Abnormalities of Thyroid Function in Chronic Dialysis Patients

Normal Thyroid Hormone Physiology

The production of thyroid hormone is stimulated by TSH from the pituitary, which in turn is regulated by TSH-releasing hormone (TRH) from the hypothalamus. While T4 is solely produced by the thyroid gland, 80% of T3 is generated from the deiodination of T4-to-T3 by the type 1 and 2 5’-deiodinase enzymes (D1 and D2) in peripheral tissues. In humans, D2 is believed to be the principal enzyme responsible for peripheral T4-to-T3 production. Consequently, both TSH and TRH are regulated by feedback inhibition from circulating T4, which is converted to T3 in the pituitary and hypothalamus by D2.

Thyroid Functional Disease Leading to Kidney Disease

While the mechanistic link between thyroid and kidney disease has not been fully elucidated, growing data suggest the relationship is bidirectional ( Fig. 52.2 ). With respect to thyroid dysfunction as a risk factor for CKD, experimental models have shown that hypothyroidism adversely affects kidney size and structure both in development and adulthood. For example, in neonatal rats, hypothyroidism has been shown to result in decreased kidney-size-to-body-weight-ratio, truncated tubular mass, and decreased glomerular basement membrane (GBM) volume. Hypothyroidism has also led to diminished compensatory hypertrophy following unilateral nephrectomy in animal models, and histologic data has demonstrated that hypothyroidism is associated with GBM architectural changes such as reduced GBM area, GBM thickening, mesangial matrix expansion, and glomerular capillary permeability.

Hypothyroidism may also lead to decreased kidney function , presumably due to reduced kidney blood flow from (1) decreased cardiac output resulting from systolic dysfunction, diastolic impairment, and decreased blood volume, (2) intrarenal hemodynamic derangements due to impaired vasodilator (e.g., nitric oxide, adrenomedullin) synthesis and activity, (3) decreased renin-angiotensin-aldosterone activity leading to impaired autoregulation of kidney perfusion, and (4) alterations in chloride channel expression with increased distal tubular chloride delivery, kidney afferent arteriole vasoconstriction, and lower glomerular filtration rate (GFR) (i.e., increased tubulo-glomerular feedback). For example, animal studies have shown that hypothyroidism leads to decreased single nephron GFR, kidney plasma flow, and glomerular transcapillary hydrostatic pressure. Human case series have also confirmed that severe hypothyroidism results in reversible plasma flow reductions, serum creatinine elevations, and decreased GFR as measured by indirect estimating equations and gold standard isotopic kidney scans, confirming that changes in creatinine levels were due to actual changes in GFR as opposed to underlying myopathy or alterations in creatinine metabolism.

In large population-based studies, while multiple cross-sectional analyses corroborate a link between milder forms of hypothyroidism and kidney dysfunction, longitudinal studies have been sparse, with mixed findings. In a longitudinal study of 104,633 patients with normal baseline kidney function who underwent annual to biennial TSH measurements, patients whose baseline TSH levels were in the highest quintile (TSH 2.85–5.00 mIU/L) had a 26% higher risk of incident CKD (defined as eGFR < 60 mL/min/1.73m ² ) vs. those in the lowest TSH quintile (TSH 0.25–1.18 mIU/L). Similarly, in a study of 41,454 elder adults with normal baseline kidney function who underwent repeated TSH measurements over time, those with subclinical hypothyroidism (defined as TSH > 3–5 mIU/L) and overt hypothyroidism (defined as TSH > 10–99 mIU/L) were each at higher risk of developing subsequent CKD (defined as eGFR < 60 mL/min/1.73m ² or abnormal proteinuria levels) compared to those who were euthyroid. Yet in studies of the Atherosclerosis Risk in Communities Study and Leiden-85 Plus (i.e., population-based study of 85-year old residents of Leiden, the Netherland) cohorts, whereas cross-sectional analyses showed that baseline hypothyroidism was associated with kidney dysfunction, longitudinal analyses of these cohorts did not confirm a relationship with incident CKD or eGFR decline. However, it bears mentioning that these two studies assessed TSH levels only at a single point in time (i.e., baseline TSH only), which may have led to thyroid status misclassification over time. It should also be noted that cystatin C should not be used as a metric of kidney function in patients with thyroid functional disease, given that its production may be affected by thyroid hormone independent of GFR.

Limited observational data also suggest that thyroid hormone replacement is associated with reduced CKD progression in patients with subclinical hypothyroidism. In a study of 309 patients with stages 2–4 CKD and subclinical hypothyroidism, after a median follow-up of 35 months, patients who received thyroid hormone replacement therapy were less likely to experience a halving of eGFR or development of incident ESKD compared to those who were untreated. Given the potential role of thyroid dysfunction as a modifiable risk factor for kidney disease, further studies are needed to determine the longitudinal impact of thyroid status and its treatment upon incident CKD and CKD progression.

Kidney Disease Leading to Thyroid Functional Disease

Kidney disease may also lead to thyroid functional disease via several pathways (see Fig. 52.2 ). First, metabolic acidosis has been associated with lower T3, lower T4, and higher TSH levels in nondialysis patients. In one study of hemodialysis patients, correction of metabolic acidosis with sodium citrate normalized FT3 concentrations but had no impact on FT4 or TSH levels. In a secondary analysis of hemodialysis patients from the Frequent Hemodialysis Network (FHN) Trials, while significant correlations were observed between changes in serum bicarbonate and changes in FT3 and FT4 levels, these findings were no longer significant after adjusting for changes in normalized protein catabolic rate (nPCR) levels; notably, this study excluded patients with serum TSH levels > 8 mIU/L and/or received thyroid hormone supplementation who were presumed to have treated or untreated hypothyroidism and did not take into consideration TSH levels in the analyses. Second, selenium deficiency is common in hemodialysis patients and may impair peripheral T4-to-T3 conversion, leading to lower T3 levels. Third, iodine retention from iodinated contrast-enhanced imaging studies, fistulograms, angiograms, povidone-iodine solutions used to sterilize peritoneal dialysis catheter tips, and dietary sources may lead to hypothyroidism via the Wolff-Chaikoff effect or hypothyroidism via the Jod-Basedow phenomenon. Fourth, testosterone deficiency is also common in dialysis patients, and animal studies have been associated with reduced peripheral deiodination of T4-to-T3. Fifth, as the vast majority of circulating T3 and T4 (> 99%) are bound to carrier proteins such as thyroid-binding globulin, transthyretin, albumin, and lipoproteins, heavy urinary losses of these proteins in nephrotic syndrome may lead to thyroid hormone deficiency. Sixth, malnutrition, inflammation, and underlying comorbidities prevalent in dialysis patients may lead to nonthyroidal illness (i.e., thyroid function test alterations associated with underlying ill health in the absence of thyroid pathology) ( Table 52.2 ). Lastly, various medications commonly prescribed in dialysis patients may lead to thyroid function test alterations ( Table 52.3 ).

Effects of Dialysis on Thyroid Function Tests

Limited data suggest that dialysis therapy may contribute to alterations in thyroid hormone metabolism. Two case series of peritoneal dialysis patients demonstrated that 10%–30% of daily T4 production was lost in peritoneal dialysis effluent as a free and protein-bound hormone; however, some have posited that the predominant etiology of hypothyroidism in peritoneal dialysis patients is iodine excess from povidine-iodine cleaning agents as opposed to peritoneal effluent thyroid hormone losses. In hemodialysis patients, one study that measured thyroid function tests pre- and postdialysis showed that TSH levels remained stable, whereas T3 and T4 demonstrated a significant rise postdialysis; these changes were thought to be due to medication effects and extravascular shifts in thyroid hormone. Notably, in a secondary analysis of FHN trial participants among whom the prevalence of hypothyroidism was 11% (defined as receipt of thyroid hormone supplementation and/or having a TSH level ≥ 8 mIU/L), among patients in the in-center frequent hemodialysis and nocturnal home hemodialysis arms (i.e., receipt of hemodialysis six times per week), changes in TSH, FT3, and FT4 levels were not observed after a 12-month period. Yet, in another study of 22 incident hemodialysis patients, those who were treated with long nocturnal hemodialysis were less likely to have low FT3 levels vs. those treated with conventional hemodialysis.