Does immunosuppressive pharmacotherapy affect isoagglutinin titers?
ABSTRACT Preoperative reduction of isoagglutinins leads to successful ABO-incompatible (ABOi) renal transplantation. The strategy includes pretransplantation plasmapheresis, more potent immunosuppressive drugs, splenectomy, and anti-CD20 antibody. It has been reported that low isoagglutinin antibody titers posttransplant were observed among ABOi renal transplants with favorable outcome. The isoagglutinin titers may increase slightly when plasmapheresis is discontinued; however, it never returns to the pretreatment level under immunosuppressive therapy. This raises the question of what occurs to the isoagglutinin titer in ABO-compatible renal transplants under maintenance immunosuppressive pharmacotherapy.
We analyzed 10 renal transplant recipients, including seven living and three cadaveric donors. Patients were treated with basiliximab (20 mg) intravenously on day 0 and day 4. Maintenance immunosuppressive therapy involved a calcineurin inhibitor, mycophenolate mofetil, and steroid. Anti-human globulin isoagglutinin titers were routinely examined 1 day before and day 0 and 1, 2, 3, 4, 8, 12, and 24 weeks posttransplant. No ALG or intravenous immunoglobulin or plasmapheresis treatment was provided in the follow-up period.
Our preliminary data showed nearly no influence on isoagglutinin titer levels in 6-month follow-up under maintenance immunosuppressive therapy. In addition, no significant difference in isoagglutinin titer was observed between tacrolimus and cyclosporine groups.
Maintenance immunosuppressive pharmacotherapy did not affect isoagglutinin titer levels in ABO-compatible kidney transplants. Further study is needed to investigate the mechanisms of persistent low-level isoagglutinin titers among successful ABOi renal transplantation patients.
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ABSTRACT: Up to 2005, the number of patients on dialysis therapy exceeded more than 250,000 in Japan; however, only 200 deceased and 800 living kidney transplants have been performed annually. We have been making continuous efforts in ABO-incompatible kidney transplantation since 1989 to expand the opportunities for living kidney transplantation in Japan. From the Japanese registry, we have reviewed the long-term patient and graft outcome of ABO-incompatible kidney transplantation. This survey focused on 685 patients who received ABO-incompatible kidney grafts from January 1989 to December 2004 in whom monitoring follow-up could be achieved in 75 institutions. The overall patient survival rates at 1, 3, 5 and 10years after transplantation were 94%, 91%, 87% and 82%, with overall graft survival rates of 87%, 83%, 76% and 57%, respectively. The graft survival rate was significantly higher in patients aged 29 and younger compared with those aged 30 and older. Especially in children aged 15 and younger, they have shown excellent graft survival rate. The patients with anticoagulation therapy showed significantly higher graft survival rate than those without anticoagulation. There were no significant differences between A- and B-incompatibility with respect to clinical outcomes. There were also no significant difference in numbers of HLA mismatches, induction and maintenance calcinurine inhibitors (ciclosporine vs. tacrolimus) and donor/recipient relationships with respect to the outcomes. A result of most recent 245 cases since 2001 had dramatically improved with 1-year graft survival is 96% and there is a significant difference between the groups in 2001 onwards and before. This study confirms that the outcome of ABO-incompatible living kidney transplantation in Japan is excellent and is similar to that in ABO-compatible cases. ABO-incompatible kidney transplantation has already become one of a standard, safety and effective treatment choice for end-stage renal disease.International Congress Series 01/2006; 1292:35-41.
- Transplantation Proceedings 01/1988; 19(6):4538-42. · 0.95 Impact Factor
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ABSTRACT: Historically, ABO-incompatible kidney transplantations have only been undertaken after splenectomy and unspecific plasmapheresis and with quadruple drug immunosuppression plus B-cell specific drugs. We have evaluated a protocol for ABO-incompatible kidney transplantation without splenectomy using antigen-specific immunoadsorption, rituximab, and a conventional triple-drug immunosuppressive regimen. The protocol called for a 10-day pretransplant conditioning period starting with one dosage of rituximab and followed by full dose tacrolimus, mycophenolate mofetil, and prednisolone. Antigen-specific immunoadsorption was performed on pretransplant days -6, -5, -4, and -1. After the last session, 0.5 g/kg of intravenous immunoglobulin was administered. Postoperatively, three more apheresis sessions were given every third day. Furthermore, if there was a significant increase in the antibody titers, extra sessions were considered. Four patients have received transplants with this protocol. The donor-recipient blood groups were A2/O, B/O, B/A, and A1/O. The ABO-antibodies were readily removed by the antigen-specific immunoadsorption and were kept at a low level posttransplantation by further adsorptions. There were no side effects, and all patients have normal renal-transplant function. We conclude that after one infusion each of rituximab and intravenous immunoglobulin and antigen-specific immunoadsorption, blood-group-incompatible renal transplantations can be performed with standard immunosuppression and without splenectomy.Transplantation 09/2003; 76(4):730-1. · 3.78 Impact Factor
Does Immunosuppressive Pharmacotherapy Affect Isoagglutinin
J.-P. Chuang, C.-J. Hung, S.-S. Chang, T.-C. Chou, and P.-C. Lee
Objective. Preoperative reduction of isoagglutinins leads to successful ABO-incompatible
(ABOi) renal transplantation. The strategy includes pretransplantation plasmapheresis,
more potent immunosuppressive drugs, splenectomy, and anti-CD20 antibody. It has been
reported that low isoagglutinin antibody titers posttransplant were observed among ABOi
renal transplants with favorable outcome. The isoagglutinin titers may increase slightly
when plasmapheresis is discontinued; however, it never returns to the pretreatment level
under immunosuppressive therapy. This raises the question of what occurs to the
isoagglutinin titer in ABO-compatible renal transplants under maintenance immunosup-
Methods. We analyzed 10 renal transplant recipients, including seven living and three
cadaveric donors. Patients were treated with basiliximab (20 mg) intravenously on day 0
and day 4. Maintenance immunosuppressive therapy involved a calcineurin inhibitor,
mycophenolate mofetil, and steroid. Anti-human globulin isoagglutinin titers were rou-
tinely examined 1 day before and day 0 and 1, 2, 3, 4, 8, 12, and 24 weeks posttransplant.
No ALG or intravenous immunoglobulin or plasmapheresis treatment was provided in the
Results. Our preliminary data showed nearly no influence on isoagglutinin titer levels in
6-month follow-up under maintenance immunosuppressive therapy. In addition, no
significant difference in isoagglutinin titer was observed between tacrolimus and cyclo-
Conclusion. Maintenance immunosuppressive pharmacotherapy did not affect isoagglu-
tinin titer levels in ABO-compatible kidney transplants. Further study is needed to
investigate the mechanisms of persistent low-level isoagglutinin titers among successful
ABOi renal transplantation patients.
These antigens are expressed not only on the surface of red
blood cells, but also in various organs including the kidneys.
Immunofluorescence studies with monoclonal antibodies
have shown that ABO antigens are located on vascular
endothelium, as well as in the convoluted distal and collect-
ing tubules of the kidney.1 In addition, humans have
antibodies against ABO antigens absent in the individual’s
own tissues according to the law formulated by Land-
steiner.2 Therefore, ABO blood type incompatibility be-
tween a donor and recipient is generally considered to be a
contraindication to kidney transplantation, because of the
risk of preformed antibody-mediated, hyperacute rejection.
HE ABO BLOOD GROUP SYSTEM is the most
important antigen in solid organ transplantation.
The current shortage of cadaveric allografts available for
transplantation is a global problem. In 1987, Alexandre and
colleagues published a historic series of 23 recipients of
ABO-incompatible renal transplants from living donors:
From the Department of Surgery (J.-P.C.), Tainan Hospital,
Taiwan, and Division of Organ Transplantation (C.-J.H., S.-S.C.,
T.-C.C., P.-C.L.), Departments of Surgery, National Cheng Kung
University Hospital, College of Medicine, National Cheng Kung
University, Tainan, Taiwan.
Address reprint requests to Dr Po-Chang Lee, Department of
Surgery, National Cheng Kung University Hospital, College of
Medicine, National Cheng Kung University, 138, Sheng Li Road,
Tainan 70428, Taiwan. E-mail: firstname.lastname@example.org
© 2008 Published by Elsevier Inc.
360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter
Transplantation Proceedings, 40, 2685–2687 (2008)2685
1-year graft survival was 79%, with 88% survival among
living related donor recipients.3The success of Alexandre’s
protocol was attributed to a desensitization protocol, con-
sisting of preoperative plasmapheresis, three-drug immuno-
suppression (antilymphocyte globulin, azathioprine, and
corticosteroids), and concomitant splenectomy. By prevent-
ing early anti-blood group antibody rebound, most proto-
cols prevent antibody mediated rejection during the first 2
or 3 weeks posttransplant, when it is most likely to lead to
graft loss.4When measuring serum antibody titers post-
transplant, we have observed that in cases with favorable
comes, antibody titers may increase slightly after the post-
transplant plasmapheresis treatments were discontinued,
but never achieved levels as high as pretreatment isoagglu-
tinin titers. However, there is still insufficient scientific
evidence to address the question: Is the persistent low-level
isoagglutinin titer achieved by maintenance immunosup-
pressive pharmacotherapy or other mechanism?
From October 2006 through February 2007, we examined 10
patients who received living or cadaver ABO-incompatible donor
kidney transplants at our institute. The mean observation period
was 8 months (range, 6–10 months). The mean age of the 10
recipients was 45 years (range ? 25–62 years). The recipients
comprised 5 (50%) men and 5 (50%) women. The ABO blood
types of the donors and recipients are shown in Table 1 The results
of all direct crossmatch tests before transplantation were negative.
Standard immunosuppressive therapy used for ABO-compatible
kidney transplantation consisted of induction therapy with basilix-
imab (20 mg) intravenously before graft reperfusion, followed by a
second infusion on day 4. Maintenance immunosuppressive ther-
apy involved a calcineurin inhibitor, mycophenolate mofetil, and
steroid. All anti-human globulin (AHG) phase isoagglutinin titers
were routinely checked pretransplant day 1, posttransplant day 0,
and 1, 2, 3, 4, 8, 12, and 26 weeks. ALG or intravenous immuno-
globulin or plasmapheresis treatment was performed during the
There were four patients of blood type A, three blood type
B patients, and three blood type O patients. All patients
showed good renal graft function on discharge. There was
no acute rejection episode in the follow-up period. Patient
07 with blood type B was lost to follow-up at 2 months
posttransplant due to mortality caused by sepsis. Our data
showed a slight influence of the level of isoagglutinin titer in
all patients (Figs 1–3). There was no significant difference in
isoagglutinin titer between tacrolimus and cyclosporine
ABO antigens are found in exocrine secretions as well as
expressed on the vascular endothelium of various organs.
The blood-group antigenic determinants are carried on the
Table 1. Characteristics of 10 Patients
AgentCNI ALG Cr
S, simulect two doses of 20 mg prior to transplantation and day 4; CNI,
calcineurin inhibitor; F, FK506; C, cyclosporine; ALG, ; Cr, patient serum
creatinine level on discharge day.
Anti-B isoagglutinin titers of blood type A patients (n ? 4).
Anti-A isoagglutinin titers of blood type B patients (n ? 4).
2686CHUANG, HUNG, CHANG ET AL
peripheral regions of carbohydrate chains linked to protein
and lipid residues in the cell membrane. The composition of
the terminal trisaccharide defines the ABO phenotype. It is
genetically controlled by glycosyltransferases, which are
highly specific. ABO antibody titers were determined using
standard serologic techniques.5Briefly, serial dilutions of
patient plasma were prepared in 0.9% saline. Group A or
group B indicator cells were incubated at room temperature
for 30 minutes, followed by 30 minutes at 37°C, and then
the AHG test phase. The titer endpoint was considered to
be the reciprocal of the highest dilution demonstrating
agglutination in the AHG phase.
Several investigators here reported that lowering the titer
of the offending anti-ABO antibodies pretransplantation
and maintaining the low levels for several weeks posten-
graftment allows good survival.6–8In cases of favorable
outcomes antibody titers may increase slightly under immu-
nosuppressive pharmacotherapy9,10after posttransplant
plasmapheresis treatments were discontinued, but never
achieve levels as high as the pretreatment isoagglutinin
titers. Someone may hypothesize that the persistently low
posttransplant isoagglutinin titer levels in successful ABO-
incompatible renal transplantation are largely caused by
ongoing immunosuppressive pharmacotherapy. However,
in our observation, immunosuppressive pharmacotherapy
showed nearly no influence on isoagglutinin titer levels over
6 months follow-up.
In conclusion, the increasing success of ABO-incompatible
living donor kidney transplantation has made this option
much more attractive. Our result suggested the mainte-
nance immunosuppressive pharmacotherapy alone may not
affect the level of isoagglutinin titer. Further immunologic
study is needed to investigate the mechanisms of persis-
tently low isoagglutinin titer levels posttransplant among
successful ABO-incompatible renal transplantations.
1. Takahashi K, Saito K, Tanabe K, et al: First report of a 7-year
survey on ABO-incompatible kidney transplantation in Japan. Clin
Exp Nephrol 5:119, 2001
2. Nobel Foundation, Nobel Lectures, Physiology or Medicine
1922–1941. Amsterdam: Elsevier; 1965
3. Alexandre GP, Squifflet JP, De Bruyere M, et al: Present
experiences in a series of 26 ABO-incompatible living donor renal
allografts. Transplant Proc 19:4538, 1987
4. Takahashi K: Excellent long-term outcome of ABO-incompatible
living donor kidney transplantation in Japan. Am J of Transplant
5. Brecher M, ed: Technical Manual, 14 ed. Arlington, VA:
American Association of Blood Banks; 2002, p 792
6. Montgomery RA, Zachary AA, Racusen LC, et al: ABO
incompatible high-titer renal transplantation without splenectomy
or anti-CD20 treatment. Am J Transplant 5:2570, 2005
7. Alexandre GPJ, Squifflet JP, Bruyere MDE, et al: Splenec-
tomy as a prerequisite for successful human ABO-incompatible
renal transplantation. Transplant Proc 17:138, 1985
8. Tyden G, Kumlien G, Fehrman I: Successful ABO-incompatible
kidney transplantations without splenectomy using antigen-specific
immunoadsorption and rituximab. Transplantation 76:730, 2003
9. Sonnenday CJ, Warren DS, Cooper M, et al: Plasmaphere-
sis, CMV hyperimmune globulin, and anti-CD20 allow ABO-
incompatible renal transplantation without splenectomy. Am J
Transplant 4:1315, 2004
10. Takahashi K: Present status of ABO-incompatible kidney
transplantation in Japan. Xenotransplantation 13:118, 2006
patients (n ? 3).
Anti-A and anti-B isoagglutinin titers of blood type O
IMMUNOSUPPRESSIVE PHARMACOTHERAPY 2687