Klotho deficiency in chronic kidney disease

Chronic kidney disease (CKD) is a global public health problem with a prevalence of 11-13% and high cardiovascular mortality. In this context, the protein Klotho has emerged as a key regulator of mineral metabolism, kidney function, and cardiovascular integrity. Identified by Kuro-o in 1997 as an anti-aging gene, Klotho acts as a soluble, transmembrane protein with pleiotropic functions in calcium, phosphorus, and vitamin D homeostasis. Under physiological conditions, Klotho forms a complex with the FGF23 receptor, regulating phosphate excretion and calcitriol synthesis. However, in CKD, its expression progressively decreases due to epigenetic mechanisms and chronic inflammation, contributing to FGF23 resistance, hyperphosphatemia, secondary hyperparathyroidism, and CKD-associated mineral bone disease. Klotho deficiency is also associated with endothelial dysfunction, arterial stiffness, and myocardial remodeling. Experimentally, exogenous administration of Klotho has demonstrated antioxidant, antifibrotic, and cardioprotective effects, mediating the inhibition of TGF-β, Wnt/β-catenin, and TRPC6 channels. Serum and urinary Klotho levels are correlated with glomerular filtration rate and CKD progression, supporting its potential as a prognostic biomarker. Despite promising evidence, the lack of methodological standardization limits its clinical application. Understanding the pathophysiology of Klotho allows us to envision therapeutic strategies aimed at restoring its function, with the goal of slowing the progression of CKD and reducing associated cardiovascular complications.