The finding could lead to the development of treatment interventions to prevent disease progression.
Chronic kidney disease occurs when there is permanent damage to the kidneys, and more than 23 million Americans are affected, with African Americans and Hispanics at especially high risk. These patients are at increased risk of developing new or worsening cardiovascular disease and suffering from progression of their disease to complete loss of kidney function, which requires dialysis or kidney transplantation. Kidney disease alone also increases the risk of premature death.
Currently, clinicians have limited ability to predict which of their patients with early stages of chronic kidney disease are at the highest risk of dying or developing renal failure, and treatments to prevent disease progression are only moderately successful. The UM team showed that patients with chronic kidney disease and elevated levels of FGF23, the phosphate regulating hormone, were more likely to progress to end-stage kidney disease and to die prematurely. Unexpectedly, the researchers found that elevated levels of FGF23 were more strongly predictive of risk of death than other proven risk factors.
The study, published in the June 15 issue of the Journal of the American Medical Association, is the first to look at FGF23 as a risk factor for death in the early stages of kidney disease.
“Our finding shows that elevated FGF23 is an independent predictor of death across the spectrum of chronic kidney disease, and is an even stronger predictor than the traditional chronic kidney disease risk factors such as renal function and protein in the urine,” said Tamara Isakova, M.D., M.M.Sc., assistant professor of medicine in the Division of Nephrology and Hypertension.
The researchers looked at the levels of FGF23 in patients when they enrolled in the Chronic Renal Insufficiency Cohort Study (CRIC). The study was established in 2003 by the National Institute of Diabetes and Digestive and Kidney Disease to examine risk factors for kidney disease progression and cardiovascular disease in patients with chronic kidney disease. A total of 3,939 racially and ethnically diverse patients from seven clinical centers across the United States enrolled in the study and have been followed over time.
As an endocrine hormone, FGF23 regulates phosphorus metabolism in the body by acting on the kidneys to alter the excretion of phosphate in the urine. FGF23 levels in the blood increase when phosphate is in excess or when kidney excretion of phosphate is impaired, as in chronic kidney disease. As kidney disease progresses and reduced kidney function progressively limits the kidneys’ ability to rid the body of excess phosphate, FGF23 levels rise. This compensatory increase in FGF23 helps to normalize the blood level of phosphate until severe renal failure occurs, and then increased phosphate levels are unavoidable.
“We have known for a long time that high phosphate levels in chronic kidney disease patients are linked to higher risk of cardiovascular complications and death, so we asked if an elevated FGF23 might actually be an earlier marker of abnormal phosphate metabolism than even the blood level of phosphate,” explains Myles Wolf, M.D., M.M.Sc., associate professor of medicine in the Division of Nephrology and Hypertension. “In previous proof-of-concept studies, we and others showed that elevated FGF23 levels in patients undergoing hemodialysis were associated with increased risk of death.
“Our current study extends these findings to patients in the early stages of chronic kidney disease, most of whom had normal phosphate levels, but already had an elevated FGF23. The findings seem to indicate that FGF23 is a better marker of phosphate-related risk in this large group of patients, who currently are not receiving any therapies targeting abnormal phosphate metabolism. When this is considered alongside data from other investigators who showed that FGF23 levels can be reduced with phosphate binding, medications that prevent absorption of dietary phosphorus in the gastrointestinal tract, it suggests that we should consider looking at whether incorporating FGF23 testing into the clinical management of patients with chronic kidney disease might be beneficial.”
The researchers suggest their findings could lead to future studies that would determine whether dietary manipulations alone or in combination with use of phosphate binders could be used to reduce elevated FGF23 levels in patients with chronic kidney disease with the aim of improving outcomes in chronic kidney disease. They also say that once the mechanism of FGF23 toxicity is better understood it may be possible to use antibodies or other therapeutic interventions to block its effects.
The study was funded by the National Institute of Diabetes, Digestive Diseases and Kidney Diseases at the National Institutes of Health.