#174 Sex-based differences in glomerular lesions linked to intrarenal lipid accumulation

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Abstract Background and Aims Women show a slower progression of chronic kidney disease and exhibit different responses to treatment compared to men. With the advent of artificial intelligence (AI) and deep learning, novel approaches are emerging in pathology to identify and quantify renal injury patterns. This study aims to identify and quantify glomerular lesions in metabolic diseases based on sex, using a semantic segmentation model and a deep neural network architecture. Method A total of 24 ApoE−/− mice (12 males and 12 females) aged 8 weeks, were placed on a hypercholesterolemic diet (1.25% cholesterol and 40% of energy from lipids) for 10 weeks. Subsequently, the animals received either enalapril (5 mg/kg/day, subcutaneous) or PBS (control) for an additional 14 weeks. A third group was administered angiotensin2 with an osmotic pump (6 mcg/kg/min, for 2 weeks) to investigate angiotensin2-induced lesions. At 22 weeks, all animals were sacrificed. Blood pressure (BP) was recorded using a tail sphygmomanometer (BP-2000, NIBP LE5001, PANLAB) at the start and end of treatment. Cholesterol, creatinine, and proteinuria were quantified. Kidneys were stained with Masson's trichrome and imaged using a 3D Histech P250 scanner. Glomerular foam cells and parietal epithelial cells (PECs) were assessed. Additional kidney sections were stained with F4/80 and anti-NF-kB to evaluate inflammation. Activated PECs were quantified based on morphology. Image analysis and lesion quantification were performed using QuPath v 0.4.2 software. A DeepLabV3Resnet18 neural network, trained via DeepMIB2 v 1.302.0.0 software, was employed for semantic segmentation of the histological images. Results Females exhibited higher LDL cholesterol levels, while males showed higher creatinine and proteinuria. Although enalapril reduced BP in both sexes, a significant reduction in proteinuria was observed only in females. Males demonstrated more severe glomerular damage, characterized by increased mesangial expansion, mesangiolysis, foam cell presence and activated PECs. Enalapril attenuated mesangial expansion and glomerular inflammation, with a greater protective effect in females. Additionally, PEC hypertrophy was reduced in males treated with enalapril. Conclusion Males exhibited more severe glomerular lesions, including mesangial expansion, mesangiolysis, foam cell accumulation, and activated PECs. Enalapril provided renal protection, with more pronounced benefits in females. These findings underscore the importance of considering sex differences in the pathophysiology and treatment of CKD.

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