At first glance, fibroblast growth factor-23 (FGF-23) seems to have all the elements of a marker that can do for CKD treatment what HbA1c has done for diabetes management: The hormone can be easily measured by means of a simple blood test or any of several commercially available enzyme-linked immunosorbent assays with good quality and reproducibility.

It yields important information on problematic levels of a substance in the blood—phosphate, in this case—and can potentially lead to dietary and pharmaceutical interventions that could benefit patients.

Like glucose levels, phosphate levels can vary greatly throughout the day. Just as HbA1c measurements give a broader picture of glycemic levels over an extended period than daily glucose readings can provide. FGF-23 appears to be a more stable, longer-term indicator of phosphorus balance and associated abnormalities than serum phosphate levels themselves.

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A problem of interpretation

There is a problem, however: Experts are not yet sure what to make of the results. “How does one interpret them? And what do they mean?” asked Orlando Gutierrez, MD, Assistant Professor of Medicine at the University of Miami Miller School of Medicine.

Dr. Gutierrez has been studying FGF-23 for the past four years. “It’s a pretty easy thing to measure and get the number, but where most people still have a lot of questions is what that number actually means, what to do about it,” he said.

“It would be interesting if you could measure the FGF-23 level in a person with kidney disease and get a sense over the course of three months, six months, maybe even a year, of what the person’s phosphorus balance is in a more sensitive manner than a single phosphate level in a single day would give you.

“But,” he continued, “it’s way, way too early to use it with respect to a biomarker of phosphorus balance because we really don’t have a good enough understanding at this point what the different factors that affect FGF-23 concentrations are.”

With so many unanswered questions related to FGF-23, the hormone that has tremendous potential to change the treatment of people with chronic kidney disease is nowhere near “ready for prime-time” as a biomarker.

“Not even close,” confirmed nephrologist and FGF-23 investigator Myles Wolf, MD, Assistant Dean of Clinical and Translational Research at Miller (Drs. Gutierrez and Wolf relocated from Boston’s Massachusetts General Hospital to continue their FGF-23 studies.)

“FGF-23 could one day be what HbA1c is for glucose, but I’d be very cautious about that,” Dr. Wolf said. “It is a nice idea but the fact that others things could stimulate FGF-23 means that it might not be as closely linked to phosphorus as we’d expect.”

Levels affected by vitamin D

For example, vitamin D is already known to be a potent stimulator of FGF-23. “So if somebody is taking vitamin D, it could cloud our ability to interpret the FGF-23 test, in which case there’s no way it could ever be as good as HbA1c because so many people are on vitamin D,” Dr. Wolf explained.

FGF-23 first garnered attention because of its role in an extremely rare disorder. In the late 1990s and early 2000s, groups of investigators seeking the cause of autosomal dominant hypophosatemic rickets (ADHR) and similar disorders identified FGF-23 excess as the apparent culprit.

Many nephrologists may not yet have heard much about FGF-23, but an ever-growing body of literature shows that higher levels of phosphate in the blood are associated with a variety of poor outcomes in CKD patients, including kidney disease progression and atherosclerosis, and death, according to Dr. Gutierrez. “The higher your phosphate, the more likely you are to die and the faster you are to die.”

These findings have inspired a great deal of interest in understanding why high phosphorus is associated with adverse outcomes and how phosphorus is being regulated in the presence of kidney disease.

Bone and mineral metabolism has always been a hot topic in renal failure, and FGF-23 research has added a fresh angle to the discussion.

“Management of disordered mineral metabolism is one of the most exciting new candidates for treatments aimed at helping people with kidney disease besides blood pressure and glycemic control,” Dr. Wolf pointed out. “I think the most exciting aspect of FGF-23 research is that it could possibly lead the way for how to treat people beginning in early-stage kidney disease.”

Potential predialysis role

In one scenario, if studies could provide evidence that decreasing phosphorus earlier in the course of kidney disease could improve outcomes, the FDA might consider approving phosphorus binders for use in predialysis kidney patients. Currently, these agents are only approved for dialysis patients.

“By the time someone gets to dialysis they usually already have accumulated a fair amount of damage from high phosphate and other sorts of cardiovascular disease events, potentially limiting the benefits of treatment for high phosphate in this population,” Dr. Gutierrez observed.

“While addressing these issues earlier in the course of kidney disease may be more beneficial, predialysis chronic kidney disease patients are often the most difficult to determine how to treat, because serum phosphate levels may not be very sensitive for being able to pick out those individuals who would benefit from early phosphorus-reduction strategies. That might be where FGF-23 has its greatest clinical impact.”

Carmine Zoccali, MD, a nephrologist in Calabria, Italy, observed in an editorial earlier this year in Nephrology Dialysis Transplantation (2009;24:1078-1081): “The discovery that [FGF-23] intimately connects skeletal biology and systemic mineral balance is one of the major breakthroughs of the last decade in renal medicine.”

He then lauded a study by Dr. Gutierrez, Dr. Wolf, and colleagues published in The New England Journal of Medicine (2008; 359:584-592), which concluded that increased FGF-23 levels appear to be independently associated with mortality among patients beginning hemodialysis treatment.

Nevertheless, Dr. Zoccali ultimately advised that although “this nice observational study is an alert that we should stay tuned to this ebullient research area,” clinical nephrologists should not rush to measure FGF-23 in dialysis patients.

Since writing those words, Dr. Zoccali’s stance has not changed. “We still lack evidence that a clinical policy incorporating FGF-23 is associated with better clinical outcomes in [end-stage renal disease] patients,” he told Renal & Urology News.

“Interesting associative studies have been published over the last year, including a cross-sectional study associating FGF-23 and left ventricular hypertrophy. However, all these studies are merely hypothesis-generating. We sorely need hypothesis-testing studies.”

Specifically, Dr. Zoccali would like to see a randomized trial in which one study arm employs a protocol allowing FGF-23 measurements and the other study arm does not. “Only if the clinical outcome in the first arm is better than that in the second are we entitled to recommend FGF-23 measurements. For now, this measurement only makes sense [to use] in some rare diseases.”

Dr. Gutierrez agreed. “There needs to be some evidence that changing the levels of this hormone actually makes a difference, or that measuring this hormone will change clinical practice,” he said. “That’s far and away the most important thing that needs to be done before [FGF-23] gets anywhere near being able to be used in clinical practice.”

Researchers are unclear what factors other than phosphorus affect FGF-23 levels. For example, influences could range from the extent of inflammation within the body to vitamin D levels and the amount of carbohydrates or other foods consumed.

In the best-case scenario, Dr. Wolf said, FGF-23 will be shown scientifically linked to a variety of bad outcomes in kidney disease and will thereby serve as a biomarker that can be used clinically to guide earlier interventions for patients. “And I’m wondering if five years might be right around the time frame when this gets to be more widely commercially available to doctors to do testing.”

He added: “If all the research can be as positive as it has been up until now, then I think at that point there’s a good chance that FGF-23 might start making its way into real practice.”