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  • Balancing Epigenetics in the Treatment of Chronic Kidney Disease

    Kidneys are the body’s filtration system. They clean our blood, removing waste and helping manage blood pressure by controlling the outflow of water. Unfortunately, when these filters stop working properly, as often happens with age or disease, you cannot simply replace the cartridge.

    An Umbrella Term

    Chronic kidney disease is an umbrella term for conditions that affect the function and output of the kidneys. A broad range of underlying causes degrade kidney function, including infections, genetic conditions, autoimmune diseases, pharmaceuticals (prescribed or illicit) and kidney stone obstructions. Similarly, chronic kidney disease severity, course of progression, and treatment options are widely varied. Kidney function can be assessed in several ways, and when a drop in function – below certain thresholds – persists for more than three months it is called chronic kidney disease.

    Chronic kidney disease in the developed world is predominantly associated with old age, diabetes, obesity, high cholesterol and high blood pressure. Kidney disease is commonly a slowly progressing disease and is most often found in people over the age of 65. With time, kidney function can decline to the point where dialysis or even transplantation is required. Chronic kidney disease is also frequently associated with a higher risk of heart disease, stroke and early death.

    The Heart of the Matter

    Ongoing research to understand the correlation between chronic kidney disease and cardiovascular disease has highlighted a critical finding: the two diseases share a common pathology.

    “In fact, it doesn’t always make sense to think of vascular disease and kidney disease as being distinct from each other,” says Dr. Kamyar Kalantar-Zadeh, Head of the Division of Nephrology and Hypertension at The University of California, Irvine School of Medicine and a Professor of Medicine, Pediatrics, and Public Health. “The same biological processes that damage small blood vessels in the heart and brain, increasing a patient’s risk of heart attack or stroke, can also affect vessels of the kidneys, negatively affecting their function.”

    Irritants in the blood – such as high glucose levels resulting from diabetes – inflame the cells that line our blood vessels. Persistent inflammation in the vasculature damages small vessels over time, and creates an environment that promotes the deposition of calcium-rich minerals in the vessel walls. Resulting obstructions and blockages reduce tissue blood flow, which starves cells of oxygen and nutrients. When this happens in the blood vessels that feed the kidneys, portions of the kidneys may be left scarred and unable to filter out waste products optimally.

    As the filtration capacity of the kidneys decline, excess water cannot be as readily cleared from the body. This raises blood pressure and puts added strain on the heart, making it more likely to fail.  The added pressure is also felt by the small vessels of the heart and brain, which increases the likelihood of heart attack and stroke.

    Targeting Common Pathways

    Many measureable indicators of the presence or severity of disease, called biomarkers, overlap between chronic kidney disease and cardiovascular disease. One important shared biomarker is alkaline phosphatase, a protein that is normally found primarily in liver, kidneys and bone. Alkaline phosphatase is a critical component in calcification required for bone healing and remodeling. However, excessive alkaline phosphatase in the bloodstream plays a pathological role in the vasculature, contributing to calcium deposition, vessel stiffness, obstruction and reduced blood flow. High levels of alkaline phosphatase in the bloodstream correlate with a greater mortality risk.

    “The broad role of alkaline phosphatase makes it a bit of a paradoxical target in chronic kidney disease,” Dr. Kalantar-Zadeh explains, “Too much is linked to poor outcomes, but if we were to remove it completely, we could upset bone healing or other important processes, which would likely make things even worse. What we need is a way to normalize alkaline phosphatase back to healthy levels.”

    This need for balance is not unique. Many of our body’s normal processes, when dysregulated, contribute to disease progression. Chronic inflammation, for example, is the consequence of high immune system activity, despite its beneficial role in the resolution of acute injury or infection.  

    “The same biological processes that are responsible for defending against infections will slowly damage tissues and organs if active for too long,” adds Dr. Kalantar-Zadeh, “It’s a matter of balance.”

    Normalizing Gene Expression

    Epigenetics is an exciting new area of research for the treatment of chronic disease. Epigenetic processes regulate the activation and deactivation of genes in our cells, controlling subsequent protein production. According to Dr. Kalantar-Zadeh, “Epigenetic regulation gives us a mechanism to tweak the amount of proteins produced by a cell and alter the activity of pathways that we know to be driving disease progression.  If we could harness that promise in a therapeutic, it would be groundbreaking.” Indeed, this is the goal of Resverlogix in the development of its lead compound apabetalone.

    The ongoing clinical trial, BETonMACE, includes monitoring of kidney function in a pre-specified subpopulation of at-risk patients. Results from these analyses will pave the way for a planned clinical trial focused on chronic kidney disease.