Idiopathic nephrotic syndrome (NS) is the most common glomerulopathy in the pediatric population. Corticosteroids are the mainstay of therapy, and because many affected children experience relapsing disease, prolonged corticosteroid exposure is common. This ongoing requirement of corticosteroids in treating frequently relapsing NS (FRNS) and steroid-dependent NS (SDNS), which is less common for steroid-resistant NS (SRNS), increases the likelihood of ocular and systemic complications [1].

Steroid-induced systemic and ocular complications, such as cataracts, glaucoma, and ocular hypertension, are major concerns in the pediatric population but are often overlooked by treating physicians [2]. Steroid-induced posterior subcapsular cataract (SI-PSC) is well known to be associated with long-term steroid treatment, and different studies have revealed that it occurs in 1%–33% of patients receiving long-term steroid treatment [3-6]. Evidence suggests that long-term steroid exposure activates glucocorticoid receptors within epithelial cells of the lens, which alters normal gene expression. These alterations disrupt cell behavior, particularly migration and differentiation, which contributes to opacification of the posterior subcapsular lens. Multiple cellular disturbances have been implicated, including increased oxidative stress, reduced sodium-potassium adenosine triphosphatase (Na⁺/K⁺-ATPase) activity, and altered vimentin expression. Together, these changes promote epithelial-to-mesenchymal transformation of lens cells, a key step in SI-PSC formation [7].

Previous studies have demonstrated steroid-associated ocular complications, including cataract formation in children with NS, emphasizing the need for regular ophthalmological surveillance during prolonged corticosteroid therapy [8,9]. No consensus guidelines for screening schedules and management protocols currently exist in Pakistan. Furthermore, because studies on this subject in Pakistan are scarce, it is difficult to infer the exact prevalence of steroid-induced cataracts in the Pakistani population. The objective of this study was thus to investigate the prevalence and predictive risk factors of SI-PSC in children with NS in Pakistan.

A total of 150 patients with a median age of 9.0 years (IQR, 6.9–12.0 years) were enrolled in our study at the time of screening for cataracts. The female-to-male ratio was 1:1.8. The median cumulative corticosteroid dose was 18,546 mg (IQR, 10,404–29,292 mg), and the median duration of corticosteroid therapy was 48 months (IQR, 24–84 months) (Table 1).

Children receiving long-term corticosteroid therapy are vulnerable to ocular complications. In our study, the incidence of SI-PSC was 15.3%, which was comparable to that in a recent study [11]. However, the incidence varies considerably across different regions of the world [3-7]. Most of our patients had early lens changes; only two patients (8.7%) had advanced changes that necessitated lens replacement. This finding contrasts with a previous report in Japanese children, among whom 23% of patients with cataracts required lens replacement [12]. In our study, other visual complications were infrequent (4.7%), consistent with the 4.5% rate reported by Zhao et al. [13].

Prolonged steroid therapy carries a substantial risk of systemic complications. Previous studies have reported that at least 62% of patients experience one or more adverse effects, most commonly hypertension, diabetes, obesity, infections, fractures, and impaired growth [14]. The most common extraocular adverse effect of corticosteroids among our patients was obesity. This finding was consistent with that of Kalra et al. [10], who reported obesity as one of the most common adverse effects of corticosteroid treatment in NS. In our study, systemic hypertension was strongly associated with SI-PSC. This finding might be attributed to the simultaneous activation of mineralocorticoid receptors by corticosteroids in epithelial cells of the lens and peripheral vascular cells [15].

A male predominance of cataract was noted in our study, which reflects the higher proportion of male patients with NS in general. Previous studies have shown inconsistent results regarding the association between NS and gender [5,13]. For instance, a predominance among female patients has been reported by Toruan et al. [16]. Age also appeared relevant in our study; younger children were more frequently affected with NS, a finding similar to observations in other cohorts [3,17]. However, our findings contradicted the findings of Nakubulwa et al. [5], who reported a higher incidence of SI-PSC among children >10 years of age. Frequent relapse was associated with a higher occurrence of SI-PSC, which echoes the trends described in earlier investigations [5,18]. Similarly, SI-PSC formation was most prevalent in the early phase of corticosteroid therapy, found in nine (39.1%) of our patients within 2 years of beginning corticosteroid therapy. This finding was consistent with the results from previous studies [19,20]. Factors predictive of SI-PSC remain difficult to define. Our data did not reveal significant associations of SI-PSC with cumulative dose, therapy duration, age at screening, or NS subtype, and these findings corroborate those from several previous reports [3,7,13]. Conversely, other regional studies have demonstrated strong associations with cumulative corticosteroid exposure and duration [4,7,10,16,17]. Agrawal et al. [21] found that cumulative dose was predictive, whereas treatment duration was not. Lee et al. [22] also reported inconclusive results regarding dose–response relationships. Sight-threatening ocular complications, along with other systemic adverse effects of long-term corticosteroid treatment, are common and significantly worsen the quality of life of the affected children [23,24]. Global data regarding the association of SI-PSC with cumulative corticosteroid dose, treatment duration, and other related factors remain highly inconsistent, rendering the relationship inconclusive. Therefore, investigators must consider additional factors that might influence individual susceptibility to cataract development. Genetic predisposition to SI-PSC in patients who have undergone renal transplantation was discovered by Fournier et al. [25], who reported that human leukocyte antigen Cw3 antigen levels correlated strongly with cataract formation. In this context, James et al. [26] demonstrated that during long-term corticosteroid treatment, specific transcriptional changes in gene expression occur within epithelial cells of the lens, which lead to abnormal cell proliferation. Zhou et al. [27] analyzed these transcription factors and identified potential genes that could be targeted for the prevention and treatment of glucocorticoid-induced cataract formation. Shi et al. [28] conducted advanced research to develop genetically based screening biomarkers associated with abnormal lens cell behavior and proliferation that increased individual susceptibility to lens opacities. Together, these insights suggest a multifactorial process wherein genetic, biochemical, and treatment-related factors converge to influence cataract susceptibility.

This study had several limitations. The short (6 months) observation period may have led to underestimation of cataract prevalence, as longer corticosteroid exposure and relapse patterns influence risk. Cataract development is multifactorial, and factors beyond cumulative dose could not be fully explored. Subgroup- and dose-stratified analyses were not performed because of the limited sample size and overlapping steroid doses. Ophthalmologic assessment was limited to slit-lamp examination, without evaluation of visual acuity and intraocular pressure. In addition, the only corticosteroid studied was prednisolone because other corticosteroids were not readily available.

Because SI-PSC often occurs in children treated for NS, routine ophthalmologic screening should be a standard component of their long-term care. Genetic susceptibility of individuals to SI-PSC might serve as a potential predictive factor and warrants further research.