Vitamin D Status and Clinical Outcomes in Pediatric Idiopathic Nephrotic Syndrome: A Prospective Observational Study from North India

Abstract

Background:

Idiopathic nephrotic syndrome frequently presents with Vitamin D deficiency due to urinary losses of Vitamin D-binding protein. The relationship between Vitamin D status and clinical outcomes remains incompletely understood.

Objective:

To evaluate Vitamin D status in children with idiopathic nephrotic syndrome and assess its association with remission time and relapse patterns.

Materials and Methods:

This prospective observational study (October 2022-March 2024) included 60 children aged 1–14 years with idiopathic nephrotic syndrome at a tertiary care center in North India. The study involved 60 patients divided into supplemented (Group I, n = 30) and control (Group II, n = 30) groups. Vitamin D levels were measured at presentation, after 1 month, and at relapse events. Primary outcomes included baseline Vitamin D status, time to remission, and 6-month relapse rates.

Results:

All participants demonstrated Vitamin D deficiency (51.7%) or insufficiency (48.3%) at presentation. Children with relapses had significantly lower baseline Vitamin D levels compared to those with initial episodes (8.76 ± 2.75 vs. 15.78 ± 2.04 ng/mL, P < 0.001). Despite this association, time to remission was similar between groups with adequate versus inadequate Vitamin D status (11.60±3.2 vs 11.93 ± 3.4 days, p = 0.994). Six-month relapse rates showed no significant correlation with baseline Vitamin D levels (r = −0.18, P = 0.17).

Conclusions:

Vitamin D deficiency is universal in pediatric nephrotic syndrome, with lower levels observed in relapsing disease. However, Vitamin D status does not appear to significantly influence time to remission or short-term relapse patterns, suggesting its role may be primarily nutritional rather than therapeutic.

INTRODUCTION

Idiopathic nephrotic syndrome represents the most common chronic glomerular disorder in children, with global incidence rates ranging from 1.15 to 16.9 per 100,000 children annually.[1] The condition is characterized by massive proteinuria (>1 g/m²/day), hypoalbuminemia (<3 g/dL), and generalized edema, primarily resulting from altered glomerular permeability.[2]

The pathophysiology involves complex immune dysregulation, with T and B lymphocytes playing pivotal roles alongside podocyte dysfunction.[3] While corticosteroids remain the cornerstone of treatment according to KDIGO 2021 and IPNA 2020 guidelines,[4,5] the condition frequently presents with various complications, including Vitamin D deficiency.

Vitamin D deficiency commonly complicates idiopathic nephrotic syndrome due to excessive urinary loss of Vitamin D-binding protein, a phenomenon that contributes to hypocalcemia, elevated parathyroid hormone levels, and subsequent metabolic bone disease.[6] Beyond its classical role in calcium homeostasis, Vitamin D possesses significant immunomodulatory properties, inhibiting pro-inflammatory cytokines while promoting anti-inflammatory responses.[7]

Emerging evidence suggests that Vitamin D influences immune cell function through its receptor and the enzyme 1-α-hydroxylase, which are expressed in most immune cells.[8] Vitamin D modulates B-cell proliferation, suppresses T-cell proliferation, and promotes a shift from Th1 to Th2 phenotypes while facilitating T regulatory cell induction.[9] These immunomodulatory effects theoretically position Vitamin D as a potential therapeutic adjunct in nephrotic syndrome management.

Previous investigations have demonstrated that Vitamin D supplementation effectively improves 25(OH) D concentrations in nephrotic syndrome patients.[10,11] However, the relationship between Vitamin D status and clinical outcomes, particularly remission time and relapse patterns, remains unclear. This knowledge gap has important implications for clinical practice, especially regarding the routine use of Vitamin D supplementation in nephrotic syndrome management.

The present study aims to evaluate Vitamin D status in children with idiopathic nephrotic syndrome and assess its association with clinical outcomes, including time to remission and relapse patterns over a 6-month follow-up period.

MATERIALS AND METHODS

Study design and setting

We conducted a prospective observational study at the department of pediatrics in a tertiary care center, serving western UP in North India. The study period extended from October 2022 to March 2024, following institutional ethics committee approval.

Participants

Children aged 1–14 years presenting with generalized edema, heavy proteinuria (>1 g/m²/day or 40 mg/m²/h), and hypoalbuminemia (serum albumin <3 g/dL) were eligible for inclusion. Exclusion criteria encompassed congenital nephrotic syndrome, steroid-dependent or steroid-resistant cases, atypical presentations (hypertension, active urinary sediment), biopsy-proven non-minimal change disease, normal baseline Vitamin D levels, concurrent tuberculosis or anti-tuberculous therapy, recent Vitamin D supplementation, or parental refusal of consent.

Clinical management

All participants received standard corticosteroid therapy according to established protocols:

• Initial episodes: Prednisolone 2 mg/kg daily (maximum 60 mg) for 6 weeks, followed by 1.5 mg/kg (maximum 40 mg) on alternate days for 6 weeks

• Relapses: Prednisolone 2 mg/kg daily until proteinuria became trace or negative for three consecutive days, followed by 1.5 mg/kg on alternate days for 4 weeks.

Data collection and definitions

Daily monitoring included weight measurement, fluid intake assessment, 24-h urine output, blood pressure recording, and bedside urine protein testing. Standard definitions were employed:[12]

• Remission: Urinary protein excretion <4 mg/m²/h or nil/trace proteinuria by dipstick for three consecutive days

• Relapse: Urinary protein excretion >40 mg/m²/h or ≥3+ proteinuria by dipstick for three consecutive days.

Laboratory analysis

Serum Vitamin D concentrations were determined using enzyme-linked immunosorbent assay methodology at presentation, one month post-treatment initiation, and at relapse events. Vitamin D status was classified as deficient (<20 ng/mL), insufficient (20–30 ng/mL), or sufficient (>30 ng/mL) according to established guidelines.

Sample size and statistical analysis

Based on previous admission data, we calculated a required sample size of 60 participants to detect clinically meaningful differences in Vitamin D status between groups. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 24.0. (Armonk, NY: IBM Corp). Continuous variables were presented as mean ± standard deviation, while categorical variables were expressed as frequencies and percentages. Appropriate statistical tests were selected based on data distribution, with statistical significance defined as P < 0.05.

RESULTS

Baseline demographics and clinical characteristics

The study cohort comprised 60 patients equally distributed between two groups for comparative analysis. Group I (supplemented group) included 30 patients with a mean age of 5.2 ± 2.8 years, while Group II (control group) comprised 30 patients with a mean age of 5.6 ± 3.0 years. Male predominance was observed in both groups. Disease presentation was similar between groups, with no significant differences in the proportion of initial episodes versus relapses, as shown in Table 1.

Table 1.

Baseline demographic and clinical characteristics

Variable	Group I (n=30)	Group II (n=30)
Age (years), mean±SD	5.2±2.8	5.6±3.0
Male sex, n (%)	22 (73.3)	19 (63.3)
Initial episode, n (%)	17 (56.7)	16 (53.3)
Relapse, n (%)	13 (43.3)	14 (46.7)

SD=Standard deviation

Vitamin D status at presentation

Universal Vitamin D deficiency or insufficiency was observed at presentation across both groups. A striking finding emerged when analyzing Vitamin D levels based on disease presentation rather than group allocation, as in Table 2. Children presenting with relapses demonstrated markedly lower Vitamin D concentrations compared to those with initial episodes, representing the most significant finding of our baseline assessment.

Table 2.

Baseline Vitamin D levels and status by presentation

Variable	At initial episode	At relapse	Test statistic	P
Vitamin D level (ng/mL), mean±SD	15.78±2.04	8.76±2.75	W=854.500	<0.001
Vitamin D status	All deficient/insufficient	All deficient/insufficient	-	-

SD=Standard deviation

Response to Vitamin D supplementation

Following 1 month of intervention, significant biochemical improvements were observed in the supplemented group, as shown in Table 3. Group I achieved substantially higher serum Vitamin D concentrations compared to controls, with over one-third of supplemented patients reaching sufficiency levels. This demonstrated the effectiveness of oral Vitamin D supplementation in correcting deficiency states.

Table 3.

Vitamin D levels and sufficiency status 1-month postintervention

Variable	Group I	Group II	Test statistic	P
Vitamin D level (ng/mL), mean±SD	17.44±4.31	11.65±4.26	t=5.231	<0.001
Vitamin D sufficiency, n (%)	11 (36.7)	0	χ2=21.110	<0.001

SD=Standard deviation

Clinical outcomes analysis

Despite the significant biochemical improvements demonstrated in Table 3, clinical outcomes analysis revealed a striking disconnect between Vitamin D status and disease course. Time to achieve remission was virtually identical between groups, and relapse patterns showed no significant intergroup differences over the 6-month follow-up period, as shown in Table 4. This represents the most important clinical finding of our study.

Table 4.

Clinical outcomes over 6-month follow-up

Outcome	Group I	Group II	Test statistic	P
Days to remission, mean±SD	11.60±3.2	11.93±3.4	W=451.000	0.994
Relapse rate (events/patient), mean±SD	0.13±0.4	0.23±0.5	W=418.000	0.471
Days to relapse, mean±SD	132±25	140±30	W=10.000	0.762

SD=Standard deviation

Vitamin D status during relapse events

Analysis of patients who experienced relapses revealed sustained differences in Vitamin D status between groups, as shown in Table 5. Group I patients maintained sufficient Vitamin D levels at the time of relapse, while Group II patients remained deficient or insufficient. However, this biochemical advantage provided no clinical protection against relapse occurrence or timing, further supporting the disconnect between Vitamin D status and clinical outcomes.

Table 5.

Vitamin D levels and sufficiency status at relapse

Variable	Group I	Group II	Test statistic	P
Vitamin D level at relapse (ng/mL), mean±SD	30.60±4.62	12.33±5.04	t=5.903	0.001
Vitamin D status at relapse	All sufficient	All deficient/insufficient	χ2=10.000	0.005

SD=Standard deviation

DISCUSSION

This study provides insights into the relationship between Vitamin D status and clinical outcomes in pediatric idiopathic nephrotic syndrome through both observational and comparative analysis. Our findings demonstrate universal Vitamin D deficiency or insufficiency at presentation, with a clear inverse relationship between Vitamin D levels and relapse history, yet no significant impact on clinical disease course.

Vitamin D deficiency patterns and disease presentation

The most striking finding was the significant difference in baseline Vitamin D levels between children presenting with initial episodes versus relapses (15.78 ± 2.04 vs. 8.76 ± 2.75 ng/mL, P < 0.001), as demonstrated in Table 2. This pattern suggests that recurrent episodes contribute to progressive Vitamin D depletion, likely reflecting cumulative losses of Vitamin D-binding protein through repeated episodes of massive proteinuria.[6] This observation aligns with the pathophysiology of nephrotic syndrome, where proteins with molecular weights similar to albumin, including Vitamin D-binding protein (58 kDa), are preferentially lost in urine.[13]

The universal presence of Vitamin D deficiency or insufficiency at presentation underscores the clinical significance of this complication in pediatric nephrotic syndrome. Our demographic findings [Table 1] mirror established epidemiological patterns, with predominant involvement of young males and align with previous reports from South Asian populations.[14]

Biochemical efficacy of supplementation

The supplementation phase of our study demonstrated significant biochemical efficacy, with Group I achieving substantially higher Vitamin D levels compared to controls (17.44 ± 4.31 vs 11.65 ± 4.26 ng/mL, P < 0.001), as presented in Table 3. Notably, over one-third (36.7%) of supplemented patients achieved sufficiency levels, while no control group participants reached this threshold. This biochemical response confirms the effectiveness of oral Vitamin D supplementation in correcting deficiency states in nephrotic syndrome patients.

Despite the significant biochemical improvements, our clinical outcomes analysis [Table 4] revealed a striking disconnect between Vitamin D status and disease course. Time to remission was virtually identical between groups (11.60 ± 3.2 vs. 11.93 ± 3.4 days, P = 0.994), and relapse patterns showed no significant differences over the 6-month follow-up period. This finding challenges the hypothesis that Vitamin D’s immunomodulatory properties translate into clinically meaningful benefits in nephrotic syndrome management.

Perhaps most compelling was our analysis of patients who experienced relapses during follow-up [Table 5]. Despite Group I patients maintaining sufficient Vitamin D levels at relapse (30.60 ± 4.62 ng/mL) compared to deficient/insufficient levels in Group II (12.33 ± 5.04 ng/mL, P = 0.001), this biochemical advantage provided no clinical protection against relapse occurrence or timing. This observation strongly suggests that Vitamin D’s role in nephrotic syndrome is primarily nutritional rather than disease-modifying.

Our findings align with the randomized controlled trial by Banerjee et al., who similarly demonstrated biochemical efficacy of Vitamin D supplementation without clinical benefit regarding relapse prevention.[15] Their study showed significant improvements in 25(OH) D levels but no effect on bone mineral density or relapse rates over 6 months, supporting our conclusions about the limited therapeutic role of Vitamin D supplementation.

Selewski et al. reported universal Vitamin D deficiency at nephrotic syndrome diagnosis with improvement following supplementation, supporting routine assessment and correction.[11] However, their study did not evaluate clinical outcomes, making our contribution valuable in bridging this knowledge gap.

More recently, Maji et al. demonstrated that Vitamin D deficiency prevalence increases with relapse frequency, with 75.0% deficiency in first-episode patients increasing to 90.9% in frequently relapsing cases.[13] Our findings extend this observation by showing that even when the deficiency is corrected, clinical outcomes remain unchanged.

Study limitations

The relatively small sample size may have limited statistical power to detect modest clinical effects. The 6-month observation period may have been insufficient to capture delayed effects on relapse prevention. We did not evaluate other potential benefits of Vitamin D supplementation, such as effects on bone mineral density, growth parameters, or long-term complications. Additionally, our study population was limited to a single center in North India, potentially limiting generalizability to other populations with different baseline Vitamin D status or genetic backgrounds.

CONCLUSIONS

Vitamin D deficiency is universal in children with idiopathic nephrotic syndrome, with significantly lower levels observed in those with relapsing disease. While Vitamin D supplementation effectively corrects biochemical deficiency, it does not appear to significantly influence time to remission or short-term relapse patterns. These findings suggest that Vitamin D’s role in nephrotic syndrome is primarily nutritional rather than therapeutic.

Our results support routine Vitamin D assessment and supplementation for biochemical correction in nephrotic syndrome patients while highlighting the need for realistic expectations regarding direct clinical benefits. Future research should explore optimal dosing regimens, treatment duration, and potential benefits in specific patient subgroups or for long-term outcomes.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.