B. Inflammation

Chronic low-grade inflammation develops locally in the expanding adipose cells from macrophage but becomes systemic through the release of pro-inflammatory mediators that include cytokines into the blood stream. Elevated levels of free fatty acids (FFAs) in obese individuals may enhance vascular a-adrenergic sensitivity, inhibit Na+, K+-ATPase and the sodium pump increasing vascular smooth muscle tone and vascular resistance, activate epidermal growth factor receptor, and produce reactive oxygen species and protein kinase C. A variety of biologically active cytokines are produced in adipose cells, including reactive oxygen species, proinflammatory and inflammatory molecules (interleukin-1β, interleukin-6, tumor necrosis factor-α, C-reactive protein), angiogenetic factors (vascular

endothelial growth factor), hemostasis modulating compounds (plasminogen activator inhibitor-1, thromboxane A2), acute phase reaction proteins (serum amyloid A proteins, C-reactive protein), and activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and IκB kinase (IKK), pathways that promote endothelial dysfunction and microvascular disease [33]. Different pathophysiological mechanisms may contribute to the development of CKD from gut microbiota dysbiosis such as production of uremic toxins mainly trimethylamine-N-oxide (TMAO), reduced prophylactic short-chain fatty acids, enhanced inflammation and immune response, reduced nitric oxide (NO), and peptides that block the angiotensin-I converting enzyme [41].

C. Hormones

Insulin resistance induces glomerular hyperfiltration, endothelial dysfunction, increased vascular permeability, angiogenesis, and other pathways implicated in microvascular damage that is associated with albuminuria [42]. Hyperglycemia activates pathways that increase production of advanced glycation end-products (AGEs), activate protein kinase C isoforms, and increase transforming growth factor β that enhances extracellular matrix production by mesangial cells inducing renal fibrosis [43]. Podocytes block proteinuria through arrangement of actin cytoskeleton in their foot processes. Decreased podocyte number and podocyte foot process effacement have been reported in diabetic patients with early phases of kidney damage. Insulin action in podocytes is critical for the glomerular function and structure affecting morphology, cytoskeleton remodeling, and finally their survival [44].

Leptin is a small peptide hormone that is produced in adipose tissue and increases in the blood of obese subjects. The circulating leptin associates with adipose tissue mass and regulates food intake through its hypothalamic actions that release other neurotransmitters. Leptin can modify insulin actions, induce angiogenesis, reduce endothelial NO synthase, and interact with the immune system. Leptin is cleared by the kidney and is increased in patients with chronic renal failure associated with anorexia and weight loss in ESKD patients. Leptin triggers glomerular endothelial cells secretion of TGF-beta, to which sensitized mesangial cells may respond inducing development of focal glomerulosclerosis and proteinuria [45]. Additional effects of leptin on the kidney include natriuresis, increased sympathetic nervous activity, and stimulation of reactive oxygen species [33].

Adiponectin is an adipose tissue derived peptide hormone, reduced in obese subjects, that acts as lipolytic factor and regulates insulin sensitivity. Adiponectin prevents the atherogenic process by inhibiting foam-cell formation. Adiposity is characterized by adiponectin deficiency. Plasma adiponectin levels are inversely related to insulin levels. Adiponectin knockout mice demonstrate a diet dependent insulin resistance and atherogenesis [33]. Adiponectin increases AMPK activity, reducing podocyte permeability [46,47]. Finally, resistin, an inflammatory adipokine produced by the monocyte macrophage cells, is increased in patients with low GFR [48]. In adults with hypertension and diabetes, circulating resistin levels were associated with reduced estimated glomerular filtration rate and albuminuria [49].
