Lang, Susanne M.

Schiffl, Helmut

Wendinger, H.

English

H. Schiffl

H. Wendinger

S.M. Lang

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Ultrapure Dialysis Fluid and Response to Hepatitis B Vaccine

Universität München: Elektronischen Publikationen

Letter to the Editor
Nephron 2002;91:530–531
Ultrapure Dialysis Fluid and Response to
Hepatitis B Vaccine
H. Schiffla H. Wendingera S.M. Langb
aKuratorium für Dialyse und Nierentransplantation, Dialysezentrum München-Laim, München,
bMedizinische Klinik Innenstadt, Ludwig-Maximilians Universität München, München, Deutschland
Prof. Dr. H. Schiffl
Kuratorium für Dialyse und Nierentransplantation
Elsenheimerstrasse 63
D–80687 München (Germany)
Tel. +49 89 547 26720, Fax +49 89 570 57 27, E-Mail hschiffl@hotmail.com
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 2002 S. Karger AG, Basel
0028–2766/02/0913–0530$18.50/0
Accessible online at:
www.karger.com/journals/nef
Dear Sir,
Hepatitis B virus infection has remained
a serious threat to maintenance hemodialy-
sis patients in spite of improvements in in-
fection control and dialysis techniques. Mul-
tiple reasons may explain the persistence of
this problem. Hemodialysis patients are at a
greater risk of infection, the seroconversion
rate after vaccination is still less than in the
general population (50–75 versus 95%) and
the duration of immunity is shorter [1].
The lack of response to hepatitis B vac-
cine may arise from reduced costimulation
and effector activation of T cells and corre-
lates with an increased production of proin-
flammatory cytokines by monocytes [2, 3].
There is considerable evidence that endotox-
in fragments and other bacterial products
derived from contaminated dialysis fluid
can cross dialyzer membranes and induce
enhanced cytokine release by monocyte acti-
vation [4]. This cytokine release may be cir-
cumvented by the use of on-line produced
ultrapure dialysis fluid, which results in a
lower systemic inflammatory response [5,
6].
The purpose of our prospective random-
ized investigation was to test the hypothesis
that the microbiological quality of dialysis
fluid affects the response to hepatitis B vac-
cination.
Patients with end-stage renal disease re-
ceiving hemodialysis were eligible. Inclu-
sion criteria were as follows: hepatitis B sur-
face antigen (HbsAg) negative, antibody to
HbsAg negative and no previous hepatitis
vaccination. Exclusion criteria were acute or
chronic inflammatory disorders or infec-
tions, use of immunosuppressive drugs and
malignancy. 72 early hemodialysis patients
(32 female, 40 male; age 62 B 8 years) gave
informed consent. Patients were randomly
assigned to either conventional, i.e. poten-
tially contaminated, dialysis fluid or ultra-
pure dialysis fluid (produced on-line by one-
step additional ultrafiltration using an endo-
toxin-adsorbing polysulfone filter). All pa-
tients received hemodialysis 3 times per
week (Kt/V of at least 1.2) utilizing volu-
metrically controlled ultrafiltration (MTS
4008, Fresenius, Oberursel, Germany) and
high-flux polysulfone dialyzers (APS 650
Asahi, Tokyo, Japan). The vaccination
schedule encompassed four doses of 40 Ìg of
recombinant hepatitis B vaccine (Gen H-B-
Vax D, Aventis Pasteur MSD, Leimen, Ger-
many) given at 0, 1, 2 and 6 months in the
deltoid muscle. Antibody titers to HbsAg
were measured by the AUSAB IMX system
(Abbott Laboratories, Chicago, Ill., USA)
one month after the last dose. An antibody
titer of 10 IU/l or more represented serocon-
version. The nonconverters were those who
did not reach an antibody titer of 10 IU/l or
more after completion of the vaccination
program. Laboratory tests [hemoglobin, in-
tact parathyroid hormone (PTH), serum al-
bumin], calculation of body mass index and
EPO doses were determined as previously
described [7]. Statistical significance was cal-
culated for differences between means using
an unpaired t test and for observed/expected
frequencies by means of ¯2 analysis (two-
tailed Fisher’s exact test). A p value of less
than 0.05 was considered significant. All val-
ues in tables are expressed as means B SD.
There were no statistically significant dif-
ferences in age, gender, body weight, etiology
of renal disease, time on hemodialysis, Kt/V,
hemoglobin concentration, number of pa-
tients receiving EPO, intact PTH levels or
parameters of nutritional status between the
two study groups. The ultrapure dialysis
fluid group, however, had significantly lower
CRP and IL-6 concentrations and need for
rHuEPO (table 1).
The overall seroconversion rate was 78%
(56 out of 72 patients). Of these 56, 32
patients were in the ultrapure dialysis fluid
group and 24 patients were in the conven-
tional mildly contaminated dialysis fluid
group (89 vs. 67%; Fisher’s exact two-tailed
test, p = 0.045). The antibody titers obtained
4 weeks after the last vaccination dose were
significantly higher in the ultrapure dialysis
fluid group (table 2). In 8 out of the 12 non-
responding patients of the conventional
dialysis fluid group, seroconversion was
achieved by a second vaccination protocol
(identical to the first) after switching to ultra-
pure dialysis fluid.
Our prospective randomized investiga-
tion demonstrates that the use of ultrapure
Number of patients
Responders
Ultrapure Dialysis Fluid and Response to
Hepatitis B Vaccine
Nephron 2002;91:530–531 531
dialysis fluid results in a higher seroconver-
sion rate in response to intramuscular vacci-
nation against hepatitis B virus in early
maintenance hemodialysis patients. The dif-
ferences in the rate of seroconversion be-
tween the two groups could not be explained
by differences in the demographic or renal
characteristics of the two study groups.
Moreover, there was no evidence of under-
dialysis, malnutrition, excessive hyperpara-
thyroid hormone secretion or lower inci-
dence of rHuEPO therapy. Our data indicate
that endotoxins derived from mildly con-
taminated dialysis fluid are related to in-
creased cytokine release by monocyte activa-
tion and contribute to the uremia-associated
immune defect.
In the past, a number of measures have
been taken to increase the seroconversion
rate and duration of immunity against hepa-
titis B virus vaccination in end-stage renal
disease patients [1]. They consisted of an
increased number of doses, increased anti-
gen load per dose, different routes of admin-
istration (intradermally vs. intramuscularly),
addition of IL-2 to the protocol or vaccina-
tion earlier in the course of progressive renal
failure. However, these different approaches
have not been successful in a reproducible
way. However, any decrease in the incidence
of hepatitis B virus infection depends exclu-
sively on immunity to hepatitis B virus in-
fection by successful vaccination [8]. Ultra-
pure dialysis offers a safe and cost-efficient
strategy to increase the immunity to hepati-
tis B in end-stage renal disease.
In conclusion, the present investigation
demonstrated for the first time that a high
conversion rate and high titer response to
hepatitis B vaccination can be achieved in
end-stage renal disease patients treated with
ultrapure dialysis fluid.
Table 1. Patient characteristics at recruitment
Ultrapure dialysis
fluid group
Conventional dialysis
fluid group
36 36
Age, years 64B10 60B6
Gender (female/male) 15/21 17/19
BMI, kg/m2 24B3 26B5
Etiology of renal disease (major type)
Chronic glomerulonephritis 10 8
Nephroangiosclerosis 8 7
Diabetes mellitus 7 8
Polycystic kidney disease 4 3
Tubulo-interstitial nephritis 4 4
Time on hemodialysis, months 6B2 5B3
Kt/V 1.3B0.1 1.2B0.1
Hemoglobin, g/dl 10.4B0.6 10.2B0.8
Number of patients on rHuEPO 26 25
Dose of rHuEPO, U/kg/week 62B4* 98B18
Intact PTH, pg/ml 104B45 96B38
Serum albumin, g/dl 4.0B0.3 3.8B0.2
CRP, mg/dl 0.6B0.2* 1.2B0.4
IL-6, pg/ml 14B4* 45B6
BMI = Body mass index.
* p ! 0.05 versus corresponding values in patients receiving conventional dialysis fluid.
Table 2. Antibody titers after vaccination in responding patients
receiving different dialysis fluids
Ultrapure dialysis
fluid group
Conventional dialysis
fluid group
32* 24
Antibody titer, IU/l 616B123* 268B108
* p ! 0.05 versus corresponding values in patients receiving con-
ventional dialysis fluid.
References
1 Rangel MC, Coronado VG, Euler GL, Strikas
RA: Vaccine recommendations for patients on
chronic dialysis. The Advisory Committee on
Immunization Practices and the American
Academy of Pediatrics. Semin Dial 2000;13:
101–107.
2 Sester U, Sester M, Hauk M, Kaul H, Kohler
H, Girndt M: T-cell activation follows Th1
rather than Th2 patterns in haemodialysis pa-
tients. Nephrol Dial Transplant 2000;15:1217–
1223.
3 Girndt M, Sester M, Sester U, Kaul H, Köhler
H: Defective expression of B7–2 (CD86) on
monocytes of dialysis patients correlates to the
uremia-associated immune defect. Kidney Int
2001;59:1382–1389.
4 Lonnemann G: The quality of dialysate: An
integrated approach. Kidney Int Suppl 2000;
76:S112–S119.
5 Canaud B, Bosc JY, Leray H, Morena M, Stec
F: Microbiologic purity of dialysate: Rationale
and technical aspects. Blood Purif 2000;18:
200–213.
6 Sitter T, Bergner A, Schiffl H: Dialysate related
cytokine induction and response to recombi-
nant human erythropoietin in haemodialysis
patients. Nephrol Dial Transplant 2000;15:
1207–1211.
7 Schiffl H, Lang SM, Stratakis D, Fischer R:
Effects of ultrapure dialysis fluid on nutritional
status and inflammatory parameters. Nephrol
Dial Transplant 2001;16:1863–1869.
8 Lewis-Ximenez LL, Oliveira JM, Mercadante
LA, De Castro L, Santa Catharina W, Stuver S,
Yoshida CF: Serological and vaccination pro-
file of hemodialysis patients during an out-
break of hepatitis B virus infection. Nephron
2001;87:19–26.


Ultrapure dialysis fluid and response to hepatitis B vaccine

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Letter to the EditorNephron 2002;91:530–531Ultrapure Dialysis Fluid and Response toHepatitis B VaccineH. Schiffla H. Wendingera S.M. LangbaKuratorium für Dialyse und Nierentransplantation, Dialysezentrum München-Laim, München,bMedizinische Klinik Innenstadt, Ludwig-Maximilians Universität München, München, DeutschlandProf. Dr. H. SchifflKuratorium für Dialyse und NierentransplantationElsenheimerstrasse 63D–80687 München (Germany)Tel. +49 89 547 26720, Fax +49 89 570 57 27, E-Mail hschiffl@hotmail.comABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 2002 S. Karger AG, Basel0028–2766/02/0913–0530$18.50/0Accessible online at:www.karger.com/journals/nefDear Sir,Hepatitis B virus infection has remaineda serious threat to maintenance hemodialy-sis patients in spite of improvements in in-fection control and dialysis techniques. Mul-tiple reasons may explain the persistence ofthis problem. Hemodialysis patients are at agreater risk of infection, the seroconversionrate after vaccination is still less than in thegeneral population (50–75 versus 95%) andthe duration of immunity is shorter [1].The lack of response to hepatitis B vac-cine may arise from reduced costimulationand effector activation of T cells and corre-lates with an increased production of proin-flammatory cytokines by monocytes [2, 3].There is considerable evidence that endotox-in fragments and other bacterial productsderived from contaminated dialysis fluidcan cross dialyzer membranes and induceenhanced cytokine release by monocyte acti-vation [4]. This cytokine release may be cir-cumvented by the use of on-line producedultrapure dialysis fluid, which results in alower systemic inflammatory response [5,6].The purpose of our prospective random-ized investigation was to test the hypothesisthat the microbiological quality of dialysisfluid affects the response to hepatitis B vac-cination.Patients with end-stage renal disease re-ceiving hemodialysis were eligible. Inclu-sion criteria were as follows: hepatitis B sur-face antigen (HbsAg) negative, antibody toHbsAg negative and no previous hepatitisvaccination. Exclusion criteria were acute orchronic inflammatory disorders or infec-tions, use of immunosuppressive drugs andmalignancy. 72 early hemodialysis patients(32 female, 40 male; age 62 B 8 years) gaveinformed consent. Patients were randomlyassigned to either conventional, i.e. poten-tially contaminated, dialysis fluid or ultra-pure dialysis fluid (produced on-line by one-step additional ultrafiltration using an endo-toxin-adsorbing polysulfone filter). All pa-tients received hemodialysis 3 times perweek (Kt/V of at least 1.2) utilizing volu-metrically controlled ultrafiltration (MTS4008, Fresenius, Oberursel, Germany) andhigh-flux polysulfone dialyzers (APS 650Asahi, Tokyo, Japan). The vaccinationschedule encompassed four doses of 40 Ìg ofrecombinant hepatitis B vaccine (Gen H-B-Vax D, Aventis Pasteur MSD, Leimen, Ger-many) given at 0, 1, 2 and 6 months in thedeltoid muscle. Antibody titers to HbsAgwere measured by the AUSAB IMX system(Abbott Laboratories, Chicago, Ill., USA)one month after the last dose. An antibodytiter of 10 IU/l or more represented serocon-version. The nonconverters were those whodid not reach an antibody titer of 10 IU/l ormore after completion of the vaccinationprogram. Laboratory tests [hemoglobin, in-tact parathyroid hormone (PTH), serum al-bumin], calculation of body mass index andEPO doses were determined as previouslydescribed [7]. Statistical significance was cal-culated for differences between means usingan unpaired t test and for observed/expectedfrequencies by means of ¯2 analysis (two-tailed Fisher’s exact test). A p value of lessthan 0.05 was considered significant. All val-ues in tables are expressed as means B SD.There were no statistically significant dif-ferences in age, gender, body weight, etiologyof renal disease, time on hemodialysis, Kt/V,hemoglobin concentration, number of pa-tients receiving EPO, intact PTH levels orparameters of nutritional status between thetwo study groups. The ultrapure dialysisfluid group, however, had significantly lowerCRP and IL-6 concentrations and need forrHuEPO (table 1).The overall seroconversion rate was 78%(56 out of 72 patients). Of these 56, 32patients were in the ultrapure dialysis fluidgroup and 24 patients were in the conven-tional mildly contaminated dialysis fluidgroup (89 vs. 67%; Fisher’s exact two-tailedtest, p = 0.045). The antibody titers obtained4 weeks after the last vaccination dose weresignificantly higher in the ultrapure dialysisfluid group (table 2). In 8 out of the 12 non-responding patients of the conventionaldialysis fluid group, seroconversion wasachieved by a second vaccination protocol(identical to the first) after switching to ultra-pure dialysis fluid.Our prospective randomized investiga-tion demonstrates that the use of ultrapureNumber of patientsRespondersUltrapure Dialysis Fluid and Response toHepatitis B VaccineNephron 2002;91:530–531 531dialysis fluid results in a higher seroconver-sion rate in response to intramuscular vacci-nation against hepatitis B virus in earlymaintenance hemodialysis patients. The dif-ferences in the rate of seroconversion be-tween the two groups could not be explainedby differences in the demographic or renalcharacteristics of the two study groups.Moreover, there was no evidence of under-dialysis, malnutrition, excessive hyperpara-thyroid hormone secretion or lower inci-dence of rHuEPO therapy. Our data indicatethat endotoxins derived from mildly con-taminated dialysis fluid are related to in-creased cytokine release by monocyte activa-tion and contribute to the uremia-associatedimmune defect.In the past, a number of measures havebeen taken to increase the seroconversionrate and duration of immunity against hepa-titis B virus vaccination in end-stage renaldisease patients [1]. They consisted of anincreased number of doses, increased anti-gen load per dose, different routes of admin-istration (intradermally vs. intramuscularly),addition of IL-2 to the protocol or vaccina-tion earlier in the course of progressive renalfailure. However, these different approacheshave not been successful in a reproducibleway. However, any decrease in the incidenceof hepatitis B virus infection depends exclu-sively on immunity to hepatitis B virus in-fection by successful vaccination [8]. Ultra-pure dialysis offers a safe and cost-efficientstrategy to increase the immunity to hepati-tis B in end-stage renal disease.In conclusion, the present investigationdemonstrated for the first time that a highconversion rate and high titer response tohepatitis B vaccination can be achieved inend-stage renal disease patients treated withultrapure dialysis fluid.Table 1. Patient characteristics at recruitmentUltrapure dialysisfluid groupConventional dialysisfluid group36 36Age, years 64B10 60B6Gender (female/male) 15/21 17/19BMI, kg/m2 24B3 26B5Etiology of renal disease (major type)Chronic glomerulonephritis 10 8Nephroangiosclerosis 8 7Diabetes mellitus 7 8Polycystic kidney disease 4 3Tubulo-interstitial nephritis 4 4Time on hemodialysis, months 6B2 5B3Kt/V 1.3B0.1 1.2B0.1Hemoglobin, g/dl 10.4B0.6 10.2B0.8Number of patients on rHuEPO 26 25Dose of rHuEPO, U/kg/week 62B4* 98B18Intact PTH, pg/ml 104B45 96B38Serum albumin, g/dl 4.0B0.3 3.8B0.2CRP, mg/dl 0.6B0.2* 1.2B0.4IL-6, pg/ml 14B4* 45B6BMI = Body mass index.* p ! 0.05 versus corresponding values in patients receiving conventional dialysis fluid.Table 2. Antibody titers after vaccination in responding patientsreceiving different dialysis fluidsUltrapure dialysisfluid groupConventional dialysisfluid group32* 24Antibody titer, IU/l 616B123* 268B108* p ! 0.05 versus corresponding values in patients receiving con-ventional dialysis fluid.References1 Rangel MC, Coronado VG, Euler GL, StrikasRA: Vaccine recommendations for patients onchronic dialysis. The Advisory Committee onImmunization Practices and the AmericanAcademy of Pediatrics. Semin Dial 2000;13:101–107.2 Sester U, Sester M, Hauk M, Kaul H, KohlerH, Girndt M: T-cell activation follows Th1rather than Th2 patterns in haemodialysis pa-tients. Nephrol Dial Transplant 2000;15:1217–1223.3 Girndt M, Sester M, Sester U, Kaul H, KöhlerH: Defective expression of B7–2 (CD86) onmonocytes of dialysis patients correlates to theuremia-associated immune defect. Kidney Int2001;59:1382–1389.4 Lonnemann G: The quality of dialysate: Anintegrated approach. Kidney Int Suppl 2000;76:S112–S119.5 Canaud B, Bosc JY, Leray H, Morena M, StecF: Microbiologic purity of dialysate: Rationaleand technical aspects. Blood Purif 2000;18:200–213.6 Sitter T, Bergner A, Schiffl H: Dialysate relatedcytokine induction and response to recombi-nant human erythropoietin in haemodialysispatients. Nephrol Dial Transplant 2000;15:1207–1211.7 Schiffl H, Lang SM, Stratakis D, Fischer R:Effects of ultrapure dialysis fluid on nutritionalstatus and inflammatory parameters. NephrolDial Transplant 2001;16:1863–1869.8 Lewis-Ximenez LL, Oliveira JM, MercadanteLA, De Castro L, Santa Catharina W, Stuver S,Yoshida CF: Serological and vaccination pro-file of hemodialysis patients during an out-break of hepatitis B virus infection. Nephron2001;87:19–26.

CF: Serological and vaccination profile of hemodialysis patients during an outbreak of hepatitis B virus infection.

Defective expression of B7–2 (CD86) on monocytes of dialysis patients correlates to the uremia-associated immune defect.

Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters.

F: Microbiologic purity of dialysate: Rationale and technical aspects. Blood Purif 2000;18:

Schiffl H: Dialysate related cytokine induction and response to recombinant human erythropoietin in haemodialysis patients.

T-cell activation follows Th1 rather than Th2 patterns in haemodialysis patients.

The quality of dialysate: An integrated approach. Kidney Int Suppl

Vaccine recommendations for patients on chronic dialysis.

http://epub.ub.uni-muenchen.de/16609/1/10_1159_000064303.pdf

Ultrapure dialysis fluid and response to hepatitis B vaccine

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