ARTICLE IN PRESS

The Effect of Induction Therapy on Antibody-Mediated Rejection in

Kidney Transplantation: A Network Meta-Analysis Using Recent Data
Jin Ho Leea, Heeryong Leea, Kipyo Kimb, Seoung Woo Leeb, Joon Ho Songb, and Seun Deuk Hwangb*
a
Division of Nephrology, Department of Internal Medicine, Leesin Hemodialysis and Intervention Clinic, Busan, South Korea; and
b
Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University College of Medicine, Incheon, South Korea

ABSTRACT
Background. Various induction regimens are available for kidney transplantation (KT); how-
ever, which is superior remains unclear. Moreover, although the induction regimens are effective
and important for reducing side effects, their respective relationships with antibody-mediated
rejection (AMR) after transplantation remain unclear. Therefore, this study aimed to elucidate
the most effective induction regimen for AMR reduction through network analysis.
Methods. We performed a comprehensive search of databases, including basiliximab, alemtu-
zumab, antithymocyte globulin (ATG), and daclizumab as induction regimens for KT from
inception to September 1, 2022. Using a network meta-analysis, we investigated the priorities
of 5 induction regimens for patient survival, graft failure, and graft rejection after ABO-
incompatible KT.
Results. In total, 25 studies comprising 1768 people were included in this network meta-anal-
ysis. The primary outcome was the AMR rate of other induction regimens compared with that of
basiliximab, whereas the secondary outcomes were heart failure, stroke, hospitalization, periph-
eral artery disease, myocardial infarction, anemia, leukopenia, herpes zoster, or adverse events.
Notably, ATG reduced the AMR rate by 59% (odds ratio, 0.41; 95% credible interval,
0.20-0.90), whereas the other drugs did not show statistical significance. Furthermore, secondary
outcomes did not significantly differ between the induction regimens.
Conclusion. ATG is widely used in KT induction regimens. Our results showed that ATG
reduced the risk of AMR in KT recipients when compared with other induction drugs; therefore,
it appears to be an efficient choice of induction regimen to reduce AMR after KT.

K IDNEY transplantation (KT) is the best treatment option

for patients with end-stage renal disease. In fact, a previ-
ous study comparing the effectiveness of hemodialysis and peri-
toneal dialysis with KT in patients with end-stage renal disease
concluded that KT was superior [1]. However, KT is problem-
atic because there are fewer donors than those awaiting trans-
plantation. In addition, complications such as acute cellular
rejection (ACR), antibody-mediated rejection (AMR), and
increased incidence of other infections and cancer occur after
transplantation [2−4]. Continuing research regarding the best
induction regimen for KT has been conducted, and recent
efforts have been made to reduce rejection and infection rates
while improving graft and patient survival rates.
Currently, basiliximab is the most widely used induction regi-
men. It is usually administered twice, on day 0 and postoperative
day 4, without dose adjustment [5]. It is the most popular drug
used worldwide because it effectively reduces the frequency of
ACR, AMR, and infection. However, despite these efforts, the
incidence of AMR after KT has not decreased. In fact, to increase
the donor pool, transplants are being performed using donor kid-
neys with a high risk of rejection; thus, the fear of AMR is inten-
sifying. Accordingly, various induction regimens such as
J.H.L. and H.Y.L. contributed equally to this work.
*Address correspondence to: Seun Deuk Hwang, Division of
Nephrology and Hypertension, Department of Internal Medicine,
Inha University College of Medicine, Inha University Hospital 27
Inhang-Ro, Jung-gu, Incheon 22332, Republic of Korea, Tel: +82-
32-890-2229, Fax: +82-32-882-6578 E-mail: lakisis79@hanmail.
net

© 2024 Published by Elsevier Inc. 0041-1345/20

230 Park Avenue, New York, NY 10169 https://doi.org/10.1016/j.transproceed.2024.01.021

Transplantation Proceedings, 000, 1−4 (2024) 1

 ARTICLE IN PRESS
alemtuzumab and daclizumab have been studied and used clini-
cally; however, research regarding which drugs reduce AMR
more effectively is lacking. Therefore, this study aimed to identify
the most effective induction regimen for AMR reduction through
network analysis [6].
MATERIALS AND METHODS
Ethics Statement
All results are presented in accordance with the guidelines of the Pre-
ferred Reporting Items for Systematic Reviews and Network Meta-
Analyses statement (Supplementary Checklist S1). All analyses were
based on previously published studies; therefore, ethical approval and
patient consent were not required.
Data Sources, Searches, and Inclusion and Exclusion Criteria
We performed a comprehensive search of the following databases from
their inception until September 1, 2023: MEDLINE (via PubMed),
Embase, CINAHL, Web of Science, and the Cochrane Central Register
of Controlled Trials in the Cochrane Library. We searched for important
keywords according to patient groups and interventions.
Adult patients (aged >18 years) were included in the study, whereas
reviews, observational studies, and clinical trials that did not clearly
define the outcomes or those that did not have graft failure as an out-
come were excluded. The search was limited to human studies and was
not restricted to any particular language or publication date. Reference
lists of all available review articles were manually searched.
Study Selection and Data Extraction
The abstracts and full texts were independently evaluated by 2 researchers
(S.D.H. and J.H.L.), and 2 reviewers extracted and reevaluated the data.
Disagreements were resolved through discussion and consultation with
another researcher (H.R.L.). Publications used in the analysis included
studies referring to at least 2 of the eligible induction doses of basiliximab,
alemtuzumab, antithymocyte globulin (ATG), or daclizumab.
Risk of Bias Assessment
No randomized controlled studies were identified in the search. Two
researchers (S.D.H. and J.H.L.) independently assessed the risk of bias
in each trial using the Risk of Bias in Non-Randomized Studies of Inter-
ventions tool, whereas the Newcastle-Ottawa Scale was used for obser-
vational studies. The Newcastle-Ottawa Scale assigns a maximum of 9
points, and studies with a total score of >7 are defined as high quality.
We confirmed the quality of the included studies using the Downs and
Black scores, which were assigned to the corresponding quality levels
as previously reported: excellent (26-28), good (20-25), fair (15-19),
and poor (<14). Furthermore, the Risk of Bias in Non-Randomized
Studies of Interventions tool judged the risk of bias as follows: low risk
of bias, moderate risk of bias, serious risk of bias, critical risk, and no
information. Discrepancies were resolved through discussion with S.D.
H. and J.H.L.
Statistical Analysis
We conducted a Bayesian network meta-analysis to compare the effi-
cacy of 5 different induction medications in terms of patient survival,
graft failure, and graft rejection after kidney transplantation. Direct and
indirect network meta-analyses were performed using Bayesian models,
and different inductions were ranked using generation−mixed treatment
comparisons and Stata version 13 (StataCorp LLC) [7−9]. The relative
ranking probability of each treatment was estimated, and the treatment
hierarchy of competing interventions was obtained using rankograms,
surface under cumulative ranking curves, and mean ranks. The network
meta-analysis included studies that recorded multiple treatments, allow-
ing us to estimate the pooled effects of each treatment [10]. For multi-
arm trials, correlations among treatment effects between arms were
included in the investigations. Studies with j+1 treatment arms are
based on a comparison of the treatment effects with a reference treat-
ment through a multivariate normal distribution, whereas treatment-as-
usual studies are based on the homogeneity between study variances
across treatments [11,12].
Inconsistency tests, homogeneity analyses, and sensitivity analyses
were performed using the node analysis method in R software. The
results of the inconsistency tests were assessed according to the Bayes-
ian P value, where P < .5 was considered evidence for the existence of
a significant inconsistency [13,14]. To assess homogeneity, an I2 test
was performed, with I2 >50% indicating significant heterogeneity. Fur-
thermore, a sensitivity analysis was conducted by comparing the differ-
ences between the fixed- and random-effects models. Clinical outcome
indicators were evaluated using mean differences or odds ratios (ORs)
with a 95% CI (mean differences for continuous outcomes and ORs for
binary outcomes) [11,15].
In cases where a loop was connected to the 3 treatments, we evalu-
ated the inconsistency between the direct and indirect evidence [16].
We also used the node-splitting method, which separates evidence for a
particular comparison between direct and indirect evidence [14]. We
then evaluated the agreement between direct and indirect evidence and
reported the Bayesian P value. Sensitivity analyses were performed
using the same methods after excluding data obtained from specific
studies, including studies with a small number of patients and events in
a specific treatment arm and those with a large population that may
dominate the data of specific treatment arms [17].
RESULTS
Effects of the Interventions
Data obtained from all 25 studies (n = 1768) were included in
the network analysis. The primary endpoint of this study was
the AMR rate of the other drugs compared with that of basilixi-
mab, which was used as a reference.
Compared with basiliximab, the incidence of AMR was
approximately 59% lower in the ATG group (OR, 0.41; 95%
credible interval [CrI], 0.20-0.90). Moreover, when alemtuzu-
mab and daclizumab were compared with basiliximab, their
AMR rates were lower by approximately 48% and 42%, respec-
tively; however, these differences were not statistically signifi-
cant (OR, 0.52; 95% CrI, 0.22-1.2 and OR, 0.58; 95% CrI,
0.20-1.90, respectively). Furthermore, when comparing the con-
trol group with the group using other immunosuppressants for
induction, ATG significantly reduced AMR by approximately
72% (OR, 0.28; 95% CrI, 0.10-0.81), whereas alemtuzumab
and daclizumab reduced AMR by 65% and 61%, respectively;
however, these differences were not statistically significant
(OR, 0.35; 95% CrI, 0.12-1.1 and OR, 0.39; 95% CrI, 0.11-
1.60, respectively).
Notably, no differences regarding secondary outcomes,
including heart failure, stroke, hospitalization, peripheral artery
 ARTICLE IN PRESS
disease, myocardial infarction, anemia, leukopenia, herpes zos-
ter, and adverse events, were found between the interventions.
Rank Probabilities
The rank probability of ATG related to induction was 63.6%,
which was the highest probability among the drugs and, there-
fore, the most efficient. The second highest was alemtuzumab,
with a probability of 42.2%, whereas that of daclizumab was
40.0%, which was the third highest.
The model-fit statistic for Deviance Information Criterion
was 60.8, whereas the residual deviance, which compared the
incidences of AMR, was 35.3. Network heterogeneity was esti-
mated by comparing the common heterogeneity variance (tau
[t]) within each network with the empirical distribution of het-
erogeneity variances. The AMR network indicated substantial
heterogeneity, with t = 0.61.
DISCUSSION
KT is the most effective and proven treatment for end-stage renal
disease. However, there are various concerns regarding the suc-
cessful engraftment of a new kidney into the body of a patient
with end-stage renal failure, the most widely known of which are
rejection and infection [18]. Recently, various induction regimens
and maintenance immunosuppression treatments have been devel-
oped to overcome complications that lower the survival rate of
transplant recipients, including the administration of antibacterial,
antiviral, and antifungal agents before and after transplantation,
leading to successful transplantation [19−21]. Although the graft
survival rate is currently overwhelmingly higher than that in the
past, the biggest barrier to long-term graft survival is AMR. To
reduce the disparity caused by insufficient donors compared with
recipients, transplantation of highly sensitized patients and ABO-
incompatible, secondary, tertiary, and quaternary KTs are being
performed [22,23]. Therefore, the frequency of AMR has not
decreased but rather shows a trend similar to that of the past, and
the occurrence of AMR is becoming the largest barrier to success-
ful transplantation.
Various regimens have been developed to reduce the fre-
quency of AMR, with the most frequently used drugs being
basiliximab, ATG, alemtuzumab, and daclizumab. Basiliximab
is the most commonly used induction therapy worldwide. How-
ever, the frequency of AMR is not decreasing, and the develop-
ment and use of other drugs are, therefore, gradually increasing.
Few studies have compared the effectiveness of different induc-
tion regimens in reducing AMR. Therefore, this study used a net-
work meta-analysis to analyze previously published randomized
controlled trials (RCTs) regarding the effectiveness of induction
regimens. We found that, in terms of rank probabilities, ATG
was the most effective among the induction regimens in reducing
AMR. Following ATG in terms of rank probabilities were alem-
tuzumab and daclizumab. Notably, secondary outcomes such as
heart failure, stroke, hospitalization, peripheral artery disease,
myocardial infarction, anemia, leukopenia, herpes zoster, and
adverse events did not differ between the regimens. Therefore, in
terms of the ability to reduce AMR, ATG showed the most
advanced results, with statistical significance.
However, this study had some limitations. First, when select-
ing an induction regimen, the rejection rate is important; how-
ever, the infection rate is also considered to be of similar or
even greater importance. During the early stages of transplanta-
tion, induction regimens and high doses of maintenance immu-
nosuppressants increase the risk of bacterial, viral, and fungal
infections. Although salvage treatment for AMR is difficult,
patients can survive even after treatment failure; however, sur-
vival is not probable after treatment failure for infection.
Second, although ATG has a comparative advantage over
other regimens in terms of AMR, no analysis of dosage on its
effects has been performed. The regimen used in most trans-
plant centers involves reducing ATG from the initial 2 to
5 mg/kg to 1 mg/kg. Therefore, additional analysis of the risk
of AMR according to the ATG dosage is necessary.
Third, compared with basiliximab or ATG, alemtuzumab and
daclizumab are more recently used drugs. However, there are
limited data on recently used drugs compared with those used
in the past. Therefore, as more randomized controlled trials are
performed in the future, the priorities elucidated by this study
may change.
Fourth, in addition to AMR, which was the focus of this
study, various motivations exist for choosing an induction regi-
men. Therefore, future analyses regarding the frequency of
ACR, differences in patient compliance with regard to cost, and
differences according to whether the drugs are available in the
country or center are required.
Despite its limitations, this study has indicated ATG as a first-
line induction regimen to support the efforts of KT researchers in
reducing AMR. Although high doses of ATG carry the risk of
infection, administering an appropriate dose to each patient as an
induction regimen may serve as an opportunity to overcome
AMR, which is a major cause of reduced graft survival. There-
fore, this study may serve as a milestone in overcoming AMR.
DATA AVAILABILITY
Data will be made available on request.
DECLARATION OF COMPETING INTEREST
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: This network meta-analysis was supported by grants
from the Basic Science Research Program through the Bio &
Medical Technology Development Program of the National
Research Foundation (NRF) and funded by the Korean govern-
ment (MSIT) (SDH: NRF-2019M3E5D1A02069619). This
work was supported by an Inha University Research Grant.
SUPPLEMENTARY MATERIALS
Supplementary material associated with this article can be found
in the online version at doi:10.1016/j.transproceed.2024.01.021.
 ARTICLE IN PRESS
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