Klotho revisited: tubular heterogeneity reshapes mineral metabolism, aging, and CKD.

α-Klotho (hereafter Klotho) was discovered as an aging-suppressor protein whose function is intrinsically dependent on the kidney. Its shed ectodomain, soluble Klotho (sKlotho), is detectable in blood and urine. As an obligate co-receptor for endocrine fibroblast growth factor 23, Klotho operates at the intersection of mineral metabolism and chronic kidney disease (CKD). Within the kidney, Klotho expression is moderate in the proximal tubule but strongly enriched in the distal nephron, although the functional significance of this heterogeneity remains unclear. Recent findings from nephron segment-specific Klotho knockout mice reveal functional specialization of tubular Klotho along the nephron. According to the revised model, distal nephron Klotho regulates calcium reabsorption, bone remodeling, and urinary sKlotho levels. By contrast, proximal tubular Klotho regulates phosphate and vitamin D metabolism and is likely the principal source of circulating sKlotho; its loss recapitulates hyperphosphatemia, FGF23 resistance, and ageing-like phenotypes. This review re-evaluates the long-standing paradigm of renal Klotho biology in light of emerging evidence for functionally distinct proximal and distal nephron Klotho. Together, these insights place the kidney and its tubular Klotho heterogeneity at the center of mineral metabolism, aging and CKD.