Urinary extracellular vesicles detect altered renal circulation in human obesity

Aim: Obesity may induce renal microvascular injury, particularly in peritubular capillaries (PTCs). Early detection of these changes may help patient management. We tested the hypothesis that levels of PTC-derived urinary extracellular vesicles (uEVs) reflecting early renal microvascular alterations would be elevated in obese individuals with preserved kidney function.

Methods: Urinary samples were collected from 22 obese and 11 lean subjects. uEVs were characterized using flow cytometry for markers of PTC (CD31, plasmalemma vesicle-associated protein [PLVAP], and CD144), angiogenesis (delta-like-ligand-4 [DLL4]), and inflammation (monocyte chemoattractant protein-1 [MCP-1]). For confirmation, PTC density was quantified and correlated with clinical parameters in kidney biopsies from additional matched groups.

Results: Obese individuals had higher body mass index (BMI), glucose, insulin, urinary protein, and urinary MCP-1 levels than lean controls (P < 0.05), indicating metabolic and inflammatory changes, despite no significant difference in serum creatinine or estimated glomerular filtration rate (eGFR). They also exhibited elevated levels of CD31^-/PLVAP⁺/CD144^- PTC-derived uEVs expressing DLL4⁺ and/or MCP-1⁺ (P < 0.05 each). Levels of angiogenic PTC-derived DLL4⁺ uEVs correlated with BMI and systemic insulin, vascular endothelial growth factor-A, and angiopoietin-2 levels in our cohorts, whereas MCP-1⁺ uEVs derived from inflamed PTC correlated with BMI, glucose, blood pressure, and urinary neutrophil gelatinase-associated lipocalin. PTC density was also increased in kidney biopsies from obese individuals, correlating with BMI and glucose.

Conclusion: DLL4⁺/MCP-1⁺ PTC-derived uEVs levels reflecting early renal microvascular changes are elevated in obese individuals, despite preserved kidney function. These findings may indicate that microvascular remodeling is dissociated from renal dysfunction in patients with obesity.