Association between thyroid dysfunction and renal function: Findings from a tertiary care center in India

Introduction

The interplay between the thyroid gland and kidney function has been recognized for decades. Thyroid hormones exert a profound influence on renal physiologynot only during embryonic development but also in adult lifeaffecting glomerular filtration, tubular secretory and absorptive capacities, electrolyte balance, and water homeostasis. These effects are partly mediated through direct renal mechanisms and partly through thyroid hormone-induced cardiovascular changes such as altered cardiac output and vascular tone [1,2] . As a result, both hypothyroidism and hyperthyroidism are known to significantly alter key renal parameters, including the glomerular filtration rate (GFR), urinary albumin-tocreatinine ratio (ACR), and markers of tubular function. Hypothyroidism, in particular, is often associated with a measurable reduction in GFR, elevated serum creatinine, and, in some cases, hyponatremia, even in subclinical cases. Importantly, these abnormalities generally improve with the initiation of levothyroxine therapy [3,4] .

Epidemiology of Thyroid Disorders

Globally, thyroid disorders are among the most common endocrine diseases, with hypothyroidism prevalence ranging between 4-10% in general adult populations, depending on geographic and demographic factors [5] . The burden is particularly high in women and increases with advancing age. Regional patterns vary significantly; iodine deficiency remains a major contributor in developing countries, while autoimmune thyroiditis predominates in iodine-sufficient areas. In India, hypothyroidism has an estimated prevalence of ~10.95% among adults, with higher rates reported in women, elderly populations, and residents of iodine-deficient or Himalayan regions such as the Darjeeling District and sub-Himalayan Terai [6] . Despite widespread iodized salt use, some regions continue to report inadequate iodine sufficiency, contributing to a persistently elevated thyroid disorder burden [7,8] .

Pathogenesis and Biochemical Interplay

From a biochemical standpoint, thyroid hormones play critical roles in maintaining renal hemodynamics, including modulation of renal blood flow, sodium and water reabsorption, and regulation of the renin-angiotensinaldosterone system (RAAS) [2,4] . Hypothyroidism reduces cardiac output and increases systemic vascular resistance, leading to decreased renal plasma flow and GFR [4,9] . Additionally, thyroid hormones directly affect renal tubular transport processes, impacting free water clearance and concentrating abilities. In severe hypothyroidism, reduced synthesis of erythropoietin can also contribute to anemia, further impairing renal oxygen delivery. Elevated serum creatinine observed in hypothyroid states is primarily due to reduced renal clearance, not increased muscle breakdown. These interwoven pathways highlight the importance of thyroid status in evaluating renal function and interpreting biochemical parameters such as eGFR and ACR [3,6,10] .

AIM

To evaluate the impact of thyroid dysfunction, particularly primary hypothyroidism, on renal function parameters and to explore the associations between thyroid hormone levels and renal indices in patients attending tertiary care centers in India.

Objectives 1. To compare serum TSH, free T 4 , serum creatinine, serum urea, eGFR (by MDRD and CKD-EPI equations), and urinary albumin-to-creatinine ratio (ACR) among euthyroid controls, drug-naïve primary hypothyroid patients, and hypothyroid patients under treatment. 2. To assess the correlations between thyroid hormone levels (TSH, free T 4 ) and renal function parameters (serum creatinine, urea, eGFR, ACR) in patients with primary hypothyroidism.

Materials and Methods

Place of Study

Data Collection and Parameters Measured

After obtaining informed consent, participant dataincluding demographic details, anthropometric measurements, and family historywere collected using semi-structured questionnaires. Blood and urine samples were collected to analyze serum TSH, free T 4 , serum creatinine, serum urea, and urinary albumin-to-creatinine ratio (ACR). These biochemical markers were processed and recorded systematically.

Exclusion Criteria

To ensure a homogenous study group and minimize confounding variables, strict exclusion criteria were applied. Individuals were excluded if they had a history of hypertension, diagnosed cardiovascular disorders, diabetes (frank or impaired glucose tolerance), acute or chronic infections, renal diseases (such as nephrotic/nephritic syndrome, nephropathy, urinary tract infections, or kidney stones), chronic diseases (including tuberculosis, leprosy, or HIV/AIDS), autoimmune disorders (such as rheumatoid arthritis or systemic lupus erythematosus), other endocrine dysfunctions (like Cushing's syndrome or acromegaly), secondary thyroid dysfunction due to pituitary or hypothalamic causes, or were under medications known to affect renal or thyroid function (such as ACE inhibitors, ARBs, diuretics, lithium, amiodarone, phenytoin, steroids, salicylates, beta blockers, rifampicin, or cytotoxic drugs). Pregnant women and individuals with malignancy were also excluded.

Data Collection and Parameters Measured

After obtaining informed consent, participant dataincluding demographic details, anthropometric measurements, and family historywere collected using semi-structured questionnaires. Blood and urine samples were collected to analyze serum TSH, free T 4 , serum creatinine, serum urea, and urinary albumin-to-creatinine ratio (ACR). These biochemical markers were processed and recorded systematically.

eGFR Calculation Methods

The estimated glomerular filtration rate (eGFR) was calculated using both the four-variable Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. These equations, standardized to IDMS (isotope dilution mass spectrometry), are considered the most reliable for estimating eGFR in adults over 18 years. The MDRD equation is defined as: GFR = 175 × (sCr)-1.154 × (age)-0.203 × (0.742 if female), where sCr is serum creatinine in mg/dL. The CKD-EPI equation is defined as:

where sCr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, and α is-0.329 for females and-0.411 for males. Random urine samples were analyzed to calculate ACR by measuring urinary microalbumin and urinary creatinine.

Statistical Analysis

All data were compiled and analyzed using the Statistical Package for the Social Sciences (SPSS), version 20.0, and Microsoft Excel 2010. Descriptive statistics were expressed as mean±standard deviation (SD) for continuous variables.

To compare mean values across the three study groups (euthyroid controls, drug-naïve primary hypothyroid patients, and primary hypothyroid patients under treatment), one-way analysis of variance (ANOVA) was performed, followed by Bonferroni post hoc tests to identify specific group differences. The chi-square (χ²) test was used to analyze categorical variables, including sex distribution. Pearson's correlation coefficient (r) was calculated to assess the strength and direction of association between thyroid hormone levels (TSH, free T 4 ) and renal function parameters (serum creatinine, urea, eGFR, ACR) among hypothyroid patients. A p-value of <0.05 was considered statistically significant, and for multiple comparisons, Bonferroni-adjusted significance thresholds were applied. Table 2 highlights the statistical significance of differences observed in renal function parameters between the control group, drug-naïve hypothyroid patients, and treated hypothyroid patients. Using post hoc Bonferroni correction, serum creatinine, eGFR (both CKD-EPI and MDRD), and urinary ACR showed highly significant differences (p<0.001) across all group comparisons, indicating clear renal functional alterations associated with untreated hypothyroidism and partial improvement following treatment. Interestingly, serum urea was significantly elevated only when comparing drug-naïve hypothyroid patients to controls and treated patients, while no significant difference (p = 1.0) was observed between controls and treated patients, emphasizing the normalization of urea levels after thyroid hormone therapy. Table 3 presents the Pearson correlation between serum TSH levels and renal function parameters. Among patients with primary hypothyroidism, there was a strong positive correlation between TSH and serum creatinine (r = 0.655, p<0.001), serum urea (r = 0.487, p<0.001), and urinary ACR (r = 0.829, p<0.001), indicating that worsening hypothyroidism is associated with impaired renal filtration and increased albuminuria. In contrast, eGFR values showed a strong negative correlation with TSH (CKD-EPI: r =-0.668; MDRD: r =-0.648; both p<0.001), reflecting the decline in filtration efficiency with rising TSH levels. Interestingly, no significant correlations were observed within the control group, suggesting that these associations become prominent only in the hypothyroid pathological state. Table 4 shows the Pearson correlation between serum free T 4 levels and renal function parameters. In hypothyroid patients, free T 4 was negatively correlated with serum creatinine (r =-0.620, p<0.001), serum urea (r =-0.484, p<0.001), and urinary ACR (r =-0.680, p<0.001), indicating that lower free T4 levels are linked to worsening renal function and greater albumin leakage. Conversely, eGFR values correlated positively with free T 4 (CKD-EPI: r = 0.639; MDRD: r = 0.621; both p<0.001), supporting the role of thyroid hormone sufficiency in maintaining glomerular filtration efficiency. Again, no significant correlations were seen in the control group, reinforcing that these renal changes are specific to thyroid dysfunction.

Results

Discussion

Thyroid hormones influence nearly every organ system, including the kidneys, where they impact both developmental and adult renal function [12,13] . Thyroid and kidney functions are intricately interlinked, with each organ influencing the physiology and homeostasis of the other. Thyroid hormones play a critical role in regulating renal development, renal blood flow, glomerular filtration rate (GFR), sodium and water reabsorption, and the activity of multiple transporters and enzymes in the nephron. In return, the kidney contributes to the metabolism, degradation, and excretion of thyroid hormones. Therefore, disruptions in thyroid function, whether hypothyroidism or hyperthyroidism, can profoundly alter renal hemodynamics, filtration capacity, and electrolyte balance, leading to measurable biochemical changes such as elevated serum creatinine, reduced GFR, altered urea clearance, and increased urinary albumin excretion. Numerous clinical and epidemiological studies have shown that hypothyroidism, even in its subclinical form, is associated with reduced GFR, increased serum creatinine, and sometimes the development of microalbuminuria or proteinuria, while hyperthyroidism can lead to hyperfiltration states with elevated GFR. These renal alterations are often reversible upon correction of the underlying thyroid abnormality, highlighting the dynamic and functional nature of the thyroid-renal axis.

Understanding this bidirectional relationship is essential for clinicians, as thyroid dysfunction can mask or mimic renal disease, and undiagnosed hypothyroidism may delay appropriate renal management. This study aims to clarify and quantify these associations in a population with a high burden of thyroid disease. In this study conducted at North Bengal Medical College and Hospital, we investigated renal function alterations in hypothyroid patients within a population with a known high prevalence of thyroid disorders. The study population was divided into three groups: newly diagnosed drug-naïve primary hypothyroid patients (n = 42), patients under treatment for primary hypothyroidism for over two months (n = 42), and healthy euthyroid controls (n = 40). Key renal parameters assessed included serum creatinine, serum urea, urinary ACR, and estimated GFR (eGFR) calculated by CKD-EPI and MDRD formulas.

Based on our study, serum TSH > 4.2 µIU/mL was considered hypothyroid. We observed that controls had mean TSH 1.61±1.12 µIU/mL and free T4 1.27±0.16 ng/dL, whereas drug-naïve hypothyroid patients had significantly elevated TSH (19.10±9.75 µIU/mL) and reduced free T4 (0.75±0.22 ng/dL). Treated hypothyroid patients showed improved values (TSH 3.58±1.65 µIU/mL; free T4 1.21±0.19 ng/dL), with both groups showing highly significant differences (p<0.001) compared to controls. Accurate estimation of GFR is critical because even small rises in serum creatinine can mask substantial GFR reductions [14] . Therefore, we employed both MDRD and CKD-EPI equations, which incorporate age, gender, and ethnicity to estimate GFR more precisely [10,11] . In hypothyroidism, reductions in GFR by up to 40% have been documented, accompanied by elevated serum creatinine [2,15,16] , as seen in both human and animal studies [17,18] . This decline is largely reversible upon thyroxine replacement, provided no permanent histological damage has occurred [2,18] .

Several mechanisms contribute to reduced GFR in hypothyroidism: diminished cardiac output and blood volume, impaired renin-angiotensin-aldosterone system activity, reduced atrial natriuretic peptide [2,16,19] , and lower renal expression of chloride channels, which alter tubuloglomerular feedback [17] . Additionally, decreased levels of insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) further reduce renal perfusion, which improves with thyroid hormone therapy [12,20] . [21] , which showed reduced GFR in both overt and subclinical hypothyroidism, as well as prior research by Adrees et al. and Woodward et al. [22,23] . Serum creatinine levels in our cohort were significantly elevated in untreated hypothyroid patients (1.16±0.13 mg/dL) compared to controls (0.81±0.09 mg/dL) and treated patients (0.88±0.11 mg/dL; p<0.001). This agrees with studies by Arora et al. (24) and Montenegro et al. (18), both of which documented decreased serum creatinine after thyroid hormone therapy. Although cystatin C is another marker of renal function, it was not included in our calculations, as thyroid dysfunction alters its metabolism, making creatinine-based equations more reliable in this context [25,26] . We also noted significantly higher serum urea levels in drug-naïve hypothyroid patients (25.30±6.45 mg/dL) compared to controls (18.60±2.39) and treated patients (16.45±3.32; p<0.001), supporting the reversible nature of renal filtration impairment in hypothyroidism (2, 4, 21). These results align with Montenegro et al. [18] but contrast with Arora et al. [24] , who found no significant urea alterations. Urinary ACR was markedly elevated in untreated hypothyroid patients (116.10±30.80 mg/gm), indicating microalbuminuria, which decreased significantly following treatment (47.50±17.10; p<0.001), though treated patients still had higher ACR than controls (24.50±3.40; p<0.001). Zhou et al. [27] first reported the inverse relationship between thyroid hormones and microalbuminuria in a large Chinese population. Our findings reinforce these observations and suggest that microalbuminuria in hypothyroidism may be independent of thyroid autoimmunity, as indicated by Asvold et al. [21] and Zhou et al. [27] , though we did not assess anti-TPO status in this study.

Correlation analyses in our study revealed that TSH was positively associated with serum creatinine, urea, and ACR, and negatively with eGFR (p<0.001), while free T 4 showed the opposite pattern (p<0.001). These associations are consistent with prior Indian data [29,30] , as well as international observations by Attaullah et al. [30] and Zhou et al. [27] . Notably, Montenegro et al. [18] did not find such correlations, likely due to their smaller sample size. Thus, our findings confirm that hypothyroidism significantly alters renal function through both direct renal and systemic effects, most of which are reversible with thyroid hormone therapy [31] . However, the long-term renal outcomes, especially in cases with prolonged untreated hypothyroidism, remain uncertain and warrant further investigation.

Conclusion

This study highlights the significant impact of primary hypothyroidism on renal function, demonstrating clear alterations in key biochemical parameters, including elevated serum creatinine, reduced estimated glomerular filtration rate (eGFR), increased serum urea, and microalbuminuria. Importantly, these impairments were shown to improve with appropriate levothyroxine therapy, underscoring the reversible nature of thyroid hormonerelated renal dysfunction when promptly treated. The positive correlations between serum TSH and renal impairment markers, alongside the negative correlations with eGFR, reinforce the strong interplay between the thyroid and renal systems.

Given the high prevalence of hypothyroidism in Indian populations, especially in iodine-deficient and high-risk regions, routine thyroid function screening in patients with unexplained renal abnormalities is crucial. Early diagnosis and treatment of hypothyroidism not only restore thyroid balance but may also prevent the progression to chronic kidney disease, thereby improving overall patient outcomes. Further longitudinal and interventional studies are recommended to explore long-term renal recovery patterns and the potential role of thyroid hormone modulation in kidney health preservation.

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