Curcumin - A promising nutritional strategy for chronic kidney disease patients

Journal of Functional Foods 40 (2018) 715–721

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Journal of Functional Foods journal homepage: www.elsevier.com/locate/jff

Curcumin - A promising nutritional strategy for chronic kidney disease patients

T

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Livia de Almeida Alvarengaa, , Viviane de Oliveira Lealb, Natália Alvarenga Borgesc, Aline Silva de Aguiard, Gerd Faxén-Irvinge, Peter Stenvinkelf, Bengt Lindholmf, Denise Mafraa,c a

Graduate Program in Medical Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil Nutrition Faculty, UFF, Niterói, RJ, Brazil c Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil d Juiz de Fora Federal University, Institute of Biological Sciences, Department of Nutrition, Juiz de Fora, Minas Gerais, Brazil e Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, and Function Area Clinical Nutrition, Karolinska Institutet, Stockholm, Sweden f Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Technology and Intervention, Karolinska Institutet, Stockholm, Sweden b

A R T I C L E I N F O

A B S T R A C T

Keywords: Curcumin Chronic kidney disease Inflammation Bioactive compound

Many studies have been conducted to identify therapeutic strategies to modulate inflammation and oxidative stress, complications that contribute to the increased morbidity and cardiovascular mortality in patients with chronic kidney disease (CKD). Among several non-pharmacological strategies, the use of bioactive compounds has emerged as a potential approach to reduce these complications in CKD patients. In this context, turmeric/ curcumin may have positive consequences in terms of cardiovascular and nephroprotection because of its antibacterial, antiviral, anti-inflammatory and anti-oxidative effects. The aim of this review is to discuss the role of curcumin as a nutritional strategy to reduce cardiovascular risk factors as inflammation and oxidative stress in CKD patients.

1. Introduction Chronic kidney disease (CKD) patients have many complications associated with protein energy wasting, ageing, inflamed adipose tissue, systemic inflammation and oxidative stress, which are closely related to the progression of renal failure and cardiovascular disease (CVD). Bioactive compounds present in some foods have been considered non-pharmacological nutritional strategies to combat oxidative stress and to modulate chronic inflammation in these patients (Correa et al., 2013; Pakfetrat, Akmali, Malekmakan, Dabaghimanesh, & Khorsand, 2015; Stenvinkel & Haase, 2017). Curcumin, a natural phenolic compound extracted from the root of turmeric, used in traditional medicine in China and even more so in India, has been extensively studied because of its anti-proliferative and anti-inflammatory activities and it is thought to be a promising agent with potential applications such as in cancer prevention, cardiovascular, gastrointestinal disorders and diabetes (Hajavi et al., 2017; Khajehdehi, 2012; Ravindran, Nirmal Babu, & Sivaraman, 2007; Tapia et al., 2013). Curcumin is designated by the United States Food and

Drug Administration as a food additive that is generally recognized as safe (GRAS), and it used as a supplement and sold in several forms as capsules, tablets, and energy drinks (Gupta, Patchva, & Aggarwal, 2013). There are several hypotheses that can explain the anti-inflammatory effect of curcumin as downregulation of transcription factors like cyclooxygenase-2 (COX-2), Signal transducer and activator of transcription 3 (STAT3) and IκB kinase β (IKKβ) (inhibitor of nuclear factor kappa-B - NF-kB). Curcumin seems able to decrease cytokines synthesis, improve nitric oxide (NO) bioavailability and scavenging of reactive oxygen species (ROS) that promote inflammation and oxidative stress, which are common complications in several chronic diseases, including CKD (Campbell & Fleenor, 2017; Serafini, Catanzaro, Rosini, Racchi, & Lanni, 2017; Shehzad, Qureshi, Anwar, & Lee, 2017). However, although these actions of curcumin are promising, most studies about curcumin in CKD are still experimental and there are only few studies on turmeric supplementation in CKD patients and therefore information on the dose and time of supplementation are still uncertain. This review describes briefly the mechanisms of action of curcumin as well as discusses its use as a nutritional strategy to reduce oxidative

⁎ Corresponding author at: Unidade de Pesquisa Clínica - UPC, Hospital Universitário Antônio Pedro, Avenida Marquês do Paraná nº303, 6ºandar. Centro, Niterói – Rio de Janeiro, 24033-900, Brazil. E-mail addresses: [email protected] (L. de Almeida Alvarenga), [email protected] (V.d.O. Leal), [email protected] (N.A. Borges), [email protected] (A. Silva de Aguiar), [email protected] (G. Faxén-Irving), [email protected] (P. Stenvinkel), [email protected] (B. Lindholm), [email protected] (D. Mafra).

https://doi.org/10.1016/j.jff.2017.12.015 Received 25 September 2017; Received in revised form 6 December 2017; Accepted 6 December 2017 1756-4646/ © 2017 Elsevier Ltd. All rights reserved.

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Pefeiffer, Shulz, & Dempe, 2013; Panahi et al., 2017). Thus, several strategies have been tested to improve its bioavailability such as use of liposomes or nanoparticles, chitosan, formation of self-micro emulsifying drug delivery systems, complexation with phospholipids or essential oils and, solid-lipid micro particles based technique utilizing bovine serum albumin, synthesis of structural analogues of curcumin. More recently, intranasal administration also been identified as nanotechnology to increase the bioavailability of curcumin (Aggarwal et al., 2016). In 2011, Cuomo et al. (2011) observed that the bioavailability of curcumin could be improved with the lecithin formulation. Zhang, Tang, Xu, and Li (2013) improved the curcumin bioavailability using a curcumin-phytosome-chitosan complex microspheres, which was based on the combination of polymeric and lipid base. This system increased absorption and delayed elimination of curcumin. Purpura et al. (2017) improved the solubility, dispersibility and absorption of curcumin in healthy humans using cyclodextrins from the cyclic oligosaccharide family. Vecchione et al. (2016) showed that unformulated curcumin had no anti-inflammatory activity. However, when administered together with piperine (a pungent alkaloid found in black pepper), the curcumin given to rats (0.8 mg of curcumin per kg of rat and even at low doses as 0.2 mg of curcumin per kg), showed anti-inflammatory activities based on the reduction of several cytokines and serum lipopolysaccharides (LPS) levels. Chakraborty, Bhattacharjee, and Kamath (2017) observed that Wistar albino rats treated with a combination of curcumin (50 mg/kg) with piperine (20 mg/kg) presented better cardioprotection when compared to curcumin alone (200 mg/kg). In another study, it was observed that piperine could be used for the inhibition of UDP-glucuronyl transferase enzymes and sulfotransferases expression, which contribute to a lower absorption of curcumin and are responsible for the biotransformation of curcumin into O-glucuronide curcumin and O-sulfate curcumin (Zeng et al., 2017). Currently, studies are lacking that could help to define specific curcumin dose requirements for CKD patients. Thus, the doses used to study the action of curcumin in CKD are usually the same as for the nonCKD population. In animal studies, doses are often between 60 and 150 mg/kg/day (Aparicio-Trejo et al., 2017; Chiu, Khan, Farhangkhoee, & Chakrabarti, 2009; Correa et al., 2013). In most studies in humans, turmeric doses used vary from 824 to 1500 mg/day (Khajehdehi et al., 2011; Moreillon et al.,2013; Pakfetrat et al., 2015; Shelmadine et al., 2017). The results obtained in these studies are summarized in Table 1. There are no reports in the literature on the use of components that can improve the absorption and bioavailability of curcumin in CKD. Until such studies are performed one may need to accept that the strategies already studied for other conditions can be used also in CKD (Chakraborty et al., 2017; Vecchione et al., 2016; Zeng et al., 2017).

stress and inflammation in CKD. 2. Chronic kidney disease The definition and classification of CKD have evolved over time, but current international guidelines define this condition as decreased kidney function shown by glomerular filtration rate (GFR) of less than 60 mL/min per 1 · 73 m2, or markers of kidney damage, or both, of at least 3 months duration, regardless of the underlying cause (Webster, Nagler, Morton, & Masson, 2016). There is a strong relationship between CKD and CVD, which could be explained by a typical clustering of several risk factors in CKD, such as hypertension, proteinuria, volume overload, activation of the reninangiotensin system, and other autocrine and paracrine mechanisms (García-Trejo et al., 2016). Moreover, in CKD patients nuclear factor erythroid-derived 2 (Nrf2) is downregulated coupled to an upregulation of NF-kB expression. Given the contribution of the impaired Nrf2 system in the pathogenesis of oxidative stress and inflammation, this adds to the imbalance between ROS production and insufficient endogenous antioxidant defense mechanisms in CKD. These common findings are considered to play a critical role in the progression of CKD and related complications, mainly the increased risk of developing CVD, which is the major cause of death in these patients (Antunovic et al., 2017; Esgalhado, Stenvinkel, & Mafra, 2017). Many studies have been conducted in an attempt to identify therapeutics strategies to modulate inflammation and oxidative stress in CKD (Machowska, Carrero, Lindholm, & Stenvinkel, 2016). In this context, turmeric/curcumin has been linked to nephroprotection and protection against CVD because of its capacity to interact with several signaling pathways, and by exercising anti-inflammatory and anti-oxidant effects. 3. Bioavailability of curcumin The main dietary source of curcumin is the turmeric, a member of the Zingiberaceae family. Curcumin is responsible for the bright yellow color of the turmeric root and its chemical name is 1,7-bis (4-hydroxy 3methoxyphenyl)-1,6-heptadiene-3,5-dione (1E-6E) (Ravindran et al., 2007). Turmeric is usually used as a spice, giving flavor and natural coloring to food and its average intake by Asians varies from 0.5 to 1.5 g/day/person, which does not produce toxic symptoms (Chattopadhyay, Biswas, Bandyopadhyay, & Banerjee, 2004; Jurenka, 2009). Since archaic times, curcumin is widely used by Chinese and Indian medicine and after many studies concluded that curcumin is an active polyphenol; numerous citations in the literature have been reported (Tyagi, Prasad, Yuan, Li, & Aggarwal, 2015). Curcumin is commercially available as capsules containing powder, extracts and curcuma-based dye. In animal studies, curcumin seems to have effects at doses of 100 and 200 mg/kg body weight in Wistar rats (Eigner & Scholz, 1999). Doses of up to 300 mg/kg were also used and no adverse effects were observed (Chainani-Wu, 2003). Animal and human studies have demonstrated that high doses of curcumin are required for significant pharmacological effects and, rats as well as humans have showed that even at high doses, curcumin is safe (Aggarwal, Chacko, & Kuruvilla, 2016; Mirzaei et al., 2017; Satyajit & Nahar, 2007). Clinical trials in humans indicate that using 1–2.5 g of curcumin per day appears to be safe. However, its bioavailability is low and the levels in plasma and target tissues are low (Bharti, Donato, & Aggarwal, 2003). Thus a major problem associated with the use of curcumin is its low bioavailability because of slow intestinal absorption, rapid metabolism and conjugation to hydrophilic molecules in the liver with biliary excretion, poor solubility in water and clearance of the body. In addition, curcumin is not a chemically stable molecule and it is sensitive to alkaline pH, oxygen and irradiation (Aggarwal et al., 2016; Metzler,

3.1. Curcumin metabolism The metabolism of curcumin, both in phase I and in phase II, has been studied mainly in vivo and in vitro models. The phase I studies of metabolism of curcumin is described as a process of successive reduction of three double bonds of the heptadiene-3,5-dione system. The enzymes responsible for the reduction process are present in hepatocytes and enterocytes. These processes are dependent on the enzyme alcohol dehydrogenase or occur through the NADPH-cytochrome P450 reductase (Metzler et al., 2013). The autoxidation of curcumin is initiated by H-abstraction from a phenolic hydroxyl followed by formation of a phenoxyl radical in a sequential proton loss electron transfer (SPLET) process. Once the initial radical is formed, the transformation of curcumin proceeds as a radical chain reaction resulting in stable incorporation of two oxygen atoms, one of which comes from O2 and one from H2O, and two cyclization reactions to form the final bicyclopentadione product (Luis et al., 2017). However, there are no studies published to date demonstrating exactly the enzymes involved in the phase I metabolism of 716

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Table 1 Summary of studies involving curcumin supplementation and its metabolic effects in CKD. References

Sample/Study

Intervention

Results

CKD: Animals Studies Ghosh et al. (2009)

5/6 NX rats

75 mg/kg/d for 9 weeks

Correa et al. (2013)

5/6 NX rats

120 mg/kg/d for 2 months

Soetikno et al. (2013)

5/6 NX rats

75 mg/kg/d for 8 weeks

Tapia et al. (2013)

5/6 NX rats

120 mg/kg/d for 8 weeks

Hernández-Reséndiz et al. (2015)

5/6 NX rats

120 mg/kg/d for 4 weeks

Ghosh et al. (2015)

5/6 NX rats

100 mg/kg/d for 16 weeks

Aparicio-Trejo et al. (2017)

5/6 NX rats

60 mg/kg/d for 1 week before 5/6NX

↓ Macrophage influx in the kidney ↓ TNF-α ↑ PPAR γ mRNA expression. ↓ Activation of the NF-kB pathway ↓ Necrotic areas of hearts ↓ ROS, MDA production in hearts ↑ Nrf2 phosphorylation ↑ CAT, GST ↓ Oxidative stress, inflammation and renal fibrosis ↑ Nrf2 expression ↓ LDL and ↑ HDL ↓Proteinuria ↓ Systemic and glomerular hypertension ↓ SBP and proteinuria Restored heart function ↓ ROS ↓ Cytochrome c, improving mitochondrial integrity ↓ LPS, creatinine and urea plasma levels ↑ Intestinal barrier function ↑ glucose tolerance ↓ Lesion of the aorta by 63% ↓ TNFα, macrophages and IL-6 in kidneys ↓ Mitochondrial ROS production ↑ CAT, glutathione reductase

Moreillon et al. (2013)

40 non-dialysis DM CKD patients (proteinuria > 500 mg/d). 16 non-dialysis CKD patients

Pakfetrat et al. (2015)

50 HD patients

RCT- 500 mg of turmeric (22.1 mg of curcumin) (3 capsules daily) for 2 months RCT - 824 mg purified turmeric extract, 95% curcuminoids, and 516 mg Boswellia serrata extract for 2 months RCT - 500 mg of turmeric (22.1 mg of curcumin) (3 capsules daily) for 2 months

Jimenez-Osorio et al. (2016) Shemaldine et al. (2017)

101 non-dialysis DM and non-DM patients

320 mg/day of curcumin for 2 months

16 stage 2 and 3 non-dialysis CKD patients

824 mg purified turmeric extract, 95% curcuminoids for 2 months

CKD: Patient Studies Khajehdehi et al. (2011)

↓ TGF-β and IL-8 serum levels ↓ Proteinuria ↓ IL-6

↑ GPX, glutathione reductase, SOD, CAT ↑ Albumin ↓ MDA ↑ GPX, glutathione reductase, SOD, CAT ↓ MDA Group-effect and a trend for group x time interaction were detected only for prostaglandin E2

Abbreviations: Chronic kidney disease (CKD); Hemodialysis (HD); Nephrectomized (NX); reactive oxygen species (ROS); malondialdehyde, MDA; catalase, CAT, glutathione S-transferase, GST, glutathione peroxidase, superoxide dismutase, SOD; Diabetes Mellitus, DM; randomized clinical trial (RCT), Blood urea nitrogen (BUN), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 2 (MIP-2), extracellular matrix (ECM), lipopolysaccharide (LPS). transforming growth factor β (TGF-β).

3.2. Curcumin target pathways

curcumin (Metzler et al., 2013). In phase II studies, curcumin and its reduced metabolites, appear to be readily conjugated with glucuronic acid (glucuronidation) and sulfate in the epithelium of human intestines, mediated by uridine 5′-diphosphate (UDP) glucuronosyltransferase (UGT) and, in liver mediated by promoter of the UDP-glucuronosyltransferase 1 (UGT1A1) gene, producing curcumin glucuronide and curcumin sulfate that after bioreduction produce tetrahydrocurcumin, hexahydrocurcuminol and hexahydrocurcumin that are major metabolites of curcumin in body fluids. The intestinal tract plays an important role in curcumin metabolism (Lou, Zheng, Hu, Lee, & Zeng, 2015). The conjugation process promotes increased molecular weight and solubility of the molecules thereby facilitating the process of their excretion by kidneys or liver (Lee et al., 2013; Luis et al., 2017; Metzler et al., 2013). Nevertheless, some curcumin reaches the colon where it is extensively bio-transformed by gut microbiota to reduced curcumin moieties, such as hydroxylated curcumin and its hydrogenated derivatives, and acetylated curcumin and its derivatives (Lou et al., 2015). In fact, curcumin represents the remarkable case of a molecule capable of forming a reactive metabolite that is quenched by itself with the help of molecular oxygen (Luis et al., 2017).

Curcumin has broad biological functions. It has been reported that curcumin is a bifunctional antioxidant because of its ability to react directly with reactive species and to induce an up-regulation of various cytoprotective and antioxidant proteins. It has been established that curcumin exerts antioxidant activity directly by reducing scavenging ROS such as superoxide anion (O2%), hydroxyl radicals (%OH), hydrogen peroxide (H2O2), singlet oxygen (1O2) peroxynitrite and peroxyl radicals (ROO%), therefore, these mechanisms might explain some of the cytoprotective effects of this compound (Trujillo et al., 2013). Moreover, in the mitochondria, due to the high flow of electrons during the process of oxidative phosphorylation, ROS are produced and usually are partially removed by antioxidant enzymes located in the mitochondrial matrix, such as manganese-dependent superoxide dismutase (SOD) and / or released into the cytosol and detoxified by endogenous antioxidant systems. Excess ROS production associated with deficiency of the endogenous antioxidant system may lead to the oxidation of specific mitochondrial biomolecules, resulting in mitochondrial dysfunction. A large body of evidence has shown that mitochondrial dysfunction is the main culprit of different diseases, especially in non-communicable diseases such as cancer, neurodegenerative diseases and CVD (Oliveira, Jardim, Setzer, Nabavi, & Nabavi, 2016). Curcumin 717

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β (TGF-β). Among various factors involved in the genesis of CKD and pathogenesis of primary and secondary glomerulonephritis, TGF-β is considered as a key factor in the cascade of events leading to glomerulosclerosis, tubule interstitial fibrosis and CKD (Khajehdehi, 2012). Most in vitro studies confirmed anti-inflammatory and anti-fibrotic properties of curcumin (Bharti et al., 2010; Hu, Mou, Yang, Tu, & Lin, 2016; Shing, Adams, Fassett, & Coombes, 2011). Curcumin was able to inhibit NF-kB and suppress Th1 cytokine induction in peripheral blood lymphocytes of renal transplanted patients (Bharti et al., 2010). In peripheral blood mononuclear cells from non-dialysis CKD patients, curcumin decreased inflammatory markers (IL-6 and IL-1β) in a similar magnitude as fish oil (Shing et al., 2011). In primary vascular smooth muscle cells (VSMC), curcumin inhibited ROS increase and VSMC mineralization (Roman-Garcia, Barrio-Vazquez, Fernandez-Martin, RuizTorres, & Cannata-Andia, 2011). Ghosh et al. (2012) showed that curcumin, by antagonizing the pro-inflammatory cytokines, could significantly reduce cyclooxygenases in mesangial cells and macrophages. Recently, Hu et al. (2016) revealed that curcumin attenuated renal fibrosis by suppressing CpG methylation in the Klotho promoter and, thus, induced Klotho expression, which inhibited TGF-β signaling. In animal studies, curcumin (Correa et al. 2013; Ghosh et al., 2009; Hernandes-Reséndiz et al., 2015) and theracurmin, a novel formulation of curcumin (Buqyei, 2016), were found to have therapeutic potentials by attenuating oxidative stress-related events as cardiac remodeling, mitochondrial dysfunction and cell death; changes that potentially could be of value in the treatment of heart disease in CKD. Alterations in mitochondrial dynamics, bioenergetics and oxidative stress may lead to renal dysfunction. Curcumin pretreatment in nephrectomized rats decreased these mitochondrial alterations in nephrectomized rats, suggesting that this intervention potentially could be contribute to preservation of renal function (Aparicio-Trejo et al., 2017). The uremic phenotype is associated with high incidence of cardiovascular complications. Therefore, Correa et al. (2013) reported in a study with rat model of subtotal nephrectomy (5/6NX), that oral administration of 120 mg/kg of curcumin for 60 days protected against pathological remodeling of heart, diminished ischemic events, and preserved cardiac function in uremic rats. These effects appeared to be due to a decrease of necrotic areas of hearts, decreased levels of ROS, reduction of malondialdehyde (MDA) production in the heart, and increased Nrf2 phosphorylation, CAT and GST. Hernández-Reséndiz et al. (2015) observed that 5/6NX rats treated with curcumin exhibited reduction in blood pressure and proteinuria as well as reduced production of ROS, and that heart function and mitochondrial integrity was restored. Aparicio-Trejo et al. (2017), showed for the first time, that curcumin pretreatment could result in nephroprotection by decreasing blood urea nitrogen, plasma creatinine and renal vascular resistance and by increasing glomerular filtration rate and renal blood flow. Curcumin was given at the dose of 60 mg/kg/day by oral administration 7 days before 5/6 NX. Since no significant changes were found in renal function markers curcumin pretreatment did not influence kidney function. On the other hand, the curcumin pretreated group showed a higher concentration of low molecular weight antioxidants such as lipoic acid, ubiquinonone, plasmalogen, uric acid, glutathione, conjugated-bilirubin, melatonin, and various amino acids in the kidney and mitochondria of these rats. Meanwhile, pretreatment with curcumin significantly prevented 5/6NX-induced increased fusion and decreased fission of mitochondria, decreasing 5/6NX-induced increments of mitofusin 1 and optic atrophy 1 and resulted in decrement of mitochondrial fission 1 protein and dynamin-related protein 1. Taken together, these observations suggest that the antioxidant curcumin decreases early 5/6NX-induced altered mitochondrial dynamics, bioenergetics and oxidative stress, effects that potentially may associated with preservation of renal function. Ghosh et al. (2009) reported that curcumin antagonized the TNF-αmediated decrease in PPAR-γ and blocked transactivation of NF-kB and

also exerts antioxidant effects upon mitochondria through decreased production of ROS and upregulation of antioxidant enzymes, thus, inhibiting mitochondrial damage and contributing to the preservation of the important functions of this organelle (Aparicio-Trejo et al., 2017). In addition, experimental studies have demonstrated that curcumin may trigger mitochondrial biogenesis (Oliveira et al., 2016). Moreover, this bioactive compound is able to induce the master regulator of antioxidant response, the Nrf2 (Tapia et al., 2012). Treatment with curcumin significantly increased Nrf2 and hemo-oxygenase1 (HO-1) expression in the neonatal rats with hypoxic-ischemic brain injury (Cui, Song, & Su, 2017). Nrf2 is bound to its cytosolic repressor protein, Kelch-like ECH-associated protein 1 (Keap1). Curcumin may modulate Nrf2 by modification of Keap 1, thereby releasing Nrf2. Then Nrf2 translocate into the nucleus where it binds as a heterodimer to the antioxidant responsive element (ARE) in DNA to initiate target gene expression including: quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), HO-1, glutathione peroxidase (GSH-Px), glutamatecysteine ligase (GCL), catalase (CAT), SOD (Cardozo et al., 2013). Thus, curcumin up-regulates the activity of Nrf2, which is crucial for cytoprotection against various forms of stress due to the ability of the Nrf2 to antagonize the transcription factor nuclear factor-κB (NF-κB), an important regulator of genes encoding pro-inflammatory cytokines during inflammatory responses (Cardozo et al., 2013; Zhao et al. 2013). In addition, curcumin has been found to attenuate NF-κB activity by inhibiting IκB degradation, thus preventing NF-κB translocation to the nucleus, suppressing pro-inflammatory gene expression and down-regulating pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL-)1 and IL-6 (Liu et al., 2014; Rahimi et al., 2016). Curcumin is also a natural agonist of peroxisome proliferator-activated receptor- γ (PPAR-γ), a member of the nuclear receptor superfamily of ligand-activated transcription factors that has been found to be involved in anti-inflammatory signaling pathways (Liu et al., 2011; Liu et al., 2013). PPAR-γ binds to PPAR-responsive elements (PPRE) in the regulatory region to initiate target gene expression. Inhibitory effects of PPAR-γ on NF- κB activation have been demonstrated in multiple cell systems (Liu et al., 2014). Liu et al. (2014), in an in vitro study with cortical neurons cells from rats, showed that PPAR-γ physically interacts with the NF-κB p65 subunit, thereby blocking NF- κB activation and inhibiting downstream activation of p65-dependent gene expression. Thus, PPAR-γ pathway may be a critical mediator of the protective anti-inflammatory effects of curcumin (Liu et al., 2014). Additionally, curcumin has a powerful effect on gene expression involved in cell signaling, apoptosis and the control of cell cycle. Curcumin affects several signaling pathways known to represent important pathogenic pathways, such as the PI3-k/Akt-1/mTOR, Ras/Raf/ MEK/ERK, JAK2/STAT and the GSK-3beta pathways (Huminiecki, Horbańczuk, & Atanasov, 2017). The effect of curcumin on downregulation of STAT3 was also observed in a glioblastoma stem cell study (Gersey et al., 2017) and curcumin seems to inhibit cell proliferation and cell cycle activities, reducing cell metabolism (Gersey et al., 2017; Ooko, Kadioglu, Greten, & Efferth, 2017). Curcumin also is a regulator of the expression of microRNAS and it can also induce specific methylation genes in cancer diseases and non-cancer diseases (Huminiecki et al., 2017; Momtazi, Derosa, Maffioli, & Banach, 2016; Zhou et al., 2017). Fig. 1 summarizes the curcumin mediating anti-inflammatory and antioxidant effects involving Nrf2, NF-κB, PPAR-γ and mitochondria. Although the effects of curcumin have been studied in many chronic diseases, there is paucity of studies in CKD. 4. Curcumin and CKD In 2004, Gaedeke, Noble, and Border (2004) observed in vitro that curcumin blocked the profibrotic actions of transforming growth factor 718

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Fig. 1. Curcumin mediated anti-inflammatory and antioxidant effects in CKD. The curcumin mediated antiinflammatory and antioxidant effects involving Nrf2, NF-κB, PPAR-γ and mitochondria. Abbreviations: O2%: superoxide anion, %OH: hydroxyl radicals, H2O2 :hydrogen peroxide, 1O2 singlet oxygen, ROO%: peroxyl radicals. Nrf2: Nuclear factor erythroid-derived 2; Keap1: Kelch-like ECH-associated protein 1; ARE: antioxidant responsive element. NQO1: quinone oxidoreductase 1; GST: glutathione S-transferase, HO-1: heme oxigenase-1; GSH-Px: glutathione peroxidase; GCL: glutamate cysteine ligase, SOD: superoxide dismutase. IkB: inhibitor of kinases; NF-κB: nuclear factor-κB; PPAR-γ: peroxisome proliferator-activated receptor-γ, PPRE: PPAR-responsive elements; IAP: intestinal alkaline phosphatase; LPS: lipopolysaccharides; IL: interleukin; TNF-α: tumor necrosis factor alpha.

inflammation, fibrosis and apoptosis occurring in adenine-induced CKD (Ali et al., 2017). In addition, curcumin could also be interesting to treat intestinal dysbiosis; a common problem in uremia (Mafra et al., 2014). Curcumin can alter the biochemical milieu of the intestinal tract and, as such, may alter the structure, composition, and function of microbial flora resulting potentially in changes in the secretion of inflammatory toxins such as oxalate and uric acid. Ghosh et al. (2015) observed that curcumin significantly reduced lipopolysaccharide (LPS) levels in the circulation of nephrectomized animals fed with Western diet and, based on the changes in plasma LPS, the authors emphasized that inflammation appeared to be due to LPS secreted from the gut. Furthermore, curcumin can restore the intestinal barrier function not only by upregulating the tight junction proteins but also by increasing intestinal alkaline phosphatase (ALP) activity which can dephosphorylate LPS rendering it inactive, a mechanism representing first line of defense of the intestinal lumina (Patcharatrakul & Gonlachanvit, 2016). Although clinical studies of curcumin in CKD are scarce and small they deserve more attention. Below we discuss the results of the studies in these patients. Khajehdehi et al. (2011) investigated the effects of tumeric on serum and urinary TGF-β, IL-8 and TNF-α, as well as proteinuria in 40 diabetic CKD patients. They showed that 500 mg of turmeric per day (22.1 mg of curcumin) for 2 months was effective in reducing the plasma levels of TGF-β, IL-8, and proteinuria. Moreillon et al. (2013) assessed the effects of an herbal supplement composed of Curcuma longa and Boswelliaserrata on systemic inflammation and anti-oxidant status in 16 CKD patients with glomerular filtration rate around 46 mL/min. The patients were randomly allocated to receive the herbal supplement or placebo for 8 weeks. A significant time effect and time × compliance interaction effect were observed for IL-6 levels. No statistical difference was observed for circulating concentrations of TNF-α, glutathione peroxidase and C-reactive protein (CRP). In another prospective, double-blind, randomized clinical trial in 50 hemodialysis patients, they received 3 capsules daily (one after each meal) containing 500 mg of turmeric (corresponding to 22.1 mg of the active ingredient curcumin). After 8 weeks, there was an increase in levels of antioxidant enzymes including CAT, glutathione peroxidase and glutathione reductase, and reduction of plasma levels of malondialdehyde (Pakfetrat et al., 2015). However, in a randomized double-blind placebo-controlled clinical trial treatment with curcumin did not improve proteinuria, estimated

repression of PPAR-γ, indicating that the anti-inflammatory property of curcumin may be responsible for alleviating CKD in animals in a dose dependent manner. Chiu et al. (2009) showed that curcumin administered intraperitoneally (150 mg/kg/day) in male Sprague-Dawley rats prevented the development of diabetic nephropathy due to the inhibition of p300, a histone acetyltransferase that plays a role in regulating gene expression through its interaction with the transcription NF-kB; moreover, TGF-β and endotelin-1 were reduced in the kidneys. Therapeutic strategies, based on curcumin treatment, aimed to preserve renal antioxidant pathways, such as Nrf2, can in experimental models help to retard the progression of CKD (Ali et al., 2017; Tapia et al., 2016). Soetikno et al. (2013) found that curcumin treatment associated with attenuation of Nrf2 protein expression and HO-1 levels in uremic rats. In addition, uremic untreated animals had significantly higher kidney MDA concentration and lower glutathione peroxidase activity, which was associated with the upregulation of NF-kB p65, TNF-α, TGF-β, COX-2, and accumulation of fibronectin in the remnant kidney. Interestingly, all of these changes were ameliorated by curcumin treatment. Thus, curcumin could effectively attenuate oxidative stress, inflammation and renal fibrosis by modulating Nrf2-Keap1 pathway. Jacob et al. (2013) showed in the chronic serum sickness (CSS) model induced by complement factor H deficient (Cfh−/−) mice and potentially resulting in renal disease, that curcumin improved kidney function and protected against renal failure, by reduction of mRNA expression of inflammatory proteins monocyte chemoattractant protein-1 (MCP-1) and TGF-β and matrix proteins, fibronectin, laminin and collagen. Curcumin can reverse glomerular hemodynamic alterations and oxidant stress in 5/6 nephrectomized rats, through attenuation of proteinuria and structural changes such as, interstitial fibrosis, fibrotic glomeruli, tubular atrophy and mesangial expansion (Tapia et al. (2013). In addition, curcumin was able to decrease hemodynamic changes such as glomerular hypertension and hyperfiltration, and oxidative stress, as reflected by a decrease in MDA and increased activities of antioxidant enzymes such as CAT, glutathione peroxidase, glutathione reductase and glutathione-S-transferase. Based on these findings the authors suggested that curcumin may be useful to reverse established glomerular hemodynamic alterations and renal injury in CKD. Curcumin also is associated to nephroprotection by alleviation of elevations in blood pressure, urinary albumin/creatinine ratio, plasma urea and creatinine, indoxyl sulfate, inflammatory markers (IL-1β, IL-6 and TNF-α), morphological damage and histopathological markers of 719

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glomerular filtration rate, or lipid profile but enhanced the antioxidant capacity in diabetic proteinuric CKD patients. No effect of curcumin was observed on the activity of antioxidant enzymes or Nrf2 activation (Jiménez-Osorio et al., 2016). Regarding the action of curcumin on the lipid profile, Cicero et al. (2017) has shown that curcumin may lower plasma cholesterol; however, curcuminoid lipid-lowering mechanisms are unclear and the results are still controversial. Another topic discussed is the action of curcumin on the quality of HDL particles. Curcumin can modulate the markers of HDL function and improve conditions in which HDL is dysfunctional, contributing to the decrease of CVD (Ganjali et al., 2017). Although curcurmin may represent an interesting strategy for dyslipidemia in CKD patients, more studies are still necessary in this population. Shelmadine et al. (2017) studied the effects of a supplement containing curcumin and B. serrata on eicosanoid derivatives in 16 patients with CKD stage 2 and 3 (i.e., non-dialysis CKD patients) who were randomized into treatment or placebo group. After 8 weeks of supplementation, a significant group-effect and a trend for group × time interaction were detected only for prostaglandin E2 (and not for 5-hydroxyicosatetraenoic acid, 12-hydroxyicosatetraenoic acid, 15hydroxyicosatetraenoic acid, and 13-hydroxyoctadecadienoic acid). Taken together, a limited number of studies have evaluated the effect of curcumin in CKD (Table 1).

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5. Conclusions Several signaling pathways could be a potential target of curcumin and this broad mechanism of action of curcumin may make this spice a promising adjuvant therapy for CKD patients. This is because CKD is characterized by profound metabolic and nutritional alterations resulting in increased systemic inflammation and oxidative stress that are thought to be due to factors such as downregulation of Nrf2 and upregulation of NF-kB that directly or indirectly could be affected by curcumin. Thus, some of the more important pathways for the antiinflammatory, anti-proliferative and antioxidant activities of curcumin seems to be through NF-kB and Nrf-2 modulation. Despite promising data from basic studies, only a limited number of clinical studies have so far evaluated the effect of curcumin supplementation (around 500 mg of turmeric per day) on expression of transcription factors, mitochondrial functions and the inflammation process in patients with CKD. Thus, further studies are essential to verify the appropriate dose, duration of supplementation, and long-term efficacy and safety of turmeric/curcumin use in all stages of CKD. Acknowledgements The Heart and Lung Foundation and “Njurfonden” support Peter Stenvinkel’s research. Conselho Nacional de Pesquisa (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Clinical Research Unit (UPC) at Fluminense Federal University (UFF) support Denise Mafra research. Baxter Novum is the result of a grant from Baxter Healthcare to Karolinska Institutet. Bengt Lindholm is employed by Baxter Healthcare. References Aggarwal, M., Chacko, K., & Kuruvilla, B. (2016). Systematic and comprehensive investigation of the toxicity of curcuminoid-essential oil complex: A bioavailable turmeric formulation. Molecular Medicine Reports, 13, 592–604. Ali, B. H., Al-Salam, S., Al Suleimani, Y., Al Kalbani, J., Al Bahlani, S., Ashique, M., ... Schupp, N. (2017). Curcumin ameliorates kidney function and oxidative stress in experimental chronic kidney disease. Basic & Clinical Pharmacology & Toxicology. http://dx.doi.org/10.1111/bcpt.12817. Antunovic, T., Stefanovic, A., Barhanovic, N. G., Miljkovic, M., Radunovic, D., Ivanisevic,

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