REVIEW
The critical role of plasmapheresis in ABO-incompatible
renal transplantation
Aaron A.R. Tobian, R. Sue Shirey, Robert A. Montgomery, Paul M. Ness, and Karen E. King
BACKGROUND: Thousands of patients with chronic
renal failure die yearly and are unable to have a kidney
transplant due to the severe shortage of donors. Thera-
peutic plasma exchange (TPE) is performed to remove
ABO antibodies and permit ABO-incompatible (ABO-I)
kidney transplants, but there is only limited research
within this area and a lack of standardized protocols for
TPE. This article reviews the literature to provide a his-
torical perspective of TPE for ABO-I kidney transplanta-
tion and also provides the Johns Hopkins Hospital
protocol with a focus on both titers and TPE.
STUDY DESIGN AND METHODS: The TPE treatment
plan is based on ABO titers with the goal of a titer of 16
or less at the anti-human globulin (AHG) phase before
surgery. Pretransplant therapy consists of every-other-
day TPE followed immediately by cytomegalovirus
hyperimmune globulin. ABO antibody titers are closely
monitored before and after transplantation. After trans-
plantation, TPE therapy is performed for all patients to
prevent rebound of anti-A and anti-B titers until toler-
ance or accommodation occurs. TPE is discontinued
and reinstituted based on the clinical criteria of creati-
nine levels, biopsy results, and ABO titer.
RESULTS: Fifty-three ABO-I kidney transplants have
been completed with no episodes of hyperacute
antibody-mediated rejection (AMR) and only three epi-
sodes of AMR. One-year death-censored graft survival
is 100 percent and patient survival is 97.6 percent.
CONCLUSIONS: While randomized clinical trials are
needed to evaluate the optimal method and protocol to
remove ABO antibodies, the current literature and our
results indicate a critical role for TPE in ABO-I renal
transplantation.
L
andsteiner discovered the ABO blood group
antigen system on red blood cells (RBCs) more
than a century ago. Further investigations dem-
onstrated that these antigens are expressed
throughout the body,1 including embryonic kidney cells,2
vascular endothelium, convoluted distal tubules, and col-
lecting tubules.3 It is the naturally occurring antibodies
that are produced against ABO antigens that are not
present in one’s own tissues that are key mediators of
antibody-mediated rejection (AMR) and prevent renal
transplantation across ABO barriers.4,5 In hyperacute
rejection, it is the existing circulating antibodies directed
against ABO, HLA, or other alloantibody-to-donor endot-
helial surface antigens that usually lead to rejection within
minutes to hours. The alloantibodies bind to peritubular
and glomerular capillaries and activate complement.4
The chronic form of AMR can occur years after
transplantation.
The ideal treatment of end-stage renal failure is
kidney transplantation. Unfortunately, a severe donor
shortage has significantly limited this practice. In 2005,
there were more than 80,000 patients awaiting kidney
transplantation and more than 4000 patients that died
waiting for a kidney transplant (11.1 patients per day).6
The median wait time for patients of different ABO blood
ABBREVIATIONS: ABO-I = ABO-incompatible; AHG = anti-
human globulin; AMR = antibody-mediated rejection; CMVIg =
cytomegalovirus immune globulin intravenous;
FK506 = tacrolimus; MMF = mycophenolate mofetil;
TPE = therapeutic plasma exchange.
From the Department of Pathology, Transfusion Medicine Divi-
sion, The Johns Hopkins Hospital, Baltimore, Maryland.
Address reprint requests to: Aaron A.R. Tobian, Department
of Pathology, Transfusion Medicine Division, The Johns Hopkins
Hospital, 600 N. Wolfe Street, Carnegie 667, Baltimore, MD
21287; e-mail: atobian1@jhmi.edu.
Received for publication March 28, 2008; revision received
May 27, 2008; and accepted May 28, 2008.
doi: 10.1111/j.1537-2995.2008.01857.x
TRANSFUSION 2008;48:2453-2460.
Volume 48, November 2008 TRANSFUSION 2453
TOBIAN ET AL.
groups varies significantly. If registered in 2001, the
median wait time for patients of blood group O is 1836
days, while patients of blood group AB wait only 732 days.6
Owing to the cadaveric organ shortage and the different
frequency of each blood group, ABO immunologic barri-
ers are being reevaluated. Removing this barrier could
expand the donor pool, increase availability of organs for
transplantation, and decrease time on the organ waiting
list, ultimately facilitating transplantation before patients
experience comorbid conditions. It has been estimated
by blood group distributions that there is a 36 percent
probability that any two individuals in the population
are ABO-incompatible (ABO-I).7 While ABO-I kidney
transplantation is currently an American Society for
Apheresis (ASFA) Category II indication for therapeutic
plasma exchange (TPE), there is only limited research in
this area; no clinical trials evaluating different TPE
procedures; and a lack of standardized protocols, moni-
toring, and reporting.7,8
Historical perspective
The ABO blood group transplantation barrier was revered
as insurmountable until recently due to initially poor
experiences crossing the barrier. In 1955, Hume and col-
leagues9 reported an ABO-I renal transplant. The donor
was blood group B+ and the recipient was blood group O+.
The allograft never showed significant function and the
recipient died within 25 days of the transplant.9 In 1964,
Starzl and colleagues10 initially stated that transplantation
across ABO was acceptable, but then amended their
manuscript after further experience. They did, however,
establish that the pattern of acceptable tissue transfer is
similar to blood transfusions with group O patients as
universal donors and AB patients as universal re-
cipients. Overall, ABO-I transplantation was principally
abandoned.10
In 1970, Bier and colleagues11 began to show the
potential role of TPE in ABO-I renal transplantation when
they demonstrated that selective TPE reduces circulating
antibody and significantly delays rejection of porcine
kidney xenografts in dogs. Subsequently, Bensinger and
colleagues12 documented 81 patients who had TPE or
immunoadsorption to remove ABO antibodies and then
successfully engrafted ABO-I marrow. That same year, a
case report was published of a patient with blood group O
that inadvertently received a mismatched kidney. The
patient was treated with TPE, had rapid reversal of clinical
and pathologic manifestations of rejection, and had
normal renal function and normal biopsies 20 months
after transplantation.13 These studies allowed clinicians to
evaluate the role of TPE to permit ABO-I renal transplants.
In the 1980s, there was some success in the transplan-
tation of A2 kidneys into O recipients without TPE.14,15 The
most common subgroups of blood group A are A1 and A2.
2454 TRANSFUSION Volume 48, November 2008
While both subgroups react strongly with anti-A in direct
agglutination testing, there is both a qualitative and a
quantitative difference.16 Approximately 80 percent of the
Western population is A1 and the remaining 20 percent is
A2. Anti-A1 is produced in 1 to 2 percent of A2 individuals
and 25 percent of A2B individuals.16 Since the
A1-transferase is more efficient at converting H substance
into A antigen and capable of making repetitive Type 3 or
Type 4 A structures, there are approximately five times
more A antigen sites on A1 RBCs than A2 RBCs.16,17 Type 4 A
structures are the dominant compound expressed on
kidneys.17,18 Owing to the difference in antigen and anti-
body production A2 kidneys were more compatible in O
recipients.
In 1987, Alexandre and coworkers19 monitored 26
recipients of live-donor ABO-I kidney transplants. The
donors received triple drug immunosuppressive therapy,
splenectomy, and preoperative TPE to remove naturally
occurring anti-A and anti-B antibodies. There was a 1-year
graft survival of 88 percent among living-related donor
recipients.19 The authors stated that TPE and splenectomy
are important. In a separate article, the authors report a
loss of three grafts due to aggressive AMR in patients who
did not have a splenectomy.20 Bannett and colleagues21
also documented six cases of ABO-I renal allografts in
recipients that received preconditioning therapy of immu-
noadsorption to remove ABO antibodies, immunosup-
pression, and splenectomy. While these groups of
clinicians made significant contributions to the advance-
ment of ABO-I renal transplantation, the practice was
limited in the Western hemisphere due to increased organ
sharing and efforts to optimize the availability of cadav-
eric kidneys.
The extreme shortage of organs in Japan, however,
forced surgeons to continue to examine the possibility of
ABO-I kidney transplants. The Tokyo Women’s Medical
College is the most prolific in documenting their results
in the literature. To remove ABO antibodies and prevent
hyperacute rejection, Toma and colleagues18,22 used
double-filtration plasmapheresis with or without immu-
noadsorption before transplantation. Double-filtration
plasmapheresis has a plasma separator for the first filter
and a plasma fractionator with a smaller pore size for the
second filter and consequently requires less replacement
fluid (typically 0.5-1.0 L of an 8% albumin solution) com-
pared to centrifugation plasmapheresis.18,23,24 For immu-
noadsorption, they used a column that has chemically
synthesized human blood group ABO antigens covalently
linked to crystalline silica.18 Before transplantation, the
Japanese group performed TPE until immunoglobulin M
(IgM) and immunoglobulin G (IgG) titers of anti-A and
anti-B decreased to 16 or less.22 The Japanese protocol also
involved quintuple drug immunosuppression (methyl-
prednisolone, cyclosporine, azathioprine, antilymphocyte
globulin, and deoxyspergualin).18,25 More recently,
 PLASMAPHERESIS IN ABO-INCOMPATIBLE RENAL TRANSPLANTATION

patients received tacrolimus (FK506) and mycophenolate
mofetil (MMF) with improved results.22,26,27 The Japanese
group believes that splenectomy is important in ABO-I
renal transplants.22 Toma and colleagues18,22 maintain
anti-A and anti-B titers below 16 with posttransplant TPE.
With the extensive pretransplant preparative
regimen, the Tokyo Women’s Medical University had
encouraging results. Compared to the 620 patients who
had ABO-compatible kidney transplants, the survival rate
for the 105 patients who had ABO-I transplantation was
not significantly different with a 1-year survival of 92
percent and a 10-year survival of 89 percent.22 Graft sur-
vival, however, is lower in ABO-I recipients. Acute rejec-
tion was the most frequent cause of graft loss in ABO-I
kidney transplantation occurring in 12.4 percent of
patients (13 of 105 cases) compared to only 2.4 percent of
ABO-compatible recipients (15 of 620 cases).22
While the Japanese protocol was initially encourag-
ing, they continued to modify their techniques. The phy-
sicians at Tokyo Women’s Medical University initially
found that high ABO antibody titers correlate with
increased graft loss. In one study, all 93 patients had anti-A
and anti-B titers below 4 immediately after transplant.
While 75 percent of patients continued to have low titers,
25 percent of patients (23 cases) had posttransplant titers
that increased to greater than 16. Among these 23 cases, 11
of 16 patients (69%) with titers greater than or equal to 32
lost their graft. Among the remaining 7 patients with an
elevated titer of 16, only 1 of 7 (14%) lost their graft.28 The
same group also evaluated preoperative ABO titers and
found that initial high antibody titers are associated with a
requirement for posttransplant TPE and an increase inci-
dence of humoral rejection.29 The authors found that the
graft survival rate of patients with an initial maximum IgG
titer less than 16 was 81 percent, while those patients that
had an initial titer greater than 128 only had a 42 percent
1-year graft survival.29 After the Japanese group changed
from their original quintuple immunosuppressive therapy
to tacrolimus, MMF, and steroids, however, they did not
find a correlation between preoperative ABO antibody
titer and graft survival.30
and liver disease. The initial laboratory testing of patients
includes HLA and ABO typing and titers, T-cell cross-
match, comprehensive metabolic panel, complete blood
count, coagulation studies, and infectious disease screen-
ing (hepatitis A, hepatitis B, hepatitis C, Treponema
pallidum, Epstein-Barr virus, CMV, and human immuno-
deficiency virus). All patients are vaccinated for Strepto-
coccus pneumoniae, Neisseria menigitidis, and
Haemophilus influenzae regardless of splenectomy status.
Titers
Our titration procedure is similar to the method described
by Winters and colleagues.31 ABO antibody titers are per-
formed using donor-type indicator RBCs and incubation
at phases that include room temperature (22°C) test phase
that is generally reflective of IgM antibody activity, fol-
lowed by 37°C incubation and conversion to the anti-
human globulin (AHG) phase for optimum detection of
IgG antibody.
Most centers performing ABO-I kidney transplants
use the antiglobulin (IgG) antibody titer endpoint as the
critical titer when assessing patients before and after
transplantation. In fact, some centers routinely determine
titers using dithiothreitol-treated serum to inactivate IgM
antibodies so that the titer will correspond only to the
level of IgG antibodies that are present in the sample.32-35
Therapeutic plasmapheresis
The foundation of the TPE treatment plan is based on the
anti-A and anti-B titers with the goal of achieving ABO
titer at the AHG phase of 16 or less before surgery. Owing
to the generally predictable nature of antibody removal by
TPE, the number of necessary treatments before trans-
plant is estimated by the titer (Table 1). Higher titers
require greater numbers of TPE procedures. For example,
a patient with an antibody titer of 256 will usually require
between seven and eight preconditioning treatments. This

TABLE 1. Guidelines for the number

MATERIALS AND METHODS of TPE/CMVIg treatments based on initial
antibody titer
The Incompatible Kidney Transplant Program at Johns Number of treatments
Hopkins Hospital allows patients to receive an ABO-I ABO antibody titer* Before transplant After transplant
kidney from a living donor of incompatible blood group. <16 2 2
To be eligible for the program, the recipient must have 16 2 2
32 3 3
end-stage renal disease without significant complications
64 4 3
such as malignancy and lack an appropriate ABO- 128 5-6 3
compatible donor. The donor and the recipient undergo 256 7-8 4
512 9-10 4
extensive medical, psychological, and social work evalua-
1024 10-12 4
tions. The recipient must also be willing to undergo TPE >1024 >15 5
before and after the transplant and be evaluated for other * Antibody titer at the AHG phase.
comorbid conditions that complicate TPE such as heart

Volume 48, November 2008 TRANSFUSION 2455

TOBIAN ET AL.
same patient will also likely need four posttransplant
treatments. Owing to the variability of titers and cross-
match sensitivities among different laboratories and
programs, however, Table 1 should only be used as a
guideline.
After each TPE procedure, low-dose (100 mg/kg)
cytomegalovirus immune globulin intravenous (CMVIg;
Cytogam, MedImmune, Inc., Gaitherburg, MD) is given
(TPE/CMVIg). TPE/CMVIg is the mainstay of our antibody
reduction therapy. Low-dose CMVIg is thought to immu-
nomodulate by replacing removed antibody and sup-
pressing de novo antibody production, so-called antibody
rebound. CMVIg together with TPE consequently is asso-
ciated with durable elimination and suppression of
antibody titers. CMVIg is used at Johns Hopkins Hospital
rather than intravenous immune globulin (IVIG) due to
increased availability historically and subsequent clinical
success. TPE/CMVIg is used to precondition patients and
also to rescue kidneys undergoing AMR. If the transplant
is not performed soon after preconditioning, the antibody
titers may rebound.
Pretransplant therapy consists of every-other-day
TPE followed immediately by CMVIg. An apheresis system
(COBE Spectra, Gambro BCT, Lakewood, CO) is used for
TPE. Each TPE session consists of 1-plasma-volume
exchange replaced at 100 percent volume with 5 percent
serum albumin. Four milliliters of 0.465 mEq calcium
gluconate is added to each 500-mL bottle of 5 percent
albumin. Acid citrate dextrose-A (ACD-A) is used as the
anticoagulant at a whole blood to ACD-A ratio of 13 to 1. If
a patient is at risk for bleeding due to either biopsy or
surgery, plasma that is matched for donor and recipient is
used as part of the replacement fluids.
An individualized plan is developed for each patient
by first setting the date of transplant and determining the
number of treatments. TPE is generally performed every
other day. For example, if it is determined that the patient
will need five TPE/CMVIg treatments to achieve the end-
point of therapy, then TPE would begin 10 days before
transplant (Fig. 1). Antibody titers are determined before
and after TPE. Rarely, if the endpoint of therapy is not
achieved by the day of the planned procedure, additional
daily procedures may be added (including the day of
surgery) or the transplant may be delayed to a later day so
that more TPE treatments can be performed.
ABO antibody titers are closely monitored after trans-
plantation and it is important for all patients to routinely
receive several posttransplant TPE/CMVIg treatments.
Posttransplant TPE therapy appears to be helpful in pre-
venting rebound of anti-A and anti-B titers until tolerance
or accommodation occurs. The number of posttransplant
treatments is based on the initial antibody titer and the
level of risk of AMR. For example, high-risk patients have
higher antibody levels, previous early graft losses, and
rebounding titers between treatments. Antibody screen-
2456 TRANSFUSION Volume 48, November 2008
Anti-CD20
and/or
splenectomy
Anti-CD20
FK506
MMF and/or
Steroids splenectomy
Daclizumab
Tx
PP/Ig PP/Ig PP/Ig PP/Ig PP/Ig PP/Ig PP/Ig PP/Ig
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6
Time in days
Fig. 1. Schematic of an example treatment plan for a patient
with anti-A or anti-B titer of 128. FK506 and MMF are begun
after the first TPE/CMVIg treatment (PP/Ig). On the day of
transplant (Tx), a high-risk patient has splenectomy and/or
anti-CD20 therapy. Methylprednisolone and daclizumab are
also initiated on the day of surgery. All patients receive post-
transplant TPE/CMVIg.
ing is performed before and after each posttransplant
TPE/CMVIg treatment; 72 hours after the last planned
treatment; at weekly intervals for the first month; and at 2,
3, 6, and 12 months. For ABO-I renal transplantation, the
ABO titer alone cannot predict graft failure. Thus, TPE is
discontinued and reinstituted based on the clinical crite-
ria of creatinine levels, biopsy results, and ABO titer.
AMR is assessed by serum creatinine and kidney
biopsy.36,37 The predominant and milder form of AMR is
treated by reinitiating every-other-day TPE/CMVIg and
administering pulse steroids. The endpoint of therapy is
resolution of AMR, decreasing titers, and decreasing crea-
tinine levels. The severe form of AMR that is found by a
rapid increase in serum creatinine followed closely by the
onset of anuria, severe vasculitis with fibrin thrombi
occluding arterioles and glomeruli, and intense C4d
staining is rare.36 Treatment for this form of AMR, however,
should be initiated immediately and aggressively. The
patient may be given anti-CD20 and/or emergent sple-
nectomy and TPE/CMVIg. TPE/CMVIg can be performed
daily with monitoring of coagulation status (to avoid
bleeding from excess TPE procedures) until the titer is
brought under control.
Immunosuppression
At the time TPE is initiated, FK506 (4 mg/day divided into
two doses) and MMF (2 g/day into two doses) are started
to suppress both T cells and B cells. Steroids (100 mg of
dexamethasone intraoperative and then 25 mg every 6 hr
for six doses) and daclizumab (Zanapax, Roche, Nutley,
NJ; 2 mg/kg) are administered on the day of surgery. After
transplant, the steroids are tapered and the patient is
given 30 mg of prednisone daily as soon as the FK506 is
therapeutic after transplant. Four additional doses of
 PLASMAPHERESIS IN ABO-INCOMPATIBLE RENAL TRANSPLANTATION
daclizumab (1 mg/kg) are given at 2-week intervals. Long
term, the patients are maintained on FK506, MMF, and
low-dose prednisone (5-10 mg/day).
Splenectomy, particularly for immunosuppressed
patients, is a major concern of ABO-I kidney transplanta-
tion. Splenectomy reduces early graft loss from AMR but
does not appear to affect graft survival after the first 3
months. Our center and others have used anti-CD20 (a
monoclonal antibody against B cells) as an alternative to
splenectomy with excellent results in recipients of A1, A2,
and B kidneys.38,39 We have recently demonstrated,
however, that patients with high AHG titers (>64) can be
successfully pre-conditioned with TPE/CMVIg without
splenectomy or anti-CD20.40,41 Splenectomy (performed
just before the transplant using laparoscopic techniques)
and anti-CD20 are now reserved for high-risk patients.
Alternative approaches
While the Mayo Clinic uses similar preconditioning
methods as Johns Hopkins Hospital,31,42 the Stockholm
experience demonstrates that immunoadsorption using
columns with synthetic A- or B-trisaccharide carbohy-
drate epitopes linked to a Sepharose matrix may be used
to remove ABO antibodies. The group initially found that
the ABO columns (Glycosorb, Glycorex Transplantation,
Lund, Sweden) have high capacity for antibody removal
without nonspecific protein adsorption, activation of
coagulation factors, or activation of complement.43 One
disadvantage of the immunoadsorbent columns is that
they must be connected in a series to remove both anti-A
and anti-B antibodies. The columns may also be costly
because they are only designed for single use. The Swedish
investigators, however, found that the columns can be
regenerated with a similar method that is designed for
protein A column regeneration.44 The Swedish group also
demonstrated that splenectomy is not needed when
immunoadsorption and anti-CD20 are used for precondi-
tioning of ABO-I kidney transplants.45,46
RESULTS
A total of 53 ABO-I renal transplants involving all of the
different combinations of ABO blood groups have been
performed at Johns Hopkins Hospital using TPE precon-
ditioning.41 The mean follow-up period is 24.9 months
(range, 1-93.3 months). Overall, there is excellent allograft
performance and no episodes of hyperacute rejection.
Three patients (5.7%) experienced AMR. AMR was
reversed in two of these patients with TPE and one
required splenectomy. The majority of these AMR epi-
sodes was successfully treated with TPE and increased
immunosuppression. At Year 3, the median serum creati-
nine concentration is 1.2 mg per dL (range, 0.8-3 mg/dL)
and the glomerular filtration rate is 63.4 mL per minute
(range, 22.8-113.5 mL/min). Overall, there is a 100 percent
1-year graft survival among those who did not die (death
censored graft survival), 93.4 percent 3-year graft survival,
and 97.6 percent patient survival.41 Complications from
TPE are minimal and include nausea, citrate toxicity,
hypotensive symptoms, and allergic reactions.
Among these ABO-I renal transplants, we also found
that TPE/CMVIg preconditioning can simultaneously
suppress ABO and HLA titers to permit renal transplanta-
tion across two immunologic barriers.47 Unlike the initial
Japanese data that showed high pretransplant anti-A and
anti-B titers correlate with increased graft loss,28,29 we did
not find this correlation.
TPE for ABO-I renal transplants is also being success-
fully performed at other institutions. For 26 ABO-I renal
transplants, the Mayo Clinic had no episodes of hyper-
acute rejection. AMR occurred in 46 percent of patients,
but was reversed in 83 percent by TPE and increased
immunosuppression.31 They had a graft survival of 85
percent and patient survival of 92 percent.31 Initially, all
patients had splenectomy; however, later the Mayo Clinic
determined that splenectomy may be replaced by anti-
CD20.48 In addition, the Swedish group demonstrated
through a multicenter study of 60 ABO-I kidney trans-
plants using preconditioning methods of immuno-
adsorption, IVIG, anti-CD20, and conventional
immunosuppression that they could achieve a graft sur-
vival of 97 percent and patient survival of 98 percent.49
These successful transplants suggest that the protocol
described in this article can be used at other institutions.
CONCLUSIONS
In this review, we demonstrate that ABO-I kidney trans-
plantation can be successfully performed after a precon-
ditioning regimen of TPE/CMVIg. Patients who have high
initial ABO antibody titers often require more TPE/CMVIg
treatments to achieve therapeutic endpoints. Our patients
have had excellent graft and overall patient survival with
minimal complications due to TPE. Work by other institu-
tions confirms that procedures similar to ours can be per-
formed successfully. While there are several protocols for
TPE to reduce antibody titers, there is a lack of clinical
trials to provide a standardized procedure.
In addition to controlled clinical trials, further basic
science work needs to be conducted on incompatible
transplants. There is still a lack of understanding of the
immunologic mechanism for a temporary reduction of
ABO titer to permit organ survival. While the presence of
ABO antibodies leads to hyperacute rejection after ABO-I
transplantation, these same antibodies can return from
low levels and the graft continues to function well, a situ-
ation termed accommodation. The mechanism of accom-
modation is still uncertain, but is hypothesized to be due
to an increase in resistance of graft endothelial cells to
Volume 48, November 2008 TRANSFUSION 2457
TOBIAN ET AL.
injury mediated by the host immune system.50 Further
work should be performed in understanding the mecha-
nisms of both accommodation and tolerance. This work
may also lead to understanding more efficient approaches
to decrease titers.
Further research is also needed to streamline ABO
antibody titer determinations. Using a semiquantitative
titration method, the titer endpoint is affected by many
variables including the RBC phenotype (e.g., group A1 or
A2) and concentration of the indicator RBCs, as well as
incubation times and temperatures.51 Thus, reproducibil-
ity, interpretation, and comparison of anti-A or anti-B
titers reported for ABO-I kidney transplant recipients are
problematic. The lack of a universally accepted titer pro-
tocol makes comparative studies from different institu-
tions difficult. Cohney and coworkers52 recently reported
that ABO antibody titers by a gel card method showed
better clinical correlation than standard test tube titers.
Undoubtedly, the gel card method, as well as automated
methods for determining ABO antibody titers, will be
further explored to find the ideal method for monitoring
ABO-I renal transplant patients. In addition, research to
identify the clinical relevance of titer endpoints in rela-
tionship to graft survival is needed.
The ABO blood group transplantation barrier is now
being crossed and ABO-I kidney transplants are becoming
more common. Further research and clinical trials should
be performed to determine the optimal protocol for TPE
to remove ABO antibodies and prevent AMR. Both TPE
and titer determinations, however, are a growing area
where the reference laboratory and transfusion medicine
physicians perform a critical and expanding role.
REFERENCES
1. Szulman AE. The histological distribution of blood group
substances A and B in man. J Exp Med 1960;111:785-800.
2. Hogman C. The principle of mixed agglutination applied to
tissue culture systems; a method for study of cell-bound
blood-group antigens. Vox Sang 1959;4:12-20.
3. Breimer ME, Molne J, Norden G, Rydberg L, Thiel G,
Svalander CT. Blood group A and B antigen expression
in human kidneys correlated to A1/A2/B, Lewis, and
secretor status. Transplantation 2006;82:479-85.
4. Colvin RB. Antibody-mediated renal allograft rejection:
diagnosis and pathogenesis. J Am Soc Nephrol 2007;18:
1046-56.
5. Montgomery RA, Hardy MA, Jordan SC, Racusen LC,
Ratner LE, Tyan DB, Zachary AA; Antibody Working Group
on the diagnosis, reporting, and risk assessment for
antibody-mediated rejection and desensitization protocols.
Consensus opinion from the antibody working group on
the diagnosis, reporting, and risk assessment for antibody-
mediated rejection and desensitization protocols. Trans-
plantation 2004;78:181-5.
2458 TRANSFUSION Volume 48, November 2008
6. 2006 Annual Report of the U.S. Organ Procurement and
Transplantation Network and the Scientific Registry of
Transplant Recipients: Transplant Data 1996-2005. Rock-
ville (MD): Department of Health and Human Services,
Health Resources and Services Administration, Healthcare
Systems Bureau, Division of Transplantation; Richmond
(VA): United Network for Organ Sharing; Ann Arbor (MI):
University Renal Research and Education Association;
2006.
7. Montgomery RA. ABO incompatible transplantation: to B
or not to B. Am J Transplant 2004;4:1011-2.
8. Szczepiorkowski ZM, Bandarenko N, Kim HC, Linenberger
ML, Marques MB, Sarode R, Schwartz J, Shaz BH, Wein-
stein R, Wirk A, Winters JL; American Society for Apheresis;
Apheresis Applications Committee of the American Society
for Apheresis. Guidelines on the use of therapeutic apher-
esis in clinical practice: evidence-based approach from the
Apheresis Applications Committee of the American Society
for Apheresis. J Clin Apheresis 2007;22:106-75.
9. Hume DM, Merrill JP, Miller BF, Thorn GW. Experiences
with renal homotransplantation in the human: report of
nine cases. J Clin Invest 1955;34:327-82.
10. Starzl TE, Marchioro TL, Holmes JH, Harmann G, Brittain
RZ, Stonington OH. Renal homografts in patients with
major donor-recipient blood group incompatibilities.
Surgery 1964;55:195-200.
11. Bier M, Beavers CD, Merriman WG, Merkel FK, Eiseman B,
Starzl TZ. Selective plasmapheresis in dogs for delay of
heterograft response. Trans Am Soc Artif Intern Organs
1970;16:325-33.
12. Bensinger WI, Buckner CD, Thomas ED, Clift RA. ABO-
incompatible marrow transplants. Transplantation 1982;33:
427-9.
13. Slapak M, Naik RB, Lee HA. Renal transplant in a patient
with major donor-recipient blood group incompatibility:
reversal of acute rejection by the use of modified plasma-
pheresis. Transplantation 1981;31:4-7.
14. Nelson PW, Helling TS, Pierce GE, Ross G, Shield CF, Beck
ML, Blake B, Cross DE. Successful transplantation of blood
group A2 kidneys into non-A recipients. Transplantation
1988;45:316-9.
15. Rahman T, Harper L. Plasmapheresis in nephrology: an
update. Curr Opin Nephrol Hypertens 2006;15:603-9.
16. Brecher ME. Technical manual. 15th ed. Bethesda (MD):
American Association of Blood Banks; 2005.
17. Rydberg L. ABO-incompatibility in solid organ transplanta-
tion. Transfus Med 2001;11:325-42.
18. Toma H. ABO-incompatible renal transplantation. Urol
Clin North Am 1994;21:299-310.
19. Alexandre GP, Squifflet JP, De Bruyere M, Latinne D,
Reding R, Gianello P, Carlier M, Pirson Y. Present experi-
ences in a series of 26 ABO-incompatible living donor
renal allografts. Transplant Proc 1987;19:4538-42.
20. Alexandre GP, Squifflet JP, De Bruyere M, Latinne D,
Moriau M, Ikabu N, Carlier M, Pirson Y. Splenectomy as a
 PLASMAPHERESIS IN ABO-INCOMPATIBLE RENAL TRANSPLANTATION
prerequisite for successful human ABO-incompatible renal
transplantation. Transplant Proc 1985;17:138-43.
21. Bannett AD, McAlack RF, Raja R, Baquero A, Morris M.
Experiences with known ABO-mismatched renal trans-
plants. Transplant Proc 1987;19:4543-6.
22. Toma H, Tanabe K, Tokumoto T. Long-term outcome of
ABO-incompatible renal transplantation. Urol Clin North
Am 2001;28:769-80.
23. Bosch T. Therapeutic apheresis—state of the art in the year
2005. Ther Apher Dial 2005;9:459-68.
24. Tanabe K. Double-filtration plasmapheresis. Transplanta-
tion 2007;84 12 Suppl:S30-2.
25. Tanabe K, Takahashi K, Sonda K, Tokumoto T, Ishikawa N,
Kawai T, Fuchinoue S, Oshima T, Yagisawa T, Nakazawa H,
Goya N, Koga S, Kawaguchi H, Ito K, Toma H, Agishi T, Ota
K. Long-term results of ABO-incompatible living kidney
transplantation: a single-center experience. Transplanta-
tion 1998;65:224-8.
26. Ishida H, Miyamoto Nm Shirakawa H, Shimizu T, Toku-
moto T, Ishikawa N, Shimmura H, Setoguchi K, Toki D,
Iida S, Teraoka S, Takahashi K, Toma H, Yamagucki Y,
Tanabe K. Evaluation of immunosuppressive regimens in
ABO-incompatible living kidney transplantation—single
center analysis. Am J Transplant 2007;7:825-31.
27. Ishida H, Tanabe K, Furusawa M, Ishizuka T, Shimmura H,
Tokumoto T, Hayashi T, Toma H. Mycophenolate mofetil
suppresses the production of anti-blood type anitbodies
after renal transplantation across the ABO blood barrier:
ELISA to detect humoral activity. Transplantation 2002;74:
1187-9.
28. Ishida H, Koyama I, Sawada T, Utsumi K, Murakami T,
Sannomiya A, Tsuji K, Yoshimura N, Tojimbara T, Nakajima
I, Tanabe K, Yamaguchi Y, Fuchinoue S, Takahashi K,
Teraoka S, Ito K, Toma H, Agishi T. Anti-AB titer changes in
patients with ABO incompatibility after living related
kidney transplantations: survey of 101 cases to determine
whether splenectomies are necessary for successful trans-
plantation. Transplantation 2000;70:681-5.
29. Shimmura H, Tanabe K, Ishikawa N, Tokumoto T, Taka-
hashi K, Toma H. Role of anti-A/B antibody titers in results
of ABO-incompatible kidney transplantation. Transplanta-
tion 2000;70:1331-5.
30. Shimmura H, Tanabe K, Ishida H, Tokumoto T, Ishikawa N,
Miyamoto N, Shirakawa H, Setoguchi K, Nakajima I, Fuchi-
noue S, Teraoka S, Toma H. Lack of correlation between
results of ABO-incompatible living kidney transplantation
and anti-ABO blood type antibody titers under our current
immunosuppression. Transplantation 2005;80:985-8.
31. Winters JL, Gloor JM, Pineda AA, Stegall MD, Moore SB.
Plasma exchange conditioning for ABO-incompatible renal
transplantation. J Clin Apheresis 2004;19:79-85.
32. Nelson PW, Hughes TM, Beck ML, Warady BA, Aeder MI,
Helling TS, Landreneau MD, Luger AM, Pierce GE, Ross G.
Stratification and successful transplantation of patients
awaiting ABO-incompatible (A2 into B and O) transplanta-
tion by A-isoagglutinin-titer phenogroup. Transplant Proc
1996;28:221-3.
33. Nelson PW, Landreneau MD, Luger AM, Pierce GE, Ross G,
Shield CF 3rd, Warady BA, Aeder MI, Helling TS, Hughes
TM, Beck ML, Harrell KM, Bryan CF. Ten-year experience
in transplantation of A2 kidneys into B and O recipients.
Transplantation 1998;65:256-60.
34. Bryan CF, Shield CF 3rd, Nelson PW, Pierce GE, Ross G,
Luger AM, Warady BA, Helling TS, Aeder MI, Martinez J,
Hughes TM, Beck ML, Harrell KM. Transplantation rate of
the blood group B waiting list is increased by using A2 and
A2B kidneys. Transplantation 1998;66:1714-7.
35. Alkhunaizi AM, de Mattos AM, Barry JM, Bennett WM,
Norman DJ. Renal transplantation across the ABO barrier
using A2 kidneys. Transplantation 1999;67:1319-24.
36. Montgomery RA, Zachary AA. Transplanting patients with
a positive donor-specific crossmatch: a single center’s per-
spective. Pediatr Transplant 2004;8:535-42.
37. Haas M, Rahman MH, Racusen LC, Kraus ES, Bagnasco
SM, Segev DL, Simpkin CE, Warren DS, King KE, Zachary
AA, Montgomery RA. C4d and C3d staining in biopsies of
ABO- and HLA-incompatible renal allografts: correlation
with histologic findings. Am J Transplant 2006;6:1829-40.
38. Sonnenday CJ, Warren DS, Cooper M, Samaniego M, Haas
M, King KE, Shirey RS, Simpkins CE, Montgomery RA. Plas-
mapheresis, CMV hyperimmune globulin, and anti-CD20
allow ABO-incompatible renal transplantation without
splenectomy. Am J Transplant 2004;4:1315-22.
39. Tyden G, Kumlien G, Genberg H, Sandberg J, Lundgren T,
Fehrman I. ABO incompatible kidney transplantations
without splenectomy, using antigen-specific immunoad-
sorption and rituximab. Am J Transplant 2005;5:145-8.
40. Segev DL, Simpkins CE, Warren DS, King KE, Shirey RS,
Maley WR, Melancon JK, Cooper M, Kozlowski T, Mont-
gomery RA. ABO incompatible high-titer renal transplanta-
tion without splenectomy or anti-CD20 treatment. Am J
Transplant 2005;5:2570-5.
41. Montgomery RA, Locke JE. ABO-incompatible trans-
plantation: less may be more. Transplantation 2007;84(12
Suppl):S8-9.
42. Gloor JM, Lager DJ, Moore SB, Pineda AA, Fidler ME,
Larson TS, Grande JP, Schwab TR, Griffin MD, Prieto M,
Nyberg SL, Velosa JA, Textor SC, Platt JL, Stegall MD. ABO-
incompatible kidney transplantation using both A2 and
non-A2 living donors. Transplantation 2003;75:971-7.
43. Rydberg L, Bengtsson A, Samuelsson O, Nilsson K, Breimer
ME. In vitro assessment of a new ABO immunosorbent
with synthetic carbohydrates attached to sepharose.
Transpl Int 2005;17:666-72.
44. Kumlien G, Ullstrom L, Losvall A, Persson LG, Tydén G.
Clinical experience with a new apheresis filter that specifi-
cally depletes ABO blood group antibodies. Transfusion
2006;46:1568-75.
45. Tyden G, Kumlien G, Fehrman I. Successful ABO-
incompatible kidney transplantations without
Volume 48, November 2008 TRANSFUSION 2459
TOBIAN ET AL.
splenectomy using antigen-specific immunoadsorption
and rituximab. Transplantation 2003;76:730-1.
46. Tyden G, Kumlien G, Genberg H, Sandberg J, Sedigh A,
Lundgren T, Gjertsen H, Fehrman I. The Stockholm experi-
ence with ABO-incompatible kidney transplantations
without splenectomy. Xenotransplantation 2006;13:105-7.
47. Warren DS, Zachary AA, Sonnenday CJ, King KE, Cooper
M, Ratner LE, Shirey RS, Haas M, Leffell MS, Montgomery
RA. Successful renal transplantation across simultaneous
ABO incompatible and positive crossmatch barriers. Am J
Transplant 2004;4:561-8.
48. Gloor JM, Lager DJ, Fidler ME, Grande JP, Moore SB,
Winters JL, Kremers WK, Stegall MD. A comparison of sple-
nectomy versus intensive posttransplant antidonor blood
group antibody monitoring without splenectomy in ABO-
incompatible kidney transplantation. Transplantation
2005;80:1572-7.
2460 TRANSFUSION Volume 48, November 2008
49. Tyden G, Donauer J, Wadstrom J, Kumlien G, Wilpert J,
Nilsson T, Genberg H, Pisarski P, Tufveson G. Implementa-
tion of a protocol for ABO-incompatible kidney
transplantation—a three-center experience with 60
consecutive transplantations. Transplantation 2007;83:
1153-5.
50. King KE, Warren DS, Samaniego-Picota M, Campbell-Lee
S, Montgomery RA, Baldwin WM 3rd. Antibody, comple-
ment and accommodation in ABO-incompatible trans-
plants. Curr Opin Immunol 2004;16:545-9.
51. Klein HG, Mollison PL, Anstee DJ, Mollison PL. Mollison’s
blood transfusion in clinical medicine. 11th ed. Malden
(MA); Oxford: Blackwell Pub.; 2005.
52. Cohney SJ, Hogan C, Haeusler M, Neander E, Fairweather
H. Variability of anti-blood group titers accordng to meth-
odology and clinical relevance in ABO-incompatible renal
transplantation. Am J Transplant 2007;7 s2:157.