The thyroid and the kidney: a complex interplay in health and disease

Impact of thyroid hormones on kidney growth and development

The increased prevalence of renal abnormalities in children with congenital hypothyroidism (25) indicates that thyroid hormone plays a crucial role on kidney evolution during embryogenesis. Data from animal studies report that thyroid hormone influences renal growth and function (26-27-28). Hyperthyroidism in neonatal rats enhances protein turnover (27) and leads to renal hypertrophy by activation of the intrarenal RAS (29), whereas hypothyroidism has an opposite effect on protein synthesis and cellular development with a concomitant decrease in cell number and in size of the kidney (26, 28).

There is indirect evidence that RAS mediates changes of kidney structure caused by thyroid hormone alterations, but the exact mechanism has not fully elucidated (26, 29). In support of this hypothesis, Kobori et al (30) reported that administration of an antagonist of the angiotensin receptor attenuates kidney hypertrophy induced by hyperthyroidism. However, there are anecdotal reports that long-term use of angiotensin converting enzyme (ACE) inhibitors or AT II receptor blockers (ARBs) did not regress renal hypertrophy in hyperthyroid animals (31, 32). Thyroid hormone participates in the development of many co-transport systems in the renal tubule including renal Na⁺ co-transported phosphate, cortical Na⁺/H⁺ exchanger (NHE), and Na⁺- K⁺ adenosine-triphosphatase (33-34-35-36-37). Notably, Wijkhuisen et al (38) suggested that thyroid hormone regulates the development of several energy metabolism enzymes of proximal convoluted tubule of perinatal rats such us the enzyme 3-ketoacid-CoA transferase, citrate synthase and carnitine acetyltransferase. In addition, depletion of thyroid hormone in neonatal rats may cause deficits in the development of renal alpha-adrenergic receptors, beta-adrenergic receptors and may lead to modifications of adenylate cyclase in the kidney (39). An increased activity of adenylate cyclase and ornithine decarboxylase has been observed in rats with hyperthyroidism (40).

Thyroid disorders and glomerular filtration rate

Primary hypothyroidism is associated with a reversible increase in Scr and a decrease of GFR in both adults and children (8-9-10, 41). A similar effect on Scr and GFR has been also reported in patients with subclinical hypothyroidism (42) (Tab. I). In the mid-nineties, Montenegro et al (43) reported a decrease of GFR measured by creatinine clearance in 41 patients and an increase of Scr in 22 patients with hypothyroidism. Moreover, the authors reported normalization of these defects after treatment with thyroid hormone (43). Van Welsem and Lobatto (44) observed that replacement therapy with levothyroxine led to a significant improvement of renal function in a patient with severe hypothyroidism and CKD. In accordance, Elgadi et al. (45) reported a similar effect of hormone replacement therapy on renal function in children.

This association between renal function and hypothyroidism has been observed and in other studies using the Modification of Diet in Renal Disease (MDRD) creatinine-based equation and/or the newly introduced Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (46, 47). Data from studies using more precise GFR measuring methods (inulin or ⁵¹Cr-EDTA) concluded that hypothyroidism is associated reduced GFR (10). All these studies confirmed that restoration of thyroid hormone levels can increase GFR. Thus, thyroid hormone screening is required in order to detect hypothyroidism in patients with unexplained increases of Scr.

The decrease of GFR observed in hypothyroid humans has several causes. Hypothyroidism may cause hemodynamic and vascular changes leading to decreased RBF (48). In addition, decreased cardiac output (CO) and circulating volume, decreased activity of RAS, and decreased levels of atrial natriuretic factor have been associated in hypothyroid status, contributing to a decrease in renal perfusion with a concomitant reduction of GFR (49). Bradley et al (26) reported in hypothyroid rats that a decrease in glomerular surface area due to growth retardation may contribute to the decrease of GFR. Data from hypothyroid animals showed an adaptive pre-glomerular vasoconstriction mechanism in response to a filtrate overload due to deficient sodium and water reabsorption in the epithelial cells of the proximal tubule (50). Additionally, a chloride load in distal tubuli of hypothyroid rats, caused by a disturbed activity of chloride channels CIC-2, activated the tubulo-glomerular feedback leading to decreased GFR (49). Moreover, hypothyroidism causes a reduction of the expression of several glomerular vasodilators including insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF), contributing to the reduction of GFR (51).

In contrast, hyperthyroidism has the opposite effect on Scr and GFR. In clinical states of thyrotoxicosis, RBF and GFR has been reported to be increased whereas Scr decreases (11, 12). A reduction of Scr has been also observed in patients with subclinical hyperthyroidism (42). Similarly to hypothyroidism, normalization of thyroid function by appropriate treatment may lead to normalization of renal function (52).

The etiology is multifactorial. Firstly, hyperthyroidism increases the CO due to its positive chronotropic and inotropic heart effects. Moreover, the increased blood volume due to the activation of RAS contributes to the increase of RBF (49). Thyroid hormone in excess causes a decrease in the resistance of afferent glomerular arterioles leading to an increase in the glomerular hydrostatic pressure and GFR (53). An enhanced CIC activity with increased chloride absorption in the segments of proximal tubule and Henle’s loop cause a decrease chloride load with subsequently increase of GFR by activation of tubulo-glomerular feedback (54). Given all these finding, variations of Scr observed in various thyroid disorders can be explained by the effect of thyroid hormone on GFR. Alterations in creatinine tubular secretion (increased in hyperthyroidism and decreased in hypothyroidism) and in creatinine generation (muscle mass) are common contributing factors (Tab. I)

Interestingly, thyroid status affects serum CysC levels. CysC concentration in contrast to Scr is lower in hypothyroid status and thyroid hormone replacement therapy leads to an increase of the levels of CysC (55). Moreover, in hyperthyroid status CysC levels are higher despite an increase in GFR (55). Thyroid hormone acting on general metabolism may influence the production rate of CysC, thus thyroid status must be considered in the measurement of renal function using CysC equations (14).

Thyroid disorders and tubular function

The majority of the tubular ion transporters are influenced by thyroid disorders. Hypothyroidism is associated with a decrease in transporter function and the opposite occurs in hyperthyroidism (Tab. I). Moreover, a decrease in kidney-to-body ratio and a compensatory increase in protein/DNA ratio with unchanged the DNA content of renal cells has been found in rats with hypothyroidism (49). Karanikas et al (10) reported that the effect of short-term hypothyroidism on tubular functions is modest and it depends on the duration of hypothyroidism. Data from animal studies, reported a decreased activity of Na⁺K⁺- ATPase only in the proximal convoluted tubule, straight tubule and in the cortical and medullar collecting tubules of animals with short-term hypothyroidism (56-58). In contrast, in animal models with induced long-term hypothyroidism, a decreased activity of Na⁺ - K⁺- ATPase has been observed in all segments of the nephron (59).

In severe hypothyroidism with myxedema, increased release of antidiuretic hormone (ADH) and decreased delivery to the diluting tubular segments caused by reduced CO and GFR led to hyponatremia (60). The urine concentrating ability is impaired in hypothyroid state due to decreased osmotic driving force in the collecting duct, to decrease response of vasopressin and to impaired water handling (61, 62). In addition, Na⁺ reabsorption through NHE and Na+ -Pi co-transporter activity are decreased in animals with hypothyroidism (63). Notably, a decrease urinary acidification with increased sodium and bicarbonate excretion rates has been reported in hypothyroid rats (63).

In experimental animal models with hyperthyroidism, renal tubules are hypertrophic and hyperplastic (64). Thus, the tubular mass and kidney weight are increased. An increase in the mitotic index and in the DNA content without changes of protein/DNA ratio has been observed in these animal models (64). Notably, an increased tubular secretory and re-absorptive capacity of renal cells in these animals has been reported (65, 66). This phenomenon achieved by increasing the gene expression, the synthesis and activity of the majority of carrier proteins including Na⁺ - K⁺- ATPase across the basolateral membrane and NHE (65, 66). Vargas et al (67) reported that the enhanced tubular reabsorption of sodium due to increased activity of NHE in combination with the decreased load of filtered sodium cause a decrease in the pressure-diuresis-natriuresis response.

The ability to concentrate urine may be diminished in patients with thyrotoxicosis but does not present any clinical significance (68, 69). Moreover, the combined effect of the direct down regulation of aquaporin 1 and 2 by thyroid hormones in excess combined with the increased blood pressure, CO and RBF may cause polyuria (70). The hypertrophy and hyperplasia in combination with an increased activity lead to damage of the tubular cells.

Thyroid, the kidney and the renin-angiotensin system

Thyroid hormones can regulate BP either by increasing the response of cardiovascular system to the action of the sympathetic nervous system or/and by activating directly the RAS. An increased density and activity of β – adrenergic receptors in kidney cortex has been observed in experimental animal models with hyperthyroidism (71). In addition, Atlas et al (72) reported that blockade of β – adrenergic receptors leads to a decrease in plasma renin activity (PRA), whereas stimulation of β – adrenergic receptors enhances PRA, indicating a connecting link between RAS and β-adrenergic activity (73). Interestingly, administration of ACE-inhibitors in hyperthyroid animals with hypertension led to a decrease in BP to normal levels with increased heart rate and CO, indicating that in hyperthyroidism the predominant factor of hypertension is the RAS system and not the increased CO (31).

Data from in vitro studies reported that administration of thyroid hormones increases the synthesis and secretion of renin by the rat juxtaglomerular cells (74). Notably, there are no data regarding the synthesis or/and secretion of pro-renin and thyroid hormones.

There are contradictory data regarding of plasma angiotensinogen concentrations in adult animals with hyperthyroidism (16, 17, 75). Sernia et al (76) reported that the plasma angiotensinogen concentration does not change in experimental hyperthyroidism in dogs. On the contrary, Ruiz et al. (77) reported that in vitro administration of T3 and T4 increase the synthesis and release of angiotensinogen by hepatocytes.

The kidney represents one of the main sites of ACE synthesis. An enhanced ACE activity and expression has been observed in kidney rats treated with thyroid hormones (78). In addition, thyroid hormones induce ACE synthesis in endothelial cells (79). Decreased ACE concentrations were found in neonatal and adult rats with hypothyroidism, whereas elevated serum ACE levels were reported in human and animals with hyperthyroidism (80). Moreover, the correlation between serum ACE levels and thyroid hormones levels is positive (80). Notably, findings from animal studies treated with thyroid hormones suggest that the regulation of ACE transcription and activity are tissue-dependent. An increase in ACE expression and activity were observed in the kidney of these animals (80).

Fluctuations of renin and angiotensinogen levels by the presence or absence of thyroid hormones may consequently affect AT II levels. In hyperthyroid animals, increased plasma AT II levels are associated with the increase in PRA and angiotensinogen plasma levels (17). On the contrary, a decrease in all these components of RAS system has been found in hypothyroid rats. There are contradictory data regarding the expression of the different subtypes of AT II receptors (AT1, AT2) in the kidney. Whereas the mRNA expression of AT1 was decreased in the kidneys of animals treated with thyroidectomy, the mRNA expression of AT2 was found to be increased (81). Marchant et al (17) reported an increase in AT2 density in both hyper-and hypothyroidism, while AT1 density remained unaltered in hypothyroidism and decreased markedly in hyperthyroidism.

Glomerular diseases and thyroid disorders

In nephrotic syndrome serum total T4, and T3 levels in a lesser degree, decrease due to urinary losses of several hormonal binding proteins including albumin, thyroxine binding globulin, and transthyretin (82). Thyroid hormonal changes depend on the degree of albuminuria and serum albumin concentration (82). However, free T3 and T4 levels remain in the normal range probably due to a compensatory mechanism of the thyroid gland to urinary losses (5). Thus, these patients are often considered as euthyroid. Nevertheless, there are reports linking non-autoimmune hypothyroidism with nephrotic syndrome in adults and children (83, 84). These patients probably have a low thyroid reserve, which is not able to compensate the thyroid urinary loses. Moreover, the degree, selectivity, and TSH levels at nephrotic syndrome onset and during its progression may contribute to the development of non-autoimmune hypothyroidism in these patients (84). Duration of nephrotic syndrome and inhibition of the tubular absorption of hormone-protein bindings may be implicated in the pathogenesis of hypothyroidism. Notably, an increase in exogenous levothyroxine may be needed in order to maintain an euthyroid state in patients with hypothyroidism and nephrotic syndrome (85). In some cases, hypothyroidism resolves after nephrotic syndrome remission (83). Primary hypothyroidism has also been associated with congenital nephrotic syndrome due to thyroxine urinary losses and to alterations of hypothalamus-pituitary-thyroid axis (86).

Thyroid disorders (both hyper and hypothyroidism) (87-88-89) and most commonly auto-immune thyroiditis are associated with glomerulonephritis (GN), including membranous nephropathy (88, 90, 91), focal segmental glomerulosclerosis (92), minimal change (89, 92), membranoproliferative GN (93) IgA nephropathy (94), and amyloidosis (92). Interestingly, anti-neutrophil cytoplasmic antibody (ANCA) positive crescentic GN has been reported after treatment with propylthiouracil for hyperthyroidism and membranous nephropathy after ¹³¹I administration (95, 96).

The exact mechanism of the link between GN and auto-immune thyroiditis is not clear. Generally, several glomerular diseases are often associated with auto-immune mechanisms, as in the case of ANCA associated vasculitis or lupus nephritis which may be accompanied by autoimmune thyroid disease. In addition, circulating immunocomplexes are very common in patients with various thyroid diseases including Hasimoto’s goiter, asymptomatic thyroiditis, spontaneous myxedema and Graves’ disease (97). Probably, the activation of the immune system by thyroid or/and kidney disorders may induce the formation of immunocomplexes. Akikusa et al (98) have found deposits of the same antigen-antibody complexes along both thyroid epithelial follicular basement lamine and glomerular basement membrane of a patient with Hashimoto’s thyroiditis and membranous GN. The authors suggested that the same circulating antigen-antibody complexes may be involved in the pathogenesis of both diseases (98). Shima et al (99) revealed in the kidney biopsy of a child with membranous GN and Graves’ disease thyroid peroxidase deposits, indicating that not only immune complexes of thyroglobulin but also immune complexes of thyroid peroxidase can cause membranous GN. Notably, the association of thyroid antibody levels with the degree of renal decline in immune-mediated GN has not been yet elucidated (92). It could be speculated that immune-mediated GN and autoimmune thyroidits share common pathways of autoimmunity activation. Another hypothesis is that the association of glomerular diseases and autoimmune thyroiditis may be attributed to cross-reacting antigens, but all these hypothesis remain to be proven.

CKD and thyroid diseases

The prevalence of hypothyroidism in CKD patients is higher compared with the general population (2, 3). Interestingly Lo et al (2) reported an increased prevalence of both subclinical and clinical hypothyroidism in CKD patients, independent of age, gender, and race/ethnicity. Moreover, the prevalence of subclinical and clinical hypothyroidism increases with decreased GFR, ranging from 5% up to 25% (2). Chonchol et al (3) reported a gradual increase in the prevalence of subclinical hypothyroidism from 7% at estimated GFR ≥90 ml/min per 1.73 m² to 17.9% in patients with estimated GFR ≤60 ml/min. Moreover, the authors reported that there is an escalating probability of subclinical primary hypothyroidism with progressively lower estimated GFR .

The difference between clinical and subclinical hypothyroidism is that in the subclinical type serum level of TSH is increased without the presence of the overt clinical manifestation of hypothyroidism. Similarly, the rate of “low T3 syndrome’’ also referred as “the euthyroid sick syndrome” in patients with CKD increases consistently with declining GFR and it varies from 20% to 80% (100-101-102-103).

Euthyroid sick syndrome is the most common thyroid disorder in CKD patients. This clinical condition is characterized by a lowering of T3 without any underlying intrinsic thyroid disorder, whereas free T3 (fT3) levels are increased due to decreased renal clearance. Low T4 levels have also been reported in CKD patients. These thyroid hormones disarrangements are similar for both hemodialysis (HD) and peritoneal dialysis (PD) (23, 24, 104). Low thyroid hormones recover during the first three months after kidney transplantation and low fT3 levels are associated with poor renal graft function (105).

The etiology of thyroid dysfunction in CKD patients is multifactorial and it has not been fully elucidated (Tab. II). Tissue and circulating levels of T3 are low in progressive CKD due to a reduced deiodinase activity which reduces the peripheral conversion of T4 to T3 (4). Other contributing factors for disturbed iodothyronine deiodination are malnutrition and metabolic acidosis (106). Inorganic iodide accumulates in advanced stages of CKD due to reduced renal excretion, leading to impaired thyroid hormone synthesis (100). An abnormal TSH response to thyrotropin-releasing hormone due to uremic toxins contributes to thyroid dysfunction (107). Moreover, several uremic toxins in combination with chronic metabolic acidosis and heparin used in HD as an anticoagulant, inhibit protein binding of T4 (100, 108). Advanced age, Hepatitis C infection, chronic inflammation and drugs such as amiodarone, steroids or β-blockers have also been implicated (5, 101).

It should be emphasized that thyroid replacement therapy in CKD patients with primary or subclinical hypothyroidism may preserve renal function (109-110-111). As mentioned above, normalization of T3 levels by replacement therapy may improve RBF and subsequently GFR. Moreover, this beneficial effect of thyroid replacement therapy on renal function may also be attributed to improved cardiac function and better lipid profile in combination with reversed endothelial dysfunction. In contrast to other thyroid disorders, the rate of hyperthyroidism in CKD patients is similar to the general population.

Associations of thyroid disorders with CKD and CVD

According to the HEMO study, more than 80% of HD patients have cardiac disease (112). Interestingly, cardiovascular disease (CVD) is the main cause of death among HD patients (112). CVD is highly prevalent before initiation of dialysis due to several cardiovascular risk factors such as hypertension, dyslipidemia, endothelial dysfunction, arterial stiffness, and accelerated atherosclerosis. There is clinical evidence that subclinical or primary hypothyroidism and low T3 syndrome are strongly associated with CVD and mortality in the general population and in CKD patients (18-19-20-21-22-23-24).

The role of thyroid hormones on BP regulation is well known; moreover hypothyroidism causes hypertension by increasing peripheral vascular resistance. Hypertension leads to left ventricular hypertrophy or/and to diastolic dysfunction inducing deterioration of cardiac function and increase in CVD mortality. Enia et al. (113) observed a negative association between fT3 and diastolic blood pressure in patients on PD.

Endothelial dysfunction has been reported in patients with hypothyroidism. Yilmaz et al (114) reported a strong correlation between decreased fT3 and endothelial dysfunction in stage 3 to 4 CKD patients and Tatar et al (115-116) reported an association of low fT3 and several parameters of CVD mortality, such as endothelial dysfunction and inflammation in HD and PD patients.

Dyslipidemia is common in CKD and it can be aggravated by the altered thyroid metabolism observed in these patients (18). It is well known that dyslipidemia may contribute to the progression of CKD and to accelerated atherosclerosis (117). Notably, Liu et al (118) reported a positive association between fT3 level and high-density lipoprotein cholesterol level and a negative association between f T3 levels, low-density lipoprotein cholesterol and triglycerides in HD patients.

Hypertriglyceridemia is due to a decrease in lipoprotein lipase activity observed in patients with hypothyroidism (18). Bommer et al (119) reported in a single blind placebo controlled study, that low dose D-thyroxine may reduce elevated lipoprotein a (Lp(a)) concentration in HD patients.

Arterial stiffness is the cumulative effect of atherosclerosis, hypertension, volume overload, arterial calcification, oxidative stress and increased lipid oxidation on vascular system of CKD patients. Arterial stiffness worsens the cardiovascular profile of CKD patients and it predicts an increased risk for CVD mortality (21). Several studies reported a strong correlation between clinical and subclinical hypothyroidism and arterial stiffness in the general population (120, 121).

Interestingly, treatment with levothyroxine in hypothyroid patients reverses arterial stiffness by decreasing systolic blood pressure (121). Low T3 levels are inversely correlated with arterial stiffness and atherosclerosis in HD patients (115). There is evidence that inflammation is the link between hypothyroidism and arterial stiffness (101, 115, 116). Moreover, inflammation has been associated with atherosclerosis, cardiac disease and increased mortality in CKD patients.

Carrero et al. (101) reported that there is a correlation between low T3 levels, several markers of inflammation including C-reactive protein (CRP), interleukin 6 (IL-6) and albumin and cardiac disease in CKD patients. Moreover, these authors observed that decreased levels of total T3, but not fT3, were associated with increased all-cause mortality in CKD patients (101). Zoccali et al (122) investigated the effect of low thyroid hormones on cardiac function in ESRD patients and reported that low T3 levels were associated with left ventricular dysfunction and left ventricular hypertrophy and that these associations were mediated by inflammation. A diminished left ventricular systolic function has been reported in PD patients with subclinical hypothyroidism (123). Recently, Meuwese et al (24) confirmed that HD patients with low levels of T3 and T4 (in repeated measurements for 3 months) presented an increased mortality risk mainly due to cardiovascular causes. Rhee et al (124) in the larger retrospective study in the literature reported that hypothyroidism was associated with higher mortality in dialysis patients and could be ameliorated by thyroid hormone supplementation. On the contrary, Fernandez-Reyes et al (125) reported that low fT3 levels are not predictive of long term mortality in HD patients.

Several studies reported that hypothyroidism may be a cause of erythropoietin resistance in patients undergoing HD (126). Hypothyroidism is mainly a cause of macrocytic anemia. Anemia in CKD has been associated with CVD and increased risk mortality. Thus, anemia resistant to treatment due to hypothyroidism may be another link between CKD, CVD, and mortality. However, the causal nature of all these findings remains still uncertain.

Clinical interpretation of thyroid dysfunction in CKD

Despite the negative impact of hypothyroidism on GFR, some investigators reported that hypothyroidism could be described as rather beneficial for the progression of CKD (127-128). This hypothesis is based on experimental findings that animals with induced renal insufficiency that underwent thyroidectomy presented reduced proteinuria and a reduction in the deterioration of renal function (127, 128). Moreover, long-term hyperthyroidism in experimental animal models may aggravate or result into CKD by inducing glomerular hyperfiltration and concomitant proteinuria, or by enhancing oxidative stress and RAS activity (49). Thus, it could be speculated that low T3 is an adaptive mechanism in order to slow the progression and the consequences of CKD. On the other hand, treatment of hypothyroidism in CKD patients improves GFR and renal function (109-110-111). The positive association of T3 levels with graft function impoverishes the hypothesis that hypothyroidism is beneficial for CKD (105). Moreover, the experimental findings from animal studies may be species specific and their extrapolation to human disease process remains difficult to be proven.

CKD is a hypercatabolic status (129) and in this respect, hypothyroidism and low T3 in CKD may represent an adaptive mechanism aiming to decrease energy demands in chronic illness, but failing to ensure the survival of these patients. However, the association of low thyroid hormones with inflammation and increased mortality risk (101) suggests that this mechanism is rather maladaptive than adaptive. In summary, it could speculated that low T3 levels in patients with CKD and CVD are the result of the inflammation which is observed in these conditions, and are associated with worse outcomes only as an epiphenomenon. Whether low thyroid hormones are the cause or the result of inflammation in chronic illness which characterizes by both CVD and CKD remains to be clarified. Eventually, low thyroid hormones in CKD patients may reflect a marker of poor health or poor nutritional status (101, 113) and a higher risk of frailty in these patients, which are not causally correlated with CVD.

Another issue that must be addressed is which CKD patient should be treated with thyroid hormone replacement therapy and when? If low thyroid levels reflect an adaptive mechanism in energy demands, replacement hormone therapy may have the opposite effect, as T3 administration may increase muscle catabolism leading to a negative nitrogen balance.

Does the administration of hormone replacement therapy in these patients make them hyperthyroidic? In clinical practice, elevation of TSH value less than 20 IU/ml with or without decreased T3 and T4 levels does not usually warrant thyroid replacement treatment. However, all these issues needed to be addressed with caution. The beneficial effect of thyroid replacement on CVD patients is well established (121, 130). At present, there are no data regarding the effect of thyroid hormone replacement therapy on the well-being or/and the survival of CKD patients. The decision to initiate thyroid hormone replacement therapy in CKD patients is not always straightforward and the clinician should balance both the possible manifestations of clinical (or subclinical) hypothyroid and the risks of overtreatment.