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Updated: Apr 19, 2026
Assessment of Vascular Function in Patients With Chronic Kidney Disease
Published on: June 16, 2014
Recent advances in understanding the pathogenesis of atherosclerosis in CKD patients
Sudhir V Shah1, Ashutosh M Shukla2, Chhanda Bose1
1Renal 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.
Insights
Novel therapies targeting inflammation, catalytic iron, and protein carbamylation show promise for improving cardiovascular outcomes in chronic kidney disease patients. These approaches address key mechanisms driving cardiovascular events in this high-risk population.
Area of Science:
- Nephrology and Cardiovascular Medicine
- Pathophysiology of Chronic Kidney Disease
- Novel Therapeutic Strategies
Background:
- End-stage kidney disease (ESKD) patients face a high burden of cardiovascular disease (CVD).
- Existing therapies have limited efficacy in mitigating CVD risk in ESKD.
- Novel pathophysiological mechanisms require targeted therapeutic interventions.
Purpose of the Study:
- To explore the potential of anti-inflammatory agents, catalytic iron modulation, and protein carbamylation inhibition for treating CVD in chronic kidney disease (CKD).
- To investigate hydroxychloroquine's effects on vascular compliance and atherosclerosis.
- To assess the role of catalytic iron and protein carbamylation as CVD risk factors and therapeutic targets in CKD.
Main Methods:
- Preliminary studies using ApoE-/- mice to evaluate hydroxychloroquine's impact on vascular health.
- Analysis of catalytic iron levels in the general population and dialysis patients, correlating with CVD prevalence.
- Investigation of carbamylated low-density lipoprotein's (LDL) atherogenic properties in vitro.
- Clinical studies assessing plasma carbamylated protein levels as predictors of CVD and mortality.
Main Results:
- Hydroxychloroquine preserved vascular compliance and reduced atherosclerosis in mice.
- High catalytic iron levels are strongly associated with increased CVD risk, particularly in dialysis patients.
- Carbamylated LDL demonstrated key atherogenic effects, including endothelial injury and inflammation.
- Elevated plasma carbamylated protein levels independently predicted higher CVD and mortality risk in clinical studies.
Conclusions:
- Targeting inflammation with agents like hydroxychloroquine may improve vascular health in CKD.
- Catalytic iron represents a significant, targetable risk factor for CVD in CKD patients, suggesting potential utility of iron chelators.
- Protein carbamylation contributes to atherosclerosis and serves as an independent predictor of adverse cardiovascular outcomes and mortality in CKD.
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.
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