1
RESEARCH ARTICLE Open Access
Association of response to hepatitis B
vaccination
and survival in dialysis patients
2
3
4 Shih-Yi
Lin1,2, Jiung-Hsiun Liu2,3, Shu-Ming Wang2,3, I-Kuan Wang1,2,3, Chen-An
Tsai4, Yao-lung Liu2,3*,
5 Hsin-Hung
Lin1,2, Chiz-Chung Chang2,3 and Chiu-Ching Huang2,3
6 Abstract
7 Background:
The status of immunocompromised patients is well recognized in end stage
renal disease (ESRD). As
8 described
recently, this acquired immune dysfunction in the uremic milieu may be one of the
main pathogenic
9 factors
for mortality in ESRD. The aim of this study was to determine the relationship
between the immune
10 response
following a hepatitis B vaccination (HBV vaccination) and the survival of
maintenance dialysis patients.
11 Methods:
A total of 156 patients (103 on hemodialysis and 53 on continuous ambulatory
peritoneal dialysis) were
12 recruited.
After receiving a full dose of the HBV vaccination, all patients were followed up for
to 5 years to evaluate
13 the
association of patient survival, cause of mortality, and immune response.
14 Results:
The response rate to the hepatitis B vaccination was 70.5%. There was no
significant association between
15 the
immune response and the 5-year survival rate (p =0.600) or between the
post-vaccination anti-HBs titers and
16 the
5-year survival rate (p = 0.201). The logistic prediction model with the coefficient as
non-response following HBV
17 vaccination,
diabetes mellitus, old age, and low albumin level could significantly predict
infection-cause mortality
18 (sensitivity
= 0.842, specificity = 0.937).
19 Conclusion:
There was no significant association between the immune response to HBV
vaccination and the 5-year
20 survival
rate. However, non-response following HBV vaccination might be associated with
infection-cause mortality
21 in
dialysis patients.
22 Keywords:
Hepatitis B vaccination, Immune response, Post-vaccination anti-HBs titers
23 Background
24 End-stage
25 the
renal disease (ESRD) significantly increases
risk of mortality and morbidity. The leading cause of
26 death
in ESRD is cardiovascular disease (CVD), which
27 accounts
28 with
for more than half of deaths in uremic patients,
infection the second leading cause [1,2]. Previous
29 studies
30 thelial
have investigated the relationships among endo-
dysfunction, inflammation, and atherosclerotic
31 vascular
32 related
disease in chronic kidney disease [3,4]. Uremic-
inflammation, which commonly occurs during
33 pre-dialysis
34 regarded
35 and
and persists even after dialysis, is now
as an important predictor of cardiovascular
all-cause mortality in the ESRD population [5].
Currently, it is speculated that acquired immune dys- 36
function in the uremic milieu may be one of the main 37
pathogenic factors, mediated through CVD and infec- 38
tions, in most ESRD-related deaths. Concomitant im- 39
munosuppression and immune activation in uremia 40
would predispose patients to infection and CVD, re- 41
spectively [6]. 42
Although it is well established that aging, diabetes 43
mellitus (DM), and the presence of co morbid conditions 44
predict a poor prognosis in ESRD, few studies have 45
investigated immune dysregulation as a determinant of 46
mortality in ESRD [7]. Furthermore, acquired immune 47
dysfunction in uremic patients has various clinical fea- 48
tures, ranging from proness to infection to impaired im- 49
mune response to vaccinations. The aim of our study 50
was to link the clinical immune parameter, immune re- 51
sponse and anti-HBs titers one month following HBV 52
vaccination with mortality in ESRD populations. 53
* Correspondence: liuyaolung@yahoo.com
2Division
of Nephrology and Kidney institute, China Medical University
Hospital, Taichung, Taiwan
3School
of Medicine, China Medical University, Taichung, Taiwan
Full list of author information is available at the end of the article
© 2012 Lin et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Lin et al. BMC Nephrology 2012, 13:97
http://www.biomedcentral.com/1471-2369/13/97
54 Methods
55 This
clinical study complied with the Declaration of Hel-
56 sinki
and was approved by the Medical Ethics Commit-
57 tee
of the China Medical University Hospital, Taichung
58 (Taiwan,
59 This
ROC).
was a retrospective study of ESRD patients who
60 underwent
61 China
dialysis therapy at the dialysis unit of the
Medical University Hospital (Taichung, Taiwan)
62 from March
63 up
2002 to March 2008 and who were followed
until March 2009.
64 The
HBV vaccine was offered to all patients who
65 tested
66 and
negative for the HBV surface antigen (HBs Ag)
anti-HBs and who had not previously received the
67 HBV
vaccination. We excluded patients who had malig-
68 nancies,
69 or
who were receiving immunosuppressive agents,
who did not receive all four vaccinations. All patients
70 were
given four doses (40 μg per dose) of the hepatitis B
71 vaccine
(Engerix-B, GlaxoSmithKline Biologicals, Phila-
72 delphia,
USA) in the deltoid muscles at 0, 1, 2, and
73 6
months. Anti-HBs titers were measured by an ELISA
74 kit
(AUSAB-EIA, Abbot Labs, Chicago, USA) one month
75 after
76 We
77 to
the final dose and annually thereafter.
defined responders and non-responders according
the level of anti-HBs one month after the final injec-
78 tion
(non-responders: < 10 IU/L; responders: ≥ 10 IU/L).
79 These
patients were followed up to assess the relation-
80 ship
between the initial immune response to vaccination
81 and
the 5-year-survival. In addition, over the 5-year fol-
82 low-up
period, we assessed the effect of one-month
83 post-vaccination
84 To
anti-HBs titers on survival.
determine the factors related to HBs antibody for-
85 mation
following vaccination, we recorded the patient age,
86 gender,
presence of diabetes mellitus (DM), hemoglobin,
87 serum albumin,
88 sugar,
triglyceride, cholesterol, fasting blood
presence of hepatitis C antibodies, and dialysis mo-
89 dality at
the initiation of vaccination [8-10].
90 Statistical analysis
91 All
statistical tests were performed with SPSS (version
92 15.0).
93 cant.
94 test
A P value < 0.05 was considered statistically signifi-
For categorical variables, we used the Chi-squared
and presented data as absolute numbers or percen-
95 tages.
For continuous variables, we used Student’s t-test
96 and
presented the data as means ± standard deviations.
97 The
Cox regression model was used to investigate the as-
98 sociation
between seroconversion and mortality and the
99 relationship
between post-vaccination anti-HBs titers
100 and
mortality.
101 We
adjusted for age, level of albumin, presence of
102 DM,
dialysis modality, and gender to determine the
103 adjusted
hazard ratios with the immune response to
104 mortality.
105 We
adapted the logistic regression model as fol-
106 lows:
β0+ β1*Non-response + β2*(presence of DM)+
β3*Age+β4*Albumin+β5*(presence of DM)*Albumin + 107
β6*Age*Albumin. We used this equation to evaluate 108
the effects of non-response, diabetes mellitus, age, 109
and the level of albumin in predicting mortality due 110
to infection. 111
Results 112
A total of 156 patients (64 males, 92 females) were 113
recruited, with 110 responders and 46 non-responders 114
(Table 1). Mean ages were higher for non-responders 115 T1
(62.63 ± 9.95 years) than for responders (55.75 ± 14.31 years, 116
P = 0.003). The prevalence of diabetes or anti-HBV vaccin- 117
ation at the start of the study was 32.0%. 118
Univariate analysis indicated no significant differences 119
between responders and non-responders in terms of gen- 120
der, presence of DM, presence of hepatitis C antibodies, 121
hemoglobin, albumin, dialysis modality, triglyceride, 122
cholesterol, and several other relevant factors (Table 1). 123
By the time of the 5-year follow up, 35 patients had died. 124
The most common cause of death was infection (54.3%; 125
19 patients, including 8 cases of severe pneumonia, 4 126
cases of peritonitis, 2 cases of infective endocarditis, and 127
1 case of either meningitis, diabetic foot infection, septic 128
arthritis, urosepsis, and septicemia), followed by cardio- 129
vascular events (25.7%, 9 patients), gastrointestinal bleed- 130
ing (5.7%, 2 patients), gastrointestinal perforation (5.7%, 131
2 patients), and others (8.6%, 3 patients). By the end of 132
the study, the prevalence of DM in all available subjects 133
(including those that died during the study) was 30%, but 134
the impact of DM on the loss of anti-HBs Ab was not 135
significant (p = 0.308). 136
We followed up on all patients after the vaccination to 137
investigate the association between seroconversion and 138
mortality. Figure 1 shows that there was no significant 139 F1
survival difference for responders and non-responders 140
(P = 0.297). A Cox regression analysis, which considered 141
patient age, presence of DM, initial serum albumin 142
Table 1 Baseline characteristics of HBV vaccine t1:1
responders and non-responders t1:2
Characteristic Non-responders Responders P value t1:3
Number of pts. 46 110 t1:4
Age 62.63 ± 9.95 55.75 ± 14.31 0.003 t1:5
Gender(M/F) 17/29 47/63 0.507 t1:6
DM 19 31 0.111 t1:7
HCV infection 9 (19.6%) 15 (13.6%) 0.353 t1:8
Hemoglobin(g/dL) 9.49 ± 1.42 9.55 ± 1.38 0.786 t1:9
Albumin(g/dL) 3.47 ± 0.37 3.50 ± 0.39 0.696 t1:10
Dialysis modality (HD:PD) 31:15 72:38 0.817 t1:11
Cholesterol(mg/dL) 184.71 ± 50.07 181.33 ± 42.66 0.669 t1:12
Triglyceride(mg/dL) 187.93 ± 131.87 176.58 ± 124.46 0.610 t1:13
Note: data are shown as the number (%) or mean ± SD, as appropriate. t1:14
Abbreviations: M, male; F, female. t1:15
Lin et al. BMC Nephrology 2012, 13:97 Page 2 of 7
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143 levels,
seroconversion after HBV vaccination, dialysis
144 modality,
and gender, showed that advanced age and
145 malnutrition
were associated with increased mortality
T2 146 (P = 0.035 and P = 0.032, respectively) (Table 2).
147 We
also evaluated the association between one-month
148 post-vaccination
149 was
no significant survival difference between immune
150 sustainers
151 analysis
152 min
153 p
anti-HBs titers and mortality. There
and non-sustainers (P = 0.201). Cox regression
indicated that only age and low levels of albu-
were associated with mortality (p = 0.04 and
= 0.032, respectively).
154 The
predictive model of mortality due to infection in
155 dialysis
156 age,
patients demonstrated that non-response, DM,
and low levels of albumin all predicted significantly
T3 157 higher mortality rates due to infection (Table 3). This
158 model
performs well and has high sensitivity and high
159 specificity
(sensitivity = 0.842, specificity = 0.938, positive
160 predictive
values = 0.941, negative predictive value =
0.833). The area under the ROC curve (AUC) provides 161
an overall measure of the model’s classification accuracy, 162
with a value of one representing perfect accuracy. The 163
ROC curve shows a high capacity for discriminating 164
infection-cause mortality vs. non-infection cause mortal- 165
ity, with an AUC = 0.9112 (Figure 2). The immune re- 166 F2
sponse following HBV vaccination and other co-factors 167
were not associated with CV mortality (data not shown). 168
Discussion 169
In this study, we showed that the seroconversion rate of 170
our dialysis patients was 70.5% after four double doses 171
(40 μg per dose) of the hepatitis B vaccine administered 172
over 6 months. We also found that responders were 173
Figure 1 Cumulative survival of HBV vaccine responders and non-responders over 5 years.
t2:1 Table 2 Cox proportional hazards regression of immune
t2:2 response to HBV vaccination and mortality
t2:3 Parameter P- value
t2:4 Age 0.035
t2:5 Modality 0.210
t2:6 Seroconversion of HBV vaccination 0.600
t2:7 Albumin 0.032
t2:8 Gender 0.060
t2:9 Diabetes Mellitus 0.670
Table 3 The predictive model of infection-cause mortality t3:1
in dialysis patients Logit (probability of infection-cause t3:2
mortality) =β0 + β1*Retiter + β2*DM+ β3*Age + t3:3
β4*Albumin + β5*DM*Albumin + β6*Age*Albumin t3:4
Covariates Coefficient p-value t3:5
Intercept 143.4122 0.0232 t3:6
Seroconversion t3:7
following t3:8
HBV vaccination t3:9
−4.7392 0.0068
Presence of DM −5.3569 0.0084 t3:10
Age −1.9758 0.3333 t3:11
Albumin −40.2689 0.0234 t3:12
DM*Albumin 13.1720 0.0089 t3:13
Age*Albumin 0.5699 0.0317 t3:14
Lin et al. BMC Nephrology 2012, 13:97 Page 3 of 7
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174 significantly
younger than non-responders (P = 0.003).
175 Seroconversion
to HBV vaccination and one-month
176 post-vaccination
177 mortality in
178 adjusting
179 sis
anti-HBs titers did not predict all-cause
our maintenance dialysis patients. After
for age, DM, albumin levels, gender, and dialy-
modality, non-seroconversion following HBV vaccin-
180 ation
could independently predict mortality due to
181 infection
in ESRD dialysis patients. This novel and inter-
182 esting
finding demonstrates the possible relationship be-
183 tween
the vaccination response and the specific cause of
184 mortality in
ESRD patients.
185 Our
study dialysis subjects displayed a similar subopti-
186 mal
immune response to patients in previous studies. In
187 ESRD
patients, the response rate to HBV vaccination is
188 approximately
189 response
50%–80%, which is lower than the 90%
rate in the general population, with advanced
190 age
being a significant negative factor associated with
191 this
poor immune response [11-13]. Numerous factors
192 associated
with the impaired immune response following
193 HBV
vaccination in ESRD, such as age, albumin levels,
194 HCV
infection, and gender, have been well studied [8-
195 10,13].
Current studies have focused on the insufficient
196 acquired
immunity due to uremia to account for the
197 suboptimal
198 [14].
response rates following HBV vaccination
Recent studies have proposed that the immunodefi-
199 ciency in
ESRD results from the impaired function of
200 antigen-presenting
201 weakened
202 ance
cells, alteration of toll-like receptors,
activation of T lymphocytes, and the imbal-
of T-helper lymphocytes (Th 1/Th 2 ratio) [14-16].
In the present study, we demonstrated that DM, age, 203
low albumin levels, and non-response following HBV 204
vaccination could predict mortality due to infection. 205
Several negative determinants of mortality in ESRD, 206
such as old age, DM, and malnutrition, have been docu- 207
mented [7]. Immune dysfunction in uremia is also 208
recognized as a determinant of mortality. However, our 209
findings are important because they demonstrate a link 210
between infection-cause mortality and insufficient im- 211
mune responses to HBV vaccination in ESRD, since 212
these two clinical presentations involve homogenous but 213
varied interactions between the immune, innate immune 214
and the adaptive immune systems. A recent review indi- 215
cated that in dialysis patients innate immunity plays an 216
important role in fighting infections, while acquired im- 217
munity (via antibody production) also makes a signifi- 218
cant contribution [14]. We therefore hypothesize that T 219
cell dysfunction may be the main link between the high 220
mortality due to infection and the insufficient antibody 221
response to vaccination in ESRD patients. Impaired 222
cytotoxic CD8 T cell response limits the fight of the 223
infected host defense system against the pathogens, 224
while the inadequate function of helper CD4 T cells 225
weakens the humoral immune system. The results of 226
studies by Alvarez-lara et al. and Meier P et al. support 227
this hypothesis, finding increased apoptosis of T cells in 228
uremia [17-19]. An alternative interpretation is that the 229
key linking factor between high mortality due to infec- 230
tion and the impaired vaccination response lies upstream 231
Sensitivity: 0.8421 ; Specificity: 0.9375
PPV: 0.9412 ; NPV: 0.8333
Figure 2 The ROC curve shown used to examine the performance of logistic regression model.
Lin et al. BMC Nephrology 2012, 13:97 Page 4 of 7
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232 of
T-cell activation, i.e., the pattern of recognition and
233 the
antigen presenting cell or secondary dysregulation or
234 activation
235 It
of cytokines [6,14,20].
has been proposed that both the innate and acquired
236 immune
systems may play a role in the progression of
237 atherosclerosis,
the major pathogenic factor responsible
238 for
most deaths in ESRD patients [21]. Interestingly, we
239 did
not find an association between seroconversion and
240 all-cause
241 cause
mortality in dialysis patients. The correlations
242 among
243 tions,
persistent inflammation, CVD, immune dysfunc-
and infections in ESRD have become apparent in
244 recent
years [5,6,22-24].
245 Chronic
246 and
mortality or between seroconversion and CV-
inflammation as a result of hypercytokinemia
an imbalance in the pro-inflammatory to anti-
247 inflammatory ratio
248 [25].
The dysregulation of various cytokines due to the
249 uremia
milieu may link inflammation-atherosclerosis to
250 impaired
251 [14].
252 and
253 et
has been well recognized in ESRD
immunity inflammation in dialysis patients
Several studies have attempted to link the levels
types of cytokines with clinical outcomes. Girndt
al. determined that higher levels of IL-6 and TNF-α
254 correlated
with an immunocompromised status, that is,
255 non-seroconversion
256 [26].
Kimmel et al. assessed immune parameters such as
257 cytokines
258 up.
in 230 HD patients, with a three-year follow
Their results showed that increased levels of IL-6,
259 TNF-α,
IL-1, and IL-13 correlated with a higher relative
260 mortality risk.
261 and
to HBV vaccinations in HD patients
High levels of IL-2, IL-4, IL-5, and IL-12,
T cell functions were associated with survival in HD
262 patients.
263 tality in
264 tions
The authors did not analyze the causes of mor-
their patients or further investigate the associa-
between the causes of mortality and cytokines.
265 Interestingly,
they noted that the patterns of cytokines
266 involved
may be more important than the individual
267 cytokine
levels in interpreting survival outcomes [27].
268 Among
the other studies on cytokines’ ability to pre-
269 dict
mortality in ESRD, the study by Badiou et al. mea-
270 sured
levels of both pro-inflammatory cytokines and
271 anti-inflammatory cytokines
272 found
273 ity.
in 134 HD patients and
that IL-6 levels could strongly predict CV mortal-
In addition, (IL-4+ IL-6+ IL-10)/(IL-2 + IFN-γ) was
274 associated
275 lated
that examination of the Th1/Th2 cytokine relation
276 might
277 [28].
be more relevant for predicting non-CV mortality
These findings indicate that the laboratory immune
278 parameter,
279 implies
280 ical
with non-CV mortality. The authors specu-
especially the Th1/Th2 cytokine ratio that
defective immunity, may be able to predict clin-
outcomes. The clinical immune parameters and the
281 immune
response following HBV vaccination may be
282 able
to correlate with mortality in ESRD patients.
283 The
study by Fernandez et al. of 64 HD patients noted
284 that
low levels of albumin negatively influenced the re-
285 sponse
to HBV vaccination. In the study’s survival
analysis of 31 patients, non-responders had higher mor- 286
tality and morbidity [29]. The authors did not adjust for 287
albumin levels or age in the survival analysis of these 288
HD subjects. However, our Cox regression survival ana- 289
lysis of 156 dialysis patients reveals that only old age and 290
low levels of albumin have significantly higher mortality 291
but that non-response following HBV vaccination did 292
not. Since low albumin levels are recognized as an inde- 293
pendent factor of mortality in ESRD [30], we speculate 294
that low albumin levels account for the concomitant 295
impaired immune response following HBV vaccination 296
and increased mortality in the Fernandez et al. study. 297
The Kimmel et al. study suggests that better T cell 298
function and humoral immunity are associated with a 299
survival advantage in HD patients [27]. Unlike the pre- 300
dictive value of the cytokine ratio on mortality men- 301
tioned above, our study demonstrated no significant 302
relationship between the clinical immune response fol- 303
lowing HBV vaccination and all-cause mortality. The 304
levels and types of cytokines in dialysis patients were 305
the result of the interacting influences of residual renal 306
function, dialysis adequacy, comorbidity, and current 307
treatment [31]. Our dialysis patients received HBV vac- 308
cinations at the initiation of renal replacement therapy. 309
Some of our study subjects, especially the PD patients, 310
retained some residual renal function, which would 311
affect the immune response to HBV vaccinations. In 312
the Badiou et al. and Kimmel et al. studies, the levels 313
of circulating cytokines (either Th1 or Th2-related) 314
were significantly higher in the HD patients than in 315
the control patients [27,28]. The effects of these un- 316
usual levels of circulating cytokines may not correlate 317
well with their baseline local immunological functions 318
[31]. These circulating cytokines may operate in a 319
more sophisticated pathophysiologic network, causing 320
erythropoietin resistance, hypoalbuminemia, frailty, ath- 321
erosclerosis, and dyslipidemia [31,32]. Therefore, the 322
clinical outcomes, survival and immune response fol- 323
lowing HBV vaccination may be the diverse results of 324
the differing interactions of various cytokines at spe- 325
cific cellular, organ, and system targets. We therefore 326
could not determine whether a direct association exists 327
between seroconversion and all-cause mortality in dia- 328
lysis patients despite the well-recognized immunodefi- 329
ciency, hypercytokinemia, and high mortality in ESRD 330
populations [1,14,24,33,34]. 331
We did not check the antibody of the core HBV anti- 332
gen (anti-HBc). The finding of a positive anti-HBc in the 333
absence of HBs Ag or anti-HBs is relatively uncommon 334
[35]. Chen et al. found that the responsiveness rates of 335
the hepatitis B vaccination were the same between iso- 336
lated anti-HBc positive and normal subjects [36]. 337
We recognize that our study has certain limitations, 338
such as the relatively small number of dialysis patients 339
Lin et al. BMC Nephrology 2012, 13:97 Page 5 of 7
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340 included
341 tality.
to determine the infection-based and CV mor-
Moreover, infection was the leading cause of mor-
342 tality among
our study subjects, despite being the
343 second
344 as
leading cause of deaths in the ESRD population
a whole. The immune status of dialysis patients may
345 change
after losing residual renal function. The results
346 of
our study need to be replicated in prospective studies
347 of
using larger populations of chronic, stable dialysis
348 patients.
349 Conclusions
350 In
conclusion, we demonstrated that non-response fol-
351 lowing
HBV vaccination might be associated with
352 infection-cause
353 ever,
the clinical immune response following HBV vac-
354 cination
355 in
mortality in our dialysis patients. How-
would not be associated with all-cause mortality
our dialysis patients.
356 Competing interests
357 The authors declare that they have no competing interests.
358 Authors’ contributions
359 SL carried out the data collection and drafted the manuscript. JL, SW, and I
360 W participated in the design of the study. CT, HL, CC, and CH performed the
361 statistical analysis. YL conceived of the study, and participated in its design
362 and coordination. All authors read and approved the final manuscript.
363 Author details
364 1Graduate Institute of Clinical Medical Science, College of Medicine, China
365 Medical University, Taichung, Taiwan. 2Division of Nephrology and Kidney
366 institute, China Medical University Hospital, Taichung, Taiwan. 3School of
367 Medicine, China Medical University, Taichung, Taiwan. 4Department of
368 Agronomy, National Taiwan University, Taipei, Taiwan.
369 Received: 24 October 2011 Accepted: 27 August 2012
370 Published: 30 August 2012
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480 vaccination and survival in dialysis patients. BMC Nephrology 2012 13:97.