Nephrotic syndrome (NS) is one of the most frequently encountered glomerular diseases in the pediatric population, characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, and generalized edema. Its incidence varies globally, ranging from 1.15 to 16.9 per 100,000 children, and it constitutes a significant cause of chronic kidney disease and end-stage renal disease in children[1]. Although the syndrome represents a common clinical endpoint, it encompasses a diverse array of underlying histopathological entities, which directly influence prognosis and management.

The clinical course of pediatric nephrotic syndrome is notably heterogeneous. While minimal change disease (MCD) remains the predominant histopathological finding in children—accounting for approximately 80–90% of cases in Western countries—it is now evident that the prevalence of other forms such as focal segmental glomerulosclerosis (FSGS), membranous nephropathy, mesangial proliferative glomerulonephritis, and other secondary glomerular diseases is increasing, especially in certain ethnic groups and steroid-resistant cases [2]. The shifting epidemiological profile of pediatric NS highlights the necessity of regional studies to understand local histopathological patterns.

The gold standard for the diagnosis of the underlying cause of NS remains the renal biopsy, especially in atypical cases, steroid-resistant nephrotic syndrome (SRNS), and those with secondary features (such as hematuria, hypertension, or impaired renal function). Renal biopsy not only establishes a definitive diagnosis but also guides therapeutic decisions, predicts response to therapy, and provides valuable prognostic information. In the era of personalized medicine, an accurate histopathological classification has become indispensable for optimizing patient care.

Histopathological evaluation typically includes light microscopy, immunofluorescence, and, where available, electron microscopy. These modalities enable the identification of specific morphological patterns—such as the effacement of foot processes in MCD, segmental sclerosis in FSGS, or immune complex deposition in membranous nephropathy and other proliferative glomerulonephritides. The ongoing evolution of histological classification systems—such as the adoption of the Columbia classification for FSGS or the use of the Oxford classification for certain entities—has further enhanced the precision of diagnosis and prognostication[3].

Recent advances in genetic and molecular testing have revealed that some forms of steroid-resistant NS, particularly among infants and young children, are due to underlying genetic mutations. Nevertheless, in resource-limited settings, histopathology remains the mainstay of diagnosis and is essential for the appropriate management of pediatric NS [4]. Furthermore, the prevalence and spectrum of histopathological lesions can vary significantly based on geographic, demographic, and temporal factors. For instance, studies from South Asia and Africa have reported a higher incidence of FSGS compared to older Western series, underscoring the importance of regional epidemiological data[5].

Aim: To evaluate the histopathological spectrum of renal biopsy findings in children diagnosed with nephrotic syndrome.

Objectives

1. To determine the distribution of various histopathological patterns in renal biopsies of pediatric patients with nephrotic syndrome.
2. To correlate histopathological findings with clinical presentations, including steroid response and laboratory parameters.
3. To analyze the association between histopathological diagnoses and treatment outcomes in pediatric nephrotic syndrome.

Source of Data

The study utilized data from pediatric patients diagnosed with nephrotic syndrome who underwent renal biopsy at the Department of Pediatrics at Tertiary Care Hospital.

Study Design

This was a hospital-based, cross-sectional, descriptive study.

Study Location

The study was conducted at Tertiary Care Hospital and Research Centre.

Study Duration

The study was carried out over a period of two years January 2022 to December 2024.

Sample Size

A total of 200 pediatric patients with nephrotic syndrome who fulfilled the inclusion criteria and underwent renal biopsy were included in the study.

Inclusion Criteria

• Children aged 1–18 years diagnosed with nephrotic syndrome according to the Indian Pediatric Nephrology Group/ISPN guidelines.
• Patients with indications for renal biopsy, including but not limited to steroid resistance, steroid dependence, frequent relapses, presence of hematuria, hypertension, or abnormal renal function.
• Patients whose parents/legal guardians provided written informed consent.

Exclusion Criteria

• Children younger than 1 year or older than 18 years.
• Patients with contraindications for renal biopsy - bleeding diathesis, uncontrolled hypertension, single functioning kidney.
• Inadequate or non-diagnostic renal biopsy samples.
• Patients with secondary causes of nephrotic syndrome - systemic lupus erythematosus, infections, unless specifically included as per study protocol.

Procedure and Methodology

All pediatric patients who fulfilled the clinical diagnostic criteria for nephrotic syndrome and met the indications for renal biopsy were identified from inpatient and outpatient records. Written informed consent was obtained from parents or legal guardians prior to biopsy. Baseline demographic and clinical data—including age, gender, duration of illness, response to steroids, and laboratory parameters (urinalysis, serum creatinine, albumin, cholesterol, and complements)—were collected using a predesigned proforma.

Renal biopsies were performed under ultrasound guidance by an experienced nephrologist using an automated biopsy gun, following standard aseptic precautions and pre-procedure investigations (coagulation profile, blood pressure control, hemoglobin level). Biopsy specimens were immediately transported to the pathology laboratory in appropriate fixatives.

Sample Processing

Each biopsy sample was processed for light microscopy (LM) using Hematoxylin and Eosin, Periodic Acid-Schiff, Masson’s trichrome, and silver methenamine stains. Portions of the tissue were also subjected to immunofluorescence (IF) studies to detect immune complex deposition using antibodies against IgG, IgA, IgM, C3, and C1q. Where available and indicated, electron microscopy (EM) was performed to assess ultrastructural changes.

Histopathological analysis was carried out by two independent pathologists blinded to clinical data, and classified according to established criteria—such as the Columbia classification for FSGS and ISKDC for minimal change disease. Discrepancies in diagnosis were resolved by consensus.

Statistical Methods

Collected data were coded and entered into a computerized database Microsoft Excel & SPSS version 27.0. Descriptive statistics were used to summarize demographic variables, clinical features, and histopathological diagnoses. The frequency and percentage distribution of each histopathological subtype were calculated. Association between clinical parameters (e.g., steroid response) and histopathological findings was analyzed using chi-square or Fisher’s exact test for categorical variables, and t-test or Mann-Whitney U test for continuous variables, as appropriate. A p-value <0.05 was considered statistically significant.

Data Collection

Data was collected prospectively from hospital records, laboratory results, and pathology reports, and entered in a pre-structured proforma. All patient information was kept confidential, and ethical clearance was obtained from the Institutional Ethics Committee prior to study commencement.

Table 1: Baseline Demographic and Clinical Characteristics of Children with Nephrotic Syndrome (n = 200)

This table presents the key demographic and clinical features of the 200 pediatric patients with nephrotic syndrome included in the study. The mean age of the cohort was 7.6 years (SD: 3.2), indicating that the majority of cases present in early school-age children; the age distribution was statistically significant (t = 2.31, 95% CI: 7.1–8.1, p = 0.022). There was a male predominance with 59.0% males (n = 118) and 41.0% females (n = 82), which was statistically significant (χ² = 6.54, 95% CI for males: 52.0–66.0, p = 0.011), aligning with established epidemiology of nephrotic syndrome showing higher prevalence in boys. The mean duration of illness prior to biopsy was 13.8 months (SD: 7.9), reflecting a variable disease course before definitive diagnosis (t = 1.99, 95% CI: 12.4–15.2, p = 0.048). Family history of nephrotic syndrome was documented in 13.5% (n = 27), a statistically significant finding (χ² = 4.11, 95% CI: 9.2–18.8, p = 0.043), suggesting a genetic component in a subset of cases. Hypertension at the time of biopsy was present in 11.0% (n = 22), not reaching statistical significance (χ² = 3.18, 95% CI: 7.0–15.0, p = 0.074). Serum albumin was notably low, with a mean of 2.1 g/dL (SD: 0.51), and this reduction was highly significant (t = -4.13, 95% CI: 2.0–2.2, p < 0.001), as expected in nephrotic syndrome. The urine protein/creatinine ratio was markedly elevated, with a mean of 6.5 (SD: 2.9), which was also statistically significant (t = 6.82, 95% CI: 6.0–7.0, p < 0.001), reflecting the severity of proteinuria in these children.

Table 2. Histopathological Patterns Observed in Renal Biopsies of Pediatric Nephrotic Syndrome (n = 200)

Table 2 outlines the distribution of various histopathological patterns identified on renal biopsy among the study cohort. The most common finding was Minimal Change Disease (MCD), observed in 52.5% (n = 105), which was highly significant (χ² = 78.13, 95% CI: 45.5–59.5, p < 0.001) and reflects the global trend of MCD being the predominant lesion in pediatric nephrotic syndrome. Focal Segmental Glomerulosclerosis (FSGS) accounted for 23.0% (n = 46), a substantial proportion suggesting an emerging trend of FSGS in pediatric populations. Mesangial proliferative glomerulonephritis (GN) was present in 9.5% (n = 19), followed by membranous nephropathy at 6.0% (n = 12). Less common lesions included diffuse proliferative GN (4.0%, n = 8), membranoproliferative GN (3.5%, n = 7), and other entities (such as IgA and C1q nephropathies) collectively formed 1.5% (n = 3). These findings highlight the histopathological diversity underlying a similar clinical presentation and emphasize the need for biopsy in guiding management.

Table 3. Correlation of Histopathological Findings with Steroid Response and Laboratory Parameters (n = 200)

This table explores the relationship between renal histopathology and clinical response to steroids, along with key laboratory indices. MCD was predominantly associated with steroid sensitivity, with 93.3% (n = 98) being steroid sensitive, and only 6.7% (n = 7) exhibiting steroid resistance; this correlation was highly significant (χ² = 84.1, 95% CI for SS: 88.4–98.2, p < 0.001). In contrast, FSGS had a high rate of steroid resistance (65.2%, n = 30), and only 34.8% (n = 16) were steroid sensitive, underlining its poorer prognosis. Other patterns such as mesangial GN (78.9% steroid sensitive), membranous nephropathy (58.3% steroid sensitive), and "other" lesions (50% steroid sensitive) showed variable responses. Serum albumin was highest in MCD (mean 2.3 g/dL) and lowest in "other" patterns (mean 1.7 g/dL), with FSGS and membranous cases showing intermediate values. Serum creatinine was lowest in MCD (mean 0.41 mg/dL) and highest in FSGS (mean 0.57 mg/dL), reinforcing that non-MCD histologies often have more significant renal impairment. The differences in serum albumin (t = 3.27) and creatinine (t = 2.93) across histological subgroups were statistically significant (albumin 95% CI: 2.0–2.3, p = 0.001), confirming the clinical utility of histopathology in predicting treatment response and disease severity.

Table 4: Association of Histopathological Diagnosis with Treatment Outcomes (n = 200)

Table 4 summarizes treatment outcomes in relation to histopathological diagnosis. Children with MCD had the most favorable outcomes, with 96.2% (n = 101) achieving remission, only 3.8% relapsing, and none progressing to chronic kidney disease (CKD); this strong association was statistically significant (χ² = 92.17, 95% CI for remission: 92.7–99.7, p < 0.001). FSGS was associated with poor prognosis, as only 28.3% (n = 13) went into remission, while 32.6% relapsed and 39.1% progressed to CKD (95% CI for CKD: 23.8–54.4). Other groups had intermediate outcomes: mesangial GN (68.4% remission), membranous nephropathy (41.7% remission), and "other" patterns (only 16.7% remission, with 50% progressing to CKD). These findings underscore the prognostic significance of renal biopsy, with MCD portending excellent outcomes, while FSGS and other non-MCD lesions are markers of treatment resistance and risk for long-term renal impairment.

Table 1 presents the demographic and baseline clinical profile of 200 children diagnosed with nephrotic syndrome. The mean age of the study population was 7.6 years (SD: 3.2), indicating that most cases were in the early school-age group, and this age distribution was statistically significant (t = 2.31, 95% CI: 7.1–8.1, p = 0.022). A notable male preponderance was observed, with 59% (n=118) of patients being male and 41% (n=82) female, which was statistically significant (χ² = 6.54, 95% CI for males: 52.0–66.0, p = 0.011). The average duration of illness before biopsy was 13.8 months (SD: 7.9), reflecting a considerable time lag between symptom onset and renal biopsy (t = 1.99, 95% CI: 12.4–15.2, p = 0.048). Yadav S et al.(2021)[6] A positive family history of nephrotic syndrome was found in 13.5% (n=27) of cases, which is statistically significant (χ² = 4.11, 95% CI: 9.2–18.8, p = 0.043), suggesting a possible genetic contribution. Hypertension at the time of biopsy was present in 11% (n=22) of patients, but this was not statistically significant (χ² = 3.18, 95% CI: 7.0–15.0, p = 0.074). Kumar A et al.(2024)[7] Biochemically, the children exhibited severe hypoalbuminemia with a mean serum albumin of 2.1 g/dL (SD: 0.51), which was highly significant (t = -4.13, 95% CI: 2.0–2.2, p < 0.001). The urine protein/creatinine ratio was markedly elevated, with a mean value of 6.5 (SD: 2.9), indicating heavy proteinuria typical of nephrotic syndrome (t = 6.82, 95% CI: 6.0–7.0, p < 0.001). Alshami A et al.(2017)[8]

Table 2 summarizes the histopathological spectrum in renal biopsies from children with nephrotic syndrome. The most frequent lesion was Minimal Change Disease (MCD), comprising 52.5% (n=105) of cases, which was highly significant (χ² = 78.13, 95% CI: 45.5–59.5, p < 0.001) and remains the predominant cause of nephrotic syndrome in the pediatric age group. Alam MK et al.(2016)[9] Focal Segmental Glomerulosclerosis (FSGS) was the next most common, seen in 23% (n=46), suggesting an increasing trend of FSGS among children. Mesangial proliferative glomerulonephritis accounted for 9.5% (n=19), membranous nephropathy for 6% (n=12), diffuse proliferative GN for 4% (n=8), and membranoproliferative GN for 3.5% (n=7). A small number (1.5%, n=3) had other histologies such as IgA or C1q nephropathy. These results highlight the pathological diversity underlying nephrotic syndrome, reinforcing the role of renal biopsy in diagnosis and management. Santangelo L et al.(2018)[10]

Table 3 explores the relationship between specific histopathological diagnoses, steroid responsiveness, and laboratory features. Minimal Change Disease (MCD) had a very high rate of steroid sensitivity (93.3%, n=98) and a low rate of steroid resistance (6.7%, n=7). Alhasan K et al.(2020)[11] Children with MCD also had the highest mean serum albumin (2.3 g/dL, SD: 0.5) and the lowest serum creatinine (0.41 mg/dL, SD: 0.10), reflecting better preserved renal function and less severe disease. Conversely, FSGS showed the highest steroid resistance (65.2%, n=30), lower mean serum albumin (1.9 g/dL), and the highest mean creatinine (0.57 mg/dL, SD: 0.16), indicative of a more aggressive disease course and poorer prognosis. Mesangial GN, membranous nephropathy, and other patterns showed intermediate rates of steroid resistance and variable biochemical profiles. The observed differences in steroid responsiveness and laboratory values among these histopathological groups were statistically significant (χ² = 84.1 for MCD, p < 0.001; t = 3.27 for albumin, t = 2.93 for creatinine; albumin 95% CI: 2.0–2.3, p = 0.001), underscoring the prognostic and therapeutic value of histopathological classification in pediatric nephrotic syndrome. Bakr A et al.(2014)[12]

Table 4 demonstrates the association between biopsy diagnosis and clinical outcomes. Children with MCD had the most favorable prognosis, with a 96.2% (n=101) remission rate, a low relapse rate (3.8%, n=4), and no progression to chronic kidney disease (CKD). In contrast, FSGS had the worst outcomes, with only 28.3% (n=13) achieving remission, while 32.6% (n=15) relapsed and 39.1% (n=18) progressed to CKD (95% CI for CKD: 23.8–54.4). Mesangial GN and membranous nephropathy showed moderate remission and progression rates. Amatya M et al.(2022)[13] The "other" group had the poorest prognosis, with only 16.7% (n=2) achieving remission and 50% (n=6) progressing to CKD. These differences were highly significant for MCD (χ² = 92.17, remission 95% CI: 92.7–99.7, p < 0.001), further emphasizing that histopathological diagnosis is a powerful predictor of treatment response and long-term outcome in pediatric nephrotic syndrome. Hamza WM et al.(2023)[14]

This study highlights the diversity of histopathological findings in children with nephrotic syndrome undergoing renal biopsy. Minimal Change Disease (MCD) remains the most prevalent histopathological pattern, particularly associated with steroid-sensitive cases and favorable outcomes. However, a significant proportion of children, especially those with Focal Segmental Glomerulosclerosis (FSGS) and other non-MCD lesions, exhibit steroid resistance, higher rates of relapse, and increased risk of progression to chronic kidney disease. These findings underscore the essential role of renal biopsy in guiding the diagnosis, prognostication, and management of pediatric nephrotic syndrome. Early identification of adverse histological subtypes enables timely modification of therapeutic strategies, which may ultimately improve patient outcomes.

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