Sex-specific mechanisms in the pathogenesis and progression of chronic kidney disease

Chronic kidney disease (CKD) is a growing global public health concern, marked by increasing prevalence and substantial economic burden. Notably, CKD demonstrates significant physiological sex differences. Epidemiological evidence indicates that men are more susceptible to developing CKD in early to middle adulthood due to accelerated declines in renal function, whereas postmenopausal women exhibit a sharp rise in CKD incidence and progression. These findings suggest that sex hormones may play a critical regulatory role in CKD pathogenesis. The “bidirectional effects” of sex hormones are considered a fundamental mechanism driving these sex-based disparities. Androgens exacerbate renal inflammation and fibrosis by activating the TGF-β/TNF-α axis and the renin–angiotensin–aldosterone system (RAAS)/20-HETE pathway, in concert with NLRP3 inflammasome activation, thereby worsening glomerular hypertension and metabolic dysfunction. In contrast, estrogens exert protective effects by inhibiting RAAS activity, upregulating the ACE2/Ang-(1–7) pathway, activating the GPER/Sirt1 signaling network, and enhancing antioxidant capacity, thereby preserving renal hemodynamic homeostasis. Furthermore, this review incorporates a range of additional factors—including hormone-like compounds, sex-specific gut microbiota–host metabolic interactions, sex chromosome inactivation or loss, ectopic lipid deposition, and unfavorable lifestyle behaviors—to construct a comprehensive pathological model of sex-specific CKD progression. Elucidating the mechanisms by which sex differences influence kidney disease, and identifying sex-dependent contributors to CKD onset and advancement, may provide critical insights for developing personalized therapeutic strategies. Sex differences in CKD. Males exhibit increased susceptibility to kidney damage due to Y chromosome loss and androgen-mediated pathways, whereas females are protected via X chromosome dosage compensation, estrogen signaling, and anti-inflammatory gut microbiota, with environmental factors further modulating disease progression. • Systematically elucidate the bidirectional regulatory mechanisms of sex hormones underlying sex differences in CKD. • Integrate sex-dependent, multidimensional factors to provide a theoretical foundation for precision treatment in CKD patients. • Propose novel intervention strategies, including age-stratified hormone replacement therapy and gene editing targeting sex chromosome escape genes.