Dig Dis Sci (2012) 57:1366–1372
DOI 10.1007/s10620-011-1987-1
ORIGINAL ARTICLE
Meta-Analysis: The Impact of Nutritional Status on the Immune
Response to Hepatitis B Virus Vaccine in Chronic Kidney Disease
Fabrizio Fabrizi • Vivek Dixit • Paul Martin •
Michel Jadoul • Piergiorgio Messa
Received: 1 May 2011 / Accepted: 15 November 2011 / Published online: 6 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract
Background Patients with chronic kidney disease (CKD)
typically show a diminished immune response to hepatitis
B virus (HBV) vaccine compared with individuals with
intact kidney function. A number of inherited or acquired
factors have been implicated in this suboptimal response.
Patients with chronic kidney disease frequently have a
compromised nutritional status; however, the impact of
malnutrition on the immune response to hepatitis B virus
vaccine in chronic kidney disease patients remains unclear.
Aim To evaluate the influence of nutrition status on the
immune response to HBV vaccine in CKD population by
performing a systematic review of the literature with a
meta-analysis of clinical studies.
Methods Study-specific relative risks were weighted by
the inverse of their variance to obtain fixed- and random-
effects pooled estimates of impaired vaccine response
across the published studies. The risk of poor serological
response to HBV vaccine in chronic kidney disease pop-
ulation according to nutritional parameters was regarded as
the most reliable outcome end-point. Only studies per-
forming multivariate analysis in order to make adjustments
for potential confounders were included.
F. Fabrizi (&)
P. Messa
Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS
Foundation, Pad. Croff, Via Commenda 15, 20122 Milan, Italy
e-mail: fabrizi@policlinico.mi.it
V. Dixit
P. Martin
Division of Hepatology, School of Medicine,
University of Miami, Miami, FL, USA
M. Jadoul
Division of Nephrology, Cliniques Universitaires St. Luc,
Universitè Catholique de Louvain, Brussels, Belgium
123
Results We identified seven studies (15,172 unique
patients with CKD). The serum protection rate after a full
course of recombinant or plasma-derived vaccine towards
HBV ranged between 40 and 86%. Aggregation of study
results showed an independent and adverse effect of poor
nutrition status, as mostly detected by serum albumin
levels, on the protection rate after HBV vaccine course; the
summary estimate for adjusted RR was 1.50 with a 95%
confidence interval (CI) of 1.02, 2.21; Ri = 0.01 (random-
effects model). The P value for study heterogeneity was
significant (Q = 0.0001). In the subgroup of patients who
received HBV recombinant vaccine, the relative risk of
impaired serological response after HBV vaccination was
1.63 (95% CI, 1.08, 2.45), Ri = 0.90, Q = 0.00001, with
poor nutritional parameters at baseline.
Conclusions An increased risk exists of impaired sero-
logic response to HBV vaccine response among chronic
kidney disease patients having poor nutrition status.
Additional studies are needed to understand better the
mechanisms underlying the relationship between nutri-
tional status and serological response to HBV vaccine
among patients with CKD.
Keywords Hepatitis B virus
Recombinant vaccine

Nutritional status
Chronic kidney disease
Meta-analysis
Introduction
Abundant information exists in the scientific literature on
the epidemiology and clinical significance of hepatitis B
virus infection in patients on long-term dialysis in the
developed world. The frequency of HBV infection, as
detected by persistent positive status for hepatitis B surface
antigen (HBsAg) in serum, is low but not negligible among
Dig Dis Sci (2012) 57:1366–1372
patients with chronic kidney disease receiving maintenance
dialysis [1, 2]. In addition, outbreaks of HBV infection in
HD units continue to occur [3]. Prevalence and incidence
rates of HBV infection remain much higher within dialysis
units in developing countries [4]. It is well known that
CKD patients show a lower immunological response to
recombinant HBV vaccine compared with individuals with
intact kidney function: the frequency of responder patients
is lower, and the antibody titers of responders are reduced
and decline faster over time [5].
It has been previously claimed that undernourished or
malnourished patients with intact kidney function and
individuals on long-term dialysis suffering from malnutri-
tion exhibit low responses to HBV vaccines. Indeed,
nutritional status has impact on the responses to vaccines
[6], and response to HBV vaccine is no exception. A few
studies on HBV vaccination of patients with CKD having
suboptimal nutritional status have been published and
preliminary results have been provided.
The goal of this study was to investigate the available
evidence on the relationship between nutritional status and
immune response to HBV vaccination in CKD population
by performing a systematic review of the literature with a
meta-analysis of clinical studies.
Materials and Methods
Search Strategy and Data Extraction
Electronic searches of the National Library of Medicine’s
MEDLINE database, Current Contents, Cochrane Library
and manual searches of selected specialty journals were
performed to identify all pertinent literature. It has been
previously demonstrated that MEDLINE searches alone
may lack sensitivity. We searched MEDLINE (PubMed
and OVID Technologies), EMBASE (OVID Technolo-
gies), Current Contents (Institute for Scientific Informa-
tion), and the Cochrane Library (Update Software). The
keywords ‘chronic kidney disease’, ‘dialysis’, ‘hepatitis B
virus’, ‘recombinant vaccine’, ‘nutritional status’, and their
synonyms or related terms were used. References lists from
qualitative topic reviews and published clinical trials were
also searched. Our search was limited to human studies that
were published in the English literature. All articles were
identified by a search from 1990 to April 2011. Data
extraction was conducted independently by two investiga-
tors (F.F., V.D.) and consensus was achieved for all data.
Studies were compared to eliminate duplication of results
for the same patients, which included contact with inves-
tigators when necessary. Eligibility and exclusion criteria
were pre-specified.
1367
Criteria for Inclusion
We included studies evaluating patients with CKD under-
going maintenance dialysis or at pre-dialysis stage. Both
case–control and cohort studies were considered eligible
for inclusion in the analysis. Studies that restricted to stu-
dents, military recruits, or other cohorts that involved
subjects \19 years of age were excluded. Many studies
have identified an effect of nutritional parameters on
response rate to HBV vaccine. However, only studies
which specified a relative risk for vaccine response among
CKD patients according to nutritional parameters were
considered for final inclusions. We included studies using
plasma-derived or recombinant DNA hepatitis B vaccine.
Patients who underwent primary vaccination schedule
(naı̈ve patients) or those who had failed to respond to prior
vaccine schedule (non-responder patients) against HBV
vaccine were enrolled.
The decision as to inclusion or exclusion of clinical
studies was not related to results. All dose schedules and
routes of administration were included, as long as they
involved primary vaccination regimens and not just booster
doses. If data were duplicated in more than one publication,
only the more recent one was included in the analysis. We
contacted the authors of the publication if further expla-
nation was necessary.
Ineligible Studies
Studies were excluded if they reported inadequate data on
measures to response, or included individuals with positive
serology for HBsAg, antibodies to HBsAg (HBsAb), or
human immunodeficiency virus (HIV). Studies that were
published in abstract form or as interim reports were
excluded; letters and review articles were not considered in
this analysis. Studies that involved renal transplant recipi-
ents were excluded.
End Points of Interest
The primary end-point was the adjusted relative risk (aRR)
and 95% confidence interval (95% CI) of failure to develop
protective anti-HBs titers in CKD patients after HBV
vaccination according to nutritional status. The aRR was
specified by multivariate analysis in each study. Multivar-
iate analysis was made to estimate the independent role of
nutritional status on the development of protective anti-
bodies after hepatitis B vaccine by adjustment for potential
confounders (e.g., age, gender, dialysis adequacy, anti-HCV
serological status, diabetes mellitus, among others).
Patients vaccinated against HBV are considered immune
if protective titers of anti-HBs antibody can be demon-
strated after completion of vaccination. The level of
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1368 Dig Dis Sci (2012) 57:1366–1372

antibody production that defines serological protection was to final inclusion and exclusion of studies reviewed based
C10 IU/ml, 1 month after completing vaccine schedule, on the predefined inclusion and exclusion criteria.
across the studies. These definitions were consistent with
standards published in the scientific literature. Patient Characteristics

Some salient demographic characteristics of subjects

Statistical Methods enrolled in the studies included are shown in Tables 1, 2
and 3. Three studies were from North America, and four
A summary estimate of the aRR of failure to develop from Asia. The mean age of subjects ranged from 43 to
protective anti-HBs antibody after receiving hepatitis B 63 years of age. The gender distribution ranged from 35 to
virus (HBV) vaccine among chronic kidney disease 64% male. Frequency of diabetes mellitus ranged between
patients according to nutritional status was generated by 14 and 59.6%.
weighting the study specific RR’s by the inverse of their Some variability occurred in the parameters used to
variance [7]. We computed fixed and random effect esti- define nutritional status in CKD patients who received
mates. Ri (the proportion of total variance due to between- HBV vaccine. Five studies [10, 12, 13, 15, 16] evaluated
study variance) was used to assess heterogeneity. Hetero- nutritional status by serum albumin levels. The body mass
geneity was also measured by a parametric version (1,000 index (BMI) was calculated by Chow et al. [14], and Chin
replications) of the DerSimonian and Laird Q test [8], as [11] measured normalized protein catabolic rate (nPCR).
the number of studies to be meta-analysed was not large. The seroprotection rate in each study, after completing
To further explore the origin of heterogeneity, we restricted HBV vaccine course, is shown in Table 3. As listed in
the analysis to subgroups of studies defined by study Table 4, recombinant hepatitis B vaccine was administered
characteristics such as country (developed/less-developed in the majority of clinical studies.
countries), or size (single-center/population-based studies).
Also, we stratified studies according to parameters for Table 1 Characteristics of clinical trials: demographic and clinical
definition of malnutrition status (serum albumin/others), data
route of vaccine administration (intramuscular/intra- Authors Patients, n Reference year Country
dermal), CKD stage (dialysis/pre-dialysis), and vaccine
DaRoza et al. 165 2003 Canada
type (recombinant/plasma-derived). Statistical analysis was
Chin et al. 97 2003 U.S.
done using HEpiMA software, version 2.1.3 [9]. The 5%
Weinstein et al. 29 2004 Israel
significance level was used for alpha risk. Every estimate
Lacson et al. 14,546 2005 U.S.
was given with its 95% confidence intervals (CI).
Chow et al. 64 2006 Hong Kong
Afsar et al. 188 2009 Turkey
Results Liu et al. 83 2009 Taiwan

Literature Review
Table 2 Characteristics of clinical trials: demographic and clinical
data
Our electronic and manual searches identified 257 studies,
Authors Age, years Male, n Dialysis
of which 138 were considered potentially relevant and mode
were selected for full text review. The complete list of
these studies is available on request. Seven studies, pro- DaRoza et al. 59.8 ± 14.9 106 (64%) Pre-dialysis
viding information on a total of 15,172 unique patients, CKD
were included in our meta-analysis [10–16]. One study Chin et al. 51 ± 2/59 ± 2a NA HD (100%)
reported by multivariate analysis a significant and inde- Weinstein et al. 62.9 (28–81) 18 (62%) HD (93%)
pendent relationship between poor nutritional status and Lacson et al. 60.5 ± 1/61.7 ± 1b 55.4% HD (93.8/
91.4%)b
failure to seroconvert after HBV vaccination among dial-
Chow et al. 43 ± 12 51% HD (19%)
ysis patients but was excluded as aRR and 95% CI were not
Afsar et al. 45.1 ± 14/49.1 ± 8a 66 (35%) HD (100%)
given [17]. At least seven reports [18–24] found a signifi-
Liu et al. 58.1 ± 13/61.2 ± 10c 31 (37%) HD (61.4%)
cant relationship between under-nutrition, as assessed
mostly by serum albumin levels, and failure to develop NA not available
a
anti-HBs antibody after HBV vaccination but were not Data are shown as responder/non-responder groups
b
included as only univariate analysis was carried out. There Data are shown as Engerix/Recombivax groups
c
was a 100% concordance between reviewers with respect Data are shown as EPO/no-EPO groups

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Dig Dis Sci (2012) 57:1366–1372 1369

Table 3 Characteristics of clinical trials: demographic and clinical

data
Authors Diabetes Time on dialysis, Seroprotection
mellitus, n months rate, n

DaRoza et al. 46 (28%) NA 136 (82%)

Chin et al. 48 (49%) NA 64 (66%)
Weinstein et al. 4 (14%) 76.1 25 (86%)
Lacson et al. 59.6/ 11.2/15.7a 58/40%a
57.7%a
Chow et al. 10 (16%) 8.5 (1–33) 51 (81%)
Afsar et al. 34 (18%) 99.1 ± 6/ 151 (80%)
80.7 ± 5b
Liu et al. 25 (30%) 54.5 ± 3/ 74/73%c
43.1 ± 3c
NA not available Fig. 1 Estimated RR for each study and 95% Confidence Intervals
a
Data are shown as Engerix/Recombivax groups (95% CI). The vertical line represents the pooled aRR of failure to
b seroconvert to HB vaccine (random-effects model) according to
Data are shown as responder/non-responder groups nutritional status
c
Data are shown as EPO/no-EPO groups

effects confidence bounds were wider than those calculated

Table 4 Vaccine schedules of studies included in the analysis by the fixed effects model.
Authors Vaccine route Vaccine Vaccine Our stratified analysis, performed in various subgroups
schedule, dose, mcg of interest (i.e., cohort studies only, or studies from
months developed countries) showed persistent heterogeneity
Da Roza et al. Recombinant, IM 0, 1 and 6 40 mcg between studies, as shown by Ri and P values (Q tests)
Plasma-derived, IM 0, 1, 2 and 6 (Table 5). In the subgroup of studies enrolling only patients
Chin et al. Recombinant, IM 0, 1 and 6 40 mcg who received recombinant vaccine towards HBV, the rel-
Weinstein et al. Recombinant, IM 0, 1 and 6 10 mcg
ative risk of impaired serological response after HBV
Lacson et al. Recombinant, IM 0, 1 and 6 40 mcg
vaccination was 1.63 (95% CI, 1.08; 2.45), Ri = 0.90,
Q = 0.00001, with poor nutritional parameters at baseline
0, 1, 2 and 6
(Table 5).
Chow et al. Recombinant, IM 0,1, and 6 80 mcg
(37.5%)
40 mcg
(40.6%) Discussion
20 mcg
(21.9%) Patients with renal failure are generally poor responders to
Afsar et al. Recombinant, IM 0,1,2 and 6 40 mcg vaccination with various antigens including HBsAg. The
Liu et al. Recombinant, IM 0,1,2, and 6 40 mcg impaired efficacy of HBV vaccine has been linked to
numerous parameters notably immune compromise because
of uraemia, older age, diabetes mellitus, serological posi-
Summary Estimates of Outcomes tivity for human immunodeficiency virus (HIV) or hepatitis
C virus (HCV) infection, blood transfusion history and
Table 5 reports the pooled relative risks (RR) and 95% possession of the major histocompatibility complex aplo-
Confidence Intervals (95% CI) for failure to seroconvert type HLA-B. In addition, the failure to complete a full
after HBV vaccination in patients having malnutrition at course of vaccine towards HBV may cause a poor active
baseline. As listed in Fig. 1, the summary estimate for immunization. The mechanism underlying the phenomenon
adjusted RR was 1.50 with a 95% CI of 1.02, 2.21 of CKD-associated hepatitis B immune non-responsiveness
according to the random-effects model (all studies). We is largely unknown, but a decreased antigen-specific T-cell
observed significant heterogeneity between studies proliferation by monocyte-derived dendritic cells (moDC)
(Ri = 0.91, P value by Q test of 0.00001). Thus, there is has recently been discovered [25].
evidence that there is not one underlying risk ratio, even Malnutrition and cachexia are prevalent in chronic
though they were adjusted using a multivariate analysis kidney disease individuals, especially those on long-term
which would make them more comparable. The random dialysis, but the link between poor nutritional status and the

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1370 Dig Dis Sci (2012) 57:1366–1372

Table 5 Summary estimates for adjusted relative risks (aRR) of seroprotection after HBV vaccine in CKD population in various subgroups of
interest
Pooled studies Studies, RR (95% CI) RR (95% CI) Ri P (Q test)
n fixed effects random effects

All studies 8 1.84 (1.66, 2.04) 1.50 (1.02, 2.21) 0.91 0.0000
Studies based on serum albumin measurements 5 1.91 (1.71, 2.13) 1.45 (0.86, 2.47) 0.94 0.0000
Studies on HD pts 2 3.95 (1.7, 9.16) 4.52 (1.35, 15.13) 0.48 0.1973
Cohort studies 6 1.21 (1.0, 1.47) 1.29 (0.92, 1.81) 0.61 0.0386
Studies on dialysis patients 6 1.91 (1.71, 2.12) 1.63 (1.08, 2.45) 0.90 0.0000
Studies from developed world 5 1.85 (1.66, 2.05) 1.46 (0.97, 2.19) 0.92 0.0000
Studies based on IM vaccine route 7 1.83 (1.65, 2.03) 1.5 (1.02, 2.2) 0.90 0.0000
RR relative Risk, CI confidence interval, Ri Proportion of total variance due to between-study variance
DaRoza et al.: aRR adjusted for age, gender, diabetes mellitus, CKD stage, haemoglobin level, erythropoietin use, serum albumin concentration
Chin: aRR adjusted for age, weight, diabetes mellitus, normalized protein catabolic rate
Weinstein et al.: aRR adjusted for age, gender, CKD aetiology, dialysis mode, weight, haemoglobin, albumin, dialysis adequacy
Lacson et al.: aRR adjusted for age, gender, hepatitis C, diabetes mellitus, haemoglobin, time on dialysis, serum albumin, race
Chow K, et al.: aRR adjusted for age, body mass index, diabetes mellitus, haemoglobin, vaccine dose
Afsar et al.: aRR adjusted for age, gender, body mass index, time on dialysis, dialysis adequacy, hepatitis C virus, diabetes mellitus, serum
albumin, haemoglobin, phosphorus, quality of life, cholesterol, trygliceride, history of previous renal transplantation, coronary artery disease
Liu et al.: aRR adjusted for serum albumin, ferritin level, transferrin saturation, intravenous iron dosage, erythropoietin dose

reduced immune response to the HBV vaccine in the CKD
population remains controversial. Recent data support the
notion that wasting-cachexia and/or malnutrition are linked
to inadequate nutrition and other factors such as systemic
inflammation, metabolic acidosis, and insulin or insulin-
like growth factor resistance [26]. Our meta-analysis
determined that patients having biochemical parameters
typical of poor nutritional status show a lower sero-pro-
tection rate to HBV vaccine than well-nourished individ-
uals in the CKD population. Stratified analysis in various
subgroups yielded only minimal changes on the effect size.
Our data give emphasis to the role of an inappropriate
nutritional status upon the immune response to hepatitis B
vaccine as the studies of the current meta-analysis included
several background parameters (i.e., age, and dialysis
adequacy, among others) as covariates in their regression
analyses. An independent and significant link between
lower response to vaccine and malnutrition was discovered.
The impact played by an inadequate nutritional status on
the immunological sero-response to HB vaccine is bio-
logically plausible as numerous changes in cellular and
humoral responses have been described in non-uraemic
patients with poor nutritional parameters. As an example, it
has been recently suggested that poor nutritional status
hampers the differentiation of monocyte-derived dendritic
cells (moDC) by production of various cytokines such as
interleukin-6 (IL-6) or TNF-alpha [25].
Our findings are consistent with data from other sources.
An extensive review of the medical literature on this topic
revealed numerous reports [18–24] promoting a link
between impaired response to HBV vaccine and poor
nutritional status, as detected by low serum albumin
[18–21, 24], body weight [22], or normalized protein
nitrogen appearance [23] in the CKD population. These
studies were not included in our study due to a lack of a
modern statistical analysis. On the other hand, four reports
[27–30] did not demonstrate a relationship between failure
to seroconvert after HBV vaccine and low serum albumin.
This meta-analysis is potentially limited in a number of
ways. First, as with all meta-analyses, this study has the
potential limitation of publication bias. Negative trials are
less likely to be published: we postulated that those
investigators who found a statistical association between
under-nutrition and response rate to HBV vaccine would be
likely to comment on such a finding in published manu-
scripts, whereas investigators who failed to find such an
association would be less likely to give any comment. This
is of particular concern, given that the evaluation of vac-
cine response according to nutritional status was not a
primary objective of many studies included in our analysis.
Inclusion criteria, established a priori, were chosen to
increase the likelihood that high quality studies would be
included. Our approach was to obtain data from as many
sources as possible. However, we did not include trials
published as abstracts; information presented in abstract
form often lacks sufficient details to include in a meta-
analysis. Secondly, we made a meta-analysis of observa-
tional studies, and it is well-known that a meta-analysis of
randomized clinical trials provides better accuracy and
reliability. The difficulties in the implementation of ran-
domized clinical trials on this topic, and the high number
(n = 15,172) of patients available for our meta-analysis,

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Dig Dis Sci (2012) 57:1366–1372
strengthen our data. Finally, a large amount of heteroge-
neity (Ri [ 0.75) was found in this analysis, and this can be
attributed to various reasons notably conflicting back-
ground parameters of the study populations or differences
in the criteria used to define nutritional status. A wasting
surrogate, such as serum albumin, was used in the majority
of studies included in the current meta-analysis. Body
impedentiometric analysis (BIA) provides a reliable esti-
mate of lean body mass in patients on long-term dialysis;
that nutritional status, as assessed by BIA, may interfere
with the serological response after anti-HBV vaccination in
dialysis population has already been noted [21]. Finally,
individual data from each study (‘meta-analysis at patient
level’) were not available; thus, it was impossible to per-
form our own adjustments, but the studies we included in
our meta-analysis had already been adjusted for several
important factors that could impact the results.
Recent evidence has been accumulated showing the
adverse effects of malnutrition and/or cachexia/wasting on
survival in dialysis population [26]. Approximately two-
thirds of all maintenance dialysis patients in the USA
exhibit low albumin levels, and serum albumin is measured
regularly in all dialysis patients as it is the most readily
available indicator of protein-energy wasting (PEW), as
suggested by the National Kidney Foundation Kidney
Disease Quality Outcome Initiative [26]. Another nutri-
tional indicator predicting low response to anti-HBV vac-
cine in the dialysis population seems to be serum
transferrin level [19]. To the best of our knowledge, at least
10 randomized controlled trials of nutritional therapy exist
in the CKD population [26]. In the majority of these studies
with serum albumin as a surrogate outcome measure, sig-
nificant improvement in hypoalbuminemia was reported.
No data were given on the serologic response to various
vaccine antigens including HBsAg.
Various approaches have been made in order to improve
the response rate to hepatitis B vaccine in the CKD pop-
ulation including increased vaccine doses or shots. The
Centers for Disease Control (CDC) currently recommend
that dialysis patients receive by intramuscular route double
doses (20 mcg 92) of recombinant HBV vaccine at 0,1,2,
and 6 months with regular monitoring of antibody levels to
ensure that antibody concentrations remain C10 m IU/ml
[5]. Clinical studies concerning adapted vaccine schedules
in the subgroup of dialysis patients with inadequate nutri-
tional status, as detected by BIA parameters, are under
way.
In conclusion, our meta-analysis of observational studies
showed a link between poor nutritional status and impaired
serologic response towards HBV vaccine which is typical
of CKD patients. Studies that incorporate measurements of
various BIA parameters, in order to provide a more accu-
rate estimate of nutritional status, are under way.
1371
Acknowledgment The authors’ work is supported in part by the
grant ‘Project Glomerulonephritis’; in memory of Pippo Neglia.
Conflict of interest The authors of this manuscript have no conflicts
of interest to disclose.
References
1. Labriola L, Jadoul M. The decades-long fight against HBV
transmission to dialysis patients: slow but definite progress.
Nephrol Dial Transplant. 2010;25:2047–2049.
2. Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ. National
surveillance of dialysis-associated diseases in the United States.
Semin Dial. 2005;18:52–61.
3. Thompson ND, Perez JF, Moorman AC, Holmberg SD. Non-
hospital health-care associated hepatitis B and C virus transmis-
sion: United States, 1998–2008. Ann Intern Med. 2009;150:
33–39.
4. Burdick RA, Bragg-Gresham JL, Woods JD, et al. Patterns of hep-
atitis B prevalence and seroconversion in haemodialysis units from
three continents: the DOPPS. Kidney Int. 2003;63:2222–2229.
5. Rangel M, Coronado V, Euler G, Strikas R. For the Advisor
Committee on Immunization Practices and the American Acad-
emy of Pediatrics. Vaccine recommendations for patients on
chronic dialysis. Semin Dial. 2002;13:101–107.
6. Chandra RK. Cellular and molecular basis of nutrition-immunity
interactions. Adv Exp Med Biol. 1990;262:13–18.
7. Takkouche B, Cadarso-Suarez C, Spiegelman D. Evaluation of
old and new tests for heterogeneity in epidemiologic meta-anal-
ysis. Am J Epidemiol. 1999;150:206–215.
8. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control
Clin Trials. 1986;7:177–188.
9. Costa-Bouzas J, Takkouche B, Cadarso-Suarez C, Spiegelman D.
HepiMA: software for the identification of heterogeneity in meta-
analysis. Comput Methods Progr Biomed. 2001;64:101–107.
10. DaRoza G, Loewen A, Djurdjev O, et al. Stage of chronic kidney
disease predicts seroconversion after hepatitis B immunization:
earlier is better. Am J Kidney Dis. 2003;42:1184–1192.
11. Chin A. Hepatitis B virus vaccine response in haemodialysis:
baseline patient characteristics. Hemodial Int. 2003;7:296–303.
12. Weinstein T, Chagnac A, Boaz M, et al. Improved immunoge-
nicity of a novel third-generation recombinant hepatitis B vaccine
in patients with end-stage renal disease. Nephron Clin Pract.
2004;97:c67–c72.
13. Lacson E, Teng M, Ong J, Vienneau L, Ofsthun N, Lazarus J.
Antibody response to Engerix-B and Recombivax-HB hepatitis B
vaccination in end-stage renal disease. Hemodial Int. 2005;9:
367–375.
14. Chow K, Law M, Leung C, Szeto C, Li P. Antibody response to
hepatitis B vaccine in end-stage renal disease patients. Nephron
Clin Pract. 2006;103:c89–c93.
15. Liu J, Liu Y, Lin H, et al. Intravenous iron attenuates post-vac-
cination anti-HBsAg titers after quadruple hepatitis B vaccination
in dialysis patients with erythropoietin therapy. Int J Clin Pract.
2009;63:387–393.
16. Afsar B, Elsurer R, Eyileten T, Yilmaz M, Caglar K. Antibody
response following hepatitis B vaccination in dialysis patients:
does depression and life quality matter? Vaccine. 2009;27:
5865–5869.
17. Fernandez E, Betriu M, Gomez R, Montoliu J. Response to the
hepatitis B virus vaccine in haemodialysis patients: influence of
malnutrition and its importance as a risk factor for morbidity and
mortality. Nephrol Dial Transplant. 1996;11:1559–1563.
123
1372
18. Morais E, Resende M, Oliveira A, et al. Intradermal hepatitis B
vaccination in patients with advanced chronic renal failure: immu-
nogenicity and follow-up. Aliment Pharmacol Ther. 2007;25:
849–855.
19. Fabrizi F, Di Filippo S, Marcelli D, et al. Recombinant hepatitis B
vaccine use in chronic haemodialysis patients. Nephron. 1996;72:
536–543.
20. Kara I, Yilmaz M, Suner A, Kadiroglu A, Isikoglu B. The evalu-
ation of immune responses that occur after HBV infection and
HBV vaccination in haemodialysis patients. Vaccine. 2004;22:
3963–3967.
21. Lombardi M, Pizzarelli F, Righi M, et al. Hepatitis B vaccina-
tion in dialysis patients and nutritional status. Nephron. 1992;61:
266–268.
22. Vagelli G, Calabrese G, Mazzotta A, Pratesi G, Gonella M. More
about response to hepatitis B vaccine in haemodialysis patients.
Nephron. 1988;49:171.
23. Chow K, Lo S, Szeto C, et al. Extra-high-dose hepatitis B vac-
cination does not confer longer seroprotection in peritoneal
dialysis patients: a randomized controlled trial. Nephrol Dial
Transplant. 2010;25:2303–2309.
24. Radziszewski A, Gajda M, Pituch-Noworolska A, et al. The eval-
uation of the effectiveness of multiple dose intradermal hepatitis B
re-vaccination in haemodialysis patients not responding to standard
method of immunization. Prezegl Lek. 2007;64:470–475.
123
Dig Dis Sci (2012) 57:1366–1372
25. Verkade M, Druningen C, op de Hoek C, Weimar W, Betjes M.
Decreased antigen-specific T-cell proliferation by moDC among
hepatitis B vaccine non-responders on haemodialysis. Clin Exp
Med. 2007;7:65–71.
26. Mak R, Ikizler A, Kovesdy C, Raj D, Stenvinkel P, Kalantar-
Zadeh K. Wasting in chronic kidney disease. J Cachexia
Sarcopenia Muscle. 2011;2:9–25.
27. Liu Y, Kao M, Huang C. A comparison of responsiveness to
hepatitis B vaccination in patients on haemodialysis and perito-
neal dialysis. Vaccine. 2005;23:3957–3960.
28. Peces R, de la Torre M, Alcazar R, Urra J. Prospective analysis of
the factors influencing the antibody response to hepatitis B vac-
cine in haemodialysis patients. Am J Kidney Dis. 1997;29:
239–245.
29. Elwell R, Neumann M, Bailie G. Factors associated with long-
term antibody production induced by hepatitis B vaccine in
patients undergoing haemodialysis: a retrospective cohort study.
Pharmacotherapy. 2003;23:1558–1563.
30. Navarro J, Teruel J, Mateos M, Marcen R, Ortuno J. Antibody
level after hepatitis B vaccination in haemodialysis patients:
influence of hepatitis C virus infection. Am J Nephrol. 1996;16:
95–97.
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