UDP-glucose as a diagnostic for Acute Kidney Injury: how basic research led us into the clinic
Pr. D. Brown - Professor of Medicine at Harvard Medical School
Director of Program in Membrane Biology at the Massachusetts General Hospital (MGH).
He received his Ph. D. from the University of East Anglia, Norwich, UK, and then spent 10 years working at the University of Geneva Medical School in Switzerland, before moving to MGH in 1986. Dennis Brown is an internationally recognized authority on membrane protein trafficking in epithelial cells, with special focus on water channels (aquaporins). His work is aimed at understanding basic cell physiology in order to develop novel therapeutic strategies for kidney disease. He has published over 370 articles in peer reviewed journals. He was Editor-in-Chief of the American Journal of Physiology (Cell Physiology) until July 2008, and is currently the Editor-in-Chief of Physiological Reviews, which has an impact factor of 30, and is one of the World’s most highly cited scientific journals. After serving on its National Council for three years, he is now the President of the American Physiological Society (APS), since April 2017.
He has received numerous awards including the Carl Gottschalk Award for excellence in nephrology research from the APS Renal Section in 1999, the Robert Schrier endowed lectureship at the 2008 American Society of Nephrology meeting, the Hugh Davson Award for excellence in cell biology research from the APS Cell Section in 2011, and the prestigious Robert Pitts Lecture in Renal Physiology at the 2013 meeting of the International Union of Physiological Sciences in Birmingham, UK. In July 2013 he was awarded an honorary Doctor of Sciences degree by his alma mater, the University of East Anglia (UK) for his outstanding contributions to cell biology and physiology.
He is the Director of the MGH Office for Research Career Development (ORCD) and has a long track record of developing young scientists, both basic researchers and clinical investigators. He was awarded the prestigious A. Clifford Barger “Excellence in Mentoring” award from Harvard University in 2005 and received the HMS Dean’s Award for the Advancement of Women in Science in 2012.
He has obtained continuous support from the NIH since arriving in the USA in 1986, and one of his current grants received rare «MERIT» Award status (10 years of support) in 2008. Finally, Dr. Brown has served on numerous NIH study sections and was the chair of the NIH KMBD (Kidney Molecular Biology and Development) grant reviewing Study Section for 3 years from June 2010 until June 2013.
UDP-glucose as a diagnostic for acute kidney injury (AKI): how basic research led us to the clinic
This is the story of how basic research on kidney function led to an unexpected discovery that has the potential to not only diagnose, but also lead to a potential therapy for acute kidney injury (AKI). One third of intensive care unit (ICU) patients will develop AKI – around 300,000 die each year in the USA alone, more than from diabetes, breast cancer, prostate cancer and heart failure combined. AKI is also a causal factor in longer term chronic kidney disease (CKD), often requiring dialysis or transplantation. Among the major causes of AKI are cardiac surgery, sepsis, reduction of renal blood flow (ischemia), and dehydration – which is of special importance to this audience. Remarkably, AKI causes no symptoms during its early stages, and more than 50% of kidney function has already been lost before it can be diagnosed using current tests. Consequently, AKI is often referred to as “the silent killer”.
We have recently identified a marker that detects AKI within a few hours of onset, rather than 2-3 days later when it may be too late to intervene to prevent the inexorable loss of kidney function. How did we find this marker? We are interested in defining the role of different cell types in the kidney. Some of these cells (intercalated cells) are involved in acid/base balance in the body. While examining these acid-regulating cells, we noticed that they express large amounts of a membrane protein called P2Y14, a member of the family of the purinergic receptor family. We could not ignore this protein (it was so abundant), and we learned that it is a receptor for a molecule called UDP-glucose (UDP-G). It turns out that damaged cells, in the kidney or elsewhere in the body including the heart, release UDP-G, which builds up in the kidney, where it interacts with P2Y14 on intercalated cells. This interaction causes these cells to release cytokines, molecules which attract inflammatory cells, thus provoking an inflammatory response. This is an early and important step in the onset of AKI. Thus, our finding provides a link between remote tissue damage (e.g., during surgery) and subsequent kidney injury, caused by UDP-G release and its interaction with the P2Y14 receptor in kidney intercalated cells.
Based on this, we suspected that because UDP-G is released into the blood by damaged tissues and is filtered into the urine, it might be a sensitive marker for AKI. By following ICU patients, we demonstrated in a pilot study that UDP-G in patient urine reliably predicts AKI up to 48 hours before the standard test (serum creatinine). It outperforms other AKI biomarkers in its ability to selectively and specifically detect AKI. This would give physicians around 48 h advanced warning of AKI, allowing them to take early steps to prevent further damage. Importantly, we also have a compound in hand called PPTN, which blocks the interaction between UDP-G and its P2Y14 receptor. This represents a new potential therapeutic avenue for AKI. Thus, we believe that UDP-G is an actionable marker, and that targeting the UDP-G/P2Y14 pathway represents a very promising therapeutic approach for the prevention/mitigation of AKI in critically ill patients.