SOD Polymorphisms and the Klotho–FGF-23 Axis in Heart Failure-Associated Kidney Disease: A Narrative Review

Kidney dysfunction is common in patients with chronic heart failure (CHF) and is associated with poor clinical outcomes. However, the severity of kidney dysfunction does not always reflect the degree of haemodynamic disturbance. Tubular injury, interstitial inflammation and fibrosis in many of these kidneys are not fully explained by renal hypoperfusion and venous congestion, which has drawn attention to non-haemodynamic mechanisms of injury. Two candidate mechanisms, impaired antioxidant defence and disturbance of the Klotho–FGF-23 axis, have so far been studied separately rather than together. Superoxide dismutase (SOD) isoenzymes provide the first line of defence against superoxide in the cytosol, mitochondria and extracellular matrix and common coding variants in SOD2 and SOD3 have been associated with nephropathy and cardiovascular disease. The kidney is the main source of α-Klotho, a protein that helps protect against oxidative stress, inflammation and fibrosis. Klotho expression in the kidney decreases early in kidney disease, while circulating fibroblast growth factor 23 (FGF-23) levels generally increase as kidney function declines. Elevated FGF-23 has been associated with left ventricular hypertrophy, myocardial fibrosis, incident heart failure and death. Experimental work links the two systems: oxidative stress down-regulates Klotho expression and Klotho up-regulates FoxO3- and Nrf2-dependent antioxidant programmes, including mitochondrial SOD. This review brings together the redox, genetic and mineral-endocrine literature in a single testable framework in which genetically determined antioxidant capacity may influence the redox–Klotho–FGF-23 network and, through it, renal vulnerability in CHF. The contribution of this narrative review is therefore conceptual: it combines evidence from separate areas of research, indicates the strength of each link and presents the pathway as a hypothesis to be tested. The individual components of the framework are supported very unevenly: the strongest evidence is observational and comes from chronic kidney disease rather than chronic heart failure; the reciprocal Klotho–superoxide dismutase link rests on cell and animal work alone; the genetic modifier is untested; and no study identified has measured SOD genotype, SOD activity, soluble Klotho and FGF-23 in a CHF cohort with renal endpoints. This gap points to a concrete translational agenda: prospective cardiorenal cohorts that combine genetic, redox, endocrine and tubular injury measurements and assess renal outcomes rather than surrogate markers. The integrated pathway has not been validated in clinical cohorts and should not be read as established pathophysiology.