Thyroid function in chronic kidney disease

INTRODUCTION — The kidney normally plays an important role in the metabolism, degradation, and excretion of several thyroid hormones. It is not surprising, therefore, that impairment in kidney function leads to disturbed thyroid physiology. All levels of the hypothalamic-pituitary-thyroid axis may be involved, including alterations in hormone production, distribution, and excretion. (See "Thyroid hormone synthesis and physiology".)

As a result, abnormalities in thyroid function tests are frequently encountered in patients with chronic kidney disease (CKD). However, the overlap in symptomatology between the uremic syndrome and hypothyroidism requires a cautious interpretation of these tests. Nevertheless, it is ordinarily possible in the individual patient with CKD to assess thyroid status accurately by physical diagnosis and thyroid function testing.

Epidemiologic data suggest that predialysis patients with chronic kidney disease have an increased risk of hypothyroidism [1,2]. Many cases are subclinical.

The changes in thyroid hormone metabolism that occur in the nephrotic syndrome and the general issue of thyroid function in nonthyroidal illness are discussed elsewhere. (See "Endocrine dysfunction in the nephrotic syndrome" and "Thyroid function in nonthyroidal illness".)

THYROID HORMONE METABOLISM — The kidney normally contributes to the clearance of iodide, primarily by glomerular filtration. Among patients with kidney failure, there is diminished iodide excretion and an increase in plasma inorganic iodide, which results in increased uptake of the iodide by the thyroid gland [3]. Increases in total body inorganic iodide can potentially block thyroid hormone production (the Wolff-Chaikoff effect). Such a change may explain the slightly higher frequency of goiter and hypothyroidism in patients with chronic kidney disease [4].

Hypothyroidism can also result from increased exposure to iodine among patients with kidney failure. As an example, in one study, four children receiving peritoneal dialysis developed iodine overload and hypothyroidism that was attributed to chronic exposure to a povidone-iodine-impregnated gauze from the transfer set [5]. Other aspects and causes for acquired hypothyroidism in children are discussed elsewhere. (See "Acquired hypothyroidism in childhood and adolescence".)

Low T3 levels — Most patients with end-stage kidney disease (ESKD) have decreased plasma levels of free triiodothyronine (T3), which reflect diminished conversion of T4 (thyroxine) to T3 in the periphery [6-8]. This abnormality is not associated with increased conversion of T4 to the metabolically inactive reverse T3 (rT3), since plasma rT3 levels are typically normal. This finding differentiates the patient with CKD from patients with chronic illness [6,8]. In the latter setting, the conversion of T4 to T3 is similarly reduced, but the generation of rT3 from T4 is enhanced.

These changes refer to the total T3 concentration. In contrast, circulating levels of serum T3 sulfate may be increased in patients with ESKD, possibly due to reduced renal clearance [9].

Low levels of total T3 also may reflect metabolic acidosis [10] and reduced protein binding. With respect to the latter, circulating thyroid hormones are normally bound to thyroid hormone-binding globulin (TBG) and, to a lesser extent, to prealbumin and albumin. Although circulating TBG and albumin levels are typically normal in patients with CKD (in the absence of the nephrotic syndrome), retained substances due to impaired kidney clearance may inhibit hormone binding to these proteins. As examples, urea, creatinine, indoles, and phenols all strongly inhibit protein binding of T4 [11]. This inhibition may explain why some patients with chronic kidney disease have low serum T4 levels. Another possible contributing factor is that binding inhibitors may inhibit T4 binding to solid-phase matrices such as resin and activated charcoal used in measuring T4 levels [12]. (See "Uremic toxins".)

Free fatty acids and heparin also interfere with T4 binding to TBG. Thus, the routine use of heparin to prevent clotting in the dialysis tubing may explain the transient elevation in serum T4 levels that commonly occurs during hemodialysis [13].

Low plasma free T3 levels may also be associated with decreased survival and the malnutrition-inflammation syndrome [14,15]. The latter is a common chronic condition in patients on dialysis associated with markedly increased cytokine levels. (See "Inflammation in patients with kidney function impairment".)

Hypothalamic-pituitary dysfunction — The plasma concentration of thyroid-stimulating hormone (TSH) is usually normal in chronic kidney disease [6,7,16]. However, the TSH response to exogenous thyrotropin-releasing hormone (TRH) is often blunted and delayed, with a prolonged time required to return to baseline levels [17,18]. Reduced renal clearance may contribute to delayed recovery since TSH and TRH are normally cleared by the kidney. However, the blunted hormone response also suggests disordered function at the hypothalamic-pituitary level that may be induced by uremic toxins. When compared with normals, patients with chronic kidney disease have an attenuated rise in TSH levels during the evening hours [19], and the normally pulsatile secretion of TSH is smaller in amplitude [20].

Despite these perturbations, TSH release responds appropriately to changes in the circulating level of thyroid hormones. Exogenous T3 lowers TSH levels [16] and can totally suppress the secretory response to exogenous TRH [17]. On the other hand, TSH production increases appropriately in response to thyroid ablation [21]. The latter response is important clinically since TSH levels should rise (as in normals) when a uremic patient develops hypothyroid [6].

CLINICAL SIGNIFICANCE — Low T3 concentrations, although initially thought to be an adaptive response to chronic illness, have been associated with all-cause and cardiovascular mortality in patients with CKD [15,22,23]. As an example, in one study of 210 patients on hemodialysis, low T3 concentrations, particularly if persistent throughout the 38-month study, were associated with a higher risk of all-cause and cardiovascular mortality, with hazard ratios of 2.7 and 4.0, respectively [23]. A low T4, but not thyroid-stimulating hormone (TSH), was also associated with all-cause and cardiovascular mortality. T3, T4, or TSH did not correlate with noncardiovascular mortality. In another study, lower T3 levels at the initiation of peritoneal dialysis were found to be a predictor of long-term all-cause and cardiovascular mortality, independent of comorbidities and markers of nutrition and inflammation [24]. Whether low T3 and T4 are markers for some other clinical process that associates more directly with mortality or have a causal role remains to be determined, as does the pathophysiologic basis for this association.

In general, there is substantial clinical overlap between chronic kidney disease and hypothyroidism. In addition to low total and plasma free T3 levels, there are a number of symptoms that are common to both conditions, including cold intolerance, puffy appearance, dry skin, lethargy, fatigability, and constipation. Furthermore, the frequency of goiter is markedly increased in end-stage kidney disease [6,25]. Despite these findings, most patients with CKD are considered to be euthyroid, as evidenced by normal plasma concentrations of TSH and free T4 and normal basal metabolic rate and tendon relaxation time [6,7,16,26].

The latter observations are important because they suggest that some of the clinical findings used to diagnose hypothyroidism in subjects with normal kidney function can also be applied to patients with impaired kidney function. Hypothyroidism can occur in patients with kidney disease, with a frequency that may be slightly greater than that in the general population [6,27]. The diagnosis can be established by the demonstration of an elevated serum TSH concentration, usually associated with a reduced serum-free T4 concentration and normal thyroid hormone-binding globulin (TBG) levels (algorithm 1) [6]. Delayed deep tendon relaxation may be a confirmatory clinical finding.

Despite the euthyroid status of most uremic patients, there is some evidence for blunted tissue responsiveness of T3 [16]. Although basal oxygen utilization is normal in kidney failure, the expected increase following the administration of T3 is not seen. It has also been suggested that the decreased T3 production may have a protective effect by minimizing protein catabolism [21].

Thyroid gland size — Thyroid gland size is often increased in patients with chronic kidney disease [28]. How this occurs is not clear. The subtle changes in thyroid hormone metabolism noted above do not appear to be sufficient to produce this alteration. It is possible that kidney failure is associated with the accumulation of an unidentified goitrogen.

Nodules and carcinoma — Patients with chronic kidney disease may have a slightly higher frequency of thyroid nodules and thyroid carcinoma [4,27]. Why this might occur is not known.

SUMMARY

●Thyroid hormones in chronic kidney disease – Chronic kidney disease (CKD) is associated with multiple disturbances in thyroid metabolism that are manifested by low serum-free and total T3 levels and normal rT3 and free T4 concentrations. The serum thyroid-stimulating hormone (TSH) concentration is normal, and most patients are euthyroid. (See 'Thyroid hormone metabolism' above.)

●Clinical significance – Low T3 and T4 concentrations have been associated with increased mortality in patients with CKD, especially from cardiovascular causes. Whether low T3 and T4 are markers for some other clinical process that associates more directly with mortality or have a causal role remains to be determined. (See 'Clinical significance' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William L Henrich, MD, MACP, who contributed to earlier versions of this topic review.