A Review of the Role of Fibroblast Growth Factor 23 (2023)

Adapted from the IRIS education article by Jonathan Elliott, Rebecca Geddes, and Rosanne Jepson, Departments of Comparative Biomedical Sciences and Clinical Sciences and Services, Royal Veterinary College, University of London (2023). The phosphate targets have been updated to the IRIS treatment recommendations for cats as modified in 2026.

Summary

This article reviews current knowledge of the physiology and pathophysiology of fibroblast growth factor 23 (FGF23). Sections 1 to 3 cover the physiology of phosphate balance and how FGF23 fits into the systems that regulate both phosphate and calcium. Section 4 explores the role of FGF23 in the mineral and bone disturbance of chronic kidney disease (CKD). Sections 5 and 6 present the evidence behind measuring serum FGF23, which is now commercially available, when managing the different stages of CKD. These recommendations were incorporated into the 2023 IRIS treatment guidelines for cats with CKD, remain in the 2026 version, and are summarized as step-by-step guides in Section 6. Section 7 describes the harmful effects of very high FGF23 concentrations inside and outside the kidney, and how these might contribute both to progressive kidney injury and to the uremic syndrome seen in later-stage CKD.

1. Introduction

Although phosphorus is a major element in mammals, the systems that regulate its balance are still not fully understood. When chronic kidney disease prevents the body from regulating serum phosphate, secondary renal hyperparathyroidism develops, and primary disorders of the parathyroid gland also disturb circulating phosphate concentrations. In the 1980s, parathyroid hormone (PTH) and calcitriol were therefore thought to be involved in regulating phosphate. It was recognized, however, that the main role of these two hormones is to regulate calcium, and that phosphate regulation is secondary. The search continued for a hormone whose main job is to regulate phosphorus, a so-called "phosphatonin."

As with many endocrine systems, clues to how phosphate is regulated came from disorders in which a hormone is overactive. Phosphate-wasting diseases that were not accompanied by high blood calcium, as would be the case in primary hyperparathyroidism, were identified in human patients, and genetic analysis led to the discovery of two distinct disorders: X-linked hypophosphatemic rickets (The HYP Consortium, 1995) and autosomal dominant hypophosphatemic rickets (ADHR; The ADHR Consortium, 2000). The first was eventually shown to be caused by an inactivating mutation of the PHEX gene (phosphate-regulating endopeptidase, X-linked), which encodes an enzyme involved in the metabolism of FGF23. The second led to the discovery of FGF23 itself, a new member of the fibroblast growth factor family, with activating mutations proposed as the cause of ADHR.

At around the same time, the "anti-aging" gene klotho was discovered in 1997 (Kuro-o et al., 1997). Knocking out this gene caused premature aging together with high blood phosphate, early osteoporosis, and calcification of soft tissues. Similar changes were seen when FGF23 was knocked out in mice, which led to the realization that FGF23 and klotho act on a common signaling pathway and work together to regulate phosphate, with klotho being an essential co-receptor that allows FGF23 to activate FGF receptor 1 (Kurosu et al., 2006). These landmark discoveries underpin our current understanding of the FGF23-klotho axis in phosphate balance, and of the adaptive and maladaptive changes that occur in CKD, described below.

2. Where FGF23 Is Produced and What Controls Its Synthesis and Secretion

Calcium and phosphate are the main minerals of the skeleton. One of the adaptations that made life on land possible was the development of an internal skeleton, together with ways of keeping calcium and phosphate dissolved in the fluids around soft tissues while allowing them to be deposited in bone and teeth. One such adaptation is the formation of calciprotein particles (CPPs) in the blood. These allow complexes of calcium and phosphate ions to exist in colloidal form, bound to proteins such as fetuin-A, matrix Gla protein, and Gla-rich protein (see Smith et al., 2020). The particles form first as monomers, calcium and phosphate complexes bound to fetuin-A that are about 10 nm in diameter, and then as primary particles 30 to 100 nm in diameter, which are taken up at sites of bone turnover and removed from the blood by Kupffer cells in the liver. Primary particles increase in the blood after a meal and buffer rapidly absorbed calcium and phosphate, limiting changes in the free concentrations of these ions (Tiong et al., 2022). Primary particles can mature into secondary calciprotein particles, which are 100 to 250 nm across, spiky in shape, pro-inflammatory, and linked to vascular calcification. This happens when phosphate is present in excess, or when magnesium, fetuin-A, or vitamin K (needed to modify matrix Gla protein and Gla-rich protein after they are made) is low (see Smith et al., 2020).

It seems logical, therefore, that bone should be closely involved in sensing phosphate and in making and secreting the phosphate-regulating hormone. Osteocytes are the main site of production of FGF23, a protein hormone of 251 amino acids. How bone cells sense phosphate ions and respond by increasing the synthesis and secretion of FGF23 has proved difficult to determine and is still not fully understood (see Vervloet, 2022). Low blood phosphate does not completely suppress FGF23 secretion, so phosphate ions, although an important stimulus, are not the only factor influencing FGF23 synthesis and secretion. There appears to be a delay of up to 24 hours between an increase in dietary phosphate intake and a rise in FGF23 secretion by bone. This also seems to be true in cats: feeding phosphate did not increase serum FGF23 concentrations during the first 6 hours after a meal (Coltherd et al., 2019), whereas eating the same diets for 2 weeks led to persistently increased plasma FGF23 concentrations (Alexander et al., 2019).

Three main pathways linking phosphate concentration to FGF23 secretion have been proposed:

• The activity of the phosphate transporter PiT-2 (SLC20A2) in the membranes of osteocytes (Bon et al., 2018).
• FGF receptor 1 on osteocytes, to which phosphate ions bind. This activates second-messenger systems that increase the expression of GALNT3 (GalNAc-T3), an enzyme that O-glycosylates the FGF23 molecule and so protects it from inactivating enzymes in the Golgi apparatus (Takashi et al., 2019).
• Calciprotein particles, which are sensed by osteocytes and lead to increased transcription of the FGF23 gene. Both calcium and phosphate ions contribute to the formation of CPPs, and it appears to be the primary form of these particles that regulates FGF23 synthesis (Akiyama et al., 2020).

The delay between phosphate entering the body through the intestine and the rise in plasma FGF23 seems to arise because FGF23 is regulated at the level of gene transcription and processing of the protein after it is made, rather than by release of stored hormone from secretory granules in osteocytes. The relative importance of the three mechanisms listed above is not known. Much of the regulation of FGF23 appears to happen during processing of the protein in the trans-Golgi network, where the molecule can be cut so that inactive C-terminal FGF23 is released rather than intact FGF23. Where processed FGF23 is stored before secretion is not understood, although classical secretory granules do not appear to be involved (Yamamoto et al., 2016). O-glycosylation at a critical cleavage site prevents the intact molecule from being cut, phosphorylation makes cutting more likely, and mutations in the enzymes involved can cause disorders of phosphate balance (Tagliabracci et al., 2014). It is therefore important to know which part of the molecule a diagnostic assay detects. The intact molecule is the physiologically active form of FGF23.

3. How FGF23 Works With Other Hormones That Regulate Calcium and Phosphate

Other physiological factors that regulate FGF23 synthesis and secretion include calcitriol (active vitamin D3) and PTH, both of which increase plasma FGF23 concentrations (Lavi-Moshayoff et al., 2010; Kolek et al., 2005). The relationship between PTH and FGF23 is complex, because the main stimulus for PTH synthesis is a low ionized calcium concentration, sensed through the calcium-sensing receptor. FGF23 secretion requires plasma ionized calcium to be above a threshold level. As plasma ionized calcium rises above that threshold, plasma FGF23 concentrations increase, and plasma calcium is an independent factor related to serum FGF23 in many species, including the cat (Geddes et al., 2013a). PTH may therefore only stimulate FGF23 secretion once ionized calcium has returned to a more normal value, which is another reason why the rise in FGF23 may lag behind an increase in plasma PTH.

PTH, calcitriol, and FGF23 appear to be linked by feedback loops. PTH activates calcitriol synthesis, which increases the absorption of calcium and phosphate from the intestine. PTH also increases osteoclast activity, releasing calcium and phosphate from bone, while acting on the kidney to conserve calcium (in the distal tubule) and excrete phosphate (in the proximal tubule). Both PTH and calcitriol increase FGF23 secretion. FGF23 then prevents plasma phosphate from rising by further reducing phosphate reabsorption in the proximal tubules (by down-regulating the sodium-phosphate transporters; Segawa et al., 2003), by inhibiting calcitriol synthesis (Shimada et al., 2004), and by inhibiting PTH secretion (Krajisnik et al., 2007). This limits further entry of calcium and phosphate into the extracellular fluid from the diet and from bone. It shows how bone, intestine, and kidney work together to regulate calcium and phosphate: bone mass is maintained, ionized calcium is tightly controlled, and phosphate is not allowed to stay high enough to cause mineralization of soft tissues rather than bone.

How this mineral-regulating system is fully integrated is not yet understood. The effects of FGF23 described above, inhibiting PTH synthesis and secretion and inhibiting calcitriol synthesis, together with its inhibition of phosphate transporters in the proximal convoluted tubule, which causes its phosphate-excreting effect, all appear to require alpha-klotho, a protein in the cell membrane that allows FGF23 to activate FGF receptor 1. Alpha-klotho can be cut from the cell membrane and released into the circulation as soluble klotho, whose physiological importance is poorly understood. Soluble klotho and FGF23 may each have effects that do not depend on the other. For example, klotho on its own increased the expression of TRPV5 channels in the distal tubule of the kidney, increasing calcium reabsorption (Wolf et al., 2014). For FGF23, effects that do not depend on klotho may be more important in disease than in normal physiology (see below).

4. The Role of FGF23 in the Mineral and Bone Disturbance of CKD

In human patients with CKD whose vitamin D status is normal, the first sign of the mineral and bone disturbance of CKD is an increase in plasma FGF23 (Isakova et al., 2011). This appears to be an adaptive response to phosphate retention in the body as a whole: as GFR declines, the kidneys can no longer excrete the same amount of phosphate each day. By reducing phosphate reabsorption in the proximal tubule, FGF23 allows each remaining functioning nephron to excrete more phosphate, so that the fasting plasma phosphate concentration stays stable on the same diet despite the fall in GFR.

The same pattern of changes most likely occurs in cats and dogs. Most is known so far about the cat. Plasma FGF23 was increased in apparently healthy cats that went on to develop azotemic CKD within 12 months of screening, compared with cats that remained healthy and non-azotemic 12 months after screening (Finch et al., 2013). In dogs, FGF23 also appears to be an early indicator of mineral and bone disorder (Harjes et al., 2017), and it predicts the development of high blood phosphate and the progression of CKD (Miyakawa et al., 2021).

Intact FGF23 is a 32 kDa protein that is cleared from the plasma by the kidneys, so part of the reason it rises in CKD is reduced renal clearance. Nevertheless, plasma phosphate is an independent predictor of plasma FGF23 in cats with CKD. In one study, cats were grouped by IRIS CKD stage and classified as either hyperphosphatemic or normophosphatemic for their stage, using the stage-related IRIS plasma phosphate targets. Cats that were hyperphosphatemic for their stage had significantly higher plasma FGF23 concentrations than those that were normophosphatemic, despite no difference in creatinine concentrations (Geddes et al., 2013a), which shows how important phosphate is in determining the circulating intact FGF23 concentration. Other factors independently related to plasma FGF23 in this study were plasma total calcium and packed cell volume (PCV), which was inversely related: the lower the PCV, the higher the plasma FGF23.

Another important factor influencing plasma FGF23 in cats with CKD, which was not measured in these early studies, is plasma magnesium. Van den Broek et al. (2018) showed that low plasma magnesium concentrations were associated with higher plasma FGF23 concentrations. This is consistent with the human literature and suggests that plasma magnesium should be measured when assessing the mineral and bone disturbance of CKD.

Plasma FGF23 at the initial diagnosis of CKD appears to be a risk factor for death from any cause, independent of age and plasma creatinine, and for future progression of CKD in cats, defined as an increase in plasma creatinine of more than 25% within 12 months (Geddes et al., 2015). Similar findings on CKD progression and survival have been reported in dogs (Miyakawa et al., 2021; Rudinsky et al., 2018). These findings show the value of plasma FGF23 as a prognostic biomarker in feline and canine CKD. However, such epidemiological risk-factor studies cannot show whether FGF23 causes poor outcomes or is merely a biomarker indirectly associated with them.

They do suggest, though, that at some point increasing plasma FGF23 becomes a maladaptive response of bone cells to CKD. When the appropriate, adaptive response, which allows plasma phosphate to be regulated despite the loss of kidney function, turns into a maladaptive one, with soft tissue mineralization and bone disease, remains to be determined in veterinary species. In people, it has been suggested that this transition happens as the kidney's expression of klotho declines. Tissue klotho expression is reduced in CKD (Sakan et al., 2014), as a result of uremic toxins such as indoxyl sulfate and p-cresyl sulfate (Young and Wu, 2012) and of proteinuria (Delitsikou et al., 2020). FGF23 then becomes much less able to activate FGF receptor 1, which needs klotho as a co-receptor. At that point, plasma PTH starts to rise, because FGF23 no longer inhibits PTH synthesis and secretion, and eventually plasma phosphate starts to increase and ionized calcium to decrease. An independent association between serum indoxyl sulfate and FGF23 concentrations has also been found in cats (Liao et al., 2019), but changes in klotho expression have yet to be assessed in veterinary species.

Other disease processes that may raise plasma FGF23 in clinical patients, and that have not been studied in any detail in veterinary patients, include chronic inflammation and iron deficiency, which may occur together with anemia in veterinary CKD patients. Iron deficiency increases FGF23 gene expression through HIF-1α, a factor whose breakdown depends on iron. The result is an increase in circulating C-terminal FGF23 (cFGF23), because processing of the protein prevents intact FGF23 from being secreted. However, some of the intravenous iron products used to treat iron deficiency, such as iron polymaltose and ferric carboxymaltose, block this processing and so increase plasma intact FGF23. Recombinant erythropoietin increases FGF23 gene expression and serum cFGF23 concentrations, and in high doses, or combined with intravenous iron, it may increase plasma intact FGF23, although the clinical importance of this in human medicine is unclear. See Wheeler and Clinkenbeard (2019) and Zhang et al. (2021) for reviews of this topic.

Cytokines such as TNFα, IL-1β, and IL-6 are potent stimuli for FGF23 secretion from osteocytes, and they have been shown to increase intact FGF23 in experimental models of both acute kidney injury and chronic kidney disease (Durlacher-Betzer et al., 2018). The interplay between chronic inflammation, iron deficiency, and anemia in CKD is complex and clinically relevant, particularly in the later stages of CKD. There, as well as these factors increasing circulating FGF23, very high FGF23 concentrations can themselves promote inflammation, by activating FGF receptor 4 on macrophages, and can worsen anemia by inhibiting erythropoietin production (see Babitt and Sitara, 2019).

5. Clinical Use of FGF23 Measurement

Intact FGF23 is now offered by commercial laboratories as a diagnostic test to help monitor the treatment of CKD. In early CKD, diagnosed without an increased plasma creatinine, the need for dietary phosphate restriction cannot be judged from serum phosphate. All veterinary patients diagnosed in Stage 1 CKD, and a good proportion of cats diagnosed in Stage 2, have plasma creatinine within the laboratory reference interval, with the diagnosis of CKD based on other clinical and laboratory findings. Most of these patients will have plasma phosphate below the upper limit of the IRIS target range for their stage (see the target ranges below). Plasma intact FGF23 could help identify which of these cats have evidence of mineral and bone disturbance and so will benefit from dietary phosphate restriction. A baseline FGF23 measurement in these patients also makes it possible to assess their response to treatment. Geddes et al. (2013b) showed that when azotemic, normophosphatemic cats were moved onto a phosphate-restricted diet, their plasma FGF23 fell 4 to 8 weeks later.

IRIS Target Ranges for Serum Phosphate in Cats With CKD

• Stages 1 and 2: keep serum phosphate between 2.7 and 4.5 mg/dL (0.9 to 1.5 mmol/L).
• Stage 3: keep serum phosphate between 2.7 and 5.0 mg/dL (0.9 to 1.6 mmol/L).
• Stage 4: keep serum phosphate between 2.7 and 6.0 mg/dL (0.9 to 1.9 mmol/L).

Plasma calcium, ideally ionized calcium, should be assessed in all cats when CKD is diagnosed, because idiopathic hypercalcemia has been associated with CKD (van den Broek et al., 2017). Some cats tend to develop hypercalcemia when fed a phosphate-restricted diet (Geddes et al., 2021), particularly when a markedly phosphate-restricted diet is introduced in cats with relatively low plasma phosphate (Tang et al., 2021). Cats that respond to phosphate restriction with an increase in plasma calcium seem to show an increase, rather than a decrease, in plasma FGF23, which again emphasizes the importance of monitoring both phosphate and calcium after a diet change.

In CKD patients whose plasma phosphate is above the IRIS target range for their stage, there is no need to measure plasma FGF23, because plasma phosphate can be used to monitor the response to treatment. Once plasma phosphate falls into the target range for the stage, measuring plasma FGF23 becomes valuable for continuing to monitor the response. If FGF23 levels off well above the recommended concentration, additional measures to restrict intestinal phosphate absorption should be started, such as changing to a more phosphate-restricted kidney diet or adding an intestinal phosphate binder. In human medicine, meta-analyses of clinical trial data have shown that phosphate binders that do not contain calcium reduce plasma FGF23, whereas calcium-containing binders are less effective (Takkavatakarn et al., 2022; Zhao et al., 2022). It therefore seems prudent to recommend binders that do not contain calcium for veterinary patients, such as those containing aluminum or lanthanum.

FGF23 may also be increased in CKD patients for reasons not directly related to phosphate balance. These should be considered when FGF23 stays high although plasma phosphate has been controlled within the IRIS target range:

• Low blood magnesium (hypomagnesemia) worsens the mineral and bone disturbance and increases FGF23 secretion, even in cats with normal phosphate. In theory, adding magnesium to the diet could correct hypomagnesemia in such cases, but there is currently no evidence on the safety and effectiveness of this approach in veterinary patients.
• Chronic inflammatory disease can activate osteocytes through circulating cytokines and increase plasma FGF23. Treating specific causes of chronic inflammation where possible, for example periodontal disease, may help control the mineral and bone disturbance of CKD. Evidence on the risks and benefits of this approach in veterinary patients is currently lacking, and it would need to be judged for each patient, for example weighing the welfare benefit of treating dental disease against the risk of an acute worsening of CKD caused by the procedure.
• Iron deficiency can worsen the mineral and bone disorder of CKD, as discussed above. Iron deficiency can result from chronic inflammation, through increased hepcidin and impaired iron recycling, and can contribute to the anemia of CKD, and all three factors affect the regulation of FGF23 synthesis and secretion (see Babitt and Sitara, 2019). Iron status is difficult to assess accurately in CKD patients, even when anemia is present, because the laboratory tests are hard to interpret definitively. The iron product used for replacement should also be chosen carefully, based on experience in human medicine, where some injectable preparations increase intact FGF23 secretion (see Babitt and Sitara, 2019).

6. Interpreting Plasma Intact FGF23 Concentrations

The current recommendations for plasma intact FGF23 concentrations are based on published data from cats diagnosed with early, non-azotemic CKD. These cats, in IRIS Stage 1 or in Stage 2 with serum creatinine still within the laboratory reference interval, were identified either because they developed azotemic CKD within 12 months of screening (Finch et al., 2013) or because their SDMA was increased above 14 µg/dL (Sargent et al., 2019). The recommendations are also based on the normal changes in FGF23 seen when dietary phosphate intake was increased from a low to a moderate level in healthy adult cats, in which long-term feeding of the moderately phosphate-supplemented diet had no harmful effects on kidney health (Coltherd et al., 2021). In that study, the plasma FGF23 response to increased phosphate intake rarely exceeded 400 pg/mL, and once the cats had been eating the diets for 2 to 3 months, plasma FGF23 was below 300 pg/mL in about 90% of cats.

These recommendations are based on an ELISA for intact human FGF23 made by Kainos Laboratories in Japan and offered as a veterinary diagnostic test by IDEXX Laboratories.

Early CKD in Cats: Using FGF23 to Decide on Phosphate Restriction

For cats diagnosed with CKD while their plasma creatinine is still within the laboratory reference interval:

• FGF23 above 400 pg/mL: there is evidence of mineral and bone disturbance, and treatment with an early kidney diet, with moderate phosphate restriction, is appropriate.
• FGF23 between 300 and 400 pg/mL: the cat should be monitored, with FGF23 rechecked over time.
• FGF23 below 300 pg/mL: there is no evidence of mineral and bone disturbance, so dietary phosphate restriction is not needed.

Calcium should be checked before and after starting a phosphate-restricted diet, as described in Section 5.

Azotemic CKD in Cats: Using FGF23 to Monitor Phosphate Restriction

Recommendations for using FGF23 to monitor the response of azotemic cats to phosphate restriction are currently empirical, based on the epidemiological study showing a relationship between FGF23 and survival. The quarter of cats with the lowest plasma FGF23 at diagnosis of CKD survived longest, and these cats had plasma FGF23 below 700 pg/mL. The suggested approach is:

1. While plasma phosphate is above the IRIS target range for the cat's stage, use phosphate itself to monitor treatment.
2. Once plasma phosphate is well within the target range, measure plasma FGF23.
3. Aim to reduce FGF23 below 700 pg/mL. Without an intestinal phosphate binder, this may only be achievable in Stage 2 cats and a minority of Stage 3 cats, and it can take weeks to months of continued dietary phosphate restriction, with or without a phosphate binder, to bring FGF23 down to its lowest level.
4. If FGF23 stays well above 700 pg/mL, increase phosphate restriction, for example by moving to a more phosphate-restricted kidney diet or adding a phosphate binder that does not contain calcium.
5. If FGF23 remains high even though phosphate is controlled, look for other causes, such as low blood magnesium, chronic inflammatory disease, and iron deficiency.

The IRIS treatment recommendations for cats, as modified in 2026, use the same thresholds. An FGF23 above 400 pg/mL, in the absence of hypercalcemia, anemia, or marked inflammatory disease, is an indication to start dietary phosphate restriction, and if total calcium rises above 12 mg/dL (3 mmol/L), the cat should be moved to a less phosphate-restricted diet. Once phosphate is within the target range, an FGF23 above 700 pg/mL is a reason to increase phosphate restriction, and an FGF23 below 500 pg/mL indicates excellent control of mineral and bone disturbance.

In time, IRIS may have the evidence to set target FGF23 concentrations for each stage of CKD in cats whose plasma phosphate is well controlled within the current target ranges. This will require larger numbers of cats to be monitored over time, to assess the effect of treatment on FGF23 and how this predicts outcome.

At present, it is not possible to make similar recommendations for dogs, because the published data needed to support them are not available.

7. Harmful Effects of FGF23

One way in which FGF23 may harm the kidney and cause stress to the tubules is through its normal job of inhibiting phosphate reabsorption in the proximal convoluted tubule. People and cats eating prepared foods supplemented with highly available forms of phosphate, such as sodium dihydrogen phosphate, have a peak in plasma phosphate after meals and increased formation of calciprotein particles (Tiong et al., 2022). Phosphate and the smallest CPPs (CPP monomers) are freely filtered by the glomerulus. Both FGF23 and PTH reduce the proportion of filtered phosphate that is reabsorbed in the proximal convoluted tubule. This raises the phosphate concentration of the tubular fluid by the S3 segment of the tubule and leads to the formation of larger CPPs, which bind to TLR4 receptors on the tubular lining cells. The receptors and particles are taken into the cells, which triggers tubular stress. A persistently high phosphate concentration in the S3 tubular fluid, 3 mmol/L or more, is associated with inflammation and fibrosis of the kidney interstitium in laboratory animal models (Shiizaki et al., 2021). Theoretical calculations suggest that such concentrations do occur in the last part of the proximal tubule when cats are fed high levels of soluble phosphate, which has been associated with damage to kidney health (Alexander et al., 2019; Elliott and Geddes, 2022).

Whether FGF23 directly harms the kidney once its plasma concentrations start to rise in CKD remains to be determined. There is evidence that FGF23 can be directly responsible, even in the absence of klotho, for some of the harmful effects outside the kidney of the mineral and bone disorder that accompanies CKD in human patients and experimental models. Therapies that inhibit FGF23, such as blocking antibodies like burosumab, have proved effective in clinical trials in genetic disorders and tumors that cause excess FGF23 secretion (Insogna et al., 2018). These therapies are now being studied in models of CKD before moving into clinical trials in people with CKD.

Once klotho deficiency develops in a CKD patient and bone produces ever-increasing amounts of FGF23, there is clear evidence from laboratory and animal studies that FGF23 contributes to the heart muscle thickening (cardiac hypertrophy) and vascular calcification associated with CKD. Both contribute to the cardiovascular disease that is often the cause of death in people with CKD maintained on dialysis. These effects appear not to depend on klotho, and there is strong evidence that the cardiac hypertrophy is driven by FGF23 activating FGF receptor 4, an effect made worse by the heparin routinely given to patients on long-term dialysis (Yanucil et al., 2022).

Our understanding of the direct harmful effects of FGF23 in veterinary patients is at an early stage. In cats with CKD, clinical evidence of cardiovascular disease is not well documented, apart from systemic hypertension. Nevertheless, in one long-term study of cats with CKD, 19% died or were euthanized because of a cardiovascular complication of their CKD, such as aortic thromboembolism, sudden collapse and death, or congestive heart failure (Elliott et al., 2000). FGF23 also tends to be higher, and plasma magnesium lower, in cats with hypertension and CKD than in normotensive cats with CKD (van den Broek, 2018). In addition, there appears to be a strong correlation between plasma FGF23 and plasma aldosterone concentrations in several species, including the cat (Radloff et al., 2021), which suggests that FGF23 may play a role in the development of hypertension associated with feline CKD.

8. Conclusion

The discovery of FGF23 as a regulator of phosphate balance has changed our understanding of how the bone, kidney, and intestine work together to regulate calcium and phosphate. With commercial assays now available, the value of FGF23 as a biomarker in CKD patients is beginning to be realized in veterinary medicine. At present, plasma intact FGF23 appears to have a place in deciding which cats with early CKD would benefit most from moderate phosphate restriction, and in monitoring the response to diet therapy in cats whose plasma phosphate is within the IRIS target ranges. FGF23 may also become a target for treatment in future, because mechanistic studies in experimental animals strongly suggest that it is central to the progression of CKD and to the effects of the mineral and bone disorder of CKD outside the kidney.

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