FGF23 –Klotho Axis Dysregulation in Type 4 Cardiorenal Syndrome: Molecular Mechanisms, Paediatric Perspectives, and Emerging Therapeutic Targets

ABSTRACT

Cardiorenal syndrome (CRS) represents a bidirectional interplay between cardiac and renal dysfunction, but CRS cases involving paediatric patients represent only a minority of cases overall. CRS type‐4 (CRS4), a long‐term reno‐cardiac syndrome driven by chronic kidney disease (CKD), is not the most frequently reported subtype in paediatric cohorts, where type 1 CRS predominates (1); it is, however, the subtype most relevant to children with established CKD and the one in which FGF23–α‐Klotho signalling is most directly implicated. Beyond traditional haemodynamic and neurohormonal mechanisms, dysregulation of the fibroblast growth factor 23 (FGF23)–α‐Klotho axis has emerged as a pivotal molecular contributor to the pathophysiology of CRS. FGF23, primarily secreted by osteocytes, regulates phosphate and vitamin D homeostasis via fibroblast growth factor receptors in concert with the co‐receptor α‐Klotho; however, the cardiac hypertrophic actions of FGF23 in CRS are mediated through FGFR4 and do not require α‐Klotho. In CKD, early α‐Klotho deficiency leads to FGF23 resistance, hyperphosphatemia, and maladaptive cardiovascular remodelling, including left‐ventricular hypertrophy and vascular calcification. These alterations are compounded by inflammation, activation of the renin‐angiotensin‐aldosterone system, and iron deficiency, all of which can modulate FGF23 expression and signalling. Experimental and clinical evidence implicates this axis in both renal injury progression and direct cardiac toxicity, with distinct physiological considerations in paediatric populations due to developmental variations in bone turnover, mineral metabolism, and elevated baseline phosphate flux. This review highlights paediatric‐specific gaps, synthesizes current mechanistic insights, and assesses how emerging targeted strategies such as phosphate restriction might be tailored to paediatric CRS4 rather than being extrapolated from adult CKD populations. Standardization of biomarker assays and longitudinal paediatric studies remains critical for translating these molecular insights into early diagnostic tools and targeted interventions in CRS.