REVIEW ARTICLE Year : 2021  |  Volume : 10  |  Issue : 4  |  Page : 149-158

Potential benefits of selenium supplementation in patients with kidney disease

Shirinsadat Badri1, Sahar Vahdat2, Morteza Pourfarzam3, Samaneh Assarzadeh4, Shiva Seirafian2, Sara Ataei5
1 Department of Clinical Pharmacy and Pharmacy Practice, Isfahan University of Medical Sciences; Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
2 Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of Clinical Biochemistry, Isfahan University of Medical Sciences, Isfahan, Iran
4 Department of Clinical Pharmacy and Pharmacy Practice, Isfahan University of Medical Sciences, Isfahan, Iran
5 Department of Clinical Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

Date of Submission16-Jan-2022Date of Acceptance08-Feb-2022Date of Web Publication25-May-2022

Correspondence Address:
Dr. Samaneh Assarzadeh
Department of Clinical Pharmacy and Pharmacy Practice, Isfahan University of Medical Sciences, Isfahan
Iran

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jrpp.jrpp_3_22

Trace element deficiency is common among patients with end-stage renal disease (ESRD); the reason is that since these patients undergo dialysis, they lose these elements more than healthy people, and also the use of trace elements is restricted due to loss of appetite. Selenium (Se) is a trace element that is essential for the oxidative stress defense system. Se deficiency leads to some complications similar to those often seen in ESRD patients, such as all-cause mortality due to cardiovascular diseases, bone loss, uric acid elevation, and anemia. This article aims to review the evidence on consequences of Se deficiency in ESRD patients, as well as effects of Se supplementation in hemodialysis patients. Multiple databases were searched to summarize the available evidence on selenium's role in kidney diseases. Since the complications of ESRD and those of Se deficiency are mostly similar, this triggers the idea that Se deficiency may be considered as a cause of these problems, but it needs to be more assessed that Se deficiency is a single factor or there are other factors participated in. Also the role of Se supplementation on resolving the mentioned complications, needs to be more studied through well-designed clinical studies.

Keywords: Hemodialysis, kidney disease, peritoneal dialysis, Selenium supplementation

How to cite this article:
Badri S, Vahdat S, Pourfarzam M, Assarzadeh S, Seirafian S, Ataei S. Potential benefits of selenium supplementation in patients with kidney disease. J Res Pharm Pract 2021;10:149-58
How to cite this URL:
Badri S, Vahdat S, Pourfarzam M, Assarzadeh S, Seirafian S, Ataei S. Potential benefits of selenium supplementation in patients with kidney disease. J Res Pharm Pract [serial online] 2021 [cited 2022 May 27];10:149-58. Available from: https://www.jrpp.net/text.asp?2021/10/4/149/345841   Introduction 

Chronic kidney disease (CKD) is an umbrella term for several conditions that affect the kidneys, but it generally means permanent and usually progressive damage to the kidneys caused by a variety of conditions.[1] End-stage renal disease (ESRD) is a terminal illness defined as having a glomerular filtration rate of <15 mL/min. The most common cause of ESRD in the US is diabetic nephropathy, followed by hypertension. Despite extensive advancements over the past years in kidney transplantation and dialysis as well as novel methods of pharmacotherapy, death is still quite high among dialysis patients compared to a normal population.[2]

Cachexia and protein loss during hemodialysis are two key factors that lead to an oxidative stress situation and loss of essential amino acids and trace elements, which act as positive feedback and worsen patients' health. Because of the loss of proteins and low intake of proteins and amino acids secondary to loss of appetite, wasting plays a crucial role in oxidative stress. Because of oxidative stress, there is a risk of cardiovascular diseases (CVDs) 10-to-30-fold higher than normal people; also, the condition of the kidneys worsens.

Low intake and extended loss of selenium in ESRD patients result in weakened defense against oxidative stress secondary to impaired GPx activity.[3],[4] The use of selenium in ESRD patients either orally or parenterally increases selenium levels.[5],[6],[7] Accordingly, in this paper, first we will become more familiar with Se, Se in the human body and its intake criteria, then review the effect of selenium deficiency on ESRD patients and finally review studies that intervened to recompense selenium deficiency in ESRD patients (also with respect to animal studies).[8]

  Methods 

Data for this review were identified by searching Medline, PubMed, Scopus, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Keywords used as search terms were “selenium,” “chronic kidney diseases,” “kidney disease,” “hemodialysis,” and “peritoneal dialysis.” This search was performed without time limitations. Major well-designed studies which used selenium supplementation as an intervention in patients with kidney disease were included.

  Results 

The most common cause of ESRD in the US is diabetic nephropathy, followed by hypertension. Other etiologies can include glomerulonephritis, cystic kidney disease, recurrent kidney infection, chronic obstruction, etc., The symptoms of the disease may include nausea, vomiting, metabolic, hematologic, electrolyte derangements, seizures, coma, bleeding diathesis, refractory fluid overload, and hypertension unresponsive to pharmacotherapy, uremic pericarditis, etc., Vigilant monitoring of glomerular filtration rate (GFR) and proteinuria in diabetics and nondiabetics is essential to managing disease progression in patients with CKD.[9] Early referral to specialists is necessary for timely dialysis or renal transplant planning.[10],[11]

According to the United States Renal Data System, in 2015, there were 124,411 new ESRD diagnoses, reflecting an increasing burden of kidney failure. The disease prevalence has been steadily increasing at a rate of around 20,000 cases each year.[12],[13]

Coronary heart disease is a significant complication of CKD and is the most common cause of death in this population. Patients on dialysis have a 10-to-30-fold higher risk of cardiovascular mortality compared to the general population.[8] Peripheral vascular disease is also commonly seen in these patients.[14]

Common complications of progressive renal failure are as follows: hypertension, mineral and bone disorders (secondary to hyperparathyroidism and Vitamin D deficiency), hyperuricemia, metabolic acidosis, hyperphosphatemia, hypoalbuminemia, and anemia.[10]

Selenium is a chemical element with atomic number 34. It is a nonmetal element (rarely considered a metalloid) with properties that are intermediate between the elements above and below in the periodic table, sulfur, and tellurium; also, it has similarities to arsenic. Selenium was discovered in 1817 by Jöns Jacob Berzelius.[15]

A history of the important discoveries of the biological processes that selenium participates in, and a point-by-point comparison of the chemistry of selenium with the atom it replaces in biology, sulfur; shows that redox chemistry is the largest chemical difference between the two chalcogens. This difference is significant for both one-electron and two-electron redox reactions; it is mostly due to the inability of selenium to form π bonds of all types. The outer valence electrons of selenium are also more loosely held than those of sulfur. As a result, selenium is a better nucleophile and reacts with reactive oxygen species faster than sulfur, but the resulting lack of the π-bond character in the Se–O bond means that the Se-oxide can be much more readily reduced compared to S-oxides. The combination of these properties means that replacement of sulfur with selenium in nature results in a selenium-containing biomolecule that resists permanent oxidation.[16]

Selenium is an essential component of several major metabolic pathways, including thyroid hormone metabolism, antioxidant defense systems, and immune function.[17]

There is also evidence that selenium has a protective effect against some types of cancer; also, it may enhance male fertility, decrease CVD mortality, and regulate the inflammatory mediators in asthma.[17]

Selenium is incorporated into proteins as selenocysteine. Selenium mainly acts through these selenoproteins. In the human genome, 25 genes for selenoproteins have been identified.[18] Among enzymatically active selenoproteins, selenocysteine is a central component of the active center and is directly involved in redox reactions. Glutathione peroxidase (GPx), thioredoxin reductase (TrxR), and deiodinases are among the group of well-characterized selenoproteins. The five human selenium-containing GPx, catalyze the reduction of hydroperoxides.[19] Selenoprotein P (SePP) is essential for the distribution and transportation of selenium, in particular to the brain and testicles.[20]

Criteria for the assessment of selenium supply

The following parameters are used as biomarkers for selenium supply: The concentration of selenium in plasma or serum, along with the GPx activity in plasma (GPx3), erythrocytes (GPx1), thrombocytes (GPx1), or whole blood (GPx3 and GPx1), as well as the concentration of SePP in plasma or serum. In general, the measurement of selenoproteins reflects the functional selenium pool bound to selenoproteins, while the total selenium content also includes selenomethionine that is nonspecifically incorporated into proteins.

Most reference values are based on the measurement of GPx activity in plasma. However, the SePP concentration in plasma is deemed to be the most conclusive marker to determine the optimum supply of selenium.[21],[22],[23] The SePP concentration does not indicate a maximum level until a plasma selenium concentration of 100 μg/L to 120 μg/L is reached, while GPx activity in plasma reaches its optimum at a lower level of approximately 90 μg/L.[24],[25] In addition, nowadays, there are improved analysis methods that allow the determination of SePP. Based on human intervention studies, it is assumed that any further increase in selenium supply above a plasma selenium concentration of 120 μg/L will not lead to any further increase in selenoprotein expression.[26]

Similar complications in ESRD and Se deficiency

Physiologically, high selenium levels are associated with a decreased risk of CVD incidence and mortality.[27] Some studies have analyzed the effect of selenium on all-caused CVD mortality among patients. A meta-analysis study showed that participants with the highest selenium concentration had a lower risk for all-cause CVD mortality.[28] Another systematic review and meta-analysis of randomized controlled trials showed that a decreased risk with antioxidant mixtures was seen for CVD mortality when selenium was part of the mixture with no association when selenium was absent. Similarly, when selenium was part of the antioxidant mixture, a decreased risk was seen for all-cause mortality. It is concluded that the addition of selenium should be considered for supplements containing antioxidant mixtures if they are associated with CVD and all-cause mortality risk reduction.[29]

It is worth mentioning that most of these studies have been conducted on cases with normal kidney function, or at least the chief complaint of patients has not been associated with altered function of the kidneys.

Although some studies have concluded that low selenium content might be a risk factor for the development of hypertension,[30] recent studies have shown that high serum selenium concentrations are associated with a higher prevalence of hypertension;[31] for instance, a study showed that even in a population with very low serum selenium concentrations, higher serum selenium concentrations were associated with higher blood pressure levels and a higher prevalence of hypertension.[32] A positive association was found between serum selenium and hypertension, irrespective of age or antihypertensive medication intake.[33] Another study proved that long-term excessive selenium supplementation induced hypertension in rats.[34] It is important to closely monitor the amount of selenium intake and control its range, which could have adverse effects.

Emerging evidence supports the view that selenoproteins are essential for maintaining bone health. Antioxidant selenoproteins, including GPx and TrxR, as a whole, play a pivotal role in maintaining bone homeostasis and protecting against bone loss. GPx1, a major antioxidant enzyme in osteoclasts, is upregulated by estrogen, an endogenous inhibitor of osteoclastogenesis. TrxR1 is an immediate-early gene in response to 1α, 25-dihydroxyvitamin D3, an osteoblastic differentiation agent. The combination of 1α, 25-dihydroxyvitamin D3, and selenium generates a synergistic elevation of TrxR activity in Se-deficient osteoblasts. Of particular concern, pleiotropic TrxR1 is implicated in promoting nuclear factor-κB activation. Coincidentally, TrxR inhibitors (such as curcumin and gold compounds) exhibit potent osteoclastogenesis inhibitory activity. Studies in patients with mutations of selenocysteine insertion sequence-binding protein 2, a key trans-acting factor for the co-translational insertion of selenocysteine into selenoproteins, have clearly established a causal link of selenoproteins in bone development. Selenium transport to bone relies on SePP. Plasma SePP concentrations have been found to be positively correlated with bone mineral density in elderly women.[35]

Uric acid (UA) is the end product of purine metabolism in humans. UA has powerful antioxidant properties as ascorbic acid and accounts for nearly half of the antioxidant capacity in plasma. However, it can be deleterious pro-oxidant as well, resulting in vascular smooth muscle cell proliferation and endothelial dysfunction.[36] Excessive UA production or reduced urate excretion leads to hyperuricemia and gout. Furthermore, hyperuricemia plays a crucial role in the development and prognosis of hypertension, hyperlipidemia, insulin resistance, and other CVDs.[37] It was found that urinary selenium concentrations were inversely associated with serum UA (SUA) levels in males. In addition, under the exposure of vanadium and arsenic, only if high selenium content existed, no significantly increased SUA levels and hyperuricemia risk in both sexes can be found.[38]

Low serum selenium is associated with anemia among older adults in the US. Serum selenium levels were lower in anemic adults compared with nonanemic adults. The prevalence of anemia was high in the lowest quartile and low in the highest quartile of serum selenium.[39]

Nonclinical studies on the use of Selenium

Some studies have shown the antioxidant effect of selenium in animals such as goose, sheep, and acute heat stress-exposed quails. The antioxidant effect of selenium increases the protective effect of neutrophils, has a positive effect on cellular immunity, and finally increases the activity of the immune system. This increase in the immune system, in addition to the antioxidant effect of selenium, has been proven to increase the serum concentration of total immunoglobulins and circulatory immune complexes and had significantly heavier spleen and bursa in broilers. However, it was found in this study that Vitamin E has a synergistic effect with selenium.[40]

Furthermore, this increase in the immune system has been observed in newborn calves, and even studies conducted by Liu. on pigs showed that selenium deficiency had negative effects on cell-dependent immunity.[41],[42] Another well-documented benefit of selenium is its ability to decrease oxidative stress. This benefit in animals, such as sheep, was associated with improved spermatogenesis. Improvement of semen with selenium in chicken was seen as a marked increase in the concentration of total lipids and phospholipids in the seminal plasma from the control group. Improvement of spermatogenesis was also demonstrated in sheep. [Table 1] summarizes some nonclinical studies on the use of selenium.

Clinical trials on the use of Selenium in hemodialysis patients

Based on clinical trials in hemodialysis or peritoneal dialysis patients, selenium increased plasma concentration of selenium and red blood cell GPx (RBC GSH-Pxs) activities. Although it is debatable whether selenium supplementation can increase plasma GPx activity, some studies have shown that plasma GPx activity can be increased by selenium supplementation in combination with one or two more components, such as erythropoietin. [Table 2] summarizes some clinical trials on the use of selenium in dialysis patients or patients with altered renal function.

  Discussion 

[Figure 1] demonstrates the concept for Se role in CKD, especially ESRD. It is clear that loss of appetite has a direct relation with decrease of GFR. Hence, with CKD progression and consequently loss of appetite, the intake of trace elements and particularly Se decrease. Of course, patients with early CKD have restricted diets and by disease progression, it gets worsen. On the other hand, by starting dialysis, the loss of proteins, amino acids, nutrients, and trace elements increase. While trace element deficiency occurs, the body radical scavenging system weakens so it could not fight against oxidative stress efficiently. In addition, loss of proteins and low intake of them results in wasting, which increases the extent of oxidative stress. Moreover, in the end, we know that oxidative stress has a main role in increase the risk of CVD, anemia, bone disorders, and other complications that ESRD patients face with.

It seems that selenium supplementation in ESRD patients can be beneficial and improve the radical scavenging system. However, further studies are needed to determine if selenium supplementation alone can reduce oxidative stress in patients with impaired renal function.

  Conclusion 

In summary, a total of 20 animal studies, 8 randomized controlled trials on a variety of kidney diseases, especially HD patients have been reviewed. The most results from most of these studies consistently demonstrate the effect of selenium supplementation on increasing selenium levels in plasma, which Se deficiency is proved among them.

It can be accepted that Se supplementation is beneficial in reaching Se optimum plasma concentration in either those healthier ones or CKD patients. Furthermore, it should keep in mind that increase in Se plasma concentration more than optimum will result in side effects like blood hypertension. On the other hand, there are controversial results that compensation of Se deficiency may not affect ESRD patients. There is the point here that there needs a short period to achieve optimum Se plasma concentration, but the beginning of effect of this intervention is not clear; for example, the effect of Se supplementation in the elderly was assessed during 5 years and in this time course its advantages became obvious. Hence, there should be studies that assess the beginning of Se compensation effect in ESRD patients.[65]

In the study of Omrani et al., it was seen that the serum level of selenium in dialysis patients who received selenium supplements was significantly different from the control group. In that study, they claimed that taking (400 mg) twice a week for 2 months improved the oxygen radical scavenging system, increased plasma and red blood cell selenium concentrations, and increased selenium-dependent GPx activity; however taking selenium supplements in hemodialysis patients does not help much to reduce the harmful level of blood lipids, although lowering low-density lipoprotein-C and cholesterol and the contradictory results of other research studies show that more similar studies are needed in a larger population.

Since the complications of ESRD and those of Se deficiency are mostly similar, this triggers the idea that Se deficiency may be considered as a cause of these problems, but it needs to be more assessed that Se deficiency is a single factor or there are other factors participate in.

Hence, strong interventional studies are still necessary to determine whether plasma selenium depletion has adverse effects in CKD patients. Finally, differences in effectiveness between different augmentation therapies have not been compared in the literature.

  Authors' Contribution 

S. Badri, S. Vahdat, S. Seirafian, and M. Pourfarzam developed the idea of research and criticized the findings. S. Assarzadeh, and S. Ataei searched and recruited the studies. All authors contributed in manuscript preparation and revision.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

  References 
1.Filler G, Felder S. Trace elements in dialysis. Pediatr Nephrol 2014;29:1329-35.  
    2.Gholipur-Shahraki T, Feizi A, Mortazavi M, Badri S. Effects of carnitine on nutritional parameters in patients with chronic kidney disease: An updated systematic review and meta-analysis. J Res Pharm Pract 2018;7:57-68.  
[PUBMED]  [Full text]  3.Prodanchuk M, Makarov O, Pisarev E, Sheiman B, Kulyzkiy M. Disturbances of trace element metabolism in ESRD patients receiving hemodialysis and hemodiafiltration. Cent European J Urol 2014;66:472-6.  
    4.Bronislaw AZ. Chapter five – Selenium and selenium-dependent antioxidants in chronic kidney disease. Adv Clin Chem 2015;68:131-51.  
    5.Salehi M, Sohrabi Z, Ekramzadeh M, Fallahzadeh MK, Ayatollahi M, Geramizadeh B, et al. Selenium supplementation improves the nutritional status of hemodialysis patients: A randomized, double-blind, placebo-controlled trial†. Nephrol Dial Transplant 2012;28:716-23.  
    6.Temple KA, Smith AM, Cockram DB. Selenate-supplemented nutritional formula increases plasma selenium in hemodialysis patients. J Ren Nutr 2000;10:16-23.  
    7.Koenig JS, Fischer M, Bulant E, Tiran B, Elmadfa I, Druml W. Antioxidant status in patients on chronic hemodialysis therapy: Impact of parenteral selenium supplementation. Wien Klin Wochenschr 1997;109:13-9.  
    8.Fujii H, Kono K, Nishi S. Characteristics of coronary artery disease in chronic kidney disease. Clin Exp Nephrol 2019;23:725-32.  
    9.Badri S, Dashti-Khavidaki S, Ahmadi F, Mahdavi-Mazdeh M, Abbasi MR, Khalili H. Effect of add-on pentoxifylline on proteinuria in membranous glomerulonephritis: A 6-month placebo-controlled trial. Clin Drug Investig 2013;33:215-22.  
    10.Benjamin O, Lappin SL. End-stage renal disease. In: StatPearls [Internet]. Last Update on September 16, 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK499861/.  
    11.Badri S, Dashti-Khavidaki S, Lessan-Pezeshki M, Abdollahi M. A review of the potential benefits of pentoxifylline in diabetic and non-diabetic proteinuria. J Pharm Pharm Sci 2011;14:128-37.  
    12.Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: A review of current evidence. Diabetologia 2019;62:3-16.  
    13.Ishigami J, Matsushita K. Clinical epidemiology of infectious disease among patients with chronic kidney disease. Clin Exp Nephrol 2019;23:437-47.  
    14.Matsushita K, Ballew SH, Coresh J, Arima H, Ärnlöv J, Cirillo M, et al. Measures of chronic kidney disease and risk of incident peripheral artery disease: A collaborative meta-analysis of individual participant data. Lancet Diabetes Endocrinol 2017;5:718-28.  
    15.Arago F, Gay-Lussac JL. Annales De Chimie Et De Physique. CHEBI:27568 - selenium atom: Chez Crochard; 1841. Available at: https://www.ebi.ac.uk/chebi/searchId.do?chebiId=27568#:~:text=Selenium%20is%20a%20chemical%20element,also%20has%20similarities%20to%20arsenic. [Last accessed: December 2021].  
    16.Reich HJ, Hondal RJ. Why nature chose selenium. ACS Chem Biol 2016;11:821-41.  
    17.Brown KM, Arthur JR. Selenium, selenoproteins and human health: A review. Public Health Nutr 2001;4:593-9.  
    18.Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigó R, et al. Characterization of mammalian selenoproteomes. Science 2003;300:1439-43.  
    19.Brigelius-Flohé R, Maiorino M, Ursini F, Flohé L. Selenium: an antioxidant? Handbook of antioxidants. New York: CRC Press; 2001. p. 652-83.  
    20.Hill KE, Zhou J, McMahan WJ, Motley AK, Atkins JF, Gesteland RF, et al. Deletion of selenoprotein P alters distribution of selenium in the mouse. J Biol Chem 2003;278:13640-6.  
    21.Hurst R, Collings R, Harvey LJ, King M, Hooper L, Bouwman J, et al. EURRECA – estimating selenium requirements for deriving dietary reference values. Crit Rev Food Sci Nutr 2013;53:1077-96.  
    22.Ashton K, Hooper L, Harvey LJ, Hurst R, Casgrain A, Fairweather-Tait SJ. Methods of assessment of selenium status in humans: A systematic review. Am J Clin Nutr 2009;89:2025S-2039S.  
    23.Kipp AP, Strohm D, Brigelius-Flohé R, Schomburg L, Bechthold A, Leschik-Bonnet E, et al. Revised reference values for selenium intake. J Trace Elem Med Biol 2015;32:195-9.  
    24.Xia Y, Hill KE, Byrne DW, Xu J, Burk RF. Effectiveness of selenium supplements in a low-selenium area of China. Am J Clin Nutr 2005;81:829-34.  
    25.Xia Y, Hill KE, Li P, Xu J, Zhou D, Motley AK, et al. Optimization of selenoprotein P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: A placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects. Am J Clin Nutr 2010;92:525-31.  
    26.Rayman MP. Selenium and human health. Lancet 2012;379:1256-68.  
    27.Kuria A, Tian H, Li M, Wang Y, Aaseth JO, Zang J, et al. Selenium status in the body and cardiovascular disease: A systematic review and meta-analysis. Crit Rev Food Sci Nutr 2021;61:3616-25.  
    28.Li J, Lo K, Shen G, Feng YQ, Huang YQ. Gender difference in the association of serum selenium with all-cause and cardiovascular mortality. Postgrad Med 2020;132:148-55.  
    29.Jenkins DJ, Kitts D, Giovannucci EL, Sahye-Pudaruth S, Paquette M, Blanco Mejia S, et al. Selenium, antioxidants, cardiovascular disease, and all-cause mortality: A systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr 2020;112:1642-52.  
    30.Mihailović MB, Avramović DM, Jovanović IB, Pesut OJ, Matić DP, Stojanov VJ. Blood and plasma selenium levels and GSH-Px activities in patients with arterial hypertension and chronic heart disease. J Environ Pathol Toxicol Oncol 1998;17:285-9.  
    31.Laclaustra M, Navas-Acien A, Stranges S, Ordovas JM, Guallar E. Serum selenium concentrations and hypertension in the US Population. Circ Cardiovasc Qual Outcomes 2009;2:369-76.  
    32.Berthold HK, Michalke B, Krone W, Guallar E, Gouni-Berthold I. Influence of serum selenium concentrations on hypertension: The Lipid Analytic Cologne cross-sectional study. J Hypertens 2012;30:1328-35.  
    33.Bastola MM, Locatis C, Maisiak R, Fontelo P. Selenium, copper, zinc and hypertension: An analysis of the National Health and Nutrition Examination Survey (2011-2016). BMC Cardiovasc Disord 2020;20:45.  
    34.Grotto D, Carneiro MF, de Castro MM, Garcia SC, Barbosa Junior F. Long-term excessive selenium supplementation induces hypertension in rats. Biol Trace Elem Res 2018;182:70-7.  
    35.Zhang Z, Zhang J, Xiao J. Selenoproteins and selenium status in bone physiology and pathology. Biochim Biophys Acta 2014;1840:3246-56.  
    36.Rock KL, Kataoka H, Lai JJ. Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol 2013;9:13-23.  
    37.Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-21.  
    38.Navarro-Alarcón M, López-G de la Serrana H, Pérez-Valero V, López-Martínez C. Serum and urine selenium concentrations as indicators of body status in patients with diabetes mellitus. Sci Total Environ. 1999;228(1):79-85.  
    39.Semba RD, Ricks MO, Ferrucci L, Xue QL, Guralnik JM, Fried LP. Low serum selenium is associated with anemia among older adults in the United States. Eur J Clin Nutr 2009;63:93-9.  
    40.Wang Y, Jiang L, Li Y, Luo X, He J. Effect of different selenium supplementation levels on oxidative stress, cytokines, and immunotoxicity in chicken thymus. Biol Trace Elem Res 2016;172:488-95.  
    41.Liu F, Celi P, Cottrell J, Chauhan S, Leury B, Dunshea F. Effects of a short-term supranutritional selenium supplementation on redox balance, physiology and insulin-related metabolism in heat-stressed pigs. J Anim Physiol Anim Nutr 2018;102:276-85.  
    42.Feldmann M, Jachens G, Höltershinken M, Scholz H. Effects of a selenium/vitamin E substitution on the development of newborn calves on selenium-deficient farms. Tierarztl Prax Ausg G Grosstiere Nutztiere 1998;26:200-4.  
    43.Malbe M, Klaassen E, Kaartinen L, Attila M, Atroshi F. Effects of oral selenium supplementation on mastitis markers and pathogens in Estonian cows. Vet Ther 2003;4:145-54.  
    44.Contreras PA, Wittwer F, Matamoros R, Mayorga IM, van Schaik G. Effect of grazing pasture with a low selenium content on the concentrations of triiodothyronine and thyroxine in serum, and GSH-Px activity in erythrocytes in cows in Chile. N Z Vet J 2005;53:77-80.  
    45.Biswas A, Mohan J, Sastry KV. Effect of higher levels of dietary selenium on production performance and immune responses in growing Japanese quail. Br Poult Sci 2006;47:511-5.  
    46.Dimitrov SG, Atanasov VK, Surai PF, Denev SA. Effect of organic selenium on turkey semen quality during liquid storage. Anim Reprod Sci 2007;100:311-7.  
    47.Hall JA, Bailey DP, Thonstad KN, Van Saun RJ. Effect of parenteral selenium administration to sheep on prevalence and recovery from footrot. J Vet Intern Med 2009;23:352-8.  
    48.Baowei W, Guoqing H, Qiaoli W, Bin Y. Effects of yeast selenium supplementation on the growth performance, meat quality, immunity, and antioxidant capacity of goose. J Anim Physiol Anim Nutr (Berl) 2011;95:440-8.  
    49.Ceballos-Marquez A, Barkema HW, Stryhn H, Wichtel JJ, Neumann J, Mella A, et al. The effect of selenium supplementation before calving on early-lactation udder health in pastured dairy heifers. J Dairy Sci 2010;93:4602-12.  
    50.Leal ML, de Camargo EV, Ross DH, Molento MB, Lopes ST, da Rocha JB. Effect of selenium and vitamin E on oxidative stress in lambs experimentally infected with Haemonchus contortus. Vet Res Commun 2010;34:549-55.  
    51.Speight SM, Estienne MJ, Harper AF, Crawford RJ, Knight JW, Whitaker BD. Effects of dietary supplementation with an organic source of selenium on characteristics of semen quality and in vitro fertility in boars. J Anim Sci 2012;90:761-70.  
    52.Ren Y, Wang Q, Shi L, Yue W, Zhang C, Lei F. Effects of maternal and dietary selenium (Se-enriched yeast) on the expression of p34cdc2 and CyclinB1 of germ cells of their offspring in goats. Anim Reprod Sci 2011;123:187-91.  
    53.Alhidary IA, Shini S, Al Jassim RA, Gaughan JB. Effect of various doses of injected selenium on performance and physiological responses of sheep to heat load. J Anim Sci 2012;90:2988-94.  
    54.Brummer M, Hayes S, Adams AA, Horohov DW, Dawson KA, Lawrence LM. The effect of selenium supplementation on vaccination response and immune function in adult horses. J Anim Sci 2013;91:3702-15.  
    55.Shi L, Zhao H, Ren Y, Yao X, Song R, Yue W. Effects of different levels of dietary selenium on the proliferation of spermatogonial stem cells and antioxidant status in testis of roosters. Anim Reprod Sci 2014;149:266-72.  
    56.Del Vesco A, Gasparino E, Zancanela V, Grieser D, Stanquevis C, Pozza P, et al. Effects of selenium supplementation on the oxidative state of acute heat stress-exposed quails. J Anim Physiol Anim Nutr 2017;101:170-9.  
    57.White S, Warren L. Submaximal exercise training, more than dietary selenium supplementation, improves antioxidant status and ameliorates exercise-induced oxidative damage to skeletal muscle in young equine athletes. J Anim Sci 2017;95:657-70.  
    58.Elgendy R, Giantin M, Castellani F, Grotta L, Palazzo F, Dacasto M, et al. Transcriptomic signature of high dietary organic selenium supplementation in sheep: A nutrigenomic insight using a custom microarray platform and gene set enrichment analysis. J Anim Sci 2016;94:3169-84.  
    59.Wang Y, Jiang L, Li Y, Luo X, He J. Excessive selenium supplementation induced oxidative stress and endoplasmic reticulum stress in chicken spleen. Biol Trace Elem Res 2016;172:481-7.  
    60.Zachara BA, Adamowicz A, Trafikowska U, Trafikowska A, Manitius J, Nartowicz E. Selenium and glutathione levels, and glutathione peroxidase activities in blood components of uremic patients on hemodialysis supplemented with selenium and treated with erythropoietin. J Trace Elem Med Biol 2001;15:201-8.  
    61.Zachara BA, Gromadzinska J, Palus J, Zbrog Z, Swiech R, Twardowska E, et al. The effect of selenium supplementation in the prevention of DNA damage in white blood cells of hemodialyzed patients: A pilot study. Biol Trace Elem Res 2011;142:274-83.  
    62.Sedighi O, Zargari M, Varshi G. Effect of selenium supplementation on glutathione peroxidase enzyme activity in patients with chronic kidney disease: A randomized clinical trial. Nephrourol Mon 2014;6:e17945.  
    63.Tonelli M, Wiebe N, Thompson S, Kinniburgh D, Klarenbach SW, Walsh M, et al. Trace element supplementation in hemodialysis patients: A randomized controlled trial. BMC Nephrol 2015;16:52.  
    64.Omrani H, Golmohamadi S, Pasdar Y, Jasemi K, Almasi A. Effect of selenium supplementation on lipid profile in hemodialysis patients. J Renal Inj Prev 2016;5:179-82.  
    65.Alehagen U, Aaseth J, Alexander J, Brismar K, Larsson A. Selenium and coenzyme Q10 supplementation improves renal function in elderly deficient in selenium: Observational results and results from a subgroup analysis of a prospective randomised double-blind placebo-controlled trial. Nutrients 2020;12:3780.  
    
  [Figure 1]
 
 
  [Table 1], [Table 2]