The pathogenesis of CKD complications; Attack of dysregulated iron and phosphate metabolism

Abstract Chronic kidney disease (CKD) patients have a tremendously higher risk of developing cardiovascular disease (CVD) and infection than the non-CKD population, which could be caused by intertwining actions of hyperphosphatemia and CKD associated misdistribution of iron. CVD is often associated with vascular calcification, which has been attributed to hyperphosphatemia, and could be initiated in mitochondria, inducing apoptosis, and accelerated by reactive oxygen species (ROS). The production of ROS is principally linked to intracellular ferrous iron. For infection, the virulence and pathogenicity of a pathogen is directly related to its capacity to acquire iron for proliferation and to escape or subvert the host's immune response. Iron administration for renal anemia can sometimes be overdosed, which could decrease host immune mechanisms through its direct effect on neutrophils, macrophages and T cell function. Hyperphosphatemia has been demonstrated to be associated with an increased incidence of infection. We hypothesized two possible mechanisms: 1) fibroblast growth factor-23 levels are increased in parallel with serum phosphate levels and directly impair leukocyte recruitment and host defense mechanisms, and 2) circulating non-transferrin-bound iron (NTBI) is increased due to decreased iron binding capacity of the carrier protein transferrin in high-phosphate conditions. From these observations, maintaining an adequate serum range of phosphate levels and minimizing intracellular iron accumulation could attenuate the development of CKD complications.