Clinical Laboratory Strategies: August 25, 2011
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Exploring a New Marker in Kidney Disease

Hormone Found to Outperform Traditional Markers
By Bill Malone

Levels of fibroblast growth factor 23 (FGF-23) increase as kidney function declines, and the hormone has been known to be associated with mortality in patients with end-stage renal disease (ESRD). This issue of Strategies examines a recent study that found FGF-23 to be an independent risk factor for ESRD in patients with early kidney disease and for mortality across the spectrum of chronic kidney disease (CKD).

Although all of the mechanisms of (FGF-23) are not completely understood, researchers believe that rising levels of the hormone are a response to the kidney’s inability to rid the body of excessive phosphate. FGF-23 inhibits renal reabsorption of phosphate, and excess phosphate has been shown to be associated with mortality and cardiovascular events even in healthy individuals. A new study found that in patients with early stage CKD, FGF-23 showed a strong link to both ESRD and death (JAMA 2011;305:2432-2439).

Researchers from the University of Miami Miller School of Medicine examined the relationship between FGF-23 and mortality and ESRD in 3,879 people enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008 with CKD stages 2 through 4.During a median follow-up of 3.5 years, 266 participants died and 410 developed ESRD. FGF-23 levels were significantly higher in those who died or reached ESRD.

In adjusted models, the authors found that FGF-23 most strongly correlated with mortality. Participants in the highest vs. the lowest quartile demonstrated a 4.3-fold greater risk of death. Hazard ratios increased by quartile in the fully adjusted model from 1.3 for the second quartile to 3.0 for the fourth quartile. The authors included demographic characteristics, estimated glomerular filtration rate (GFR), urine albumin-to-creatinine ratio, serum albumin, hemoglobin, calcium, phosphate, parathyroid hormone, and cardiovascular disease (CVD) risk markers.

Surprisingly, FGF-23’s link with mortality outperformed traditional CVD and CKD-specific risk factors, including reduced estimated GFR and proteinuria. “This suggests that FGF-23 is an extremely powerful biomarker,” said Myles Wolf, MD, an author of the study. “That it can even surpass markers like proteinuria for instance—which currently we use as a very powerful predictor in clinical practice—that really demonstrates the power of this as a potential biomarker to predict risk.” Wolf is an associate professor of medicine at the University of Miami Miller School of Medicine in Miami, Florida, a staff nephrologist at the University of Miami Hospital and Jackson Memorial Hospital in Miami, and the director of clinical research in the nephrology and hypertension division of the University of Miami and director of the University of Miami Clinical Research Center.

The association with ESRD was more complex, the authors noted. Elevated FGF-23 was independently associated with significantly higher risk of ESRD among participants with an estimated GFR between 30 - 44 mL/min/1.73 m2 and ≥45 mL/min/1.73 m2. Reduced estimated GFR was still the strongest predictor of ESRD in the fully adjusted model.

“The association between FGF 23 and mortality was very strong in this study, even though the authors adjusted for all of the other data that they had available, and it was pretty impressive that there was a very consistent relationship through all the levels of GFR,” said Michal Melamed, MD, MHS, assistant professor of medicine and epidemiology and population health at Albert Einstein College of Medicine in the Bronx, N.Y. “There have been a few small studies that have shown similar results, but this was a bigger study with more available data and more participants with a large range of GFRs.” Melamed was not involved in the study.

The stronger link between FGF-23 and mortality raises several new questions, including whether the hormone has a causal connection to kidney disease. With the hormone’s important role in phosphate metabolism, researchers speculate that there is much more to be learned about this pathway, Wolf said. “Having a higher FGF-23 is a response to more severe disordered phosphorus metabolism, and we think this biomarker will have the greatest promise in people who have normal blood levels of phosphate, but nevertheless have abnormal phosphorus metabolism,” he explained.

Wolf believes the marker could be an aid in guiding treatment for disordered phosphorus metabolism if it were shown to improve clinical outcomes. “Potentially, you could use FGF-23 testing to help identify candidates for treatment, whereas the current standard approach to delivering phosphorus-related therapies is restricted to people with high levels of phosphorus in the blood,” he said. “High phosphorus is actually quite uncommon in people with early stage CKD, but it’s very common in dialysis patients, so there are many people walking around with normal serum phosphate levels and as a result do not get any consideration for any treatment of phosphorus metabolism. FGF-23 could be used to determine who needs therapy even with normal phosphate levels.”

Melamed agreed that if this line of thinking proves correct in further research, treatment for disordered phosphorus metabolism along with an FGF-23 test to guide therapy would be a significant advance. “If we find that FGF-23 has a causal role and there is something you can do about it, that would be the Holy Grail for CKD. If future studies show that this association with FGF-23 is real and that if we decrease levels of FGF-23, people live longer, I think that’s what we’re looking for. Because people with kidney disease and people with ESRD have dismal survival,” she commented.

In addition to processes of mineral metabolism, the authors also emphasized the powerful link between FGF-23 and the CVD risk factors in the study, suggesting a possible connection between FGF-23 and mortality in CKD patients that relates just as strongly to the cardiovascular system as it does phosphorus metabolism. One clue to this hypothesis is FGF-23’s relationship to klotho, a coreceptor for the hormone expressed in the kidneys and parathyroid glands that the authors note has demonstrated “anti-aging and vascular-protective effects.”

“Klotho is actually really interesting,” Melamed noted. “We know that klotho knockout mice age more quickly and develop vascular calcifications and overexpression of klotho leads to a longer lifespan in mice. Many of our ESRD patients develop vascular calcification, but we don’t know if it’s potentially FGF-23 that’s causing the problem, or maybe it’s a lack of klotho that is actually the problem.”

Honing in on the strong link to mortality, Wolf noted that other markers of mineral metabolism did not demonstrate the same association as FGF-23, pointing toward a mechanism of action that transcends the regulation of phosphate. “Not only was FGF-23 a more powerful predictor than established risk factors, but it was also much more powerfully predictive than all the other measures of mineral metabolism that it regulates,” he said. “This suggests that the underlying mechanism of whatever it is that we are scratching the surface of might not necessarily have anything to do with the classic effects of FGF-23 on mineral metabolism. So the most obvious hypothesis to emerge from that is that perhaps FGF-23 is somehow directly contributing to harm through mechanisms that are as yet unknown.”

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Exploring a New Marker in Kidney Disease