Pediatr Transplantation 2011: 15: 502504

2011 John Wiley & Sons A/S.

Pediatric Transplantation
DOI: 10.1111/j.1399-3046.2011.01480.x

ABO-incompatible kidney transplantation in children

Tyden G, Kumlien G, Berg UB. ABO-incompatible kidney transplantation in children. Pediatr Transplantation 2011: 15: 502504. 2011 John Wiley & Sons A/S. Abstract: We designed a new protocol to enable safe ABO-incompatible kidney transplantation. The new protocol utilizes antigen-specic immunoadsorption rather than unspecic plasma exchange to remove existing anti A/B antibodies and rituximab rather than splenectomy to prevent rebound of antibodies. Sixty patients have so far been successfully transplanted with this protocol and 10 of those have been children. When compared with ABO-compatible transplantations, we could not nd any dierences in success rate, renal function, or adverse events. Gunnar Tydn1, Gunilla Kumlien2 and Ulla B. Berg3
Departments of 1Transplantation Surgery, 2 Transfusion Medicine, and 3Pediatrics, Karolinska University Hospital, Stockholm, Sweden Key words: ABO incompatibility pediatric renal transplantation Gunnar Tydn, MD, Department of Transplantation Surgery, Karolinska University Hospital, S-14186 Stockholm, Sweden Tel.: +46 8 58580000 Fax: +46 8 7743191 E-mail: gunnar.tyden@karolinska.se Accepted for publication 10 December 2010

There is an urgent need to expand the pool of potential living donors, not only because of the increasing discrepancy between the number of available deceased donor organs and the number of patients waiting for a transplant but also, and more signicantly, because of the superior graft and patient survival rates found in living donor transplants. Historically, ABO-incompatible kidney transplantations in children have been performed after several sessions of plasmapheresis to remove existing anti-A or -B antibodies, followed by splenectomy and a conventional triple-drug immunosuppressive protocol being reinforced with antilymphocyte globulin and B-cell specic drugs such as cyclophosphamide or deoxyspergualine, to prevent rebound of antibodies (1, 2). However, because splenectomy, a reinforced immunosuppressive protocol, and multiple sessions of plasmapheresis carry signicant morbidity and even mortality, we introduced a new protocol, enabling safe ABO-incompatible kidney transplantation, in 2001 (3). The new protocol utilizes antigen-specic immunoadsorption (GlycoSorb; Glycorex Transplantation AB, Lund, Sweden) rather than plasma exchange to remove existing anti-A or anti-B antibodies and rituximab rather than splenectomy to prevent the
Abbreviations: CMV, cytomegalovirus; GFR, glomerular ltration rate; IVIG, intravenous immunoglobulin.

rebound of antibodies, in combination with conventional tacrolimus, mycophenolate mofetil, and prednisolone immunosuppression. We have now successfully performed 60 ABO-incompatible renal transplantations, and of that total, 10 have been in children.
Materials and methods
Between June 2003 and April 2007, 38 pediatric renal transplantations were performed in our institution. Of those, 10 were ABO-incompatible; the remaining 28 ABOcompatible transplantations served as controls in the present study. The immunosuppressive protocol consisted of one dose of rituximab (375 mg/m2), given four wk before immunoadsorption. It was followed by a conventional triple-drug immunosuppressive protocol consisting of tacrolimus, mycophenolate mofetil, and prednisolone. All patients received antiviral prophylaxis with valaciclovir for three months. CMV-negative recipients of CMV-positive organs received valganciclovir. Bactrim was given as prophylaxis against pneumocystis pneumonia for six months. Preoperatively, the anti-A and anti-B antibodies were removed using antigen-specic immunoadsorption (Fig. 1). The GlycoSorb ABO column is a low-molecular carbohydrate column with the terminal trisaccaride of the A or B blood-group antigen linked to a sepharose matrix. Details on the apheresis procedure and titration technique have been published previously (4). The protocol calls for four preoperative apheresis sessions, and we aimed for a preoperative antibody titer of IgG 1:8. If this level was not achieved after four sessions, the transplantation was postponed for one wk, and four more sessions were performed. In three infants, the antibody titer was 1:2 or less, and the

502

Pediatric ABO-incompatible transplantation

Tacrolimus/MMF/prednisolone

Rituximab Glycosorb 1:128 1:64 1:32 1:16 1:8 1:4 1:2 1:1 <1:1
30 13 6 4 2

IVIG

Tx

10

12

Time (days)

Fig. 1. The eect of antigen-specic immunoadsorption (Glycosorb) on antibody titers. The timing of the dierent components of the immunosuppressive protocol is also shown.

preoperative sessions were therefore canceled. One dose (0.5 g/kg) of IVIG was given following the last of the preoperative apheresis sessions. Post-operatively, three more apheresis sessions were given every third day over a total period of nine days. Furthermore, if there was a signicant increase in the antibody titer (two dilutions), extra sessions were considered. GFR was determined by renal clearance of inulin or plasma clearance of iohexol, at three months after transplantation and thereafter yearly. The protocol was approved by the local ethics committee at Karolinska University Hospital, Huddinge.

and the transplantation was therefore postponed for one wk, and another four apheresis were performed. In three infants with low anti-A/antiB titers preoperatively, no antigen-specic immunoadsorption was performed. However, because we were uncertain about the infants antibodyresponse to the massive antigenexpression of the adult kidney, we did perform the three post-operative adsorptions in the rst two cases, but because we did not observe any antibody rebound, they were omitted in the third case. In all the patients, the post-operative course has been remarkably uneventful, and none of the patients have experienced any rejection episodes related to rebound of ABO antibodies. Furthermore, we have not observed any late reappearance of antibodies during the whole follow-up time. When the outcome of the 10 ABO-incompatible children was compared with that of the 28 ABO-compatible children, we could not nd any signicant dierence in GFR between the two groups up to three yr of follow-up (Table 2). One ABO-incompatible and two ABO-compatible grafts have been lost, two because of poor compliance and one because of rapid recurrence of disease.

Ant ti-A1 IgG t titre

Results

Ten children have been treated with the protocol, and all have successfully received transplants. The donor and recipient characteristics, the ABO-combinations, the anti-A/B titers before and after apheresis, and the number of apheresis sessions needed are given in Table 1. In all patients, the antibodies were readily removed by the antigen-specic immunoadsorption. However, in one child, a rebound of antibodies was observed after the rst four apheresis sessions,
Table 1. ABO-incompatible pediatric transplantations Patient n = 10 HB WR AR EH EA PE SS NS JA LN Age yr 1 1 1 11 12 13 13 13 14 16 Anti-A/B titer before apheresis 2 1 1 32 16 128 256 32 16 32

Table 2. GFR (mL/min/1.73 m2) measured by clearance of inulin or iohexol in the 10 ABO-incompatible and 28 ABO-compatible pediatric renal transplantations performed during the same time period (20032008) ABO-incompatible Time from tx Age at tx (yr) 3 1 2 3 months yr yr yr n 10 9 10 9 8 9.9 6.2 GFR 74 46 58 17 59 17 59 17 ABO-compatible n 26 24 25 25 19 7.7 GFR 77 71 65 63 5.0 22 21 21 19 p 0.28 0.77 0.08 0.50 0.61

ABO-incompatible B-O A1-O B-O A1-B A1-O A1-O A1-O A2-O A1B-A A1-O

No. of apheresis sessions needed 0 0 0 4 4 8 4 4 4 4

Anti-A/B titer after apheresis n.a. n.a. n.a. 4 2 2 2 4 2 2

Donor Uncle Grandmother Grandmother Friend of mother Father Father Father Mother Father Father

Diagnosis Urethral valve Nephrosis Nephrosis Renal arterial thrombosis Dysplasia Nephronophtisis Dysplasia Nephronophtisis Renal vein thrombosis Urethral valve

503

 Tyden et al. Discussion

Following the implementation of our protocol for ABO-incompatible transplantations, we have considered all suitable donors irrespective of blood group. This is of special importance in pediatric populations where many highly motivated parents and grandparents previously have been rejected as donors because of incompatible blood groups. We did not observe any complications associated with the procedure, and the results were equal to those obtained in ABO-compatible transplantations in children. To avoid splenectomy, which was previously mandatory in all ABO-incompatible transplant protocols, we instead gave one dose of the humanized monoclonal anti-CD20 antibody, rituximab. The eect of one dose of rituximab is complete elimination of all B lymphocytes in peripheral blood (5). Nevertheless, we could not nd any increase in infectious complications because of the use of rituximab. This nding is in accordance with a previous randomized, double-blind study on the use of rituximab as induction in renal transplantation (6). An explanation of the absence of infectious complications could be that whereas the reduction of B lymphocytes in peripheral blood is 100%, in lymphatic tissue, it is only 50 75% (4). Adsorption of blood-group antibodies with the GlycoSorb ABO carbohydrate column was highly eective, lowering the antibody titers by approximately 24 steps for each session. Because the antigen-specic immunoadsorption specically depletes only anti-A or anti-B antibodies, side eects usually associated with conventional plasmapheresis were absent. Thus, there were no coagulation disorders, and the antibody titers against previously encountered antigens such as viruses and vaccinations were not aected. Because of the mobilization of antibodies between the adsorptions, at least four

pretransplant sessions were found to be necessary. In accordance with previous observations (7), we did not nd signicant levels of A or B antibodies in the three infants. Consequently, they did not need any pretransplant adsorptions. Because the antigen-specic immunoadsorption was without side eects, we decided also to perform preemptive post-operative adsorptions rather than wait for an increase in antibody titers. Interpretation of post-operative antibody titers is obscured by a low antibody titer not precluding antibody production because the antibodies may actually be adsorbed by the graft. We conclude that after one infusion each of rituximab, IVIG, and antigen-specic immunoadsorption, blood-group incompatible renal transplantations in children can be performed with excellent results using standard immunosuppression and no splenectomy.
References
` 1. Alexander GPJ, Squifflet JP, De Bruyere M, et al. Present experience in a series of 26 ABO-incompatible living donor renal allografts. Transpl Proc 1987: 19: 45384542. 2. Shishido S, Asanuma H, Tajima E, et al. ABO-incompatible living-donor kidney transplantation in children. Transplantation 2001: 72: 10371042. 3. Tyden G, Kumlien G, Genberg H, Sandberg J, Lundgren T, Fehrman I. ABO incompatible kidney transplantation without splenectomy, using antigen-specic immunoadsorption and rituximab. Am J Transplant 2005: 5: 145148. 4. Kumlien G, Ullstrom L, Loswall A, Persson L-G, Tyden G. Clinical experience with a new apheresis lter that specically depletes ABO blood group antibodies. Transfusion 2006: 46: 15681575. 5. Genberg H, Hansson A, Wernersson A, Wennberg L, Tyden G. Pharmacodynamics of rituximab in kidney allotransplantation. Am J Transplant 2006: 6: 24182428. 6. Tyden G, Genberg H, Tollemar J, et al. A randomized, doubleblind, placebocontrolled, study of single dose rituximab as induction in renal transplantation. Transplantation 2009: 87: 13251329. 7. West L, Pollock-Barziv S, Dipchand A, et al. ABO-incompatible heart transplantation in infants. N Engl J Med 2001: 344: 793800.

504