Although it does not yet have a place in everyday practice, fibroblast growth factor 23 (FGF-23) may one day be an important marker of and therapeutic target for very early-stage chronic kidney disease for the clinical nephrologist. Orlando M. Gutiérrez, MD, Assistant Professor of Medicine in the Division of Nephrology at the University of Alabama at Birmingham, has studied in depth this bone-derived hormone, which regulates phosphorus and vitamin D.
You got involved with FGF-23 research about seven years ago. What got you so interested?
Dr. Gutiérrez: FGF-23 came around in a period of time during which many of us were trying to understand what major factors regulate phosphorus metabolism in individuals with early kidney disease as well as what major factors account for the vitamin D deficiency that people with early kidney disease develop.
Back then, in 2003 or 2004, people were writing editorials and review articles about how there was some missing component regarding how the kidney, in very early disease, regulates phosphorus and vitamin D, and there was a lot of speculation as to what factors might be involved with that. And around that time, FGF-23 was just coming on line in terms of being able to be measured in the blood, in assays, and those sorts of things.
So my interest in it was that it seemed to come around right at the time that we had a lot of questions about what are all the different factors that regulate phosphorus in kidney disease.
As recently as late 2009, you and others were somewhat cautious when discussing whether FGF-23 could eventually become “the HbA1c of kidney disease” (Renal & Urology News, December 2009: “An ‘HbA1c’ for Phosphate Management?”). Now, a few years later, do you think FGF-23 has that potential?
Dr. Gutiérrez: The data that have come out since then have continued to support the idea that FGF-23 is a better, longer-term marker of phosphorus balance than just about anything else that we have available.
Some of the more recent studies have shown in large, population-based samples that FGF-23 is the first blood biomarker to become abnormal in the course of kidney disease—going from people who have very, very mild kidney disease to worse. One of my colleagues termed it “the first bellwether of problems.”
FGF-23 becomes abnormal before parathyroid hormone does, before phosphorus does, before calcium does. It appears to become abnormal even before creatinine starts to increase.
What this suggests is that FGF-23 is telling us something that’s going on very early on, that is probably related to disturbances in phosphorus metabolism, and it could be used in a similar manner as hemoglobin A1c , potentially allowing clinicians to get a sense of, “Okay, what has this person’s phosphorus homeostasis metabolism been like over the past several months, and do I need to do something about that?”
So that’s an area of active interest: Can you use FGF-23 as an earlier, more sensitive marker of disturbances in phosphorus homeostasis than some of these other markers that we have? It’s possible that that might be the case.
We know high HbA1c levels mean hyperglycemia, and low means hypoglycemia, but what do extra-high or extra-low FGF23 levels signify?
Dr. Gutiérrez: We know, mostly from population-based studies, that a high FGF-23 is very strongly associated with death and with cardiovascular events such as congestive heart failure and stroke, and that it is associated with faster progression of kidney disease in people who already have kidney disease.
We don’t really know very much about what is a low FGF-23 level, because that’s something that’s not really seen in clinical practice very much. Most people have normal or high FGF-23 levels. We don’t really see very low levels so we don’t have a very good sense of what the opposite is. The animal models would suggest that you don’t do very well if you have FGF-23 levels too low, but we just don’t see that very often in human models of disease.
Can you give us a general measurement for what a normal FGF-23 level is?
Dr. Gutiérrez: Part of the problem with it is, it depends on which assay you’re talking about. There are two major assays out there right now that measure FGF-23, and they’re on different units. In the assay that’s used most often, the units are reference units per mL—RU per mL. While no one has come out with what is a “normal” FGF-23 range, what people have done is looked at [the question of], “Well, in a population of individuals with normal kidney function, what is the plausible upper limit of normal?”
And they’ve usually defined that as 2.5 standard deviations above the median in the population, or levels that are above the 90th percentile. Those are pretty standard definitions for what would be the upper limit of normal within the general population. And that number turns out to be around 100 RU per mL, so 100 RU per mL is kind of the upper limit of normal. So anything above that is thought to be distinctly abnormal in the general population.