Thyroid Status in Chronic Renal Failure Patients

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Epidemiology of Thyroid Dysfunction in Kidney Disease

Thyroid functional disease, and in particular hypothyroidism, is a common condition in the general population that is typically ascertained using a combination of biochemical tests, which include serum thyrotropin (TSH) and free thyroxine (FT4). Landmark data from the Third National Health and Nutritional Examination Survey (NHANES III) have shown that approximately 10 million adults in the United States are affected by hypothyroidism. Data across various heterogeneous cohorts suggest that 4%–10% of the general population have subclinical hypothyroidism (defined as an elevated TSH and normal FT4), and 0.1%–2% of the general population have overt hypothyroidism (defined as an elevated TSH and low FT4) ( Table 27.1 ). Various expert groups have recommended thyroid functional test screening in selected populations ( Table 27.2 ).

Epidemiologic data also show that CKD patients, including those receiving dialysis, have a substantially higher prevalence of hypothyroidism compared to their non-CKD counterparts ( Table 27.3 ). For example, in a study of 14,623 NHANES III participants, Lo et al. demonstrated that there is an increasing prevalence of hypothyroidism (defined as a TSH >4.5 mIU/L and/or receipt of thyroid hormone replacement therapy) with incrementally impaired kidney function: 5.4%, 10.9%, 20.4%, 23.0%, and 23.1% of participants with estimated glomerular filtration rates (eGFRs) of >90, 60–89, 45–59, 30–44, and <30 mL/min per 1.73 m ² , respectively [defined using the Modification of Diet in Renal Disease (MDRD) formula]. Even after multivariable adjustment for age, sex, and race/ethnicity, there remained a twofold higher risk of hypothyroidism among participants with an eGFR <30 mL/min per 1.73 m ² (reference: eGFR >90 mL/min per 1.73 m ² ). More recently, in a study of 461,607 US veterans with stages 3–5 CKD who underwent repeated measurements of serum creatinine and TSH at identical time points, Rhee et al. found that a 10 mL/min per 1.73 m ² decrement in eGFR defined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was associated with an 18% higher risk of hypothyroidism (defined as a TSH >5.0 mIU/L and/or receipt of thyroid hormone replacement therapy) independent of sociodemographic characteristics and comorbidities.

Although there have been comparatively fewer studies of hypothyroidism in large population-based analyses of dialysis-dependent CKD patients, existing data suggest that they have a similarly high prevalence of hypothyroidism ( Table 27.3 ). While estimates vary depending on the diagnostic criteria and severity of disease, various cross-sectional analyses indicate that the prevalence of hypothyroidism overall (i.e., overt and subclinical hypothyroidism combined) may range from 13% to 23% in the dialysis population. However, there is likely underrecognition of thyroid functional disease in this population given that their symptoms may overlap with uremia (e.g., fatigue, weakness, impaired cognition, depression).

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Thyroid Physiology

In normal thyroid physiology, production of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) are stimulated by TSH released from the anterior pituitary gland, which in turn is regulated by thyrotropin-releasing hormone (TRH) that is released from the hypothalamus. The vast majority of T4 is generated by the thyroid gland, whereas ∼80% of T3 is produced by the deiodination of T4 to T3 by the type 1 and 2 5′-deiodinase enzymes in peripheral organs. It is believed that type 2 5′-deiodinase is the principle enzyme responsible for peripheral T4 to T3 conversion in humans. In turn, both TSH and TRH are regulated by feedback inhibition from circulating T4, which is converted to T3 in the pituitary and hypothalamus by the type 2 5′-deiodinase.

Circulating thyroid hormone may enter cells by carrier-mediated transport or diffusion, or may be locally available via intracellular T4 to T3 production. Thyroid hormone may alter protein synthesis and substrate turnover through its binding to nuclear receptors and formation of thyroid hormone–nuclear receptor complexes that bind to DNA and modify gene transcription. As T3 binds to nuclear receptors with a 10- to 15-fold higher affinity than T4, T4 is considered to be a prohormone.

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Thyroid Functional Test Derangements in Kidney Disease

Various thyroid functional test alterations may be observed in kidney disease resulting from impaired metabolism, degradation, and excretion of thyroid hormone and its derivatives ( Table 27.4 ). Furthermore, the presence of uremic toxins may lead to alterations in the hypothalamic–pituitary–thyroid axis, as well as impaired performance of routinely used thyroid functional test assays. The latter may subsequently result in thyroid functional test alterations among euthyroid predialysis and dialysis-dependent CKD patients.