Arterial oxygen content regulates plasma erythropoietin independent of arterial oxygen tension: a blinded crossover study

The production of erythropoietin (Epo) is modulated by renal tissue oxygen tension, which in principle depends on both arterial oxygen content (CaO2) and arterial oxygen tension (PaO2). Uncontrolled observational studies suggest that alterations in CaO2 fundamentally regulate Epo synthesis. We sought to establish whether reduced CaO2 enhances plasma Epo concentration independently of PaO2. In a blinded crossover study, 8 healthy young subjects were exposed to three conditions: room air (normoxia); 11% oxygen balanced in nitrogen, which lowers both CaO2 and PaO2 (hypoxia); and carbon monoxide plus normoxia, which decreases CaO2 to the same degree as hypoxia while preserving PaO2 (hypoxemia). Arterial blood samples were obtained prior to and throughout the 5 hours of exposure to each condition. In the hypoxic conditions, average CaO2 was reduced to similar levels, whereas PaO2 was only decreased with exposure to hypoxia. Plasma Epo concentration was increased in both hypoxic conditions relative to normoxia after 150 min of exposure and was augmented more than two-fold after 300 min, with no difference between hypoxic conditions. Reduced CaO2 induces similar increases in circulating Epo concentration irrespective of PaO2 manipulation, demonstrating that CaO2 is the critical variable regulating Epo production.