AKI is often accompanied by a systemic inflammatory response. Pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and IL-1β can stimulate FGF23 gene expression in bone. IL-6 in particular has been shown to directly induce FGF23 transcription via STAT3 signaling in osteocytes (Durlacher-Betzer et al., 2018). In AKI patients and models, IL-6 levels rise sharply; this has been causally linked to FGF23 upregulation. For instance, Radhakrishnan et al. demonstrated that AKI in mice triggers IL-6, which in turn induces hepatic expression of the nuclear receptor ERRγ, driving FGF23 production in the liver (Radhakrishnan et al., 2021). In summary, acute inflammation during AKI provides a potent stimulus for FGF23 production, both in bone and ectopically (e.g., liver), through cytokine-driven transcriptional pathways (Czaya and Faul, 2019).

Ischemia-reperfusion injury in AKI leads to cellular metabolic stress. One novel pathway involves glycerol-3-phosphate (G-3-P), a glycolytic byproduct that accumulates during renal ischemia (Zhou et al., 2022). Simic et al. discovered that injured kidneys release G-3-P into circulation; in bone, G-3-P is converted to lysophosphatidic acid, which activates osteocyte LPA_1 receptors and markedly increases FGF23 secretion (Simic et al., 2020). This mechanism provides a direct link between acute tubular injury and remote bone endocrine function. Hypoxia-inducible factors (HIFs) activated in ischemic kidneys may also play a role in FGF23 regulation, as they do in conditions like iron deficiency (Edmonston and Wolf, 2020). Thus, AKI-related hypoxia and metabolic reprogramming can send FGF23-inductive signals to bone.

Even a short-lived decline in GFR will reduce the kidney’s ability to catabolize and excrete FGF23 (11). FGF23 is normally filtered and possibly degraded by kidneys; hence AKI can cause retention of circulating FGF23 (Mace et al., 2015). Studies suggest this is a contributing factor but not the sole explanation, given the outsized increase of FGF23 relative to the degree of GFR drop in many AKI cases (Zhang and Qin, 2023). Nonetheless, impaired clearance likely augments the hormone’s accumulation during AKI.

AKI is known to cause an acute loss of Klotho through renal shedding and reduced expression (Hu et al., 2010). Diminished Klotho might paradoxically feedback to drive FGF23 higher, as tissues sense FGF23 resistance. Moreover, Klotho itself has renoprotective effects; its loss could exacerbate injury. Preclinical studies show exogenous Klotho can ameliorate AKI severity (Hu et al., 2021), suggesting a complex interplay where FGF23 rises and Klotho falls during AKI, each potentially influencing the other’s levels.

AKI is associated with early disturbances in iron handling and erythropoiesis (van Swelm et al., 2020). Inflammatory AKI raises hepcidin, causing functional iron deficiency; in turn, iron deficiency stabilizes HIF-1α in osteocytes, which increases FGF23 transcription (Rroji et al., 2023). Additionally, high doses of erythropoietin (EPO) given in acute illness can acutely raise FGF23 production (with increased cleavage, so intact hormone changes may be muted) (Martínez-Heredia et al., 2024). While these factors are more established in chronic disease, they may also contribute if AKI is accompanied by anemia management and inflammation.

Multiple interlocking mechanisms drive the sustained upregulation of FGF23 in CKD. These can be viewed as initially adaptive responses to declining renal function that later become maladaptive contributors to pathology.

Reduced nephron mass in CKD leads to decreased phosphate excretion (Rodelo-Haad et al., 2025). Even before serum phosphate rises, the body senses phosphate “loading,” which stimulates osteocytes to secrete more FGF23 to enhance phosphaturia (Pereira et al., 2009). This is a key homeostatic driver: FGF23 increases in an attempt to maintain neutral phosphate balance despite falling GFR (Rodelo-Haad et al., 2025). Early CKD studies showed an inverse relationship between renal phosphate clearance and FGF23 levels (Komaba and Fukagawa, 2009). However, as CKD advances, even massive FGF23 elevations cannot prevent hyperphosphatemia because the kidneys simply cannot excrete enough phosphate (Vogt et al., 2019). In essence, chronic phosphate retention is the fundamental stimulus for chronic FGF23 elevation. Notably, interventions like phosphate binders or low-phosphate diet can reduce FGF23 levels in CKD, underscoring phosphate as a driving factor (Zhao et al., 2022; Cozzolino et al., 2013).

The failing kidney produces less Klotho (Lu and Hu, 2017). Declining Klotho expression is a hallmark of CKD and has two major effects on FGF23 dynamics. First, low renal Klotho makes the kidney less responsive to FGF23, meaning phosphate excretion does not increase appropriately even as FGF23 rises (Vogt et al., 2019). This resistance causes a vicious cycle: sensing ineffectiveness, osteocytes secrete even more FGF23 in compensation (Vogt et al., 2019). Second, Klotho deficiency extends to the parathyroid glands and perhaps other tissues, where the FGFR–Klotho complex is needed for FGF23’s hormonal actions. In advanced CKD, parathyroid glands have reduced Klotho/FGFR1, rendering them less sensitive to FGF23’s usual PTH-suppressing effect. Consequently, FGF23 loses its ability to inhibit PTH in late CKD–high FGF23 and high PTH coexist because the signal to the parathyroid is resisted (Czaya and Faul, 2019). This contributes to secondary hyperparathyroidism. Overall, early Klotho loss in CKD both triggers a maladaptive FGF23 surge and nullifies some of FGF23’s regulatory feedback, exacerbating mineral imbalance (Nakagawa and Komaba, 2024).

As FGF23 rises, it suppresses 1,25-dihydroxyvitamin D, which lowers calcium absorption and contributes to hypocalcemia and hyperparathyroidism (Bergwitz and Jüppner, 2010). Meanwhile, by late CKD, PTH is markedly elevated (Nakagawa and Komaba, 2024). PTH itself may influence FGF23: studies suggest PTH can stimulate FGF23 production, and conversely, high FGF23 normally suppresses PTH(34). In CKD, this cross-talk is disrupted. The net effect is a feed-forward loop: declining calcitriol and rising PTH both drive more FGF23 secretion (Sharma and Ix, 2023). Thus, the normal endocrine axes are skewed, with FGF23, PTH, and vitamin D locked in a pathological imbalance.

CKD is a state of persistent low-grade inflammation (Czaya and Faul, 2019; Oberg et al., 2004). Circulating levels of IL-6, TNF-α, and other cytokines are often elevated in CKD patients, especially as GFR falls. These inflammatory mediators can chronically stimulate FGF23 production in bone (Munoz Mendoza et al., 2012). Moreover, there is evidence that FGF23 itself can exacerbate inflammation: FGF23 signalingparticularly via FGFR4may promote production of inflammatory cytokines in certain contexts (Singh et al., 2016). A cycle may thus form where inflammation raises FGF23, which in turn feeds back to worsening inflammation and tissue injury, contributing to CKD progression (Czaya and Faul, 2019). Oxidative stress, often linked with inflammation, can activate osteocyte signaling pathways (like NF-κB or HIF) that upregulate FGF23 transcription (Rodelo-Haad et al., 2025; Czaya and Faul, 2019). In summary, the inflammatory milieu of CKD adds a smoldering stimulant to FGF23 synthesis beyond the direct mineral metabolism factors.

CKD patients frequently develop anemia and functional iron deficiency (Courbon et al., 2020). This has a complex effect on FGF23 regulation. Iron deficiency in bone triggers increased FGF23 gene transcription via HIF-1α, but it also increases FGF23 cleavage, so intact FGF23 may not rise proportionally unless iron deficiency is accompanied by inflammation or CKD (Rroji et al., 2023). In CKD, there is both increased production and reduced degradation of FGF23, so iron deficiency tends to raise total and intact FGF23. Treatment with erythropoiesis-stimulating agents (ESAs) like EPO can acutely raise total FGF23, but also enhance FGF23 cleavage–resulting in transiently higher C-terminal fragment levels without a large spike in intact hormone (Czaya and Faul, 2019). Notably, in CKD animals that have impaired FGF23 cleavage, EPO injection does elevate intact FGF23 significantly (Hanudel et al., 2019b). This suggests that in advanced CKD, EPO therapy could contribute to higher active FGF23. On the flip side, FGF23 itself affects iron and erythropoiesis: it suppresses renal EPO production and increases hepatic hepcidin via inflammatory cytokine induction (Czaya and Faul, 2019; Coe et al., 2014). This bidirectional relationship ties anemia management to FGF23 levels. Clinically, correcting iron deficiency in CKD has been shown to lower FGF23 levels in many cases, improving both anemia and reducing FGF23’s potential toxicity (Martínez-Heredia et al., 2024; Courbon et al., 2020). Thus, iron/EPO disturbances in CKD represent another layer of FGF23 regulation.

In combination, these mechanisms paint a picture of FGF23 regulation in CKD as initially compensatory but eventually pathologic. Phosphate retention provides the initial push; Klotho loss removes the brakes; disordered feedback with PTH/vitamin D, chronic inflammation, and anemia-related factors all further fuel FGF23 overproduction. The result is a hormone that becomes drastically elevated and part of the CKD pathophysiology itself. Addressing these upstream drivers–phosphate burden, Klotho deficiency, inflammation, and iron deficiency–is central to managing CKD-MBD and could modulate FGF23 levels.

Unlike AKI or ordinary CKD where FGF23 originates mainly from bone, ADPKD seems to feature extra-osseous FGF23 production, particularly in the liver. ADPKD patients commonly have polycystic liver disease. Bienaimé et al. showed that severely polycystic livers express FGF23 mRNA and protein, and that circulating FGF23 levels in ADPKD correlated with liver cyst volume (Bienaimé et al., 2018). This suggests the liver cyst epithelium can produce FGF23, contributing to systemic levels. The mechanism may involve the polycystin-1/2 mutation effect on the liver or the local environment of cystic liver tissue. Ectopic hepatic production helps explain why some ADPKD patients have high FGF23 even when their kidney function is relatively intact–an additional source independent of renal clearance. Thus, ADPKD represents a scenario where FGF23 regulation is not solely bone-kidney; the liver becomes an endocrine organ for FGF23 (Hanudel et al., 2019a).

There is evidence that FGF23 is produced within cystic kidneys themselves. Animal models of PKD have shown cyst-lining cells in the kidney expressing FGF23 mRNA and protein (Spichtig et al., 2014). The microenvironment in polycystic kidneys is characterized by regional ischemia, hypoxia (Theodorakopoulou et al., 2019), and inflammation (Mun and Park, 2016). Hypoxia-inducible factor 1α (HIF-1α) is known to upregulate FGF23 transcription by binding hypoxia-response elements in the FGF23 gene (Hanudel et al., 2019a). ADPKD cysts likely experience hypoxia, which could induce local FGF23 production. In a human ADPKD study, one patient with extensive liver cysts had extraordinarily high FGF23 levels and evidence of bone FGF23 expression, supporting the concept that cystic disease can drive FGF23 (Hanudel et al., 2019a). Chronic inflammation in the cystic kidney may also contribute, similar to CKD. Therefore, cystic remodeling of organs in ADPKD provides a nidus for FGF23 production through hypoxia and inflammatory signaling.

ADPKD kidneys exhibit reduced Klotho expression even at early stages (Pavik et al., 2012). Akiyama et al. found that ADPKD patients had lower soluble Klotho levels than non-ADPKD CKD controls at the same eGFR, and higher FGF23 levels, consistent with relative FGF23 resistance (Akiyama et al., 2017). Low Klotho in ADPKD would make the kidney less responsive to FGF23’s phosphate-wasting signal, potentially causing an even greater increase in FGF23 production as compensation. This mechanism mirrors CKD but is noteworthy in ADPKD because Klotho deficiency appears out of proportion to GFR. FGF23 resistance might also manifest as an inappropriately normal or high TmP/GFR despite high FGF23 (Gitomer et al., 2021) – in other words, the phosphate reabsorption in ADPKD kidneys might be higher than expected for the level of FGF23, because of Klotho loss. The net effect is a feedback loop: cystic kidneys are “deaf” to FGF23, phosphate excretion is impaired relative to FGF23 levels, leading osteocytes to further ramp up FGF23 secretion.

Paradoxically, many ADPKD patients waste phosphate (Xue et al., 2024). This could be due to specific proximal tubular defects or FGFR resistance patterns in the kidney. ADPKD mutations in PKD1/PKD2 affect cilia and cellular signaling, possibly altering how tubules handle minerals. Some hypothesize that primary cilia dysfunction in osteocytes or kidney cells could dysregulate FGF23 production or response (Righini et al., 2024; Mekahli and Bacchetta, 2013). Additionally, as cysts expand, normal nephron segments may become less responsive or structurally altered, leading to impaired phosphate reabsorption. The high copeptin levels in ADPKD and possible differences in tubular transporters might contribute to a lower phosphate reabsorption threshold. The DIPAK study mentioned earlier suggests that a portion of ADPKD patients have an intrinsic proximal tubular defect causing phosphate leak, which correlates with disease severity (Xue et al., 2024).

Some research indicates that ADPKD might influence the processing of FGF23. Bienaimé et al. noted that ADPKD patients with preserved GFR had a disproportionately high C-terminal FGF23 relative to intact FGF23, suggesting enhanced cleavage of FGF23 into fragments (Bienaimé et al., 2018). This could be due to upregulation of proteases (like furin) in the liver or bone triggered by ADPKD-related factors, or perhaps an effect of the PKD gene on FGF23-producing cells. If FGF23 is being cleaved more, it could create a scenario of high total FGF23 but moderated intact levels in early disease. As ADPKD progresses and CKD sets in, cleavage might decrease, leading to a sharp rise in intact FGF23. Such complexities mean that interpreting FGF23 levels in ADPKD might require understanding the fragment composition. Regardless, altered post-translational processing is another facet of how ADPKD can uniquely modulate FGF23 regulation (Hanudel et al., 2019a; Bienaimé et al., 2018).

In essence, ADPKD’s effect on FGF23 is multi-factorial: part CKD-like, part unique (cystic liver and kidney producing FGF23, early Klotho loss, phosphate handling quirks). The heterogeneity even among ADPKD patients is notable–some with early high FGF23 and phosphorus wasting, others not until later. This likely reflects genetic and structural variability.

High FGF23 is one of the strongest known independent predictors of adverse outcomes in CKD. Large cohort studies have shown that CKD patients with elevated FGF23 have higher risks of death, cardiovascular events, and progression to end-stage renal disease (Kendrick et al., 2011; Isakova et al., 2011b). For instance, in a study of patients with CKD stages 4–5, FGF23 was a significant predictor of progression to dialysis and mortality, even after adjusting for eGFR and phosphate (Kendrick et al., 2011). Another cohort (CKD stages 2–3) found FGF23 levels were independently associated with faster kidney function decline and greater all-cause mortality (Isakova et al., 2011b). These findings have been consistent: each increase in FGF23 correlates with worse survival. The prognostic power of FGF23 is comparable to or stronger than traditional factors like phosphate or PTH. Therefore, FGF23 is increasingly recognized as a key risk stratifier in CKD, potentially guiding how aggressively to manage a patient’s mineral disorder or cardiovascular risk factors.

Chronic high FGF23 has direct toxic effects on the cardiovascular system. In CKD, elevated FGF23 is strongly linked to left ventricular hypertrophy (LVH), arterial stiffness, and vascular calcification (Vogt et al., 2019; Martínez-Heredia et al., 2024; Courbon et al., 2020). Mechanistic studies by Faul et al. showed that FGF23 acts on cardiomyocytes via FGFR4 to induce hypertrophic signaling, activating the PLCγ–calcineurin–NFAT pathway and leading to LVH (Faul et al., 2011). This is supported by animal models: rodents given FGF23 develop cardiac hypertrophy, whereas FGFR4 blockade can prevent it even with high phosphate diet (Grabner et al., 2017). Clinically, CKD patients with higher FGF23 levels have greater left ventricular mass and a higher prevalence of heart failure. FGF23 also may contribute to vascular dysfunction–it has been implicated in promoting arterial stiffness and possibly enhancing calcium deposition in vessels (Vogt et al., 2019; Martínez-Heredia et al., 2024). Additionally, FGF23 can activate the renin-angiotensin-aldosterone system and increase sodium retention via effects on the Na-Cl cotransporter, thereby worsening hypertension (Vogt et al., 2019). These multiple pathways qualify FGF23 as a “cardiovascular toxin” in CKD. The recognition of FGF23’s role in uremic cardiomyopathy has prompted interest in therapeutically lowering FGF23 or blocking its cardiac receptors to improve outcomes.

FGF23 is a central player in CKD-mineral and bone disorder (CKD-MBD). By suppressing calcitriol and driving secondary hyperparathyroidism, high FGF23 contributes to renal osteodystrophy and bone fragility in CKD (Komaba, 2023). Some CKD patients develop an adynamic bone disease partly due to oversuppression of PTH by treatments, leading to low bone turnover (Bover et al., 2014). Conversely, early in CKD, high FGF23 with normal PTH can indicate subtle bone mineral abnormalities even before overt changes in bone density or turnover markers (Vogt et al., 2019; Ott, 2012). Monitoring FGF23 might help identify patients at risk for skeletal complications or who might benefit from interventions like vitamin D analogues or calcimimetics (Stubbs et al., 2007).

There is emerging evidence that FGF23 might worsen kidney fibrosis and disease progression (Isakova et al., 2011b; Kosugi et al., 2025), as mentioned earlier in the AKI-to-CKD context. In CKD models, excess FGF23 signaling, especially via FGFR4, can activate pro-fibrotic pathways (Lu et al., 2023). Whether lowering FGF23 would slow CKD progression in humans is not yet proven, but it remains an intriguing hypothesis. It has been observed that interventions reducing FGF23 can associate with stabilization of kidney function, though cause-effect is hard to establish given confounders (Courbon et al., 2020; Damasiewicz et al., 2011).

Managing FGF23 in CKD is complex because FGF23 elevation is a consequence of adaptive responses. Directly targeting FGF23 could normalize FGF23 levels but at the cost of precipitating hyperphosphatemia and calcitriol increases, which could accelerate vascular calcification (Vogt et al., 2019). In fact, animal studies confirm that indiscriminate FGF23 blockade in CKD leads to dangerous hyperphosphatemia and greater vascular calcifications (Shalhoub et al., 2012). Therefore, the consensus is that indirect strategies are safer: reducing the stimuli for FGF23 or blocking its harmful effects rather than FGF23 itself. Key approaches include.

Dietary phosphate restriction, phosphate binders, and optimized dialysis are mainstays, which can reduce FGF23 by 20%–50% in CKD patients (Vogt et al., 2019; Zhao et al., 2022). Notably, iron-based binders (ferric citrate) both bind phosphate and treat iron deficiency, yielding significant FGF23 reductions and improved anemia (Zhao et al., 2022; Agoro and White, 2022).

Active vitamin D sterols can suppress PTH, but they raise FGF23. Calcimimetics reduce PTH and calcium × phosphate product, which might indirectly lower FGF23 or at least mitigate its drivers (Koizumi et al., 2012). Trials have not primarily focused on FGF23, but one analysis (EVOLVE trial) noted that patients with greater FGF23 reductions had better outcomes (Moe et al., 2015).

Correcting iron deficiency in CKD can lower FGF23, especially C-terminal fragments, by reducing HIF-driven production and perhaps increasing FGF23 cleavage (Agoro and White, 2022). Intravenous iron, interestingly, acutely raises intact FGF23 by reducing cleavage, but over time, both IV and oral iron reduce total FGF23 and improve anemia (Takkavatakarn et al., 2022). New therapies like HIF-prolyl hydroxylase inhibitors (used for anemia) have been shown in animal studies to reduce FGF23 levels while improving iron utilization (Noonan et al., 2020). Keeping hemoglobin in the target range with minimal ESA dosing may also stabilize FGF23 levels (Agoro and White, 2022).

Rather than neutralize FGF23, an alternative is to block its deleterious pathways. One example is FGFR4 inhibitors to prevent cardiac hypertrophy. Experimental studies show that FGFR4 blockade can protect the heart from FGF23-induced hypertrophy without affecting the kidney which primarily uses FGFR1/Klotho for FGF23 (Grabner et al., 2017).

Restoring Klotho levels could improve FGF23 sensitivity and mitigate the compensatory FGF23 hypersecretion. Animal models of CKD treated with Klotho have shown improved phosphate handling and less vascular calcification (Hu et al., 2017; Hum et al., 2017). While not yet available clinically, Klotho-targeted therapies are being explored for CKD, which in theory would help “reset” the FGF23-Klotho axis toward normal.

Because FGF23 can rise early in ADPKD, it may serve as a marker of underlying disease burden that is not captured by GFR or serum creatinine (Pavik et al., 2012). An ADPKD patient might have normal kidney function yet significant cystic changes and hepatic involvement that lead to high FGF23. Bienaimé et al. demonstrated that FGF23 levels correlated with liver cyst severity (Bienaimé et al., 2018), suggesting FGF23 as a proxy for extrarenal (liver) cyst involvement. Thus, FGF23 could be explored as a non-invasive biomarker to identify patients with extensive cystic disease who might benefit from more aggressive therapy or monitoring, even before kidney function declines. It might also help distinguish ADPKD from other causes of CKD in cases where the diagnosis is uncertain.

Growing evidence links higher FGF23 levels in ADPKD to more rapid disease progression. A notable study (HALT-PKD and others) found that ADPKD patients with higher baseline FGF23 had faster increase in total kidney volume (TKV) and more rapid decline in GFR over time (Chonchol et al., 2017). El Ters et al. reported that serum FGF23 was an independent prognostic biomarker for renal enlargement and function loss, as well as mortality, in early-stage ADPKD (El et al., 2021). This means FGF23 might help stratify patients by risk.

ADPKD patients, like CKD patients, suffer cardiovascular issues even before ESRD. High FGF23 in ADPKD likely contributes similarly to cardiac remodeling and vascular dysfunction as it does in other CKD. Studies have observed that ADPKD patients with elevated FGF23 have greater left ventricular mass and arterial stiffness (Righini et al., 2024), paralleling CKD findings. Additionally, ADPKD has unique bone metabolism aspects: these patients often exhibit an adynamic bone disorder early in CKD (Righini et al., 2024; Gitomer et al., 2021). FGF23 excess, along with low 1,25D and perhaps elevated sclerostin, might contribute to this low bone turnover state. However, interestingly, ADPKD patients on dialysis do not have a higher fracture risk than other dialysis patients (Gitomer et al., 2021), suggesting some differences in bone quality. Nonetheless, systemically controlling FGF23 in ADPKD could be beneficial for reducing cardiovascular risk and improving overall mineral and bone health.

Ultimately, an ADPKD patient who develops advanced CKD will be subject to the same potential therapies for high FGF23 as any CKD patient. While there is no direct anti-FGF23 therapy in ADPKD, several interventions in ADPKD might indirectly influence FGF23 levels and effects: Tolvaptan, a vasopressin V2 receptor antagonist, is an approved disease-modifying treatment for ADPKD that slows cyst growth and preserves renal function (Gittus et al., 2025). By slowing the progression of CKD in ADPKD, tolvaptan may indirectly modulate FGF23 trajectorie. Additionally, by reducing cyst burden and possibly mitigating some aspects of cyst-induced injury, tolvaptan could reduce some stimuli for FGF23 production.