Oxygen is one of the key building blocks of life on earth. Every cell in your body requires oxygen to stay alive. The air you breathe contains around 21% oxygen. As the air fills your lungs, oxygen is transferred to your red blood cells, which then transport oxygen to each cell in your body. But what happens when the air you breathe contains less than 21% oxygen?
We have known for a long time that our bodies are able to respond and adapt to differing oxygen levels. What has not always been clear, however, is how. Solving the mystery of how the body adapts to different levels of oxygen to function optimally led to a Nobel Prize winning discovery with big implications for people experiencing lower oxygen levels for a different reason: anaemia.
Find out more about the consequences of anaemia and why we are developing solutions for patients with anaemia due to chronic kidney disease.
Anaemia and chronic kidney disease
Anaemia is a condition in which the body has fewer red blood cells than is normal. Red blood cells have the essential job of transporting oxygen from the lungs to all the various organs and tissues that rely on it to survive. Without enough oxygen, in the short term, people will experience symptoms such as weakness, fatigue and shortness of breath. In the longer term, anaemia can put extra pressure on the organs, leading to organ damage and even heart failure.
There are different types of anaemia and many different causes. Anaemia is a common complication of kidney disease, because the kidneys play an important role in regulating red blood cell production.[1] Chronic kidney disease (CKD) affects one in 10 people worldwide[2]and was responsible for over one million deaths in 2017.[3]
Healthy kidneys are the major organs that produce a hormone called erythropoietin, commonly known as EPO, which prompts the bone marrow to make red blood cells.[1] People whose kidneys are damaged due to CKD may not make enough EPO, meaning fewer red blood cells are produced.[1] As a result, many patients with CKD will develop anaemia.[1] For these patients, the impact can be hard-hitting, with many experiencing a reduced quality of life and increased risk of cardiovascular disease, hospitalisation and mortality.[4]
CKD-related anaemia remains an area of significant unmet patient need, and researchers have been working for many years to develop potential new medicines. A scientific breakthrough that unlocked the key to how the body responds to low oxygen levels has brought us a vital step closer to meeting the needs of these patients.
Following the science
Last year, a trio of scientists, William Kaelin Jr, Gregg Semenza and the Francis Crick Institute’s Sir Peter Ratcliffe, were awarded the Nobel Prize in medicine for their work spanning the last three decades that completely transformed our understanding of one of life’s most adaptive processes – how the body responds to changes in oxygen levels.[1]
They discovered that when oxygen levels are low it causes a group of molecules to assemble into what is known as a protein complex in most cells of the body. This protein complex (called hypoxia-inducible factor, or HIF) signals to the kidneys to release EPO, thereby increasing production of red blood cells leading to more oxygen being circulated around the body.[2]
This pioneering discovery revealed the key trigger to launching the body’s physiological response to low oxygen levels. Could this be harnessed to help people whose CKD had resulted in debilitating symptoms of anaemia?
Tackling the challenges of CKD-related anaemia
Our advance in understanding the scientific discoveries like that of Sir Peter Ratcliffe and his fellow prize winners, has provided an important platform for the research and drug discovery that we are undertaking at GSK.
In CKD the kidneys are often not releasing enough EPO, leading to anaemia. Clinical research has shown that when the body’s own physiological response to low oxygen levels is triggered, through boosting the size of the HIF signal to the kidneys, even diseased kidneys can often provide enough EPO to stimulate red blood cell production.[3]
This story helps demonstrate the potential of what we at GSK call ‘disease-agnostic research’. We believe that following the science and working hard to better understand the human body will present us with new and unexpected opportunities to solve health problems and deliver real benefits to people everywhere.
We recognise there is more to do to meet the needs of patients with CKD-related anaemia, and that challenges remain. However, we are confident that by following the science these challenges can be overcome.
[1] National Institute of Diabetes and Digestive and Kidney Diseases. Anaemia in Chronic Kidney Disease. Available at: https://www.niddk.nih.gov/health-information/kidney-disease/anemia Last accessed June 2020
[2] Hill, N.R et al. Global Prevalence of Chronic Kidney Disease – A Systematic Review and Meta-Analysis. PLoS One. 2016 Jul 6;11(7):e0158765.
[3] GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systemic analysis for the Global Burden of Disease Study 2017. The Lancet. Volume 395, Issue 10225, p709-733; February 29, 2020.
[4] Babitt, J.L and Lin, H.Y. Mechanisms of Anemia in CKD. J Am Soc Nephrol. 2012 Sep 28; 23;(10):1631-1634.
[5] The Guardian. Nobel prize in medicine awarded to hypoxia researchers. Available at: https://www.theguardian.com/science/2019/oct/07/nobel-prize-in-medicine-awarded-to-hypoxia-researchers Last accessed June 2020.
[6] Schodel, J and Ratcliffe, P.J. Mechanisms of hypoxia signalling: new implications for nephrology. Nat Rev Nephrol. 2019 Oct;15(10):641-659.
[7] Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a potential new treatment for anemia in patients with CKD. Am J Kidney Dis. 2017.1;69(6):815-26.
