title: Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia.
abstract: 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 Pi overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary Pi 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 Pi concentrations ranging from 0.3% to 1.2% for 8 wk. CKD rats showed dietary Pi 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 Pi overload. Regression analysis showed that serum Pi levels closely correlated with the extent of inflammation, malnutrition, and VC. Also, in cultured human vascular smooth muscle cells, high-Pi medium directly increased the expression of TNF-α in advance of the increase in osteochondrogenic markers. Our data suggest that dietary Pi overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and that inhibition of Pi loading through dietary or pharmacological interventions or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tokumoto
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
authors.forename: Narihito
authors.initials: N
authors.lastname: Tatsumoto
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
authors.forename: Masatomo
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
authors.forename: Hideko
authors.initials: H
authors.lastname: Noguchi
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
authors.forename: Kosuke
authors.initials: K
authors.lastname: Masutani
authors.affiliation: Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ooboshi
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Integrated Therapy for Chronic Kidney Disease, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and tsuruya@intmed2.med.kyushu-u.ac.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tsuruya
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000225:Adenine / Q000009:adverse effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D044342:Malnutrition / Q000139:chemically induced* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010710:Phosphates / Q000009:adverse effects* / Q000494:pharmacology*; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014511:Uremia / Q000378:metabolism* / Q000503:physiopathology; D061205:Vascular Calcification / Q000139:chemically induced* / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D010710:Phosphates; D014409:Tumor Necrosis Factor-alpha; D000225:Adenine
keywords: chronic kidney disease; inflammation; malnutrition; malnutrition-inflammation-atherosclerosis syndrome; phosphate; vascular calcification