Gender Differences in Renal Toxicity Induced by Hemoglobin and the Protective Role of Estrogen

Hemoglobin (Hb) toxicity, resulting from free Hb released during conditions such as hemolytic anemias and medical interventions (i.e. ECMO), poses significant risks to multiple organ systems, particularly the kidneys. Free Hb outside red blood cells becomes unstable and highly reactive, contributing to oxidative stress, inflammation, and cellular injury. Despite these well-documented effects, the mechanisms underlying Hb-induced renal damage and the role of sex hormones in modulating this toxicity remain poorly understood. This study investigated sex-specific differences in renal responses to Hb toxicity using male and female Sprague Dawley rats. A 20% blood exchange with a 5 g/dL Hb solution was performed, and renal function was assessed at 2- and 24-hours post-exchange. Female rats in the estrous phase, characterized by high estrogen levels, exhibited minimal changes in glomerular filtration rate (GFR) compared to baseline. In contrast, males and low-estrogen females showed significant GFR reductions two hours post-exchange, with slower recovery by 24 hours. Histological analysis and injury biomarker evaluation supported these findings, revealing reduced renal injury in high-estrogen females compared to males and low-estrogen females. These results suggest that elevated estrogen levels may confer protection against Hb-induced renal damage. This protective effect underscores the importance of considering biological sex and hormonal status in understanding Hb toxicity and developing therapies. These insights could inform approaches to mitigate renal injury in clinical scenarios involving Hb releases to avoid associated morbidities or even mortality. NIH grants R01HL159862, R01HL158076, and R01HL162120 and NHLBI T32 graduate research training grant HL160507. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.