CHAPTER FIVE

Selenium and SeleniumDependent Antioxidants in Chronic Kidney Disease Bronislaw A. Zachara*,†,1,2 *Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Lodz, Poland † College of Health Sciences, Bydgoszcz, Poland 1 Present address: 33/67 Nowodworka Street, 85-120 Bydgoszcz, Poland. 2 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 1.1 Reactive oxygen species in chronic kidney disease 2. The Role of Selenium in Kidney Disease 3. Glutathione Peroxidases in Chronic Kidney Disease 3.1 Red blood cell glutathione peroxidase (GSH-Px 1) 3.2 Plasma glutathione peroxidase (GSH-Px 3) 4. Selenium Supplementation in CKD 5. Conclusion Acknowledgments References

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Abstract Oxidative stress plays a key role in numerous disease processes including chronic kidney disease (CKD). In general, oxygen metabolism leads to the formation of reactive oxygen species (ROS) dangerous to cells. Although enzymes and low-molecular-weight antioxidants protect against ROS, chronic imbalances of formation and elimination can eventually overwhelm endogenous defenses leading to deleterious consequences. In CKD, glutathione peroxidases (GSH-Px) play an important role in ROS metabolism. Plasma GSH-Px is synthesized in the kidney and requires selenium (Se) as a cofactor. Interestingly, Se and plasma GSH-Px are both significantly reduced in CKD, especially for those patients on hemodialysis. Supplementation of Se in these patients results in modest increases of GSH-Px, presumably from residual renal tissue. Kidney transplantation rapidly restores plasma GSH-Px. In this chapter, the relevance of these findings to CKD is explored with emphasis on renal disease processes and impact on attendant disorders including cancer and cardiovascular disease.

Advances in Clinical Chemistry, Volume 68 ISSN 0065-2423 http://dx.doi.org/10.1016/bs.acc.2014.11.006

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2015 Elsevier Inc. All rights reserved.

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1. INTRODUCTION 1.1. Reactive oxygen species in chronic kidney disease Chronic kidney disease (CKD) is now recognized to be a worldwide problem associated with significant morbidity and mortality. In recent years, there has been a steep increase in number of patients with end-stage renal disease (ESRD) [1]. The disease is characterized by complex changes in cell metabolism, leading to increased production of oxygen radicals that play a key role in numerous diseases including CKD [2]. Under normal conditions, oxygen metabolism leads to oxidative stress, which manifests as formation of highly reactive intermediates called free radicals or reactive oxygen species (ROS) [3,4]. These dangerous molecules include superoxide radical (O2  ), hydroxyl radical (OH%), and singlet oxygen (1O2) [5,6]. Some believe that hydrogen peroxide (H2O2) also belongs to this group because it easily penetrates membranes and, in the presence of transition metals (copper or iron), can be reduced to OH% via the Fenton reaction [3,6,7]: H2 O2 + Cu + =Fe2 + ! OH• + OH + Cu2 + =Fe3 + Hydroxyl radical, the strongest oxidant generated in biologic systems, has an extremely short half-life [3,8]. The generation of free radicals, however, occurs continuously as part of normal cellular function. Unfortunately, excess free radical production is associated with a variety of clinical disorders including atherosclerosis, cancer, diabetes, CKD, and others [3,9,10]. Because free radicals react with a variety of molecules, their harmful effects most often include damage to DNA (strand breaks and oxidation of purine bases), oxidation of lipids (mainly polyunsaturated fatty acids), oxidation of amino acids in proteins, and oxidative inactivation of specific enzymes by oxidation of cofactors [4,7]. Mammalian cells have several compounds that eliminate ROS. As long as there is a balance between the generation and decomposition of ROS, there is no damage to cellular components. Disturbance in this balance is associated with the aforementioned diseases [10]. In CKD, antioxidant efficiency is reduced in direct proportion to disease development and is the lowest at end-stage kidney disease [11]. Mammalian cells are protected against ROS by two lines of defense: an endogenous mechanism that mainly involves enzymes and an exogenous mechanism that utilizes low-molecular-weight free-radical scavenger

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SOD

GSH-Px 2H+

O2

O2 e

H+ H2O2

e

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e

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Catalase

Figure 1 Antioxidant enzymes: all three enzymes are not localized in the same compartments of cells: SODs are either in the cytosol (Cu–Zn SOD) or in the mitochondria (Mn SOD); GSH-Px is mainly cytosolic; catalase is mainly found in peroxisomes. Adapted from Joseph [12].

compounds [12]. There are four predominant antioxidant enzymes. These include superoxide dismutases (SODs), catalases (CATs), glutathione peroxidases (GSH-Px) [3,13,14], and probably selenoprotein P (SePP) [15]. Antioxidant defense may also include other enzymes, i.e., glutathione reductase and glutathione transferase [16]. The role of GSH-Px, an enzyme very important in kidney disease, and other antioxidant enzymes in ROS removal are depicted (Fig. 1). An important role in antioxidant defense is played by compounds called small molecular antioxidants [6]. These include vitamins A (and its precursors—carotenes), C and E (tocopherols and tocotrienols), GSH, uric acid, bilirubin, ceruloplasmin, and others [3,17]. Antioxidants are widely used as dietary supplements for prevention of diseases such as cancer, coronary heart disease, and others [17]. Although selenium (Se) is commonly referred to as an antioxidant nutrient, it has no antioxidant activity itself and is instead required for the synthesis and activity of some antioxidant enzymes [18,19].

2. THE ROLE OF SELENIUM IN KIDNEY DISEASE The indispensability of Se in mammals was demonstrated in 1957 when Schwarz and Foltz [20] showed that Se and vitamin E deficiency led to dietary necrotic liver degeneration in rats. Addition of Se prevented such damage. The mechanism of Se activity was explained a dozen years later. For a long time, Se requirements in humans remained unknown. Based on animal studies in the 1980s, the American National Academy of Sciences recommended that people over the age of 7 should consume 50–200 μg Se/day [21]. Human studies demonstrated that the daily dietary requirement for Se is 55 μg (females) and 70 μg (males), i.e., 1 μg/kg body weight [22].

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Intake, however, should be appropriate to achieve a 100 ng/ml concentration in plasma. Some, however, believe that adults should increase this requirement to 250–300 μg/day [23]. No side effects were noted with Se intake up to 600 μg/day. Additional details regarding Se and dosage in humans can be found in an excellent publication by Rayman [24]. For example, most studies on the influence of Se in humans were performed at a dosage of 200 μg/day in the form of Se-enriched yeast. Interestingly, Se from this source is predominantly (54–90%) selenomethionine (SeMet). In healthy individuals, the plasma concentration of Se is 0.5–2.5 μmol/l, depending on geographic location [25]. The majority of Se circulates as SePP (50–60% or more), while the rest is incorporated as selenocysteine (Sec) in GSH-Px or as SeMet bound to albumin [26]. Deagen et al.[26] showed that Se was distributed as SePP (57%), GSH-Px (20%), and albumin (23%) in plasma irrespective of concentration (21–162 ng/ml). Similar results, 60% Se in SePP, were obtained by Read et al. [27]. As a component of some proteins, Se plays an important role in many disorders including cancer, cardiovascular, and kidney disease [28]. The kidneys play a central role in the homeostasis of many small molecules and elements, including Se [29,30]. In fact, the kidneys and thyroid gland have the highest Se concentration of all human organs [31,31a]. Se transport from the liver to the kidneys is conducted as SePP, which contains at least 10 Se atoms [15,30]. In CKD, Se was significantly lower in whole blood, plasma, serum, and rbc (red blood cells) versus healthy subjects [11,13,32–35]. In fact, several have shown that decreases in Se are proportion to disease progression [11,36]. Decreased but statistically insignificant Se has been noted in whole blood and plasma at early disease stage [11,36]. In contrast, whole blood and plasma Se was significantly lower (50%) in ESRD versus healthy controls (p < 0.0001) [37]. In patients on hemodialysis, the Se concentration was even lower [11]. The significance of low blood Se is not fully understood. Decreased serum Se without severe deficiency has been associated with cardiomyopathy in dialysis patients [37a]. Mild Se deficiency appears to increase the susceptibility to oxidant stress, which may be relevant to HD patients in whom oxidative stress is markedly increased [for review, see Ref. 38]. The question arises as to what is the cause of low Se in CKD? Blood component Se concentration is clearly influenced by diet, i.e., the principal source of this element. In uremia, decreased whole blood and plasma Se appears associated with decreased protein intake and increased urinary protein loss. Under these circumstances, patients are advised to consume limited protein to relieve uremic symptoms and slow progression. Because protein is

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a major source of Se, dietary intake is substantially reduced [39]. Other factors such as impaired intestinal absorption, abnormal binding proteins that transport Se or drug therapy may also be responsible for this phenomenon [4,40,41]. Se is excreted in the urine (50–70%) and feces [42]. Urinary concentration depends on the Se form and amount consumed. Yang et al. [43] studied the relationship between Se intake and urinary excretion in Chinese people living in different regions. Se excretion increased proportional to intake and was likely dependent on soil concentration of this element in different geographic locations. Se is excreted in the urine in various forms. For a long time, it was thought that the main urinary form was trimethylselenonium (TMSe) [44,45]. Interestingly, Palmer et al. [46] demonstrated that TMSe represented 20–50% of Se excretion in rat urine. In 2004, TMSe was also detected in human urine [47]. Subsequent studies identified Se-containing carbohydrates as the major urinary metabolites [29]. Following hepatic metabolism, Se is transported to the kidney [48,49] with excess Se excreted as selenosugar. TMSe is now considered to be a less significant metabolite. Progression of CKD is typically assessed via measurement of plasma creatinine concentration, creatinine clearance, or glomerular filtration rate (GFR) [50]. In CKD, plasma creatinine concentration is several fold higher than healthy subjects [51] and is highest in ESRD. Although creatinine may even be higher in HD and peritoneal dialysis, HD, itself, does not influence creatinine concentration [52]. In our study, we demonstrated a significant negative correlation between creatinine and Se in CKD (Fig. 2) [36]. Others presented similar findings [11,53]. r = −0.380, p < 0.0001, n = 129 Selenium concentration in plasma (ng/ml)

160 140 120 100 80 60 40 20

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4 8 12 16 Creatinine concentration in plasma (mg/dl)

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Figure 2 Correlation between plasma selenium and creatinine concentrations in control group and in different stages of chronic kidney disease. Adapted from Ref. [4].

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3. GLUTATHIONE PEROXIDASES IN CHRONIC KIDNEY DISEASE As mentioned above, Se itself is not an antioxidant but acts as a cofactor for antioxidant enzymes. To date, at least 25 selenoproteins have been partially or fully characterized [54]. More than 10 have enzymatic activity. The best characterized are five human GSH-Px [16,17]. These include cytosolic (cellular, classical, GSH-Px 1), gastrointestinal (GSH-Px 2), plasma (extracellular, GSH-Px 3), phospholipid (GSH-Px 4), and sperm nuclei (GSH-Px 5) [16,55]. Using GSH as a substrate, all metabolize H2O2 and other organic hydroperoxides [56,57]. Two GSH-Px are present in blood: GSH-Px 1 in rbc and GSH-Px 3 in plasma. Both are tetramers and contain one Se per subunit in the form of Sec, i.e., the 21st amino acid discovered at the end of the last century [58,59]. In healthy subjects, Se supplementation induces the synthesis of these enzymes [60].

3.1. Red blood cell glutathione peroxidase (GSH-Px 1) GSH-Px 1 was first discovered and characterized in rbc. In 1957, Mills [61] identified a protein which in the presence of glutathione efficiently protected hemoglobin from oxidative breakdown by H2O2. He called it as glutathione peroxidase. In 1973, scientists from two centers, Flohe´ et al. (T€ ubingen, Germany) [62] and Rotruck et al. (Madison, WI, USA) [63] independently demonstrated that rbc GSH-Px contained Se in its active site. Five years later, Forstrom et al.[64] partially purified the enzyme and showed that the Se moiety is Sec. GSH-Px is composed of 201 amino acid residues and Sec is located in the active site at amino acid position 45. Human rbc GSH-Px binds 10–15% of circulating Se [65] (Fig. 3). GSH-Px present in rbc is synthesized during erythropoiesis. In mature cells, there is no de novo synthesis. The process of maturation resulted in decreased GSH and decreased activities of almost all antioxidant enzymes in normal subjects and in some diseases, indicating decreased scavenging capacity [66]. However, studies on the importance of this enzyme in CKD have been inconsistent. For example, some reported significantly lower [36,51,67,68] or higher [11,69] activity or did not observe any difference in ESRD [35,36,52,70–72]. HD did not influence enzyme activity [72]. Bone marrow synthesis GSH-Px 1 is unaffected in CKD. Although whole blood and plasma Se was decreased in CKD, rbc GSH-Px activity

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Figure 3 Structure of the tetrameric form of red blood cell GSH-Px. In each subunit, Sec is located in the active site at position 45. Adapted from Diamond et al. [62a] with permission.

was unchanged [36]. In CKD, enzyme activity was significantly lower but similar at all disease stages [51]. Temple et al. [70] found that rbc GSH-Px activity was within the normal range in HD patients. Ceballos-Picot et al. [11] reported that rbc GSH-Px activity was significantly higher in CKD at the incipient stage and remained elevated to the same degree up to advanced stages. In HD patients, enzyme activity was similar to that observed in ESRD. Crawford et al. [73] demonstrated that rbc GSH-Px activity in CKD was significantly increased and highest in ESRD (Fig. 4).

3.2. Plasma glutathione peroxidase (GSH-Px 3) Similarly to GSH-Px 1, plasma GSH-Px 3 is a tetrameter composed of four identical subunits each containing 1 g atom of Se [74,75]. Unlike the classical enzyme, GSH-Px 3 is an extracellular protein [65]. Plasma GSH-Px 3 is structurally and antigenically distinct from the rbc enzyme and the enzyme from other cells [74]. The enzyme consists of 226 amino acid residues with the Sec located at amino acid position 73. In 1987, the enzyme was purified and shown to have a molecular weight of 90 kDa [65,74,75]. As plasma selenoproteins, both GSH-Px 3 and SePP serve as nutritional markers, i.e., their concentration is proportional to circulating Se. In humans, measurement of GSH-Px 3 is used to assess nutritional status [76].

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Figure 4 Antioxidant activities in all subjects (n ¼ 454) in the different stages of CKD. (A) Plasma GPx, (B) rbc GPx. Number of controls and patients in stages: Stage 1, n ¼ 28 and n ¼ 0; Stage 2, n ¼ 166 and n ¼ 9; Stage 3, n ¼ 30 and n ¼ 104; Stage 4, n ¼ 0 and n ¼ 91, and Stage 5, n ¼ 0 and n ¼ 26. *p < 0.05; **p < 0.001, significant difference from Stage 1. Adapted from Crawford et al. [73], with permission of authors and publisher, Dustin-Verlag.

In humans, the main source of GSH-Px is the proximal renal tubules, from which the protein is secreted into plasma and other body fluids [77]. Chu et al. [78] has shown that GSH-Px 3 is synthesized at low levels in other organs including liver, lung, heart, breast, brain, skeletal muscle, and placenta. Although the physiologic role of plasma GSH-Px has not been fully elucidated, its expression is likely related to local extracellular antioxidant protection [74,79]. In fact, this enzyme is responsible for the overall reduction of organic hydroperoxides in human plasma [74]. Studies on plasma GSH-Px activity in kidney disease have produced very clear results. In CKD, the activity of this enzyme is decreased (34–52%) relative to healthy individuals (for review, see Ref. [13] and Fig. 4). During

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disease progression, enzyme activity gradually decreases reaching single percent values in ESRD [11]. Decreased enzyme activity is not, however, associated with Se deficiency [80] but appears to result from nephron loss associated with disease development. Others have presented similar views [11,35,81]. In ESRD, the presence of very low GSH-Px 3 activity may be due to its synthesis in residual undamaged kidney cells and from other tissues/organs that synthesize small amounts of this enzyme. In one study, plasma Se was comparable in HD patients versus controls (118 ng/ml vs. 130 ng/ml), but GSH-Px activity was substantially lower (42%) (p < 0.001) [77]. In kidney transplant patients, Se and GSH-Px were measured before and after transplantation. Although Se concentration was comparable before and after surgery, plasma GSH-Px activity was eightfold higher posttransplantation. Several months posttransplantation, GSH-Px activity returned to normal. Plasma activity was not influenced by circulating inhibitors or uremic toxins as suggested by others [82,83]. Another study in transplant patients showed comparable results [84]. Although plasma Se concentration decreased slightly (64.3–57.0 ng/ml; p < 0.05), GSH-Px increased almost twofold (76.7–140 U/l, p < 0.0001) 7 days posttransplantation. At 2 weeks, GSH-Px activity was comparable to controls (177 U/l vs. 196 U/l). SePP plays an important role in delivering Se to the kidney. SePP is synthesized in the liver, secreted into the blood, and used for Se transport to the kidneys as well as other tissues [54,85]. Saito et al. [86] have shown that SePP fulfills two functions, enzymatic activity (N-terminal with one Sec in the active site at amino acid position 40) and Se supply (C-terminal having nine Sec residues marked as U, Fig. 5). Due to its relatively low molecular weight and high Se content, this protein is a good marker of Se status [87]. The renal proximal tubule epithelium contains megalin, a glycosylated SePP receptor protein with a molecular weight of 600 kDa [85,86]. Immunohistochemical studies have revealed that cells of the proximal convoluted tubules are responsible for SePP uptake from glomerular filtrate for GSH-Px 3 synthesis [76].

4. SELENIUM SUPPLEMENTATION IN CKD In healthy individuals, Se supplementation results in increased synthesis of GSH-Px activity in blood and in other tissues [88,89]. Although plasma GSH-Px activity plateaus after 3–4 weeks of supplementation, rbc activity

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O

O

CH

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U

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UxU U T UxU 338 352

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Figure 5 Domains of rat SePP. Panel (A) depicts the N-terminal domain (residues 1–244) that contains one selenocysteine residue (U). Panel (B) depicts the C-terminal seleniumrich domain (residues 245–366) containing nine selenocysteine residues. It has a single occupied O-glycosylation site. SePP1 isoforms terminate before the selenocysteine residues at positions 245, 263, and 352 as indicated by .. Adapted from Burk and Hill [76], with permission.

increases much more slowly due to long cellular life span [90]. As such, plasma GSH-Px activity is a more sensitive index of short-term Se status, whereas rbc provide long-term status. Se is a key component in a number of important functional selenoproteins [91]. Serum Se concentration of 100 μg/l is required for optimal GSH-Px activity. Low blood concentration should be treated with a diet rich in this element, including Se-yeast which has higher bioavailability than Se from inorganic sources [24]. Supplementation, organic or inorganic should be considered for patients with ESRD and on HD. Administration of Se to CKD patients increases blood concentration of the element similar to that observed in healthy individuals [84]. Studies on Se administration in CKD patients on HD have yielded ambiguous results with respect to GSH-Px activity. In an early study of HD patients, Saint-Georges et al. [84] showed decreased Se plasma concentration and decreased rbc and plasma GSH-Px activity. Following supplementation with oral sodium selenite (500 μg/day for 3 months then 200 μg/day for 3 months), plasma Se was notably increased in the first week and plateaued to control levels after 3 weeks. GSH-Px activity in rbc reached a higher value than controls after 1 month. Plasma GSH-Px activity increased slowly and reached a plateau after 16 weeks, but remained 30% lower versus controls. Others, who supplemented CKD patients with different Se forms and doses, also observed an increased plasma GSH-Px activity. Richard et al. [92] injected HD patients with sodium selenite and zinc gluconate (50 μg Se and 5 mg Zn per dialysis session three times a week for 5 weeks and then 100 μg Se per session for 15 weeks) and observed significantly increased Se in plasma Se (0.58–0.89 μmol/l) and increased GSH-Px activity in rbc (29.6–43.0 U/g

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Hb) and plasma (62–151 U/l). Plasma zinc concentration did not change appreciably. The significant increase in plasma GSH-Px activity (143%) was likely due to Se as well as to coadministered Zn. In another study, Koenig et al. [93] administered 400 μg Se (as sodium selenite) intravenously to HD patients for 8 weeks and monitored Se concentration and SOD, CAT, and GSH-Px antioxidant activity. Initial plasma Se concentration was 52% lower than controls. After 2 weeks supplementation, plasma Se reached the control group value and remained at the same level throughout the study. SOD and CAT were significantly higher than controls (p < 0.001) and gradually decreased over the study. GSH-Px activity was 52% lower and gradually increased reaching a value significantly higher than baseline (p < 0.05), but still lower (30%) than controls (p < 0.05). Another group [94] administered oral sodium selenite for 10 weeks at a dose of 10 μg/kg body weight/day (equivalent to 600–700 μg for 60–70 kg body mass) to patients with stable chronic renal failure at early disease stage. Although plasma GSH-Px activity was significantly lower than controls (99.5 U/l vs. 114.4 U/l, p < 0.05), it increased significantly (132.1 U/l, p < 0.001) by the end of the study. It is likely that increased plasma GSH-Px activity in response to Se supplementation reflected higher residual kidney function in these early disease and stable patients. The above premise supports research carried out by others [51]. Patients at different stages of CKD were supplemented for 3 months with 200 μg Se per day in the form of Se-enriched yeast. In the initial stages of uremia, Se supplementation significantly increased plasma GSH-Px activity. In contrast, the increase was substantially lower or did not occur at all in late stages. Similar observations were made by Schiavon et al. [53], who suggested that plasma GSH-Px activity could potentially complement measurement of serum creatinine and creatinine clearance in CKD. Together these markers may provide additional value in assessing disease progress. Kidneys are incapable of synthesizing appropriate amounts of GSH-Px 3 in late stage disease. Another study, in which patients were supplemented with Se-enriched yeast for 3 months, demonstrated that plasma GSH-Px activity was unchanged [81]. Coadministration of erythropoietin was also unsuccessful with enzyme activity remaining at baseline level. It is apparent that reduced plasma GSH-Px activity in ESRD is associated with kidney damage. The low level of activity likely reflects residual synthesis in kidney tissue as well as endogenous production from other tissues [78]. More recent studies have confirmed that GSH-Px 3 is synthesized predominantly in the kidney [77–79]. Kidney transplantation in a group of

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patients previously treated with dialysis resulted in increased enzyme activity. Although whole blood and plasma Se concentration was reduced immediately after the surgery, this finding was likely associated with low protein intake diet following surgery. In these patients, Se concentration typically reaches baseline value after 2 weeks. Se concentration in whole blood and plasma and GSH-Px activity in plasma in CKD is shown (Figs. 6 and 7). A statistically significant negative correlation is apparent between plasma GSH-Px and creatinine in these patients (r ¼ 0.588; p < 0.001). In CKD, changes in GSH-Px likely reflect decreased activity, decreased synthesis, or both. It has been suggested that blood contains endogenous toxic compounds inhibitory to this enzyme. Yoshimura et al. [35] determined the activity and concentration of GSH-Px in plasma from nondialyzed patients. Enzyme activity was substantially decreased (50%) in concert with decreased protein concentration suggestive of impaired renal synthesis. Discrepant results, however, were reported by Roxborough et al. [95]. Using specific antibodies against GSH-Px, they found that enzyme activity before dialysis was >50% higher than healthy individuals. Although it significantly increased after dialysis, it did not reach control levels. In addition, plasma GSH-Px protein concentration did not change

Selenium concentration (ng/ml)

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Plasma

120 a

100

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0

3

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14

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Time of study (days after transplantation) Statistics: ap < 0.001 vs. controls; bp < 0.01 vs. initial values; cp < 0.05 vs. initial value

Figure 6 Selenium concentration in whole blood and plasma in patients with ESRD before and after renal transplantation and in control group. Adapted from Wlodarczyk et al. [83].

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Plasma GSH-Px activity (U/L)

350 300 250 200 b

150 a

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0

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Time of study (days after transplantation) Statistics: ap < 0.0001 versus controls; bp < 0.0001 versus initial value

Figure 7 Plasma glutathione peroxidase activity in patients with ESRD before and after renal transplantation and in healthy subjects. Please note a very rapid increase in the activity of this enzyme. Adapted from Wlodarczyk et al. [83].

before and after dialysis, Furthermore, it did not differ from those levels observed in healthy individuals. In another study, Zachara et al. [96] supplemented 30 HD patients with 200 μg Se/day (yeast Se) for 3 months. They reported that plasma Se concentration significantly increased from 42 (0 day) to 102 (1 month) and 132 ng/ml (3 months) (p < 0.0001). Plasma GSH-Px protein 11.4 μg/ml (0 day) was substantially lower than controls (48.4 μg/ml) and did not change appreciably (11.8 μg/ml) after 3 months. Se supplementation had no effect on plasma GSH-Px protein content (Fig. 8). Despite these promising findings, the question as to whether Se should be administered to CKD patients has not been conclusively demonstrated. Several authors have shown a benefit via increased GSH-Px 3 activity, but others found no significant effect. Conflicting reports may result from confusion as to which GSH-Px is actually measured in these studies. For example, rbc and other organs produce a cytosolic GSH-Px [97]. This form is similar to GSH-Px 3 and enzymatically degrades hydroperoxides and H2O2, thus protecting the body from ROS. Bonomini and Albertazzi [98] proposed that moderate Se supplementation may have a beneficial effect on the antioxidant system in uremic patients. Kiss [99] confirmed this proposition and extended it to include patients with severe ESRD including those undergoing HD.

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70 60 50 40 a

30

a

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HD 0 HD 1 Groups and months of study

HD 3

Figure 8 Plasma GSH-Px protein level in healthy subjects and in CKD patients on HD supplemented with selenium and placebo. CKD patients on hemodialysis at the beginning of the study (HD 0) and after 1 and 3 months (HD 1 and HD 3, respectively) of Se or placebo supplementation. HD patients: white columns ¼ placebo, filled columns ¼ + Se. Statistics: ap < 0.0001 versus controls. Adapted from Zachara et al. [96].

Irrespective of its effect on GSH-Px, Se appears to prevent disease development in a number of disorders including cancer [28,100] and cardiovascular disease [28,101,102]. Se appears to play a role in preventing DNA damage in HD patients [103]. It is noteworthy that the incidence of cancer and cardiovascular disease is several times higher in CKD patients, particularly those at ESRD and on HD, than the general population [104,105]. As such, Se supplementation should be considered as a viable option specifically for these patients as well as individuals with low plasma low Se in general [102].

5. CONCLUSION Oxidative stress plays a key role in numerous disease processes including CKD. GSH-Px are important cellular components in balancing the chronic formation and elimination of ROS in these patients. As can be seen, Se plays an integral role in maintaining this balance. Despite its preliminary nature, supplementation of Se should be strongly considered as a viable nutritional option in CKD. It is obvious that additional and more wellcontrolled studies are required to fully support these initial findings in CKD especially when potential comorbidities, i.e., cancer and cardiovascular disease, are considered.

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ACKNOWLEDGMENTS This study was partly financed by the State Committee for Scientific Research (KBN), Warsaw, Poland (Grant No. 2 P05D 097 27). The author expresses his gratitude to the Foundation for Polish Science (FNP, “Nestor”), for providing an individual grant. I am very grateful to Mr. Jerzy Tomaszczyk for translating the text into English. Disclosure: The author reports no conflicts of interest in this work.

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Selenium and selenium-dependent antioxidants in chronic kidney disease.

Oxidative stress plays a key role in numerous disease processes including chronic kidney disease (CKD). In general, oxygen metabolism leads to the for...
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