Transfusion and Apheresis Science

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1 Transfusion and Apheresis Science 43 (2010) Contents lists available at ScienceDirect Transfusion and Apheresis Science journal homepage: Isoagglutinin adsorption in ABO-incompatible transplantation Helena Genberg a,c, *, Gunilla Kumlien b,c, Lars Wennberg a,c, Gunnar Tydén a,c a Department of Transplantation Surgery, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden b Department of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden c Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden article info abstract Keywords: ABO-incompatible Kidney transplantation Therapeutic apheresis Antigen-specific immunoadsorption Rituximab As the demand for kidney transplantation is constantly growing methods to expand the donor pool have become increasingly important. ABO-incompatibility has hitherto been regarded as an absolute contraindication to living donor donation. However, as ABOincompatibility has accounted for the majority of living donor exclusions, efforts have been made to overcome this immunologic barrier. Successful desensitization protocols thus far, have combined plasmapheresis for antibody removal with splenectomy to reduce the antibody producing B-cell pool, in addition to quadruple immunosuppression. Although good graft function has been achieved, the high risks involved have been deterrent. We have developed a protocol for ABO-incompatible kidney transplantation based on antigen-specific immunoadsorption and rituximab, in combination with standard maintenance immunosuppression (tacrolimus, mycophenolate mofetil and corticosteroids). We hypothesized that the anti-a/b antibodies could be effectively eliminated and good graft function achieved, without the complications of coagulopathy and transfusion reactions associated with plasmapheresis. Furthermore, we hypothesized that the substitution of splenectomy with a single dose of the anti-cd20 antibody rituximab would further reduce surgical risk as well as the risk of infectious complications. In 2001 the program for ABO-incompatible kidney transplantation was started at our center. To date 50 ABO-incompatible kidney transplantations have been performed according to the protocol based on antigen-specific immunoadsorption and rituximab. Safety and efficacy of the protocol has been evaluated in several studies, all showing that the antigenspecific immunoadsorption is well tolerated and without any serious side effects. Patient and graft survival as well as kidney function have been comparable to that of ABO-compatible living donor kidney transplantation and the incidence of antibody-mediated rejection 0%. We conclude that AB0-incompatible kidney transplantation using a protocol based on antigen-specific immunoadsorption and rituximab, in combination with triple immunosuppressive therapy is safe and effective. ABO-incompatibility following this protocol does not have a negative impact on graft function. ABO-incompatible kidney transplantation is equivalent to standard ABO-compatible living donor kidney transplantation. Ó 2010 Published by Elsevier Ltd. Abbreviations: ABOi, ABO-incompatible; ABOc, ABO-compatible; GFR, glomerular filtration rate; HLA, human leukocyte antigen; LD, living donor; DD, deceased donor; mab, monoclonal antibody; TA, therapeutic apheresis. * Corresponding author at: Department of Transplantation Surgery, Karolinska University Hospital Huddinge, Stockholm, Sweden. address: helena.genberg@karolinska.se (H. Genberg). 1. Introduction As the demand for kidney transplantation is continuously growing, methods to expand the donor pool are becoming increasingly important. New ways to expand the donor pool are therefore being explored, including /$ - see front matter Ó 2010 Published by Elsevier Ltd. doi: /j.transci

2 232 H. Genberg et al. / Transfusion and Apheresis Science 43 (2010) the use of donors after cardiac death, expanded criteria donors, and paired exchange lists for living donors as well as the development of special immunosuppressive protocols to overcome immunological barriers such as the ABO barrier, conventionally regarded as a contraindication to living donor donation. Living donors could not only be a means to expand the total donor pool, but also offers superior patient and graft survival compared with deceased donor (DD) transplantation [1,2], Fig. 1. However, immunologic barriers pose a limitation to living donor (LD) transplantation [3]. As a matter of fact, preformed antibodies in the recipient, directed against various antigens expressed in the donor kidney, is the most common contraindication to LD donation [4]. Transplantation in the presence of such antibodies can evoke a hyperacute rejection. Commonly present preformed donor-specific antibodies include ABO antibodies and human leukocyte antigen (HLA) antibodies. The immunological barrier posed by the ABO system account for an estimated 20 30% of all LD refusals. Therefore, effective desensitization, eliminating the anti-a/b antibodies, could yield a substantial increase in the number of transplantations performed Background Patient survival (%) Living donor recipients (n=336) Deceased donor recipients (n=501) Years after transplantation Fig. 1. Patient survival in living donor and deceased donor kidney recipients transplanted at the Karolinska University Hospital between 1990 and ABOi kidney transplantation was first attempted at any larger scale in 1970s, using A 2 donors for DD kidney recipients of blood groups O and B. Only regular immunosuppression was used [5]. As experience grew, it became clear that low initial anti-a/b antibody titers in the recipient (1:4), were a prerequisite for the transplantations to be successful, significantly limiting the number of potential candidates [6]. Primarily owing to poor results, most centers attempting ABO-incompatible kidney transplantation using A 2 donors without conditioning, had abandoned this strategy by the end of 1980s. To overcome major ABOincompatibility (non-a 2 -incompatibilities) in kidney transplantation, Alexandre et al. instigated the first larger study in 1982 in Belgium [7,8]. The protocol included repeated plasmapheresis, splenectomy, the use of donor platelet transfusion and the intravenous administration of A and B trisaccharide depending on the A/B incompatibility, in addition to antilymphocyte globulin and triple maintenance immunosuppression (corticosteroids, azathioprine and cyclosporine). Using this protocol a 1-year graft survival of 75% was achieved. Based on this success, similar protocols were implemented at a few other centers worldwide, most notably in Japan. In comparison, graft survival (without any specific conditioning) was approximately 4% after accidental ABOi transplantation during the same period [9]. The first ABOi kidney transplantations in Japan were performed in There, ABOi kidney transplantation rapidly gained much attention, as the Japanese kidney transplant programs relied nearly exclusively on living donors. Already at an early stage the Japanese achieved results of the ABOi kidney transplantations similar to those of AB0-compatible (ABOc) kidney transplantation, further supporting the ABOi programs [10,11]. The ABOi programs in Japan have in fact been very successful and to date >1000 AB0i kidney transplantations have been performed. Following the good results reported by the Japanese together with an increasing demand and the development of new immunosuppressive therapies, ABO-incompatible kidney transplantation gained a renewed interest in Europe and USA in the early 2000s [12 14]. Herein a brief report of current experience in ABOi kidney transplantation is given, focusing on the protocol developed at the Karolinska University Hospital. 2. Current protocols Current desensitization protocols for ABOi kidney transplantation are all based on the same principles: to remove existing antibodies and to prevent rebound of anti-a/b antibodies in the kidney recipient after transplantation. Generally several apheresis sessions are needed for efficient antibody removal, both prior to and after the transplantation. To prevent rebound, apheresis is combined with immunosuppressive therapy. The donor-specific antibody levels are monitored and transplantation performed when the antibodies are sufficiently reduced. This process normally takes 1 2 weeks. For this reason desensitization is almost exclusively limited to LD transplantation Therapeutic apheresis In ABOi transplantation, currently used therapeutic apheresis (TA) techniques include plasma exchange/plasmapheresis, double-filtration plasmapheresis, protein A immunoadsorption and antigen-specific immunoadsorption. The major difference between these techniques is their level of selectivity. The selective TA techniques are generally both safer and more effective and therefore normally preferred [15]. As no coagulation factors are removed, large plasma volumes can be processed, increasing the therapeutic efficacy compared with plasma exchange [16,17]. However, plasma exchange/plasmapheresis is the most commonly used TA technique in ABOi transplantation worldwide and may have some advantages over selective techniques. Firstly, plasma exchange is readily available and as antibody removal is sometimes required urgently, in the treatment of antibody-mediated rejection, availability may be of importance. Secondly, in AB0i kidney recipients with donor-specific antibodies other than anti-a/b antibodies, plasma exchange allows

3 H. Genberg et al. / Transfusion and Apheresis Science 43 (2010) for simultaneous removal of all antibodies, regardless of the antibody specificity. Thirdly, complement is reduced by plasma exchange. As allograft injury caused by anti-a/ B antibody is partly mediated via complement activation, a reduction of complement could be advantageous [18]. The two most commonly used selective methods are double-filtration plasmapheresis and antigen-specific immunoadsorption using the Glycosorb-ABO system (Glycorex Transplantation AB, Lund, Sweden). Double-filtration plasmapheresis is a system developed in Japan that allows for the removal of the plasma fraction containing the immunoglobulins [19,20]. In this procedure two filtrations are performed, a primary filtration in the plasma separator, and a second filtration in the plasma fractionator. After separation of plasma from whole blood, the plasma is passed through the plasma fractionator where plasma components of a certain molecular weight are filtered out. The remaining plasma is subsequently returned to the patient, while the targeted plasma fraction is discarded. Removal of coagulation factors, etc. is hereby avoided and only small amounts of replacement fluid are needed [21]. Outside Japan the use of double-filtration plasmapheresis is very limited. In 2001 the Glycosorb- ABO system for specific removal of the anti-a/b antibodies became available. This system is based on a column containing immobilized A or B trisaccharide. These terminal trisaccharides are bound covalently to a Sepharose matrix, via a six-spacer hydrocarbon molecule [22]. The first clinical transplantation, using this system, was done at our center in September 2001 [14]. Since then another 50 AB0i kidney transplantations have been performed here and >400 immunoadsorptions conducted, using the system B-cell depletion In ABOi transplantation, after the first successful kidney transplantations in the 1980s using a combination of immunosuppressive agents and splenectomy [8,23], a general belief was that splenectomy was necessary in order to avoid hyperacute rejection. By performing splenectomy, the B-cell population was partially reduced, including some of the antibody-producing plasma cells. Most protocols for ABOi transplantation have therefore included splenectomy at time of transplantation. At nearly all Japanese transplant centers, splenectomy has formed part of the ABOi protocol. In the USA, splenectomy has also been included in most protocols for AB0i kidney transplantation until very recently [12]. Anti- CD20 Start of tac/mmf/corticosteroids Immunoadsorption IVIG POD TX Fig. 2. The protocol for ABO-incompatible kidney transplantation based on antigen-specific immunoadsorption and rituximab. Today the B-cell population can also be targeted by the monoclonal antibodies (mabs) rituximab and alemtuzumab. In Europe and to a large extent also in the USA, rituximab as a B-cell depleting therapy, has now come to replace splenectomy in ABOi transplantation. A recent study has also demonstrated that ABOi kidney transplantation can be performed successfully, completely without B-cell depletion, leaving out both splenectomy and anti-cd20 mab [24]. The outlines of the protocol for ABOi kidney transplantation developed at the Karolinska University Hospital are shown in Fig. 2 [25]. 3. Results The protocol based on antigen-specific immunoadsorption and rituximab, developed at the Karolinska University Hospital protocol has been evaluated at several stages and already published elsewhere [14,25 28]. An initial analysis was done in a pilot study including the first four ABOi transplantations [14]. This study showed that ABOi kidney transplantation could successfully be performed without splenectomy. A comparative study was then undertaken, including the first 15 adult ABOi transplantations and a control group of 30 ABOc kidney recipients [25]. In this study no significant difference in patient and graft survival or in kidney function, as assessed by s-creatinine and glomerular filtration rate, at 1, 2 and 3 years could be demonstrated when comparing the ABOi kidney recipients with those receiving an ABOc transplant Fig. 3. However, ABO-incompatible kidney transplantation was associated with an additional cost of 32,000 compared with standard ABO-compatible LD kidney transplantation. To further evaluate safety and efficacy of the protocol, a collaborative study was also undertaken together with the transplant centers in Freiburg, Germany and in Uppsala, Sweden, comparing the results of 60 consecutive ABOi kidney transplantations with 274 consecutive ABOc kidney transplantations [27]. In this study, no difference in patient and graft survival or in serum-creatinine could be demonstrated either: Patient survival was 98% in both groups and graft survival 97% in the Serum-creatinine (micromol/l) p=ns 1 year 2 years 3 years ABOi(mean) ABOc(mean) Fig. 3. Mean serum-creatinine in ABO-incompatible and ABO-compatible adult kidney recipients 1, 2 and 3 years postoperatively. The broken lines represent the 95% confidence interval.

4 234 H. Genberg et al. / Transfusion and Apheresis Science 43 (2010) ABOi group compared with 95% in the ABOc group. Mean serum-creatinine was 127 lmol/l in the ABOi group and 133 lmol/l in the ABOc group. This study also showed that implementation of the protocol was uncomplicated. Altogether, these studies show that the protocol is effective and well tolerated. The incidence of acute antibody-mediated rejection so far has been 0%. 4. Discussion The constantly growing demand for renal replacement therapy has lead to a renewed interest in ABOi kidney transplantation. In the Caucasian population the probability that two unrelated individuals are ABO-incompatible is around 35% [29]. Consequently ABO-incompatibility is the most common contraindication to living donor transplantation. Successful ABOi kidney transplantation is therefore a means to substantially increase the number of living donor transplantations. In 2001 a protocol for ABOi kidney transplantation based on antigen-specific immunoadsorption and rituximab in combination with standard immunosuppressive therapy (tacrolimus, mycophenolate mofetil and corticosteroids), was introduced at our center. The primary aim when developing the protocol was to reduce the medical risk compared with previous protocols for ABOi kidney transplantation. For this purpose plasmapheresis was replaced by antigenspecific immunoadsorption using the Glycosorb-ABO Ò system. We assumed that complications associated with plasma exchange such as coagulopathy and transfusion reactions could be avoided [30 32]. To further reduce surgical risk and the potentially life-long hazard of infectious complications, splenectomy was substituted by a single dose (375 mg/m 2 body-surface area) of rituximab. In a pilot study, this protocol was evaluated, showing that both tolerability and efficacy were good. To date, 50 kidney transplantations using this protocol have been performed at our center. The protocol has been evaluated in several studies, all showing that the protocol is effective and well tolerated. No serious side effects have been observed. In addition, in a collaborative study with the transplant centers in Uppsala, Sweden and Freiburg, Germany, we demonstrated that the protocol could be implemented elsewhere without difficulty [27]. Consequently, the protocol has been implemented at some 20 centers worldwide and to date more than 160 transplantations performed. Moreover, long-term results in ABOi LD transplantation reported by Japanese and American transplant centers, also show that ABOi LD transplantation is equivalent to ABOc LD transplantation. Montgomery et al. obtained a 5-year patient and graft survival of 89% following ABOi kidney transplantation at Johns Hopkins Hospital. Tanabe et al. in Tokyo have also achieved a 5-year graft survival of nearly 90% in their ABOi and ABOc LD kidney recipients [33]. At the Mayo Clinic, Gloor et al. report a 1-year graft function equal to that of ABOc LD kidney transplantation [34,35]. The same centers have also reported a decrease in the incidence of antibody-mediated rejection following ABOi kidney transplantation when compared with earlier studies. To summarize, recent data support that ABOi LD kidney transplantation is a superior alternative to DD ABOc transplantation and possibly not inferior to LD ABOc transplantation. Patient and graft survival as well as kidney function following ABOi kidney transplantation using current protocols is similar to that of standard ABOc kidney transplantation. ABOi LD kidney transplantation is a good therapeutic alternative for patients in the need of a kidney transplant. References [1] Cecka JM. The UNOS renal transplant registry. Clin Transplants 2001:1 18. [2] Cecka JM. 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