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Exploiting genetic models of the proximal tubule tight junction to dissect the role of hyperphosphatemia in cardiovascular disease

Todd Alexander
University of Alberta
Kidney Health Research Grant Research
2024 - 2026
$120,000
Chronic Kidney Disease

Lay Abstract

Lay Abstract Title: Is it phosphate, FGF23 or kidney disease itself that causes heart disease in people with kidney disease? Background: Heart disease is common in people with kidney disease and the most common killer. However, what causes heart disease in people with kidney disease is unclear. At least three different mechanisms have been proposed. It has been speculated that 1) increased blood phosphate levels in and of themself, or 2) a phosphate regulating hormone called FGF23 or 3) kidney disease itself causes heart disease in patients with kidney disease. The applicant, Dr. Alexander, has developed mouse models that display increased blood phosphate with and without increased FGF23 and all models have normal kidney function. He will leverage these unique animal models to answer the question as to if increased blood phosphate causes heart disease. Purpose: to determine if phosphate itself causes heart disease, independent of FGF23 and kidney disease. Method: we will look for heart disease in mouse models with increased blood phosphate levels with and without increased FGF23 and all without kidney disease. Previous work has shown that mice with kidney disease and increased blood phosphate (but not with kidney disease) get heart disease. Thus, a group without kidney disease is not needed. The mice, which will be employed were developed in the Alexander laboratory and lack a protein that prevents phosphate absorption from the gut. They can be made to have high blood phosphate levels by feeding the animals phosphate. We will look at hardening of blood vessels, for increased heart size and decreased function by ultrasound. This model displays increased FGF23. We have also developed another mouse model that displays increased blood phosphate without increased FGF23 levels. These models will be used to determine the role of increased blood phosphate independent of FGF23 in causing heart disease. Anticipated Outcomes: we predict increased blood phosphate is sufficient to cause heart disease (specifically increased heart size, decreased heart function and hardening of the blood vessels) without either increased blood FGF23 levels or kidney disease. Patient Engagement: our work with patient partners in the KRESCENT program has informed us as to the significant pill burden imposed by the treatment of increased blood phosphate levels in kidney patients. This is a preclinical mouse study so we have not directly engaged patients on study design but instead have discussed the work with patient partners and incorporated their comments on this abstract. We will present this data to broad audiences including interested patient partners and the lay community through the principal applicant’s involvement with the KFoC and CANSOLVE CKD. Importantly, this work could provide evidence that patients should lower their blood phosphate levels thereby improving heart function and survival. Relevance to patient/community: understanding why persons with kidney disease have heart disease is an essential first step to determining treatment targets and goals. Should we demonstrate that increased plasma phosphate, independent of altered FGF23 levels or kidney disease, is sufficient to cause heart disease it will provide strong rationale to lower plasma phosphate in kidney disease patients. Given the pill burden for phosphate lowering treatments it will also provide strong support to find improved phosphate lowering therapies. If we determine heart disease is the result of another mechanism then treatments can focus on that i.e. lowering plasma FGF23 or trying to determine what else that occurs with kidney disease is driving heart disease in persons with kidney disease. Conclusion: This work will provide an important step into understanding why people with kidney disease suffer from heart disease and help inform treatment strategies to prevent heart disease in kidney patients, the most common killer of persons with kidney disease.