Methods
Literature search
A literature search was done in February 2009. We searched for articles in PubMed and Embase. Relevant thesaurus terms and/or free-text terms for NS, epidemiology, cohort, retrospective and prospective study types were used. The searches were limited to the age group of 0–18 years and articles written in English, French, German, Dutch or Arabic. Inclusion criteria were all studies on NS that describe the incidence or epidemiology of NS in children 0–18 years in a nationwide or a hospital population.
Study design
The registry was started by the working group Idiopathic Nephrotic Syndrome, which consists of all paediatric nephrologists in The Netherlands in collaboration with the Dutch Pediatric Surveillance Unit hosted by The Netherlands Institute of Applied Science [Nederlands Signalerings Centrum Kindergeneeskunde (NSCK) at TNO, Leiden]. The NSCK is a voluntary national registry used by paediatricians to report various rare or new paediatric disorders and is one of 13 paediatric surveillance units in the world. Our study includes all children with newly diagnosed NS between 1 January 2003 and 1 January 2007. The case definition was any child <18 years with symptoms of NS defined as oedema, proteinuria (> 3 + on a dipstick), low serum albumin (<25 g/l) and normal renal function (serum creatinine in normal range for age when not volume depleted), without signs of systemic disease or macroscopic haematuria. The study was conducted in The Netherlands. All paediatricians in The Netherlands received a monthly blue card or Web link to an electronic card and were asked to return the card to the NSCK if they had a patient with a newly diagnosed NS. A questionnaire was sent to the registering paediatrician, which had to be returned to the Idiopathic Nephrotic Syndrome Working Group at the VU University Medical Center, where data were analyzed. When the questionnaires were incomplete, secondary phone calls and visits were carried out to try to complete them as far as possible. The coded questionnaires showed only initials, birth date and a part of the postal code. Medical ethical approval was thought not to be necessary due to the anonymous submission of the questionnaires. Informed consent forms were filled in by the parents of the patients. The number of responding paediatricians working in The Netherlands in 2003–2006 was 694 (mean) divided over 96 paediatric practices and eight university centres with a paediatric nephrology department.
Statistical analysis
The incidence of NS was calculated by relating the number of de novo NS patients to the number of children <18 years who were living during the 4 years of registration in the several provinces separately and in The Netherlands as a whole. The population numbers were extracted from the official statistics organ (Statistics Netherlands). These data can be found on the Web site and are freely available. Male:female ratio and median and mean age of the affected children were calculated from the available data. Pearson’s chi-square test was used to compare the incidences of the years and the provinces. A p value <0.05 was considered to be significant.
Discussion
The articles found in the literature review relate mostly to retrospective studies from around the world (Table
1). They describe different populations, backgrounds and a large variability in genetics. All these factors influence the comparability.
Historic retrospective study dates are reported from 1946 onwards (Erie County, OH, USA) till 1998 (Yorkshire, UK) [
5‐
13]. From the three prospective studies, one was from France (1985–1992) (Bouissou et al. ESPN 1993) and the other two from New Zealand and Australia in 1998–2004 (Table
1) [
3,
14]. The retrospective articles merely studied a hospital population or part of the population in a city, region, county or several districts. Thus, results from a wide variety of populations make them difficult to compare. A retrospective incidence in different age groups was reported as 1.8–11.6:100,000 patients/year [
5‐
13]. The two more recent prospective population studies in New Zealand and Australia were quite similar to the one in The Netherlands, and they also used the Paediatric Surveillance Unit to register all new cases of NS [
3,
14]. To our knowledge, the Dutch study is the largest and longest prospective study so far.
We registered all children with NS in The Netherlands for 4 years. The NSCK shows a response rate of 92.75% [
4]. Beyond that, we extensively explored possible nonregistered cases by regular announcements, personal telephone calls and e-mail contacts with nearly all Dutch paediatricians. We believe that we have registered all children with newly diagnosed NS in The Netherlands, so defining a reliable incidence. The three prospective studies revealed an incidence of 1.15–2.1 per 100,000 [
3,
14] children per year, which was comparable with the Dutch incidence of 1.52 per 100,000 children per year in 2003–2006. In contrast to the studies in Australia [
3] and France (Bouissou et al, ESPN 1993), our Dutch population showed a higher male preponderance, whereas the study in New Zealand [
13] showed an even higher male:female ratio (2.5:1). In comparison with the retrospective studies the male:female ratio of 2.04:1 is similar to the ones found in the study by Schlesinger et al. in Erie County, OH, [
8] and Wyatt et al. in the eastern part of Kentucky in the United States [
11]. The other studies show a lower male:female ratio [
5‐
7,
9,
10,
12,
13]. Even if the older children (>15 years) were left out, compared with the registration in Australia [
14], this predominance still existed. In the general population in The Netherlands, the male:female ratio is 1.05:1,
and in Australia this ratio is also 1.05:1; thus, this does not explain the difference between the two countries. Wong et al. do not explain why they think that the ratio found in their study differs from the rest of the studies [
14]. We do not have a thorough explanation for the difference in male:female ratio between the studies. Boyer et al. [
15] described that patients with FSGS were older at diagnosis and that the female gender was slightly overrepresented in comparison with children with another aetiology of NS. In our study, the male predominance was present in nearly all age groups.
The definition of NS was similar in all studies in relation to symptoms and laboratory findings. However, the inclusion criteria of ethnic background and age were not comparable. Our registry included all children aged from 0 to 18 years. After we completed the database, children with congenital NS were excluded because of the difference in pathogenesis. During the 4 years of registration, four children with congenital NS were excluded. According to this registration, the incidence of CNS in The Netherlands was one child with CNS per year. Exclusion of CNS is the reason that some studies started registration from 3 months onwards.
Wong et al. [
13], Srivastata et al. [
10] and McKinney et al. [
7] reported a median age of, respectively, 4.5, 5.0, 4.5 (SSNS) and 6.0 (SRNS) years; mean age differed from 3.4 to 7.4 years [
7,
10,
13]. Some studies did not mention a median or mean age. The median age found in our study was 3.9 years and is lower than the ones found in the reviewed literature, where mean age appeared to be 5.1 years. Due to the fact that some ethnic groups seem to be more prone to developing FSGS (e.g. African American and Indian children) rather than MCNS [
16], retrospective studies might be biased, because they are mostly based on medical charts in one centre or region of a country. In our prospective study, a question about the ethnic background was not included. Ethnicity will be explored in a follow-up study planned to begin soon. Some paediatricians spontaneously mentioned the ethnicity of their patient in the questionnaire. For 32 patients, ethnicity is not known (14%). With the gathered information in the questionnaires so far and the informed consent forms, we were able to divide the rest of the patients into Western and non-Western ethnic group. The majority of patients (60.1%) were of Dutch nationality (from western origin). The non-Western patients (25.9%) came from a wide variety of countries divided over all continents.
The mortality rate in this study is preliminary because it only shows the number of patients who died at presentation. To our knowledge, other series do not report mortality at presentation. This means that NS is still a serious disease, even at presentation. Two other authors published mortality rates, but all in earlier years, and were not comparable with idiopathic NS as stated in the definition [
8,
13].
In conclusion, our study showed an incidence in the same range as the few other prospective studies. Idiopathic NS in children in the Dutch population is as much a rare disease as in any other country in the world. We found a statistically significant male:female ratio in this study, which is not fully explained but is in line with one other prospective study that described a similar or even higher male:female ratio in their cohort. Given the rarity of the disease and the lack of understanding of the exact pathogenesis of NS in children, more research is needed, preferably done in international collaboration studies.