OVERVIEW

The Treatment of Acute Antibody-Mediated Rejection

in Kidney Transplant RecipientsVA Systematic Review
Darren M. Roberts,1,2,4 Simon H. Jiang,1 and Steven J. Chadban1,3
Background. Antibody-mediated rejection (AMR) is a recognized cause of allograft loss in kidney transplant recipients. A range of therapies targeting removal of circulating donor-specific antibodies (DSAs), blocking their effect or
reducing production have been reported.
Methods. We conducted a systematic review to determine the efficacy of treatments for acute AMR in renal allografts.
Electronic databases, reference lists, and conference proceedings were searched for controlled trials. Nonrandomized
publications were reviewed for the purpose of discussion.
Results. We identified 10,388 citations, including five randomized and seven nonrandomized controlled trials. The
randomized studies were small (median, 13 patients/arm; range, 5Y23), of which, four examined plasmapheresis
(one suggested benefit) and one for immunoadsorption (also suggesting benefit). Marked heterogeneity was evident, including the definition and severity of AMR and the treatment regimen. The end point of graft survival was
common to all studies. Small, nonrandomized controlled studies suggested benefit from rituximab or bortezomib.
The effects of dose and regimen on the clinical response to any of the current treatments were not apparent from
the available data.
Conclusions. Data describing the efficacy of treatments for AMR in renal allografts are of low or very low quality.
Larger randomized controlled trials and dose-response studies are required.
Keywords: Antibody, Rejection, Kidney Transplantation, Treatment, Review.
(Transplantation 2012;94: 775Y783)

dvances in immunosuppression over recent decades

have contributed to improved outcomes for kidney
transplant recipients (KTR), particularly graft survival. The
introduction of cyclosporine and anti-thymocyte antibodies
in the 1980s significantly reduced the incidence of early rejection and reduced the need for precise matching of human
leukocyte antigens (HLAs). Antibodies directed toward donor HLA antigens (donor-specific antibodies [DSAs]), contribute to the occurrence of allograft rejection (1Y13).

The authors declare no funding or conflicts of interest.

1
Statewide Renal Services, Royal Prince Alfred and Concord Repatriation
General Hospitals, New South Wales, Australia.
2
School of Medicine, University of Queensland, Herston, Queensland,
Australia.
3
School of Medicine, University of Sydney, Camperdown, New South
Wales, Australia.
4
Address correspondence to: Darren M. Roberts, M.B.B.S., Ph.D., F.R.A.C.P.,
Statewide renal services, Royal Prince Alfred Hospital, Missenden Road,
Camperdown, New South Wales, Australia, 2050.
E-mail: 1darren1@gmail.com
D.M.R. and S.H.J. proposed the study, designed the search criteria, reviewed the results, and analyzed the data, with input from S.J.C. All
authors contributed to the writing of the paper and its submission to
Transplantation.
Received 6 March 2012. Revision requested 28 March 2012.
Accepted 30 April 2012.
Copyright * 2012 by Lippincott Williams & Wilkins
ISSN: 0041-1337/12/9408-775
DOI: 10.1097/TP.0b013e31825d1587

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& Volume 94, Number 8, October 27, 2012

Preformed DSAs develop after sensitizing exposures such

as blood transfusion, pregnancy, or previous transplantation. Donor-specific antibodies are encountered in patients
with end stage renal failure awaiting kidney transplantation
and require expert care with HLA matching and consideration of desensitization before transplantation (14Y17).
Posttransplantation, the development of de novo DSA
or reappearance or increase in titers of DSA may be associated with allograft rejection, particularly antibody-mediated
rejection (AMR), previously referred to as humoral rejection
(1Y13). The diagnostic criteria for AMR have evolved over
recent years. Renal biopsies in patients with detectable
DSA in serum, which showed histologic features of endothelial damage including neutrophil infiltration, necrosis,
apoptosis, and thrombosis, have traditionally been termed
vascular rejection (18). Several papers before 2003 established
the role of DSA in the condition suggesting a diagnosis of
AMR. The 2003 update of the 1997 Banff criteria defined
AMR on the basis of three criteria: the presence of anti-HLA
DSA in serum, allograft histology (polymorphonuclear-rich
glomerular and/or peritubular inflammation) and allograft
immunohistochemistry (positive staining for C4d+ in peritubular capillaries)(19). The diagnostic criteria continue to
be an area of scientific and clinical interest (20).
Antibody-mediated rejection occurs because of direct
and complement-mediated effects of the DSA on the allograft (18). Acute AMR is most commonly observed within
3 months posttransplant but can occur beyond this time,
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typically in response to excessive reduction in immunosuppression or nonadherence (2, 15, 21). The incidence of
AMR varies worldwide, depending on the diagnostic criteria
used, recipient sensitization and the immunosuppressive regimen, ranging from 3.1% (22) to as high as 30% to
40% (4, 15, 23). Antibody-mediated rejection in KTRs
responds poorly to corticosteroids and antithymocyte agents
alone, which are the standard treatment of the vastly more
common acute cellular rejection (24).
International guidelines do not define an evidencebased treatment for AMR. KDIGO recommends the use of
one or more of either corticosteroids, plasmapheresis (plasma exchange, PP), intravenous immunoglobulin (IVIG),
anti-CD20 antibodies, or lymphocyte-depleting antibodies
(25). Various recent reviews have discussed controversies
and options in the treatment of AMR; however, a systematic
review that also describes the strength of evidence for current treatments has not been published. Therefore, we conducted a systematic review of the literature to determine
the efficacy of treatments for acute AMR in KTRs. The primary studies sought were double-blind randomized controlled trials determining the effect of a treatment on graft
survival. We also wished to identify priorities for future research in the treatment of AMR.

RESULTS
The search strategy yielded 10,338 citations in electronic databases, from which five randomized controlled
trials (RCTs) and seven other controlled studies in patients
with acute AMR or vascular rejection were identified (Fig. 1).
Five of these evaluated the effect of PP. A range of treatments (Table 1) and doses were used across these studies
(and within individual centers, e.g., (21)). Some treatments
were used over an extended period (e.g., IVIG and PP),
whereas others were used for shorter periods (e.g., cyclophosphamide, tacrolimus, and biologic agents) reflecting
the development of new therapies (Fig. 2).
Controlled Trials
The 12 controlled studies are summarized in Table 2.
Marked heterogeneity was observed among these, including
diagnostic criteria, severity of rejection, time since transplantation, and the treatment regimen. Of the RCTs, the
median size of each arm was 13 patients (range, 5Y23), and
four were conducted over 25 years earlier and used outdated
diagnostic criteria. Mixed rejection (AMR plus cell-mediated)
was either reported, or possible, in each of the RCTs identified. Donor-specific antibodies were only measured in three
RCTs (26Y28), but these were not used to titrate therapy.
Baseline immunosuppression typically included steroids
and antiproliferative agents, with variable use of calcineurin
inhibitors (Table 2).
The most promising results were reported from an
RCT using a protein A immunoadsorption (IA) column
(26). Nine of the 10 patients in this study were hemodialysis
dependent at the time of enrollment (5 in intervention arm,
4 in control arm) because of AMR by Banff 1997 criteria;
IVIG was not administered. At 3 weeks postenrollment, all
patients in the active arm were dialysis independent. In contrast, renal function in the four hemodialysis-dependent

Transplantation

FIGURE 1.

& Volume 94, Number 8, October 27, 2012

Flow diagram demonstrating search results.

patients in the control arm did not recover. This study was
terminated on interim analysis because of significant benefit
in the experimental arm and emerging data from uncontrolled studies reporting benefit from PP and IVIG. Donorspecific antibodies were not detected in all patients in this
study, C4d+ deposition was less in the treatment group,
and cellular rejection was present in one patient in each
treatment arm.
Four RCTs evaluated the effect of plasma exchange: it
was reported to be beneficial in one study (27), potentially
harmful in another study (29) and no effect in two studies
(28, 30). The regimen used varied in dose, frequency, and
treatment intervals among the studies, and IVIG was not
administered.
Controlled but nonrandomized studies supported the
effect of rituximab (31Y34), PP (32Y35), and bortezomib
(33, 36) (Table 2). Some studies used a combination of these
therapies, so the relative importance of an individual treatment could not be determined. For example, a difference
in effect was not observed between bortezomib and a combination of rituximab, PP, and IVIG (37); therefore, it is not
clear from this study if any of these treatments were useful.
Because the controlled trials were all small in size and
differed with respect to inclusion criteria and treatment regimens, statistical analyses were not conducted.
Other Publications
A large number of case series and case reports were
identified, and similar marked heterogeneity was observed
in diagnostic criteria, treatment, and dosing regimens.
Reflecting the trends in treatment, and potentially the increasing incidence of AMR, the relative frequency with
which the more popular treatments were administered during the last 40 years is shown in Figure 2.
Newer, costlier treatments, such as rituximab, bortezomib, and eculizumab, were increasingly used to treat refractory AMR, rather than as initial therapy. A systematic
review presented in abstract form suggested that rituximab

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Roberts et al.

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777

TABLE 1. Therapeutic agents used against DSAs in the treatment of antibody-mediated rejection and the evidence
supporting their role
Action

Evidence supporting the treatmenta

Decrease the titer and block the effect of DSA

Decrease the titer of DSA
Decrease the titer and block the effect of DSA
Decrease production of DSA
Decrease inflammation caused by DSA in graft and
decrease production of DSA, suppression of T cells
Reduce production of DSA by decreasing Helper T cells,
suppression of T cells
Block complement activation resulting from
DSA activation
Block the effect and decrease production of DSA,
suppression of T cells
Decrease production of DSA
Decrease production of DSA
Decrease production of DSA, suppression of T cells
Decrease production of DSA
Decrease production of DSA, Suppression of T cells

Low, benefit not consistently demonstrated

Low, seems beneficial
Very low
Very low
Very low

Therapy
Plasmapheresis (PP)b
Immunoadsorption (column)
IVIG
Bortezomib
Corticosteroids
Anti-thymocyte preparations
Eculizumab
Mycophenolate
Rituximab
Cyclophosphamide
Deoxyspergualin
Splenectomy
Tacrolimus
a
b

Very low
Very low
Very low
Very low
Very low
Very low
Very low
Very low

According to the GRADE system, as described in the Materials and Methods section.
Plasmapheresis may have other effects, which block the effect of DSA, including removal of other circulating factors such as complement (28, 62Y65).

was potentially effective in the treatment of refractory AMR

(odds ratio, 9; 95% confidence interval, 4.5Y18). Given the
likelihood that these studies were small and of low methodologic quality, the significance of the odds ratio is unclear;
similarly, the authors concluded that an RCT was required
to confirm this observation (38).
An evidence-based practice guideline recommended
that IVIG be administered after PP for the treatment of
AMR. It was also stated that this suggestion was based on
low-quality studies and that the optimal dose of IVIG was unclear (published doses varied between 0.1 and 2 g/kg) (39).
A randomized controlled trial demonstrated that IVIG
was effective for the treatment of steroid-resistant rejection,
and although this study has been mentioned by some to support the use of IVIG, it was ineligible for inclusion in our
systematic review because 83% of the patients had Banff 1
(pure cellular) rejection on biopsy (40).
Grading of the Evidence
The evidence supporting the efficacy of each proposed
treatment is shown in Table 1. Because of the small size of
the RCTs, generally outdated diagnostic criteria, and inadequate documentation of allocation, the evidence supporting
these treatments was downgraded to low. The evidence
supporting all other interventions was classified very low.
We considered upgrading rituximab to low, given the results
of the systematic review (38), but it has only been published
in abstract form, and the inclusion criteria was limited to
treatment refractory cases.

DISCUSSION
There is insufficient evidence to adequately guide the
treatment of AMR. Overall, relevant RCTs were of low quality. No RCTs for IVIG in the treatment of AMR were identified, and yet it is a popular treatment (Fig. 2), presumably

FIGURE 2. Trends in the use of treatments for AMR over

time on the basis of all publications identified in the systematic review. Using a gray scale, black represents the most
commonly used (in the case of PP, approximately 700 patients
were treated between 2007 and 2011), whereas no color
(white) means that it was not used. This includes patients from
any observational, treatment, or epidemiology-based study
identified in the systematic review. The use of tacrolimus and
mycophenolate in patients with AMR is likely to be underrepresented in this figure because in recent years, these
treatments are commonly used as baseline immunosuppression for high-risk KTRs, whereas the data included here
only included new treatments administered to patients in
response to a diagnosis of AMR/vascular rejection.

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Banff 97

AMR resistant
to ATG

Vascular,
MP
resistant

Lefaucheur et al.,
2009 (32)

Kaposztas et al.,
2009 (31)

Franco et al.,
1987 (35)

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Historical control

Historical control

Historical control

Stratified RCT

Low

Low

Low

Unclear

Deceased donor; mean, 35 d;

AZA, PNL, CsA. ATG
if cellular rejection
present

70% deceased donor; G30 d;

PP (5 doses), PNL,
CNI, mTOR, or MMF
and IVIG if low serum
IgG concentrations

PP (5 treatments)

Source unclear; G 3 mo; AZA,

PNL. Rejection therapy
included MP, radiation;
ATG if no improvement
after 6 d of PP
Deceased donor; median
15 d; IVIG, PNL,
MMF, tacrolimus

PP (6 doses)

Rituximab

PP (4 doses),
rituximab
(2 doses)

PP (6 treatments)

Deceased donor; 1 mo; MP,

PNL, AZA, heparin

PP (8 treatments)

PP (3Y7 treatments)

IA (protein A; 9Y14
sessions)

Intervention,
dose

24,14

26, 28

12, 12

19,19

13, 14

12, 12

23, 21

5, 5

N=(I,C)

6, 13 (at 3 mo) OR=0.4

(95% CI, 0.1Y1.3)

2, 8 (at 2 yr) (deaths: 1,3),

OR=0.2 (95%
CI, 0.04Y1.09)

1, 6 (at 3 yr) OR=0.1

(95% CI, 0.008Y0.9)

Overall
benefit

No (trend to harm
at 220 d)

No (trend to harm)

Yes

Yes (early
termination
of trial)

Yes

Yes

Yes

4, 6 (at 6 mo), RRR=0.3

No
(95% CI 0.001Y0.8);
10,13 (at 5 yr), RRR=0.2
(95% CI, 0.001Y0.5)

6, 3 (at 1 mo), RRI=0.5

(95% CI, 0.001Y0.8)
3, 4 (at 6 d), RRR=0.2
(95% CI 0.001Y0.8);
11, 9 (at 220 d),
RRI=0.2 (95% CI,
0.001Y0.5)

7, 17 (at 2 wk), RRR=0.6

(95% CI, 0.3Y0.8)

0, 4 (at 3 weeks), ARR=0.8

(95% CI, 0.2Y0.9)

Efficacy: hemodialysis
dependency or graft
loss (I,C)

Comments

In a further 10 patients,
histopathology
was diagnosed as
chronic rejection.

Recurrent rejection
occurred in 25%
of patients in
each group

DSA titers measured

DSA titers measured.

Experience with
an additional 10
nonrandomized
patients were also
described, but
are not included
in this table
A high proportion of
patients experienced
recurrent rejection

More C4d+in allografts

of intervention
group. DSA titers
measured.
Nonsignificant
trend toward lower
pretransplant PRA
in the treatment
group
DSA titers measured

Transplantation

Vascular

High

RCT

Deceased donor; 1 mo; MP

Source unclear; 10Y11 mo;

MP, cyclophosphamide

Source unclear; G3 mo;

MP, ALG, tacrolimus

Allograft source; time since

transplant; baseline
immunosuppressiona

www.transplantjournal.com

Blake et al.,
1990 (30)c

Unclear

RCT

Kirubakaran et al., Vascular

1981 (29)
Allen et al.,
Vascular,
1983 (28)
MP
resistant

Unclear

RCT

Vascular,
MP
resistant

High

Quality b

Bonomini et al.,
1985 (27)

Stratified RCT

Design

Banff 97

Criteria

Summary of the controlled trials

Bohmig et al.,
2007 (26)

Study

TABLE 2.

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AMR

Macaluso et al.,
2011 (33)

AMR with DSA Historical cohort

AMR with DSA Nonrandomized

case control
trial

Waiser et al.,
2010 (37)

Lubetzky et al.,
2011 (36)

Low

Low

Low

Low

Low

Unknown source; unknown

time since transplant;
unknown baseline
immunosuppression
(IVIG and ATG given
to patients in both
groups, but in a higher
proportion of the
bortezomib recipients)

Unknown source; unknown

time since transplant;
unknown baseline
immunosuppression
but MP given to
each patient
Unknown source; unknown
time since transplant;
unknown baseline
immunosuppression

Unknown source; unknown

time since transplant;
IVIG and ATG (1 dose)

5 deceased and 2 live donors;

15 months; AZA, PNL
and cyclophosphamide,
15, 24

4, 3

1, 10 (at 3 mo) (death 0, 2)

OR=0.1 (95%
CI, 0.01Y0.9)

1, 3

Bortezomib (4 doses)
vs. rituximab
(1 dose), PP
(6 doses) and
IVIG (30 g)
Rituximab vs.
bortezomib
11, 15

10, 9

3, 1 (at 6 mo) OR=5.3

(95% CI, 0.5Y59.3)

2, 3 (at 6 mo) OR=0.5

(95% CI, 0.06Y4.0)

OKT3 vs. IVIG vs.

29 vs. 13 vs. 22 HR=0.19 (vs. OKT3)
PP and rituximab
HR=0.11
(doses not
(vs. IVIG
reported for
any group)

Bortezomib
(4 doses),
rituximab
(1 dose),
PP (5 doses

PP (4Y5 doses)

Presented in
abstract form

Presented in abstract
form. HR
determined by an
adjusted analysis

Presented in abstract
form, unclear if
IVIG given to
Bortezomib group,
discrepancy in
numbers reported

Decrease in DSA
only observed in
PP group

Yes for bortezomib Presented in

abstract form.
Bortezomib
associated with
greater decrease
in DSA titers

No

Yes (for PP and

rituximab)

Yes

Yes

Any combination of these treatments were used.

Assessed using standardized criteria described by the Cochrane Collaboration (59); see the Methods section for more details.
c
The intention of the authors was to administer PP for the purpose of treating humoral rejection, and it was given to all cases of rejection rather than those with histologic proof because of stated difficulty with
identifying humoral mediators. The patients were randomized before an episode of rejection and administered this treatment for each episode of rejection over a 3-month period (67). Interim analyses of this study
were published on two occasions (67, 68). The final publication included 85 patients, of which, 38 had developed vascular rejection. A difference in death, development of CKD, or proteinuria was not observed
between the two groups (30).
# Given in some cases.
I, Intervention group; C, control group; HD, hemodialysis dependent, including due to graft loss; MP, methylprednisolone; ALG, antilymphocyte globulin; AZA, azathioprine; PNL, prednisolone; MMF, mycophenolate mofetil; CsA, cyclosporin A; CNI, calcineurin inhibitors; HR, hazard ratio; OR, odds ratio; ARR, absolute risk reduction; RRR, relative risk reduction; RRI, relative risk increase.

Vascular with
DSA

Loupy et al.,
2011 (34)

Nonrandomized
case control
trial

Nonrandomized
case controlled
trial

Vascular,
Nonrandomized
anti-HLAs
case controlled
trial

Vangelista et al.,
1982 (66)

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on the merit of case series and experimental data. As a result of the long period covered by this systematic review,
varied and often outdated diagnostic criteria were used, and it
is probable that cases differing to our current understanding
of AMR were included. Baseline immunosuppression commonly differed to the modern practice of calcineurin inhibitors and mycophenolate, further limiting the relevance
of a number of these studies to current practice. A large
number of case reports and case series were identified for
which treatment regimens varied markedly. Dose-response
studies were not found, further limiting our ability to recommend an optimal dose regimen. The majority of studies
report positive responses to existing therapy (allograft survival of 70%Y100%, patient survival of 94%Y100% (41)),
although it is well established that uncontrolled or poorly
blinded studies favor positive outcomes. Although knowledge
of the diagnosis and pathophysiology of AMR is advancing,
evidence supporting existing treatments is poor. Future research should focus on adequately controlled trials, requiring multicenter recruitment because of the rarity of AMR,
consistent diagnostic criteria, and rationalization of existing treatment regimens for the purpose of decreasing complications, inconvenience, and expense.
Evidence Supporting the Current Treatments
for AMR
Use of the treatments described in Table 1 is largely ad
hoc, extrapolating from other clinical conditions and supported by experimental data. The current rationale for treatment of AMR is to interfere with multiple pathophysiologic
pathways using combination therapy. Although some combinations are popular, on the basis of the current data, we
could not determine the optimal treatment regimen nor
the relative importance of one therapy over another. The
low incidence of AMR has also limited the opportunity to
define the optimal dosing regimen for many treatments.
This is reflected in current regimens; for example, IVIG
doses in the literature vary between 0.1 and 2 g/kg (39, 41).
Of the more commonly used treatments listed in
Table 1, IA has the strongest evidence (based on one small
RCT that was terminated after an early interim analysis suggested a strong treatment effect). Despite its apparent efficacy,
few reports of IA for the treatment of AMR exist (Fig. 2).
Randomized controlled trials have not confirmed a
benefit from plasmapheresis (Table 2), and a review in 1983
reported marked variability in its apparent effect with response rates between 0% and 93% in 13 noncontrolled case
series (42). However, the treatment regimen used in these
earlier studies did not routinely include IVIG, in contrast to
current practice, so the risk-benefit reported by these older
studies may differ to current practice. Despite the serious
limitations of older studies, PP is a common treatment for
AMR (Fig. 2).
In the absence of high level evidence supporting existing regimens for treatment of AMR, treatment decisions
may be supported by data from desensitizing protocols.
For example, both IA and PP decrease DSAs and PRA
(14Y16, 43Y50); IVIG also lowers the PRA in highly sensitized patients, and the effect may persist for months (17,
51Y54). A single cycle of bortezomib did not decrease the
DSA titer posttransplantation (55), and there is marked

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interindividual variability in the magnitude of response to

rituximab pretransplantation (56). Eculizumab seems to
reduce the incidence of AMR in highly sensitized individuals when administered immediately posttransplant (23).
These observed effects may differ in patients posttransplantation with AMR because of ongoing antigenic stimulation;
however, it may be possible to extrapolate from these studies
to determine that a certain dose of a treatment may have
an effect.
Thus, the optimal treatment of AMR is unknown. A
topical question is the risk-benefit of biologic agents. Although current regimens may be effective in the treatment
of acute AMR, they may also be associated with unnecessary adverse effects, inconvenience, or cost. Therefore,
further studies are required to determine the optimal
treatment of AMR.
Future Studies
More clinical studies, ideally RCTs, are required to optimize the treatment of AMR and given the low incidence of
AMR this is likely to require multicenter involvement. Such
studies should vary a single therapy, or dose, and continue
other treatments. Uncontrolled studies suggest possible benefit of existing combinations of treatment, so there may be
some hesitation with comparing the therapy with placebo.
Alternative approaches are to compare existing treatments,
to clarify the dose-response relationship, and to validate biomarkers that may be used to tailor treatment. Some of these
issues were discussed in a recent FDA open workshop (57).
Plasmapheresis is a common treatment despite immunoadsorption having superior evidence and a similar mechanism of action, and therefore, direct comparison of these
treatments would be appropriate. Given the increasing use
of rituximab and bortezomib (Fig. 2) with conflicting data
on efficacy (58), it would be useful to establish the optimal
dose and to compare these treatments directly.
Future clinical trials should also explore the role of a
biomarker-based approach to monitoring the response to
therapy. The most commonly used biomarkers are plasma
creatinine concentration and urine output, but these are
nonspecific because they reflect multiple physiologic and
pathologic processes. Few studies identified in this systematic review reported biomarkers considered more specific to
AMR, including changes in plasma DSA titers or PRA, and
histology or histochemical (i.e., C4d deposition) on renal
biopsy.
A biomarker approach to treatment is appealing because it may allow the dose and duration of treatment to
be adjusted to the individual. For example, it may be useful
for identifying patients in which treatment is required, those
requiring an augmentation in treatment, or for indicating
when a treatment may be reduced or ceased. However, there
are limitations with existing biomarkers, and validation of
alternatives is a field of ongoing research.
In conclusion, data supporting current treatments for
AMR in KTRs are of low quality. Therefore, more research
is required to confirm the effect of existing regimens. This
should include large, multicenter randomized controlled
studies. The effect of dose on the response, and use of biomarkers to guide therapy, should be explored further. This
is a step toward rationalizing the current treatment of

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Roberts et al.

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AMR and to optimize benefits and minimize hazards, including prevention of adverse reactions and minimizing cost
and futility.

METHODS
This systematic review was conducted according to the PRISMA guidelines (http://www.prisma-statement.org/). Our study was not registered with
the prospective registration database PROSPERO (http://www.crd.york.
ac.uk/prospero/) because it was commenced before the database being
established.

781

Where available, the following were obtained from the controlled trials:
the diagnostic criteria for rejection, time since transplantation, source of
kidney (deceased or live donor), recipient sensitization (as per (60)), type
and dose of each intervention after the diagnosis, background immunosuppression, primary and secondary outcomes, creatinine at the time of diagnosis and after treatment, response to treatment including graft loss,
mortality and graft function, adverse events (infection, malignancy, and
death), and the incorporation of biomarkers in treatment decisions. The intervention was considered to be beneficial overall if a statistically significant
improvement in allograft survival was reported.

Grading of the Evidence

Data Source
We searched MEDLINE (1950 to March, Week 1 2011), EMBASE (1980
to March, Week1 2011), the Cochrane Register of Controlled Trials (CENTRAL 2009-latest issue), and conference proceedings from 2010 and 2011
(American Transplantation Congress, World Congress of Nephrology,
American Society of Nephrology, European Dialysis and Transplantation
Association, World Transplant Congress and Transplantation Society of
Australia and New Zealand) for controlled trials, case series, and reports
of the treatment of AMR. Experts in the field were contacted to ascertain
unpublished or additional papers. No restrictions were imposed on the basis
of publication status.
The databases were searched using a highly sensitive search strategy (see
Appendix) identifying IVIG, monoclonal antibodies (rituximab or eculizumab), proteasome inhibitors (bortezomib), and PP as either text word or
medical subject headings (MeSH). Plasmapheresis and plasma exchange
were considered interchangeable treatments. Antibody-mediated rejection
was defined by current Banff classification (19). In the pre-Banff classification period, we included articles examining vascular rejection because
this was believed to be antibody mediated at the time. Graft rejection,
antibody-mediated rejection, humoral rejection, and vascular rejection
were searched as text words and MeSH terms. These terms were searched
by kidney or renal transplantation. Pediatric patients and dual kidneypancreas transplants were excluded. Two authors (S.J. and D.R.) independently reviewed titles and abstracts, selecting papers that potentially met
the inclusion criteria. The reference lists were also reviewed for other relevant publications.

Using the GRADE system (61), the strength of evidence supporting the
efficacy of each of the proposed treatments was determined. Here, the evidence supporting a treatment was graded as high if randomized controlled trials were available, low if data were limited to that obtained
from nonrandomized controlled studies, and very low if limited to uncontrolled studies, including case series and case reports. A treatment could
be reclassified to a higher grade if (i) a large magnitude of effect exists, (ii) a
dose-response gradient was present, or (iii) if all plausible confounders or
other biases increase confidence in the estimated effect. Furthermore, a
treatment could be reclassified to a lower grade in the presence of the following: (i) a serious limitation to study quality, (ii) important inconsistency, (iii) some uncertainty about directness, (iv) imprecise or sparse data, or
(v) high probability of reporting bias.
Grading was performed independently by D.R. and S.J., and where
there was disagreement about a final grade, this was resolved by an arbitrator (S.C.).

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Inclusion Criteria
We identified all publications (controlled trials, case series, or case
reports) pertaining to the treatment of antibody-mediated, humoral, or vascular rejection in KTRs. A histopathologic diagnosis on kidney biopsy was
required for full text publications. In the case of conference abstracts, if
the diagnosis was stated to be AMR, then this was considered sufficient as
histopathologic changes are required by current Banff criteria. No language
restrictions were imposed, and relevant non-English language publications
were translated.
Each potentially relevant publication was reviewed by two authors (S.J.
and D.R.), and in the case of disagreement regarding whether it fulfilled inclusion criteria, this was resolved by an arbitrator (S.C.).
Case series and reports were also reviewed to determine the types of treatments given to patients with AMR for the purpose of ascertaining trends in
the therapy of AMR over time.

Data Extraction and Trial Quality

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As per this tool, allocation concealment was considered adequate if the
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adequate if the patients were analyzed by the group to which they were allocated at the time of randomization. Loss to follow-up was defined by
the proportion of population who discontinued the treatment and in whom
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Appendix. Search criteria used for this

systematic review
1
2
3
4
5
6

exp Kidney Transplantation/ (69824)

(transplant* adj40 (kidney* or renal*)).tw. (62122)
1 or 2 (84222)
exp Antibodies, Monoclonal/ (153289)
(monoclonal* adj40 antibod*).tw. (154724)
(monoclonal* adj40 anti-bod*).tw. (52)

Roberts et al.

7 exp Immunoglobulins, Intravenous/ (7994)

8 (intravenous* adj40 immunoglobulin*).tw. (7577)
9 IvIg.tw. (3382)
10 octagam.tw. (12)
11 intragam*.tw. (16)
12 exp Plasmapheresis/ (7011)
13 plasmapher*.tw. (6216)
14 exp Plasma Exchange/ (4270)
15 (plasma* adj40 exchange*).tw. (11807)
16 rituximab*.tw. (5827)
17 (anti-cd20* adj40 antibod*).tw. (1632)
18 (CD20* adj30 antibod*).tw. (2948)
19 bortezomib*.tw. (2081)
20 (proteasome* adj40 inhibit*).tw. (7697)
21 eculizumab*.tw. (108)
22 (C5* adj40 antibod*).tw. (4796)
23 or/4-22 (259861)
24 exp Graft Rejection/ (45141)
25 (acute* adj30 (reject* and humoral*)).tw. (563)
26 (antibod* adj40 reject*).tw. (6372)
27 (anti-bod* adj40 reject*).tw. (7)
28 (humor* adj40 reject*).tw. (1413)
29 (allograft* adj40 reject*).tw. (16159)
30 or/24-29 (52160)
31 3 and 23 and 30 (2636)

Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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