Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia

Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to an increased risk of cardiovascular death in CKD. However, the effects of P_i overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary P_i loading on the interactions among inflammation, malnutrition, and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different P_i concentrations ranging from 0.3% to 1.2% for 8 wk. CKD rats showed dietary P_i concentration-dependent increases in serum and tissue levels of TNF-α and urinary and tissue levels of oxidative stress markers and developed malnutrition (decrease in body weight, serum albumin, and urinary creatinine excretion), VC, and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by P_i overload. Regression analysis showed that serum P_ilevels closely correlated with the extent of inflammation, malnutrition, and VC. Also, in cultured human vascular smooth muscle cells, high-P_i medium directly increased the expression of TNF-α in advance of the increase in osteochondrogenic markers. Our data suggest that dietary P_i overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and that inhibition of P_i loading through dietary or pharmacological interventions or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.