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The Use of Immunoglobulin Therapy for Patients Undergoing Solid
Organ Transplantation: An Evidence-Based Practice Guideline
Nadine Shehata, Valerie A. Palda, Ralph M. Meyer, Tom D. Blydt-Hansen, Patricia Campbell, Carl Cardella,
Steven Martin, Peter Nickerson, Kevork Peltekian, Heather Ross, Tom K. Waddell, Lori West,
David Anderson, John Freedman, and Heather Hume
This guideline for the use of immunoglobulin (IG) for
sensitized patients undergoing solid organ transplantation (SOT) is an initiative of the Canadian Blood
Services and the National Advisory Committee on
Blood and Blood Products of Canada to (1) provide
guidance for Canadian practitioners involved in the
care of patients undergoing SOT and transfusion
medicine specialists on the use of IG and (2)
standardize care, limit adverse events, and optimize
patient care. A systematic expert and bibliography
literature search up to July 2008 was conducted, with
791 literature citations and 45 reports reviewed. To
validate the recommendations, the guideline was sent
to physicians involved in SOT in Canada and a patient
representative. The recommendations identify (1) sensitized patients undergoing SOT that would have a
better survival and decreased morbidity by receiving IG
preoperatively, postoperatively, and for the treatment
of organ rejection; (2) patients who may not have any
benefit from receiving IG; and (3) potential adversities
to IG.
© 2010 Elsevier Inc. All rights reserved.
T
HE RISK OF human leukocyte antigen (HLA)
antibody-mediated graft rejection/loss or ABO
incompatibility is a barrier to solid organ transplantation for many patients in need of this therapy.
Although the optimal approach to this problem is to
develop strategies to increase the availability of
compatible donors and/or organs for transplantation, transplant physicians continue to investigate
treatment options to decrease the rejection/loss rate
in sensitized patients. The administration of intravenous immunoglobulin (IVIG) is among the
immunomodulatory therapies that are currently
being used to overcome these barriers. However,
the use of IVIG in this setting is not a licensed
indication for IVIG and, to our knowledge, has not
previously been reviewed in the medical literature.
Since 2004, the Canadian Blood Services and
Canada's National Advisory Committee on Blood
and Blood Products have been involved in a joint
initiative to develop guidelines for IVIG utilization. The history and rationale for the involvement of these two bodies in IVIG guideline
development are described in the introductory
article of this supplement.1 Given the increasing
use in Canada of IVIG in the setting of solid
organ transplantation, this setting was chosen for
the development of the fourth set of guidelines in
this series. The first two guidelines, which
From the Department of Medicine, University of Toronto, St.
Michael's Hospital, Canadian Blood Services, Toronto, Ontario,
Canada; Departments of Medicine and Health Policy
Evaluation, University of Toronto, St. Michael's Hospital,
Toronto, Ontario, Canada; National Cancer Institute of
Canada Clinical Trials Group and Departments of Oncology,
Medicine and Community Health and Epidemiology, Queen's
University, Kingston, Ontario, Canada; Department of
Medicine, University of Alberta Hospital, Edmonton, Alberta,
Canada; Department of Medicine, University of Manitoba,
Canadian Blood Services, Winnipeg, Manitoba, Canada;
Division of Pediatric Nephrology, Children's Hospital,
Winnipeg, Manitoba, Canada; Department of Pediatrics,
University of Alberta, Edmonton, Alberta, Canada; Department
of Medicine, University of Toronto, University Health Network,
Toronto, Ontario, Canada; Department of Pediatrics, Université
de Montréal, Hôpital Ste Justine, Montreal, Quebec, Canada;
Department of Surgery, University of Toronto, University Health
Network, Toronto, Ontario, Canada; Li Ka Shing Knowledge
Institute, Canada; Department of Medicine, Dalhousie
University, Halifax, Nova Scotia, Canada; Departments of
Medicine, Community Health and Epidemiology and Pathology
Dalhousie University, Halifax, Nova Scotia, Canada, and
Canadian Blood Services, Ottawa, Ontario, Hôpital Sainte
Justine, Montreal, Quebec, Canada.
STATEMENT OF CONFLICT OF INTEREST: Dr L West
receives research funding from the US National Institutes of Health
(Grant P01-HL079067). Drs Nadine Shehata and Peter Nickerson
are employees of Canadian Blood Services, as were Drs Heather
Hume and John Freedman during the period of the development of
these guidelines. Funding was provided from an unrestricted
education grant from Bayer, Inc, to Canadian Blood Services.
Bayer did not have any role in the selection of panel members, the
literature search, the selection of articles, or the development of the
recommendations.
Address reprint requests to Nadine Shehata, MD, Queen
Wing, 2-080, St. Michael's Hospital, 30 Bond Street, Toronto,
Ontario, Canada M5B 1W8.
E-mail: [email protected]
0887-7963/09/$ - see front matter
© 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.tmrv.2009.09.010
Transfusion Medicine Reviews, Vol 24, No 1, Suppl 1 (January), 2010: pp S7-S27
S7
S8
SHEHATA ET AL
addressed IVIG use in hematologic and neurologic disorders, were published in a supplement of
Transfusion Medicine Reviews in 2007; and the
third guideline, for the use of immunoglobulin in
primary immune deficiencies, is published along
with this guideline in the current Transfusion
Medicine Reviews supplement.2-4
SCOPE AND PURPOSE OF THE GUIDELINE AND
TARGET AUDIENCE
The specific objectives of this guideline are (1)
to examine the evidence for the use of IVIG in
patients who are candidates for solid organ
transplantation and are sensitized to HLAs or
ABO antigens, (2) to provide guidance for
physicians in Canada (and potentially elsewhere)
involved in the care of these patients on the optimal
utilization of IVIG therapy in this setting, (3) to
identify areas where further research is required,
and (4) to provide assurance for funders of the
Canadian blood system that the effectiveness of
immunoglobulin therapy is being assessed.
These guidelines are intended for use (1) for
adult and pediatric patients who are sensitized to
HLA or ABO antigens and are scheduled for
kidney, heart, liver, or lung transplantation; (2)
for adult and pediatric patients who experience
acute and chronic rejection after solid organ transplantation; and (3) by physicians responsible for
evaluating requests for IVIG or involved in the
development of transfusion policy.
DEVELOPMENT OF THE GUIDELINE
In 2007, a panel consisting of solid organ
(kidney, heart, lung, and liver) transplantation
experts, guideline methodologists, and members
from Canada's National Advisory Committee on
Blood and Blood Products was convened to
develop an evidence-based practice guideline for
the use of IVIG in patients undergoing solid organ
transplantation. The panel did not include a patient
representative; however, the experts' knowledge of
patient tolerances and preferences of immunoglobulin therapy was considered in the development
of recommendations.
The panel identified clinical areas of solid organ
transplantation that would benefit from treatment
with IVIG and generated pertinent clinical questions.
The questions were developed via electronic correspondence and teleconferences using a modified
Delphi process. Methodologists attended all meet-
ings to ensure methodological rigor. Each expert was
assigned a question to review and generate a
recommendation. The questions were used to
identify search terms. The data were abstracted to
evidence tables that described the characteristics and
quality of the studies and pertinent clinical
outcomes. The tables were distributed to the panel
before a consensus meeting where each panel
member presented their recommendations.
Recommendations were developed based on
the best evidence available. The levels of
evidence and grading of recommendations were
adapted from the Canadian Task Force on
Preventative Health Care (available at http://
www.ctfphc.org/). The levels of evidence describe the methodological rigor of the study,
whereas the grades of recommendation comprise
the level of evidence and clinical expertise. If the
evidence was insufficient for a recommendation,
the consensus section describes the rationale for
the recommendation. Areas of disagreement were
resolved through consensus verification with all
committee members.
National experts from the Canadian Society of
Transplantation and a patient representative from
the Kidney Foundation of Canada reviewed the
final guideline to validate the relevance of the
guideline and recommendations. Their agreement
to each recommendation and their evaluation of the
entire guideline were elicited.
The National Advisory Committee on Blood and
Blood Products will ensure adequate dissemination
of the guideline to Canadian physicians involved in
the care of patients undergoing solid organ
transplantation; will assess the utilization of the
guideline; and will perform periodic revisions of the
guideline to ensure that recommendations reflect
current practices, expertise, and evidence.
Identification and Selection of Studies
A systematic search was conducted of the
MEDLINE (to October 2007), In Process (to
October 2007), Cochrane Clinical Trials (to issue
3, 2007), and Embase (1980 to week 45, 2007)
databases. The search was updated to July 2008.
The search terms are illustrated in Appendix A.
We included studies that met the following
inclusion criteria: (1) an original report; (2)
published in English; and (3) a randomized
controlled trial, cohort/case series, systematic
review, or guideline. We excluded studies that (1)
IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION
did not report a clinical outcome, (2) were abstracts
or letters, or (3) had five or fewer patients. One
reviewer (NS) assessed the citations for inclusion
and extracted data to generate tables containing
information about trial design, quality, and outcome
results. These tables were used as a basis for
discussion by the panel.
The guideline is organized according to the organ
transplantation specialty, that is, kidney, heart,
lung, and liver and for each specialty, by clinical
question. As the evidence for the use of IVIG is
limited for heart, lung, and liver transplantation,
these sections focused on the use of IVIG where
evidence was available. The relevant background, a
summary and critical appraisal of the evidence, the
consensus process, and the recommendation statement accompanied by a level of evidence and grade
of recommendation follow each question. The
evidence is shown in detail in Tables 2 to 9.
Literature Search Results
Seven hundred ninety-one citations were retrieved, and panel members identified three additional citations. Five studies were excluded for the
following reasons: the primary objective of one
study was to study the effect of IVIG on
autoregulatory antibodies5; one study described
survival for patients who received cytomegalovirus
immunoglobulin (CMVIG) for the treatment of
CMV disease6; two studies addressed the effect of
IVIG on the development of alloimmunization7,8;
and one study was a report of preliminary results of
unpublished data.9 Forty-four reports were used for
this guideline.10-53 A summary of the categorization of the reports is found in Table 1. One
additional report examined adverse events only and
Table 1. Characterization of Studies
Disease category
HLA desensitization for
kidney transplantation
ABO-incompatible kidney
transplants
Rejection after kidney
transplantation
Desensitization for heart
transplantation
Desensitization for lung
transplantation
Desensitization for liver
transplantation
Randomized
controlled trials (n)
Observational
studies (n)
2
17
0
6
1
10
0
6
0
1
0
1
S9
was also included.54 Tables 2 to 9 describe the
characteristics and results of the reports included in
this guideline.
KIDNEY TRANSPLANTATION
Is there evidence that the use of IVIG for patients who
are sensitized (HLA or ABO) and are undergoing
kidney transplantation decreases sensitization,
improves access to transplantation, and/or improves
any of the following outcomes: the frequency of acute
rejection, graft survival, and overall survival?
The incidence and prevalence of end-stage renal
disease continue to rise in Canada.55-57 The options
for management are dialysis and transplantation.
The annual expenditure to the health care system
for a patient receiving hemodialysis is $104 277 per
year, whereas the annual expenditure beyond the
first year for transplantation is $32 196 per
year.55,58 The number of patients receiving transplantation has, however, decreased over time,56
although the life expectancy for patients with renal
failure who receive a transplanted kidney is double
the life expectancy without transplantation.55,59
Up to 30% of patients with end-stage renal disease
waiting for transplantation in Canada have HLA
panel-reactive antibodies of 20% or more and receive
fewer than 5% of transplants in Canada.55 These
patients have been exposed to HLAs from pregnancy,
prior transfusion, or prior transplantation and have
preformed antibodies. Thus, they are sensitized,
increasing their risk for early rejection and graft
loss.55 Overall, 32% of patients are excluded from
receiving a transplanted kidney from a living donor
because of an HLA-positive crossmatch; and 22% are
excluded because of ABO antibodies.60
All recipients require pretransplant immunologic
risk assessment (ie, determination of prior exposure
to HLA antigens and donor ABO compatibility)
and management, which before 2005 had not been
standardized in Canada.55 Currently in Canada,
transplant programs have moved to standardize
pretransplant immunologic risk assessment in heart,
lung, and kidney patients using sensitive flow
cytometric–based technologies for determination of
the presence and specificity of an HLA antibody.
Immunomodulation of the sensitized patient is a
highly specialized evolving field that borders on
research, which may either represent a “care gap” or
make it hard to “provide guidance” because of the
lack of well-designed randomized controlled trials.
S10
SHEHATA ET AL
Table 2. Characteristics of the Studies for the Use of Immunoglobulin for Desensitization in Kidney Transplantation
1st author, year
Study design
Randomized controlled trials
Jordan SC, 200410 Multicenter
RCT, DB, PC
Peraldi, MN, 199611 Single-center
RCT
Observational studies
Case series
Vo AA, 200853
Anglicheau D,
200712
Prospective
case series
Living or
deceased
donor
Method to
determine
sensitization
Definition of
sensitization
NR
30 mo
Negative CXM
20 mo
FXM, CDC CXM,
T-cell CDC-PRA
Mean prestudy
PRA 77%,
or had DSA
12 mo
T- and B-cell CDC
and AHG-CDC/
PRA using MLA
FXM CDC CXM
(1) Negative T-CDC
CXM at 1:2 dilution,
(2) negative T-cell
FXM or positive
(with a mean
flow-channel shift
of b250), or (3) both.
NR
Positive T-cell AHG
CXM and/or DSA
(negative CXM at Tx)
DSA but negative
Lack of rejection/
CXM
graft loss
PRA ≥20%
Transplantation
PRA using MLA
Second
deceased
T and B CXM PRA
Both
Deceased
Bielman D, 200713 Prospective
case series
Mahmoud KM,
Prospective
200714
case series
Prospective
Kayler L, 200629
case series
Both
Living
CDC CXM, PRA
by ELISA
T-AHG-CDC, B-CDC,
FXM, anti-A IgG
antibody for non-A2
Stegall MD, 200615 Cohort
Living
FC T-AHG-CDC
Thielke J, 200516
Case series
Living
FXM
Akalin E, 200517
Case series
Living
FXM, CDC
Mahmoud K,
200418
Akalin E, 200319
Case series
Living
Prospective
case series
Prospective
case series
Both
PRA-ELISA CDC
CXM
AHG-CDC, FXM
Prospective
Jordan SC,
case series
200321
Zachary A, 200322 Case series
Both
PRA using frozen
lymphocyte antibody
panel and T-cell
AHG-CDC
PRA using MLA
NR
Both
CDC and FXM
Glotz D, 200223
Prospective
case series
Both
PRA using MLA or
T-cell IgG CXM
Sonnenday CJ,
200224
Schweitzer EJ,
200025
Retrospective Living
case series
Prospective
Living
case series
AHG-CDC or FXM
Glotz D 199526
Prospective
case series
PRA
Gloor JM, 200320
Living
NR
Follow-up
PRA ≥50%
monthly × 3 mo
NR
Both
Living
Definition of
response
AHG-CDC
Positive (N10%)
T-AHG-CDC or
B-CDC or T or B FXM
(15 and 30) or IAT
Mean channel
fluorescence shift
N52 for T-cells
and N106 for B-cells
Channel shifts for
T-cells N+20 and
B-cells N+40
Positive T- and
B-cell FXM or CDC
PRA ≥20%
Negative CXM
or IgG titer ≤1:8
Positive AHG-CDC
or FXM
NR mean peak
PRA-69%
NR
6 mo
Before
transplantation
Mean = 16 mo
Negative
T-AHG-CXM
1y
Negative CXM
18 mo
NR
6-34 mo
NR
6 wk
Positive B-cell CDC NR
and B- or T-cell FXM
T-cell AHG-CDC
Negative CXM
FXM: median channel
ratio N3; CDC: N10%
cell death
PRA N50% or
positive T-cell CXM
25 mo
Negative or
“acceptable” CDC CXM
NR
15 mo
15 mo
2y
2-90 mo
Deceased: 50%
1y
decrease in antibodies;
living: negative CXM
Negative CXM
17 mo
Negative AHG-CDC;
no donor-specific
reactivity by ELISA
NR
3-26 mo
NR
S11
Table 2 (continued)
1st author, year
ABO incompatible
Tyden G, 200727
Tyden G, 200628
Tyden G, 200530
Winters JL, 200431
Sonnenday CJ, 200432
Gloor JM, 200333
Study design
Prospective
cohort
Prospective
case series
Case series
Prospective
case series
Retrospective
case series
Retrospective
case series
Method to
determine
sensitization
Definition of
sensitization
Saline method (IgM),
IAT (IgG)
DAT and IAT
ABO incompatible
Saline method for
IgM and IAT for IgG
IAT, AHG-T-cell
cytotoxicity assay
IAT
Mean acceptable
titer b1:128
ABO incompatibility
DAT and IAT, method
for PRA NR
ABO incompatible
Definition of
response
Preoperative IgG
titer b1:8
IgG and IgM titer
b1:8
Titer b1:8
Follow-up
2-61 mo
1-49 mo
3-34 mo
Mean = 13 mo
ABO incompatibility
AHG titer ≤16
until 2001 then b4
Titer ≤1:16
ABO incompatibility
NR
1y
Median = 1 y
Abbreviations: CXM, crossmatch; DB, double blind; DAT, direct antiglobulin test; DSA, donor-specific antibodies; ELISA, enzyme-linked
immunosorbent assay; FC, flow cytometry; FXM, flow cytometry crossmatch; IAT, indirect Coomb test; MLA, microlymphocytoxicity assay;
NA, not applicable; NR, not reported; PC, placebo controlled; PRA, panel-reactive antibody; RCT, randomized controlled trial; T-AHG-CDC,
T-cell antiglobulin enhanced complement-dependent cytotoxicity crossmatch; Tx, transplantation.
The treatment options for sensitized patients are (1)
immunomodulation, that is, reduction/removal of
HLA antibodies, or (2) the development of
strategies to find a donor to whom the sensitized
recipient has not developed antibodies (ie, living
donor paired exchange or mandated allocation of
organs to sensitized patients when an acceptable
mismatch becomes available).
Intravenous immunoglobulin has been used for
desensitization for patients who have HLA antibodies and has been also used perioperatively in
combination with other immunomodulating agents
in this patient population to (1) directly block the
ability of donor-specific HLA antibodies to activate
complement, (2) neutralize donor-specific antibodies via anti-idiotypic HLA antibodies contained in
IVIG, or (3) down-regulate HLA antibody production by donor-specific B-cells.
Intravenous immunoglobulin has also been used
for ABO-incompatible renal transplantation, although
its use for this indication is an emerging clinical
entity and these transplants are only being conducted
in a small number of centers. Most desensitization
protocols for patients receiving an ABO-incompatible
transplant use IVIG as a cointervention.
HLA Sensitization
Tables 2 and 3 illustrate the characteristics and
results of the studies for the use of immunoglobulins for desensitization for HLA antibodies. There
were 2 randomized controlled trials6,11 and 17
cohort/case series12-26,29,53 for the use of IVIG for
HLA-sensitized renal transplant recipients and
seven cohort/case series27-33 for the use of IVIG
in ABO-incompatible transplantation.
Only one of the two randomized controlled trials
was a double-blind trial (Tables 2 and 3).6 Both
reports indicated that the groups were comparable.6,11 None of the trials specified whether there
was concealment of allocation or whether intent-totreat analysis was used.
Jordan and colleagues reported a trend in
improvement in desensitization rates and a statistically significant decrease in time to transplantation for patients treated with IVIG.10 However,
acute rejection occurred more frequently in patients
treated with IVIG; and there was no information
provided on donor/recipient compatibility or HLA
antibody titer. A standardized immune suppression
protocol was not used peritransplantation, and an
analysis between living and deceased donors was
not provided.
Peraldi and colleagues11 randomized patients
having a second deceased donor transplant. It was
unclear whether donor-specific antibodies were
present because only the panel-reactive antibody
test was used. Five-year survival was not different
between the groups; however, graft survival was
superior in patients treated with IVIG.
Most of the remaining reports were case series.
Three were publications in non–peer-reviewed
journals.16,18,24
S12
SHEHATA ET AL
Table 3. Results of the Studies for the Use of Immunoglobulin for Desensitization in Kidney Transplantation
1st author, year
Patients
Adult
Jordan SC,
200410
Peraldi MN,
199611
Adult
Adult
Vo AA,
200853
Anglicheau
D, 200712
Adult
Bielman D,
200713
Mahmoud
KM, 200714
Adults
Kayler L,
200629
Adult HLA
and ABO
incompatible
Stegall MD,
200615
Adult
Adults
Thielke J,
200516
Adult †
Akalin E,
200517
NR
Mahmoud K,
200418
Adult
N
Transplant regimen
48 IVIG 2 g/kg q 4 wk × 4 mo, at
12 and 24 mo if not transplanted
50 Placebo
Immunosuppression
determined by center
21 IVIG 400 mg/(kg d) days 0-4
20 No IVIG; all received steroids,
AZA, CYA, ATG/OKT3
20 IVIG 2g/kg day 0 and day 30,
rituximab 1g day 7 and day
22 + alemtuzumab, MMF,
steroids, TAC
38 IVIG 2 g/kg days 0, 21, 42,
and 63; TG or basiliximab,
TAC or CYA, MMF, steroids
9 IVIG 400 mg/(kg d) days 1-4,
TG, TAC, MMF, prednisone
11 IVIG 500 mg/kg × 6 doses
in 2 wk, and after 2 mo,
simvastatin 20 mg/d × 2 mo
12 PP 2-7 d then CMVIG
100 mg/kg + MMF, TAC,
steroids, daclizumab;
splenectomy (for ABO, n = 3),
PP/CMVIG post-Tx
32 PP/IVIG (100 mg/kg) daily,
rituximab, splenectomy (n = 19)
13 IVIG 2 g/kg × 1 before Tx
(n = 2, 3 g/kg)
16 PP/IVIG (100 mg/kg) daily,
rituximab 375 mg/m2 × 1, TG,
then PP/IVIG day post-Tx &
posttransplant, DSA monitoring,
+PP/IVIG days 1-3 post-Tx,
TG, TAC, MMF, prednisone
16 PP + IVIG (100 mg/kg) q
2nd day 1 wk before Tx,
Rituxan (n = 6; Genentech,
USA); post-Tx: PP,
IVIG q 2nd day × 1 wk +
TAC, TG, MMF, steroids
7 IVIG (100 mg/kg) × 3 d, TG,
CYA (n = 5), TAC +
MMF + prednisone (n = 2)
11 IVIG 500 mg/kg × 6 doses
Success of
desensitization
17/48 (35%)
10/50 (20%)
(P = .07)
received a
transplant
No difference
in reduction
of PRA
Humoral
rejection
9/17 (53%)
(& cellular)
1/10 (10%)
(P = .04)
Graft survival
12/16
(75%)
5/8 (62%)
Survival
4 Patients
died
8 Patients
died
(P = .29)
No difference 5 y 68%
in acute
vs 50%,
rejection
P = .002
episodes
5 y 90%
vs 95%
16/20 (80%)
16%
94%
(n = 16)
100%
(n = 16)
≈30%-40% %
reduction in
PRA in n = 27
who had PRA
at Tx
NR
4/38 (11%)
36/38
(95%)
37/38
(97%)
4/9 (44%)
NR
NR
PRA 39% ±
18% before
IVIG vs 37% ±
17% post-IVIG
(P = .36); 0%
was crossmatch
negative
100%
NR
NR
NR
4/12
(30%)
1 y 100%
1 y 100%
27/32 (84%)
11/30 (37%) NR ⁎
NR ⁎
5/13 (36%)
4/5 (80%)
14/16 (88%)
4/14 (29%)
12/16 (75%)
3/12 (25%)
100%
100%
NR
2/7 (28%)
6/7 (86%)
100%
0%
NR
NR
NR
S13
Table 3 (continued)
1st author, year
Patients
Akalin E,
200319
Adult
Gloor JM,
200320
Adult
Jordan SC,
200321
Adult and
pediatric
renal,
cardiac, liver ‡
Zachary A,
200322
NR
Glotz D,
200223
Adult
Sonnenday
CJ, 200224
Adult
Schweitzer
EJ, 200025
Adult
NR
Glotz D,
199526
ABO incompatible
Tyden G,
Adult and
200727
children
ABO
incompatible
ABO
compatible
NR
Tyden G,
200628
Tyden G,
200530
Adult and
pediatric
Winter JL,
200431
NR
N
Transplant regimen
8 IVIG 100 mg/kg day 0,
2 doses between days 1-4;
TG, CYA, MMF (n = 7),
rapamycin (n = 1), steroids
14 PP/IVIG 100 mg/kg days −4,
−3, −1, 0, +1, +3, FFP day
+1, rituximab day −4, +
splenectomy + TG, MMF,
TAC, prednisone
26 IVIG 2 g/kg for living donor
17 IVIG 2g/kg q month × 4 and
1 mo after Tx for deceased
heart (2) or kidney; all
patients received Zenapax
(Roche Pharmaceuticals, USA),
TAC, MMF, steroids
49 ║ PP q 2nd day + CMVIG
100 mg/kg + TAC, steroids,
MMF, daclizumab
15 IVIG 2 g/kg/4 wk for 12 wk
pre-Tx, then IVIG 2 g/kg, MMF,
steroids, TG, TAC at Tx, then
IVIG 2 g/kg days 20 and 40
18 PP and CMVIG 100 mg/kg q
2nd day until response, +
TAC, MMF, prednisone,
daclizumab
15 ¶ MMF, TAC, prednisone,
PP 3×/wk in weeks 2 and 3,
IVIG 500 mg/kg over 7 d
week 2, OKT3 PO days 1-10
10 IVIG 400 mg/kg × 4 d
60 Rituximab, TAC, MMF,
steroid, IA × 4, IVIG 0.5 g/kg
Success of
desensitization
Humoral
rejection
Survival
NR
1/8 (12%)
7/8 (88%)
100%
100%
6/14 (43%)
11/14 (79%)
12/14 (86%)
100% (n = 2
required more
IVIG)
16/17 (94%)
13/42
(31%) §
89%
98%
63% lost
Not clear
antibody to donor
HLA, 27%
lost antibody
to 3rd-party HLA
13/15 (87%)
1/13 (7%)
Not clear
NR
10/13 (77%)
11/13 (85%)
100%
5/18 (28%)
17/18 (94%)
NR
11/15 (73%)
11/11 (100%) NR
4/10
3 (27%)
Humoral,
1 (9%)
cellular
0/4
4/4
4/4
100%
0
97%
98%
95%
98%
274 NR
21 IA × 4 pre-Tx and × 3 post-Tx,
IVIG 500 mg/kg × 1,
rituximab, TAC, MMF,
prednisone
11 Rituximab, TAC, MMF,
prednisone, IA + IVIG
500 mg/kg after last session,
IA × 3 PO
26 PP days −4, −2, −1,
0 followed by IVIG
100 mg/kg days −4, −2, −1,
FFP day 0, TG, TAC, MMF,
prednisone, + splenectomy
Graft survival
100%
0
20/21 (95%)
100%
100%
0
100%
100%
100%
12/26
(46%)
22/26%
(85%)
24/26
(92%)
(continued on next page)
S14
SHEHATA ET AL
Table 3 (continued)
1st author, year
Patients
Sonnenday C, Adult
200432
Gloor JM,
200333
Adult ABO
incompatible
Adult ABO
compatible
N
Transplant regimen
6 PP + CMVIG 100 mg/kg ×
5 q 2nd day pre-Tx and ×
3 post + TAC, MMF,
steroids, rituximab, daclizumab,
18 TG, TAC, MMF, steroids
(8 did not receive pre-Tx
conditioning) + PP; PP and
IVIG (10 g/d) for patients
replaced with albumin,
splenectomy for non-A2
81 HC: TAC, MMF, steroids
Success of
desensitization
Humoral
rejection
Graft survival
Survival
100%
0
100%
NR
NR
5/18
(28%)
89%
94%
NR
96%
99%
Abbreviations: ATG, antilymphocyte globulin; AZA, azathioprine; CYA, cyclosporine A; FFP, fresh frozen plasma; HC, historical controls;
IA, immunoadsorption; MMF, mycophenolate mofetil, PO, postoperatively; q, every; TAC, tacrolimus, TG, thymoglobulin.
⁎ Survival was only reported for the entire cohort.
† One patient received a kidney and pancreas transplant.
‡ All patients had to have had in vitro evidence that IVIG could reduce cytotoxicity.
§ The type of rejection was not specified.
║ The authors also included patients with ABO-incompatible transplants and patients treated for rejection with PP and CMVIG.
¶ Two individuals had kidney and pancreas transplantation. These transplants were unsuccessful.
One report compared single-dose IVIG to two
regimens containing IVIG and plasmapheresis (PP).
The pretransplant regimen also included the use of
rituximab and thymoglobulin.15 Successful desensitization was defined as a negative anti-human
globulin complement-dependent cytotoxicity
(AHG-CDC) crossmatch pretransplantation. Intravenous immunoglobulin as a single agent was associated with inferior desensitization rates and higher
rates of rejection. This report, although with a few
patients, described the success of desensitization
based on the preimmunomodulation AHG-CDC
crossmatch titer of donor-specific HLA antibody.
Patients who had an AHG-CDC titer of 1:32 or more
predesensitization were less likely to achieve a
negative AHG-CDC crossmatch independent of the
desensitization regimen.
One small observational report used low-dose
IVIG 500 mg/kg only.14 Desensitization with this
protocol was unsuccessful.14 Seven reports used
lower-dose (ie, 100-500 mg/kg) IVIG/CMVIG in
combination with PP and various immunosuppressive regimens.15,16,20,22,24,25,29 A total of 201
patients were included in these studies. The success
of desensitization ranged from 63% to 100%. The
frequency of antibody-mediated rejection ranged
from 25% to 43%, and graft survival was from 79%
to 100% (Table 2).
Five reports,12,15,21,23,53 including 177 adult
patients, used higher doses of IVIG (ie, 2 g/kg).
Rates of desensitization ranged from 36% to 100%,
and the frequency of antibody-mediated rejection
occurred in 7% to 80% of patients transplanted
(Table 2).
ABO-Incompatible Kidney Transplantation
Seven observational reports described the use
of IVIG/CMVIG in patients undergoing ABOincompatible renal transplantation (Tables 2 and
3). 27-33 All reports used IVIG concurrently
with other immune modulating agents. Graft
survival ranged from 80% to 100%, and patient
survival was greater than 90%. Two reports
compared graft survival and overall survival
with patients receiving ABO-compatible transplants and reported comparable outcomes
(Tables 2 and 3).27,33
Is there evidence that the perioperative use (ie,
prophylactic use) of IVIG for sensitized (HLA or
ABO) patients who have been desensitized or who
have a positive crossmatch and are undergoing
kidney transplantation decreases the frequency of
acute rejection and chronic rejection, and
improves graft survival and overall survival?
Four reports addressed the administration of IVIG
peritransplantation; three included patients with
a positive crossmatch at transplantation, 12,17,19
and one included patients with donor-specific
antibodies.13 High graft survival and overall
survival rates with IVIG were reported in three
reports (Tables 1 and 2).12,17,19
What are the adverse effects of IVIG in patients
undergoing kidney transplantation?
The use of IVIG has been associated with several
adverse events such as thrombosis, hemolytic
anemia, renal failure, and aseptic meningitis.61
Few reports in the renal transplantation population
discussed complications associated specifically
with IVIG. One study did not find any differences
in viral or bacterial infections in patients treated
with IVIG or OKT3.34 Headaches were described
in two reports,6,12 and aseptic meningitis associated
with IVIG was reported in one individual.43 Renal
failure was not found to occur in any patient treated
with IVIG in the latter study.43 Other adverse
events reported in patients who received both IVIG
and other immune-suppressive agents include
CMV disease,12,33,34,40 BK virus,12 bacterial infection,12,33 fungal infection,33,40 and thrombosis.12
The contribution of IVIG specifically to these
events could not be conclusively attributed.
One retrospective review addressed adverse
events associated with IVIG in 279 patients at a
single center and included 180 sensitized patients
who were treated with IVIG before solid organ
transplantation.54 Three products were used: Gamimune-N 10% (Bayer Biological, USA), Carimune
(CSL Behring, USA), and Polygam (Baxter Hyland
Immuno, USA). Significant adverse events, defined
as acute myocardial infarction and acute renal
failure, were noted with Polygam and Carimune,
respectively. In addition, thrombotic events occurred in 4.7% of patients receiving Polygam
compared with 0% in patients who received
Carimune and Gamimune. The acute renal failure
was attributed to sucrose in Carimune, and the high
sodium chloride base of Polygam (ie, an osmolality
of 1250 mosm/L in the 10% preparation) was
postulated to be the factor resulting in thrombotic
events. Headaches were the most frequent adverse
events reported with Gamimune-N 10%.
CONSENSUS FOR KIDNEY TRANSPLANTATION
HLA Desensitization
Although there were a number of reports
describing the use of IVIG for sensitized patients
undergoing renal transplantation, there were several
S15
limitations. The definition of sensitization was not
consistent among the studies, and the type and titer
of the antibody were often not reported. The assays
to detect HLA antibodies were variable; that is,
some used flow cytometric assays, others used
enzyme-linked immunosorbent assays. Several
studies failed to provide sufficient methodological
details to permit interpretation of the data. Thus, the
true immunologic risk of the recipients was difficult
to evaluate.
The definition of response and the proportion of
patients who responded were often not indicated.
Of the reports that described a definition of
response, most indicated a negative AHG-CDC
crossmatch was equivalent to response. The dose of
IVIG and timing of IVIG were also variable.
Nonetheless, the use of IVIG was associated with
acceptable outcomes, that is, acute rejection and
short-term graft and patient outcomes. Details on
long-term outcomes were limited, but evidence is
mounting that patients who have persistently
positive crossmatches at the time of transplantation
or have too high a titer of donor-specific HLA
antibodies (ie, AHG-CDC crossmatch titer N1:32)
to start desensitization have inferior outcomes in the
long term.15 However, as these patients may not
have been able to receive a transplant and as they
have a high risk for morbidity and mortality while
receiving dialysis, many physicians consider graft
survival and overall survival acceptable compared
with dialysis.
For patients who are sensitized as defined by a
positive CDC crossmatch, IVIG 2 g/(kg mo) for
4 months and PP/IVIG (100 mg/kg) in the
perioperative period to achieve a negative
cytotoxicity crossmatch pretransplant were considered equivalent treatment modalities. Although
higher doses of IVIG have been used in
combination with PP in a few reports, there is
no evidence to suggest that higher doses are
superior to 100 mg/kg. For patients who were
sensitized as defined by a positive crossmatch by
flow cytometry, IVIG 2 g/kg once and PP/IVIG
(100 mg/kg) to achieve a negative flow crossmatch pretransplant were considered equivalent
options. Although the maximum dosage of IVIG
has not been determined, the panel felt that based
on previous studies,6,36 IVIG should be administered at a maximum single dose of 2 g/kg and
not exceed 180 g, as the efficacy and safety of
higher doses have not been evaluated.
S16
ABO-Incompatible Transplantation
There is uncertainty about the best strategy for
these patients. Outcomes cannot be separated by a
single therapeutic modality because there are
usually several therapeutic agents used concurrently. Intravenous immunoglobulin is used as part of a
regimen by several centers for ABO-incompatible
renal transplantation; however, whether it plays an
essential role in immune modulation in these cases
has yet to be determined.
Perioperative Use of IVIG
There is limited literature available on the
perioperative use of IVIG in the transplantation
setting, and the use of IVIG in the perioperative
setting is often center dependent. Intravenous
immunoglobulin is used perioperatively for patients
who have donor-specific antibodies detected by
solid-phase assays or who have undergone desensitization and whose AHG-CDC crossmatch is
negative pretransplant. These patients may still
have a positive crossmatch by flow cytometry at
transplantation; and as the treatment of these
patients is center dependent, some centers may
not proceed with transplantation with a crossmatch
that is positive by flow cytometry.
Given the favorable graft survival and overall
survival, IVIG was recommended as a treatment
option, that is, IVIG 2 g/kg once or PP followed
by IVIG (100 mg/kg) in the first week after
transplantation. It has been previously recommended in Canada that, after transplantation,
solid-phase–based HLA antibody assessment and
pathology monitoring be performed routinely in
these high-risk patients.55
Adverse Events
There are several formulations of IVIG available
in Canada; however; there is no evidence to suggest
that there is a difference in outcomes or adverse
events according to the formulation. In addition,
Carimune and Polygam are no longer available
in Canada.
Patients with renal disease are susceptible to
vascular complications and are also susceptible to
infections due to the various immunosuppressive
agents used perioperatively. There are insufficient
data to confirm whether IVIG further increases
the thrombosis risk associated with renal disease;
but as this population often has significant
SHEHATA ET AL
vascular disease, there may potentially be an
increased risk of thrombosis with IVIG. The
committee did not consider IVIG to contribute to
infectious risk.
RECOMMENDATIONS
HLA Sensitization
1. When transplantation will involve use of a
kidney from a living donor to whom the patient is
sensitized, IVIG is recommended to decrease
donor-specific sensitization.
Level of evidence: I-II 2-3
Grade of recommendation: B
Clinical considerations: For patients who are
sensitized to their donor as defined by a positive
CDC crossmatch, give IVIG 2g/(kg mo) for 4
months to achieve a negative AHG-CDC crossmatch before transplantation. The committee is also
aware that alternate strategies such as PP followed
by IVIG (100 mg/kg) have also been used and
consider these acceptable strategies. The use of PP
followed by IVIG (100 mg/kg per dose) is generally
restricted to the perioperative period. Aim for a
negative AHG-CDC crossmatch or negative flow
cytometric crossmatch and not a change in the
percentage of panel-reactive antibody. Emerging
studies suggest that high-titer (ie, AHG-CDC
crossmatch N1:16) donor-specific HLA antibodies
may limit the effectiveness of desensitization.12
Although the data are not derived from the pediatric
population, the committee felt that it was reasonable
to use IVIG similarly in the pediatric population.
With respect to clinical efficacy and adverse
events, there is insufficient evidence to recommend
one formulation of IVIG over another.
Qualifying statement: For sensitized patients who
have received a transplant from a deceased donor,
desensitization with IVIG is generally not used in
Canada because of limited availability of deceased
donors. Although the evidence from this systematic
review supports the use of IVIG for desensitization
before transplantation for highly sensitized patients
receiving kidneys from deceased donors, the routine
use of IVIG might result in unnecessary wastage, as
it is not guaranteed that recipients will have access to
donors within 2 years. The recommendation against
the use of IVIG for recipients of deceased donor
transplants is subject to the availability of deceased
donors. Should deceased donor kidneys become
S17
there is insufficient evidence to recommend one
formulation of IVIG over another for currently
available products.
4. Intravenous immunoglobulin is not recommended for patients who do not have donor-specific
antibodies.
Level of evidence: III
Grade of recommendation: D
readily available, IVIG would be recommended for
the sensitized recipient.
2. There is insufficient evidence to make a
recommendation for or against the use of IVIG for
ABO-incompatible kidney transplantation; however, other factors may influence decision-making.
Level of evidence: II-2-III
3. Intravenous immunoglobulin is recommended for patients undergoing kidney transplantation who have donor-specific antibodies
perioperatively to reduce the incidence of acute
antibody-mediated rejection.
Clinical considerations: There is insufficient
evidence to recommend one treatment regimen.
With respect to clinical efficacy and adverse events,
In patients with acute rejection or chronic
rejection, is there evidence that the use of IVIG
improves graft survival or overall survival?
Rejection after transplantation is a significant and
frequently occurring problem associated with
substantial morbidity. Rejection of the renal
allograft is associated with peritransplant immunosuppression and can be categorized as (1) acute
antibody-mediated rejection, (2) steroid-resistant
Table 4. Characteristics of the Studies for the Use of IVIG for Kidney Transplant Rejection
1st author, year
Study design
Living or
deceased donor
Single-center Both
Casadei D,
RCT
200134
Observational Studies
Vasilescu ER, Retrospective Deceased
200635
case series
Both
Type of rejection
Mean PRA
CYA, AZA, steroids NR
2y
Antibody
mediated
NR †
NR
1y
Antibody
mediated (C4d+)
Acute humoral
67% ± 25%
NR
White NB,
200438
Retrospective Both
case series
Acute humoral
NR
Rocha P,
200339
Retrospective Both
case series
T: 47 ± 11;
B: 31 ± 10
Luke PPW,
200140
Retrospective NR
case series
Montgomery
RA, 200041
Casadei D,
199842
Jordan SC,
199843
Casadei D,
199644
Retrospective Living
case series
Cohort
NR
Acute humoral
and acute cellular
rejection
Steroid or
antilymphocyte
antibody-resistant
rejection
Acute humoral
Steroid-resistant
rejection
Acute humoral ±
cellular rejection
Steroid-resistant
rejection
Both
Retrospective Both
case series
Follow-up
NA
Case series
Case series
Definition of
response
Steroid-resistant
rejection ⁎
Jordan SC,
200536
Lehrich RW,
200537
Retrospective Both
case series
Maintenance
immunosuppression
T: 39% ± 8.7%; TAC/CYA, MMF,
B: 43% ± 8.9% prednisone
Basiliximab, TAC,
prednisone,
sirolimus (n = 6),
MMF (n = 3)
TAC/CYA, MMF,
MP
Return to nearnormal creatinine
or loss of DSA
NR
4y
Return to normal Mean
renal replacement 29 mo
therapy
NR
1y
Outcome of renal
allograft
1.5 y
NR
MMF (n = 6), TAC
(n = 16), CYA
(n = 1)
Reversal of
rejection
Mean
22 mo
NR
NR
NR
TAC, MMF,
prednisone
NR
NR
Mean
30 mo
2 mo
NR
NR
NR
5 mo-5 y
NR
CYA + AZA +
prednisone
NR
1 mo
Abbreviation: MP, methylprednisone.
⁎ Steroid-resistant rejection defined as failure to improve renal function within 7 days of pulse methylprednisone.
† No correlation between antibody-mediated rejection and panel-reactive antibodies.
S18
SHEHATA ET AL
acute cellular rejection, (3) “simple” acute cellular
rejection, and (4) chronic active antibody-mediated
rejection. A mixed picture may also occur.
Intravenous immunoglobulin is commonly used to
treat antibody-mediated rejection.
There were seven case series that included a total
of 166 patients with antibody-mediated rejection
(Tables 4 and 5).35-39,41,43 All but one43 of these
studies used a combination of IVIG and PP.
However, various additional immunosuppressive
agents were also used in the treatment of these
patients. Definitions of acute humoral rejection
differed. The doses of IVIG administered ranged
from 100 mg/kg to 2 g/kg. Graft survival ranged
from 60% to 100%, and patient survival was from
90% to 100%. The survival rate is comparable with
3-month graft survival of historical controls that has
been reported at 50%, despite treatment with
antilymphocyte antibody preparations in 92%
of patients.62
For patients at increased immunologic risk
(sensitized recipient having undergone desensitiza-
tion protocols to achieve transplantation) with acute
antibody-mediated rejection, one case series with
18 patients reported a 60% graft survival using
IVIG and steroid treatment.36 In those who did not
respond, addition of thymoglobulin and plasma
exchange could not rescue the organ. Two other
case series with a combined total of 39 patients that
also included patients who were sensitized reported
favorable results (Tables 4 and 5).37,39
One randomized controlled trial,34 one cohort
study,42 and two case series40,44 addressed the use of
IVIG in patients having steroid-resistant rejection.
The cohort study may have been a preliminary report
of the randomized controlled trial.42 Patients in the
randomized controlled trial were treated with IVIG or
OKT3. Comparable graft and patient survivals were
reported (Table 5).34 A lower recurrence rate of acute
rejection occurred with IVIG (46% with IVIG
compared with 75% with OKT3, P = .4).34 In one
case series, graft survival was similar to that observed
in the randomized controlled trial (71%).40 This is
comparable to historical data in patients treated with a
Table 5. Results of Studies for the Use of IVIG for Kidney Transplant Rejection
1st author, year
Patients
Adult
Casadei D, 200134
N
Graft survival
Survival
80%
80%
78/80 (98%)
78/80 (98%) NR
72%
20/23 (87%)
11/18 (61%) NR
20/23 (87%) 22/23 (96%)
8/9 (89%)
8/9 (89%)
15/16 (93%)
13/16 (81%) 15/16 (93%)
Jordan SC, 199843
PP, IVIG/CMVIG 100 mg/kg until
response q 2nd day + MP, MMF, TAC
NR
18 IVIG 2 g/kg, pulse steroids ± PP or TG
Adult
23 4 Daily PP followed by IVIG 2g/kg
(variable dose); PP only (n = 1), +
MP (n = 11), +TG or OKT3 (n = 7)
Adult
9
PP followed by IVIG 250/500 mg/kg
q 2nd day +MP
Adult, ± 16 4 Daily PP followed by IVIG 2 g/kg;
pancreas
PP only (n = 1), IVIG only (n = 1) +
MP + OKT3 (n = 3) + TG (n = 1)
NR
17 IVIG 2 g/kg over 2-10 d (additional
IVIG, n = 4) + steroids (n = 10), +
MMF (n = 7),
7 were
10 Rejection; PP + IVIG/CMVIG
adults
100 mg/(kg d) q 2nd day until
improvement or no DSA
NR
11 IVIG 500 mg/kg × 7 d
12 OKT3 5 mg/d for 14 d
NR
10 ⁎ IVIG 2 g/kg + MP ± OKT3 ± CY ± TAC
Casadei D, 199644
NR
Jordan SC, 200536
Lehrich RW, 200537
White NB, 200438
Rocha P, 200339
Luke PPW, 200140
Montgomery RA,
200041
Casadei D, 199842
IVIG 500 mg/(kg d) × 7 d
OKT3 5 mg/kg × 14 d
Response rate
11/15 (73%)
13/15 (87%)
Vasilescu ER, 200635 Adult
15
15
Treatment regimen
80
22
IVIG 500 mg/kg ×7 d
Abbreviation: CY, cyclophosphamide.
⁎ Three patients had heart transplantation.
87%
92%
NR
Resolution of
12/17 (71%) 16/17 (95%)
rejection = 9/17 (53%)
NR
9/10
NR
8/11 (73%)
10/12 (83%)
100%
NR
NR
21/25 (84%)
NR
100%
100%
1/3 Cardiac
(33%), not
reported for
kidney
NR
calcineurin inhibitor-based immunosuppression protocol, where 6-month graft survival is reported to
be 59%.63
There were no studies with a sufficient sample size
(ie, N5 patients) that addressed the use of IVIG for the
treatment of simple acute cell-mediated rejection or
chronic active antibody-mediated rejection.
Consensus
There is sufficient evidence to propose that IVIG
be used for the treatment of patients with acute
antibody-mediated rejection. There are insufficient
data to draw conclusions regarding treatment of
antibody-mediated rejection using IVIG alone,
without the use of concomitant PP. In most
published reports, IVIG is used after PP. Cytomegalovirus immunoglobulin has also been administered at some centers with PP; however, there are no
data to indicate that CMVIG is superior to other
IVIG preparations. In addition, there are no trials
that compare IVIG and PP to other rejection
therapies or that compare IVIG alone to PP.
Randomized controlled trials are required to
compare these treatment options.
There are limited data on the use of IVIG in patients
with increased immunologic risk who experience
acute antibody-mediated rejection, and there are no
data comparing the use of IVIG in the patient with
increased immunologic risk to its use in the standardrisk patient. Nonetheless, because immune mechanisms of rejection are similar in such patients, IVIG use
was also considered a treatment option in these
patients, although they may be less responsive.
Intravenous immunoglobulin is not presently
considered as first-line therapy for the treatment of
steroid-resistant rejection, as there are no data to
indicate that IVIG is superior to alternate therapies.
Comparative studies of IVIG are promising, but
have not included current standard polyclonal
antilymphocyte antibody treatments, which are
better tolerated than previous monoclonal antilymphocyte preparations. The use of IVIG may be
reserved for situations where standard treatments
have been ineffective or are contraindicated.
Intravenous immunoglobulin has less toxicity
associated with its use compared with other standard
therapies and should be studied further.
There are also limited data on the use of IVIG for
chronic active antibody-mediated rejection. Randomized controlled trials are required to define the
role of IVIG in this patient population.
S19
There are little pediatric data. The immunologic mechanisms of acute humoral rejection and
steroid-resistant rejection are similar, and children are expected to have a similar benefit from
IVIG treatment.
Recommendations
5. Give IVIG after PP for patients who have
received a living donor or deceased kidney donor
transplant and who have acute antibody-mediated
rejection to improve graft survival.
Level of evidence: II-3
Clinical considerations: Intravenous immunoglobulin is typically administered as part of a
treatment protocol that includes PP. Regimens for
administration of IVIG include IVIG after each PP
treatment (100 mg/kg per treatment day) or as a set
dose of 2 g/kg total, after the final PP treatment.
There are no comparative data to indicate which of
these approaches is superior. Cytomegalovirus
immunoglobulin has also been administered at a
dose of 100 mg/kg after each PP treatment. The
optimal number and frequency of PP treatments
needed are beyond the scope of these recommendations. With respect to clinical efficacy and adverse
events, there is insufficient evidence to recommend
one formulation of IVIG over another for currently
available products.
6. In patients who have received a living/
deceased donor kidney transplant and who have
steroid-resistant rejection, consider IVIG to improve graft survival when other therapies are
deemed unacceptable or ineffective.
Level of evidence: I, II-2, III
Clinical considerations: Intravenous immunoglobulin can be administered over a period of up to
10 consecutive days, at a total dose of 2 to 3.5 g/kg.
Longer administration periods with smaller doses
can be used in selected patients where fluid
overload is a potential risk. Assessment of treatment response should include measurement of renal
function and reassessment of renal histology. There
is insufficient evidence to recommend one formulation of IVIG over another.
7. There is insufficient evidence to make a
recommendation for or against the routine use of
IVIG for other forms of rejection.
Grade of recommendation: I
S20
SHEHATA ET AL
CARDIAC TRANSPLANTATION
There remains a great deal of controversy over
quantification, evaluation, and management of the
sensitized potential cardiac transplant recipient. What
is certain is that highly sensitized patients, including
those with donor-specific antibodies, have an
increased risk of antibody-mediated rejection, cardiac
allograft vasculopathy, and early graft loss after
transplantation.64,65 In addition, the use of mechanical circulatory support as a bridge to transplantation
has been associated with an increasing incidence of
de novo sensitization (approximately 30% depending
on the definitions used) due in part to transfusions,
especially platelets, at the time of implantation.66
Multiple strategies to desensitize the potential
cardiac transplant recipient have been proposed
including treatment with mycophenolate mofetil or
cyclophosphamide, PP, IVIG, rituximab in isolation or in combination with other agents, before
transplantation, perioperatively, or immediately
after transplantation. Results have been variable,
and the interpretation of analyses is limited by
inconsistent use of classification of outcomes.
Six observational studies reported on the use of
IVIG in cardiac transplantation (Tables 6 and 7).45-50
Three studies included the same cohort of patients
who were treated with IVIG for desensitization
aiming for a negative crossmatch.47,48,50
Four reports did not define response to treatment.45,46,48,49 The reduction of antibody level with
IVIG as a single modality was not measured in any
report. A decreased panel-reactive antibody was
detected in two reports,45,49 and four reports did not
show a change in panel-reactive antibodies.46-48,50
Three reports demonstrated a reduced time to
transplantation but included the same patient co-
hort.47,48,49 One small study showed a survival
benefit in sensitized heart transplant recipients who
received pretransplant treatment with PP and IVIG.45
One report included a pediatric population, and
outcomes were not improved with the use of IVIG.46
Only one study reported complications associated with IVIG.48 The use of IVIG resulted in
immune complex disease (ie, fevers, arthralgias,
and maculopapular rash) in four patients (15%).
Four patients also experienced reversible renal
insufficiency defined as a 50% increase in serum
creatinine level. The renal insufficiency resolved in
all patients 3 weeks after IVIG infusion.48
Consensus
There were several limitations in the available
literature. Different methodologies were used for
the detection of panel-reactive antibodies. The
reports that included rejection as an outcome
reported both acute cellular and antibody-mediated
rejection and did not use the current International
Society for Heart and Lung Transplantation's
standardized definition of antibody-mediated rejection. The use of other interventions with IVIG such
as PP and other immunosuppressive agents precluded assessment of the impact of any given
therapy. There was also a paucity of data for
transplantation rates and outcomes.
Although one report found a survival benefit,45
these results have not been reproduced, the numbers
are small, and no data on donor-specific antibody
were given. The available literature on renal
transplantation suggests that transplantation in the
setting of an acceptable antigen mismatch (ie, in the
presence of an HLA antibody but not directed against
the donor HLA type) is associated with comparable
Table 6. Characteristics of the Studies for the Use of IVIG for Desensitization for Cardiac Transplantation
1st author, year
Study design
Leech SH, 200645
Jacobs J, 200446
Case series
Retrospective
cohort
Retrospective
cohort
Retrospective
cohort
Retrospective
cohort
Prospective
cohort
John R, 200347
Itescu S, 200248
Pisani BA, 199949
John R, 199950
Method to determine sensitization
Definition of sensitization
Definition of response
CDC CXM, PRA by FC
Cytotoxic PRA
PRA N10%
PRA N10%
NR
NR
Mean 21 mo
17 d-8 y
Follow-up
Lymphocytotoxic
CXM
Lymphocytotoxic
assay
AHG CDC
NR
Negative CXM
1y
NR
NR
12 mo
PRA N10%
NR
Mean 22 mo
CDC
Anti-HLA reactivity
N20%
Negative CDC
CXM
NR
S21
Table 7. Results of the Studies for the Use of IVIG for Desensitization for Cardiac Transplantation
1st author,
year
Leech SH,
200645
Jacobs J,
200446
John R ‡,
200347
Patients
Sensitized
post LVAD
John R ‡,
199950
Transplant regimen
Sensitized adults 35 PP and IVIG 20 g × 5 or
for OHT ⁎
PP × 1 then IVIG 20 g
Nonsensitized
277 All received MMF, MP,
adults
TG TAC ± basiliximab
Sensitized
8 IVIG weekly (dose NR) +
children for OHT
PP + CY + MMF
Nonsensitized
52 No treatment; all 60–IVIG,
steroids, TG as induction,
then TAC/CYA, AZA/MMF
Sensitized
26 1-3 monthly CY, IVIG 2 g/kg +
post-LVAD
AZA, CYA, steroids CY and
MMF posttransplantation
Sensitized
45 No IVIG + AZA,
post-LVAD
CYA, steroids
Itescu S ‡, Sensitized
200248
post-LVAD
Pisani BA,
199949
N
Sensitized
adults for OHT
Nonsensitized
Sensitized
post-LVAD
Sensitized
post-LVAD
Not sensitized
post-LVAD
26 1-3 monthly CY, IVIG 2 g/kg
44 No treatment
16
102
16
4
28
All received triple
immune suppression +
AZA/MMF
PP +IVIG (20g),
preoperatively
No treatment
All received MP,
CYA + AZA +
OKT3 (n = 3)
1-3 monthly IVIG 2 g/kg (n = 6,
IVIG 3g/kg), monthly CY
1-3 monthly, IVIG 2 g/kg + PP
2-3×/wk × 1-2 mo, monthly CY
No treatment
Success of
desensitization
Decrease in PRA
Humoral rejection
7/35 (20%)
vs NR
NR
1 Rejection
episode/pt
vs 0.7/pt †
(P = .2)
54%
NR
vs 33%
vs 48%
transplanted
(P = .04)
within 2 mo
0% died awaiting NR ¶
transplantation
(n = 23)
vs 14% (P = .08)
88% vs
84%
(P = NS)
1/16 (6%)
NR
NR
NR
87%
vs 10/102
(10%) (P = NS)
TTT reduced
3.3 mo
NR
Survival
85%
(P = .04)
22%
TTT reduced
to 3.3 mo
(n = 23) ║
20% reduction in
PRA after PP
Graft survival
32/35 (91%) 31/35
(88%)
vs NR
vs 58%
(P = .04)
NR
50% vs
NR
vs (84%)
(P = NS)
NR
NR
7.1 mo, P b .05
Abbreviations: LVAD, left ventricular assist device; NS, not significant, OHT, orthotopic heart transplantation; pt, patient; TTT, time to transplantation.
§The time to transplantation was 1.7 months for individuals who were treated with IVIG vs 2.8 months for individuals not treated (P b .01).
⁎ Two patients also received a kidney transplant.
† The type of rejection was not specified.
‡ The same patient population was used for all studies.
║ There was a 33% reduction in immunoglobulin G anti-HLA I/II.
¶ The results were not reported according to subgroup.
outcomes to patients without any HLA antibody
present. Hence, in the absence of data on donorspecific antibodies, it is difficult to formulate
recommendations based on the results of this study.45
Thus, the panel considered that there were
insufficient data to formulate a recommendation
on the routine use of IVIG for desensitization in
cardiac transplantation.
Recommendation
There is insufficient evidence to recommend for or
against the routine use of IVIG for desensitization for
Table 8. Characteristics of the Studies for the Use of IVIG for Desensitization in Lung and Liver Transplantation
1st author, year
Study design
Appel JZ ⁎, 200551
Urbani L, 200852
Retrospective cohort
Retrospective case series
Method to determine sensitization
Definition of sensitization
Definition of response
Follow-up
FC for PRA
NR
NR
ABO incompatible
NR
NR
3y
18 mo
⁎ The study excluded patients not surviving until hospital discharge or longer than 90 days.
S22
SHEHATA ET AL
patients undergoing heart transplantation to improve
graft/overall survival or to treat rejection; however,
other factors may influence decision-making.
Level of evidence: II-2-III
rejection; however, other factors may influence
decision-making.
Level of evidence: II-3
LIVER TRANSPLANTATION
LUNG TRANSPLANTATION
The role of IVIG or any other desensitization
therapy in patients undergoing lung transplantation who are sensitized to HLA antigens is
unknown. Recent studies have identified increased
morbidity and mortality associated with HLA
sensitization, whereas earlier reports did not.67-70
Interpretation of these reports is difficult given
different diagnostic techniques.
There has been only one report on the use of IVIG
in lung transplantation (Tables 8 and 9).51 Twelve
patients were treated with IVIG and extracorporeal
immunoadsorption for removal of preformed antibodies beginning from the time of transplantation.
There were no statistically significant differences in
freedom from bronchiolitis obliterans or acute
rejection. An additional 8 patients who developed
de novo antibodies and declining graft function were
treated with IVIG 500 mg weekly as “rescue
therapy.” There was no statistically significant effect
on declining lung function. There have been no other
studies to substantiate these results.
Recommendation
There is insufficient evidence to make a
IVIG for desensitization for patients undergoing
lung transplantation or for the treatment of
Antibody-mediated rejection is rare after liver
transplantation, and evaluation of recipients for
HLA antibody formation is not routinely performed. Consequently, desensitizing protocols
with IVIG have not been required. Intravenous
immunoglobulin has been used as specific therapy
for posttransplant complications including hypogammaglobulinemia,71 thrombocytopenia,72 and
demyelinating polyradiculoneuropathy.73 In adults
receiving ABO-incompatible liver transplants,
IVIG has been incorporated into successful protocols but always added to various combinations of
immunosuppressive agents such as PP, extracorporeal photopheresis, and anti-CD20 antibody therapy.74 Benefits from the immunomodulatory effects
of IVIG have been proposed in the existing
literature; that is, CMVIG prophylaxis appeared to
offer a survival benefit independent of its antiviral
effect in one report.75 However, there have been no
studies specifically designed to prospectively assess
the role of IVIG/CMVIG in rejection and survival
after liver transplantation.
One observational report fulfilled inclusion criteria (Tables 8 and 9).52 This report52 focused on the
use of IVIG for ABO-incompatible liver transplantation and reported favorable graft and overall
survival and reduced rejection rates in patients
treated with IVIG. However, the group that received
IVIG also received extracorporeal photopheresis.
Table 9. Results of Studies for the Use of IVIG for Desensitization in Lung and Liver Transplantation
1st author,
year
Appel JZ,
200551
Urbani L,
200852
Patients
N
Transplant regimen
Sensitized patients 12 IVIG 2 g/kg at transplant, 500 mg/kg
weeks 1-4 + taper weeks 5-24
ECI at transplant, daily week 1,
weekly weeks 2-4
Sensitized patients 23 No treatment
Adult undergoing
ABO-incompatible
transplantation
11 PP
Success of
desensitization
Rejection
Graft
survival
Freedom from
BOS 95%
0.4
vs 50%,
P = .32
NR
vs 1.2
(P = .05)
72%
46%
63%
vs 0
vs 88%
(P = .01) (P ≤ .001)
vs 86%
(P = NR)
8 PP, IVIG 1 g/kg during anhepatic
phase and for 14 d if anti-ABO titer
N8, ECI days 2, 4, 6, weekly × 4 wk
then depending on liver function tests
Abbreviations: BOS, bronchiolitis obliterans syndrome; ECI, extracorporeal immunoadsorption.
NR
Survival
NR
S23
Table 10. Responses From Reviewers to General Statement Regarding the Guideline
Item
n (%)
Generally, I do not think practice guidelines are useful.
The rationale for developing this guideline, as stated in the
“Introduction” section of the report, is clear.
There is a need for a guideline on this topic.
The literature search is relevant and complete.
The results of the trials described in the report are interpreted
according to my understanding of the data.
The draft recommendations in the report are clear.
This report should be approved as a practice guideline.
If this report were to become a practice guideline, how likely
would you be to make use of it in your own practice?
Agree
1
10
Neither agree nor disagree
Disagree
9
8
8
8
2
2
2
9
7
1
2
1
Unsure
3
Unlikely
1
Likely
5⁎
NOTE. Reviewers were asked to check one box to signify their agreement with the statements.
⁎One individual did not respond to this question.
Table 11. Responses From Reviewers Regarding Their Agreement With Guideline Recommendations
Agreement
Recommendation
1. When transplantation will involve use of a kidney from a living donor to whom
the patient is sensitized, IVIG is recommended to decrease donor-specific
sensitization.
2. There is insufficient evidence to make a recommendation for or against the use
of IVIG for ABO-incompatible transplantation; however, other factors may
influence decision-making.
3. IVIG is recommended perioperatively for patients who have donor-specific
antibodies to reduce the incidence of accelerated acute humoral rejection.
4. IVIG is not recommended for patients who do not have donor-specific
antibodies.
5. Give IVIG with plasmapheresis for patients who have received a living donor or
deceased donor transplant and who have acute antibody-mediated rejection to
improve graft survival.
6. In patients who have received a living/deceased donor transplant and who have
steroid-resistant rejection, consider IVIG to improve graft survival when other
therapies are deemed unacceptable or ineffective.
7. There is insufficient evidence to make a recommendation for or against the
routine use of IVIG for other forms of rejection.
8. There is insufficient evidence to recommend for or against the routine use of
IVIG for desensitization for patients undergoing heart transplantation to
improve graft/overall survival or to treat rejection; however, other factors
may influence decision-making.
9. There is insufficient evidence to recommend for or against the routine use
of IVIG for desensitization for patients undergoing lung transplantation to
improve graft/overall survival or to treat rejection; however, other factors
may influence decision-making.
10. There is insufficient evidence to recommend for or against the routine use of
IVIG for desensitization for patients undergoing liver transplantation to improve
graft/overall survival or to treat rejection; however, other factors may influence
decision-making.
This is not my area
of expertise (n)
Agree
(n)
Neither agree nor
disagree (n)
3
5
1
2
6
1
3
5
1
3
5
2
5
1
2
6
1
2
7
4
5
3
6
3
6
Disagree
(n)
1
1
NOTE. Reviewers were asked to check one box to signify their agreement with the recommendations. One individual did not respond to
this section.
S24
Recommendation
There is insufficient evidence to make a
IVIG for patients undergoing liver transplantation
or for the treatment of rejection/ABO-incompatible
liver transplantation.
Guideline Appraisal
The guideline was sent to 11 national experts in
transplantation and transfusion medicine as well as a
patient representative to appraise the guideline. Ten
reviews were received. The reviewers were asked to
evaluate the guideline and to rate their agreement to
each of the recommendations. Tables 10 and 11
illustrate a summary of the responses to questions.
The reviewers' comments and the panel's responses
to the comments are available upon request.
Future Research
There is limited methodologically rigorous evidence for the use of IVIG for solid organ
transplantation. Future studies are needed to delineate the effect of IVIG on desensitization using
standardized methods for desensitization; the effect
of IVIG on acute rejection rates, graft survival, and
overall survival; the use of the combined modality
IVIG and PP compared either to PP or IVIG alone;
and the optimum dosage of IVIG.
When immunoglobulin is used for renal, cardiac,
lung, or liver transplantation, the committee recommends the following elements for data capture:
impact on antibody specificity and titers, transplant
rates, time to transplantation, graft function, graft
survival, and frequency and outcomes of rejection
(cellular and antibody mediated).
Disclaimer
Care has been taken in the preparation of the
information contained in this document. Nonetheless, any person seeking to apply or consult these
guidelines is expected to use independent medical
judgment in the context of individual clinical
circumstances or seek the supervision of a qualified
clinician. The National Advisory Committee on
Blood and Blood Products and the Canadian Blood
Services make no representation or warranties of
any kind whatsoever regarding their content or use
SHEHATA ET AL
or application and disclaim any responsibility for
their application or use in any way.
ACKNOWLEDGMENTS
We thank Drs P Acott, A Dipchand, J Hannon,
D Lane, V Ng, J Pendergast, L Shepherd, L
Singer, and K Tinckham and Ms B Baerwald for
reviewing the guideline and their insightful
comments. We thank Corinne Holubowich for
conducting the literature searches and Dolly
Cordi, Colleen Bruneau, and Jennifer Joly for
their administrative assistance.
APPENDIX A. SEARCH TERMS
The following search terms were used: intravenous
immunoglobulin$.mp., immunoglobuolin$, intravenous.mp., IVIG.mp., carimune.mp., endobulin$.mp.,
flebogamma.mp., gamastan.mp., gamimmun$.mp.,
gamimun$.mp., gamulin rh.mp., gamunex.mp., gammabulin$.mp., gammagard$.mp., gammar?P$.mp.,
gammar-Iv.mp., gammonativ$.mp., gammunex.mp.,
globulin-n.mp., immune globulin, intravenous.mp.,
intraglobin$.mp, intravenous antibod$.mp., intravenous ig.mp., IV-IgG.mp., iv immunoglobulin$.mp.,
iveegam$.mp., modified immune globulin$.mp, sandoglobulin$.mp., venimmune$.mp., venoglobulin$.
mp., vivaglobin$.mp., cytogam$.mp., CMV-IGIV$.
mp., cytomegalovirus immune globulin$.mp., cytomegalovirus immunoglobulin$.mp., transplants.sh.,
transplantation.sh., cell transplantation.sh., cell
transplant$.mp., organ graft$.mp., organ transplant
$.mp., tissue graft$.mp., tissue transplant$.mp.,
recipient, transplant$.mp., tissue transplantation.
sh., organ transplantation.sh., transplant$, recipient$.mp., transplant$, cell$.mp., islets of langerhans
transplantation.sh., islets of langerhans transplant$.
mp., graft$, islets of langerhans.mp., ransplant$,
islets of langerhans.mp., transplant$, pancreatic islet
$.mp., islet$ transplant$.mp., transplant$, island$ of
langerhans.mp., transplant$, islet$.mp., graft$,
organ.mp., transplant$, organ$.mp., bone transplantation.sh., bone transplant$.mp., graft$, bone$.mp.,
transplant$, bone$.mp., bone-patellar tendon-bone
graft.sh., tendon$, para-articular.mp., heart transplantation.sh., cardiac transplant$.mp., graft$,
heart.mp., transplant$, cardiac.mp., heart transplant$.mp., transplant$, heart.mp., kidney transplantation.sh., kidney transplant$.mp., graft$, kidney.
mp., renal transplant$.mp., transplant$, kidney.mp.,
transplant$, renal.mp., heart-lung transplantation.
sh., heart-lung transplant$.mp., graft$, heart-lung.
mp, transplant$, heart-lung.mp., liver transplantation.sh., liver transplant$.mp., graft$, liver.mp.,
hepatic transplant$.mp., transplant$, hepatic.mp.,
transplant$, liver.mp., graft$, lung.mp., lung transplantation.sh., lung transplant$.mp., transplant$,
lung.mp., pancreas transplantation.sh., pancreas
transplant$.mp., graft$, pancreas.mp., transplant$,
pancreas.mp., bone-patellar tendon-bone graft$.mp.,
replantation.mp., reimplantation.sh., reimplantation.mp.tooth replantation.sh. tooth replantation.
mp., reimplantation, tooth.mp., replantation, tooth.
mp., tooth reimplantation.mp., tissue transplantation.sh., tissue transplant$.mp., graft$, tissue.mp.,
transplant$, tissue.mp., brain tissue transplantation.
sh., brain tissue transplant$.mp., graft$, brain
tissue.mp., transplant$, brain tissue.mp., brain
S25
transplantation.sh., brain transplant$.mp., corneal
transplantation.sh., cornea$ transplant$.mp., graft
$, cornea$.mp., transplant$, cornea$.mp., keratoplasty.mp., keratoplasty.sh., epikeratophakia.sh.,
epiketophakia.mp., fetal tissue transplantation.sh.,
fetal tissue transplant$.mp., graft$, fetal tissue.mp.,
transplant$, fetal tissue.mp., fetal tissue donation$.
mp., skin transplantation.mp., skin transplant$.mp.,
transplant$, skin.mp., dermatoplasty.mp., graft$,
skin.mp., transplantation, homologous.sh., transplant$, homologous.mp., allograft.mp., homograft.
mp., transplant$, allogeneic.mp., allogeneic transplant$.mp., homologous transplant$.mp., transplant
$, isogeneic.mp., homograft, isogeneic.mp., homograft, syngeneic.mp., isograft.mp., transplant$,
syngeneic.mp., isogeneic transplant$.mp., syngeneic
transplant$.mp.
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