Clinical and Pathophysiological Aspects of Thyroid Dysfunction in Chronic Kidney Disease: A Critical Review

3.1. Spectrum and Prevalence of Thyroid Dysfunction in CKD

Available evidence consistently demonstrates that thyroid dysfunction is markedly more prevalent in patients with chronic kidney disease (CKD) than in the general population [1,2]. The spectrum of abnormalities includes subclinical hypothyroidism, overt hypothyroidism, and non-thyroidal illness syndrome (NTIS), with the latter-particularly low triiodothyronine (T₃) syndrome-being the most characteristic finding. The consolidated prevalence rates and diagnostic features of these conditions are summarized in Table 1.

Subclinical hypothyroidism represents the most frequently reported thyroid abnormality in CKD, with prevalence estimates ranging from 10% to 30%, depending on CKD stage, population characteristics, and diagnostic thresholds [5]. In patients with advanced CKD (stages 4–5), the prevalence may increase up to 40%, particularly among elderly individuals and those with comorbid diabetes mellitus. Several large cohort studies have demonstrated that even mild reductions in estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m²) are associated with a higher frequency of elevated TSH levels [6].

The prevalence increases progressively with declining glomerular filtration rate (GFR), suggesting a direct relationship between renal impairment and thyroid dysfunction. This association appears to be dose-dependent, with each decrement in renal function accompanied by a gradual increase in thyroid abnormalities [7,8].

Low T₃ syndrome is observed even more frequently, especially in advanced CKD and end-stage renal disease (ESRD). Reported prevalence ranges from 20% to 70% in dialysis populations [9]. This condition is characterized by reduced serum T₃ levels with normal or slightly altered thyroid-stimulating hormone (TSH) and thyroxine (T₄) levels. Importantly, low T₃ syndrome may occur in the absence of intrinsic thyroid disease, raising questions about its pathophysiological and clinical significance. Several studies have demonstrated that low T₃ levels correlate inversely with markers of renal function, including eGFR and creatinine clearance [10]. Furthermore, low T₃ concentrations are associated with markers of malnutrition and inflammation, such as hypoalbuminemia and elevated C-reactive protein levels, suggesting that this condition reflects systemic illness severity [11].

In contrast, overt hypothyroidism is less common but still occurs more frequently than in the general population, with reported prevalence rates ranging from 0.5% to 9% [12]. Hyperthyroidism appears to be relatively rare in CKD, although its diagnosis may be challenging due to overlapping clinical features and altered hormone metabolism. Importantly, differences in thyroid dysfunction prevalence have also been observed depending on dialysis modality. Patients undergoing hemodialysis tend to have lower T₃ levels compared with those on peritoneal dialysis, possibly due to differences in protein loss, inflammation, and metabolic status [13]. Additionally, kidney transplant recipients may exhibit partial normalization of thyroid function, although abnormalities can persist in some cases [14].

Sex- and age-related differences have also been reported. Female patients and older individuals show a higher prevalence of subclinical hypothyroidism, consistent with patterns observed in the general population but amplified in CKD [15].

Notably, significant variability exists across studies, which may be attributed to differences in iodine intake, assay methods, comorbid conditions (e.g., diabetes mellitus), medication use (such as corticosteroids or amiodarone), and dialysis modalities [16]. In addition, the lack of standardized reference ranges for thyroid hormones in CKD populations complicates interpretation and may contribute to inconsistencies in reported prevalence [17].

3.2. Alterations in Thyroid Hormone Metabolism and Regulation

CKD is associated with profound changes in thyroid hormone metabolism, transport, and regulation. One of the central mechanisms is impaired peripheral conversion of T₄ to T₃ due to reduced activity of type 1 deiodinase enzymes [3,7]. This leads to decreased circulating levels of biologically active T₃ and contributes to the development of low T₃ syndrome. In addition, reduced expression of type 2 deiodinase and increased activity of type 3 deiodinase may further promote the conversion of T₄ to reverse T₃ (rT₃), leading to accumulation of inactive metabolites and further suppression of T₃ availability [18].

In addition, uremic toxins accumulate in CKD and interfere with hormone binding to carrier proteins such as thyroxine-binding globulin (TBG), transthyretin, and albumin. This results in altered total hormone concentrations, while free hormone levels may remain relatively preserved. Furthermore, hypoalbuminemia, commonly observed in CKD, may additionally influence hormone distribution and measurement accuracy [19].

The hypothalamic–pituitary–thyroid (HPT) axis is also affected. Chronic inflammation, commonly observed in CKD, suppresses hypothalamic thyrotropin-releasing hormone (TRH) secretion and alters pituitary TSH response [20]. Proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been shown to inhibit TSH secretion and impair thyroid hormone signaling at the tissue level [21]. Consequently, TSH levels may not adequately reflect peripheral thyroid hormone status, complicating the diagnosis of true thyroid dysfunction.

Additional contributing factors include metabolic acidosis, reduced renal clearance of iodide, and changes in hormone distribution volume. Iodide retention may transiently inhibit thyroid hormone synthesis via the Wolff–Chaikoff effect, particularly in advanced CKD [22]. Moreover, altered activity of thyroid hormone transporters may impair cellular uptake of T₃ and T₄, further contributing to tissue-level hypothyroidism [23]. Hemodialysis and peritoneal dialysis may further influence thyroid hormone levels through shifts in protein binding and removal of circulating substances. Hemodialysis, in particular, may lead to fluctuations in hormone concentrations due to changes in plasma volume and protein loss, whereas peritoneal dialysis is associated with continuous protein loss that may affect hormone-binding dynamics [24].

3.3. Role of Inflammation, Oxidative Stress, and Uremic Milieu

Chronic low-grade inflammation is a hallmark of CKD and plays a critical role in thyroid dysfunction. Elevated levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), have been shown to inhibit deiodinase activity and reduce T₃ production [25].

Oxidative stress further exacerbates these effects by damaging cellular components involved in hormone synthesis and metabolism. Increased production of reactive oxygen species (ROS), coupled with impaired antioxidant defense systems in CKD, leads to oxidative modification of proteins, lipids, and nucleic acids, thereby impairing thyroid hormone signaling at both systemic and cellular levels [26].

The uremic milieu, characterized by the accumulation of toxins, metabolic waste products, and advanced glycation end-products (AGEs), disrupts endocrine signaling pathways and contributes to systemic metabolic dysregulation. Uremic toxins such as indoxyl sulfate and p-cresyl sulfate have been shown to interfere with hormone receptor activity and intracellular signaling cascades, potentially reducing tissue responsiveness to thyroid hormones [27]. In addition, these toxins may impair the binding of thyroid hormones to nuclear receptors, further contributing to functional hypothyroidism at the tissue level.

Importantly, these mechanisms overlap with those observed in non-thyroidal illness syndrome (NTIS), supporting the hypothesis that thyroid hormone alterations in CKD may represent an adaptive response aimed at reducing metabolic demand during chronic illness [28].

However, whether this adaptation is beneficial or detrimental remains a matter of debate. While some authors consider low T₃ levels a protective mechanism, others view them as a marker of disease severity and poor prognosis. Several observational studies have demonstrated that reduced T₃ concentrations are independently associated with increased cardiovascular morbidity, vascular calcification, and all-cause mortality in CKD and dialysis populations [29].

Furthermore, inflammation and oxidative stress are closely linked to malnutrition and protein-energy wasting, which are common in advanced CKD. This complex interplay, often referred to as the malnutrition–inflammation–atherosclerosis (MIA) syndrome, may further aggravate thyroid hormone abnormalities and contribute to adverse clinical outcomes [30].

Taken together, inflammation, oxidative stress, and the uremic environment form an interconnected pathophysiological network that profoundly influences thyroid hormone metabolism and action in CKD. A better understanding of these mechanisms is essential for distinguishing adaptive responses from clinically significant dysfunction and for identifying potential therapeutic targets.

3.4. Clinical Significance and Prognostic Implications of Thyroid Dysfunction

Thyroid dysfunction in chronic kidney disease is associated with adverse outcomes, particularly increased cardiovascular morbidity and mortality. Low triiodothyronine (T₃) levels are linked to cardiac dysfunction and independently predict mortality in CKD populations [9,11,14]. Subclinical hypothyroidism may contribute to disease progression and anemia, while thyroid dysfunction overall is associated with dyslipidemia, reduced quality of life, and increased healthcare utilization [24,29]. In kidney transplant recipients, low T₃ may be associated with poorer graft outcomes [31]. However, it remains unclear whether thyroid dysfunction is a modifiable risk factor or a marker of disease severity, as evidence for therapeutic intervention remains limited [32].

3.5. Therapeutic Considerations and Evidence Gaps

Despite the growing recognition of thyroid dysfunction in CKD, its management remains controversial. There is currently no consensus regarding routine screening or treatment thresholds in this population. Current clinical guidelines provide limited and often non-specific recommendations, largely due to the heterogeneity of available evidence and the absence of CKD-specific randomized trials [33].

Some studies suggest that thyroid hormone replacement therapy may improve renal function and cardiovascular outcomes in patients with subclinical hypothyroidism [13]. Potential mechanisms include improved cardiac output, reduced systemic vascular resistance, and enhanced renal perfusion. In addition, levothyroxine therapy has been associated with modest improvements in lipid profiles and endothelial function in selected patient populations [34]. However, other studies have failed to demonstrate clear benefits, particularly in patients with mild hormonal abnormalities or advanced CKD, where the impact of therapy may be attenuated by non-thyroidal factors [35].

Importantly, overtreatment with thyroid hormones may carry significant risks, especially in CKD patients who often have multiple comorbidities. Excessive thyroid hormone replacement may lead to arrhythmias, increased myocardial oxygen demand, bone loss, and worsening protein catabolism [36]. Therefore, careful dose titration and close monitoring are essential when initiating therapy in this population. In the case of low T₃ syndrome, treatment is even more controversial. Given its potential role as an adaptive response, routine thyroid hormone replacement is not currently recommended. Interventional studies using T₃ supplementation have yielded inconsistent results, and concerns remain regarding potential adverse effects, including increased metabolic demand and cardiovascular stress [37].

Another important consideration is the interpretation of thyroid function tests in CKD. Altered protein binding, inflammation, and assay variability may lead to misclassification of thyroid status. As a result, reliance on standard reference ranges may be inappropriate, and there is a growing need for CKD-specific diagnostic criteria [33,34]. Some authors suggest that dynamic assessment and longitudinal monitoring of thyroid function may be more informative than single time-point measurements.

In addition, the impact of dialysis modality on thyroid function raises important clinical questions. While some studies suggest that peritoneal dialysis may be associated with more stable thyroid hormone levels, others indicate that protein losses may exacerbate hormone deficiencies, highlighting the need for individualized assessment [38].

The role of iodine balance in CKD also remains insufficiently explored. Reduced renal clearance of iodide may predispose patients to iodine excess, which can suppress thyroid hormone synthesis via the Wolff–Chaikoff effect. At the same time, dietary restrictions and regional variations in iodine intake may contribute to iodine deficiency in certain populations [39].

These inconsistencies highlight the need for large-scale prospective studies and randomized controlled trials to clarify the clinical significance of thyroid dysfunction in CKD and to establish evidence-based management strategies. Future research should focus on identifying patient subgroups that may benefit from intervention, determining optimal treatment thresholds, and evaluating long-term outcomes associated with thyroid hormone replacement in CKD populations [40].