Risk of idiopathic nephrotic syndrome among children with asthma: a
nationwide population-based cohort study
Chang-Ching Wei1,2, Cheng-Li Lin3,4, Te-Chun Shen2,5, Yu-Fen Li4
1Department of Nephrology, Children’s Hospital, China Medical University Hospital,
Taichung, Taiwan;
2College of Medicine, China Medical University, Taichung, Taiwan;
3Management Office for Health Data, China Medical University Hospital, Taichung,
Taiwan;
4Institute of Biostatistics, China Medical University, Taichung, Taiwan;
5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
Address correspondence to Chang-Ching Wei
China Medical University Hospital, Taichung, Taiwan;
College of Medicine, China Medical University, Taichung, Taiwan;
No2, Yu-Der Road Taichung 40402, Taiwan
Tel.: +886-4-22052121-4639; Fax: 886-4-2203-2798 E-mail: [email protected]
Running title: idiopathic nephrotic syndrome in asthma
Funding Source: The study was supported in part by China Medical University Hospital (DMR-103-036), Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002), China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092), NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039 -006), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan.
Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
Conflict of Interest: None.
ABSTRACT BACKGROUND
Although clinical and immunological studies have shown a possible link between
allergy and idiopathic nephrotic syndrome (INS), the nature of the relationship remains unclear. Asthma is the most common chronic allergic airway inflammation.
However, no study has used a longitudinal design with a population cohort to
investigate INS in children with asthma.
METHODS
Using nationwide claims data from 2000 through 2007, we randomly selected 251,698 asthma cases and 1,006,791 frequency-matched controls. Incidence rates of INS and
hazard ratios (HRs) were calculated.
RESULTS
The INS incidence was 3.36-fold greater in the asthma cohort than in the non-asthma control (9.26 vs. 2.76 per 100,000 person-years; 95% confidence interval [CI]: 2.65–
4.26). The HR for INS increased for those with more asthma-related medical visits per year, from 1.49 (95% CI, 1.06–2.11) for <3 visits to 15.7 (95% CI, 11.5–21.5) for 6 visits (trend test, p < 0.0001). The HR for INS slightly decreased during the follow-up period, from 3.41 (95% CI, 2.66–4.38) for ≤5.5 years to 2.90 (95% CI, 1.33–6.30) for
>5.5 years.
CONCLUSIONS
We conclude that children with asthma had an increased incidence rate of INS, and increased incidence rate correlated with asthma-related medical visits.
INTRODUCTION
Idiopathic nephrotic syndrome (INS) is among the most common chronic kidney diseases occurring in childhood (1). Numerous studies have associated INS with allergy risk of clinical and immunological features (2-11).In the 1950s through the 1970s, few anecdotal reports described patients who developed INS after allergic reactions to inhaled allergens, vaccinations, food, or insect stings (2-5).Since 1970, several case-control studies revealed that elevated serum IgE and atopic diathesis were more common in children with INS than non-INS controls (9,11-17). Recently, levels of T helper 2 (Th2)-associated cytokine such as interleukin (IL)-4 and IL-13 were found to be elevated in relapsing INS patients (18-21). Children with INS commonly have elevated serum levels of immunoglobulin E (IgE), which also plays a central role in allergic inflammation (11-16).Although clinical and immunological studies have shown a possible link between allergic diseases and INS for 50 years, human epidemiologic study using a large cohort to investigate the relationship between these disorders are lacking (2-11). Asthma is one of the most common allergic disease in childhood, affects a multitude of patients worldwide (22). It is unknown whether childhood onset asthma would increase the subsequent risk of INS.
Therefore, we conducted a nationwide, population-based cohort study to examine the hypothesis that asthma may have positive influence on the development of INS in
children.
RESULTS
A total of 251,698 subjects in the asthma cohort and 1,006,791 in the non-asthma cohort were enrolled in this study (Table 1). Most (67.6%) of the subjects were aged
≤5 years. The asthma cohort had more boys (59.4%), residents of highly urbanized areas (59.8 %), and white-collar parents (64.6%). Figure 1 illustrates the INS-free survival rate of the asthma cohort compared with that of the non-asthma cohort. The INS-free survival rate (Fig. 1A, log-rank test p < 0.0001) was significantly lower in the asthma cohort in the non-asthma cohort. The incidence of INS was 3.36-fold greater in the asthma cohort than in the non-asthma cohort (9.26 vs. 2.76 per 100,000 person-years; Table 2). The incidence of INS decreased as age increased in the non- asthma cohort, whereas the incidence increased when age was <2 years or >12 years in the asthma cohort. As age increased, the HR for INS increased from 2.89 (95% CI:
1.87–4.47) for subjects aged ≤2 years to 5.59 (95% CI: 1.77 – 17.6) for those aged
>12 years. A sex-specific analysis showed that the incidence rate of INS was greater for boys in both cohorts. Girls with asthma had a greater risk of INS than those without asthma (HR = 3.82; 95% CI: 2.59–5.64). The INS incidence decreased with urbanization in the asthma cohort. Urbanization level- and parental occupation- specific analyses showed that children with asthma had a significantly greater risk of
INS than those without asthma. Table 3 shows the association between the frequency of medical visits per year for asthma and the incidence of INS. Compared with the non-asthma cohort, the risk of INS in the asthma cohort increased from 1.49 (95% CI:
1.06–2.11) for those with ≤3 visits to 15.7 (95% CI: 11.5–21.4) for those with ≥6 visits (trend test, p < 0.0001). The risk was similar for both sexes. Asthmatic subjects with >6 medical visits had a significantly lower INS-free survival rate than the
subjects in the non-asthma cohort (Figure 1B; log-rank test, p < 0.0001).
Table 4 presents the risk of INS stratified by median follow-up duration. The risk of INS was greater among subjects in the asthma cohort followed up for ≤5.5 years (HR = 3.41; 95% CI: 2.66–4.38), whereas the risk of INS slightly decreased (HR = 2.90; 95% CI: 1.33–6.30) among the subjects with a >5.5-year follow-up duration.
However, the association between asthma status and follow-up period was not significant (p = 0.91).
DISCUSSION
To the best of our knowledge, this is the first population-based cohort study to investigate the incidence and risk of INS among children with asthma and compare them with the non-asthmatic controls. The results suggest that children with asthma were more likely to develop INS regardless of sex, age, urbanization of living area, or parental occupation. The annual incidence of NS in children in the USA and in Europe has been estimated to be 1–7 per 100,000 children (1, 23). The present study revealed an incidence rate of 2.76 of 100,000 person-years in the non-asthma cohort and a significantly increased incidence rate of 9.21 of 100,000 person-years in the asthma cohort. Although the definition of INS in current study was based on ICD9 codes, not on histopathology findings, the incidence rate of INS was comparable to previous results. In addition, the incidence rate ratio increased with more medical
visits for asthma and school-age children with asthma.
In the current study, the incidence rate of INS decreased as age increased in non- asthma controls, that ranged from 3.53 per 100,000 person-years for children aged ≤ 2 years to 1.89 per 100,000 person-years for children aged >12 years. As the peak incidence of childhood INS is known between 2 and 6 years of age, this was reflected by the higher incidence rate of INS in the younger children in the non-asthma controls. In contrary contrast, the incidence rate ratio (HR) of INS increased as age
increased in the asthma cohorts compared to non-asthma controls, that ranged from 2.89 (95% CI 1.87-4.47) for children aged ≤ 2 years to 5.59 (95% CI 1.77-17.6) for children aged >12 years. This result may be explained as follows. Asthma is currently considered a heterogeneous disease (24). Three main phenotypes have been identified in childhood asthma, including transient wheezing, nonatopic wheezing and IgE- mediated wheezing (allergic asthma) (24). Transient wheezing phenotype typically begins in early infancy and resolves between the ages of 3–5 years when their lung function improves. This phenotype is not commonly associated with atopy. Non- atopic wheezers wheeze during the first decade of life in association with respiratory viral infection, independent of allergic sensitization. This phenotype usually presents with less severe and less persistent wheeze. Only IgE-mediated wheezing has been identified as the classic asthma phenotype (persistent asthma) with higher disease severity. The proportion of allergic asthma is higher in older children (school aged children) (24). School aged children had a higher risk of INS, as allergic asthma is more prevalent in school-aged children, the higher prevalence of INS seen in this age group was therefore consistent with an association between INS and allergic asthma.
In addition, we also found children with more asthma-related visits per year had greater risk of INS, which may reflect the association between INS risk and uncontrolled airway inflammation, more severe and persistent phenotype of asthma or
more environmental triggers, such as allergen exposure or respiratory virus in asthma children (25,26). Moreover, greater risk of INS was observed within the first 5.5 years after asthma diagnosis. This may be explained as follows. First, childhood asthma may resolve over times, especially in phenotypes of transient wheezing and nonatopic wheezing. Second, older children have less frequency of viral respiratory tract infections. Third, the asthma related airway inflammation and respiratory symptoms may be controlled with adequate treatment over times. Overall, the implication of above findings suggests that a higher burden of clinically evident asthma symptoms is
associated with the risk of INS.
A possible link between INS and allergy has been reported for >50 years (2-10).
Before 1970s, only anecdotal reports described patients who developed INS after allergic events to certain allergens (2-5). Since 1970, several case-control studies revealed that elevated serum IgE were more common in children with INS compared to normal controls (9, 11-17, 28). Subsequently, the levels of T helper 2-associated cytokines such as interleukin (IL)-4 and IL-13 were found to be upregulated in relapsing INS patients (19-21). IL-4 and IL-13 are important in B-cell IgE isotype switching (29), and IL-13 is also involved in the modulation of eosinophilic inflammation and recruitment of monocytes and T cells (29). The release of IgE by B cells is a key step in the allergic inflammation cascade in allergic asthma (29).
Recently, MCD is proposed to be a podocyte disorder. Reiser et al. reported that CD80 (also known as B7.1), a receptor normally expressed on antigen-presenting cells (30,31), can be induced expression in podocytes which is associated with actin reorganization and the development of proteinuria (32,33). Then, Garin et al found children with biopsy proven MCD expressed CD80 in their podocytes and excreted high levels of CD80 in their urine during active nephrotic syndrome(34,35).
Following these results, they reported sera from MCD patients in relapse stimulates CD80 expression in cultured podocytes (36). In addition, increased CD80 expression in podocyte, glomerular CD80 and urinary excretion of CD80 can be induced by polyIC, a Toll-like receptor 3 ligand, and were associated with proteinuria (37). It implies the important role of CD80 in the pathogenesis of MCD. Asthma is a Th2- mediated disease (38). Airway dendritic cells activate naive T cells to generate Th2 cells through costimulatory molecules, CD80/CD86, interacting with CD28 and cytotoxic T lymphocyte–associated antigen 4 after allergic triggers in the inception of asthma (38-40). These common biologic mechanisms coexisting in both asthma and
INS may partly explain the complex relationship between these 2 diseases.
Certain limitations should also be noted when interpreting our findings. Detailed information on clinical conditions (e.g. serum IgE level, severity of allergic symptoms, and environmental exposures) was not available. Furthermore, our study
population included Chinese children; thus, our findings may not be generalizable to
populations from other countries.
CONCLUSIONS
This population-based cohort study revealed a significantly increased incidence rate of INS in children with asthma. Further research is needed to explore the role of allergic diseases in the development of INS and to devise a potential strategy for diagnosis and therapeutic disease intervention.
METHODS Data Sources
In this population-based, retrospective study, data were obtained from reimbursement claims of the universal National Health Insurance Research Database (NHIRD), which is maintained by the National Health Research Institute (NHRI). We obtained claims data from 1998 through 2008 for all insured children in Taiwan and randomly selected 50% of these children for the study. Details regarding the data set were previously described (27). The International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) was used to for diagnosis. Because of personal electronic data privacy regulations, the insurants’ records are encrypted before being released to researchers; thus, informed consent was not required in this study. Although the identification information was scrambled, this study also received approval from the Institutional Review Board at China Medical University Hospital
(CMU-REC-101-012).
Study Subjects
We identified patients aged <18 years with newly diagnosed asthma (ICD-9-CM codes 493 and 494) between 2000 and 2007 as the asthma cohort. Baseline was set as the date of asthma diagnosis. In this study, we used the method of “1: 4” matching to screen the control subjects, which can increase the statistical power and control the potential confounding. Hence, we randomly selected four non-asthmatic children for
every asthmatic child using frequency matching by sex, age (in 1-year intervals), urbanization of residential area, parental occupation, and baseline year. To improve diagnostic accuracy and avoid overestimation of incidence, children with INS or asthma were defined as at least three records with respective ICD-9-CM codes in any diagnosis field of inpatient claims or ambulatory claims. Since renal biopsy is usually not indicated for first presentation of childhood INS and empirical steroid treatment can be considered prior to kidney biopsy and in our previous study (27), the most common codings of children with INS was 581.9 (86.8%, unspecific pathologic lesion in kidney), and minimal change disease (MCD, 581.3). Therefore, INS was defined as ICD-9-CM code 581.3 and 581.9 in this study. Subjects with secondary nephrotic syndrome (NS), identified with an ICD-9-CM code 581.8, were excluded from the study. Subjects with a history of NS before baseline or those lacking information on age, sex, urbanization of residence area, or parental occupation were excluded. All subjects were followed up until INS diagnosis, death, loss to follow-up, withdrawal
from the insurance system, or the end of 2008.
Statistical Analysis
In this cohort study, we used the person-years to be the denominator for estimating the incidence rate under considering about the individual follow-up duration in the study.
The date of diagnosis of asthma was defined as the index date used to initiate follow-
up person-years measurement. The follow-up person-years were measured for each child from the index date to the date the children had the diagnosis of INS, or censored because of loss to follow-up, or death, or withdraw from the insurance system, or the end of 2008. Follow-up person-years were used to estimate the incidence density rates (IR) and hazard ratios (HRs) of INS for the asthma cohort, which were compared with those of the non-asthma cohort based on age, sex, urbanization, and parental occupation. Hazard ratio was determined using the Cox proportional hazard regression model. The Cox model was also used to estimate the HR of INS associated with the annual mean medical visits for asthma. Furthermore, we analyzed if the association varied with the length of the follow-up period after asthma diagnosis. We divided the median follow-up time into 2 periods after asthma diagnosis: ≤5.5 years and >5 years. A Kaplan–Meier plot showed the probability of INS-free survival, and the log-rank test was used to test the difference between the asthma and non-asthma cohorts. We performed all data analyses using the SAS statistical software (version 9.2 for Windows; SAS Institute Inc., Cary, NC). Kaplan–
Meier survival curves were plotted using the R software (version 2.14.1; R Development Core Team, Vienna, Austria). A 2-sided p-value <0.05 was considered statistically significant.
Acknowledgement
Chang-Ching Wei, and Te-Chun Shen conceptualized and designed the study, drafted the manuscript, and approved the final manuscript as submitted. Cheng-Li Lin
conducted the initial analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Chang-Ching Wei and Yu-Fen Li coordinated and supervised the data collection, critically reviewed the manuscript, and approved the
final manuscript as submitted.
The study was supported in part by China Medical University Hospital (DMR-103- 036), Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002), China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092), NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039 -006), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan.
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Figure legends
Figure 1. Probability of event free (onset of idiopathic nephrotic syndrome) survival (A)
In children with and without asthma. — Without asthma --- With asthma.
(B)
In different frequency of annual asthma-related medical visits. — Without
Asthma---With <4 asthma-related medical visits …With 4-6 asthma-related medical visits With >6 asthma-related medical visits
23
