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: ABO-incompatible kidney transplantation is a promising strategy for enlargement of living-donor pools. In recent years, recipient desensitization by blood group antigen-specific immunoadsorption, together with rituximab and intravenous immunoglobulin, has allowed excellent graft performance after ABO-incompatible transplantation. Adopting this protocol, originally described by Tydén and coworkers, we performed four living-donor renal transplants across the ABO barrier (A1-->0, A1-->B, B-->A1, A2-->0) between July 2007 and August 2008. Recipients were aged 25-66 years, donors 49-69 years. A protocol of on-demand immunoadsorption was followed, based on serial post-transplant antibody monitoring. Substantial and sustained decrease of blood group antibody levels was achieved in all four recipients, therefore post-transplant immunoadsorption was not needed. Graft and patient survival after 4-18 months' follow-up was 100%. Current serum creatinine was 1.3-2.0 mg/dl. Two grafts showed C4d deposits in peritubular capillaries in the complete absence of typical morphological features of antibody-mediated rejection. One recipient experienced early graft dysfunction, diagnosed as Banff borderline lesion, which responded well to steroid pulse therapy. The same recipient developed de novo interstitial fibrosis/tubular atrophy and arteriolar hyalinosis, presumably the result of suboptimal control of blood pressure and/or calcineurin inhibitor therapy. Two of the four recipients developed lymphoceles necessitating surgical revision. Apart from urinary tract infection in three patients and subclinical CMV in one, no major infectious complications were reported. Notably, two stable recipients developed polyoma BK viremia without clinical or morphological manifestations of polyomavirus-associated nephropathy. The results obtained in our small series support the earlier reported high efficiency of desensitization based on antigen-specific immunoadsorption. Nevertheless, the lack of long-term data will necessitate continuous and prudent consideration of the benefits and risks of this strategy.Wiener klinische Wochenschrift 06/2009; 121(7-8):247-55. · 0.81 Impact Factor
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ABSTRACT: In the past, ABO blood group incompatibility was considered an absolute contraindication for kidney transplantation. Progress in defined desensitization practice and immunologic understanding has allowed increasingly successful ABO incompatible transplantation during recent years. This paper focused on the history, disserted outcomes, desensitization modalities and protocols, posttransplant immunologic surveillance, and antibody-mediated rejection in transplantation with an ABO incompatible kidney allograft. The mechanism underlying accommodation and antibody-mediated injury was also described.Journal of Transplantation 01/2011; 2011:970421.
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ABSTRACT: The murine and the human genome have global properties in common. So the murine anti-A-specific complementary IgM and related human innate isoagglutinin represent developmental, 2-mercaptoethanol-sensitive, complement-binding glycoproteins, which do not arise from any measurable environmentally-induced or auto- immune response. The murine anti-A certainly originates from a cell surface- or cell adhesion molecule, which in the course of germ cell development becomes devoid of O-GalNAc-transferase and is released into the circulation. In human sera the enzyme occurs exclusively in those of blood group A- and AB subjects, while in group O(H) an identically encoded protein lets expect an opposite function and appears in conjunction with a complementary anti-A reactive glycoprotein. Since O-glycosylations rule the carbohydrate metabolism in growth and reproduction processes, we propose that the ancestral histo-(blood)-group A molecule arises in the course of O-GalNAc-glycosylations of glycolipids and protein envelops at progenitor cell surfaces. Germ cell development postulates embryonic stem cell fidelity, which is characterised by persistent production of α-linked O-GalNAc-glycans. They are determined by the A-allele within the human, "complete" histo (blood) group AB(O) structure that in early ontogeny is hypothesised to be synthesised independently from the final phenotype. The structure either passes "completely" through the germline, in transferase-secreting mature tissues becoming the "complete" phenotype AB, or disappears in exhaustive glycotransferase depletion from the differentiating cell surfaces and leaves behind the "incomplete" blood group O-phenotype, which has released a transferase- and O-glycan-depleted, complementary glycoprotein (IgM) into the circulation. The process implies, that in humans the different blood phenotypes evolve from a "complete" AB(O) molecular complex in a distinct enzymatic and/or complement cascade suggesting O-glycanase involvements. While the murine and human oocyte zona pellucida express identical O-glycans, the human phenotype O might be explainable by the kinetics of the murine ovarian O-GalNAc glycan synthesis and the complementary anti-A released in parallel. The maturing murine ovary may provide insight into encoding of the physiologically superior α-linked GalNAc ancestral epitope that becomes essential in reproduction as well as in tissue renewal events. According to recent reports, O-GalNAc-transferase-determined blood group A suggests superiority in human female fertility and was called even "protective". So the minor fertility of blood-group-O females may reside in a critical timing in developmental shifting of enzyme functions affecting the formation of GalNAc-determined hormone receptors on the way to maturation. Experiments that had inserted an oocyte genome into a somatic one to generate pluripotent stem cells, might elucidate a developmental dilemma by testing oocytes from different blood group AB donors donors. Perhaps they will unmask the molecular basis of an evolutionary trend, while stem cell generation itself capitalises on the enzymatically-advantaged, lineage-maintaining (histo) blood group A-allele, which guaranties ancestral functional completeness.Immunobiology 11/2013; · 2.81 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: email@example.com
© 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