Role of selenium in the pathophysiology of cardiorenal anaemia syndrome

Abstract

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have multiple bidirectional mechanisms, and anaemia is one of the critical factors that are associated with the progression of the two disorders [referred to as cardiorenal anaemia syndrome (CRAS)]. Several lines of evidence indicate that CRAS confers a worse prognosis, suggesting the need to clarify the underlying pathophysiology. Among the micronutrients (trace elements) that are essential to humans, inadequate iron status has previously been implicated in the pathogenesis of CRAS; however, the roles of other trace elements remain unclear. Selenium critically regulates the function of selenoproteins, in which selenocysteine is present at the active centres. The human genome encodes 25 selenoproteins, and accumulating data indicate that they regulate diverse physiological processes, including cellular redox homeostasis, calcium flux, thyroid hormone activity and haematopoiesis, all of which directly or indirectly influence cardiac function. The essential role of selenium in human health is underscored by the fact that its deficiency results in multiple disorders, among which are cardiomyopathy and abnormal erythrocyte morphology. Studies have shown that selenium deficiency is not uncommon in CKD patients with poor nutritional status, suggesting that it may be an under‐recognized cause of anaemia and cardiovascular disorders in these patients. In this review, we discuss the role of selenium in the pathophysiology of CKD, particularly in the context of the interconnection among CKD, cardiac dysfunction and anaemia. Given that selenium deficiency is associated with treatment‐resistant anaemia and an increased risk of CVD, its role as a key modulator of CRAS merits future investigation.

Introduction

Selenium (Se) is a trace element discovered in 1817 by the Swedish chemist Jöns Jakob Berzelius. ¹ In the late 20th century, it was found that Se deficiency causes multiple organ dysfunction in mammals ² and in humans, ³ , ⁴ uncovering the importance of Se as an essential nutrient. In 1973, the antioxidant enzyme glutathione peroxidase (GPx) in erythrocytes was identified as the first selenoprotein, an enzyme that contains Se in the active centre. ⁵ To date, a total of 25 selenoproteins have been identified in humans, regulating diverse biological processes. ⁶

Chronic kidney disease (CKD), defined by either a glomerular filtration rate (GFR) of <60 mL/min/1.73 m² or proteinuria that persists for at least 3 months, has become a global public health concern. ⁷ Prevention and early detection of CKD are important not only because it can progress to end‐stage kidney disease (ESKD) but also because it is an independent risk factor for cardiovascular diseases (CVDs). ⁸ , ⁹ Although CKD and CVD share many common pathological pathways (such as fluid dysregulation, hypertension, anaemia, chronic inflammation and overactivation of neurohumoral factors), ¹⁰ the role of Se and selenoproteins in the pathophysiology of cardiorenal association has not been extensively studied. This study aimed to review the current evidence regarding the role of Se in the interconnection among CKD, CVD and anaemia, also known as cardiorenal anaemia syndrome (CRAS). ¹⁰ , ¹¹

Overview of Se metabolism

Se exists in both inorganic [selenate (SeO₄ ²⁻) and selenite (SeO₃ ²⁻)] and organic [selenomethionine (SeMet) and selenocysteine (Sec)] forms in nature (Figure 1). The principal nutritional source of Se in humans is its organic form, SeMet. ¹² Once digested, SeMet is either incorporated into proteins at the Met position in a random manner or metabolized in the liver. One study reported that the ratio of Se (presumably SeMet) to Met in albumin was 1:8000, which increased after SeMet supplementation, ¹³ suggesting that SeMet incorporated into proteins may serve as a reservoir pool of Se in the body.

Figure 1.

Overview of selenium (Se) metabolism and selenoprotein synthesis. In nature, Se exists in inorganic [selenate (SeO₄ ²⁻) and selenite (SeO₃ ²⁻)] and organic [selenomethionine and selenocysteine (Sec)] forms. Selenomethionine is the principal nutritional source of Se in the human diet, which is converted to Sec through the transsulfuration pathway. Sec is catalysed to selenide by Sec lyase, which is used to synthesize selenoproteins. Selenate and selenite, taken as supplements or fortified foods, are also reduced to selenide and are used for selenoprotein synthesis.

In the liver, SeMet is converted to Sec through the methionine–homocysteine cycle and the transsulfuration pathway involving selenohomocysteine, cystathionine β‐synthase and cystathionine γ‐lyase ¹² , ¹⁴ (Figure 1). Because Sec is highly reactive, it is catalysed to alanine and selenide by Sec lyase, ¹⁵ , ¹⁶ , ¹⁷ which maintains low tissue Sec levels. Selenide is the preferred Se metabolite within cells and is used to synthesize selenoproteins after conversion to selenophosphate. Se that is not incorporated in selenoproteins is mainly metabolized in the liver by glycosylation and methylation and is then excreted via urine, faeces or breath. ¹² , ¹⁸

Role of major selenoproteins in the body

The human genome contains 25 genes encoding selenoproteins (Table 1). The incorporation of Sec into these proteins is accomplished through the co‐ordinated actions of Sec tRNA (tRNA^[Ser]Sec), seryl‐tRNA synthetase, phosphoseryl‐tRNA kinase and Sec synthase. ⁶ Among the diverse roles, one of the well‐characterized functions of selenoproteins is to regulate redox status in the body. GPx, thioredoxin reductase (TR) and other selenoproteins are involved in redox homeostasis (Table 1). GPx protects organisms from oxidative damage by reducing peroxide levels. TR exerts its antioxidant effect by interacting with thioredoxin, which reduces and cleaves disulfide bonds in proteins.

Table 1.

List of selenoproteins in humans.

Abbreviation	Selenoprotein	Function
GPx1	Glutathione peroxidase 1	Reduces peroxides and protects organisms from oxidative damage
GPx2	Glutathione peroxidase 2
GPx3	Glutathione peroxidase 3
GPx4	Glutathione peroxidase 4
GPx6	Glutathione peroxidase 6
TR1	Thioredoxin reductase Type I	Reduces disulfide bonds in proteins and is involved in antioxidant defence and cellular signalling
TR2	Thioredoxin reductase Type II
TR3	Thioredoxin reductase Type III
DIO1	Deiodinase Type I	Regulates local T3 and T4 concentrations in tissues
DIO2	Deiodinase Type II
DIO3	Deiodinase Type III
MsrB1 (SelR)	Methionine‐R‐sulfoxide reductase; selenoprotein R	Reduces methionine‐R‐sulfoxide to methionine and regulates mitophagy
SelF (Sep15)	Selenoprotein F; 15 kDa of selenoprotein	Regulates redox homeostasis
SelH	Selenoprotein H	Regulates redox balance and reduces DNA damage
SelI	Selenoprotein I	Unclear
SelK	Selenoprotein K	Regulates inositol 1,4,5‐triphosphate receptor function in the ER
SelM	Selenoprotein M	Controls calcium signalling and oxidative stress
SelN	Selenoprotein N	Regulates sarcoplasmic/endoplasmic reticulum calcium ATPase and calcium uptake
SelO	Selenoprotein O	Unclear
SelP	Selenoprotein P	Supplies Se to peripheral tissues
SelS	Selenoprotein S	Inhibits oxidative stress and ER stress
SelT	Selenoprotein T	Contributes to ER homeostasis
SelV	Selenoprotein V	Unclear
SelW	Selenoprotein W	Counteracts anaemia by promoting stress erythroid progenitors development
SPS2	Selenophosphate synthetase	Catalyses the synthesis of selenophosphate

Abbreviations: ER, endoplasmic reticulum; Se, selenium.

Iodothyronine deiodinases (DIs) are a class of proteins that regulate tissue thyroid hormone signalling. ⁶ , ¹⁹ There are three DI paralogs (DI1, DI2 and DI3), all of which are integral membrane proteins with a single transmembrane domain. DI1 and DI2 convert thyroxine (T₄) to active triiodothyronine (T₃) via deiodination. DI1 and DI3 also convert T₃ and T₄ into inactive T₂ and reverse T₃ (rT₃), respectively. Fine‐tuning by these DIs regulates T₃‐dependent signalling in a tissue‐specific manner. DI2 and DI3 regulate intracellular T₃ concentrations without altering its circulating levels. ⁶ , ¹⁹

In the endoplasmic reticulum (ER), multiple selenoproteins are present and regulate cellular calcium homeostasis (Table 1). ²⁰ Selenoprotein K (SelK) is induced during ER stress ²¹ and regulates inositol 1,4,5‐triphosphate receptor function. ²² , ²³ SelK deficiency results in decreased calcium flux and impaired activation of immune cells. ²² Given that SelK is also present in cardiomyocytes, ²⁴ it is possible that SelK regulates calcium signalling in these cells. Selenoprotein N (SelN), mutations of which are associated with neuromuscular disorders in humans, ²⁵ , ²⁶ , ²⁷ is also present in the ER, where it regulates redox homeostasis and calcium signalling. ²⁰ , ²⁸ A recent study demonstrated that SelN senses luminal calcium levels through the EF‐hand domain and promotes calcium uptake. ²⁹ Other selenoproteins localized in the ER include selenoproteins M, S, F and T, which have also been implicated in ER function and calcium signalling. ²⁰

Selenoprotein P (SelP) supplies Se to the peripheral tissues. It accounts for >50% of the Se present in the plasma and contains 10 Sec in humans. ³⁰ Previous studies have shown that apolipoprotein E receptor‐2 (ApoER2) and megalin serve as cellular receptors for SelP. ³¹ , ³² Mice lacking these proteins are shown to exhibit reduced Se levels. ³¹ , ³³

It is worth noting that there is a hierarchy of selenoprotein synthesis when the Se supply is limited. ¹² Under Se‐deficient conditions, GPx1 expression is down‐regulated in the liver to maintain the synthesis of other selenoproteins, such as SelP, which supplies Se to the peripheral tissues. SelP is then taken up through ApoER2 or megalin in peripheral tissues, which helps to maintain the levels of necessary selenoproteins, such as GPx4, in the brain. ¹²

Selenoproteins such as selenoprotein W have been shown to be involved in erythropoiesis, ³⁴ , ³⁵ , ³⁶ which will be discussed later in detail.

Se deficiency and selenosis in humans

The critical importance of Se in human health was highlighted in two landmark reports published in 1979. One report from China showed the role of Se deficiency in Keshan disease, an endemic disease characterized by cardiomyopathy observed from the northeast to southwest of China. ⁴ The study indicated that the reduced Se intake owing to the low Se content in the soil caused cardiomyopathy. A recent meta‐analysis involving nearly 2 million individuals concluded that Se supplementation in the residents of affected regions reduced the incidence of Keshan disease. ³⁷ Another report from New Zealand described a case that developed muscular pain and tenderness after 30 days of total parenteral nutrition (TPN). ³ The patient lived in an area with a low Se level in the soil, and the patient's symptoms resolved after SeMet administration, showing that Se deficiency is involved in the pathologies.

Subsequently, a number of studies have revealed that Se deficiency can result in diverse symptoms, including cardiac dysfunction, arrhythmia, myopathy, nail changes, dermatitis, anorexia, retarded body growth and infertility. ³⁸ Although the molecular mechanisms through which Se deficiency causes these symptoms are not entirely clear, a significant part of this disorder can be explained by the impaired function of the selenoproteins.

Although Se deficiency triggers a variety of symptoms, inappropriately high levels of Se intake are harmful and induce Se poisoning (selenosis). Selenosis is rare but has been reported to occur mainly in residents of areas with high Se levels in the soil (such as Enshi County in China), individuals taking nutritional supplements or by accidental ingestion. ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ The symptoms of selenosis include vomiting, diarrhoea, fatigue, muscle spasms, skin damage, nail changes, hair loss, tooth discoloration and myocardial infarction.

The Se levels in food vary significantly depending on the area of production. In a study conducted in 1995, the estimated daily intake varied from 11 to 218 μg/day across the world. ⁴⁵ This variation is attributed to geographic differences in Se levels in food. Currently, the recommended daily intake of Se in adults varies among countries, such as 70 μg/day in Europe and New Zealand, 55 μg/day in the United States and 25–30 μg/day in Japan. ⁴⁶ , ⁴⁷ , ⁴⁸ Although the physiological basis for the difference in recommended daily intake is not entirely clear, it may be related to the fact that Se content in soils in Eastern Europe and New Zealand is low, which is associated with an increased risk of Se deficiency compared with other countries if Se intake is not appropriately increased. The World Health Organization recommends that there is a limit to the amount of Se that can be safely consumed by humans, with a maximum acceptable intake of 400 μg/day for adults. ⁴⁹

Se status and long‐term consequences in patients with CKD

Among various organs, the kidneys contain the highest Se levels per weight basis. ⁵⁰ Previous studies have indicated that a subpopulation of patients with CKD may be Se deficient, particularly those with advanced stages. A systematic review and meta‐analysis of 128 studies on trace elements found that Se, Zn and Mn levels were lower in patients undergoing haemodialysis than in control individuals. ⁵¹ In a study involving 1041 Japanese patients undergoing haemodialysis, serum Se levels were lower than those in control individuals. ⁵² Similar findings have been noted in patients undergoing haemodialysis in Portugal. ⁵³ However, another study reported that low serum Se concentrations were not common in Canadian patients undergoing haemodialysis. ⁵⁴ In patients with non‐dialysis‐dependent CKD, several observational studies have shown that serum Se levels decrease with a decline in GFR levels. ⁵⁵ , ⁵⁶ , ⁵⁷ Overall, these data indicate that Se levels may be low in patients with advanced CKD, although they may vary depending on demographics, geographic area and nutritional status.

There are data suggesting that a low Se status in patients with advanced CKD is associated with a worse prognosis. A study by Fujishima et al. analysed the association between serum Se levels and the risk of death in patients with advanced CKD undergoing haemodialysis. In that study, the authors found that the lowest quartile group had a significantly higher mortality rate than the other three groups. Infectious disease‐related death was also higher in this group, and the inverse relationship between serum Se and infectious disease‐related death was significant even after multivariate adjustment. ⁵⁸ Tonelli et al. conducted a prospective study involving 1278 patients undergoing haemodialysis. This study addressed the blood concentration of 25 trace elements at baseline and the subsequent occurrence of death, cardiovascular events, infection and hospitalization. ⁵⁹ Their study found that lower Se levels were independently associated with a higher risk of death and all‐cause hospitalization.

Other studies have investigated whether Se status is associated with CKD progression. In a post hoc analysis of the China Stroke Primary Prevention Trial, low plasma Se levels were significantly associated with the rapid decline in renal function [defined as a mean decline in estimated GFR (eGFR) of ≥5 mL/min/year/1.73 m²] in 935 patients with hypertension. ⁶⁰ A randomized, double‐blind, placebo‐controlled study of Se and coenzyme Q10 supplementation involving 215 older patients with low serum Se levels reported that the Se‐ and coenzyme Q10‐supplemented groups had a significantly lower concentration of creatinine after 48 months of intervention. ⁵⁷

Reduced Se levels in CKD patients are likely attributable to poor nutritional status. Several studies have shown that lower serum Se levels were associated with hypoalbuminaemia and reduced dietary protein intake in ESKD patients. ⁶¹ , ⁶² In addition to the decreased intake, ESKD patients often show impaired protein digestion and absorption in the small intestine, ⁶³ accelerating malnutrition and inflammation. Another factor that needs to be considered is dialysis‐related protein loss, which is reported to be 7–8 g per dialysis session. ⁶⁴ Given that SeMet in proteins is the primary source of dietary Se intake and the reservoir pool in the body, the factors mentioned above may contribute to inadequate Se status in CKD patients in a complex manner.

Se deficiency and CVD risk

Given that cardiac dysfunction is the central feature of Keshan disease, whether Se deficiency or low serum Se levels increase the risk of CVD has been intensively analysed. Although the causal role of low Se levels in CVD occurrence in the general population remains unclear, multiple studies and meta‐analyses have shown that low Se levels are associated with an increased CVD risk. A meta‐analysis by Flores‐Mateo et al. included observational studies and randomized controlled trials (RCTs) that addressed the role of Se in the occurrence of coronary heart disease (Table 2). ⁶⁵ In their analysis, 25 observational studies (14 cohort studies and 11 case–control studies) and 6 RCTs met the inclusion criteria. Most observational studies have found an inverse association between Se levels and coronary heart disease risk. The relative risk of the highest to lowest Se concentration categories was 0.85 [95% confidence interval (CI), 0.74–0.99] in cohort studies and 0.43 (95% CI, 0.29–0.66) in case–control studies. ⁶⁵ However, in RCTs, the pooled relative risk in comparison with the Se supplement group with placebo across the six RCTs was not statistically significant [0.89 (95% CI, 0.68–1.17)].

Table 2.

Meta‐analysis on Se status and cardiovascular diseases.

First author	Year	Included study	Main results
Flores‐Mateo	2006	Observational studies: 25 (14 cohort studies and 11 case–control studies) RCTs: 6	Observational studies: The pooled relative risk of CHD associated with a 50% increase in Se levels was 0.76 (95% CI, 0.62–0.93). RCTs: The pooled relative risk in comparison of the Se supplement group with the placebo was 0.89 (95% CI, 0.68–1.17).
Rees	2013	Twelve RCTs (seven with a duration of at least 3 months)	Se supplementation did not reduce all‐cause mortality [relative risk 0.97 (95% CI, 0.88–1.08)], CVD mortality [0.97 (95% CI, 0.79–1.2)] or non‐fatal CVD events [0.96 (95% CI, 0.89–1.04)].
Zhang	2016	Prospective observational studies: 16 RCTs: 16	In observational studies, serum Se levels were significantly associated with a lower risk of CVD within a narrow range (55–145 μg/L). In RCTs, oral Se supplements did not reduce CVD [relative risk 0.91 (95% CI, 0.74–1.10)].
Kuria	2021	Eleven observational studies and two RCTs	Significant heterogeneity was present. The risk of CVD incidence and mortality was reduced by high body Se status compared with low Se status [relative risk 0.70 (95% CI, 0.61–0.81)].

Abbreviations: CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; RCTs, randomized controlled trials; Se, selenium.

In 2013, Rees et al. conducted a meta‐analysis that included 12 RCTs (seven with a duration of at least 3 months). ⁶⁶ They focused on the role of Se supplementation in the primary prevention of CVD (including non‐fatal myocardial infarction, non‐fatal stroke and revascularization procedures) and reported that Se supplementation did not reduce CVD events. In a meta‐analysis by Zhang et al., the authors determined the dose–response relationship between baseline Se concentrations and the incidence of CVD. ⁶⁷ The authors found that the pooled relative risk was significantly lower in the highest baseline Se category (median, 101.5 μg/L) versus the lowest Se category (median, 53.7 μg/L) [relative risk, 0.87 (95% CI, 0.76–0.99)], which was consistent with the data by Flores‐Mateo et al. A dose–response relationship analysis model using a restricted cubic spine indicated that serum Se levels were significantly associated with a lower risk of CVD within a narrow range (55–145 μg/L, with a nadir at 125 μg/L). This association was lost when baseline serum Se levels exceeded 145 μg/L. A meta‐analysis of 16 RCTs showed no effect of Se supplementation on the risk of CVD.

More recently, Kuria et al. conducted a meta‐analysis of 13 observational studies and RCTs. ⁶⁸ This study found significant heterogeneity in the relative risk of CVD. Although the relative risk of the highest Se levels in CVD incidence was not significantly different from the lowest Se levels [0.66 (95% CI, 0.40–1.09)], the reduction in the relative risk of CVD mortality was statistically significant [0.69 (95% CI, 0.57–0.84)]. The relative risk of combined CVD incidence and mortality was also significantly lowered by high Se status compared with low Se status [0.70 (95% CI, 0.61–0.81)]. In the stratified analysis according to geographical area, a reduced risk of CVD mortality was observed in Asia and Europe but not in the United States, where Se intake is relatively high. ⁶⁹

After the publication of the abovementioned meta‐analysis, several observational studies analysed the association between Se status and heart failure in Europe. The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) is a cohort study that included 2516 patients with heart failure in 11 European countries. ⁷⁰ , ⁷¹  In that cohort study, heart failure was defined as a left ventricular ejection fraction of ≤40% or elevated natriuretic peptide levels [plasma BNP > 400 pg/mL or N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) > 2000 pg/mL, respectively]. In 11 countries, there were considerable geographic differences in Se status, and the prevalence of Se deficiency (defined as <70 μg/L) varied from 3% (in Italy) to 51% (in Slovenia). ⁷¹ Overall, the median serum Se level was 87 μg/L, and 20% of study participants had Se levels of <70 μg/L. Consistent with previous studies, ⁵⁵ , ⁵⁶ , ⁵⁷ patients with Se deficiency had a lower eGFR than those with normal Se levels. In addition, Se deficiency was associated with older age, lower protein intake and lower haemoglobin levels. As the primary outcome, the authors analysed the composite of all‐cause mortality and hospitalization due to heart failure, which showed that Se deficiency was significantly associated with the primary endpoint after adjustment for multiple covariates. Bomer et al. performed a cell culture study and found that Se deprivation impaired mitochondrial function in human cardiomyocytes, which was associated with increased reactive oxygen species (ROS) levels. ⁷¹

Using prospectively assessed data from the Prevention of REnal and Vascular End‐stage Disease (PREVEND), a Dutch cohort study, ⁷² Al‐Mubarak et al. performed a retrospective analysis of the association between Se levels and the risk of mortality and new‐onset heart failure. ⁷³ In that study, serum Se levels were assessed in 5973 individuals for whom samples from the second visit were available. In the stepwise analysis that determined the clinical associations of serum Se, anaemia, body mass index (BMI), smoking, iron deficiency and high‐sensitivity C‐reactive protein (hs‐CRP) levels were negatively associated with serum Se levels, whereas female sex, glucose and cholesterol levels were positively associated with serum Se levels. Furthermore, the study found a non‐significant tendency towards a lower hazard ratio for the primary outcome (the composite of all‐cause mortality and new incidence of heart failure) in individuals with higher Se levels. In a sub‐analysis that included 4288 non‐smokers, the authors found that high Se concentrations were significantly associated with lower mortality and an incidence of heart failure.

Association of Se with anaemia in the general population and in patients with CKD

In addition to cardiomyopathy, abnormal erythrocyte morphology is an essential manifestation of Se deficiency. ⁷⁴ , ⁷⁵ Several lines of evidence have suggested that impaired red blood cell (RBC) homeostasis may underlie the pathophysiology of Se deficiency and inadequate Se status.

Using data from the third National Health and Nutrition Examination Survey (NHANES III), Semba et al. analysed the relationship between serum Se and haematological indices in individuals aged ≥65 years in the United States. ⁷⁶ In that study, anaemia, defined as haemoglobin of <13 g/dL for men and <12 g/dL for women, was diagnosed in 12.9% of individuals, and its prevalence was significantly different among the quartiles of serum Se (anaemia prevalence, 18.3%, 9.5%, 9.7% and 6.9% in the lowest to highest quartiles of serum Se). The authors also found that an increase in serum Se levels was significantly associated with a reduced risk of anaemia, independent of age, race, education, BMI and chronic diseases. An inverse association between Se status and the prevalence of anaemia has also been documented in a European study. ⁷³ , ⁷⁷ In a population‐based cohort study that included people aged ≥65 years in Italy, Roy et al. analysed the association of baseline Se levels with the incidence of anaemia over 6 years of follow‐up. ⁷⁷ They found that plasma Se levels in the lowest quartile (<66.6 μg/L) predicted incident anaemia with a hazard ratio of 1.67 (95% CI, 1.07–2.59) after adjustment with multiple covariates. In the PREVEND study, which included the general population of the city of Groningen in the Netherlands, the presence of anaemia was negatively associated with serum Se concentrations independently from other clinical factors. ⁷³ An association between anaemia and low serum Se levels has also been reported in Asian adults ⁷⁸ and children. ⁷⁹ , ⁸⁰ , ⁸¹

In addition to the possible role of Se in erythrocyte homeostasis in the general population, evidence suggests that an inadequate Se status can influence the erythropoietic response to anaemia in patients with CKD. Anaemia is frequently observed in patients with CKD, which contributes significantly to the occurrence of CVD. ⁸² Although the causes of anaemia in CKD are multifactorial, one of the key components is decreased erythropoietin production due to impaired renal function. ⁸³ Accordingly, renal anaemia is generally managed using erythropoiesis‐stimulating agents (ESAs), which are recombinant forms of human erythropoietin. ⁸⁴ , ⁸⁵ Although most patients respond well to ESAs, a subpopulation of patients (approximately 10%) show an impaired response to these agents. ⁸⁶ Importantly, hyporesponsiveness to ESAs is associated with increased mortality and CVD risk in patients with advanced CKD. ⁸⁷ , ⁸⁸ , ⁸⁹

Previous studies have identified several factors that cause ESA hyporesponsiveness, including malignancy, malnutrition, inflammation and chronic blood loss. ⁸⁵ Regarding the nutritional factors that affect the impaired erythropoietic response in patients with CKD, studies have revealed that micronutrient deficiencies, such as iron, zinc and copper, are involved ⁹⁰ , ⁹¹ , ⁹² ; however, the role of Se in determining the response to ESAs has remained obscure. In our previous work, ⁹³ we evaluated serum Se levels in 173 Japanese patients undergoing haemodialysis. We found that approximately half of the patients had Se levels of <10.5 μg/dL, which is the lower limit of the population‐based reference values. ⁹⁴ Although haemoglobin levels were similar, we found that the use of ESAs tended to be more frequent in patients with low Se levels. Further analysis revealed that the erythropoiesis resistance index, which reflects hyporesponsiveness to ESAs and is calculated using haemoglobin level, body weight and ESA dose, was significantly inversely correlated with serum Se levels. This association was significant after adjusting for multiple covariates, including age, sex, iron status and dialysis vintage. Given the evidence that Se deficiency or low serum Se levels can be potentially prevalent in patients with advanced CKD, these data indicate that an inadequate Se status is a previously unrecognized cause of anaemia associated with a reduced ESA response in patients with CKD.

Mechanistic insights into the association between Se deficiency and anaemia

Consistent with the abovementioned clinical observations, experimental studies have shown that Se status influences haematopoiesis. For example, the myeloid:erythroid ratio is higher and plasma iron turnover rates tend to be lower in Se‐deficient pigs than in control animals, suggesting that erythropoiesis is decreased due to Se deficiency. ⁹⁵ , ⁹⁶ In cisplatin‐treated rats, co‐administration of Se stimulated erythropoiesis and the recovery of reduced glutathione status. ⁹⁷ In mice maintained on a Se‐deficient diet for 8 weeks, RBC and reticulocyte counts were significantly lower than those in mice receiving a Se‐adequate or Se‐supplemented diet. ⁹⁸ Similarly, in a mouse model of phenylhydrazine‐induced haemolytic anaemia, the Se‐deficient group showed increased haemolysis, whereas Se supplementation prevented haemolytic changes. ⁹⁹ These data indicate a causal role of Se deficiency in the progression of anaemia.

Regarding the mechanisms by which Se deficiency triggers anaemia, increased RBC fragility, impaired maturation of erythroblasts or both can be involved. ¹⁰⁰ , ¹⁰¹ To counteract ROS production triggered by iron contained in haem protein, ¹⁰² , ¹⁰³ erythrocytes possess high levels of antioxidative selenoproteins, such as GPx and TR. ⁶ , ¹⁰⁴ , ¹⁰⁵ Importantly, in mice lacking TR2, the size of haematopoietic colonies cultured ex vivo dramatically decreased, which is consistent with the defect in haematopoiesis observed in this mouse model. ¹⁰⁶ Furthermore, Trsp (encoding tRNA^[Ser]Sec) gene ablation results in haemolytic anaemia and the appearance of immature erythrocytes in the peripheral blood. ¹⁰⁷ Anaemia is further exacerbated by the deletion of nuclear factor erythroid 2 (NF‐E2)‐related factor 2 (Nrf2), which is associated with increased intracellular hydrogen peroxide levels in erythroblasts. ¹⁰⁷

It has also been shown that selenoproteins, including selenoprotein W, regulate stress erythropoiesis, ³⁴ , ³⁵ , ³⁶ in which erythrocyte production at extramedullary sites (such as the spleen) is induced under hypoxic conditions. ¹⁰⁸ Studies have shown that Se deficiency or depletion of selenoproteins by Trsp gene ablation blocks erythroblast maturation in response to erythropoietin, resulting in an impaired response to anaemia. Cell culture studies using murine erythroblast cells have shown that mutations in selenoprotein W result in differentiation defects. Taken together, Se plays a critical role in redox homeostasis, maintenance of structural integrity and appropriate differentiation of erythrocytes.

Se deficiency: An underestimated cause of CRAS?

CKD and CVD share multiple bidirectional mechanisms, and anaemia is one of the critical components that are involved in the association between these two disorders. ¹¹ Although the administration of ESAs along with iron is the mainstay of CRAS management, ¹⁰ erythropoietin resistance can be observed in a subpopulation of patients. Moreover, several studies have shown that patients with CRAS have a worse prognosis than patients with heart failure without CRAS. ¹¹

As we have reviewed in this article, Se is a regulator of diverse physiological processes, and its deficiency is closely linked to all components of the CRAS (Figure 2). Epidemiological studies have shown that Se deficiency is associated with a high prevalence of anaemia in the general population. ⁷⁶ It also predicts the future occurrence of anaemia and is involved in hyporesponsiveness to ESA in CKD patients. ⁷⁷ As discussed above, proposed mechanisms include increased fragility, reduced stress erythropoiesis and impaired maturation of erythroblasts, which can occur independently of iron status. Indeed, the association between Se deficiency and ESA resistance was independent of transferrin saturation and ferritin levels in ESKD patients. ⁹³ Anaemia in CRAS is often associated with absolute or functional iron deficiency; however, studies have also shown that the iron deficiency does not always result in anaemia, ¹⁰⁹ supporting that reduced RBC levels in CRAS are multifactorial.

Figure 2.

Role of selenium (Se) in the pathophysiology of cardiorenal anaemia syndrome. In chronic kidney disease (CKD) patients, suboptimal Se status and reduced selenoprotein activity trigger the occurrence of cardiovascular diseases (CVDs) through multiple mechanisms, including impaired redox homeostasis and altered Ca²⁺ signalling in the endoplasmic reticulum. In addition, Se deficiency aggravates anaemia through increased erythrocyte fragility and reduced stress erythropoiesis, which also contributes to the increased risk of CVD in CKD.

Multiple lines of evidence also indicate that Se deficiency compromises cardiovascular function. Experimental studies have shown that insufficient Se supply triggers oxidative stress and mitochondrial dysfunction in cardiomyocytes. ⁷¹ In addition, studies in animal models have shown that selenoproteins, such as SelK, regulate calcium homeostasis and that Se supplementation mitigates cardiac injury by attenuating aberrant calcium influx. ¹¹⁰ Se also regulates thyroid hormone signalling, which is an important regulator of cardiovascular function. Observational clinical studies are in line with the experimental evidence that points to the key role of Se in regulating cardiac function. ⁷³ In addition, a recent biomarker study in heart failure patients has also indicated that CKD, heart failure and anaemia share a common pathological basis, including impaired immune response, oxidative stress and inflammation, ¹¹¹  all of which are known to occur as the consequence of disturbed Se metabolism. Given that patients with CKD are prone to malnutrition, deficiency in micronutrients other than iron, such as Se, needs to be considered an underestimated cause of CRAS (Figure 2).

Lastly, several studies have investigated the role of Se in mitigating the risk of CVD in the general population. Although low Se levels have been associated with an increased risk of CVD in observational studies, RCTs have not found a reduction in CVD incidence or mortality with Se supplementation. Considering the data showing a U‐shaped relationship between serum Se concentration and mortality, ⁶⁹ Se supplementation may be cardioprotective only when daily Se intake is inappropriately low. Given the limited number of RCTs addressing this issue, these findings remain inconclusive and require further investigation.

Take‐home messages

Se is an essential trace element that regulates diverse cellular processes, and accumulating data indicate that its deficiency is not uncommon, particularly in CKD patients with poor nutritional status. Given that Se deficiency can result in treatment‐resistant anaemia and is associated with an increased risk of CVD, the possible role of Se in the pathophysiology of CRAS merits future research.

Conflict of interest statement

Shigeyuki Arai, Minoru Yasukawa and Shigeru Shibata declare that they have no conflict of interest.

Arai, S. , Yasukawa, M. , and Shibata, S. (2025) Role of selenium in the pathophysiology of cardiorenal anaemia syndrome. ESC Heart Failure, 12: 770–780. 10.1002/ehf2.14893.