In-Depth Review of Metabolic SyndromeThe metabolic syndrome and chronic kidney disease
Section snippets
Epidemiology
According to the American Heart Association, individuals with the metabolic syndrome (MetS) show 3 or more of the following conditions: (1) central or abdominal obesity (by waist circumference); (2) elevated triglyceride levels; (3) low high-density lipoproteins; (4) hypertension; and (5) elevated fasting glucose.1 The International Diabetes Federation criteria are similar, but more specific regarding the definition of central obesity categorized by country or ethnic group.2 A waist
Microvascular Remodeling
We and others have observed that in humans and animals, MetS induced renal parenchymal damages such as tubular atrophy and interstitial fibrosis.9, 15 Microvascular remodeling manifesting as arterial and arteriolar sclerosis within kidney lesions in patients with MetS have also been observed,9 and ultrasound revealed elevated resistive indices in intrarenal interlobar arteries,16, 17 indicating vasoconstriction and microvascular remodeling. Direct evidence for the effects of MetS on
Inflammation and Insulin Resistance
Low-grade chronic inflammation is a hallmark of MetS32 and its severity seems to depend on the prevalent number of components of MetS.33 In fact, the pivotal role of metabolically induced inflammation is underscored by the proposed term “metaflammation.”34
Animal studies have highlighted the kidney as a target organ often involved in the inflammatory response.15, 35 A 16-week MetS diet in pigs elevated the levels of circulating oxidized low-density lipoprotein and soluble (s)E-selectin that
Obesity
Substantial evidence has shown that obesity directly influences renal hemodynamics and structure. A 1-month high-fat diet promptly increases the extracellular fluid and causes a shift in sodium balance.74 Elevated aldosterone levels due to activation of the renin-angiotensin-aldosterone system and increased sympathetic activity in obesity are likely the major culprits that promote sodium retention75, 76 by increasing tubular reabsorption. Elevated salt reabsorption at the segment proximal to
Oxidative Stress and Mitochondrial Dysfunction
Oxidative stress, characterized by elevated reactive oxygen species (ROS) levels, causes damage to proteins, lipids, and DNA, and has been proven to play an important role in MetS.84, 85 In humans, lipid peroxidation, represented by plasma thiobarbituric acid reactive substance and urinary 8-epi-prostaglandin-F2α, correlates with BMI and waist circumference.86
A major source of ROS MetS is the NADPH oxidase (NOX) family of enzymes, and accumulating evidence has shown that NOX, particularly NOX1,
Hypertension
Hypertension is an important hallmark of MetS and a common cause of kidney disease. Several mechanisms link hypertension to MetS, among which obesity is a major contributor. Obesity alone is associated with an increase in the severity of hypertension and the number of required antihypertensive medications, and impedes achieving blood pressure control.123 The direct link between hypertension and dyslipidemia-induced obesity was shown in animal studies. In rabbits, blood pressure rises by 6%
Uric Acid (UA)
Hyperuricemia is commonly observed and strongly associated with MetS. The prevalence of MetS increased from 5.9% for UA levels under 6 mg/dL to 59.0% for levels 10 mg/dL or greater,137 and hyperuricemia correlates with elevated fasting insulin level.138 Moreover, based on a recent systemic review including 13 studies containing 190,718 participants, elevated serum UA levels showed an increased risk for development of chronic renal dysfunction.139
Animal studies have revealed that hyperuricemia
Conclusion
Clearly, the impact of the MetS on the kidney is multifactorial. The current nutritional habits and lifestyles of many modern human subjects favor metabolic overload, which underpins chronic metabolic diseases. The kidney is a target organ susceptible to MetS (Fig 2); yet, the appropriate treatment strategy for MetS-associated kidney disease remains to be identified. As MetS and type-2 diabetes share some common pathways (eg, hyperfiltration, oxidative stress, etc.), MetS-associated kidney
Acknowledgment
Conflicts of Interest: All authors have read the journal's policy on disclosure of potential conflicts of interest and have none to declare. All authors have read the journal's authorship agreement and that the manuscript has been reviewed by and approved by all named authors.
This work was partly supported by NIH Grants DK104273, DK102325, DK73608, DK100081, and HL123160.
References (144)
- et al.
Kidney pathological changes in metabolic syndrome: a cross-sectional study
Am J Kidney Dis
(2009) - et al.
Impact of metabolic syndrome on graft function and survival after cadaveric renal transplantation
Am J Kidney Dis
(2006) - et al.
Metabolic syndrome is associated with impaired long-term renal allograft function; not all component criteria contribute equally
Am J Transplant
(2004) - et al.
Rev Esp Cardiol
(2011) - et al.
Intra-renal hemodynamics and carotid intima-media thickness in the metabolic syndrome
Diabetes Res Clin Pract
(2009) - et al.
Oxidative stress in angiogenesis and vascular disease
Blood
(2014) - et al.
Effects of insulin on rat renal microvessels: studies in the isolated perfused hydronephrotic kidney
Kidney Int
(1997) - et al.
Perirenal fat promotes renal arterial endothelial dysfunction in obese swine through tumor necrosis factor-alpha
J Urol
(2016) - et al.
Glomerular-specific protein kinase C-beta-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity
Kidney Int
(2011) - et al.
Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy
Kidney Int
(2001)