Elsevier

Translational Research

Volume 183, May 2017, Pages 14-25
Translational Research

In-Depth Review of Metabolic Syndrome
The metabolic syndrome and chronic kidney disease

https://doi.org/10.1016/j.trsl.2016.12.004Get rights and content

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including insulin resistance (IR), dyslipidemia, and hypertension, which may also foster development of chronic kidney disease. The mechanisms of MetS-induced kidney disease are not fully understood. The purpose of this review is to summarize recent discoveries regarding the impact of MetS on the kidney, particularly on the renal microvasculature and cellular mitochondria. Fundamental manifestations of MetS include IR and adipose tissue expansion, the latter promoting chronic inflammation and oxidative stress that exacerbate IR. Those in turn can elicit various kidney injurious events through endothelial dysfunction, activation of the renin-angiotensin-aldosterone system, and adipokine imbalance. Inflammation and IR are also major contributors to microvascular remodeling and podocyte injury. Hence, these events may result in hypertension, albuminuria, and parenchymal damage. In addition, dyslipidemia and excessive nutrient availability may impair mitochondrial function and thereby promote progression of kidney cell damage. Elucidation of the link between MetS and kidney injury may help develop preventative measures and possibly novel therapeutic targets to alleviate and avert development of renal manifestations.

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.

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