Year : 2013 | Volume
: 24 | Issue : 3 | Page : 463--472
ABO-Incompatible kidney transplantation
Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia
Department of Nephrology, Hedi Chaker Hospital, Sfax
HLA sensitization and ABO incompatibility continue to pose a significant barrier to expansion of living donation. In fact, either anti-blood or anti-donor HLA antibodies result in the occurrence of hyperacute rejection and graft loss. Reducing this early rejection risk by planned desensitization protocols has clearly improved the outcome of ABO-incompatible (ABOi) kidney transplantation. B-cell depletive therapy has replaced splenectomy, overcoming the disadvantages of the latter. Plasma exchange techniques have considerably reduced antibody titers, allowing better results. Thus, newer immunosuppressive protocols reduced early graft loss and early rejections episodes and, consequently, improved the long-term graft survival. Therefore, ABOi kidney transplantation can be more broadly practiced, especially to expand the pool donor and to reduce the waiting time for transplantation.
|How to cite this article:|
Yaich S. ABO-Incompatible kidney transplantation.Saudi J Kidney Dis Transpl 2013;24:463-472
|How to cite this URL:|
Yaich S. ABO-Incompatible kidney transplantation. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2023 Jan 30 ];24:463-472
Available from: https://www.sjkdt.org/text.asp?2013/24/3/463/111009
Successful kidney transplantation remains the treatment of choice for end-stage renal failure. Compared with dialysis patients, kidney transplant recipients have higher rates of morbidity and mortality.  Despite advances in kidney transplantation, one of the major barriers to transplantation is shortage of donated organs.
Consequently, there is a trend to increase deceased donor transplantation (kidney transplantation from donors after cardiac arrest, expanded criteria donor) as well as living donors through desensitization protocols, paired kidney exchanges and ABOi kidney transplantation. 
Until recently, the compatibility of ABO blood groups between donor and recipient was considered as a mandatory condition before any organ transplantation. In fact, isohemagglutinin antibodies formed against blood group antigen A or B (or both in patients with blood type O) are responsible for hyperacute rejection and allograft loss.
Landsteiner's work, published in the 1990 and awarded the medicine Nobel Prize, has defined the concept of blood groups A, B and O.  It is a system of antigens (Ag) and their specific antibodies (Ab). The Ag A and B are the enzymes N-acetylgalactosaminyl transferase and galactosyl transferase D, and they are able to catalyze the addition of sugars on a substrate called substance H.
ABO antigens are present not only on the surface of red blood cells, white cells and platelets, on which they were originally described, but also on the surface of the endothelium of vessels and basement membranes of renal tubular cells. By convention, the ABO blood groups are defined by the Ag present on red blood cells. Antibodies present in serum correspond to the Ag absent on the surface red blood cells. In the determination of ABO blood group with an anti-A antibody, some cells are less strongly clustered (A2 erythrocytes, 20% of subjects) than others (A1 erythrocytes, 80% of subjects).  In whites, the A2 subtype constitutes approximately 20% of the blood group A individuals.  A2 is detected as the inability to bind the anti-A 1 lectin Dolichos biflorus or by molecular ABO typing. The A1 phenotype is qualitatively and quantitatively more expressed on the renal endothelial surface. Thus, A2 kidneys may be less likely to undergo antibody-mediated damage at a given level of anti-A antibody. 
In 1955, Hume et al reported the first cases of ABOi kidney transplantation. Unfortunately, eight of ten AB O-incompatible renal allografts were lost within the first post-operative days.  Later, some sporadic cases of ABOi kidney transplantation have been described with a variable outcome and an overall poor graft function. , It is only in 1987 that the first series of 26 successful ABO-incompatible living kidney transplantation was described by Alexandre et al.  These transplantations were performed using living donors, splenectomy and an immunosuppressive regimen with steroids, cyclosporin, azathioprine, antithymocyte globulin and donor-specific platelet transfusions.
Further, this protocol has been well developed in Japan. In fact, since 1989, more than 1000 ABO-incompatible kidney transplants have been performed in Japan.  The Japanese strategies are based on removing antibodies (preoperative plasmapheresis), reducing antibody production with splenectomy and a triple immunosuppressive regimen based on calcineurin inhibitors, steroids and antimetabolites. 
In order to prevent hyperacute rejection, isohemagglutinins are removed prior to ABOi kidney transplantation. Thus, a close and regular monitoring is necessary to guide antirejection therapy and further antibody removal. Goal titers are not standardized and differ from one center to another, ranging from ≤1:8 to ≤1:32 before undergoing surgery.  The current practice advocates antibody removal until the donor-specific IgG is below 1:8.
Historically, antibody titers' determination was manual, using serial dilutions of a patient's sample incubated for a period of time at 37°C with red blood cells aliquots of the appropriate blood type and subjected to checking for macroscopic agglutination of red blood cells (for IgM) or additional testing with antihuman globulin to detect IgG agglutination.  This technique is inaccurate and is responsible for great variation between laboratories. Kobayashi et al and Kumlien et al found an important difference in isohemagglutinin titers between laboratories for the same sera (median intercenter variability of three titer steps). , These differences are due to the lack of technique standardization.
In fact, the hemagglutination method is poorly reproducible and has a high interobserver variability. In addition, hemagglutination is better in the quantification of IgM for ABO-incompatible kidney transplantation; it is the level of IgG that determines outcome. ,
Enzyme-linked immunosorbent assay methods (ELISA) might be used to quantify ABO antibody levels, but these are not widely used. The disadvantage of this technique is the detection of autoreactive antibodies. 
Krishnan et al analyzed plasma samples from 79 blood donors and 42 successive samples collected from a patient undergoing antibody removal for ABOi kidney transplantation. The samples were tested by both hemagglutination and flow cytometry. Changes in IgG, as measured by flow cytometry, correlated well with the hemagglutination titers. Flow cytometry allowed quantitative discrimination in the range of antibody levels relevant to ABO-incompatible transplantation and had the advantages over hemagglutination of objective measurement and reproducibility.  ABO flow cytometry offers several advantages: Firstly, it measures the presence of all anti-A/B anti bodies binding to the respective ABO antigen, not only agglutinating or hemolyzing antibodies; secondly, binding of anti-A/B antibodies to natural ABO antigen is more sensitive and more specific than binding to synthetic ABO antigen (ELISA); and, finally, ABO flow cytometry directly quantifies the binding of different anti-A/B antibody isotypes and IgG sub-classes. ,, Therefore, flow cytometry can be adopted for antibody monitoring to allow comparative studies between different institutions.
The ABOi kidney transplantation has been considered high risk because of the humoral rejection induced by isohemagglutinin antibodies. In fact, the early experience with ABO-incompatible kidney transplantation was disappointing, with poor results and early graft loss due to humoral rejection. , To overcome the humoral rejection, several protocols have been employed to remove antibodies or antibody-producing cells.
These protocols were involved in different combinations: Plasmapheresis, immunoadsorption, anti-CD20, splenectomy, etc.
The spleen has a dual role as a blood filter (for removing foreign particles and destroyed blood cells) and as an antibody producer. To remove the antibody-producing plasma cells, many protocols included splenectomy either before or at the time of transplantation in ABOi kidney transplantation. ,, Splenectomy was involved in many ABO-incompatible kidney transplantation protocols after the results published by Alexandre et al showing a rapid graft loss in recipients who did not perform splenictomy. , However, the role of splenectomies in ABOi renal transplantation has been controversial. Moreover, splenectomy is associated with increased morbidity and mortality due to susceptibility to bacterial infections, principally encapsulated bacteria, and constitutes a supplementary surgical inva sion to the to the recipient. 
ABOi transplantation using A2 donors are usually performed without splenectomy in recipients with low titers of anti-A antibodies. ,
Small series of ABOi kidney transplantation have been performed successfully in patients with low levels of donor-specific blood antibodies and by using non-A2 donors. ,,
For the first time in 2001, the Stockholm group reported four cases of successful ABOi kidney transplantation without splenectomy. 
Gloor et al compared 23 patients included in a protocol involving pre-transplant plasmapheresis and splenectomy at the time of ABOi kidney transplantation and 11 patients included in a protocol involving pre-transplant anti-CD20 antibody and an intensive post-transplant plasmapheresis.  They found no difference in patient and graft survival between the groups.
Humoral rejection occurred in 18% of non-splenectomized and 30% of splenectomized patients.  The major reason for splenectomy in ABOi kidney transplantation is to remove antibody-producing cells and/or memory B cells. These cells exist not only in the spleen but also in a large number in other parts of the body, particularly in lymph nodes and bone marrow. Thus, rituximab induction can be useful in controlling antibody production through deletion of B lymphocytes.
ABOi kidney transplantation may be safely performed without splenectomy provided by initiation of pre-transplant B lymphocyte-depleting therapy combined with intensive post-transplant plasmapheresis and close monitoring of the anti-blood group antibody level.
It is now known that accommodation is established one to two weeks after transplantation. Thus, splenectomy is not necessary to inhibit antibody production, and adequate desensitization therapy before transplantation is sufficient. 
Plasmapheresis and immunoadsorption
Historically, ABOi kidney transplantation has been performed after several pre-operative sessions of plasmapheresis followed by splenectomy. In fact, plasmapheresis as well as immunoabsorption with Staphylococcus A columns is effective in removing the existing anti-A or anti-B antibodies.
Plasmapheresis is the most commonly used method worldwide, mainly in the USA and Japan. It removes anti-ABO antibodies with approximately 20% reduction with each treatment.  The advantages of plasmapheresis are their ready availability as, in some cases, particularly in the treatment of humoral rejection, the removal of antibodies should be performed rapidly. In addition, in ABOi kidney transplants with donor-specific antibodies and other anti-A/B antibodies, plasmapheresis is preferred because it removes all antibodies with no selection.  Complement is also removed by plasma exchange, which seems to be beneficial, as allograft injury caused by anti-A/B antibodies is partly mediated via complement activation. 
The main disadvantage of this technique is the increasing rate of infections because of the lack of "depletion selectivity." In fact, it is not ABO antibody specific and it removes other protective antibodies. The other disadvantage is removing clotting factors, exposing the recipients to the risk of perioperative bleeding. 
In a small series of eight patients, ABOi kidney transplant was performed after pre-operative plasmapheresis with a tacrolimus/mycophenolate mofetil/methylprednisolone/basiliximab protocol using a low-dose rituximab. The titers of anti-A/B titers were maintained at low levels post-transplantation, and all patients had stable renal function despite the occurrence of two antibody-mediated rejections. 
The two most commonly used selective methods are double filtration plasmapheresis and antigen-specific immunoadsorption using the Glycosorb-ABO system.
Double filtration plasmapheresis is well developed in Japan and consists of eliminating the plasma fraction containing the immunoglobulin.  As its name indicates, there is a first filtration in the plasma separator and a second filtration in the plasma fractionator. The plasma obtained is passed through the plasma fractionator, where plasma components of a certain molecular weight are filtered.
The remaining plasma is returned to the patient while the targeted plasma fraction is dis carded.  Coagulation factors are not removed and only small amounts of replacement fluid are needed, which constitute advantages for this technique.
Immunoadsorption has the advantage of removing only isohemagglutinin A and/or B with approximately 30% reduction of anti-A/B IgM and approximately 20% IgG after a single treatment without change of titers of other antibodies. , The immunoadsorber is a glycosorb ABO column with a low-molecular carbohydrate column with A or B blood group antigen linked to a sepharose matrix. The column effectively and specifically depletes anti-A or anti-B antibodies without any apparent side-effects.
Tydén et al reported a series of 11 ABOi kidney transplantations with excellent results using immunoadsorption sessions with one dosage of rituximab, standard immunosupression (tacrolimus, mycophenolate mofetil and prednisolone) and no splenectomy. None of their patients developed side-effects and all had normal graft function.  Patients with initial IgG anti-A/B titers above 1:128 were usually not accepted for immunoadsorption or transplantation. However, with more intensive pretransplant immunoadsorption sessions, high-titer patients could be transplanted. In fact, 11/27 patients with high titers of 1:256 were included in a protocol with repetitive antigen-specific extracorporeal treatments as needed to reach a titer of 1:4 and a target volume per treatment of 2.5-3 plasma volumes. Seven (64%) of the 11 patients were successfully transplanted. The remaining four patients did not reach the target titer and were excluded. 
Immunoadsorption or plasmapheresis is also indicated in the treatment of acute antibody-mediated rejection following ABOi kidney transplantation with high-dose methlprednisolone and intravenous immunoglobulins (IVIG). ,
Rituximab is an anti-CD20 humanized monoclonal antibody used to reduce antibody production by reducing B cells in the periphery and naïve B cells in the lymphatics and spleen. , The optimal dose of rituximab in ABO-incompatible kidney transplantation is still controversial.  Usually, a 375 mg/m 2 dose is given two to four weeks before transplantation; this single dose is often sufficient in removing CD-20-positive cells.
Tydèn et al in a series of 11 ABOi kidney transplants did not encounter any episodes of rejection, and this may be related to the pre-conditioning treatment with rituximab. No serious infectious complications were noted. The same authors reported similar results in a second series of 12 patients. , The "Stockholm group" protocol involving rituximab, immunoadsorption and a conventional triple-drug immunosupression allowed splenectomy avoidance and excellent graft survival.  In addition, substitution of anti-CD20 did not result in an increased incidence of antibody-mediated rejection. ,
Chikaraishi et al reported good results with stable graft function in a small series of eight ABOi kidney transplant with low rituximab doses and immunoadsorption. 
In a recent paper, Montgomery et al reported the result of a series of 60 consecutive ABO-incompatible kidney transplantations. They compared two eras: The first using a protocol with splenectomy or anti-CD20 or both and the second using a protocol without splenectomy or antiCD20, involving only a short course of plasmapheresis and low-dose IVIG with standard immunosupression. Their findings suggested that ABOi kidney transplantation can be accomplished with a low risk of acute humoral rejection and graft loss without the need for splenectomy or B cell ablative therapy. 
In 2011, Fuchinoue et al compared three groups of patients: ABO-compatible kidney transplantation (n = 280), ABOi kidney transplantation without rituximab induction (n = 63) and ABOi kidney transplantation with rituximab induction (n = 50). The 5-year graft survival rates were, respectively, 88%, 90% and 100%. The percentage of humoral rejection was, respectively, 2%, 16% and 4%. Their results suggested that inclusion of rituximab in the pre-operative regimen yielded an even better outcome than that of ABO-compatible kidney transplantation. 
Finally, there is little data on whether addition of rituximab causes an increase in the rate of infectious complications. ,
Most publications that described the use of rituximab did not find an increased incidence of infectious complications.
Intravenous immunoglobulins (IVIG)
IVIG are prepared from the pooled plasma of many thousands of blood donors. They have immunoregulatory properties, suppress B-cell responses and are usually used to regulate alloantibodies in highly sensitized patients.  They are able to neutralize circulating antibodies through anti-idiotype interactions.  They are usually used pre-operatively, after plasmapheresis or immunoadsorption sessions, for binding circulating antibodies and reducing isoagglutinin titers. , The number of plasmapheresis/IVIG depends on anti-blood antibodies titer.
However, IVIG preparations should contain the lowest ABOi antibody levels. Thus, high-isoagglutinin content within the IVIG preparation has the potential to induce antibody-mediated rejection when prescribed after transplantation. 
IVIG can also be used post-transplant in patients with high anti-blood titer and/or with humoral rejection. Ishida et al investigated the presence of anti-blood antibodies in 12 ABO-incompatible recipients with humoral rejection, and they reported eight patients with excellent graft function despite the presence of elevated titers of anti-blood antibodies. Both IgG and IgM were elevated in rejection patients, while the eight stable patients exhibited only slightly elevated IgG titer. IgG and IgM titers did not change after plasmapheresis and steroid pulse therapy, whereas IVIG treatment significantly blocked both IgG and IgM; IgM was blocked to a larger extent than IgG. 
Induction Immunosuppressive Therapies and Maintenance Treatment
Basiliximab is an anti-CD25 monoclonal antibody that has been used in ABO-compatible kidney transplantation. In ABO-incompatible kidney transplantation, Ando et al demonstrated that induction therapy with basiliximab allows steroid withdrawal at Day 14 without the occurrence of acute rejection. 
Ecluzimab is a monoclonal antibody directed against the complement protein C5. This antibody blocks the cleavage of C5 by its convertase and halts the process of complement-mediated cell destruction, and it is critical to the formation of membrane attack complex (MAC). Ecluzimab may be useful in reducing early and late acute rejection rates. ,
Tacrolimus and mycophenolate mofetil (MMF)
The use of tacrolimus with MMF has reduced acute rejection rates in patients with high pretransplant isohemagglutinin titers (≥1:128) and improved their outcomes to levels comparable to those with lower titers. ,
Takahashi et al studied 435 ABOi kidney transplantations performed in 59 institutions in Japan. They compared the patients' and grafts' survival rates between two periods: 1996 to 1998 and 1999 to 2002. Graft survival was higher in the second period as compared with the historical data, suggesting a contribution of tacrolimus to such improvement. 
Tanabe et al showed significantly poorer short-term graft survival under cyclosporine immunosuppression in ABOi compared with ABO-compatible kidney transplants. , Later, the same investigators reported excellent outcome in ABOi kidney transplants with seven days' pre-transplantation immunosuppression using tacrolimus, MMF and methylprednisolone with low incidence of acute rejection. 
Sirolimus (SRL) is used to avoid chronic rejection and calcineurin-related nephrotoxicity, and, recently, anti-tumor properties have also been reported. , However, there is no study evaluating it SRL ABOi kidney transplantation.
Modern immunosuppressive protocols tend to avoid over-immunosupression while preserving in allograft function. Only two studies reported results of early steroids' withdrawal in ABOi kidney transplantation; the first included 27 patients who were pre-treated with plasmapheresis and splenectomy and maintained immunosupression with cyclosporine. , Early steroid withdrawal was successful in 44% of the cases with a biopsy-proven acute rejection rate of 30% within one year.  The second study was of ten patients who received an immunosuppressive protocol including plasmapheresis, IVIG, rituximab and daclizumab. Maintenance therapy consisted of MMF, tacrolimus and steroids; the biopsy-proven acute rejection rate was 30%. 
Graft and Patient Survival
The first results with ABOi kidney transplantation were poor due to graft loss secondary to acute antibody-mediated rejection (AAMR). Schnuelle et al reported 108 cases of A2 and A2B kidneys transplanted into O and B recipients performed at eight centers from 1974 to 1996 that demonstrated a 1-year graft survival rate of only 68%, which was inferior to ABO-compatible kidney transplantation. 
In ABOi kidney transplantation, AAMR can occur in recipients who are positive for anti-ABO antibodies, anti-HLA antibodies or unexpected alloantibodies. Its incidence is greatest two to seven days after transplantation, and decreases thereafter.  AAMR was classified into two types: Type I acute antibody-mediated rejection caused by resensitization to ABO antigens, which occurs in high immunological risk patients, and type II acute antibody-mediated rejection caused by primary sensitization to ABO antigens. 
Once the type I rejection occurs, it is difficult to control with current available therapies because it is caused by resensitization. Treatment must be started early. If graft loss occurs, the graft should be removed promptly.  Type II rejection should be treated with plasmapheresis and high-dose corticosteroids.
When the recipient's anti-ABO antibodies titer is low, the risk of humoral rejection is low, with excellent graft function; successful renal transplantations were reported using A2 kidneys in 15 blood group O and B recipients, and most of them received pre-operative plasmapheresis sessions.  Allograft function was excellent with a 1-year graft survival rate of 93.3% and a patient survival rate of 100%. Other studies reported similar results using A2 or A2B kidneys with no pre-transplant plasmapheresis. ,,
The graft survival rate was significantly lower in the ABOi kidney transplantation and AAMR, and the prevalence of transplant glomerulopathy at 1-year post-transplantation was significantly higher in the AAMR group. Multivariate analysis demonstrated that anti-blood IgG titers of 1:32 at the time of transplantation and donor-specific anti-HLA antibodies were independent risk factors for AAMR. 
The risk of acute rejections is higher during the first two weeks, necessitating a close monitoring for ABO antibodies. During this time, accommodation takes place. 
Accommodation is defined as the absence of antigen-antibody interaction although antibodies are circulating in the peripheral blood and the corresponding antigen site is expressed in the renal allograft.  Moreover, there is no clinical sign of rejection or allograft damage. In these cases, there is evidence of complement activation as detected by the presence of C4d in the peritubular capillaries without allograft injury. One or more of three processes have been proposed as mechanisms for accommodation: A change in antigen, a change in antibodies or a change in the graft. Glycosyl-transferase, an enzyme implicated in the regulation of tissue A/B antigen expression, seems to play an important role in accommodation and can be impaired after transplantation due to the renal allograft damage caused by hypoxia/reperfusion.  Moreover, there is an increase in the expression of anti-apoptotic genes such as hemeoxygenase-1 and Bcl-xL in the accommodated ABOi kidney transplants.  Animal models suggest up-regulation of protective molecules in the endothelial cells, alterations in the Th2 immune response and inhibition of the MAC. , Tanabe et al  found a decrease in the expression of the donor's blood-type antigen on the endothelium of the graft.
Cost of ABO-incompatible kidney transplantation
The transplantation of ABOi kidneys requires protocols to reduce anti-blood antibodies. These protocols (plasmapheresis, rituximab) lead to an increase in resource utilization and cost of therapy. Thus, the cost of ABOi kidney transplantation is much higher than that for conventional transplants. Exchange kidney transplantation would be an option for some patients. It would be interesting to establish a waiting list for kidney exchange. In fact, ABOi kidney transplantation is expensive in resource-limited low-income countries.
The long current waiting times for a deceased donor, especially for blood groups O and B, makes it essential to develop alternative methods for transplantation. The promising results of ABOi kidney transplantation and the less-aggressive immunosuppressive protocols make this procedure more acceptable. However, this procedure is expensive and, in resource-limited low-income counties, donor exchange/paired programs are more feasible.
The keys to successful ABOi kidney transplantation are pre-conditioning protocols and a planned follow-up and close monitoring of anti-ABO antibodies to reduce the risk of humoral rejection and early graft loss.
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