title: Recent advances in understanding the pathogenesis of atherosclerosis in CKD patients.
abstract: A need exists for developing new therapies to improve cardiovascular outcomes in end-stage kidney disease. Three new areas that address novel pathophysiological mechanisms and/or therapeutic approaches toward cardiovascular events in chronic kidney disease patients include the use of an anti-inflammatory agent, the role of catalytic iron, and protein carbamylation. In preliminary studies, hydroxychloroquine, which has multiple anti-inflammatory properties, preserved vascular compliance for the aorta and major vessels, as well as reduced the extent of severity of atherosclerosis in ApoE-/- mice. The ability of iron to rapidly and reversibly cycle between 2 oxidation states makes iron potentially hazardous by enabling it to participate in the generation of powerful oxidant species. We have shown that high catalytic iron in the general population is associated with a 4-fold increase in prevalent cardiovascular disease (CVD), even after accounting for traditional risk factors. In addition, the highest levels of catalytic iron are present in dialysis patients and, more specifically, patients with prevalent CVD have several-fold higher catalytic iron levels compared with controls without CVD. These data suggest the utility of iron chelators for preventing and treating CVD in patients with chronic kidney disease and should be further investigated. Carbamylation of proteins results from nonenzymatic chemical modification by isocyanic acid derived from urea and an alternative route, the myeloperoxidase-catalyzed oxidation of thiocyanate. We have shown carbamylated low-density lipoprotein to have all the major biological effects relevant to atherosclerosis including endothelial cell injury, increased expression of cell adhesion molecules, and vascular smooth muscle cell proliferation. In 2 separate clinical studies, plasma levels of carbamylated protein independently predicted an increased risk of CVD and death.
authors.affiliation: Renal Medicine Section, Medical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Electronic address: shahsudhirv@uams.edu.
authors.forename: Sudhir V
authors.initials: SV
authors.lastname: Shah
authors.affiliation: Nephrology and Hypertension Section, North Florida/South Georgia Veterans Health System, Gainesville, Florida and Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, Florida.
authors.forename: Ashutosh M
authors.initials: AM
authors.lastname: Shukla
authors.affiliation: Renal Medicine Section, Medical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Chhanda
authors.initials: C
authors.lastname: Bose
authors.affiliation: Renal Medicine Section, Medical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Alexei G
authors.initials: AG
authors.lastname: Basnakian
authors.affiliation: Nephrology Department, Muljibhai Patel Urological Hospital in Nadiad, Gujarat, India.
authors.forename: Mohan
authors.initials: M
authors.lastname: Rajapurkar
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000150:complications* / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000503:physiopathology*; D012307:Risk Factors