In advanced CKD, when GFR declines below 30–40 mL/min/1.73 m2, there is a dysregulation of the FGF23–Klotho axis: increased FGF-23 levels are no longer able to enhance the excretion of phosphate in the remaining functioning nephrons, eventually leading to the development of overt hyperphosphatemia, which stimulates further secretion of FGF-23 from the bone. The gene discussed is FGF23; the disease is hyperphosphatemia.