*1.2. Pathology*

Obesity-Related Glomerulopathy

Physical compression of the kidneys from accumulation of adipose tissue around the organs emphasizes the possible role of visceral obesity in the development of renal disease. Deposition of extracellular matrix throughout the renal medulla is expanded and the tissue surrounding the ducts of Bellini at the vascular pole tends to prolapse. Increased numbers of interstitial cells and material rich in lipids and proteoglycans press the renal parenchyma towards the pole of the kidney resulting in the formation of round-shaped, enlarged kidney in obese subjects. Renal compression affects both vascular (the vasa recta) and tubular (the Henle's loops) elements causing activation of the RAS and increased sodium reabsorption [32–34].

The primary histologic features are few lesions of focal-segmental glomerulosclerosis, profound glomerulomegaly due to glomerular hyalinosis and fibrosis, as well as lipid accumulation in the glomeruli and adhesion to Bowman's capsule [35,36]. Altered fat metabolism in the kidneys induces lipid accumulation, suggesting that high fat intake may have a direct lipotoxicity effect in the kidneys. Ectopic lipid accumulation in the kidneys induces structural and functional changes of the mesangial cells, podocytes, and proximal tubular cells. Perivascular fat in the renal sinus appears to participate in vascular function, modifying the blood flow in the underlying arteries. Obesity increases renal mass and glomerular diameter. Podocytes need to enlarge their processes to cover an expanded area that cause podocyte detachment, loss in protein selectivity, formation of denuded areas that trigger matrix deposition, and podocyte damage.

Glomerular changes in obesity-induced renal injury are unmatched to those of diabetic nephropathy, due to the lower severity in the first in the mesangial space changes. Patients with diabetic nephropathy more frequently have albuminuria, proteinuria, and ESKD compared to obesity induced nephropathy where the results are slower and the progression to end renal disease is less frequent. Other causes of renal injury, apart from high fat intake, could include overexpression of Ang II with a consequent increase in proliferative factors such as transforming growth factor (TGF-β) and plasminogen activator inhibitor and insulinemia giving genesis to cell growth. Hyperfiltration because of sodium reabsorption, increase the blood flow to the kidney causing gradual glomerular wall sclerosis due to physical shear stress and a dangerous circle starts in which nephrons are injured leading to their apoptosis, sodium retention attenuates, while blood pressure increases to maintain sodium balance. Proteinuria of nephrotic range is rare among the obese, but albuminuria may exist [35,37]. These findings suggest that obesity-related renal damage should be defined as a special form of focal-segmental glomerulosclerosis slowly progressing to end stage renal disease. Patients with the metabolic syndrome have high prevalence of microvascular disease manifested as tubular atrophy, interstitial fibrosis, and arterial sclerosis [38].
