Background
Chronic kidney disease (CKD) is a global public health burden because of its increasing incidence and prevalence and progressive nature to end-stage renal disease (ESRD) [
1]. Therefore, it is critical to identify risk factors for CKD to allow for effective surveillance. Beyond the traditional cardiovascular risk factors, infectious disease is an under-recognized risk factor for CKD [
2].
Hepatitis B affects approximately 350 million people worldwide [
3], and is associated with high mortality and morbidity [
4]. Apart from major liver complications, clinical evidence suggests that chronic HBV infection has a negative impact on renal function. HBV infection can lead to glomerulonephritis, even in the absence of cirrhosis [
5]. A small controlled prospective study indicated that individual estimated glomerular filtration rate declined by approximately −2 ml/min/y in 60 untreated HBV-infected patients without pre-existing renal disease, diabetes, or hypertension during the median follow-up of 24 months [
6]. A 2-year cross-sectional HARPE study indicated that renal abnormalities were highly prevalent in treatment-naïve patients with chronic HBV infection [
7]. A 2-year GLOBE study indicated that Telbivudine improved renal function in patients with chronic HBV infection [
8]. Together, these findings provide a theoretical basis for further research of the negative impact of HBV infection on renal function.
Chronic HBV infection is associated with increased insulin resistance [
9] and intensification of oxidative stress [
10], and these may contribute to renal injury [
11]. Therefore, it seems biologically plausible that HBV-infected subjects have increased risk for CKD. Our prior nationwide cohort study has demonstrated that untreated chronic HBV infection is associated with increased risk of ESRD [
12]. However, four cross-sectional studies [
9,
13‐
15] on the role of HBV in the development of CKD have had disparate results.
To date, there have been no cohort studies of the association of chronic HBV infection with risk of incident CKD, and it is unclear which HBV-infected patients are more likely to develop CKD. This is a crucial issue, because the management of patients with coexisting HBV infection and CKD is a challenge [
16] and the global burden of HBV infection and CKD is rising [
17]. Taiwan has high prevalence of CKD and HBV infection, and thus provides an ideal setting for study of the relationship of both diseases. In the present study, we conducted a 13-year nationwide cohort study to examine whether untreated chronic HBV infection is associated with increased risk of incident CKD using reimbursement claims data from the Taiwan National Health Insurance Research Database (NHIRD).
Discussion
To our knowledge, this is the first large nationwide cohort study to demonstrate an increased risk for CKD in untreated subjects with chronic HBV infection and simultaneously to determine the overall risk and age- and sex-specific risks of CKD. In this study, CKD was 2.58-fold more likely in HBV-infected subjects, relative to controls, after controlling for potential confounders and competing mortality. We also found that the risk of CKD in HBV-infected subjects was somewhat similar (range from 2 to 3) in men of any age and women under the age of 50. Noteworthily, HBV was not associated with CKD risk in women aged 50 or over. This information has important clinical implications for the design of surveillance programs that assess chronic HBV infection and CKD.
The association between chronic HBV infection and the development of CKD remains controversial. Two cross-sectional studies [
7,
15] demonstrated a positive association of HBV with CKD. A 2-year multicentric cross-sectional French study reported that CKD was highly prevalent in 268 treatment-native patients with chronic HBV infection [
7]. A cross-sectional Taiwanese study [
15] reported that HBV was associated with CKD in 416 HBV-infected adults; however, another cross-sectional Taiwanese study by the same research group reported that HBV was not associated with CKD or proteinuria in 5424 HBV-infected adults [
14]. Similarly, a cross-sectional study of 328 HBV-infected adults in Beijing [
13] reported that HBV was not associated with CKD or albuminuria. On the other hand, a cross-sectional Japanese study of 130 HBV-infected adults [
9] showed that HBV was not associated with albuminuria, but was inversely associated with CKD. The discrepancies among these studies may be attributed to the cross-sectional nature of their design, use of small sample sizes, and differences among the specific populations. Moreover, cross-sectional analyses cannot establish whether HBV infection preceded development of CKD. The present study was cohort design and used a large dataset, which afforded considerable statistical power and allowed tracking of incident CKD events over 13 years. We demonstrated an increased risk of CKD in untreated patients with chronic HBV infection that was independent of the presence of diabetes or cirrhosis.
Our HBV cohort tended to be younger and male, and to have a higher socioeconomic status, consistent with our prior research [
12]. On stratified analysis, we found significant associations of HBV with CKD risk in men of any age (especially under the age of 50) and women under the age of 50, similar to our prior research [
12]. Previous research reported that men have increased risk for development of CKD [
19], and that men have a lower clearance rate than females, so are therefore more susceptible to development of chronic HBV infection [
36]. Steatosis, a characteristic feature of chronic HBV infection, can increase lipid peroxidation and plasma inflammatory biomarkers [
33], and these may contribute to endothelial dysfunction and renal injury [
11]. The biggest sex difference in steatosis occurs in subjects younger than 50 years [
33]. Taken together, these results may explain our observations regarding the effect of age and gender on the risk for development of CKD following untreated chronic HBV infection.
The pathogenesis of HBV-mediated renal injury probably depends on interactions of the virus with the host and various environmental factors [
3]. Our results indicated that CKD ensued following untreated chronic HBV infection during the mean follow-up of 5.7 years, the interval of which was similar to 60 months in a case series [
5]. HBV-related renal injury is believed to be due to the deposition of immune complexes of HBV antigens and host antibodies [
3]. Other research also explored the possible effect of HBV on the development of nephropathy. HBV antigens (HBsAg, HBcAg, and HBeAg) and HBV DNA have been detected in glomeruli [
37] and tubular epithelia [
38], respectively. HBV DNA negative or positive sera of patients with chronic HBV infection promoted apoptotic damage in renal tubular cells via up-regulation of Fas gene expression, and these patients also had a higher circulating level of transforming growth factor-β, which is implicated in the potentiation of apoptosis and renal fibrosis [
39]. HBV is associated with increased insulin resistance [
9] and oxidative stress [
10], and these are implicated in the progression of nephropathy [
11]. However, only a small number of the 350 million HBV carriers develop glomerulonephritis [
4]. This indicates that chronic HBV infection by itself is insufficient for development of nephropathy, and that additional socio-environmental conditions, alterations in cell-mediated immunity, genetic susceptibility, and other factors are also important [
3]. This may explain the lower 13-year cumulative incidence rate (6.2 %) of CKD following untreated chronic HBV infection in this study. However, the HBV-positive population is increasing by 50 million per year, despite a marked increase in vaccination rates [
40]. Therefore, it is conceivable that the burden of CKD following chronic HBV infection is increasing.
The major strength of our study is that it was designed to reduce selection bias (due to use of a large nationwide population-based and highly representative sample with random sampling), environmental effects (due to the availability of socioeconomic indicators for all subjects) [
18], and detection bias (due to consideration of complete histories of the use of medical services) [
19]. In addition, the study population was well defined and follow-up was complete because our design relied on computerized registries that provided complete nationwide coverage. Therefore, our finding of increased risk of CKD in HBV-infected subjects is robust.
Some potential limitations should be noted.
First, misclassification of diseases may occur when an administration database is used. However, the NHI Administration established an audit and penalty system for quality monitoring to ensure accuracy of claims and minimize misclassification error [
41]. Moreover, both CKD and viral hepatitis are important health problems in Taiwan, so the government has strict guidelines for diagnosis [
42].
Second, some of our control subjects may have had sub-clinical HBV infection. However, if HBV is associated with CKD, this misclassification would lead to lower HRs, thus supporting the robustness of our findings.
Third, although nucleos(t)ide analogues for HBV patients have been covered under the NHI program since October 1, 2003, this reimbursement requires patients to fulfill certain criteria, such as two-fold increase or more in serum alanine aminotransferase level and HBV DNA titer greater than 2000 IU/mL [
43]. Some HBV patients may use self-paid nucleos(t)ide analogues before October 1, 2003 or when they do not fulfill reimbursed criteria, and thus may be inappropriately classified into the untreated cohort. These potential misclassifications may lead to an underestimation of the association [
22].
Fourth, the NHIRD lacks information on family history of kidney diseases, lifestyle, body weight, and laboratory data (
e.g., levels of serum HBV DNA and HBV genotype), which may contribute to CKD risk. Thus, this may lead to the difference of propensity score between both cohorts. Nevertheless, we added CCI score into the propensity analysis in order to reach the comparability of both cohorts and included CCI score and propensity score in multivariable and stratified analyses to control confounding in healthcare administrative databases [
12,
28,
29]. Although unmeasured confounders my still exist as with any observational study, we believe the methodology used in the present study is solid and robust.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
Conceived and designed the experiments: YCC. Contributed reagents/materials/analysis tools: SKH, YCS. Performed the experiments: YCC. Analyzed the data: YCC, SKH, YCS. Wrote the paper: YCC. Provided constructive opinions and suggestions: YCC, SKH, YCS, CYL. All authors read and approved the final manuscript.