Kidney Health in Transition: The Impact of Sex Hormones from Bench to Bedside

Sex is increasingly recognized as an important determinant of chronic kidney disease (CKD) progression. Men experience faster CKD progression, higher albuminuria rates, and a greater risk of kidney failure than women, potentially in part due to the influence of sex hormones. However, the physiological and molecular pathways underlying this sexual dimorphism remain incompletely understood. Because sex hormones influence kidney physiology, gender-affirming hormone therapy (GAHT) in transgender individuals provides a unique opportunity to study the effects of sex hormones on kidney function. At the same time, understanding the implications of GAHT on kidney function is clinically important as both CKD prevalence and the number of individuals initiating GAHT continue to rise This thesis addressed three major knowledge gaps: (1) the lack of detailed characterization of intrinsic sex differences in healthy kidney physiology and cell-type–specific transcriptomes; (2) the absence of prospective human data on how changes in serum sex hormone concentrations affect glomerular hemodynamics, tubular injury, and molecular pathways; and (3) the underrepresentation of transgender individuals in nephrology research, limiting insight into the kidney effects of GAHT. Main findings First, intrinsic sex differences in kidney physiology and transcriptomics were identified. Healthy men demonstrated higher measured glomerular filtration rate (mGFR), effective renal plasma flow (ERPF), and intraglomerular pressure, indicating a hyperfiltration-prone state associated with CKD progression. Single-cell RNA sequencing revealed that male kidney tissue exhibited upregulation of pathways related to oxidative stress, inflammation, and injury across multiple cell types, compared with female tissue. Second, sex hormones were shown to influence kidney function. During feminizing therapy (estradiol plus antiandrogen), estimated GFR, mGFR and ERPF increased, without evidence of elevated intraglomerular pressure, suggesting improved kidney perfusion. Additionally, multiple tubular injury biomarkers decreased, indicating reduced tubular stress. In contrast, masculinizing hormone therapy (testosterone) was associated with a decline in estimated GFR over 12 months and increases in tubular injury markers, suggesting early kidney stress. Changes in kidney hemodynamic function were positively associated with serum estradiol and negatively with serum testosterone, while changes in injury biomarkers were primarily associated with serum testosterone. Proteomic analyses suggested that these effects may be mediated through modulation of endothelial function and inflammatory pathways. Proteins associated with improved endothelial function and reduced inflammation increased during feminizing therapy and correlated with improved kidney hemodynamic function. Third, sex hormones influenced metabolic pathways associated with CKD. During feminizing therapy whole-body insulin sensitivity improved, whereas masculinizing therapy had no significant effect. Increased insulin sensitivity was associated with decreased inflammatory and oxidative stress-related proteins. Plasma uric acid (PUA), a known risk factor for CKD, decreased during feminizing therapy and increased during masculinizing therapy. These changes were accompanied by corresponding alterations in kidney uric acid clearance and were associated with changes in body fat distribution and fat distribution-related proteins. Finally, long-term analyses showed that transgender women receiving feminizing hormone therapy did not have an increased risk of advanced CKD compared with the general population. In contrast, transgender men receiving masculinizing hormone therapy had a higher relative risk of advanced CKD compared with individuals of the same sex assigned at birth, although absolute risk remained low due to the young age of the cohort. Conclusion This thesis demonstrates that sex and sex hormones play a critical role in kidney physiology and CKD risk. Male sex is associated with a hyperfiltration-prone state and pro-inflammatory, pro-injury molecular profiles, whereas feminizing therapy appears to exert kidney protective effects through improvements in kidney hemodynamic function, endothelial function, inflammation, metabolic regulation, and uric acid clearance. Conversely, testosterone exposure may increase kidney vulnerability. These findings highlight the importance of incorporating sex, gender, and hormonal status into nephrology research and clinical practice to advance precision medicine.