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Relationship between kidney disease and endothelial function in peripheral artery disease.

ABSTRACT: We have previously shown that peripheral artery disease (PAD) is associated with marked impairment of endothelial function (EF). Given that poor EF is associated with functional status of PAD patients as well as with increased morbidity and mortality in patients undergoing vascular procedures, determination of factors associated with poor EF in a PAD cohort is important. We hypothesized that decreased kidney function is associated with impaired EF in patients with PAD.This was a cross-sectional study of PAD patients presenting to a vascular surgery outpatient clinic at the San Francisco Veterans Affairs Medical Center including patients enrolled in the OMEGA-PAD I trial (NCT01310270) and the OMEGA-PAD Cohort. Brachial artery flow-mediated vasodilation was performed to assess EF. Kidney function was characterized by estimated glomerular filtration rate with the abbreviated Modification of Diet in Renal Disease formula. Linear regression was performed to assess the relationship between EF and kidney function in claudicants.Ninety-seven patients with intermittent claudication participated in this study. Mean age was 69 ± 8 years, 97% were male, and 79% were white. Comorbidities included hypertension (91%), dyslipidemia (87%), coronary artery disease (42%), and diabetes mellitus (38%). Mean ankle-brachial index was 0.73 ± 0.14 and mean flow-mediated vasodilation was 7.0% ± 3.8%, indicating impaired EF. Linear regression showed an association between kidney function and EF (by 10 mL/min/1.73 m(2); ?, 0.12; confidence interval, 0.05-0.20; P = .001). After multivariable regression adjusting for age, race, log tumor necrosis factor ?, hypertension, dyslipidemia, and diabetes, estimated glomerular filtration rate remained significantly associated with EF (P = .033).In patients with PAD, decreased kidney function is associated with endothelial dysfunction. Further longitudinal studies are needed to better understand the impact of kidney function on PAD progression and the role of endothelial dysfunction in this process.

SUBMITTER: Chong KC

PROVIDER: S-EPMC4254442 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Relationship between kidney disease and endothelial function in peripheral artery disease.

Chong Karen C KC Owens Christopher D CD Park Meyeon M Alley Hugh F HF Boscardin W John WJ Conte Michael S MS Gasper Warren J WJ Grenon S Marlene SM

Journal of vascular surgery 20141016 6

<h4>Objective</h4>We have previously shown that peripheral artery disease (PAD) is associated with marked impairment of endothelial function (EF). Given that poor EF is associated with functional status of PAD patients as well as with increased morbidity and mortality in patients undergoing vascular procedures, determination of factors associated with poor EF in a PAD cohort is important. We hypothesized that decreased kidney function is associated with impaired EF in patients with PAD.<h4>Metho ...[more]

PMID: 25441679

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Project description:Fewer than half of individuals with peripheral artery disease (PAD) experience classic claudication, and the relationships between PAD typical or atypical symptom intensity, location, and description (classic or atypical) with ischemic changes have not previously been reported.The primary purpose of this study was to evaluate the relationship between self-reported PAD symptom intensity and calf tissue ischemia measured using the tissue saturation index (TSI) during treadmill exercise. The location and descriptors of atypical PAD symptoms in the presence of calf tissue ischemia were also identified.Adults with PAD with exercise-limiting ischemic symptoms were asked to (a) rate symptom intensity using a numerical rating scale (NRS) from 0 to 5 (0 = no pain, 1 = onset of pain, 5 = maximal pain), (b) provide symptom locations and descriptors, and (c) wear a near-infrared spectroscopy device to obtain calf TSI values during treadmill exercise. Multilevel models with TSI as the outcome variable were estimated during exercise and recovery. Covariates included were exercise time, recovery time, baseline TSI, exercise rating, recovery rating, ankle-brachial index (ABI), age, race, gender, body mass index, diabetes, neuropathy, and smoking.During three successive bouts of treadmill exercise for 40 participants (80% Caucasian men; average age = 68 years, SD = 9.2), the most rapid decline in TSI occurred between the start of exercise and symptom onset (when NRS = 1). The TSI nadir was often reached prior to report of maximum discomfort (when NRS = 5), and changes in TSI were related to exercise time (p < .001), baseline TSI (p < .001), exercise ratings (p < .001), and ABI (p < .05). During recovery, TSI increased steadily for most participants as pain eased. In the recovery model, changes in TSI were associated with recovery ratings (p < .001) and ABI (p < .03). Of 120 treadmill exercise tests, 69.2% were stopped due to discomfort in the calf with classic descriptors reported only half the time (55.4%).Exploratory analyses revealed ischemic symptoms extended beyond classic claudication locations and descriptors. Future research should evaluate changes in TSI relative to atypical locations and descriptors to improve understanding of the full range of ischemic symptoms experienced by individuals with PAD.

Project description:BACKGROUND AND AIMS:Reduced kidney function is a risk factor for lower-extremity peripheral artery disease (PAD). However, the associations of novel filtration markers with PAD are yet to be quantified. Moreover, little is known on whether bone-mineral metabolism (BMM) markers are related to incident PAD beyond kidney function. METHODS:Using data from 12,472 participants at baseline (1990-1992) of the Atherosclerosis Risk in Communities (ARIC) study, we comprehensively quantified the associations of kidney related markers with incident PAD (defined as hospitalizations with diagnosis of lower-extremity atherosclerosis, revascularization, or amputation). Kidney related markers of interest included estimated glomerular filtration rate (eGFR) (based on creatinine, cystatin C, and both), cystatin C, beta-2 microglobulin (B2M), and BMM markers (serum fibroblast growth factor 23, parathyroid hormone, calcium, and phosphorus). RESULTS:During a median follow-up of 21 years, 471 participants developed incident PAD. Low eGFR was significantly associated with future PAD risk, with slightly stronger relationship when cystatin C was used (adjusted hazard ratio [HR] 6.3-8.3 for eGFR <30 and 2.4-3.5 for eGFR 30-59 vs. eGFR ?90 mL/min/1.73 m2). Among all filtration markers, B2M had the strongest association with incident PAD (HR for top vs. bottom quartile 2.60 [95% CI: 1.91-3.54] for B2M vs. 1.20 [0.91-1.58] for creatinine-based eGFR). Among BMM markers, only phosphorus remained significant for PAD risk beyond potential confounders, including kidney function (HR 1.47 [1.11-1.94] in top quartile). CONCLUSIONS:Kidney dysfunction was independently associated with future PAD risk, particularly when assessed with cystatin C and B2M. Among the BMM markers tested, phosphorus was most robustly associated with incident PAD beyond kidney function. Our results suggest the potential usefulness of novel filtration markers for PAD risk assessment and the possible role of phosphorus in the pathophysiology of PAD.

Project description:RationalePeripheral artery disease, common in metabolic syndrome and diabetes mellitus, responds poorly to medical interventions and is characterized by chronic vessel immaturity leading to lower extremity amputations.ObjectiveTo define the role of reversible palmitoylation at the endothelium in the maintenance of vascular maturity.Methods and resultsEndothelial knockout of the depalmitoylation enzyme APT-1 (acyl-protein thioesterase 1) in mice impaired recovery from chronic hindlimb ischemia, a model of peripheral artery disease. Endothelial APT-1 deficiency decreased fibronectin processing, disrupted adherens junctions, and inhibited in vitro lumen formation. In an unbiased palmitoylation proteomic screen of endothelial cells from genetically modified mice, R-Ras, known to promote vessel maturation, was preferentially affected by APT-1 deficiency. R-Ras was validated as an APT-1 substrate, and click chemistry analyses demonstrated increased R-Ras palmitoylation in cells with APT-1 deficiency. APT-1 enzyme activity was decreased in endothelial cells from db/db mice. Hyperglycemia decreased APT-1 activity in human umbilical vein endothelial cells, due, in part, to altered acetylation of the APT-1 protein. Click chemistry analyses demonstrated increased R-Ras palmitoylation in the setting of hyperglycemia. Altered R-Ras trafficking, increased R-Ras palmitoylation, and fibronectin retention were found in diabetes mellitus models. Loss of R-Ras depalmitoylation caused by APT-1 deficiency constrained R-Ras membrane trafficking, as shown by total internal reflection fluorescence imaging. To rescue cellular phenotypes, we generated an R-Ras molecule with an inserted hydrophilic domain to circumvent membrane rigidity caused by defective palmitoylation turnover. This modification corrected R-Ras membrane trafficking, restored fibronectin processing, increased adherens junctions, and rescued defective lumen formation induced by APT-1 deficiency.ConclusionsThese results suggest that endothelial depalmitoylation is regulated by the metabolic milieu and controls plasma membrane partitioning to maintain vascular homeostasis.

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Relationship between kidney disease and endothelial function in peripheral artery disease.

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Relationship between kidney disease and endothelial function in peripheral artery disease.

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