Metabolic syndrome and renal disease

International Journal of Cardiology 164 (2013) 141–150

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Review

Metabolic syndrome and renal disease Anna Gluba a, Dimitri P. Mikhailidis b, Gregory Y.H. Lip c, Simon Hannam d, Jacek Rysz a, Maciej Banach e,⁎ a

Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, Poland Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London, London, UK c University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK d Department of Child Health, Kings College London School of Medicine, London, UK e Department of Hypertension, Medical University of Lodz, Lodz, Poland b

a r t i c l e

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Article history: Received 31 August 2011 Received in revised form 31 October 2011 Accepted 6 January 2012 Available online 2 February 2012 Keywords: Dyslipidemia Kidney disease Kidney stones Metabolic syndrome Obesity

a b s t r a c t The metabolic syndrome (MetS) is a cluster of risk factors including insulin resistance, dyslipidemia and hypertension which are also relevant for the development of chronic kidney disease (CKD). It has proven difficult to elucidate whether the renal dysfunction in MetS is due to the MetS itself or the individual risk factors. For example, obesity – which is also part of the MetS – may enhance the risk of renal dysfunction development probably through mechanisms associated with renal hyperfiltration, hyperperfusion and focal glomerulosclerosis. Insulin resistance also promotes kidney disease by worsening renal hemodynamics. In patients with MetS, tubular atrophy, interstitial fibrosis, and arteriolar sclerosis indicating the presence of vascular damage, have also been described. As yet, there has been little evidence that preventing or treating symptoms of the MetS protects patients from renal impairment. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Metabolic syndrome (MetS) is a condition characterized by the presence of at least 3 of the following: abdominal obesity, increased blood pressure (BP), impaired glucose tolerance or diabetes, dyslipidemia [elevated levels of triglycerides (TG) and low concentration of high-density proteins (HDL)] [1]. Other abnormalities have also been reported including the presence of proinflammatory and prothrombotic state [2] as well as an altered oxidative/antioxidant ratio [3]. The increase in oxidative stress markers is proportional to the number of risk factors for the MetS which are present [4,5]. There are several widely accepted definitions of MetS. They have been issued by the National Cholesterol Education Program/Adult Treatment Panel III (NCEP-ATP III) [6], World Health Organization (WHO) [7] and the International Diabetes Federation (IDF) [8]. They differ slightly in criteria of diagnosis of the MetS. The third definition underlines for the first time the importance of abdominal adiposity as a risk factor for the development of MetS. Recently, a unified MetS definition prepared by the International Diabetes Federation (IDF), the National Heart, Lung, and Blood Institute (NHLBI), the World Heart Federation (WHF), the International Atherosclerosis Society (IAS), and the American Heart Association (AHA) has been published

⁎ Corresponding author at: Department of Hypertension, Nephrology and Hypertension, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland. Tel./fax: + 48 42 639 37 71. E-mail address: [email protected] (M. Banach). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.01.013

in order to eliminate confusion regarding the identification of patients with MetS [9]. MetS is associated with an increased risk of renal injury, cardiovascular disease (CVD), development of type 2 diabetes (T2DM), fatty liver disease, polycystic ovary syndrome, sleep-disordered breathing as well as all-cause and CVD mortality [10–14]. However, it has proven difficult to elucidate whether the renal dysfunction seen in MetS is due to the syndrome itself or to the individual risk factors. In patients with MetS, tubular atrophy, interstitial fibrosis, and arterial sclerosis indicating the presence of vascular damage, have also been described. As yet, there is little evidence that preventing or treating symptoms of the MetS protects patients from renal impairment [15–17]. 2. Search strategy We searched using the electronic databases [MEDLINE (1966–May 2011), EMBASE and SCOPUS (1965–May 2011), DARE (1966–May 2011)]. Additionally, abstracts from national and international cardiovascular meetings were studied. Where necessary, the relevant authors of these studies were contacted to obtain further data. The main data search terms were: dialysis, dyslipidemia, hemodialysis, hypertension, kidney disease, metabolic syndrome, microalbuminuria, obesity and renal impairment. 3. MetS and kidney disease Being very common in developed countries, MetS is also emerging as a public health problem in developing countries [10]. The risk of

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developing MetS in patients with chronic kidney disease (CKD) can be predicted by racial origin. According to Eckel et al. [18], the prevalence of MetS ranges from 8% in French males to 60% in female Native Americans. Others demonstrated that the prevalence of the MetS ranged from 11.0% in Chinese individuals to 41.6% in Native Indians [19] and was very high (about 80% individuals with at least 2 components of MetS) in Pacific Islanders and Maoris [20,21]. However it is worth to emphasize that the number of patients diagnosed with MetS depends on the definition used [22]. According to the National Health and Nutrition Examination survey (NHANES III), the MetS is independently associated with CKD in the general population and in non-diabetic adults [1,23]. Johnson et al. [20] reported that MetS in patients with CKD correlated with oxidative stress and reduced adiponectin levels, which in turn significantly increased the risk of future cardiovascular events. The presence of MetS also seems to be a strong predictor of subsequent adverse cardiovascular (CV) events. Johnson et al. [20] also confirmed the earlier observation [24] that the prevalence of MetS was gradually rising with the decrease in creatinine clearance (18% of patients with creatinine clearance >90 mL/min, 21% of those with 45–89 mL/min and 33% of patients with b45 mL/min). The greater prevalence of MetS in patients in more advanced stages of CKD suggests that the MetS is an independent predictor of CKD development and progression [20]. CKD is associated with a poorer quality of life and a shorter life expectancy and is becoming a global public health challenge [25,26]. Hoehner et al. [27] observed that after adjusting for social, demographic, and comorbidity factors, patients with 1 or more risk factors for the MetS were more likely to develop albuminuria. Moreover, on the basis of NHANES III data obtained from over 6000 subjects from the general population in the USA, Chen et al. [28] demonstrated a significant correlation between the number of MetS traits and both albuminuria and estimated glomerular filtration rate (eGFR) b60 mL/min/1.73 m 2. Also, Palaniappan et al. [29] showed a higher risk for microalbuminuria in men and women with the MetS. These data support the importance of MetS in the development of CKD. In a cross-selectional study [27] of an American Indian population, the risk of microalbuminuria in individuals with 3 or more MetS traits was 2.3-fold increased when compared with patients without MetS. In US adults, MetS was associated with 2.60-fold increase in the risk of CKD and 1.89-fold increase in microalbuminuria [27]. In a large cohort survey of patients with type 2 diabetes mellitus [30], both MetS and microalbuminuria had strong adverse effects on the GFR, and that this effect was even more pronounced in the presence of both factors. This finding has been challenged since the presence of the MetS also predicts the new onset of CKD in patients with T2DM independently of albuminuria [31,32]. Indeed, Athyros et al. [32] demonstrated that the association between MetS and low GFR was lost after adjustment for albuminuria. Of course, the differences in the prevalence of MetS between studies may depend on the definition used [28–32]. MetS was an essential predictor of CKD in Japanese [33] and Korean [1] populations. Some studies show differences in MetS prevalence in patients with CKD, depending on criteria used for the diagnosis. For example, Young et al. [34] estimated that the MetS when diagnosed on the basis of 2 criteria was present in 69.3% of patients on chronic hemodialysis (HD), but when 3 criteria were used, it was found in 31.7% of such patients [34,35]. According to Yu et al. [36] the effect of the MetS on CKD depends on age and gender, since MetS appeared to be a risk factor for CKD only in men under the age of 60 years and in postmenopausal women. This might have been due to the presence of androgenic milieu, since neither the MetS nor its individual components were associated with CKD in men over the age of 60 years and in premenopausal women [36]. This observation suggests that MetS may not be of key importance in the development of CKD in older men who have other risk factors such as atherosclerosis [36].

Using the WHO criteria, the MetS was present in 30% of CKD patients, especially in older subjects and those on peritoneal dialysis (PD) [37]. The age-specific prevalence of MetS was also seen in the NHANES III survey where the MetS was present in 10.7% of men and 18.0% of women aged 20–39 years and in 39.7% of men and 46.1% of women aged 60 years and older [37]. Gender-dependent differences in the susceptibility to kidney disease may be due to the beneficial vascular actions of estrogens as well as the negative effects of androgens [36,38]. The progression of renal disease in premenopausal women has been shown to be slower than in men [38]. This protection is lost at the beginning of the menopause, but the introduction of estradiol replacement treatment results in the recovery of the nephroprotective effects of estrogens. Animal studies have demonstrated that the attenuation of proteinuria in aging rats with the MetS after estradiol replacement therapy results from the increase in renal blood flow and GFR [39]. A sharp increase in MetS occurrence in women has also been attributed to higher prevalence of hypertension in women with aging [36], which is, in turn, associated with an increased risk of CKD [40]. In contrast, a strong positive correlation between MetS and the risk of CKD in Korean population irrespective of age and gender has been reported [1]. This has also been seen in the Chinese population aged 40 and more where the risk of developing CKD in conjunction with the MetS was also independent of age, sex and other risk factors for CKD [41]. Chen et al. [26] also found a relationship between the MetS and CKD in the general adult population of China that was independent of age, sex and CKD risk factors such as alcohol intake, smoking, body mass index (BMI) and lack of physical activity. Indeed, the greater the number of MetS components was, the more pronounced was the risk of CKD. Due to the fact that eGFR decreased in conjunction with the increase in the number of MetS components, it was suggested that each MetS component may be independently associated with decreased eGFR and increased risk for CKD [1]. Johnson et al. [20] suggested that the influence of the MetS on patient outcomes in severe CKD, might depend on the interplay between individual risk factors for the MetS such as hypertension, BMI and serum cholesterol concentration [20]. 4. CKD, high BP and hypertension MetS is frequently associated with type 2 diabetes and hypertension. The PAMELA population study (Pressioni Arteriose Monitorate E Loro Associazioni) revealed that high normal BP values and hypertension were present in 80% of individuals with MetS [42,43]. Such a high prevalence of high BP in patients with MetS may explain the frequent occurrence of subclinical organ damage manifested by left ventricular hypertrophy, arterial stiffening and increased urinary protein excretion [42,43]. According to studies insulin resistance and central obesity have been indicated to be the main factors involved in hypertension pathophysiology in the MetS [44]. Clinical studies have revealed that MetS plays an important role in the increased salt sensitivity of BP [45–47]. Salt sensitivity of BP increased progressively with a higher number of MetS risk factors [48]. The precise mechanism of salt-induced BP elevation is not well-studied, however it was suggested that it was due to impaired renal sodium excretion [45,49]. Study results demonstrated that renal function curve of obese hypertensive patients is identical to that of salt-sensitive-type hypertensives, which confirms the observation that obese hypertensive patients have greater depressor response to salt restriction on a low-salt diet in comparison to lean hypertensive patients [46]. Several factors such as hyperinsulinemia, kidney compression, sympathetic overactivity, increased activity of the renin-angiotensin (RA) system, and aldosterone excess in plasma induce abnormal natriuresis and increased salt sensitivity of BP in MetS [45]. Obesity is thought to be responsible for 65–75% of the risk for essential hypertension [50]. Obesity increases renal sodium reabsorption by

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activating the RA and sympathetic nervous systems since adipose tissue secrets hormones/cytokines (e.g. leptin) activating the sympathetic nervous system and altering kidney function [50]. Persistent obesity finally leads to structural changes within the kidneys and to the loss of nephron function, which further increases arterial pressure and causes severe renal disease [50]. Enhancement of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS) is also induced by insulin resistance and the resulting hyperinsulinemia [44]. Overactivity of the sympathetic system plays an important role in the development of hypertension. It was shown that obese people, especially those with visceral rather than peripheral obesity, have increased levels of plasma norepinephrine and faster urine turnover of norepinephrine in peripheral tissues [51,52]. It was shown that long-term sympathetic activation present in MetS may raise the BP through a variety of mechanisms including: increased renal tubular sodium reabsorption [43,52], stimulation of vasoconstriction or remodeling of the arterioles leading to structural increment in vascular resistance [43]. Sympathetic overactivity often leads to hemodynamic changes and to glomerular damage [53]. Insulin resistance contributes to hypertension through the stimulation of angiotensin 1 receptor overactivity which further causes vasoconstriction and volume expansion [44,54]. Also aldosterone seems to play a role in obesity-associated hypertension since fat tissue produces potent mineralocorticoid-releasing factors [55]. Aldosterone may raise the BP through its action on mineralocorticoid receptors located in the vasculature and brain [43]. Increased levels of aldosterone were noted in hypertensive patients with visceral obesity [56]. Aldosterone administration in a connection with a high-salt diet induced massive proteinuria and resulted in less intense immunostaining for nephrin, which suggest that aldosterone-induced proteinuria and renal damage are attributable to the injury of podocytes which play key role in the development of albuminuria and the progression of kidney disease [45,57]. Aldosterone contributes to hypertension-induced renal damage by promoting renal inflammation, glomerular injury, and abnormal accumulation of fibrillar collagens [58,59]. Endothelial dysfunction present in MetS may also enhance the prevalence of hypertension [43]. It was shown that insulinresistance may be associated with structural arteriolar changes which limit vasodilatation due to the impairment of the phosphoinositol pathway (PI-3) and subsequent decrease in endothelial nitric oxide synthase (eNOS) activity and lower nitric oxide production [43]. Apart from insulin, other hormones such as leptin, adiponectin, estrogen, glucocorticoids, and dehydroepiandrosterone are involved in the regulation of vessel function and structure [60,61]. Low plasma adiponectin was suggested to contribute to the development of obesity-related hypertension through a direct effect on the vasculature [43,60]. It was demonstrated that sustained obesity resulted in structural changes in the kidneys and loss of nephron function which further increased arterial pressure and led to severe renal disease in some cases [50]. 5. Obesity Obesity, one of the main components of the MetS may enhance the risk of renal dysfunction development. This occurs probably via the mechanisms associated with renal hyperfiltration and hyperperfusion [62] as focal glomerulosclerosis and other histological changes have been observed in kidneys of obese patients [1,63]. Rea et al. [64] examining early renal histopathologic changes associated with obesity in renal biopsy specimens from obese kidney donors without renal dysfunction and from non-obese control subjects observed only increased glomerular planar surface area and more tubular dilation in obese patients. Elevated renal blood flow and GFR in obese patients have been ascribed to increased levels of the protein albumin in the urine (albuminuria) [10]. The prevalence of MetS is significantly associated with the severity of obesity, and in obese patients it reaches 50% [18].

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The exact mechanism linking obesity with renal disease remains unknown, however, it has been speculated that inflammatory cytokines such as: leptin, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and adiponectin may participate in the development of renal impairment [10,65,66]. This hypothesis is in agreement with a study [67] showing that glomerulosclerosis, resulting from the intrarenal up-regulation of transforming growth factor-β (TGF-β), was associated with high plasma leptin in obese subjects. The major driver in the glomerular hyperfiltration seen in the MetS is probably adipose tissue, which is a rich source of inflammatory adipokines and leptin [68]. RAAS activation associated with obesity, especially with visceral adiposity, also contributes to early glomerular and tubulointerstitial remodeling/injury resulting in part from the generation of reactive oxygen species [69,70]. Other obesity-related factors may affect kidney function stimulating the alteration of renal hemodynamics due to high dietary protein intake, excess renal sodium reabsorption, hyperlipidemia, physical compression of the kidney by adipose tissue and the activation of the RA and sympathetic nervous systems. These multiple mechanisms may lead to glomerular hyperfiltration, glomerular cell proliferation, matrix accumulation, glomerulosclerosis and the loss of nephrons [10,71]. Moreover, since GFR of extremely obese patients is increased it was also suggested that the high GFR in very obese subjects might be the result of an increase in transcapillary hydraulic pressure difference (ΔP) [72]. 6. CKD and dyslipidemia Another metabolic trait, which may alter the risk of CKD development, is dyslipidemia. According to Ruotolo and Howard [73] among major components of dyslipidemia in MetS patients there are: increased fasting and post-prandial TG-rich lipoproteins (TRLs), decreased high-density lipoprotein (HDL), and increased small, dense low-density lipoprotein (LDL) particles. Excessive hepatic production of TG and successive hypertriglyceridemia results from the increased free fatty acid flux into the liver. Reabsorption of fatty acid phospholipids and cholesterol by tubular epithelial cells can stimulate tubulointerstitial inflammation, foam cell formation and tissue injury [74]. Dyslipidemia may also damage glomerular capillary endothelial and mesangial cells as well as podocytes [75]. Hypercholesterolemia and hypertriglyceridemia are associated with podocyte injury, which further leads to mesangial sclerosis [75,76]. The accumulation of lipoproteins in glomerular mesangium can stimulate matrix production and glomerulosclerosis [74]. It was demonstrated that the exposure of mesangial cells to lipids results in the induction of mesangial cell proliferation, increased mesangial matrix deposition, enhanced secretion of macrophage chemo-attractant protein-1, IL-6, platelet-derived growth factor (PDGF), TGF-β and TNF-α. Furthermore, their contact with TG-rich lipoproteins leads to the production of fibronectin and monocyte chemoattractant protein-1 (MCP-1) expression [1,75,77,78]. The unfavorable influence of TG-rich lipoproteins on renal mesangial cells has been confirmed by Chang et al. [1] who suggested that their effect was even more pronounced than the protective effects of HDLcholesterol (HDL-C). According to Ryu et al. [79] both increased TG and low HDL-C levels were associated with significantly increased risk of CKD. These results remained unchanged, even after additional adjustment for incident hypertension and incident diabetes [79]. Patients with CKD often have hypertriglyceridemia due to catabolic defects resulting from suppressed activity of hepatic TG lipase (HTGL) [25]. Markedly lowered level of HDL (especially the HDL2 subfraction) in patients with stage 5 CKD on HD or PD was the result of both hypertriglyceridemia and impaired activity of lipoprotein lipase (LPL), HTGL and lecithin-cholesterol acyltransferase (LCAT) [25,8–82]. Impaired HDL-mediated reverse cholesterol transport due to the decreased unloading of the excess cellular cholesterol and phospholipid burden may contribute to renal tissue injury [74]. LCAT deficiency contributes

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to progressive renal disease since it was demonstrated that ACAT inhibitor administration reduced proteinuria and retard progression of renal disease in experimental animals [74].

loss of slit pore diaphragm integrity leading finally to glomerulosclerosis and tubulointerstitial injury. 8. MetS — a marker or a causative factor?

7. CKD and insulin resistance Insulin resistance which results from inflammation and impaired fasting glucose levels in non-diabetics may partly be responsible for the increased risk of CKD in subjects with MetS [23,28] and is observed in patients at early stages of renal dysfunction [83]. Insulin resistance, along with oxidative stress and inflammation have been suggested to be involved in albuminuria and declining kidney function [10]. Experiments conducted on animal models and in vitro on cell culture demonstrated that adiponectin signaling via AMPK regulates oxidative stress, segmental fusion of podocyte foot processes, and albuminuria [84,85]. It was also shown that adiponectin decreased albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis due to the restoration of VCAM-1, monocyte chemoattractant protein-1, TNF-α, TGF-β1, collagen type I/III, and Nox to the levels found in wild-type mice [85,86]. Insulin resistance promotes kidney disease by worsening renal hemodynamics through mechanisms such as: the activation of sympathetic nervous system [87], sodium retention [88], the decrease in Na +, K +-ATPase activity [89] and an increase in GFR [90]. Endoplasmic reticulum (ER) stress seems to be the factor linking inflammation and insulin resistance at the molecular level. Under conditions of pathological stress, misfolded proteins accumulate in the ER lumen where they activated the unfolded protein response pathway. This in turn led to the suppression of insulin signaling via the phosphorylation of the insulin receptor substrate (IRS-1) due to the activation of c-Jun N-terminal kinase (JNK) [91]. Increased insulin sensitivity in non-diabetic patients is in contrast to diabetics in whom JNK activity is high, and may reduce CKD risk in the first group possibly by preventing diabetes development or by blocking kidney injury [92]. ER stress in kidney is associated with proteinuria-induced podocyte damage, the alteration of nephrin N-glycosylation in podocytes, which is the underlying factor in the pathomechanism of proteinuria and involved in the pathophysiology of chronic kidney injury with tubulointerstitial damage [93]. It was demonstrated that the popular therapeutic agent for nephrosis (glucocorticoid) might exert antiproteinuric effects through the facilitation of intracellular trafficking of nephrin under an ER stress condition [94]. As suggested by Cybulsky et al. [95,96] complement-induced podocyte injury both in vitro and in vivo and membranous nephropathy were associated with ER stress. In acute and chronic kidney disease, ER stress was shown to contribute to the development and progression of glomerular and tubular disease. Hyperhomocysteinemia-induced ER stress was suggested to be involved in glomerular injury and glomerulosclerosis [97]. In animal models, injections of tunicamycin (ER stress inducer) led to the development of acute renal tubular necrosis in mice [93,98]. In glomeruli, podocyte or mesangial dysfunction ER stress stimulates the induction of the adaptive unfolded protein response (UPR), which results in ER chaperone expression and the attenuation of protein translation, to maintain ER homeostasis and ensure cell survival. UPR is also responsible for apoptosis in tubules, resulting from epithelial cell damage [93]. Up-regulation of RE stress indicators and activation of caspase-12 were observed in proximal tubules of experimental proteinuric rats [97,99]. There is accumulating evidence which indicates that ER stress is involved in organ-specific inflammation [100,101], in autoimmunity [93,102] ischemic renal tubular injury [97], and nephrotoxicity of calcineurin inhibitors [97]. According to Sowers [70] insulin resistance and inflammatory cytokine release may in part be responsible for glomerular mesangial expansion, basement membrane thickening, podocytopathy and the

It is unclear whether it is the MetS or its components that increase the risk of CKD [103]. Hypertension in patients with MetS seems to be a strong independent risk factor for renal injury, especially end stage renal disease (ESRD) [1,104]. Hypertension and hyperglycemia confer the greatest risk of CKD in MetS patients. The MetS, even after adjustments for diabetes and hypertension, remained an independent factor contributing to CKD development defined as the progression to eGFR ≤60 ml/min/1.73 m 2 over a 9-year period [28]. The study of normotensive, non-diabetic Korean men with MetS demonstrated its association with the development of CKD, even after the adjustment for HOMA-IR, high-sensitivity C-reactive protein (CRP) levels, smoking, alcohol consumption and regular exercise [79]. Thus, it was suggested that MetS might be a marker, rather than a causative factor in the development of CKD. It was also hypothesized that both proteinuria and hypertension were probably a consequence, not a cause of CKD [23]. The role of MetS in the development of renal disease is presented in Fig. 1. Impaired renal function itself is a risk factor for vascular events and also a cause of insulin resistance and dyslipidemia. According to Go et al. [105] there is a progressive increase in cardiovascular events, hospitalization and mortality when renal function declines. Serum creatinine level and/or eGFR seems to be a predictor of vascular risk [106], while microalbuminuria is an independent vascular risk factor, even at levels lower than 30 mg/24 h [107,108]. It was demonstrated that reduced apoA-I and apoA-II levels and accumulation of apoBcontaining VLDL particles were important in the development and maintenance of dyslipidemia in CKD patients [109,110]. In CKD patients, despite frequently reduced levels of total cholesterol, atherogenic lipoprotein remnants and lipoprotein (a) are usually increased [111]. Moreover, they often have decreased levels of HDL due to both reduced serum concentration of apoA-I and apoA-II protein [112] and hypoalbuminemia [111,113]. CKD also causes insulin resistance, and this also contributes to low HDL levels. In children with CKD, insulin resistance is highly prevalent and can be caused by products of protein catabolism in CKD [114,115]. Indeed, vitamin D status in CKD may be an important cause of insulin resistance [115,116]. 9. Pathological renal changes induced by the MetS High-resolution B-mode pulsed-wave Doppler ultrasound has revealed increased carotid intima-media thickness (IMT) as well as higher pulsatility (PI) and resistive (RI) indices in intra-renal interlobar arteries of patients with the MetS which may reflect end-organ damage [117] and/or functional and reversible modifications resulting from endothelium dysfunction-induced intra-renal vasoconstriction [118,119]. Increased intra-renal RI and PI values may also predict future structural changes which lead to atherosclerosis and glomerular ischemia [119,120]. MetS, especially when it coexists with type 2 diabetes, has been shown to be associated with higher values of IMT and intra-renal resistances as assessed by RI and PI. Intra-renal resistances in this study were only weakly associated with the number of MetS components. This is in agreement with the hypothesis that MetS itself, but not its single components, is related to the increased risk of developing CKD [119]. In patients with kidney disease a correlation between renal resistance indices and local renal impairment has been reported [119]. Alexander et al. [121] observed greater tubular atrophy, interstitial fibrosis, and arterial sclerosis in patients with the MetS, when compared with controls, which possibly reflect the presence of vascular damage. Moreover, patients with MetS had global and focal segmental sclerosis but no differences in glomerular volume between groups

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Fig. 1. The association of metabolic syndrome and renal disorders.Abbreviations: WHR, waist hip ratio; BMI, body mass index; IL-6, interleukin-6; TNF-α, tumor necrosis factor α; ApoB, apolipoprotein B; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; MCP-1, monocyte chemoattractant protein-1; PCOS, polycystic ovary syndrome; NAFLD, non-alcoholic fatty liver disease; NS, nervous system.

were observed [121]. In these patients, the decrease in kidney function following nephrectomy was more pronounced than in controls [121]. On the basis of these observations, it was concluded that MetS probably adversely affected kidney parenchyma thus reducing kidney reserve limit [121]. Several mechanisms of tubulointerstitial fibrosis and tubular atrophy occurrence in patients with MetS have been proposed. In animal models, hyperlipidemia-induced kidney injury was stimulated by increased oxidative stress and accompanied by the appearance of desmin-positive myofibroblasts [122,123]. Tubulointerstitial injury has also been ascribed to both hyperglycemia since it is associated with the presence of a proinflammatory state [124–126] and hypertension [127]. In hypertensive rats, angiotensin II (AngII) was shown to be a regulator of tubulointerstitial cell kinetics [127]. Angiotensin II stimulates reactive oxygen species generation by NADPH oxidase and downregulates NOS, and thus it probably contributes to vascular damage and further to tubulointerstitial injury [123,128,129]. Microvascular changes such as arterial and arteriolar sclerosis within kidney lesions in patients with MetS have been reported [125]. Arteriolar hyalinosis, which is among the earliest signs of vascular changes in diabetics, has been rarely observed in MetS patients, and therefore hyperglycemia could not be the only cause of vascular abnormalities [121]. These vascular changes may be amplified by increased blood pressure in patients with MetS [121]. Midkine, a retinoic acid-responsive factor expressed in proximal tubules, has recently been shown to play a key role in tubulointerstitial inflammation in patients with diabetic nephropathy [130]. Patients with MetS also have raised levels of serum uric acid and it has been suggested that this might play an important role in vascular injury in fructose-induced MetS [130]. Moreover, uric acid inhibits NO production thus contributing to endothelial dysfunction [131,132]. Glomerular changes may also be connected with obesity, since it has been demonstrated that obese patients with normal kidney function are more susceptible to glomerulomegaly, podocyte hypertrophy, mesangial matrix and cell proliferation [133]. Moreover, a greater glomerular cross-sectional area was observed in obese living kidney transplant donors when compared with non-obese ones [64,132]. MetS may also increase the risk of kidney stones (KS). The number of MetS traits was found to affect the prevalence of a self-reported

history of KS. The incidence of KS in the West et al. [134] study ranges from 3% in patients with 0 traits to 9.8% in those with 5 traits, and the presence of 4 or more traits was associated with a 2-fold increase in KS risk. Another study [135] reveals that MetS was associated with a twofold greater risk of objectively demonstrated nephrolithiasis. Cochat et al. [136] summarized common characteristics of nephrolithiasis associated with inborn metabolic diseases, including early onset of the disease (childhood), positive family history, associated tubular dysfunction, bilateral stones and/or nephrocalcinosis, multiple and recurrent stones and presence of extra-renal involvement. Retrospective analysis of a stone registry in Dallas revealed a high prevalence of MetS features in patients with idiopathic uric acid nephrolithiasis [137]. Also, in patients with recurrent uric acid kidney stones clinical and metabolic abnormalities consistent with MetS were present [138]. Sakhaee et al. [137] demonstrated that not only MetS but also its traits such as obesity, weight gain and T2DM were associated with the increased risk of nephrolithiasis. The study of obese men revealed that in men with the weight more than 220 lb (100 kg) the risk of KS was increased by 44%, when compared to men weighing less than 150 lb (about 70 kg) [134]. The association between obesity and risk of KS was even stronger in women [139]. Obesity is associated with the presence of multiple overlapping KS risk factors, including diet (high oxalate, protein and sodium content) and insulin resistance [134]. The impaired biologic activity of insulin in insulin-resistant individuals was associated with excessively low urinary pH, which could potentially predispose to uric acid stone formation. Insulin resistance significantly influences urinary salt supersaturation affecting urinary pH as well as calcium, phosphate, urate and citrate excretion [138,140] thus driving to phase changes in which urinary dissolved salts condense into solids forming stones [135]. Changes in insulin signaling within the kidney might be associated with increased net acid excretion and impaired buffering caused by defective urinary ammonium excretion, due to the fact that insulin is involved in the proximal tubule Na/H+ exchanger [141] and mediates proximal tubule ammoniagenesis [134,142]. This leads to excessively acidic urine and further to the development of idiopathic uric acid stones [143]. According to Abate et al. [138], obesityrelated insulin resistance considerably contributes, but does not entirely explain, the excessive urinary acidity of uric acid nephrolithiasis patients. In some patients with KS, excessively low urinary pH was independent of

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insulin resistance and obesity, however, the exact mechanism involved has not been revealed [138]. A relationship between high BP and nephrolithiasis occurrence was seen in both men and women, however, this association was even more pronounced when high BP coexisted with 1 or more components of MetS [135]. A significant relationship between hypertension and nephrolithiasis in both cross-sectional and prospective epidemiological investigations was also observed [135,144,145]. In hypertensive patients, renal tubular calcium handling is altered leading to increased urinary calcium excretion [146]. Conversely, some prospective data suggest that a history of nephrolithiasis was associated with a greater risk of the development of hypertension [147].

10. Prevention and treatment The exact mechanism by which the MetS causes kidney injury is not known [103]. Prevention and treatment of MetS should be introduced as a strategy to decrease the prevalence of CKD and the associated disease burden [26]. Adverse outcomes such as CKD and other extrarenal disease manifestations which occur as a result of MetS in patients with hypertension, dyslipidemia and diabetes could possibly be prevented by the combination of lifestyle change and aggressive treatment [103]. Although it has been reported that the control of hypertension and hyperglycemia prevents the development of microalbuminuria and overt nephropathy in diabetic patients [15,16], it is not known whether this practice is also advantageous in those with MetS [10]. Weight reduction was shown to be effective in the reduction of proteinuria in obese patients and in CKD progression protection but only prior to ESRD development [53,148]. Moreover, in patients without overt renal disease it was demonstrated to improve obesityrelated glomerular hyperfiltration [72]. Also drastic weight loss following bariatric surgery was shown to be associated with a gradual amelioration of 24 h albuminuria [149]. Bariatric surgery performed in case of morbid obesity was demonstrated to be effective in treating MetS [150]. Although the potential benefits of physical activity in the prevention of CKD in patients with MetS require further study, it exerts beneficial effects on the metabolism of glucose and lipids, reduces inflammation, and improves endothelial dysfunction [151]. Understanding the mechanisms of relationship between the MetS and BP elevation can help to better define strategies to reduce its prevalence and to reduce high cardiovascular and renal risk associated in these patients [43]. It is important for patients with hypertension and MetS to introduce changes into lifestyle such as sodium, alcohol and calorie restriction, smoking cessation, weight reduction and increased physical activity [44]. All current guidelines indicate that reduction in body mass by a proper diet and increase in physical activity are the first-line therapy of MetS [152,153]. According to Chen et al. [48] the reduction in sodium intake could be a vital component in reducing BP in patients with multiple risk factors for MetS. However, to obtain target values, pharmacological interventions aiming at BP reduction, dyslipidemia, obesity and diabetes treatment are often necessary [44]. There are 2 types of drugs interfering with the mechanisms of the MetS (insulin-sensitizers and the endogenous cannabinoid type 1 receptor blockers) [153] and drugs dealing with a particular MetS component i.e. hypertension, dyslipidemia and diabetes. It has been demonstrated that the use of PPAR-γ (peroxisome proliferatoractivated receptor-γ) agonists — thiazolidinediones which increase lipogenesis in adipose tissue thus decreasing serum free fatty acid (FFA) concentrations and increasing subcutaneous adipose tissue mass, may contribute to the decrease in plasma glucose and serum insulin levels, a reduction of plasma TG and an increase in HDL-C levels due to the fact that this drug enhances hepatic insulin sensitivity, reduces hepatic fat content and inhibits hepatic glucose production [153,154]. Thiazolidinediones have been also shown to decrease

circulating markers of vascular inflammation and they proved effective in type 2 diabetes treatment [153,154]. Trials conducted on obese subjects with dyslipidemia revealed that rimonabant, which is cannabinoid type 1 receptor blocker (CB1), had beneficial impact on most of the MetS components [153,155,156]. Rimonabant treatment resulted in body weight and waist circumference reduction, decreased levels of plasma glucose, plasma TG, insulin resistance and HDL-C and probably weight-loss associated modest SBP and DBP reductions [153,157]. However, rimonabant is no longer available due to safety concerns. The large cohort European Lacidipine Study on Atherosclerosis (ELSA) study demonstrated that effective antihypertensive treatment may counteract the effects of MetS since the outcomes of well-treated patients with MetS and those without MetS are similar [153,158]. Satisfying results in the reduction of proteinuria and CKD progression was observed while the combination of angiotensin-converting enzyme inhibitor and angiotensin II receptor blockade (ATRB) were used [17,53] as well as ACE, ATRB or calcium channel blockers in monotherapy [153]. The RAAS blockers are strongly recommended as the initial therapy of choice for renoprotection since many studies demonstrated greater reductions in proteinuria and slowed progression of renal disease development after RAAS blocker treatment, compared with other antihypertensive regimens, in both diabetic and non-diabetic nephropathy [159,160]. Among the preferred (first choice) antihypertensive drugs in patients with MetS or/and diabetics there are angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) [161]. Statins inhibit the rate-limiting enzyme in the cholesterol synthesis pathway and they are widely used to lower cholesterol concentrations [110]. However, apart from their lipid-lowering effects, statins may also exert additional pleiotropic effects such as: the reduction of oxidative stress, thrombogenesis, fibrosis and inflammation due to the decrease in IL-6, MCP-1, TGF-β and intracellular adhesion molecule-1 (ICAM) as well as the improvement of endothelial dysfunction [110,162]. It has also been demonstrated that statins exert significant BP-lowering effects, particularly on systolic BP [161,163–165]. Furthermore, animal models revealed that statins decrease the severity of lipid-induced glomerular damage and thus preserve renal function [110,166–168]. In humans, statins may have a favorable impact on the slowing of CKD progression, since it was proved that they significantly decrease proteinuria [169,170]. In prospective, controlled, open-label study, Bianchi et al. [171] observed significantly slower decrease in GFR and the reduction of urinary protein excretion in atorvastatin-treated (40 mg/day) CKD patients as compared with the placebo group. Another prospective, open-label, randomized study [172] demonstrated that treatment with rosuvastatin 10 mg/day (20 weeks) ameliorated GRF level, and resulted in concomitant decrease in LDL-cholesterol (LDL-C) and highsensitivity CRP levels. Atorvastatin treatment was demonstrated to be associated with modest improvement in annual change in eGFR, but did not influence the incidence of albuminuria or regression to normoalbuminuria [173]. Renal function improvement in statin treated patients in a post hoc analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) [174] was observed in the 6th week of treatment and was ascribed to the pleiotropic effects of statins (e.g. anti-inflammatory effects and improved endothelial function). Atorvastatin resulted in 7% statin-induced HDL-C increase and in the improving lipid variables other than LDL-C, which may also be relevant for both CHD and CKD prevention [174]. A meta-analysis [175] revealed that statins reduced the rate of kidney function loss by 76%. A post-hoc analysis [176] of patients with moderate CKD also showed that statin therapy slowed the decline in kidney function in persons with moderate to severe kidney disease, especially in those with proteinuria. Meta-analysis of clinical trials has shown the efficacy of lipid-lowering treatment in decreasing proteinuria occurrence and in slowing of the rate of GFR decline

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in patients with CKD [17]. However, it remains unknown whether such therapy is also effective in the prevention of the onset of renal impairment in patients with normal renal function [10,177]. Statins can reduce albuminuria in microalbuminuric and macroalbuminuric patients [178]. The Cholesterol and Recurrent Events (CARE) trial demonstrated that pravastatin treatment (40 mg) of patients with previous myocardial infarction, in contrast to placebo, significantly reduced the rate of renal function decline in patients with more severe renal insufficiency [176,179]. Shepherd et al. [179] observed an improvement in renal function in the diabetic cohort in the subanalysis of the TNT (Treating to New Targets) study. However, according to Rahman et al. [180], pravastatin was not superior to usual care in preventing clinical renal outcomes in hypertensive patients with moderate dyslipidemia and decreased eGFR. They suggested that benefits from statin therapy might depend on the degree of the cholesterol level decrease achieved. Management of combined dyslipidemia may require the use of a statin–fibrate combination [181]. Fibrates are hypolipidemic drugs which influence lipid parameters — they reduce TG and increase HDL levels and also exert pleiotropic actions [182]. They are used for the treatment of dyslipidemia and may prevent diabetic nephropathy and cardiovascular disease [183]. Several studies reported beneficial effects of fibrates on kidney function in individuals with diabetes or MetS [184,185]. Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) is a large study of the effects of fenofibrate in patients with type T2DM [184]. 4-month treatment with fenofibrate resulted in the decrease in plasma total-cholesterol concentration by 11%, LDL-C by 12%, TG by 29% and increase in HDL-C by 5% when compared with placebo. Fenofibrate seems not only to promote LDL catabolism via the receptormediated pathway, but also inhibits the formation of slowly metabolized potentially atherogenic LDL particles by lowering plasma TG levels [185]. Fenofibrate significantly reduced albuminuria progression rate since albuminuria regression or lack of progression was observed in 2.6% more patients on fenofibrate than on placebo [184]. Due to their effect on albuminuria, fibrates contribute to slowing down of the progression of diabetic nephropathy [181]. The Diabetes Atherosclerosis Intervention Study (DAIS) also demonstrated that fenofibrate reduced the progression from normal albumin excretion to microalbuminuria in T2DM patients [185]. However, fibrates can cause a small but noteworthy increase in serum creatinine levels [186,187], but this fenofibrate-associated elevation is fully reversible within a few weeks of ceasing therapy and thus it does not reflect permanent renal damage [188]. Moreover, it was observed that coadministration of fibrates (especially gemfibrozil) with statins was associated with a small but significant increase in death from rhabdomyolysis. Although the mechanism for that is not known, fibrates seem to increase homocysteine levels [188]. 11. Conclusions The link between MetS and CKD has been reported. However, it is unclear whether renal dysfunction is induced by MetS itself or by its components such as: hypertension and impaired glucose metabolism. Both MetS and CKD are increasingly common disorders and thus they are becoming a major public health concern. Despite the close association between MetS and renal damage, it is not known whether the treatment of risk factors such as: hypertension, renin-angiotensin system activation, dyslipidemia, glycemia and insulin resistance in MetS can prevent the development and progression of CKD. Although genetic factors undoubtedly predispose to MetS, the alteration of modifiable risk factors may prevent or delay its development. Both insulin resistance and hyperinsulinemia have deleterious effects on the kidney, increasing the CKD [161]. Epidemiological data also indicate that hypertriglyceridemia and low levels of HDL-C are independent risk factors for the development and progression of CKD. Thus, the

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