Thromb Haemost 2013; 110(05): 940-958
DOI: 10.1160/TH13-06-0499
Review Article
Schattauer GmbH

The liver and the kidney: two critical organs influencing the atherothrombotic risk in metabolic syndrome

Federico Carbone
1   Department of Internal Medicine, University of Genoa School of Medicine. IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
2   Cardiology Division, Foundation for Medical Researches, Department of Internal Medicine, University of Geneva, Geneva, Switzerland
,
Fabrizio Montecucco
1   Department of Internal Medicine, University of Genoa School of Medicine. IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
2   Cardiology Division, Foundation for Medical Researches, Department of Internal Medicine, University of Geneva, Geneva, Switzerland
,
François Mach
2   Cardiology Division, Foundation for Medical Researches, Department of Internal Medicine, University of Geneva, Geneva, Switzerland
,
Roberto Pontremoli
3   Departments of Cardio-Nephrology and Internal Medicine University of Genoa, School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
,
Francesca Viazzi
3   Departments of Cardio-Nephrology and Internal Medicine University of Genoa, School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
› Author Affiliations
Financial support: This research was funded by EU FP7, Grant number 201668, AtheroRemo to Dr. F. Mach. This work was supported by Swiss National Science Foundation Grants to Dr. F. Mach (#310030_118245) and to Dr. F. Montecucco (#32003B_134963/1).
Further Information

Publication History

Received: 20 June 2013

Accepted after major revision: 12 July 2013

Publication Date:
01 December 2017 (online)

Summary

The increased atherothrombotic risk in patients with metabolic syndrome (MetS) has been classically explained by the multiplicative effect of systemic concomitant pro-atherosclerotic factors. In particular, centripetal obesity, dyslipidaemia, glucose intolerance, hypertension (differently combined in the diagnosis of the disease) would be expected to act as classical cardiovascular risk conditions underlying accelerated atherogenesis. In order to better understand specific atherosclerotic pathophysiology in MetS, emerging evidence focused on the alterations in different organs that could serve as both pathophysiological targets and active players in the disease. Abnormalities in adipose tissue, heart and arteries have been widely investigated in a variety of basic research and clinical studies in MetS. In this narrative review, we focus on pathophysiological activities of the liver and kidney. Considering its key role in metabolism and production of soluble inflammatory mediators (such as C-reactive protein [CRP]), the liver in MetS has been shown to be altered both in its structure and function. In particular, a relevant amount of the fat accumulated within this organ has been shown to be associated with different degrees of inflammation and potential insulin resistance. In humans, non-alcoholic fatty liver disease (NAFLD) has been described as the hepatic manifestation of MetS. In an analogous manner, epidemiological evidence strongly suggested a “guilty“ association between MetS and chronic kidney disease (CKD). Some biomarkers of hepatic (such as C-reactive protein, TNF-alpha or other cytokines) and renal diseases (such as uric acid) associated with MetS might be particularly useful to better manage and prevent the atherothrombotic risk.

 
  • References

  • 1 Ford ES. et al. Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US. J Diabetes 2010; 2: 180-193.
  • 2 Jansen-Chaparro S. et al. Metabolic syndrome and vascular risk estimation in a Mediterranean non-diabetic population without cardiovascular disease. Eur J Intern Med 2012; 23: 558-563.
  • 3 Aballay LR. et al. Overweight and obesity: a review of their relationship to metabolic syndrome, cardiovascular disease, and cancer in South America. Nutr Rev 2013; 71: 168-179.
  • 4 Thomas GN. et al. The US National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) prevalence of the metabolic syndrome in a Chinese population. Diabetes Res Clin Pract 2005; 67: 251-257.
  • 5 Reaven GM. Banting lecture 1988.Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607.
  • 6 Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539-553.
  • 7 Grundy SM. et al. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109: 433-438.
  • 8 Alberti KG. et al. Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 2006; 23: 469-480.
  • 9 Bhatt DL. et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. J Am Med Assoc 2006; 295: 180-189.
  • 10 Wang TD. et al. Ethnic differences in the relationships of anthropometric measures to metabolic risk factors in Asian patients at risk of atherothrombosis: results from the REduction of Atherothrombosis for Continued Health (REACH) Registry. Metabolism Clin Exp 2010; 59: 400-408.
  • 11 Despres JP. Abdominal obesity and cardiovascular disease: is inflammation the missing link? Can J Cardiol 2012; 28: 642-652.
  • 12 Weycker D. et al. Risk-factor clustering and cardiovascular disease risk in hypertensive patients. Am J Hypertens 2007; 20: 599-607.
  • 13 Kotronen A. et al. Liver fat in the metabolic syndrome. J Clin Endocrinol Metab 2007; 92: 3490-3497.
  • 14 Bhatia LS. et al. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?. Eur Heart J 2012; 33: 1190-1200.
  • 15 Thomas G. et al. Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2011; 6: 2364-2373.
  • 16 Galassi A. et al. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006; 119: 812-819.
  • 17 Gami AS. et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007; 49: 403-414.
  • 18 Li W. et al. Association between metabolic syndrome and risk of stroke: a meta-analysis of cohort studies. Cerebrovasc Dis 2008; 25: 539-547.
  • 19 Bayturan O. et al. The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis. Arch Intern Med 2010; 170: 478-484.
  • 20 Mottillo S. et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113-1132.
  • 21 Wormser D. et al. Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. Lancet 2011; 377: 1085-1095.
  • 22 Korporaal SJ, Akkerman JW. Platelet activation by low density lipoprotein and high density lipoprotein. Pathophysiol Haemost Thromb 2006; 35: 270-280.
  • 23 Cea-Calvo L. et al. Prevalence of low HDL cholesterol, and relationship between serum HDL and cardiovascular disease in elderly Spanish population: the PREV-ICTUS study. Int J Clin Pract 2009; 63: 71-81.
  • 24 Langsted A. et al. Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med 2011; 270: 65-75.
  • 25 Scott R. et al. Impact of metabolic syndrome and its components on cardiovascular disease event rates in 4900 patients with type 2 diabetes assigned to placebo in the FIELD randomised trial. Cardiovasc Diabetol 2011; 10: 102
  • 26 Montecucco F. et al. Inflammation is a key pathophysiological feature of metabolic syndrome. Mediators Inflamm 2013; 2013: 135984
  • 27 Haque M, Sanyal AJ. The metabolic abnormalities associated with non-alcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 2002; 16: 709-731.
  • 28 Sung KC. et al. The severity of nonalcoholic fatty liver disease is associated with increased cardiovascular risk in a large cohort of non-obese Asian subjects. Atherosclerosis 2009; 203: 581-586.
  • 29 Adams LA. et al. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol 2009; 104: 861-867.
  • 30 Caballeria L. et al. Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain. Eur J Gastroenterol Hepatol 2010; 22: 24-32.
  • 31 Chen SH. et al. Relationship between nonalcoholic fatty liver disease and metabolic syndrome. J Dig Dis 2011; 12: 125-130.
  • 32 El-Koofy NM. et al. The association of metabolic syndrome, insulin resistance and non-alcoholic fatty liver disease in overweight/obese children. Saudi J Gastroenterol 2012; 18: 44-49.
  • 33 Thakur ML. et al. Nonalcoholic fatty liver disease is associated with subclinical atherosclerosis independent of obesity and metabolic syndrome in Asian Indians. Atherosclerosis 2012; 223: 507-511.
  • 34 Kim BJ. et al. The association between nonalcoholic fatty liver disease, metabolic syndrome and arterial stiffness in nondiabetic, nonhypertensive individuals. Cardiology 2012; 123: 54-61.
  • 35 Kwon YM. et al. Association of nonalcoholic fatty liver disease with components of metabolic syndrome according to body mass index in Korean adults. Am J Gastroenterol 2012; 107: 1852-1858.
  • 36 Ratziu V. et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53: 372-384.
  • 37 Day CP, James OF. Steatohepatitis: a tale of two "hits"?. Gastroenterology 1998; 114: 842-845.
  • 38 van Rooyen DM. et al. Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis. Gastroenterology 2011; 141: 1393-1403. 1403 e1-5.
  • 39 Guilherme A. et al. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 2008; 9: 367-377.
  • 40 Bjorntorp P. "Portal" adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 1990; 10: 493-496.
  • 41 Yamaguchi K. et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007; 45: 1366-1374.
  • 42 Min HK. et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell metabolism 2012; 15: 665-674.
  • 43 Hoekstra M. et al. Nonalcoholic fatty liver disease is associated with an altered hepatocyte microRNA profile in LDL receptor knockout mice. J Nutr Biochem 2012; 23: 622-628.
  • 44 Bieghs V. et al. LDL receptor knock-out mice are a physiological model particularly vulnerable to study the onset of inflammation in non-alcoholic fatty liver disease. PloS one 2012; 7: e30668
  • 45 Corey KE. et al. Non-high-density lipoprotein cholesterol as a biomarker for nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2012; 10: 651-656.
  • 46 Kim JK. et al. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 2000; 275: 8456-8460.
  • 47 Petersen KF. et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002; 109: 1345-1350.
  • 48 Fabbrini E. et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA 2009; 106: 15430-15435.
  • 49 Fabbrini E. et al. Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults. Gastroenterology 2010; 139: 448-455.
  • 50 Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012; 148: 852-871.
  • 51 Rolo AP. et al. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med 2012; 52: 59-69.
  • 52 Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Saemin Liver Dis 2008; 28: 360-369.
  • 53 Wobser H. et al. Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells. Cell Res 2009; 19: 996-1005.
  • 54 Tosello-Trampont AC. et al. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-alpha production. J Biol Chem 2012; 287: 40161-40172.
  • 55 Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88: 125-172.
  • 56 Javor ED. et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 2005; 41: 753-760.
  • 57 Hindle AK. et al. Adiponectin but not leptin is involved in early hepatic disease in morbidly obese patients. Surg Endosc 2010; 24: 1547-1551.
  • 58 Aller R. et al. Lys656Asn polymorphism of leptin receptor, leptin levels and insulin resistance in patients with non alcoholic fatty liver disease. Eur Rev Med Pharmacol Sci 2012; 16: 335-341.
  • 59 Fitzpatrick E. et al. Analysis of adipokine concentrations in paediatric non-alcoholic fatty liver disease. Pediatr Obes 2012; 7: 471-479.
  • 60 Zelber-Sagi S. et al. The association between adipocytokines and biomarkers for nonalcoholic fatty liver disease-induced liver injury: a study in the general population. Eur J Gastroenterol Hepatol 2012; 24: 262-269.
  • 61 Zelber-Sagi S. et al. Predictors for incidence and raemission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol 2012; 56: 1145-1151.
  • 62 Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 2006; 87: 1-16.
  • 63 Buechler C. et al. Adiponectin, a key adipokine in obesity related liver diseases. World J Gastroenterol 2011; 17: 2801-2811.
  • 64 Aller R. et al. Influence of insulin resistance and adipokines in the grade of steatosis of nonalcoholic fatty liver disease. Dig Dis Sci 2008; 53: 1088-1092.
  • 65 Bataller R. et al. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology 2003; 125: 117-125.
  • 66 Bataller R. et al. Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver. Am J Physiol Gastrointest Liver Physiol 2003; 285: G642-651.
  • 67 Paschos P, Tziomalos K. Nonalcoholic fatty liver disease and the renin-angiotensin system: Implications for treatment. World J Hepatol 2012; 4: 327-331.
  • 68 Neuschwander-Tetri BA. et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 2010; 52: 913-924.
  • 69 Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. J Am Med Assoc 2003; 289: 3000-3004.
  • 70 White DL. et al. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012; 10: 1342-1359. e2.
  • 71 Pacana T, Fuchs M. The cardiovascular link to nonalcoholic fatty liver disease: a critical analysis. Clin Liver Dis 2012; 16: 599-613.
  • 72 Lu H. et al. Independent Association between Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: A Systematic Review and Meta-Analysis. Int J Endocrinol 2013; 2013: 124958
  • 73 Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol 2008; 49: 600-607.
  • 74 Lucero D. et al. Pro-inflammatory and atherogenic circulating factors in non-alcoholic fatty liver disease associated to metabolic syndrome. Clin Chim Acta 2011; 412: 143-147.
  • 75 Chiang CH. et al. The severity of non-alcoholic fatty liver disease correlates with high sensitivity C-reactive protein value and is independently associated with increased cardiovascular risk in healthy population. Clin Biochem 2010; 43: 1399-1404.
  • 76 Lizardi-Cervera J. et al. Association among C-reactive protein, Fatty liver disease, and cardiovascular risk. Dig Dis Sci 2007; 52: 2375-2379.
  • 77 Caserta CA. et al. Cardiovascular risk factors, nonalcoholic fatty liver disease, and carotid artery intima-media thickness in an adolescent population in southern Italy. Am J Epidemiol 2010; 171: 1195-1202.
  • 78 Ercin CN. et al. Levels of soluble CD40 ligand and P-Selectin in nonalcoholic fatty liver disease. Dig Dis Sci 2010; 55: 1128-1134.
  • 79 Hui JM. et al. Beyond insulin resistance in NASH: TNF-alpha or adiponectin?. Hepatology 2004; 40: 46-54.
  • 80 Alaaeddine N. et al. TNF-alpha messenger ribonucleic acid (mRNA) in patients with nonalcoholic steatohepatitis. Eur Cytokine Netw 2012; 23: 107-111.
  • 81 Brea A. et al. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol 2005; 25: 1045-1050.
  • 82 Valenti L. et al. Serum ferritin levels are associated with vascular damage in patients with nonalcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2011; 21: 568-575.
  • 83 Sookoian S. et al. Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease. Atherosclerosis 2010; 209: 585-591.
  • 84 Weghuber D. et al. Vascular function in obese children with non-alcoholic fatty liver disease. Int J Pediatr Obes 2011; 6: 120-127.
  • 85 Montecucco F, Mach F. Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology 2009; 48: 11-22.
  • 86 Guarnieri G. et al. Metabolic syndrome and chronic kidney disease. J Ren Nutr 2010; 20 (Suppl. 05) S19-23.
  • 87 Maric-Bilkan C. Obesity and diabetic kidney disease. Med Clin North Am 2013; 97: 59-74.
  • 88 Isomaa B. et al. The metabolic syndrome influences the risk of chronic complications in patients with type II diabetes. Diabetologia 2001; 44: 1148-1154.
  • 89 Chen J. et al. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004; 140: 167-174.
  • 90 Beddhu S. et al. Associations of metabolic syndrome with inflammation in CKD: results From the Third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis 2005; 46: 577-586.
  • 91 Leoncini G. et al. Metabolic syndrome is associated with early signs of organ damage in nondiabetic, hypertensive patients. J Intern Med 2005; 257: 454-460.
  • 92 Tanaka H. et al. Metabolic syndrome and chronic kidney disease in Okinawa, Japan. Kidney Int 2006; 69: 369-374.
  • 93 Chen J. et al. Association between the metabolic syndrome and chronic kidney disease in Chinese adults. Nephrol Dial Transplant 2007; 22: 1100-1106.
  • 94 Iseki K. et al. Changes in the demographics and prevalence of chronic kidney disease in Okinawa, Japan (1993 to 2003). Hypertens Res 2007; 30: 55-62.
  • 95 Zhang L. et al. Metabolic syndrome and chronic kidney disease in a Chinese population aged 40 years and older. Mayo Clin Proc 2007; 82: 822-827.
  • 96 Kawamoto R. et al. An association between metabolic syndrome and the estimated glomerular filtration rate. Intern Med 2008; 47: 1399-1406.
  • 97 Chang IH. et al. Association between metabolic syndrome and chronic kidney disease in the Korean population. Nephrology 2009; 14: 321-326.
  • 98 Jang SY. et al. Chronic kidney disease and metabolic syndrome in a general Korean population: the Third Korea National Health and Nutrition Examination Survey (KNHANES III) Study. J Public Health 2010; 32: 538-546.
  • 99 Jiang L. et al. Metabolic syndrome and chronic kidney disease in a rural Chinese population. Clin Chim Acta 2011; 412: 1983-1988.
  • 100 Lin SJ HY. et al Metabolic Syndrome as an Independent Risk Factor of Chronic Kidney Disease in Southern Taiwan. Acta Nephrologica 2012; 26: 82-88.
  • 101 Leoncini G. et al. Metabolic syndrome and chronic kidney disease in high-risk Italian hypertensive patients: the I-DEMAND study. J Nephrol 2012; 25: 63-74.
  • 102 Alexander MP. et al. Kidney pathological changes in metabolic syndrome: a cross-sectional study. Am J Kidney Dis 2009; 53: 751-759.
  • 103 Lea J. et al. Metabolic syndrome, proteinuria, and the risk of progressive CKD in hypertensive African Americans. Am J Kidney Dis 2008; 51: 732-740.
  • 104 Kovács T VT. et al. Metabolic syndrome and other cardiovascular risk factors associated with the progression of IgA nephropathy. Clin Kidney J. 2012 Epub ahead of print
  • 105 Navaneethan SD. et al. Metabolic Syndrome, ESRD, and Death in CKD. Clin J Am Soc Nephrol 2013; 8: 945-952.
  • 106 Kurella M. et al. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol 2005; 16: 2134-2140.
  • 107 Bonnet F. et al. Waist circumference and the metabolic syndrome predict the development of elevated albuminuria in non-diabetic subjects: the DESIR Study. J Hypertens 2006; 24: 1157-1163.
  • 108 Ninomiya T. et al. Metabolic syndrome and CKD in a general Japanese population: the Hisayama Study. Am J Kidney Dis 2006; 48: 383-391.
  • 109 Rashidi A, Ghanbarian A, Azizi F. Are patients who have metabolic syndrome without diabetes at risk for developing chronic kidney disease? Evidence based on data from a large cohort screening population. Clin J Am Soc Nephrol 2007; 2: 976-983.
  • 110 Kitiyakara C. et al. The metabolic syndrome and chronic kidney disease in a Southeast Asian cohort. Kidney Int 2007; 71: 693-700.
  • 111 Tozawa M. et al. Metabolic syndrome and risk of developing chronic kidney disease in Japanese adults. Hypertens Res 2007; 30: 937-943.
  • 112 Lucove J. et al. Metabolic syndrome and the development of CKD in American Indians: the Strong Heart Study. Am J Kidney Dis 2008; 51: 21-28.
  • 113 Luk AO. et al. Metabolic syndrome predicts new onset of chronic kidney disease in 5,829 patients with type 2 diabetes: a 5-year prospective analysis of the Hong Kong Diabetes Registry. Diabetes Care 2008; 31: 2357-2361.
  • 114 Ryu S. et al. Incidence and risk factors for metabolic syndrome in Korean male workers, ages 30 to 39. Ann Epidemiiol 2007; 17: 245-252.
  • 115 Watanabe H. et al. Metabolic syndrome and risk of development of chronic kidney disease: the Niigata preventive medicine study. Diabetes Metab Res Rev 2010; 26: 26-32.
  • 116 Sun F. et al. Metabolic syndrome and the development of chronic kidney disease among 118 924 non-diabetic Taiwanese in a retrospective cohort. Nephrology 2010; 15: 84-92.
  • 117 Lee CC. et al. Metabolic syndrome loses its predictive power in late-stage chronic kidney disease progression--a paradoxical phenomenon. Clin Nephrol 2011; 75: 141-149.
  • 118 Cuevas-Ramos D. et al. Association of the metabolic syndrome and long-term renal function in kidney donors. Transplant Proc 2011; 43: 1601-1606.
  • 119 Yang T. et al. Impact of metabolic syndrome on the incidence of chronic kidney disease: a Chinese cohort study. Nephrology 2012; 17: 532-538.
  • 120 Cheng HT. et al. Metabolic syndrome and insulin resistance as risk factors for development of chronic kidney disease and rapid decline in renal function in elderly. J Clin Endocrinol Metab 2012; 97: 1268-1276.
  • 121 Cho JA. et al. Metabolic syndrome component combinations and chronic kidney disease: The severance cohort study. Maturitas 2013; 75: 74-80.
  • 122 Leoncini G. et al. Metabolic syndrome and microalbuminuria predict renal outcome in non-diabetic patients with primary hypertension: the MAGIC study. J Hum Hypertens 2012; 26: 149-156.
  • 123 Brantsma AH. et al. Urinary albumin excretion and its relation with C-reactive protein and the metabolic syndrome in the prediction of type 2 diabetes. Diabetes Care 2005; 28: 2525-2530.
  • 124 Halimi JM. et al. Urinary albumin excretion is a risk factor for diabetes mellitus in men, independently of initial metabolic profile and development of insulin resistance. The DESIR Study. J Hypertens 2008; 26: 2198-2206.
  • 125 van der Velde M. et al. Do albuminuria and hs-CRP add to the International Diabetes Federation definition of the metabolic syndrome in predicting outcome?. Nephrol Dial Transplant 2012; 27: 2275-2283.
  • 126 Mutinelli-Szymanski P. et al. Renal resistive index as a new independent risk factor for new-onset diabetes mellitus after kidney transplantation. Transpl Int 2012; 25: 464-470.
  • 127 Viazzi F. et al. Subclinical functional and structural renal abnormalities predict new onset type 2 diabetes in patients with primary hypertension. J Hum Hypertens 2013; 27: 95-99.
  • 128 Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 2004; 15: 2792-2800.
  • 129 Wolf G. et al. Leptin and renal disease. Am J Kidney Dis 2002; 39: 1-11.
  • 130 Hall JE. et al. Mechanisms of hypertension and kidney disease in obesity. Ann NY Acad Sci 1999; 892: 91-107.
  • 131 Puddu P. et al. Relationships among hyperuricaemia, endothelial dysfunction and cardiovascular disease: molecular mechanisms and clinical implications. J Cardiol 2012; 59: 235-242.
  • 132 Nashar K, Fried LF. Hyperuricaemia and the progression of chronic kidney disease: is uric acid a marker or an independent risk factor?. Adv Chronic Kidney Dis 2012; 19: 386-391.
  • 133 Onat A. et al. Serum uric acid is a determinant of metabolic syndrome in a population-based study. Am J Hypertens 2006; 19: 1055-1062.
  • 134 Lohsoonthorn V. et al. Prevalence of hyperuricaemia and its relationship with metabolic syndrome in Thai adults receiving annual health exams. Arch Med Res 2006; 37: 883-889.
  • 135 Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricaemia. Am J Med 2007; 120: 442-447.
  • 136 Sui X. et al. Uric acid and the development of metabolic syndrome in women and men. Metabolism 2008; 57: 845-852.
  • 137 Lim JS. et al. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 2010; 7: 251-264.
  • 138 Seki S. et al. Association of uric acid with risk factors for chronic kidney disease and metabolic syndrome in patients with essential hypertension. Clin Exp Hypertens 2010; 32: 270-277.
  • 139 Liu PW. et al. Serum uric acid and metabolic syndrome in Taiwanese adults. Metabolism 2010; 59: 802-807.
  • 140 Li Q. et al. Serum uric acid level and its association with metabolic syndrome and carotid atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol 2011; 10: 72
  • 141 Kim ES. et al. Serum uric acid level is associated with metabolic syndrome and microalbuminuria in Korean patients with type 2 diabetes mellitus. J Diabetes Complications 2011; 25: 309-313.
  • 142 Meshkani R. et al. The relationship between uric acid and metabolic syndrome in normal glucose tolerance and normal fasting glucose subjects. Acta Diabetol 2011; 48: 79-88.
  • 143 Uaratanawong S. et al. Prevalence of hyperuricaemia in Bangkok population. Clin Rheumatol 2011; 30: 887-893.
  • 144 Wang JY. et al. Predictive value of serum uric acid levels for the diagnosis of metabolic syndrome in adolescents. J Pediatr 2012; 161: 753-756. e2.
  • 145 Rodrigues SL. et al. Gender distribution of serum uric acid and cardiovascular risk factors: population based study. Arq Bras Cardiol 2012; 98: 13-21.
  • 146 Lee JM. et al. Association between serum uric acid level and metabolic syndrome. J Prev Med Public Health 2012; 45: 181-187.
  • 147 Yang T. et al. Uric acid level as a risk marker for metabolic syndrome: a Chinese cohort study. Atherosclerosis 2012; 220: 525-531.
  • 148 Go AS. et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalisation. N Engl J Med 2004; 351: 1296-1305.
  • 149 Koenig W. et al. Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate. Clin Chem 2005; 51: 321-327.
  • 150 Ix JH. et al. Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study. Circulation 2007; 115: 173-179.
  • 151 Lakka HM. et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. J Am Med Assoc 2002; 288: 2709-2716.
  • 152 Martins D. et al. Renal dysfunction, metabolic syndrome and cardiovascular disease mortality. J Nutr Metab 2010;
  • 153 Iwashima Y. et al. Additive interaction of metabolic syndrome and chronic kidney disease on cardiac hypertrophy, and risk of cardiovascular disease in hypertension. Am J Hypertens 2010; 23: 290-298.
  • 154 Agarwal S. et al. The association of chronic kidney disease and metabolic syndrome with incident cardiovascular events: multiethnic study of atherosclerosis. Cardiol Res Pract 2012; 2012: 806102
  • 155 Qing X. et al. Cystatin C and asymptomatic coronary artery disease in patients with metabolic syndrome and normal glomerular filtration rate. Cardiovasc Diabetol 2012; 11: 108
  • 156 Newman DJ. et al. Serum cystatin C measured by automated immunoassay: a more sensitive marker of changes in GFR than serum creatinine. Kidney Int 1995; 47: 312-318.
  • 157 Bokenkamp A. et al. Cystatin C--a new marker of glomerular filtration rate in children independent of age and height. Pediatrics 1998; 101: 875-881.
  • 158 Shlipak MG. et al. Cystatin-C and mortality in elderly persons with heart failure. J Am Coll Cardiol 2005; 45: 268-271.
  • 159 Shlipak MG. et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005; 352: 2049-2060.
  • 160 Stevens LA. et al. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis 2008; 51: 395-406.
  • 161 Satoh-Asahara N. et al. Urinary cystatin C as a potential risk marker for cardiovascular disease and chronic kidney disease in patients with obesity and metabolic syndrome. Clin J Am Soc Nephrol 2011; 6: 265-273.
  • 162 Chuang SY. et al. Hyperuricaemia and increased risk of ischaemic heart disease in a large Chinese cohort. Int J Cardiol 2012; 154: 316-321.
  • 163 Montecucco F, Mach F. Update on therapeutic strategies to increase adiponectin function and secretion in metabolic syndrome. Diabetes Obes Metab 2009; 11: 445-454.
  • 164 Leibowitz A, Schiffrin EL. Immune mechanisms in hypertension. Curr Hypertens Rep 2011; 13: 465-472.
  • 165 Calle MC, Fernandez ML. Inflammation and type 2 diabetes. Diabetes Metab 2012; 38: 183-191.
  • 166 Onat A, Hergenc G. Low-grade inflammation, and dysfunction of high-density lipoprotein and its apolipoproteins as a major driver of cardiometabolic risk. Metabolism 2011; 60: 499-512.
  • 167 Vazzana N. et al. Determinants of increased cardiovascular disease in obesity and metabolic syndrome. Curr Med Chem 2011; 18: 5267-5280.