This document summarizes a new protocol for ABO-incompatible kidney transplantation in children that was designed to expand the donor pool. The key aspects of the new protocol are: 1) It utilizes antigen-specific immunoadsorption rather than plasma exchange to remove existing anti-A/B antibodies pre-operatively. 2) It uses rituximab rather than splenectomy to prevent antibody rebound. 3) Ten pediatric patients have been successfully transplanted using this protocol so far with results comparable to ABO-compatible transplants in terms of graft function and adverse events.

1. Pediatr Transplantation 2011: 15: 502–504 Ó 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 transplan- Gunnar TydØn1, Gunilla Kumlien2 and
tation in children. Ulla B. Berg3
Pediatr Transplantation 2011: 15: 502–504. Ó 2011 John Wiley & Sons A/S. Departments of 1Transplantation Surgery,
2
Transfusion Medicine, and 3Pediatrics, Karolinska
Abstract: We designed a new protocol to enable safe ABO-incompatible University Hospital, Stockholm, Sweden
kidney transplantation. The new protocol utilizes antigen-specific Key words: ABO incompatibility – pediatric renal
immunoadsorption rather than unspecific plasma exchange to remove transplantation
existing anti A/B antibodies and rituximab rather than splenectomy to
prevent rebound of antibodies. Sixty patients have so far been Gunnar TydØn, MD, Department of Transplantation
Surgery, Karolinska University Hospital, S-14186
successfully transplanted with this protocol and 10 of those have been
Stockholm, Sweden
children. When compared with ABO-compatible transplantations, Tel.: +46 8 58580000
we could not find any differences in success rate, renal function, or Fax: +46 8 7743191
adverse events. E-mail: gunnar.tyden@karolinska.se
Accepted for publication 10 December 2010
There is an urgent need to expand the pool of rebound of antibodies, in combination with con-
potential living donors, not only because of the ventional tacrolimus, mycophenolate mofetil, and
increasing discrepancy between the number of prednisolone immunosuppression. We have now
available deceased donor organs and the number successfully performed 60 ABO-incompatible
of patients waiting for a transplant but also, and renal transplantations, and of that total, 10 have
more significantly, because of the superior graft been in children.
and patient survival rates found in living donor
transplants. Historically, ABO-incompatible Materials and methods
kidney transplantations in children have been Between June 2003 and April 2007, 38 pediatric renal
performed after several sessions of plasmapheresis transplantations were performed in our institution. Of
to remove existing anti-A or -B antibodies, those, 10 were ABO-incompatible; the remaining 28 ABO-
followed by splenectomy and a conventional compatible transplantations served as controls in the pres-
triple-drug immunosuppressive protocol being ent study.
reinforced with antilymphocyte globulin and The immunosuppressive protocol consisted of one dose of
rituximab (375 mg/m2), given four wk before immunoad-
B-cell specific drugs such as cyclophosphamide sorption. It was followed by a conventional triple-drug
or deoxyspergualine, to prevent rebound of anti- immunosuppressive protocol consisting of tacrolimus, my-
bodies (1, 2). However, because splenectomy, a cophenolate mofetil, and prednisolone. All patients received
reinforced immunosuppressive protocol, and antiviral prophylaxis with valaciclovir for three months.
multiple sessions of plasmapheresis carry signifi- CMV-negative recipients of CMV-positive organs received
valganciclovir. Bactrim was given as prophylaxis against
cant morbidity and even mortality, we introduced pneumocystis pneumonia for six months.
a new protocol, enabling safe ABO-incompatible Preoperatively, the anti-A and anti-B antibodies were
kidney transplantation, in 2001 (3). The new removed using antigen-specific immunoadsorption (Fig. 1).
protocol utilizes antigen-specific immunoadsorp- The GlycoSorb ABO column is a low-molecular carbohy-
tion (GlycoSorb; Glycorex Transplantation AB, drate column with the terminal trisaccaride of the A or B
Lund, Sweden) rather than plasma exchange to blood-group antigen linked to a sepharose matrix. Details
on the apheresis procedure and titration technique have
remove existing anti-A or anti-B antibodies and been published previously (4). The protocol calls for four
rituximab rather than splenectomy to prevent the preoperative apheresis sessions, and we aimed for a preop-
erative antibody titer of IgG £ 1:8. If this level was not
achieved after four sessions, the transplantation was post-
Abbreviations: CMV, cytomegalovirus; GFR, glomerular poned for one wk, and four more sessions were performed.
filtration rate; IVIG, intravenous immunoglobulin. In three infants, the antibody titer was 1:2 or less, and the
502

2. Pediatric ABO-incompatible transplantation
Tacrolimus/MMF/prednisolone and the transplantation was therefore postponed
for one wk, and another four apheresis were
Rituximab IVIG performed. In three infants with low anti-A/anti-
Glycosorb B titers preoperatively, no antigen-specific im-
1:128 munoadsorption was performed. However, be-
1:64 cause we were uncertain about the infants
titre
1:32
antibody–response to the massive antigen-
ti-A1 IgG t
1:16
1:8 expression of the adult kidney, we did perform
1:4 the three post-operative adsorptions in the first
Ant
1:2 two cases, but because we did not observe any
1:1
<1:1 antibody rebound, they were omitted in the third
–30 –13 –6 –4 –2 Tx 2 4 6 8 10 12 case. In all the patients, the post-operative course
Time (days) has been remarkably uneventful, and none of the
patients have experienced any rejection episodes
Fig. 1. The effect of antigen-specific immunoadsorption
(Glycosorb) on antibody titers. The timing of the different related to rebound of ABO antibodies. Further-
components of the immunosuppressive protocol is also more, we have not observed any late reappear-
shown. ance of antibodies during the whole follow-up
time.
When the outcome of the 10 ABO-incompat-
preoperative sessions were therefore canceled. One dose
ible children was compared with that of the 28
(0.5 g/kg) of IVIG was given following the last of the pre- ABO-compatible children, we could not find any
operative apheresis sessions. Post-operatively, three more significant difference in GFR between the two
apheresis sessions were given every third day over a total groups up to three yr of follow-up (Table 2). One
period of nine days. Furthermore, if there was a significant ABO-incompatible and two ABO-compatible
increase in the antibody titer (two dilutions), extra sessions grafts have been lost, two because of poor
were considered.
GFR was determined by renal clearance of inulin or compliance and one because of rapid recurrence
plasma clearance of iohexol, at three months after trans- of disease.
plantation and thereafter yearly.
The protocol was approved by the local ethics committee
at Karolinska University Hospital, Huddinge.
Table 2. GFR (mL/min/1.73 m2) measured by clearance of inulin or iohexol in
Results the 10 ABO-incompatible and 28 ABO-compatible pediatric renal transplan-
tations performed during the same time period (2003–2008)
Ten children have been treated with the protocol,
and all have successfully received transplants. ABO-incompatible ABO-compatible
The donor and recipient characteristics, the
Time from tx n n p
ABO-combinations, the anti-A/B titers before
and after apheresis, and the number of apheresis Age at tx (yr) 10 9.9 € 6.2 26 7.7 € 5.0 0.28
sessions needed are given in Table 1. In all GFR GFR
patients, the antibodies were readily removed 3 months 9 74 € 46 24 77 € 22 0.77
by the antigen-specific immunoadsorption. How- 1 yr 10 58 € 17 25 71 € 21 0.08
2 yr 9 59 € 17 25 65 € 21 0.50
ever, in one child, a rebound of antibodies was 3 yr 8 59 € 17 19 63 € 19 0.61
observed after the first four apheresis sessions,
Table 1. ABO-incompatible pediatric transplantations
Patient Age Anti-A/B titer No. of apheresis Anti-A/B titer
n = 10 yr ABO-incompatible before apheresis sessions needed after apheresis Donor Diagnosis
HB 1 B-O 2 0 n.a. Uncle Urethral valve
WR 1 A1-O 1 0 n.a. Grandmother Nephrosis
AR 1 B-O 1 0 n.a. Grandmother Nephrosis
EH 11 A1-B 32 4 4 Friend of mother Renal arterial thrombosis
EA 12 A1-O 16 4 2 Father Dysplasia
PE 13 A1-O 128 8 2 Father Nephronophtisis
SS 13 A1-O 256 4 2 Father Dysplasia
NS 13 A2-O 32 4 4 Mother Nephronophtisis
JA 14 A1B-A 16 4 2 Father Renal vein thrombosis
LN 16 A1-O 32 4 2 Father Urethral valve
503

3. ´
Tyden et al.
Discussion pretransplant sessions were found to be neces-
Following the implementation of our protocol sary. In accordance with previous observations
for ABO-incompatible transplantations, we have (7), we did not find significant levels of A or B
considered all suitable donors irrespective of antibodies in the three infants. Consequently,
blood group. This is of special importance in they did not need any pretransplant adsorptions.
pediatric populations where many highly moti- Because the antigen-specific immunoadsorp-
vated parents and grandparents previously have tion was without side effects, we decided also to
been rejected as donors because of incompatible perform preemptive post-operative adsorptions
blood groups. rather than wait for an increase in antibody
We did not observe any complications associ- titers. Interpretation of post-operative antibody
ated with the procedure, and the results were titers is obscured by a low antibody titer not
equal to those obtained in ABO-compatible precluding antibody production because the
transplantations in children. To avoid splenec- antibodies may actually be adsorbed by the graft.
tomy, which was previously mandatory in all We conclude that after one infusion each of
ABO-incompatible transplant protocols, we in- rituximab, IVIG, and antigen-specific immuno-
stead gave one dose of the humanized monoclo- adsorption, blood-group incompatible renal
nal anti-CD20 antibody, rituximab. The effect of transplantations in children can be performed
one dose of rituximab is complete elimination of with excellent results using standard immuno-
all B lymphocytes in peripheral blood (5). Nev- suppression and no splenectomy.
ertheless, we could not find any increase in
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