Their finding that FGF23 can cause heart disease directly challenges the long-standing assumption in the field that high FGF23 is a biomarker but not a direct cause of disease. The study is published in the October 10 online edition of the Journal of Clinical Investigation and will be in the November publication.
Chronic kidney disease, which affects about 26 million Americans, occurs when there is permanent damage to the kidneys that often leads to renal failure. Up to 90 percent of end-stage chronic kidney disease patients develop left ventricular hypertrophy, a mechanism of heart disease that causes heart muscle cells to enlarge and the heart pump to become too stiff to fill normally. This condition can lead to heart failure and life-threatening arrhythmias. A high rate of left ventricular hypertrophy is one reason that the leading cause of death in kidney patients is heart disease rather than the underlying kidney disease.
Previous studies have found that chronic kidney disease patients often have high levels of the phosphate regulating hormone FGF23. In these patients, higher levels of FGF23 have been linked to greater risk of death and greater rates of left ventricular hypertrophy. Most researchers believed that FGF23 was merely a biomarker of these complications. The current study shows for the first time that FGF23 is actually a cause of left ventricular hypertrophy.
“The fact that kidney disease raises FGF23 and causes this form of heart disease suggests a new link between how kidney disease can ultimately hurt the heart,” says Wolf. An earlier published work by the group demonstrated that higher FGF23 levels in chronic kidney disease patients are a major predictor for an increased risk of mortality (Journal of the American Medical Association, June 15, 2011).
Faul, first and co-corresponding author of the study, worked with Ansel Amaral, M.D./Ph.D. student and co-first author, in performing the laboratory experiments in the study. They collaborated with Joshua M. Hare, M.D., Louis Lemberg Professor of Medicine, and Behzad Oskouei, M.D., assistant professor of clinical medicine, to take the study into mouse models. “Our work with these models showed that FGF23 can directly contribute to cardiovascular disease,” says Faul.
Hare says the finding “represents a major new clue in unraveling the cardio-renal syndrome, a poorly understood yet extremely important clinical condition.”
Faul and Amaral’s findings in the laboratory were corroborated in 3,000 patients who are part of the Chronic Renal Insufficiency Cohort (CRIC) Study. Examining the FGF23 levels and echocardiograms of patients demonstrated a sequence that kidney disease patients developed higher levels of FGF23, followed by left ventricular hypertrophy. Wolf, who is assistant dean for clinical and translational research, says the study “was a perfect example of translational research, using multiple models to show the relevance in patients.”
Funding for the study came from the Interdisciplinary Research Initiative of the Miller School of Medicine and an F30 grant from the National Institute of Diabetes and Digestive and Kidney Diseases, awarded to Amaral to support his role in studying the effect of FGF23 on the pathogenesis of cardiovascular disease in patients with chronic kidney disease. He says they “have been able to dissect the molecular pathways by which FGF23 leads to cardiac hypertrophy, thereby unveiling a novel target for therapeutic intervention in the future.”
Wolf says the next step is to define strategies to interrupt the pathway of FGF23, whether it’s reducing amounts in the blood or blocking it from inducing damage to the heart. “We expect this research to have impact on devising effective treatments for the future.”
Jochen Reiser, M.D., Ph.D., professor and vice chair for research in the Department of Medicine and chief of the Division of Nephrology and Hypertension, says, “This study is truly visionary and has the potential to change the views we have of the functional relationship of the kidney and heart.”