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NDT Advance Access originally published online on December 8, 2007
Nephrology Dialysis Transplantation 2008 23(5):1615-1620; doi:10.1093/ndt/gfm829
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Influence of low birth weight on minimal change nephrotic syndrome in children, including a meta-analysis

Nynke Teeninga1, Michiel F. Schreuder1,2, Arend Bökenkamp1, Henriette A. Delemarre-van de Waal3 and Joanna A.E. van Wijk1

1 Department of Paediatric Nephrology, VU University Medical Centre, Amsterdam 2 Department of Paediatric Nephrology, Erasmus MC–Sophia Children's Hospital, University Medical Centre, Rotterdam 3 Department of Pediatric Endocrinology, VU University Medical Centre, Amsterdam, The Netherlands

Correspondence and offprint requests to: Michiel F. Schreuder, Department of Paediatric Nephrology, Erasmus MC–Sophia Children's Hospital, University Medical Centre, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. Tel: +31-10-4636535; Fax: +31-10-4636801; E-mail: m.f.schreuder{at}erasmusmc.nl



   Abstract
Top
 Abstract
Short summary
 Introduction
 Results
 Discussion
 References
 
Background. Low birth weight (LBW) has been shown to lead to a low nephron endowment with subsequent glomerular hyperfiltration. Additional renal disease can therefore be expected to have a more severe course. Minimal change nephrotic syndrome (MCNS) is a common chronic illness in childhood. As it is important to be able to predict prognosis in MCNS, we set out to study the effect of LBW on MCNS in a cohort of patients from our University Medical Center, and performed a meta-analysis.

Methods. A retrospective chart review of children with MCNS treated at the VU University Medical Center was performed, identifying 55 patients of whom 4 had LBW. The meta-analysis was performed using Review Manager (The Cochrane Collaboration).

Results. The meta-analysis consisted of 201 patients (25 LBW, 176 normal birth weight). More LBW patients were classified as steroid resistant [odds ratio (OR) 6.97 (95% confidence interval [CI] 2.02–24.04), P = 0.002]. The number of relapses per year of follow-up was significantly higher in the LBW patients with MCNS [weighted mean difference 0.93 (95% CI 0.71–1.15) relapse per year, P < 0.0001]. MCNS patients with LBW were significantly more likely to be treated with cyclosporine [OR 4.4 (95% CI 1.7–11.8), P = 0.003] or cytotoxic agents [OR 4.2 (95% CI 1.8–10.2), P = 0.001] during the course of their disease, and they had a higher chance of developing several complications during the follow-up period, including hypertension.

Conclusions. This meta-analysis provides support for an adverse effect of LBW on the course and prognosis of MCNS in children, which can aid clinicians and parents in assessing the expected clinical course.

Keywords: children; intrauterine growth restriction; low birth weight; meta-analysis; minimal change nephrotic syndrome



   Short summary
Top
 Abstract
 Short summary
Introduction
 Results
 Discussion
 References
 
Low birth weight is associated with a low nephron endowment and glomerular hyperfiltration, which may lead to a more severe course of additional renal disease. This meta-analysis provides support for an adverse effect of low birth weight on the course and prognosis of childhood minimal change nephrotic syndrome in children, which can aid clinicians and parents in assessing the expected clinical course.



   Introduction
Top
 Abstract
 Short summary
 Introduction
Results
 Discussion
 References
 
Nephrotic syndrome (NS), defined as the combination of heavy proteinuria, hypoalbuminaemia and oedema, is considered a common chronic illness in childhood [1]. Several diseases are associated with NS, but minimal change NS (MCNS) is the most common idiopathic form. About 60–80% of children with MCNS will show relapses, and ~40% will have more than five relapses. Corticosteroids are used for treatment of the initial episode and subsequent relapses. Complications of NS and its therapy may be serious, especially if the clinical course shows frequent relapses with the need for prolonged periods of corticosteroid use. Recent investigations have focussed on determining potential risk factors that could predict such an unfavourable course of NS in children, but no suitable prediction is possible yet [1].

Intrauterine growth retardation (IUGR), diagnosed on the basis of a low birth weight (LBW), has been shown to increase the risk of developing diseases later in life, such as obesity, insulin resistance, cardiovascular disease and hypertension [2]. The kidneys appear to be extremely susceptible to IUGR and are often found small in proportion to body weight. Several studies in animals and humans have described a reduced number of nephrons after IUGR [3–7]. The reduced number of nephrons results in an inborn decreased glomerular filtration surface area, while renal blood flow per glomerulus is increased in an attempt to maintain a normal overall glomerular filtration rate. According to the hyperfiltration hypothesis as put forward by Brenner and co-workers, this leads to glomerular hypertension and hypertrophy, which causes systemic hypertension and glomerular damage resulting in albuminuria and glomerulosclerosis [8–11]. Therefore, IUGR can eventually lead to impairment of renal function [12].

Additional renal disease in hyperfiltrating kidneys can be expected to have a protracted course and poorer prognosis. LBW has been found to be of influence on IgA nephropathy [13], membranous nephropathy [14], diabetic nephropathy [15] and MCNS in children [16–18]. It has been proposed that the haemodynamic changes occurring in IUGR kidneys, leading to glomerulosclerosis, have a negative effect on podocyte function [11]. Podocytes are affected in (childhood) NS and are thought to be in part responsible for the excessive protein loss [1]. Even though all reports on MCNS in children show a deleterious effect of IUGR, the described results differ among these three studies [16–18]. A possible explanation can be the low number of patients included, especially with LBW (only five to eight per study).

In order to shed more light on the effect of LBW on the presentation and clinical course of NS in children, we present data on a cohort of children with MCNS from our centre and perform a meta-analysis on the previously published studies [16–18].

Subjects and methods
To study the effect of LBW on NS in children, we performed a retrospective chart review of children with MCNS, referred to the Department of Paediatric Nephrology of the VU University Medical Centre between May 1992 and January 2005. The diagnosis of MCNS was based on clinical findings in combination with the response to corticosteroid treatment, or was based on renal biopsy.

MCNS was defined as proteinuria >40 mg/m2/h, plasma albumin <25 g/l and the presence of oedema. Renal biopsy was performed in children who did not respond adequately to initial corticosteroid treatment and/or who had frequent relapses. Remission was defined as the absence of proteinuria for at least three consecutive days. A relapse was scored when proteinuria reoccurred during three consecutive days. Frequent relapses were defined as two or more relapses within 6 months of initial response or four or more relapses within any 12-month period. A patient was considered to be corticosteroid dependent when relapses occurred while the corticosteroid dose was decreased, or within 2 weeks of corticosteroid cessation. Corticosteroid resistance was characterized by proteinuria continuing for over 8 weeks, in spite of full dose administration.

The initial episode was treated with oral prednisolone 60 mg/m2 of body surface area daily for 6 weeks, followed by prednisolone 40 mg/m2 on alternate days for another 6 weeks. Relapses were treated with prednisolone 40– 60 mg/m2 daily until remission, followed by a gradually tapered dose, administered on alternate days. In some of the steroid dependent children, the prednisolone dose was maintained at a low dose on alternate days in between relapses. Additional therapy was necessary with some children to manage oedema and high blood pressure, and consisted of diuretics, beta-blockers, ACE inhibitors and calcium antagonists. If the clinical course of the NS was considered to respond inadequately to initial therapy or steroid usage led to too many side effects, additional treatment with cytotoxic agents (cyclophosphamide) or ciclosporin was started. Complications of immunosuppressive therapy in MCNS children, i.e. urinary tract infection, peritonitis, sepsis and pneumonia, were scored.

Birth history, including birth weight and gestational age, was obtained from interviews with the parents, which has been shown to be reliable [19,20]. LBW was defined as a birth weight below the 10th percentile for gestational age, gender and maternal parity [21]. A recent consensus statement suggests that IUGR should be reserved for children with a birth weight and/or birth length at least 2 SD below the mean for gestational age [22]. However, in order to use the same definition as previous reports on the influence of IUGR on MCNS [16–18], we decided to use this classification but use LBW instead of IUGR. Children were excluded from the study if birth weight and/or gestational age were unavailable. Only single births were included. Patients with a follow-up period of <1 year were also excluded, as the clinical course was one of our points of study.

The group of patients from our centre consisted of 55 children, diagnosed with MCNS at the median age of 3.2 [interquartile range (IQR) 2.4–5.2] years. The study group consisted of 41 boys and 14 girls.

Statistical analysis
As the cohort of LBW patients with MCNS only consisted of four children, no statistical comparisons were performed apart from the meta-analysis. Parameters with a normal distribution are expressed as means (standard deviation) and parameters that did not have a normal distribution are presented as median (IQR). SPSS was used as a statistical analysis system.

Statistical analysis for the meta-analysis was performed with Review Manager (RevMan) version 4.2 for Windows (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2003), which enables the calculation of a pooled effect size of weighted mean differences for continuous data, and odds ratio (OR) for dichotomous data of the included studies. The weight (%) is based on study size and variation of the data (SD). Heterogeneity of the combined studies was assessed with this computer program and considered significant if P < 0.1. Other statistical differences were considered significant if P < 0.05 (two-tailed).



   Results
Top
 Abstract
 Short summary
 Introduction
 Results
Discussion
 References
 
Patients from VU University Medical Centre
Among the 55 children with MCNS included in this study, 4 had LBW, with a median birth weight of 2825 (2550–2925) g. Fifty-one children had a normal birth weight [controls: median 3200 (3000–3500) g, P < 0.001 versus LBW] and all children were born at term. Children with LBW were of similar age at the onset of MCNS as children with normal birth weights [median 3.0 (2.9–3.6) years and 3.3 (2.4–5.2) years, respectively].

Data from the clinical course of MCNS are shown in Table 1. As the achievement of remission within 7–9 days has been attributed to be indicative of fewer relapses [1], we calculated the number of patients within each group to fulfil this criterion based on the available data from the charts.


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  		Table 1 Clinical course of 55 children with minimal change nephrotic syndrome treated at the VU University Medical Centre with normal and low birth weights

 
Meta-analysis
A meta-analysis was performed using the data from our centre together with published data from Zidar et al. [16] (5 IUGR and 35 control patients), Sheu et al. [17] (8 IUGR and 42 control patients) and Na et al. [18] (8 IUGR and 48 control patients). As can be seen from Table 2, no differences in the age at onset, or the duration of follow-up, was present between the LBW and control groups. As there was significant heterogeneity between the studies (P = 0.04), no meta-analysis of serum albumin at diagnosis could be performed. Serum cholesterol was significantly higher in the LBW group at diagnosis (Table 2).


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  		Table 2 Meta-analysis of various continuous data, comparing low birth weight and control children with minimal change nephrotic syndrome

 
No significant differences were seen in the number of patients without any relapses (Table 3 and supplementary Figure 1). More LBW patients were classified as steroid resistant, but no differences in steroid dependence could be determined due to significant heterogeneity (P = 0.02). As can be seen in Table 4, both the absolute number of relapses and the number of relapses per year of follow-up were significantly higher in the LBW patients with MCNS. Even though the absolute number of relapses showed significant heterogeneity, this provides support for an adverse effect of LBW on the course of MCNS in children.


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  		Table 3 Meta-analysis of various dichotomous data, comparing low birth weight and control children with minimal change nephrotic syndrome

 

Figure 1
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  		Fig. 1 Weighted mean difference with 95% confidence interval of the separate studies and pooled data for the absolute number of relapses during follow-up (a) and the number of relapses per year during follow-up (b) between minimal change nephrotic syndrome patients with low birth weight and normal birth weight.

 

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  		Table 4 Absolute number of relapses (a) and number of relapses per year (b) in low birth weight and control children with minimal change nephrotic syndrome

 
Table 5 (and supplementary Figure 2) shows that MCNS patients with LBW were significantly more likely to be treated with cyclosporine (OR 4.42, P = 0.003) or cytotoxic agents (OR 4.24, P = 0.001) during the course of their disease. This may explain the fact that LBW patients underwent significantly more often a renal biopsy (OR 3.84, P = 0.009; Table 3). Table 3 also shows the higher chance of developing several complications during the follow-up period for the LBW MCNS patients, including hypertension. No differences in the incidence of urinary tract infections or peritonitis were found (data not shown).


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  		Table 5 Use of cyclosporine (a) and cytotoxic agents (b) in low birth weight and control children with minimal change nephrotic syndrome

 

Figure 2
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  		Fig. 2 Odds ratios with 95% confidence interval of the separate studies and pooled data for the number of patients that used cyclosporine during follow-up (a) and the number of patients that used cytotoxic agents during follow-up (b), comparing minimal change nephrotic syndrome patients with low birth weight and normal birth weight.

 


   Discussion
Top
 Abstract
 Short summary
 Introduction
 Results
 Discussion
References
 
We conclude that an LBW has an adverse effect on the clinical course of NS in children. Our results are based on an analysis of patients from our centre and a meta-analysis of all previously published studies on the effect of birth weight on the course of MCNS [16–18]. A possible explanation may be that IUGR leads to an inborn deficit of nephrons [3–7]. The remaining nephrons are subject to hyperfiltration [8–11], which has a negative effect on glomerular podocytes [11], known key roleplayers in the pathophysiology of NS in children [1].

NS in children can have serious implications for a child's health if the disease takes on a severe form, with frequent relapses and a necessity for high doses and prolonged courses of corticosteroids [1]. It is therefore important to identify factors that can be helpful to predict the clinical course of NS. However, only few clinical and laboratory parameters have been found to be of value: predictive factors of an improved course are age at onset between 4 and 8 years, good responsiveness to steroids and a low number of relapses within the first 6 months of onset [1]. Based on our meta-analysis, LBW is another non-immunologic factor that influences the course of MCNS. However, the pathways that cause MCNS to be adversely affected by LBW are not yet clear. A recent study in IUGR rats with an induced acute mesangioproliferative glomerulonephritis showed a higher expression of inflammatory and profibrotic markers, leading to more glomerulosclerosis and more extracellular matrix deposition [23]. This anti-Thy-1.1 glomerulonephritis normally shows spontaneous resolution within 2 weeks. Therefore, the authors suggest that the histological findings may be indicative of a transition from an acute form into a chronic-progressive form of glomerulonephritis [23]. A possible explanation for the poorer course of MCNS in LBW children may also be that it has turned into a chronic disease with glomerulosclerosis, based on more structural damage. However, studies into the pathophysiology of MCNS after IUGR are necessary to shed more light on this issue.

Age under 4 years has been shown to be associated with more relapses [1]. In our meta-analysis, we observed no differences in the mean age at the onset of MCNS between the groups. No data on the number of relapses within the first 6 months could be subtracted from the previous reports [16–18], so this factor was unavailable for meta-analysis. In our cohort, no statistically significant difference in the number of relapses within the first 6 months was noted. The time from onset to first relapse was shorter in LBW children, but this did not reach statistical significance either. However, this may indicate that they have a tendency to relapse earlier, which may explain the significantly higher number of relapses during the follow-up period that is indicative of an unfavourable course.

Considering an inadequate reaction to corticosteroids to indicate worse outcome of NS in children, we hypothesized that the LBW group would show a longer period of time to remission, and more corticosteroid dependence and resistance. No differences were found between the two groups regarding steroid response. However, a significantly higher percentage of steroid resistance was found in the LBW group. Also, LBW children with MCNS were more often treated with additional medication, like cyclosporine and cytotoxic drugs. In addition, a higher incidence of renal biopsy in LBW children with MCNS was found, even though a previous study has shown that steroid sensitivity rather than the histological picture is the major determinant of the prognosis in childhood NS [24]. Differences in presentation and clinical course of NS thus result from other causes, as they cannot be explained by underlying histology.

Because MCNS is treated with high doses of corticosteroids, children with MCNS are at risk for complications that occur as a result of a suppressed immune system [1]. Children experiencing frequent relapses or having poor responses to corticosteroids will probably be exposed to prolonged courses of steroids or have higher cumulative doses. As LBW children fall into this category, we hypothesized that they could be at a higher risk for occurence of complications of treatment. Our meta-analysis supports this hypothesis in that pneumonia and sepsis were seen more frequently in LBW patients, even though no differences were noted in peritonitis or urinary tract infections.

IUGR is associated with hypertension in the general adult population [2]. A possible explanation for the association can be found in the low nephron endowment that is associated with IUGR [3–7] and has been described in patients with hypertension [25]. An increased blood pressure could therefore become more apparent in individuals with LBW and additional renal disease. Zidar et al. demonstrated an increased risk for arterial hypertension in IUGR children with IgA glomerulonephritis [13]. In our meta-analysis, hypertension did indeed occur more often in LBW children.

A limitation of our study population could be that it is a somewhat selected one, since the majority of children were referred to our (tertiary) Pediatric Renal Center as a result of frequent relapses or inadequate response to corticosteroids. In our study, 32 of 55 (58%) patients with MCNS needed some form of additional therapy, which is higher than expected in an average group of children with MCNS [1]. Also, our method of obtaining information about birth history differed from previous reports [16–18], i.e. by interviewing the parents instead of acquiring this information from medical records. In the Netherlands, a large proportion of children are born at home and no national registry with birth data was available. However, previous studies have established that parental recall of birth weight and gestational age is sufficiently accurate for clinical and epidemiological use [19,20].

In conclusion, we have shown that LBW has an adverse effect on the course and prognosis of MCNS in children, which can aid clinicians and parents in assessing the expected clinical course.



   Acknowledgments
 
We would like to thank Monique Koot for excellent administrative support.

Conflicts of interest statement. None declared.



   References
Top
 Abstract
 Short summary
 Introduction
 Results
 Discussion
 References
 

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Received for publication: 17. 8.07
Accepted in revised form: 24.10.07


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