FGF-23 Steps into the Spotlight as a Key Player in Phosphate Metabolism and Kidney Disease
While the kidneys are perhaps best known for their role in cleansing the blood, another one of their important functions is to regulate the levels of various salts and minerals in the blood. One of the consequences of chronic kidney disease (CKD) is that, in addition to a diminished ability to filter waste, the kidneys are less well able to maintain the balance of salts and minerals, which can in turn have wide-ranging impacts on overall health. One important pathway under the influence of the kidney involves the regulation of phosphate. A recently characterized member of the family of fibroblast growth factors (FGFs), FGF-23, appears to play an important role in regulating the metabolism of phosphate, and may play a previously unappreciated role in the initiation and progression of CKD. Evidence supporting this hypothesis includes data from studies of animals, individuals with CKD and kidney failure, and people with acute kidney injury, suggesting that this factor may represent a broadly acting regulator of phosphate metabolism that plays a key role in kidney function.
The Kidneys and Calcium and Phosphate Metabolism
Proper kidney function is essential for life; people whose kidneys have failed must undergo dialysis or receive a kidney transplant to survive. The supply of donor organs is much smaller than the need for them, so most people with kidney failure rely on dialysis to survive. While dialysis provides a life-saving form of kidney replacement for people whose kidneys have failed, most people with CKD will die before they progress to kidney failure, with cardiovascular disease the most common cause of death.
In addition to its well-known and critical role in waste removal, the kidney plays an important role in the regulation of the balance of calcium and phosphate, two elements that are key to maintaining normal bone metabolism, cardiovascular function, and many cellular signaling processes. Calcium is the most abundant mineral in the human body. Ninety-nine percent of it is found in bone, much of it bound with phosphate; the remaining 1 percent circulates in the blood, where it plays an important role in metabolism. While approximately 10 percent of a person’s bone mass is degraded and rebuilt each year, circulating levels of calcium and phosphate are held relatively constant through a complex regulatory system.
An early sign of impaired kidney function is often a small decrease in levels of calcium circulating in the blood coupled with a small increase in circulating phosphate. In response to these changes, the parathyroid glands (located in the neck) secrete parathyroid hormone (PTH). This hormone acts on the bones, kidneys, and gut to produce an increase in circulating calcium and a decrease in circulating phosphate. As CKD progresses, calcium and phosphate levels continue to skew, and PTH levels rise further in an attempt to restore balance of these two important elements. Unfortunately, chronically elevated levels of PTH can result in devastating bone loss as the body turns to the skeleton as a source of calcium. This condition led to the concept in the early 1970s of the so-called “trade-off hypothesis,” which proposed that a ratcheting-up of PTH in people with CKD, and its attendant consequences, was the “trade-off” the body made as it tried to maintain close-to-normal mineral balance. This hypothesis grew out of research supported by the NIH’s National Institute of Arthritis, Metabolism, and Digestive Diseases, which in 1986 would become the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Although modern therapies can address the problem of bone loss in people with CKD through dietary modification and drugs, there is significant evidence that long-term exposure to elevated levels of phosphate in the blood is in and of itself a risk factor for cardiovascular disease in these individuals. These risks include mineral deposits in the blood vessels and heart that can cause tissues to stiffen. Because of this, for many years there has been a keen interest in better understanding phosphate metabolism in its own right. While PTH is recognized as one of the key regulators of phosphate, there had long been a suspicion among many researchers that PTH alone could not explain all of the intricacies of phosphate metabolism, and that some other factor or factors must be playing a role in this process. In fact, this hypothetical factor was even given a name—“phosphatonin.”
FGF-23 and Phosphate Metabolism
Much of current knowledge about calcium and phosphate metabolism grew out of fundamental research conducted over the past 40 years by researchers studying the regulation of cell growth. The cornerstone of this knowledge comes from studies of fibroblasts, cells comprising much of the tissue that provides physical and biochemical support to other tissues. Because they are relatively easy to grow in the laboratory setting, they have long been a favored experimental model for the study of the factors that influence cell growth. In the early 1970s, NIH-supported researchers showed that small amounts of a mixture of proteins isolated from pituitary glands in the brain could stimulate the growth of fibroblasts in culture. In the mid-1980s, scientists identified two distinct growth-stimulating proteins in this mixture, which they termed “acidic” and “basic” FGFs based on their chemical properties. Nearly 30 years later, over 20 additional members of the FGF family have been identified. They play roles in biological functions as diverse as embryonic development, cell differentiation, nerve cell survival, wound repair, and tumor growth.
The twenty-third member of the FGF family was identified in 2000. FGF-23 is primarily produced by bone cells. It has been shown to have an impact on mineral and salt metabolism. Initial studies of FGF-23’s physiological role in humans occurred in the context of several varied rare diseases, including hypophosphatemia (abnormally low levels of phosphate in the blood), rickets (defective mineralization of bones), and osteomalacia (softening of the bones). All of these conditions are characterized by low phosphate levels and bone loss. These diseases were ultimately found to be associated with elevated levels of FGF-23. In one, the FGF-23 protein was normal, but simply overproduced. In another, a mutation in the FGF-23 gene rendered the protein resistant to degradation. These findings represented some of the first studies to suggest a broad, direct role for FGF-23 in phosphate metabolism and disease, and that unregulated FGF-23 signaling might result in dangerous disruptions in phosphate levels that could have wide-ranging physiologic consequences.
Much of the knowledge about the molecular function of FGF-23 comes from studies conducted in mice in the early 2000s. Either the injection of FGF-23 or the implantation of cells producing high levels of FGF-23 results in markedly diminished phosphate levels in the blood and elevated levels of phosphate in the urine. Mice genetically engineered to produce high levels of FGF-23 show similar characteristics, as well as more widespread problems such as bone deformation. Conversely, mice engineered to lack the FGF-23 gene display elevated phosphate levels in the blood and have calcium deposits in many organs, abnormal bone mineralization, and a shortened lifespan. Detailed mechanistic studies in mice supported by the NIH demonstrated that FGF-23 promotes secretion of phosphate by the kidney and increases calcium absorption in the gut. Interestingly, many of these functions are the same as those that had been attributed to the hypothetical “phosphatonin.” While PTH retained an important role in the regulation of calcium and phosphate, it soon became clear that this picture was incomplete, and that FGF-23 was a key player in phosphate regulation.
FGF-23 and Kidney Disease
As FGF-23’s central role in phosphate metabolism was being characterized through studies of animal models and rare human diseases, NIDDK-supported researchers began to extend and expand studies of FGF-23, especially in individuals in whom proper phosphate metabolism was compromised, such as people with CKD. They found that in early stages of kidney disease, FGF-23 levels increase as kidney function declines. In fact, FGF-23 levels begin to rise before clinically significant changes in calcium, phosphate, and PTH are detectable in the blood. It was proposed that a small, initial rise in circulating phosphate levels very early in kidney disease may trigger an increase in FGF-23 as the body prompts the kidneys to excrete the excess phosphate. This increase in FGF-23 levels seems to precede the previously observed increase in PTH levels in CKD patients.
FGF-23 and PTH reduce the activity of phosphate transporters in the kidney, leading to diminished phosphate reabsorption and increased phosphate excretion in the urine. As CKD progresses and circulating phosphate levels rise, FGF-23 levels in the blood gradually increase to try to restore mineral balance. As kidney function further declines, more FGF-23 is produced in response to subsequent increases in serum phosphate concentrations. One NIH-supported study indicated that by the time patients reach kidney failure, FGF-23 levels can be up to 1,000-fold higher than those seen in healthy people.
While increases in FGF-23 levels are associated with a decline in kidney function, it is not clear whether FGF-23 plays a direct, causative role in this progression. Nevertheless, several lines of evidence suggest that measuring circulating levels of FGF-23 in patients with early-stage kidney disease could yield valuable information regarding their prognosis. One study of over 200 people with nondiabetic kidney disease found that increased FGF-23 levels correlated with risk of kidney disease progression, and that this risk was related to the levels of FGF-23 in the blood. Among individuals who are starting dialysis, elevated FGF-23 levels are associated with an increased risk of death both during the first year and over the first 2 years. The ability to identify and stratify patients with CKD based on their initial levels of FGF-23 would provide valuable information to physicians, suggesting that individuals at greater risk of progression due to elevated levels of FGF-23 might benefit from more aggressive care.
Premature death from all causes, and from cardiovascular disease in particular, is higher in people with CKD than in healthy adults. In fact, individuals with CKD are much more likely to die than to survive long enough to progress to kidney failure. Cardiovascular disease is the leading cause of death in people with kidney disease, and abnormally high levels of FGF-23 are associated with increased risk of cardiovascular disease in patients with CKD. Research supported by the NIDDK and other NIH components has shown that elevated FGF-23 levels are associated with an enlarged heart, which indicates that this muscle is working harder than it should to pump blood throughout the body. Support for the notion that these changes are a consequence of higher FGF-23 levels comes from NIDDK-supported experiments conducted in animals. Mice that received injections of FGF-23 developed enlarged left ventricles, suggesting that FGF-23 may actually cause this form of cardiovascular disease rather than simply be a byproduct of it.
FGF-23 and Acute Kidney Injury
In contrast to CKD, which usually progresses slowly over time, acute kidney injury (AKI), also called acute renal failure, is characterized by a relatively rapid loss of kidney function, usually over a period of several hours or days. The resulting inability to excrete waste products and maintain fluid and salt balance poses urgent health problems for patients and their physicians. AKI may arise from a number of causes, such as sepsis (a serious, whole-body inflammatory reaction caused by infection), decreased blood pressure, or kidney damage from drugs or other toxins. Even though most people with AKI will regain some degree of kidney function, many do not, and this medical condition is associated with high in-hospital mortality rates. There is no effective drug therapy to reverse AKI. The goal of treatment—which may include dialysis along with other approaches—is to prevent fluid and waste from building up in the body while waiting for the kidneys to resume functioning.
The first suggestion that FGF-23 might play a role in AKI came in 2010. An individual was admitted to the hospital and diagnosed with AKI. Analysis of his urine showed that his FGF-23 levels were more than six times higher than normal. A subsequent NIH-supported study of 12 people with AKI found significantly higher than normal FGF-23 levels. The degree of the elevation correlated with severity of AKI and those with particularly high FGF-23 levels were more likely to die. Another NIDDK-supported study of 30 people with AKI found similar results. Those with elevated FGF-23 levels were more likely to require dialysis and die. More recently, an NIH-supported analysis of data collected from more than 3,000 people over the age of 65 as part of a study of risk factors for cardiovascular disease found that higher FGF-23 levels were associated with greater risk of hospitalization for AKI over a 10-year period.
For over 40 years, researchers and physicians have thought of AKI as a condition with causes and consequences distinct from those of CKD. However, more recent analyses have suggested that both conditions, rather than being two distinct phenomena, may in fact lie on a continuum. This hypothesis proposes that these two conditions differ not so much in their fundamental nature as they do in the speed with which they emerge. Both are characterized by a loss of kidney function and each is a risk factor for the other: people who have experienced a bout of sudden AKI and who recover are at increased risk of developing CKD in the future; reciprocally, individuals with slow-developing CKD are at increased risk of AKI as their disease progresses. Furthermore, both AKI and CKD place individuals at higher risk of the subsequent development of cardiovascular disease, kidney failure, and premature death. Evidence that FGF-23 might be involved in AKI as well as in CKD, either as a marker for disease severity or prognosis or as an active contributor to the disease process, further strengthens the argument that this factor plays a key role in the maintenance of normal kidney function.
FGF-23: Biomarker, or More?
In recent years, there has been much enthusiasm regarding the potential benefits of biomarkers, which are molecules that can be easily detected and measured that may be indicators of an underlying condition that is otherwise difficult to evaluate. There seems to be fairly strong evidence that FGF-23 represents, at the very least, a potentially valuable biomarker for kidney disease initiation, prognosis, and progression. If FGF-23 can be validated as a biomarker for kidney disease—either in CKD, AKI, or both—increases in its levels could enable physicians to detect CKD early in the course of the disease using a simple blood test before overt symptoms appear and before irreversible organ damage occurs. Increased levels of FGF-23 could also allow doctors to more accurately assess the prognosis of patients with AKI. Alternatively, FGF-23 levels and trends over time could allow physicians to predict a given person’s likely clinical path. Those with more dire prognoses could be treated earlier or receive more aggressive therapy, allowing a more personalized approach to treatment. Indeed, a recent study conducted as part of the NIDDK-supported Chronic Kidney Disease Biomarkers Consortium reviewed the records of more than 13,000 healthy volunteers who enrolled in a clinical study between 1990 and 1992, and found that people with higher levels of FGF-23 when they first entered the study had an increased risk of kidney failure over the subsequent 20 years. This correlation was seen across all people, regardless of their age, race, and kidney function at the time that they enrolled.
More research is needed to elucidate the ways in which FGF-23 exerts its multiple effects. If FGF-23 can be conclusively linked to specific disease mechanisms as a causative agent in CKD progression or its complications—rather than merely an indicator of it—this protein’s impact could be quite profound. Studies in mice suggest that elevated levels of FGF-23 may play a direct role in the development and progression of CKD rather than simply be a by-product of the disease. Pilot studies in humans are currently testing medications to lower circulating levels of FGF-23 and phosphate in patients with moderate CKD in the hopes of developing strategies to lower the risk of complications. Approaches that inhibit FGF-23 action might prevent, lessen, or slow damage to the kidneys and vasculature of patients with CKD. From these studies, new insights into CKD initiation and progression may be found, new drug targets may be identified, and new treatment approaches may be developed.
Scientists have progressed a long way from a time when they felt the need to propose a hypothetical “phosphatonin” to explain the complex regulation of phosphate metabolism, to the current day, when they are characterizing the role of FGF-23 in these key physiological processes.