Hypothyroidism in Childhood Nephrotic Syndrome – An Overlooked Association

The association between glomerular diseases and endocrine dysfunction has long been a subject of investigation, especially in children with nephrotic syndrome, where protein loss extends beyond albumin to include several hormone-binding proteins.^1,2 The systematic review and meta-analysis by Das et al., published in this issue, provides clarity on this incompletely studied question.³ By analyzing 26 studies, of which 19 were included in this meta-analysis, the authors report that hypothyroidism affects about 40% with nephrotic syndrome. The pooled prevalence of hypothyroidism was 41.5% (95% CI: 32.9–50.3), with subclinical hypothyroidism more common (26%) than overt hypothyroidism (15.3%). Among children with SRNS, the prevalence was 38.1%. Children with nephrotic syndrome were nearly seventeen times more likely to have hypothyroidism than controls, with an OR of 16.9 (95% CI: 6.4–44.4).

Though clinicians have recognized biochemical thyroid disturbances during active nephrosis, the magnitude and consistency of this finding across populations were uncertain. Though well conducted, a key limitation of the meta-analysis is the heterogeneity in thyroid function assessment across included studies. While the authors acknowledge that free thyroxine (FT4) is a more reliable indicator of thyroid status in nephrotic syndrome, given that total T4 levels are influenced by urinary protein loss, several included studies appear to have reported only total T4 rather than FT4.³ However, this distinction is not clarified or standardized in the analysis. The absence of uniform FT4 measurement or sensitivity analysis stratified by assay type may therefore have introduced bias in the pooled prevalence estimates of hypothyroidism. Nevertheless, the pooled prevalence of clinical hypothyroidism was 15.31% which deserves attention for its consequences on various organ systems.

The pathophysiological basis of this association, beyond urinary loss of thyroid hormone transport proteins, remains poorly understood. The possible role of the inflammatory cytokines on the non-thyroidal axis, effects of glucocorticoids on the control of thyroid hormones, and altered deiodinase activity in non-thyroidal illness have been proposed.⁴ Given the importance of thyroid hormones for normal growth, metabolism, and cognitive development, particularly in early childhood, untreated hypothyroidism can lead to growth retardation, fatigue, and impaired school performance. When superimposed on the metabolic stress of nephrotic syndrome, these effects may compromise well-being. Regular thyroid function testing, especially in children with steroid resistance, frequent relapses, or prolonged disease, is therefore justified. Early detection of thyroid dysfunction may allow timely intervention and prevent long-term sequelae.

One strength of this meta-analysis lies in differentiating clinical from subclinical hypothyroidism. Although pediatric endocrinology guidelines generally advocate observation rather than treatment for mild subclinical hypothyroidism, the context of nephrotic syndrome may warrant a more proactive approach. Persistent protein losses may continue to deplete thyroid hormone levels despite biochemical compensation, and levothyroxine supplementation may be considered in selected cases with poor growth, fatigue, or dyslipidemia. Some studies have even suggested that correcting hypothyroidism may improve proteinuria and steroid responsiveness, highlighting the possibility of a bidirectional relationship between thyroid and renal function. The role of thyroid hormone supplementation in patients with subclinical hypothyroidism and chronic kidney disease is being evaluated in a randomized controlled trial conducted by our group, for which data analysis is currently underway.⁵

The underlying studies were mostly cross-sectional, precluding causal inferences or assessment of thyroid recovery after remission. Considerable heterogeneity (I² = 89%) reflects variations in study design, timing of thyroid testing, and laboratory cut-offs used to define hypothyroidism. Data on disease phase, whether measurements were taken during relapse or remission, were often lacking, limiting interpretation of whether thyroid changes are transient or persistent. Furthermore, few studies explored the contribution of autoimmune thyroiditis, iodine status, or malnutrition, factors that may confound thyroid profiles in low- and middle-income settings. As previously stated, the heterogeneity in the included studies with regard to analysis or free and total thyroid hormones also limits the conclusion. These issues underscore the need for standardized protocols and prospective longitudinal studies that can distinguish transient adaptive responses from permanent endocrine damage.

Despite these limitations, the message is clear. Thyroid dysfunction is common in pediatric nephrotic syndrome, clinically relevant, and not always considered. Thyroid function testing at diagnosis and during relapses is a simple, inexpensive intervention with potential long-term benefits. Children with persistent proteinuria or steroid-resistant disease are particularly vulnerable and warrant regular monitoring. Unrecognized thyroid dysfunction may compound neurocognitive deficits in nephrotic syndrome.^6,7 For clinicians, this is an opportunity to prevent an additional source of growth impairment in an already high-risk group.

The study also opens several questions for future research. Longitudinal cohorts can give information on whether hypothyroidism resolves after remission or predicts relapse frequency. Clinical trials on whether thyroid hormone replacement improves renal outcomes or modulates lipid and metabolic parameters are another promising area. The use of urinary thyroid hormone losses as biomarkers for disease activity is another promising concept. Finally, the observation of a weak inverse association between age and hypothyroidism prevalence suggests that younger children may be more vulnerable, perhaps due to immature hypothalamic-pituitary regulation, a hypothesis to be further studied.

Nephrologists should consider thyroid testing at baseline and repeat it during relapses or in the presence of poor growth, fatigue, or dyslipidemia. This simple measure aligns with the concept of holistic care in nephrotic syndrome, which extends beyond managing proteinuria to addressing systemic and developmental consequences. Hypothyroidism in these children is not a biochemical abnormality alone; it is a correctable comorbidity that, if recognized early, may improve growth, cognition, and overall health.