Pediatric nephrotic syndrome is defined by the presence of nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia [
1-
5]. Children with nephrotic syndrome often require prolonged corticosteroids or immunosuppressive therapy. Visual threatening condition, namely cataract-induced and steroid-induced glaucoma, are known to occur after long-term steroid therapy in children [
6,
7]. Neurosensorial retinal detachment and macular edema have been reported to cause acute visual loss in patients with nephrotic syndrome [
8-
12].
Recent studies have reported that children with nephrotic syndrome had a slight increase in macular thickness and reduction in retinal vessels density [
13,
14]. This has been attributed to the hypoalbuminemia induced fluid retention seen in this syndrome. However, the association of proteinuria with macular thickness has not been adequately investigated. Our study aims to add to the literature by comparing the mean macular thickness in children with nephrotic syndrome and healthy children and correlating it with visual acuity and proteinuria levels.
Materials and Methods
We conducted a comparative cross-sectional study of 66 children aged 6 to 17 years who attended the Ophthalmology and Pediatric Clinics at Hospital Universiti Sains Malaysia and Sultanah Aminah Hospital from May 2017 to April 2018. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the Research and Ethical Committee of the School of Medical Sciences, Universiti Sains Malaysia (No. USM/JEPeM/16110498) and the Medical Research and Ethics Committee, Ministry of Health of Malaysia (No. NMRR-16-2233-33332). Written informed consent was obtained from all the parents or legal guardians, and verbal assent was given by the recruited children.
Nephrotic syndrome was diagnosed as a clinical syndrome of massive proteinuria characterized by presence of edema, proteinuria of >40 mg/m
2/hr (>1 g/m
2/day), or an early morning urine protein creatinine index of >200 mg/mmol (>3.5 mg/mg, hypoalbuminemia of <25g/L, hypercholesterolemia, urine albumin excretion >40 mg/m
2/hr, or urine dipstick of ≥2+ for 3 consecutive days) [
1,
4].
All pediatric patients who were diagnosed with primary nephrotic syndrome and attended both centers were recruited based on the inclusion and exclusion criteria. The inclusion criteria for the group with nephrotic syndrome were patients diagnosed as having primary nephrotic syndrome in relapse undergoing treatment, refractive error (in spherical equivalent) within ±4.00 diopters, and clear ocular media. Inclusion criteria for the control group were healthy children, refractive error (in spherical equivalent) within ±4.00 diopters, and clear ocular media. Exclusion criteria for both groups were patients with established retinal and macular disease, congenital glaucoma, optic nerve disease, and ocular trauma.
Visual acuity was recorded in the logarithm of the minimum angle of resolution (logMAR) unit. A complete examination of anterior and posterior segments was performed for both groups. The following data was documented and analyzed: age, sex, duration of disease, number of relapses, presenting visual acuity, intraocular pressure (IOP), lens status, and proteinuria level.
The right eye was selected for measurement of macular thickness. The examinations were performed on children with nephrotic syndrome within 24 hours after confirmation of diagnosis and hospital admission by a pediatric nephrologist. Macular thickness measurements were taken using spectral domain optical coherence tomography using the Cirrus HD OCT (Carl Zeiss Meditec).
Macular image was taken based on macular map protocol according to the Early Treatment Diabetic Retinopathy Study. This consists of three concentric circles with diameters of 1 mm (central fovea), 3 mm (inner macula), and 6 mm (outer macula). There were nine subfields in these circles that included the central fovea, the superior inner macula, the inferior inner macula, the nasal inner macula, the temporal inner macula, the superior outer macula, the inferior outer macula, the nasal outer macula, and the temporal outer macula.
Data was analyzed using the IBM SPSS ver. 24.0 (IBM Corp). All continuous variables were described using mean ± standard deviation, whereas categorical data as frequency (%). Independent t-test analysis was used to compare mean macular thickness between children with nephrotic syndrome and the control group. A spearman correlation test was used to determine the correlation between mean macular thickness with visual acuity and level of proteinuria. A p-value less than 0.05 was considered statistically significant.
Results
Fig. 1 shows a patient with acute lapse. The present study showed the mean age of children with nephrotic syndrome was 10.55 ± 1.79 years old and that of the control was 10.20 ± 2.21 years old. The mean duration of disease was 3.21 ± 1.83 years. The mean number of relapses was 3.45 ± 1.06. Children diagnosed with nephrotic syndrome in relapse had a proteinuria level of 2+ (63.6%) and 3+ (36.4%). Of the children with nephrotic syndrome, 27.3% had hypertension and 3.0% had hyperlipidemia. The majority of the children received corticosteroids only or a combination of corticosteroids and levamisole/cyclosporine. All data are illustrated in
Table 1.
The mean visual acuity was 0.08 ± 0.12 logMAR in children with nephrotic syndrome, and 0.03 ± 0.09 logMAR in the control group. There was a significant difference in mean visual acuity and IOP between children with nephrotic syndrome and control group (
p = 0.049 and
p < 0.001, respectively). Posterior subcapsular cataract were documented in 21.2% of the children with nephrotic syndrome. The above data are presented in
Table 2. No cases of serous retinal detachment, macular edema, or retinal pigment epithelial detachment were documented.
Fig. 2A-2H shows the macular OCT in a healthy patient and patient with proteinuria.
Table 3 presents the mean macular thickness of both groups. There was no statistically significant difference between the mean macular thickness in the children with nephrotic syndrome and control in all subfields of macular region (
p = 0.890). There was a significant correlation between visual acuity and mean macular thickness in the superior outer macula (r = −0.41,
p = 0.019), the nasal outer macula (r = −0.41,
p = 0.019) and the inferior outer macula (r = −0.40,
p = 0.021).
The correlation between the mean macular thickness and visual acuity is shown in
Table 4. Two of our patients with visually significant cataracts were not included in this analysis. There was a trend of thicker mean macular thickness in children with proteinuria 3+ compared to proteinuria 2+. However, there was no statistically significant difference in any subfields of macular areas between children with different level of proteinuria (
p > 0.05). The data is presented in
Table 5.
Discussion
The published literature is confined to clinical pictures of children with nephrotic syndrome [
7,
15,
16]. All children received corticosteroids for more than 1 year during their illness, and 84.8% of them were on corticosteroids during data collection. Cataracts were observed in 21.2% in our study. Two of our patients had visually significant cataracts, and the resulting visual acuity was worse than 0.4 (based on logMAR). The remaining patients had visual acuity ranging from 0 to 0.3 logMAR. In our study, children with nephrotic syndrome had significantly higher IOP compared to the control group, although the levels were still within normal range. This strongly suggests that regular monitoring is mandatory, even though visual field assessments would be challenging in children.
We observed no significant difference in the mean macular thickness (
p > 0.50) between children with nephrotic syndrome and the control group. Beside those with visually significant cataracts, none of our patients had visual symptoms or had signs of macular edema or serous retinal detachment during clinical examination. We postulate that this was probably due to prompt treatment with diuretics after admission to the wards. De Benedetto et al. [
8] and Izzedine et al. [
10] reported that their patients with nephrotic syndrome who developed macular edema sustained a complete resolution and restoration of normal retinal anatomy after being treated with diuretic therapy.
Corticosteroids, which form the mainstay of treatment in nephrotic syndrome, also play a very important role in determining macular thickness. Systemic corticosteroids inhibit formation of both prostaglandins and leukotrienes, which confer local vasoconstrictive properties in the retinal layer. These vasoconstrictive properties lead to a reduction in intracellular and extracellular edema, and thus decreasing in sequestration of fluids into the interstitial space. Therefore, for nephrotic syndrome in relapse the combination of systemic corticosteroids and diuretic therapy in treatment has a synergistic effect in the rapid reduction of interstitial systemic fluids. In addition, macular edema in nephrotic syndrome might not manifest clinically because the anatomical and functional integrity of endothelium and blood-retinal barrier are relatively intact in children [
17,
18].
In contrast to our findings, Zhang et al. [
13] reported slightly different data. They observed a significantly thicker macular layer in children with nephrotic syndrome and hypoalbuminemia. Zhang et al. [
13], therefore, presumed that the above phenomenon could be related to the retention of liquid in the retina and choroid due to hypoproteinemia. This can be is explained by increased choroidal interstitial fluid, resulting in a decrease in colloid osmotic pressure in patients with nephrotic syndrome and hypoalbuminemia. The pressure difference between the choroid and retina may lead to reduced flow of fluid from the retina to the choroidal layer, culminating accumulation in the retina and subretinal region [
13]. In our study, however, we found no significant difference in macular thickness between children with proteinuria and the controls. We postulate that proteinuria may not be a strong parameter that affects the mean macular thickness in children with nephrotic syndrome. However, more studies may shed further light on the relationship between nephrotic syndrome and macular thickness.
We observed that the mean thickness of the outer macula layers was significant correlated with visual acuity in children with nephrotic syndrome (
p < 0.05). This may reflect the normal profile of the ganglion cell-inner plexiform layer (GCIPL) thickness as described by Mwanza et al. [
19]: the GCIPL of the superior hemisphere of macula was thicker than the inferior hemisphere, and the nasal sector of GCIPL was significantly thicker than the temporal area of the macula. In healthy Asian adults, increased macular and GCIPL thickness have been associated with better visual acuity and visual function [
20].
The strength of our study is its evaluation of macular thickness changes associated with proteinuria in a population free of systemic disease which might affect retinal thickness measurements. However, children with nephrotic syndrome often experience multiple relapses and remissions, which may be associated with subclinical macular edema and may result in chronic changes in retinal thicknesses, thus confounding measurements. In addition, we cannot exclude the possibility that varying responses to corticosteroids in prospective studies evaluating these changes over time and the effect of the various pharmacological therapies in this disease may improve our understanding of these processes.
In conclusion, the mean macular thickness was similar in children with nephrotic syndrome and control group. There was a correlation between outer macular layer thickness and mean visual acuity. Mean macular thickness has no correlation with the level of proteinuria.