American Journal of Physiology – Renal Physiology

The oxygen cascade in patients treated with hemodialysis and native high-altitude dwellers: lessons from extreme physiology to benefit patients with end-stage renal disease.

Jeroen P. Kooman, Peter Stenvinkel, Paul G. Shiels, Martin Feelisch, Bernard Canaud, Peter Kotanko

Patients treated with hemodialysis (HD) repeatedly undergo intradialytic low arterial oxygen saturation and low central venous oxygen saturation, reflecting an imbalance between upper body systemic oxygen supply and demand, which are associated with increased mortality. Abnormalities along the entire oxygen cascade, with impaired diffusive and convective oxygen transport, contribute to the reduced tissue oxygen supply. HD treatment impairs pulmonary gas exchange and reduces ventilatory drive, whereas ultrafiltration can reduce tissue perfusion due to a decline in cardiac output. In addition to these factors, capillary rarefaction and reduced mitochondrial efficacy can further affect the balance between cellular oxygen supply and demand. Whereas it has been convincingly demonstrated that a reduced perfusion of heart and brain during HD contributes to organ damage, the significance of systemic hypoxia remains uncertain, although it may contribute to oxidative stress, systemic inflammation, and accelerated senescence. These abnormalities along the oxygen cascade of patients treated with HD appear to be diametrically opposite to the situation in Tibetan highlanders and Sherpa, whose physiology adapted to the inescapable hypobaric hypoxia of their living environment over many generations. Their adaptation includes pulmonary, vascular, and metabolic alterations with enhanced capillary density, nitric oxide production, and mitochondrial efficacy without oxidative stress. Improving the tissue oxygen supply in patients treated with HD depends primarily on preventing hemodynamic instability by increasing dialysis time/frequency or prescribing cool dialysis. Whether dietary or pharmacological interventions, such as the administration of L-arginine, fermented food, nitrate, nuclear factor erythroid 2-related factor 2 agonists, or prolyl hydroxylase 2 inhibitors, improve clinical outcome in patients treated with HD warrants future research.

About the Contributor

Dr. Peter Kotanko, MD

RRI Research Director

SVP, Corporate Research & Development

Peter Kotanko, MD is Research Director at the Renal Research Institute (RRI), New York. Prior to joining RRI, from 1997 to 2007 he served as Vice Chair of a department of internal medicine at an academic teaching hospital in Graz, Austria. Prior to moving to Graz in 1989, he worked 1982-89 at the Department of Physiology and the University Clinic of Internal Medicine, Innsbruck, Austria...