Severe obesity associates with maladaptive glomerular haemodynamics clustered with insulin resistance and endothelial dysfunction

ABSTRACT Background Obesity is a leading risk factor for chronic kidney disease, with glomerular hyperfiltration as one of its earliest manifestations. However, absolute glomerular filtration rate (GFR) does not distinguish well between a pressure-driven hyperfiltration and the physiological forms. Insulin resistance and endothelial dysfunction have been proposed as key correlates of maladaptive renal haemodynamics, but their interplay remains unclear. Methods Cross-sectional pilot study involving 27 adults with severe obesity (mean body mass index of 43.9 kg/m²). Measured GFR (mGFR) was assessed by iohexol plasma clearance and effective renal plasma flow (ERPF) by 123I-ortho-iodohippurate clearance. A hyperfiltration index (P-score) was derived as the standardized difference between filtration fraction and effective renal plasma flow with higher values reflecting a maladaptive phenotype. Endothelial function was assessed by brachial artery flow-mediated dilation and insulin sensitivity by oral glucose insulin sensitivity. Results Participants were stratified into tertiles of P-score. Across tertiles, mGFR did not differ, but ERPF declined (756 ± 113 vs 505 ± 130 mL/min, P = .001) and of filtration fraction increased (16 ± 3% vs 26 ± 5%, P = .001) from the lowest to the highest tertile. Insulin sensitivity significantly decreased with higher P-score (384 ± 50 vs 308 ± 33, P = .019). Endothelial function was reduced in the highest vs lowest tertile (3.44 ± 1.49 vs 6.21 ± 1.76%, P = .014), while responses to nitroglycerin did not differ. In univariate analyses, P-score was inversely associated with insulin sensitivity (r = –0.36, P = .036) and endothelial dysfunction (r = –0.40, P = .022), whereas measured mGFR showed no associations. In multivariable models, the link between P-score and insulin sensitivity remained significant after adjustment. Conclusion A maladaptive phenotype characterized by elevated filtration fraction relative to renal plasma flow clustered with insulin resistance and endothelial dysfunction, whereas mGFR alone failed to capture these relationships. Comprehensive haemodynamic profiling may help to refine risk stratification in obesity.