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  • There is no single cause of chronic kidney disease. A high association, however, has been found between hypertension, obesity, and insulin resistance with the development of renal failure [5, 12, 20, 24, 30, 28, 31, 39, 46, 67, 72, 73].
  • Lifestyle related factors including smoking, alcohol abuse, and hypokinesis lead to hypertension, hyperlipidemia, and obesity and are important risk factors for cardiovascular disease, CKD, and ESRD [25]
  • Metabolic Syndrome, defined as the combination of abdominal obesity, insulin resistance, high triglycerides, low HDL (good) cholesterol, hypertension, and chronic inflammation is highly associated with the prevalence of chronic kidney disease [5, 39, 62, 66].
  • 47 million Americans have metabolic syndrome [5].
  • Hypokinesis has also been implicated in the development of kidney disease. Furthermore, animal studies have shown a renal-protective effect of exercise programs.
  • The mechanisms by which these diseases lead to renal damage are explored below.
    • Association between Obesity and CKD
      • Hall et al. (2004) [20] argue the two leading causes of CKD and ESRD are diabetes and hypertension. They point out, however, that obesity is inextricably linked to both factors (see image below). Put together, obesity, diabetes, and hypertension are three of the key players in metabolic syndrome. Metabolic syndrome leads to changes within the kidney leading to hypertension. These include:
        • Increased plasma renin activity and activation of the renin-angiotensin-aldosterone system (RAAS)
        • Impaired renal natriueris: causing sodium retention and volume expansion
        • Increased renal vasodilation
        • Increased sympathetic nervous system (SNS) stimulation
      • These changes eventually lead to increased renal bloodflow, glomerular filtration rate (GFR), and blood pressure causing glomerular injury and leading to glomerulosclerosis and loss of functional nephrons.
      • Obesity is linked to the development of glomerulomegaly and focal segment glomerulosclerosis [28]

      Click image for larger view

      Image copied from: Hall et al. (2004) [20]

      • Zhang et al. (2005) describe the increased renal blood flow, GFR, SNS, and RAAS as a compensatory mechanism in attempt to maintain sodium balance. Glomerular hyperfiltration, however, causes proteinuria/microalbuminuria and progressive renal injury.
      • There is some debate about the role of hypertension in CKD/ESRD. While progressive renal failure is linked to hypertension, it has a much higher correlation to insulin resistance and obesity [30]. Kincaid-Smith (2004) [30, 31] argues that glomerulosclerosis caused by obesity is the main factor in renal failure.
      • Kambahm et al. (2000) [28] describe obesity-related glomerulopathy (ORL) as an emerging and distinct clinical manifestation of renal dysfunction.
      • Lifestyle factors involved in metabolic syndrome including smoking, alcohol, and hypokinesis are known to lead to diabetes, hypertension, hyperlipidemia, and obesity and are important risk factors for developing cardiovascular disease, CKD, and ESRD (see image below) [5, 25, 39, 62]. Diabetes, hypertension, hyperlipidemia, and obesity are all independent risk factors for CKD and are all associated with decreased renal function [5, 21, 25].

      Click image for larger view

      Image copied from Chen et al. (2004) [5]

      • Despite the close association between metabolic syndrome and risk for developing renal damage, it remains difficult to pinpoint any individual factor as a main cause of CKD. This is thought to be due to the close relationship between those constituents [39].
    • Links between hypertension, insulin resistance, and CKD
      • Increased insulin resistance is also known to damage the kidney. Dengel et al. (1996) [12] proposed two mechanisms for this:
        1. Insulin resistance leads to glomerular hemodynamic changes leading to increased renal tubular sodium and water reabsorption.
        2. Hyperinsulinemia activates SNS activity, simulating renal vasoconstriction
      • These mechanisms lead to increases in GFR and eventually increases in glomerular injury.
      • In hypertensive patients, the additional symptoms of metabolic syndrome, including obesity and insulin resistance, lead to glomerulosclerosis and progression of renal disease [31].

      Click image for larger view

      image copied from: www.pathguy.com

      This kidney bears fhe finely granular surface typical of people with chronic hypertension. As individual nephrons are replaced by scar tissue, the contraction of the scar produces the "sandpaper kidney" effect.

    • Hypokinesis and CKD/ESRD
      • In addition to the link between metabolic syndrome and kidney disease, hypokinesis has also been implicated as a cause.
      • Zorbas et al. (1995) [76] show how hypokinesis causes detrimental renal changes including:
        • increases in urinary and plasma concentrations of electrolytes
        • decrease in GFR
        • decrease in renal blood flow
      • Chronic exercise has been shown to provide renal-protective effects in hypertensive rats (Kohzuki et al., 2001 [33]).
        • Chronic exercise significantly attenuated the incease in proteinuria and significantly protected against increases in glomerulosclerosis.
      • De Moraes et al. (2005) [10] also found a renal-protective effect of exercise in non-diabetic, non-hypertensive rabbits.
        • Exercise training gave rabbits exposed to high glucose concentrations a protective effect, thought to be due to increased levels of nitric oxide, a vasodilator.
      • Simsek et al. (2005) [66] describes a renal-protective effect of exercise combined with a vitamin C and E regimen in diabetic rats.
        • Exercise, in addition to vitamin C and E supplementation decreased albumin and total protein levels and elevated plasma creatinine and urea levels, indicating enhanced renal function. This was thought to be due to prevention of free radical generation and may influence the progression of oxidative renal damage.
      • These results have yet to be replicated in human studies. They do, however, provide evidence of a protective and disease preventative effect of exercise.

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