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Universal Hepatitis B Vaccination Reduces Childhood Hepatitis B Virus–Associated Membranous Nephropathy

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Hepatitis B Virus–Associated Membranous Nephropathy

WHAT’S KNOWN ON THIS SUBJECT: Hepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) is one of the most common extrahepatic manifestations of HBV infection. Its incidence closely parallels the incidence of HBV infection, particularly in chronic HBV carriers through horizontal transmission in the general population.

WHAT THIS STUDY ADDS: This study’s results reveal that the incidence of HBVMN significantly decreased in the 2 decades after implementation of the universal HBV vaccination program in Taiwan, possibly as a result of the significant reduction in HBV carriers via horizontal transmission.

abstract

OBJECTIVE:To compare the incidence of hepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) before and after uni-versal HBV vaccination and to identify factors underlying the change.

METHODS:This study included 471 hospitalized children with ne-phrotic syndrome (NS) and 488 long-term follow-up hepatitis B surface antigen (HBsAg)-carrier children. Horizontal transmission (negative maternal HBsAg status) of HBVMN and HBV was assessed, and the inci-dence of HBVMN was compared before and after initiation of the uni-versal HBV vaccination program started in 1984.

RESULTS:The frequency of HBVMN in children with NS was 11.6% be-tween 1974 and 1984, 4.5% bebe-tween 1984 and 1994, 2.1% bebe-tween 1994 and 2004, and 0% between 2004 and 2009. Similarly, the number of HBsAg-seropositive children with NS (mainly via horizontal infection) decreased after universal vaccination. The prevaccination frequency of HBV horizontal transmission in chronic HBsAg carriers from the gen-eral population was 36.5% compared with 5% in the postvaccination period. The incidence of HBVMN in these carriers revealed a parallel decline.

CONCLUSIONS:Our results revealed a significant decrease in the fre-quency of HBVMN in children with NS and in long-term follow-up HBsAg carriers. Children with HBVMN are primarily infected with HBV via hor-izontal transmission; thus, the significant reduction in horhor-izontal transmission in HBsAg-carrier children in the general population after universal HBV vaccination may explain the reduction of HBVMN in the vaccinated population. These findings confirm the effectiveness of HBV vaccination on reducing the incidence of HBVMN, possibly through a significant decline in horizontal HBV infection. Pediatrics 2011;128: e600–e604

AUTHORS:Min-Tser Liao, MD,a,bMei-Hwei Chang, MD,c

Fu-Gong Lin, MD,dI-Jung Tsai, MD,cYen-Wen Chang, MD,c

and Yong-Kwei Tsau, MDc

aDepartment of Pediatrics, Taoyuan Armed Forces General

Hospital, Taoyuan, Taiwan;cDepartment of Pediatrics, Hospital

and College of Medicine, National Taiwan University, Taipei, Taiwan; and Departments ofbPhysiology and Biophysics and dPublic Health, National Defense Medical Center, Taipei, Taiwan

KEY WORDS

HBV vaccination, HBV carrier, horizontal transmission, membranous nephropathy

ABBREVIATIONS HBV—hepatitis B virus MN—membranous nephropathy

HBVMN—hepatitis B virus–associated membranous nephropathy

NS—nephrotic syndrome HBsAg—hepatitis B surface antigen HBeAg—hepatitis B e antigen

NTUH—National Taiwan University Hospital

www.pediatrics.org/cgi/doi/10.1542/peds.2010-3137

doi:10.1542/peds.2010-3137

Accepted for publication May 18, 2011

Address correspondence to Yong-Kwei Tsau, MD, Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. E-mail: tsauyk@ntu.edu.tw

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2011 by the American Academy of Pediatrics

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Hepatitis B virus (HBV) infection is as-sociated with a variety of renal diseas-es; among them, membranous ne-phropathy (MN) is the most common renal manifestation in children.1 In

studies from South Africa and Taiwan, it has been suggested that most chil-dren with HBV-associated MN (HBVMN) present with steroid-resistant nephrotic syndrome (NS) contracted through hori-zontal HBV transmission.2–4

A nationwide HBV vaccination program launched in Taiwan in July 1984 re-duced the hepatitis B surface antigen (HBsAg)-carrier rate in children from 9.8% to 1.3% in 10 years,5and to1%

in 2 decades.6 The incidence of

HBV-associated hepatocellular carcinoma in children and adolescents also de-clined after HBV vaccination.7,8A

simi-lar decrease in the incidence of HBVMN in children would provide additional evidence that universal HBV vaccina-tion is effective and support the hy-potheses that HBV can cause child-hood MN. Thus, the goal of the present study was to compare the incidence of HBVMN in a tertiary medical center be-fore and after the implementation of the universal HBV vaccination pro-gram and to identify potential factors underlying the changes.

PATIENTS AND METHODS

Universal HBV Vaccination Program

The HBV vaccination program was launched in Taiwan in July 1984.9It

cov-ered only the neonates of HBsAg-carrier mothers between July 1984 and June 1986, but was extended to all neonates in July 1986. The program was then extended to preschool chil-dren in July 1987, to school chilchil-dren in 1989, and to adults in 1990.

Before July 1992, 4 doses of plasma-derived vaccine (Hevac B [Pasteur-Me’rieux, Lyon, France] or its equiva-lent derivative, Life-guard hepatitis B vaccine [Hsin-Chu, Taiwan]) were

ad-ministered at 0, 1, 2, and 12 months of age. After July 1992, 3 doses of recom-binant vaccine H-B-Vax II (5␮g/0.5 mL) (Merck Sharp and Dohme, Rahway, NJ) or Engerix-B (20␮g/1 mL) (SmithKline Beecham, Rixensart, Belgium) were administered at ⬍1 week, 1 month, and 6 months of age.

Furthermore, all pregnant women were screened for HBsAg and for hep-atitis B e antigen (HBeAg) if HBsAg was positive. There was 0.5 mL (100 IU) hep-atitis B immunoglobulin given within 24 hours after birth to neonates of HBeAg-positive or high-HBsAg-titer (re-ciprocal titer⬎1:2560 by reverse pas-sive hemagglutination test) carrier mothers.

The details of the vaccination program have been described previously.9 The

vaccination coverage rate was⬎90%.

Subjects

The study involved a medical chart re-view of children hospitalized with NS and long-term follow-up HBsAg-carrier children. The study protocol was ap-proved by the institutional review board of National Taiwan University Hospital (NTUH).

NTUH in Taipei is a tertiary referral center for pediatric nephrology ser-vices in the city of Taipei and its suburb in northern Taiwan. We retrospectively studied all children admitted with NS who were younger than 18 years of age between July 1974 and June 2009. The patients were enrolled into 4 groups according to the date of their hospital-ization: A (July 1974 –June 1984); B (July 1984 –June 1994); C (July 1994 – June 2004); and D (July 2004 –June 2009). Information was obtained from the hospital registry, and the medical charts were then reviewed. During these years, all patients with NS were screened for HBV as part of a standard protocol. Most patients with positive serum HBsAg received a routine renal biopsy. Their mothers were screened

for serum HBsAg if the result of their pregnancy screening was unknown. These data were available in the medi-cal charts of the HBsAg-seropositive nephrotic children.

The diagnostic criteria for HBVMN were (1) NS with the exclusion of lu-pus nephritis and other secondary nephropathy, (2) major pathologic changes characteristic of MN, and (3) positive serum HBsAg. The renal bi-opsy specimens were examined by us-ing light and electron microscopy and immunofluorescence, and MN was identified by the presence of classic subepithelial deposits in the glomeru-lar basement membrane. With Fab fragments of monoclonal antibodies,10

HBeAg was detected in the glomerular deposits in all these cases.

The presence of focal segmental glo-merulosclerosis, a common cause of steroid-resistant NS in children, was used as a control variable because its incidence was not expected to change during the study period.11,12

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tions of HBVMN if they had a renal bi-opsy at the onset of renal disease.

Maternal HBsAg status was obtained from the medical charts of the HBsAg-seropositive children with NS and the chronic HBsAg-carrier children. HBV horizontal infection was defined as an HBV carrier unrelated to recognized perinatal exposure (with negative ma-ternal HBsAg status),13in contrast to

HBV mother-to-infant transmission when the mother had a positive HBsAg status. The exact timing and route of horizontal infection are not known in most HBsAg-carrier children.2,10,13

Statistical Analyses

Between-group differences in fre-quency were examined using the ␹2

test, Fisher’s exact test, or the Wil-coxon signed rank-sum test as appro-priate. APvalue of⬍.05 was deemed statistically significant.

RESULTS

The present study included 471 chil-dren diagnosed with NS between July 1, 1974, and June 30, 2009. Of those, 35 patients were HBsAg-positive, and 25 (21 males and 4 females; mean age at onset 8.5 years) had biopsy-proven HBVMN. Most children with HBVMN (96%) were infected via horizontal transmission. In Table 1 the frequency is shown of HBVMN in patients with NS who were hospitalized before (group A, July 1974 to June 1984) and after (group B, July 1984 to June 1994; group C, July 1994 to June 2004; group D, July 2004 to June 2009) implementation of the universal HBV vaccination

pro-gram. After the vaccination program commenced, a significant decrease in the frequency of HBV carriers among hospitalized children with NS (primar-ily from horizontal infection) was noted. Furthermore, the incidence of children with HBVMN and patients with HBVMN infected via horizontal trans-mission showed parallel declines. In contrast, the frequency of focal seg-mental glomerulosclerosis in children with NS did not decrease during the period of observation (Table 1).

Of the 35 HBsAg-seropositive children with NS, 25 had HBVMN, 3 refused a renal biopsy, and the biopsy specimen was not adequate to provide a patho-logic diagnosis in 2 patients. In Table 2 the ratio is shown of HBVMN in HBV-carrier children with NS after exclu-sion of the 5 patients without a pathologic diagnosis. No significant difference in the frequency of HBsAg-seropositive nephrotic children was

found among the pre- and postvaccina-tion groups. The pathologic results of the renal biopsy for the other 5 HBsAg-carrier children revealed mesangial proliferation NS in 2, mesangiocapil-lary glomerulonephritis in 1, minimal-change NS in 1, and focal segmental glomerulosclerosis in 1.

The data from long-term follow-up of 488 HBsAg carriers (348 children be-fore and 140 children after initiation of the vaccination program in 1984) re-vealed 9 patients with HBVMN, and all of those infections occurred through HBV horizontal transmission. In Table 3 the transmission characteristics of the HBsAg-seropositive children are shown. More than one-third of the HBsAg carri-ers (36.5%) in the prevaccination group were infected via horizontal transmis-sion. However, horizontal transmission was not common (5%) in the postvac-cination HBsAg carriers. Nine children in the prevaccination group were

NS,n(%)a n(%)a Infection,n(%)a n(%)

A (July1974– June 1984) 138 20 (14.5) 20 (14.5) 16 (11.6) 16 (11.6) 10 (7.2)

B (July 1984–June 1994) 133 9 (6.8) 9 (6.8) 6 (4.5) 6 (4.5) 10 (7.5)

C (July 1994–June 2004) 140 5 (3.6) 4 (2.8) 3 (2.1) 2 (1.4) 11 (7.9)

D (July 2004–June 2009) 60 1 (1.7) 1 (1.7) 0 (0.0) 0 (0.0) 6 (10.0)

Wilcoxon signed rank-sum test was used to test the trend in incidence change between 1974 and 2009. Horizontal transmission infection is HBV infection with negative maternal HBsAg status.

aP.05.

TABLE 2 The Frequency of HBVMN in HBsAg-Seropositive Children With NS Between 1974 and 2009

Group Patients With HBsAg-Seropositive NS,n(N⫽30)

HBVMN,n(% Among NS) (N⫽25)

A (July1974–June 1984) 17 16 (94)

B (July 1984–June 1994) 7 6 (86)

C (July 1994–June 2004) 5 3 (60)

D (July 2004–June 2009) 1 0 (0)

TABLE 3 The Frequency of Horizontal and Mother-to-Infant Transmission of HBV and the Incidence of HBVMN in the Long-term Follow-up HBsAg-Carrier Children

Group (Birth Cohort) Total Horizontal Transmission,n(%)a

Mother-to-Infant Transmission,n(%)a

HBVMN,n(%)b

Prevaccination period 348 127 (36.5) 221 (63.5) 9 (2.6) Postvaccination period 140 7 (5.0) 133 (95.0) 0 (0.0)

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found to have HBVMN, whereas no chil-dren in the postvaccination group had HBVMN (P⫽.046). These findings dem-onstrate a significant decline in the oc-currence of HBVMN after initiation of the universal vaccination program.

DISCUSSION

HBVMN is 1 of the most common extra-hepatic manifestations of HBV infec-tion.1 The incidence of HBVMN closely

parallels the incidence of HBV infec-tion, particularly in chronic HBV carri-ers through horizontal transmission in the general population.1–4 The

patho-genic mechanism of HBVMN is un-known. However, a local process of im-mune deposit formation involving HBeAg seems to be the most likely mechanism.1,10The predominant

hori-zontal HBV infection in children with HBVMN in Taiwan in which vertical transmission from HBsAg-carrier mothers in the perinatal period is prevalent14is striking. The reason for

this phenomenon is not clear. If HBeAg plays an important role in the develop-ment of HBVMN,10these findings

prob-ably reveal a different immunopatho-logic response to HBeAg in the kidney for neonates and children. The univer-sal HBV vaccination program has re-duced the HBV carriage rate in chil-dren5,6 and has decreased the

incidence of childhood hepatocellular carcinoma in Taiwan.7,8Our results

re-veal a decline in the incidence of HBVMN in children with NS and in long-term follow-up HBsAg carriers. This finding not only confirms the effective-ness of HBV mass vaccination in de-creasing HBVMN, but also suggests a

close relationship between HBV infec-tion and childhood MN.

Xu et al15 examined the renal biopsy

data of Chinese children and reported that the incidence of HBV-associated glomerulonephritis in vaccinated chil-dren was significantly lower than that in nonvaccinated children. Further-more, this group demonstrated that the incidence of HBVMN in children has been decreasing annually since the in-troduction of the nationwide HBV vac-cination program in China in 1992; however, the decline was not statisti-cally significant until 2002. In a study of the South African vaccination pro-gram, Bhimma et al16observed no

ini-tial annual decrease in the incidence of HBVMN, but found a sharp drop in the disease 6 years after initiation of the nationwide HBV vaccination pro-gram. To investigate the difference be-tween these observations, we ex-tended our study period up to 25 years after administration of the vaccination in contrast to the short periods of ob-servation undertaken by the Chinese and South African groups. Our results reveal that the incidence of HBVMN has been significantly reduced in the 2 de-cades since the introduction of the uni-versal HBV vaccination program in Tai-wan, demonstrating the success of the HBV vaccination in reducing the hospi-tal incidence of HBVMN.

Moreover, our findings provide new data that may explain the decrease in the incidence of HBVMN. Previous re-ports have shown a reduction in HBV carriage and hepatocellular carci-noma after the introduction of the HBV vaccination program,5–8 and our

re-sults further suggest that the vaccina-tion directly protected the children against HBV infection, thus reducing the incidence of HBVMN.

Our results revealed a disproportion-ately low frequency of HBV carriage via horizontal transmission associated with a parallel decline of HBVMN after HBV vaccination in the long-term follow-up HBsAg-carrier children from the general population, highlighting the importance of HBV horizontal transmission in HBVMN. It is likely that in addition to direct protection of the children, the HBV vaccination de-creased the pool of household HBV car-riers, resulting in herd immunity. Thus, the vaccine produced a profound de-cline in HBV infection via a reduction in horizontal transmission6 as well as a

significant decrease in the overall inci-dence of HBVMN, which is closely re-lated to HBV horizontal infection.

CONCLUSIONS

Our results revealed a significant de-crease in the frequency of HBV carri-ers and of HBVMN in children with NS who received the HBV vaccination. Fur-thermore, we have demonstrated that the universal HBV vaccination pro-gram produced a significant decrease in horizontal transmission of HBV, ac-companied by a parallel decline in HBVMN in chronic HBsAg-carrier chil-dren from the general population. These findings confirm the effective-ness of the HBV vaccination in reduc-ing the incidence of HBVMN, possibly through a significant decline in hori-zontal HBV infection.

REFERENCES

1. Johnson RJ, Couser WG. Hepatitis B infec-tion and renal disease: clinical, immuno-pathogenetic and therapeutic consider-ations.Kidney Int. 1990;37(2):663– 676

2. Hsu HC, Lin GH, Chang MH, Chen CH. Asso-ciation of hepatitis B surface (HBs) anti-genemia and membranous nephropathy

in children in Taiwan.Clin Nephrol. 1983; 20(3):121–129

3. Bhimma R, Coovadia HM, Adhikari M. Hepa-titis B virus-associated nephropathy in black South African children.Pediatr Neph-rol. 1998;12(6):479 – 484

4. Lin CY. Clinical features and natural course

of HBV-related glomerulopathy in children.

Kidney Int. 1991;40 (suppl 35):S46 –S53 5. Chen HL, Chang MH, Ni YH, et al.

Seroepide-miology of Hepatitis B virus infection in children: ten years of mass vaccination in Taiwan.JAMA. 1996;(11):906 –908 6. Ni YH, Huang LM, Chang MH, et al. Two decades

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7. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med. 1997;336(26): 1855–1859

8. Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study.J Natl Cancer Inst. 2009;101(19): 1348 –1355

9. Chen DS, Hsu NHM, Sung JL, et al. A mass vaccination program in Taiwan against hep-atitis B virus infection in infants of hephep-atitis

FY. Membranous nephropathy in 52 hepatitis B surface antigen (HBsAg) carrier children in Taiwan.Kidney Int. 1989;36(6):1103–1107

11. Srivastava T, Simon SD, Alon US. High inci-dence of focal segmental glomerulosclero-sis in nephrotic syndrome of childhood. Pe-diatr Nephrol. 1999;13(1):13–18

12. Ozkaya N, Cakar N, Ekim M, Kara N, Akkok N, Yalcinkaya F. Primary nephrotic syndrome during childhood in Turkey.Pediatr Int. 2004;46(4):436 – 438

13. Hsu SC, Chang MH, Ni YH, Hsu HY, Lee CY. Horizontal transmission of hepatitis B virus

tical transmission of hepatitis B antigen in Taiwan.N Engl J Med. 1975;292(15):771–774

15. Xu H, Sun L, Zhou LJ, Fang LJ, Sheng FY, Guo YQ. The effect of hepatitis B vaccination on the incidence of childhood HBV-associated nephritis. Pediatr Nephrol. 2003;18(12): 1216 –1219

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DOI: 10.1542/peds.2010-3137 originally published online August 22, 2011;

2011;128;e600

Pediatrics

Yong-Kwei Tsau

Min-Tser Liao, Mei-Hwei Chang, Fu-Gong Lin, I-Jung Tsai, Yen-Wen Chang and

Associated Membranous Nephropathy

Universal Hepatitis B Vaccination Reduces Childhood Hepatitis B Virus

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DOI: 10.1542/peds.2010-3137 originally published online August 22, 2011;

2011;128;e600

Pediatrics

Yong-Kwei Tsau

Min-Tser Liao, Mei-Hwei Chang, Fu-Gong Lin, I-Jung Tsai, Yen-Wen Chang and

http://pediatrics.aappublications.org/content/128/3/e600

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by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

TABLE 1 HBV Seropositivity and HBVMN in Children With NS

References

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