Prevalence of Hypothyroidism in Children with Nephrotic Syndrome – A Systematic Review and Meta-analysis

Introduction

Nephrotic syndrome (NS) is among the most prevalent glomerular diseases in children.¹ The incidence of idiopathic NS alone ranges from 1.15 to 16.9 cases per 100,000 children, with notable variations based on ethnicity and geographic region.² The condition is traditionally characterized by persistent heavy proteinuria (≥40 mg/m²/hour, a urine protein-to-creatinine ratio ≥200 mg/mL, or ≥3+ protein on a urine dipstick), along with edema and hypoalbuminemia.³ NS is recognized as a risk factor for hypothyroidism, stemming from the disease’s underlying pathophysiology and the effects of its treatment.⁴

NS is characterized by glomerular damage, leading to a significant loss of proteins in the urine. Among these proteins, thyroxine-binding globulin (TBG), albumin, and thyroxine are excreted.^5-7 This proteinuria reduces serum free thyroxine (FT4) levels, prompting the anterior pituitary gland to compensate by increasing thyroid-stimulating hormone (TSH) secretion. TSH stimulates the thyroid gland to produce more thyroid hormones, which may continue to be lost due to ongoing nephrosis.

TBG and albumin are crucial carriers of thyroid hormones, acting as buffers to maintain serum thyroxine levels. Their urinary loss disrupts serum thyroid hormone concentrations in children with NS, potentially leading to hypothyroidism.⁸ Additionally, steroids like prednisolone, the mainstay of NS treatment, have been shown to suppress TSH secretion from the pituitary gland, further contributing to central hypothyroidism.⁷

Although most serum thyroxine is bound to TBG and albumin, their loss in NS primarily affects total serum thyroxine levels, leaving FT4 measurements unaffected. Therefore, FT4 is a reliable indicator of thyroid function in diagnosing hypothyroidism.⁹

Thyroid hormones play a critical role in the normal functioning of physiological systems, especially in normal growth and neurocognitive development. Untreated overt hypothyroidism can significantly impair physical growth and intellectual development in children and adolescents.^10,11 Additionally, Mario et al. reported that restoring normal thyroid function in children with NS can enhance their response to treatment for the underlying glomerular disease.⁶

Subclinical or overt hypothyroidism may exacerbate the disease burden, complicate management, and impair long-term outcomes. However, the relationship between NS and hypothyroidism is not straightforward, with several studies reporting conflicting findings.^5,12-17 Factors such as the severity of proteinuria, nutritional status, and variations in thyroid function assays contribute to the heterogeneity of results, creating uncertainty regarding the true prevalence and clinical implications of hypothyroidism in children with NS.

This complexity underscores the need for a systematic synthesis of the evidence to better understand the hypothyroidism burden in this vulnerable population. While individual studies have attempted to elucidate this relationship, a comprehensive review and meta-analysis can provide a clearer picture by consolidating data from diverse geographic regions and clinical contexts.

The objectives of this systematic review and meta-analysis are twofold: (1) to determine the pooled prevalence of hypothyroidism in children with NS, (2) to explore the prevalence of Clinical and Subclinical hypothyroidism in NS, and (3) to explore factors that may influence this prevalence. Understanding the interplay between NS and thyroid dysfunction has the potential to improve patient outcomes by ensuring timely diagnosis and appropriate treatment of hypothyroidism in this at-risk population.

Materials and Methods

This systematic review was registered in the PROSPERO database under the identifier CRD42023455277. It was conducted according to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.¹⁸ Since it was a systematic review, ethical approval and patient consent is not required.

Studies published in English from January 2000 to December 2024 focusing on the prevalence of hypothyroidism in nephrotic children (1-19 years) were included. The inclusion criteria encompassed cross-sectional, retrospective, prospective, cohort studies, trials, and protocols where NS was diagnosed using the KDIGO guideline, and hypothyroidism was diagnosed using the Nelson textbook of pediatrics.³ Participants were required to have NS with subgroups of steroid-sensitive, idiopathic, steroid-dependent, and steroid-resistant between 1 and 19 years. Only articles published in peer-reviewed journals with full-text availability were considered.

Exclusion criteria included studies on adults or mixed populations without separate pediatric data, case reports, reviews, editorials, conference abstracts, council publications, animal studies, and studies for which the full text was unavailable.

The search strategy was updated by Dec 31, 2024, at the latest. The three authors (SD, SK, SKT) conducted searches across databases, including EMBASE, Web of Science, Cochrane CENTRAL, Scopus, CINAHL, and Gray Literature, like Conference abstracts, theses repositories, clinical trial registries, manual reference lists, and Google. The keyword search was limited to titles and abstracts, employing Boolean operators such as “OR” and “AND” where applicable. The search terms included nephrotic syndrome, prevalence, hypothyroidism, children, thyroid-stimulating hormone, and thyroxine. The initial search string generated primarily on PubMed WAS: “epidemiology” [Subheading] OR “epidemiology” [All Fields] OR “prevalence” [All Fields] OR “prevalence” [MeSH Terms] OR “prevalance” [All Fields] OR “prevalences” [All Fields] OR “prevalence’s” [All Fields] OR “prevalent”[All Fields] OR “prevalently”[All Fields] OR “prevalents” [All Fields]. The risk of bias was independently evaluated using the Newcastle-Ottawa Scale (NOS) quality assessment tool. The search strategy in PICOT format has been mentioned in Supplementary Table 1.

Two authors (SK, SKT) independently screened the titles and abstracts of identified studies. Subsequently, three authors (SD, SK, SKT) reviewed the full texts to extract relevant information, finalize exclusions, and assess the risk of bias. In cases of disagreement, the senior-most author (SD) was consulted, and decisions were resolved by consensus.

SD, SK, and ST independently extracted the following information: author details, year of publication, study methodology, sample size, and participant age and sex, NS diagnostic criteria, hypothyroidism diagnostic criteria, study location and setting, sampling strategy, overall prevalence rate, and associated risk factors. Any discrepancies were resolved through consensus. Only the most recent and comprehensive data were included in the analysis for studies analyzing the same cohort.

The primary outcome of this meta-analysis was the prevalence of hypothyroidism in NS, defined as the number of hypothyroidism cases divided by the sample size in percentage. The secondary outcome focused on the prevalence of Clinical and Subclinical hypothyroidism in NS (1- 19 years) and to explore factors that may influence this prevalence.

Results

A total of 2,758 articles were identified during the search, including 97 from PubMed, 851 from Scopus, 1,479 from Embase, 142 from Web of Science, 28 from Cochrane Central, 46 from CINAHL, 115 from Google Scholar, and 17 from registries (16 trials and one protocol). After removing 1,140 duplicate records, 1,635 articles were screened, of which 1,597 were excluded based on title and abstract. A total of 38 records were assessed for eligibility, and 12 were excluded due to unavailability of full text (n = 9), incorrect study population (n = 2), and unclear outcomes (n = 1). Ultimately, 26 studies were included in the review, with 19 included in the meta-analysis^{4,8,12,17,20-41} [Figure 1].

Close

Figure 1:

PRISMA flow diagram.

Export to PPT

All hospital-based prospective, cross-sectional, and retrospective studies conducted in various parts of the world were included. The studies diagnosed NS based on standard guidelines, and participants aged 1 to 19 were considered. The studies included in this review were published between January 2000 and December 2024. Supplementary Table 1 contains the demographic features of the studies in the systematic review and meta-analysis.

A random-effects meta-analysis of 19 studies estimated a pooled prevalence rate of 41.45% (95%CI: 32.896-50.287). Figure 2 presents the forest plot of the meta-analysis, displaying the pooled prevalence estimates along with their upper and lower 95%CI. The test for heterogeneity, with Q (df = 18) = 167.1132 and p < 0.0001, indicated significant heterogeneity among the studies. A high degree of heterogeneity was observed (I² = 89.23%). Furthermore, Egger’s regression test suggested the presence of publication bias (intercept = 2.4259, p = 0.3996). The funnel plot does not show significant asymmetry, suggesting there is no substantial publication bias or small-study effects in this meta-analysis of pooled prevalence [Figure 3].

Close

Figure 2:

Forest plot showing meta-analysis of 19 studies. Black box indicates the results (point estimates; prevalence) of individual studies. C.I: Confidence interval, Ev: Events, Trt: Treatment

Export to PPT

Close

Figure 3:

Funnel Plot of nineteen studies included for meta-analysis. Blue line-vertical: Pooled prevalence rate from all studies included in meta-analysis. Sloping lines: create the “funnel” shape. They are typically set at 95% confidence intervals and represent the expected range of effect sizes for studies of varying precision. Yellow dot: represents a single study that has been included in the meta-analysis

Export to PPT

A subgroup analysis was conducted to assess the prevalence of hypothyroidism among SRNS. Eight studies reported a pooled prevalence of 38.140 (95%CI: 28.533-48.240) [Figure 3]. The studies exhibited significant heterogeneity, with Q (df = 7) = 22.9471, p <0.0001, I² = 69.50% [Supplementary Figures 1 and 2].

Out of 27 studies, 10 reporting the prevalence of clinical hypothyroidism among NS patients were included in a subgroup analysis. The pooled prevalence of clinical hypothyroidism was 15.31% (95%CI: 8.463-23.736). The studies demonstrated significant heterogeneity, with Q (df = 9) = 57.7782, p = 0.0017, I² = 84.42% [Supplementary Figure 3]. Furthermore, Egger’s regression test suggested the presence of publication bias (intercept =2.2432, P = 0.6701).

A subgroup analysis was conducted to assess the prevalence of subclinical hypothyroidism among patients with NS in ten studies. The pooled prevalence of subclinical hypothyroidism was 25.96% with a 95% confidence interval of 19.456 to 33.044. Non-significant Heterogeneity was observed among the studies, with Q (df = 9) = 30.4305, P = 0.0004, I² = 70.42% [Supplementary Figure 4]. Furthermore, Egger’s regression test suggested the presence of publication bias (intercept = -1,3645, P = 0.7215).

The meta-analysis included four studies to quantify the standardized mean difference of TSH value between the NS with and without hypothyroidism group, which was 1.86 with a wide confidence interval (0.79-2.92), suggesting a moderate to large effect size. However, the high heterogeneity (I² = 93.62%) indicates substantial variability among the studies, and p < 0.01 suggests that the heterogeneity is statistically significant. The cumulative plot shows how the pooled estimate becomes more robust as additional studies are incorporated [Supplementary Figure 5].

A subgroup meta-analysis was conducted to assess the presence of hypothyroidism among NS and control groups, including data from eight studies. The pooled odds ratio of 16.86 (95%CI: 6.40-44.38), indicates a significantly higher likelihood of the outcome in the exposed group compared to the control group. The heterogeneity is moderate (I² = 39.37%) and not statistically significant (p = 0.12), suggesting reasonable consistency among studies. The cumulative analysis shows that the pooled estimate becomes more robust as additional studies were included [Figure 4].

Close

Figure 4:

Comparison of hypothyroidism among nephrotic syndrome and control groups with odds ratio (95% CI). Black square indicates odd’s ratio of individual study and blue diamond indicated pooled odd’s ratio of meta-analysis of all studies.

Export to PPT

The bubble chart suggests a weak downward trend between age and proportion, with most observations concentrated in the younger age range in the regression analysis [Figure 5].

Close

Figure 5:

Regression analysis of age with proportion of hypothyroid children.

Export to PPT

Discussion

To the best of our knowledge, this is the most comprehensive and detailed systematic review conducted to date on the burden of hypothyroidism among children with NS. This systematic review is the first to comprehensively examine the prevalence of hypothyroidism, both clinical and subclinical, among patients with SRNS. It highlights a comparison of hypothyroidism prevalence between NS and control groups and evaluates the standardized mean difference in TSH levels between NS patients with and without hypothyroidism. These novel findings provide valuable insights into the endocrine implications of NS, enriching current knowledge.

The pooled prevalence of hypothyroidism in NS was 41.45% (95% CI: 32.896-50.287). The observed prevalence underscores a multifactorial interplay between thyroid function and NS. Hypoalbuminemia, proteinuria, and urinary loss of thyroid-binding globulin and other thyroid-related proteins are likely contributors to thyroid dysfunction in this population.

Seven studies investigating thyroid function in patients with NS did not provide specific data on the prevalence of hypothyroidism. Instead, these studies reported only the percentage of cases with elevated TSH levels or abnormal levels of T3 and T4 (either low T3 or low T4). Moreover, these studies did not explicitly define hypothyroidism in their methodology, making it challenging to determine whether the abnormalities in thyroid function tests met the clinical or biochemical criteria for hypothyroidism. As a result, these studies could not be included in the pooled analysis of hypothyroidism prevalence in NS.^{20,27-29,34,36,37}

Patients with SRNS (8 studies) exhibited a distinct pooled prevalence of 38.14 (95%CI: 28.53-48.24). This finding suggests that persistent proteinuria and refractory disease processes in SRNS might exacerbate thyroid dysfunction. Additionally, the immunological mechanisms underlying SRNS may contribute to this higher prevalence, as inflammatory cytokines are known to impact thyroid function. The pooled prevalence of hypothyroidism among SRNS is lower than the pooled prevalence of hypothyroidism among all NS cases, likely due to only 10 studies being included in the meta-analysis. This underscores the need for further research with larger datasets.^{12,24,32,33,38-41}

An essential contribution of this meta-analysis is the differentiation between clinical and subclinical hypothyroidism. The pooled prevalence of clinical hypothyroidism is 15.31% (95%CI: 8.463-23.736), characterized by elevated TSH and low T4 levels, highlighting the direct impact of NS on thyroid function. On the other hand, subclinical hypothyroidism, marked by elevated TSH with normal free T4 levels, was also significantly prevalent at 25.96% with a 95%CI: 19.456-33.04). Subclinical hypothyroidism may serve as a precursor to overt hypothyroidism, particularly in the setting of ongoing protein loss and chronic disease. The clinical implications of subclinical hypothyroidism in NS warrant further exploration, as it may impact growth, metabolic regulation, and cardiovascular health in affected individuals.

This meta-analysis identified a significant mean difference in TSH levels of 1.86 with a wide confidence interval (0.79-2.92), suggesting a moderate to large effect size between the NS with and without hypothyroidism groups. Elevated TSH levels in NS patients further substantiate the hypothesis of a disrupted thyroid axis in this condition. This elevation may reflect compensatory mechanisms in response to urinary losses of thyroid hormones and their binding proteins. Chronic inflammation and oxidative stress in NS might also contribute to altered hypothalamic-pituitary-thyroid axis function.

There is clinical heterogeneity among included studies, both in India and globally, particularly in diagnostic criteria for hypothyroidism and NS. Some studies focused solely on hypothyroidism in nephrotic children, while others compared hypothyroidism between NS patients and healthy children. A random effects model for meta-analysis was employed to account for the substantial methodological differences across the included studies.

Our systematic review highlights a significant association between NS and hypothyroidism in children, emphasizing the importance of routine thyroid function monitoring in this population. The findings align with existing literature, reinforcing the need for heightened clinical awareness and proactive management strategies.

The review indicates a notable prevalence of both subclinical and overt hypothyroidism among children with NS. This is consistent with studies such as the one conducted in Bhopal, India, which reported that 55.7% of children with NS exhibited abnormal thyroid profiles, including 27.1% with overt hypothyroidism and 28.6% with subclinical hypothyroidism. Similarly, a study from Uganda found a 23% prevalence of hypothyroidism among children and adolescents with NS, with the majority being subclinical cases. These findings underscore the clinical significance of thyroid dysfunction in NS, particularly during active disease phases characterized by proteinuria. The loss of thyroid-binding proteins and hormones through urine can lead to alterations in thyroid function tests, potentially resulting in subclinical or overt hypothyroidism.⁴²

While our review did not stratify data based on NS subtypes, existing studies suggest a higher prevalence of hypothyroidism in SRNS compared to steroid-sensitive forms. For instance, research from Nigeria reported that 26.3% of children with SRNS had subclinical hypothyroidism, compared to 8.6% in steroid-sensitive cases. Another study from India found that 20% of children with SRNS had hypothyroidism, with a significant correlation between TSH levels and proteinuria. These observations suggest that prolonged proteinuria in SRNS may lead to greater losses of thyroid hormones, increasing the risk of hypothyroidism. However, due to variability in study designs and patient populations, further research is needed to elucidate the relationship between NS subtypes and thyroid dysfunction.^43,44

The association between NS and hypothyroidism has several clinical implications: Thyroid hormones are crucial for growth and neurodevelopment in children. Untreated hypothyroidism can lead to growth retardation and cognitive impairments. Subclinical hypothyroidism has been linked to increased risks of hypertension and dyslipidemia, which are already concerns in NS patients. Regular assessment of thyroid function, especially during active NS phases, can facilitate early detection and management of hypothyroidism, potentially improving patient outcomes.

Given these implications, routine thyroid function testing should be considered in the management of children with NS, particularly those with SRNS or frequent relapses. Early identification and treatment may prevent complications and support optimal growth and development.

Our findings are consistent with the broader body of literature, demonstrating a significant prevalence of thyroid dysfunction in children with NS. However, variations in reported prevalence rates highlight the need for standardized diagnostic criteria and further research to understand the underlying mechanisms and long-term outcomes of hypothyroidism in this population.⁴⁵

The study’s strengths include a rigorous methodology and thorough quality assessment of the included studies.

While our meta-analysis provides valuable insights, several limitations were considered. First, the cross-sectional design of most studies limits causal inferences. Longitudinal studies are needed to elucidate the temporal relationship between NS and thyroid dysfunction. Second, this study underscores the scarcity of robust prevalence studies of clinical and subclinical hypothyroidism among children with idiopathic NS, FRNS, SDNS, and SRNS, addressing a critical research gap. The lack of studies analyzing risk factors for hypothyroidism in NS highlights a significant research gap. Third, excluding unpublished studies and grey literature may have influenced our findings. Future research should include a broader range of studies to mitigate the impact of publication bias and provide a more comprehensive understanding of the association between NS and thyroid dysfunction.

Future research should explore the impact of thyroid hormone replacement therapy on renal and systemic outcomes in patients with NS. The role of novel biomarkers, such as free thyroid hormone indices and urinary thyroid hormone losses, should also be investigated to enhance diagnostic accuracy and risk stratification. Moreover, studies focusing on pediatric populations are essential to address the unique developmental and metabolic challenges posed by hypothyroidism in NS.

This systematic review and meta-analysis highlight the significant burden of hypothyroidism in patients with NS, with notable differences across subtypes and severity of thyroid dysfunction. Elevated TSH levels in NS compared to control groups further underscore the impact of this renal condition on thyroid physiology. These findings call for routine thyroid function monitoring, particularly in high-risk subgroups such as SRNS.