeks before immunoadsorption, followed by a conventional
triple-drug immunosuppression consisting of tacrolimus, mycophenolate
mofetil and prednisolone, starting 1 week before immunoadsorption.
Pre-operatively, anti-A or anti-B antibodies were removed using
the Glycosorb® ABO column, a low-molecular carbohydrate
column with A or B blood group antigen linked to a sepharose
matrix. Immunoadsorption with Glycosorb® columns is very
effective, and IgG and IgM isoagglutinin titres can be reduced
by two to three titre steps with every immunoadsorption session.
Typically, four pre-operative immunoadsorption sessions were
performed, aiming for a pre-operative ABO antibody titre of
<1:8. After the last pre-operative Session, 0.5 g/kg of intravenous
immunoglobulin (IVIG) was administered. To avoid early post-operative
rebound of ABO antibodies, three more immunoadsorption sessions
were done over a period of 9 days. Based on their data with
a maximum follow-up of 4 years, it can be said that there were
no major side effects of the treatment regimen, patients showed
normal serum creatinine levels and no late reappearance of isoagglutinins
was observed during follow-up. In recent publications, similar
results using this regimen have been shown by other groups in
Germany and Sweden [
5,
6]. In summary, about 60 ABO-incompatible
renal transplants have been performed successfully in Sweden
and Germany over the last 5 years with this protocol.
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The Japanese way
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Recently, Takahashi
et al. [
1] published the surveillance data
of 494 ABO-incompatible kidney transplantations performed in
Japan between 1989 and 2001. Over this time period, a variety
of immunosuppressive regimens, including extracorporal strategies
to remove antibodies (pre-operative titre <1:8–16),
pharmacological immunosuppression, anticoagulation and splenectomy
(98%), were used. Splenectomy of the recipient was performed
due to the role of the spleen in anti-A/B antibody production.
Immunosuppressive triple therapy was based on calcineurin inhibitors,
steroids and antimetabolites, differing among centres, on the
basis of which additional immunosuppressive agents, such as
antilymphocyte globulin, deoxyspergualin or cyclophosphamide,
were administered. Antibody removal was usually not performed
after transplantation. Compared with historical cases of living
kidney transplantation (
n = 1055), the short-term results were
not as good as those of ABO-compatible cases, but the long-term
outcome showed no statistically significant difference. Patient
survival rates were 93, 89, 87 and 84% at 1, 3, 5, 7 and 9 years,
while graft survival rates were 84, 80, 71, 65 and 59%, respectively.
The graft survival rate did not show any significant differences
between A-incompatible and B-incompatible transplants or among
different ABO blood type incompatible combinations. Looking
at the outcome of the most recent cases since 2001, results
have substantially improved, with a 1- and 2-year graft survival
of 96 and 94%, showing that, based on newer immunosuppressive
regimens, short-term graft survival in ABO-incompatible renal
transplantation has improved. This improvement might be at least
partially due to the introduction of mycophenolate mofetil and
the anti-CD25 monoclonal antibody basiliximab into therapy.
Based on registry data, splenectomy has been considered to be
an essential part of successful ABO-incompatible renal transplantation.
But even with splenectomy, severe antibody-mediated rejection
can be observed [
7]. Antibody-mediated rejection typically occurred
within the first month after transplantation, particularly in
the first week. Since 2004, a desensitization protocol without
splenectomy starting 4 weeks prior to transplantation, including
double filtration plasmapheresis, anti-CD20 treatment, mycophenolate
mofetil and steroids, was introduced, showing a successful short-term
outcome. No additional post-operative antibody removal or administration
of IVIG was performed [
8].
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The American way
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The Johns Hopkins group established a pre-conditioning protocol
of plasmapheresis, CMV hyperimmune globulin (CMVIg) and anti-CD20
to allow ABO-incompatible renal transplantation without splenectomy
[
9]. The treatment protocol demands four to five pre-operative
plasmapheresis sessions to remove anti-A/B antibodies, each
session followed by the administration of cytomegalovirus hyperimmune
globulin at 100 mg/kg. After achieving a pre-transplant A/B-antibody
titre of <1: 16, 1 or 2 days prior to transplantation, a
single dose of rituximab was given at 375 mg/kg. Thereafter,
immunosuppression with tacrolimus and mycophenolate mofetil
was initiated, followed by steroids and daclizumab after transplantation.
Post-operative treatment included another three plasmapheresis/CMVIg
sessions on days 1, 3 and 5. At follow-up, mean serum creatinine
was 1.3 ± 0.1 mg/dl in the first six patients. The absence
of humoral rejection and stable kidney graft function in their
initial experience shows the potentials of pre-conditioning
regimens with the use of rituximab, avoiding the risks of splenectomy.
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ABO-incompatible renal transplantation—questions to be answered
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ABO blood group incompatibility has long been considered to
be an absolute contraindication to renal transplantation. The
recent development of desensitization protocols has been shown
to reduce and maintain anti-A/B titres against the donor blood
group sufficiently, preventing antibody-mediated rejection and
allowing successful ABO-incompatible living-donor kidney transplantation.
The key factor to successful graft outcome is the prevention
of hyperacute rejection, to establish accommodation as early
as possible. Accommodation is defined as the absence of an antigen–antibody
reaction, despite the presence of ‘foreign’ antigen
on the vascular endothelial cells within the graft and the presence
of antibody in the recipient's blood [
10]. Protocols in the
United States and Japan differ from those used in most centres
in Europe, where antigen-specific immunoadsorption, rather than
plasma exchange, is the preferred mode of removing antibodies.
Humoral rejection seems to correlate more closely with pre-transplant
antibody titre than with the antibody-lowering regimen used.
Immunoadsorption with the anti-A/B-specific Glycosorb® column
offers a very effective way of removing anti-ABO antibodies
without the known side effects of plasmapheresis, such as coagulation
disorders, the possibility of viral infection or allergic reactions
to fresh frozen plasma. Despite higher overall costs and additional
resource utilization, ABO-incompatible kidney transplantation
offers a safe option to perform renal transplantation successfully
in patients whose only living donor is blood-group-incompatible.
Depending on different patient populations and worldwide waiting
list systems, kidney paired donation or list paired donation
may be an alternative for patients with ABO-incompatible donors,
reducing the need for desensitization strategies. Despite all
efforts recently made, important questions about ABO-incompatible
transplantation are yet to be answered. We do not know the acceptable
upper limits of ABO antibody titres at the time of transplantation
to prevent antibody-mediated rejection. With recent immunosuppressive
regimens, antibody titres as high as 1:32 might be sufficient
to perform transplantation safely [
11]. Due to technical reasons,
methods for isoagglutinin monitoring and therefore reproducibility
of results differ between centres. Whether patients with anti-CD20
therapy and without a substantial rebound of antibody titre
after transplantation need additional plasmapheresis treatments
remains to be elucidated, though preliminary data from Japan
suggest successful outcomes without post-operative plasmapheresis.
Whether such a regimen is feasible for all ABO-incompatible
kidney transplantations is yet to be determined. Anti-CD20 treatment
as a B-cell ablative therapy has been shown to replace splenectomy
successfully. Interestingly, recent protocols based on rituximab
therapy showed little or no cellular rejection episodes, but
whether this is due to the addition of anti-CD20 to the immunosuppressive
regimen remains unclear. As one dose of rituximab (375 mg/kg)
often effectively removes CD20-positive cells, most centres
administer one single dose of rituximab in their pre-treatment
protocol. Concerning its off-label use and the fact that some
insurance companies do not pay for it, the question of whether
all patients for ABO-incompatible renal transplantation need
anti-CD20 pre-conditioning has been raised [
12]. Recently at
Johns Hopkins, 13 successful ABO-incompatible transplants, A1
and AB donors into O recipients with titres as high as 1: 512,
were performed without splenectomy or anti-CD20 therapy [
13].
Although many questions have yet to be answered, ABO-incompatible
renal transplantation has become a viable option for patients
who lack blood-group-compatible kidney donors. Furthermore,
collaboration between centres performing ABO-incompatible kidney
transplantation, for example, by collecting data in registries,
might answer open questions.
Conflict of interest statement. None declared.
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References
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- Alexandre GPJ, Squifflet JP, De Bryere M, et al. (1987) Present experience in a series of 26 ABO-incompatible living donor allografts. Transplant Proc 19:4538–4542.
- Takahashi K, Saito K, Takahara S, et al. (2004) Excellent long-term outcome of ABO-incompatible living donor kidney transplantation in Japan. Am J Transplant 4:1089–1096.
- Tyden G, Kumlien G, Genberg H, et al. (2005) ABO-incompatible kidney transplantations without splenectomy, using antigen-specific immunoadsorption and rituximab. Am J Transplant 5:145–148.
- Tyden G, Kumlien G, Genberg H, et al. (2006) The Stockholm experience with ABO-incompatible kidney transplantations without splenectomy. Xenotransplantation 13:105–107.
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- Ishida H, Koyama I, Sawada T, et al. (2000) Anti-AB titer changes in patients with ABO-incompatibility after living related kidney transplantations: survey of 101 cases to determine whether splenectomies are necessary for successful transplantation. Transplantation 70:681–685.
- Saito K, Nakagawa Y, Suwa M, et al. (2006) Pinpoint targeted immunosuppression: anti-CD20/MMF desensitization with anti-CD25 in successful ABO-incompatible kidney transplantation without splenectomy. Xenotransplantation 13:111–117.
- Sonnenday C, Warren DS, Cooper M, et al. (2004) Plasmapheresis, CMV hyperimmune globulin and anti-CD20 allow ABO-incompatible renal transplantation without splenectomy. Am J Transplant 4:1315–1322.
- Takahashi KA. (2005) New concept of accomodation in ABO-incompatible kidney transplantation. Clin Transplant 19:Suppl 14, 76–85.
- Shimmura H, Tanabe K, Ishikawa N, et al. (2000) Role of anti-A/B antibody titers in results of ABO-incompatible kidney transplantation. Transplantation 70:1331–1335.
- Montgomery RA, Simpkins CE, Segev DL. (2006) New options for patients with donor incompatibilities. Transplantation 82:164–165.
- Segev DL, Simpkins CE, Warren DS, et al. (2005) ABO incompatible high-titer renal transplantation without splenectomy or anti-CD20 treatment. Am J Transplant 5:2570–2575.
Received for publication: 14. 8.06
Accepted in revised form: 21. 8.06
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