Steroid induced ocular complications in idiopathic nephrotic syndrome: a cross sectional single center study

Objective: To screen children receiving steroids to identify ocular complications and their prevalence. Method: The cross-sectional study was conducted at the Paediatric Nephrology and Ophthalmology departments of the Sindh Institute of Urology and Transplantation, Karachi, from May to October 2022, and comprised patients who received at least 1500mg cumulative steroid dose for a minimum of 3 months. They were screened for steroid-sensitive or steroid-resistant nephrotic syndrome. Ocular examinations, including visual acuity, intraocular pressure, slit-lamp biomicroscopy, lens examination and fundus evaluation, were performed. Data was analysed using SPSS 22. Results: Of the 124 subjects with mean age 8.15±2.03 years (range: 6-12 years), 64(51.6%) were boys. Steroid-sensitive nephrotic syndrome was present in 97(78%) cases. The mean cumulative steroid dose was 3999.31±1564.22mg. Overall, 36(29%) children developed ocular complications. Blood pressure, number of relapses and the duration of treatment were significantly associated (p<0.05). Conclusion: Refractive errors were the most frequent side effects/complication seen among children with nephrotic syndrome who received prolonged corticosteroids.


Introduction
Nephrotic syndrome is the most common glomerular disease in children with relapsing and remitting course. 1 Steroids play a central role in the treatment of nephrotic syndrome, whether it is the initial episode or a relapse.Similarly, for the synergistic effect, steroids are inevitably added with other immunosuppressive medications, like cyclophosphamide, levamisole, mycophenolate mofetil and calcineurin inhibitors. 2 Extended use of steroids leads to complications, like Cushingoid features, obesity, hypertension, myopathy, osteoporosis and avascular necrosis. 2The reported ocular complications are keratitis, macular pigment changes, ptosis, mydriasis, atrophy of the skin of eyelid, increased intraocular pressure (IOP), and exacerbations of bacterial and viral infections. 3,4ised IOP is the most commonly studied entity in patients with steroid exposure.6][7] Steroids-induced ocular hypertension is caused by resistance to aqueous outflow at the level of the trabecular meshwork.Elevated IOP resulting from steroids is usually observed while receiving therapy, and, in most cases, it returns to normal once steroids are stopped. 8udies have described the incidence of cataract in patients treated with systemic steroids to be 18% and 20%. 4,7spite detrimental ocular complications, including complete vision-loss, there are no recommendations of surveillance for early detection and management of these adverse effects.Studies recommended a detailed eye examination before the start of treatment. 9,10e Paediatric Nephrology clinic at Sindh Institute of Urology and Transplantation (SIUT) in Karachi has observed a significant number of nephrotic children.Many of these children do not show symptoms and are unable to recognise any decline in their vision.As a result, these complications may remain unnoticed unless they undergo a proper evaluation.Detecting these serious complications early on will be beneficial in minimising additional health problems.
The current study was planned to screen children receiving steroids to identify ocular complications and their prevalence.

Patients and Methods
The cross-sectional study was conducted at Paediatric Nephrology and Ophthalmology departments of SIUT, Karachi, from May to October 2022.The sample comprised all children with steroid-sensitive nephrotic syndrome (SSNS) or steroid-resistant nephrotic syndrome (SRNS) who fulfilled the inclusion criteria of age 6-12 years, disease duration 3-24 months and being on steroid therapy for at least the preceding 2 weeks.
Children with history of ocular trauma, surgery, congenital eye abnormalities, glaucoma and systemic microvascular diseases, like diabetes, were excluded.Also excluded were patients who were unable to cooperate during ocular examination.
After taking informed written consent from the parents of the enrolled subjects, patient's demographic and clinical data along with treatment details were extracted from the hospital records.A detailed eye examination was performed by an ophthalmologist which included best corrected visual acuity (BCVA) using a Snellen chart, and IOP measurement using the air puff (Topcon CT800 Japan).Raised IOP was confirmed by applanation tonometer.The normal IOP varies with age, and some studies have proposed a formula for normal paediatric IOP; IOP = 0.71 x age (years) + 10, up to the age 10 years. 11fter the age of 10 years, it is considered adult IOP.The cornea and anterior chamber were assessed using slitlamp bio-microscopy (MW50D model).Lens was examined and the fundi were examined after dilatation with 1% tropicamide eye drops.Visual fields were also examined.
Data was analysed using SPSS 22. Continuous variables were presented as means +/-standard deviation (SD), while categorical variables were expressed as frequencies and percentages.Effect modifiers for age and gender were controlled through stratification.Post-stratification chi-square test was used for comparison.P<0.05 was considered significant.
The mean relapse rate was 2.48±1.05 in each patient.None of the children received cumulative dose of steroids <1500mg, while 75(60.6%)received the highest cumulative dosage >3000mg during the treatment.The mean cumulative dose of steroids was 3999.31±1564.22mg.The relationship between different age groups and cumulative steroid dose was assessed (Figure 1).
The mean duration of treatment was 12.46±7.9months with 54(43.5%)children receiving treatment for >12 months.Blood pressure, number of relapses and the duration of treatment were significantly associated, with patients under treatment for <6 months being more likely to have elevated and stage I blood pressure compared to the patients treated for >6 months (p<0.005).Also, children with treatment duration >1 year had a higher prevalence of relapses (3-4) compared to the children under treatment for <12 months (p=0.002).
There were no cases of stye or chalazion, and none of the children showed bacterial infection, keratitis, anterior chamber abnormalities, anisocoria, vitritis, or oedema, such as central serous chorioretinopathy.

Discussion
In the current study, ocular examination of 124 nephrotic children who had been on steroids for at least 2 weeks and had received a minimum of 1500mg of steroids was carried out.Ocular complications were seen in one-third of these children, with most of them having refractive errors.Ocular side-effects are an unavoidable accompaniment of steroid use in nephrotic patients.
There was no significant difference with respect to gender, with 64(51.6%)boys and 60(49%) girls, which was also seen in an Egyptian cohort. 13In the current cohort, there were 9(25%) cases of error of refraction in either of the eyes, followed by blepharitis in 6(16.7%)patients.In contrast, the Egyptian cohort reported a higher incidence of refractive errors in 38(79.2%)patients, followed by blepharitis in 26(54.2%)and hypertrichosis in 25(52.1%). 13onversely, an African study reported ocular complications in 80% participants, with 71% patients having hypertrichosis of the eye lashes, 56% refractive errors, 37% allergic conjunctivitis and 10% each having blepharitis and bacterial conjunctivitis. 6Hypertrichosis was not reported in any of the current patients, which could be reflective of ethnic variations.

frequency of complication in nephrotic syndrome
In the present study, 2(5.6%) cases of glaucoma, 1(2.8%) of raised IOP in both eyes, and 2(5.6%) cases of posterior subcapsular cataract (PSCC) were also noted.An Indian study 14 , in contrast, found a greater percentage of patients with PSCC and raised IOP at 26.8% and 10.9% respectively.Surprisingly, ELsharkawy MM et al. 13 did not report any case of raised IOP or PSCC despite reporting a high percentage of refractive errors in 79.2% patients.
Research has proposed that fluctuating IOPs associated with steroid use stretch the globe and temporarily lengthen the axial axis, resulting in the most common refractive error of myopic astigmatism. 15However, Kyrieleis et al. 16 studied this phenomenon and found no causal link.A dysfunctional immune system is attributed to both the nephrotic state and steroid treatment. 5esultantly, repeated eye infection in the form of mucopurulent conjunctivitis was seen in 12(25%) patients in the study by ELsharkawy MM et al. 13 It perhaps reflects colonisation of the conjunctival mucosa due to an immunocompromised state.In contrast, only a single case of viral conjunctivitis was reported in the current study.
The mean cumulative dose of steroids for each patient in the current study was 3999.31±1564.22mgover a mean treatment duration of 12.46±7.90months.Gaur et al. 14 reported an accumulative corticosteroid dose of 338.9mg/kg, but the median duration of follow-up was longer at 4.95 years.Similarly, ELsharkawy MM et al. 13 documented a cumulative steroid dose use of 7250±1110mg over a mean time period of 2.6±1.6 years.8][19] A longer treatment duration with greater dose of steroids could explain the greater frequency of complications in these studies [17][18][19] .
In the current study, presence of hypertension was statistically significant in children under treatment for <6 months.This could be attributed to the oedematous state at the onset of disease or a relapse. 20A family history of essential hypertension was also found contributory by Keshri et al. but this is yet to be explored in Pakistani children. 21arly one-third of the current patients developed 3-4 episodes of relapse and this was significantly associated with a longer duration of treatment.As reported by Williams et al. 22 up to 80% of children with steroid sensitive nephrotic syndrome experience at least one relapse, and more than half of these children go on to developing a frequent relapsing and/or steroid-dependent course as was also seen in the current study.This would necessitate frequent exposure to corticosteroids and the side effects that come with it.
The current study has its limitations.It was a crosssectional study in which patients could not be serially assessed for development or resolution of ocular complications and outcomes.Moreover, it was a singlecentre study which does not represent the nephrotic population of Pakistani children at large.Multi-centre studies are recommended to assess the ophthalmological complications associated with prolonged steroid use.

Conclusion
Ocular complications were noted in one-third of the nephrotic syndrome patients studied, with a predominance of refractive errors of the eyes.Regular and timely assessment of children on steroids can help prevent and manage ocular complications for an improved quality of life Disclaimer: None.

Figure- 1 :
Figure-1: Relationship between different age groups and cumulative steroid dose.

Table - 1
: Baseline demographics and clinical characteristics.