The metabolic syndrome is defined as a syndrome of truncal obesity, insulin resistance, elevated BP, hypertriglyceridemia, and hyperuricemia (Table 1) (1–4). The prevalence of metabolic syndrome has been increasing at an alarming rate throughout the world. In the United States, the current prevalence is estimated to be 27% (29% in women and 25.2% in men) (5); in Europe, it is 15.7% in men and 14.2% in women (6); and in China it is 13.7% (9.8% in men and 17.8% in women) (7).
The presence of metabolic syndrome is strongly associated with the development of diabetes (8), hypertension (9), cardiovascular disease (10), and all-cause mortality (11). However, recent studies have emphasized that metabolic syndrome also is both associated with and a risk for the development of chronic kidney disease (CKD). For example, in a recent study, the metabolic syndrome was found to be strongly correlated with CKD (defined as GFR <60 ml/min) and microalbuminuria, and the risk increased progressively with the number of criteria constituting the syndrome (12). In another study of Native Americans without diabetes, a positive relationship was identified between microalbuminuria and features of the metabolic syndrome (13).
The mechanism(s) by which metabolic syndrome might accelerate renal disease remains unclear. One possibility relates to the presence of obesity itself. Obesity has been found to be an independent risk factor for CKD (12,14), and treating obesity might stabilize renal function (15) or reverse early hemodynamic abnormalities and glomerular dysfunction (16). Obesity has been associated with a type of focal segmental glomerulosclerosis (FSGS) called “obesity-related glomerulopathy” (17). Hall et al. (18) proposed that lipid deposition in the inner medulla increases intrarenal pressure, leading to decreased tubular flow, which results in increased sodium reabsorption in Henle loop, volume expansion, and the development of systemic hypertension. Obesity also increases the risk factor for diabetes and hypertension and has been shown to lead to glomerular hypertension and hyperfiltration (18). The metabolic syndrome also is associated with the release of inflammatory cytokines and the presence of endothelial dysfunction and oxidative stress (19), all which could contribute to the development of glomerulosclerosis. Insulin resistance also may have a direct role in the pathogenesis of renal injury, as a consequence of stimulating the sympathetic nervous system and the renin-angiotensin-aldosterone system (20). Dyslipidemia, which is a feature of the metabolic syndrome, may induce toxic and inflammatory tubulointerstitial injury (21). Finally, the metabolic syndrome is also associated with an elevated serum urine acid, which has also been implicated in renal disease (see below). The rise in metabolic syndrome indirectly may be a major contributor to the general rise in renal disease that has been observed throughout the world in the past few decades.
Uric Acid, Fructose Intake, and Metabolic Syndrome
In the past few years, there has been increasing evidence that hyperuricemia may be a true cardiovascular and renal risk factor (reviewed in reference [22]). Hyperuricemia predicts the development of hypertension (23), metabolic syndrome (23), diabetes (24), stroke (25), and cardiovascular events (25). Epidemiologic studies also have found that hyperuricemia is an independent risk factor for renal dysfunction in the normal population (26) and in patients with hypertension (27), diabetes (28), and CKD (29). Mild hyperuricemia in normal rats induces systemic hypertension, renal vasoconstriction, glomerular hypertension and hypertrophy, and tubulointerstitial injury independent of intrarenal crystal formation (30–32). Hyperuricemia also has been found to accelerate renal disease in the remnant kidney model (33) and to accelerate experimental cyclosporine nephropathy (34). The main pathophysiologic mechanism by which uric acid causes these conditions involves an inhibition of endothelial nitric oxide bioavailability (35), activation of the renin angiotensin system (30), and direct actions on endothelial cells and vascular smooth muscle cells (36). The importance of these pathways is suggested by a recent prospective study in which lowering uric acid in individuals with hyperuricemia and renal dysfunction was associated with improved BP control and slower progression of renal disease (37).
Recently, uric acid also was found to have a causal role in the metabolic syndrome that was induced experimentally by fructose (38). Fructose rapidly raises uric acid as a consequence of activation of fructokinase with ATP consumption, intracellular phosphate depletion, and stimulation of AMP deaminase (39). Lowering uric acid in fructose-fed rats ameliorates much of the metabolic syndrome, including a reduction in BP, serum triglycerides, hyperinsulinemia, and weight gain (38). The rise in uric acid after fructose ingestion likely has a significant role in inducing insulin resistance via its effect to lower nitric oxide (35) and also possibly by a direct effect of uric acid on the adipocytes (Sautin et al., submitted).
In turn, fructose intake correlates well with the recent rise in the epidemic of metabolic syndrome, diabetes, hypertension, and kidney disease (40). Fructose constitutes 50% of table sugar and also is a major component in high-fructose corn syrup, which is used in the United States as a sweetener. Intake of fructose has increased markedly in the past few decades and correlates with the rising rates of metabolic syndrome. This leads to the hypothesis that fructose intake may be a novel mediator of the epidemic of renal disease. Future studies are planned to determine whether fructose intake may be increased in patients with progressive renal disease, particularly those with features of metabolic syndrome. The possibility that fructose may cause similar hemodynamic changes in the kidneys as uric acid also will be investigated, as well as studies to determine whether fructose can accelerate renal disease in experimental animals. A better understanding of the role of fructose and uric acid in the pathogenesis of the renal disease might make a major contribution to our understanding of the underlying mechanisms of the current epidemic.
;)
Table 1: Definition of metabolic syndrome by WHO, NCEP ATP III, and IDFa
This study was supported by National Institutes of Health grants DK-52121, HL-68607, and HL-79352.
References
1. Reaven GM: Role of insulin resistance in human disease (syndrome X): An expanded definition. Annu Rev Med 44 : 121 –131, 1993
2. World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Report of a WHO Consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Available at:
http://whqlibdoc.who.int/hq/1999/who_ncd_ncs_99.2.pdf. Accessed June 4, 2006.
3. National Cholesterol Education Program: Third report of the National Cholesterol Education Program (NCEP) on Detection and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106 : 3143 –3421, 2002
4. Alberti KGM, Zimmet P, Shaw J: Metabolic syndrome: A new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med 23 : 469 –480, 2006
5. Ford ES, Giles WH, Mokdad AH: Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care 27 : 2444 –2449, 2004
6. Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K; DECODE Study Group: Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 164 : 1066 –1076, 2004
7. Gu D, Reynolds K, Wu X, Chen J, Duan X, Reynolds RF, Whelton PK, He J; InterASIA Collaborative Group: Prevalence of the metabolic syndrome and overweight among adults in China. Lancet 365 : 1398 –1405, 2005
8. Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA: Metabolic syndrome and development of diabetes mellitus: Application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol 156 : 1070 –1077, 2002
9. Saad MF, Rewers M, Selby J, Howard G, Jinagouda S, Fahmi S, Zaccaro D, Bergman RN, Savage PJ, Haffner SM: Insulin resistance and hypertension. Hypertension 43 : 1324 –1331, 2004
10. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L: Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24 : 683 –689, 2001
11. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288 : 2709 –2716, 2002
12. Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J: The metabolic syndrome and chronic kidney disease in US adults. Ann Intern Med 140 : 167 –174, 2004
13. Hoehner CM, Greenlund KJ, Rith-Najarian S, Casper ML, McClellan WM: Association of the insulin resistance syndrome and microalbuminuria among nondiabetic native Americans. The Inter-Tribal Heart Project. J Am Soc Nephrol 13 : 1626 –1634, 2002
14. Hsu CY, McCulloch CE, Iribarren C, Darbinian J, Go AS: Body mass index and risk for end-stage renal disease. Ann Intern Med 144 : 21 –28, 2006
15. Agnani S, Vachharajani VT, Gupta R, Atray NK, Vachharajani TJ: Does treating obesity stabilize chronic kidney disease? BMC Nephrol 6 : 7 , 2005
16. Chagnac A, Weinstein T, Herman M, Hirsh J, Gafter U, Ori Y: The effects of weight loss on renal function in patients with severe obesity. J Am Soc Nephrol 14 : 1480 –1486, 2003
17. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD: Obesity-related glomerulopathy: An emerging epidemic. Kidney Int 59 : 1498 –1509, 2001
18. Hall JE, Crook ED, Jones DW, Wofford MR, Dubbert PM: Mechanisms of obesity-associated cardiovascular and renal disease. Am J Med Sci 324 : 127 –137, 2002
19. Wisse BE: The inflammatory syndrome: The role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 15 : 2792 –2800, 2004
20. Sowers JR: Insulin resistance and hypertension. Am J Physiol Heart Circ Physiol 286 : H1597 –H1602, 2004
21. Sun L, Halaihel N, Zhang W, Rogers T, Levi M: Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus. J Biol Chem 277 : 18919 –18927, 2002
22. Nakagawa T, Kang DH, Feig D, Sanchez-Lozada LG, Srinivas TR, Sautin YY, Ejaz AA, Segal MS, Johnson RJ: Unearthing uric acid: An ancient factor with recently found significance in renal and cardiovascular disease. Kidney Int 69 : 1722 –1725, 2006
23. Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML: Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension 42 : 474 –480, 2003
24. Nakanishi N, Okamoto M, Yoshida H, Matsuo Y, Suzuki K, Tatara K: Serum uric acid and risk for development of hypertension and impaired fasting glucose or type 2 diabetes in Japanese male office workers. Eur J Epidemiol 18 : 523 –530, 2003
25. Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM: Uric acid is a risk factor for myocardial infarction and stroke: The Rotterdam study. Stroke 37 : 1503 –1507, 2006
26. Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S: Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res 24 : 691 –697, 2001
27. Segura J, Campo C, Ruilope LM: How relevant and frequent is the presence of mild renal insufficiency in essential hypertension? J Clin Hypertens 4 : 332 –336, 2002
28. Tseng CH: Correlation of uric acid and urinary albumin excretion rate in patients with type 2 diabetes mellitus in Taiwan. Kidney Int 68 : 796 –801, 2005
29. Ohno I, Hosoya T, Gomi H, Ichida K, Okabe H, Hikita M: Serum uric acid and renal prognosis in patients with IgA nephropathy. Nephron 87 : 333 –339, 2001
30. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ: Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 38 : 1101 –1106, 2001
31. Nakagawa T, Mazzali M, Kang D-H, Kanellis J, Watanabe S, Sanchez-Lozada LG, Rodriguez-Iturbe B, Herrera-Acosta J, Johnson RJ: Hyperuricemia causes glomerular hypertrophy in the rat. Am J Nephrol 23 : 2 –7, 2003
32. Sanchez-Lozada LG, Tapia E, Santamaria J, Avila-Casado C, Nepomuceno T, Rodriguez-Iturbe B, Johnson RJ, Herrera-Acosta J: Mild hyperuricemia induces severe cortical vasoconstriction and perpetuates glomerular hypertension in normal rats and in experimental chronic renal failure. Kidney Int 67 : 237 –247, 2005
33. Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, Truong L, Harris R, Johnson RJ: A role for uric acid in the progression of renal disease. J Am Soc Nephrol 13 : 2888 –2897, 2002
34. Mazzali M, Kim YG, Suga S, Gordon KL, Kang DH, Jefferson JA, Hughes J, Kivlighn SD, Lan HY, Johnson RJ: Hyperuricemia exacerbates chronic cyclosporine nephropathy. Transplantation 71 : 900 –905, 2001
35. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ: Hyperuricemia induces endothelial dysfunction. Kidney Int 67 : 1739 –1742, 2005
36. Kang D-H, Park SK, Lee IK, Johnson RJ: Uric acid induced C-reactive protein (CRP) expression: Implication on cell proliferation and nitric oxide production in human vascular cells. J Am Soc Nephrol 16 : 3553 –3562, 2005
37. Siu YP, Leung KT, Tong MKH, Kwan TH: Use of allopurinol in slowing the progression of renal disease through its ability in lowering serum uric acid level. Am J Kidney Dis 47 : 51 –59, 2006
38. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ: A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290 : F625 –F631, 2006
39. Hallfrisch J: Metabolic effects of dietary fructose. FASEB J 4 : 2652 –2660, 1990
40. Nakagawa T, Tuttle KR, Short RA, Johnson RJ: Fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Clin Pract Nephrol 1 : 80 –86, 2005
