*1.3. Mechanisms*

The mechanisms of structural abnormalities of CKD are related to the obesitycomorbidities, i.e., hypertension, insulin resistance, type 2 diabetes, and atherogenic dyslipidemia, that contribute to renal damage through mechanisms that include inflammation, oxidative stress, RAAS upregulation, increased SNS activity, and endothelial dysfunction that finally induce renal damage [39], Figure 1.

A. Hemodynamics

Activation of the sympathetic nervous system (SNS) has been thought to play an important role in the pathogenesis of hypertension and CKD among obese individuals [40]. Plasma renin activity displayed significant increase in obesity and local perivascular adipose tissue angiotensin II is also increased [33]. Angiotensin II raises the efferent arteriole tone in the glomerulus, production of TGF-beta, fibrosis, and apoptosis of the podocytes. In the early stages of kidney damage associated to obesity, e-GFR is increased due to the hyperperfusion from volume overload. Intrarenal increased physical forces, generating from fat accumulation around and into the renal medulla, diminish flow rate of the filtrate at the loop of Henle and sodium retention is observed [33]. These early changes can be reverted by weight loss, salt restriction, and renin-angiotensin system blockade.

**Figure 1.** Mechanisms of obesity induced renal damage. Modified from Kotsis V et al., J Hypertens. 2018 Jul; 36(7):1427–1440.
