Peripheral Vascular Dysfunction in Chronic Kidney Disease

There is an increased prevalence of cardiovascular disease- (CVD-) related mortality in patients with chronic kidney disease (CKD). Endothelial dysfunction is a primary event in the development of atherosclerosis and hypertension and likely contributes to the elevated cardiovascular risk in CKD. Endothelial dysfunction has been shown to occur in the peripheral vasculature of patients with both severe and moderate CKD. Mechanisms include oxidative stress, L-arginine deficiency, and elevated plasma levels of ADMA. Interventions designed to restore vascular function in patients with CKD have shown mixed results. Evidence from cell culture studies suggest that the accumulation of uremic toxins inhibits L-arginine transport and reduces nitric oxide production. The results of these studies suggest that endothelial dysfunction may become less reversible with advancing kidney disease. The purpose of this paper is to present the current literature pertaining to potential mechanisms of peripheral vascular dysfunction in chronic kidney disease and to identify possible targets for treatment.

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Abstract 16926: The Effects of a Mitochondrial Targeted Ubiquinone (MitoQ) on Vascular Function in Chronic Kidney Disease

Circulation ◽

10.1161/circ.142.suppl_3.16926 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Danielle L Kirkman ◽

Ninette Shenouda ◽

Joseph M Stock ◽

Bryce J Muth ◽

Nicholas Chouramanis ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Brachial Artery ◽

Vascular Function ◽

Vascular Dysfunction ◽

Aortic Pressure ◽

Double Blind ◽

Reflected Waves ◽

Arterial Hemodynamics ◽

Artery Flow

Introduction: Aberrant vascular function contributes to the substantially high cardiovascular burden of chronic kidney disease (CKD). Mitochondrial derived oxidative stress is a potential therapeutic target to ameliorate CKD related vascular dysfunction. Hypothesis: We hypothesized that a mitochondrial targeted antioxidant (MitoQ) would improve vascular function in Stage 3-5 CKD patients without overt cardiovascular disease. Methods: In this controlled, double-blind trial, 18 CKD patients (Mean±SEM: Age, 62±3 years; eGFR, 45±3 ml•min•1.73 2 ) were randomized to receive an oral dose of MitoQ (20mg/day; MTQ) or a Placebo (PLB) for 4 weeks. Outcome measures were assessed at week 0 and week 4. Aortic pressure waves were synthesized from brachial artery waveforms acquired by oscillometry and the use of a generalized transfer function. The central pressure waveform was separated into forward and reflected waves using a triangular flow waveform. Conduit artery vascular function was assessed via brachial artery flow mediated dilation (FMD). Results: MitoQ was well tolerated and patient compliance was high (MTQ, 99.6±0.4%; PLB, 97.8±2.2%). Independent of peripheral (Baseline vs. Follow Up: MTQ, 140±6 vs. 137±6 mmHg; PLB, 136±4 vs. 134±6 mmHg; interaction p=0.7) and central (MTQ, 128±5 vs. 123±6 mmHg; PLB, 124±3 vs. 123±5 mmHg; interaction p=0.8) systolic blood pressures, MitoQ maintained forward wave amplitudes (MTQ, 31±3 vs. 29±1 mmHg; PLB, 29±3 vs. 36±3 mmHg; interaction p=0.05) and tended to reduce reflected wave amplitudes (MTQ, 18±2 vs. 16±1 mmHg; PLB, 19±2 vs. 21±2 mmHg; interaction p=0.04). MitoQ administration favored improvements in FMD (MTQ, 2.4±0.3 vs. 4.0±0.9%; PLB, 4.2±1.0 vs. 2.5±1.0%; interaction p=0.04). Conclusions: These results suggest that targeting mitochondrial derived reactive oxygen species holds promise as a potential therapeutic strategy to improve CKD related vascular dysfunction. Whether MitoQ related improvements in arterial hemodynamics are a result of augmented cardiac function or a reduction in vascular resistance warrants future investigation in larger studies.

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Circulating argonaute-bound microRNA-126 reports vascular dysfunction & response to treatment in acute & chronic kidney disease

10.1101/2020.07.14.20153353 ◽

2020 ◽

Author(s):

Kathleen M Scullion ◽

A D Bastiaan Vliegenthart ◽

Laura Rivoli ◽

Wilna Oosthuyzen ◽

Tariq E Farrah ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Vascular Function ◽

Clinical Decision Making ◽

Vascular Dysfunction ◽

Unmet Need ◽

Post Treatment ◽

Response To Treatment ◽

Serum Samples ◽

Anca Vasculitis

Background: Vascular and kidney dysfunction commonly co-exist. There is an unmet need for biomarkers of vascular health. Circulating microRNAs (miRs) are disease biomarkers; miR-126 is endothelial cell-enriched. We measured circulating miR-126 in rats with nephrotoxic nephritis (NTN) and humans with acute endothelial and renal injury (vasculitis associated with autoantibodies to neutrophil cytoplasm antigens (ANCA)). We then compared these findings to those from patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), and explored the relationship between miR-126 and markers of vascular dysfunction. Methods: In rats, NTN was induced with nephrotoxic serum. Samples were prospectively collected from 70 patients with ANCA vasculitis (at presentation and once in treatment-induced remission), healthy subjects (n=60), patients with CKD (n=30) and ESRD before and after dialysis (n=15). In humans and rats, miR-126 and miR-122 (liver-specific control) were measured and correlated with vascular function. Results: In NTN rats, miR-126 was selectively reduced. In ANCA vasculitis, pre-treatment circulating miR-126 was reduced compared to health (88-fold reduction, ROC-AUC 0.87 (0.80-0.94)). miR-126 increased 3.4-fold post-treatment but remained lower than in health (~26-fold). There was no change in miR-122. Plasma fractionation demonstrated that argonaute 2-bound miR-126 increased with treatment of ANCA vasculitis. Urinary miR-126 decreased post-treatment. miR-126 did not differ between CKD and health but its concentration significantly correlated with measures of endothelial dysfunction. miR-126 was substantially reduced in ESRD (~350 fold compared to health and CKD). Conclusions: miR-126 may be a marker of vascular inflammation and has the potential to aid in clinical decision-making.

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P2499Finerenone improves vascular function through a reduction of endothelial dysfunction and arterial stiffness in a genetic rat model of chronic kidney disease

European Heart Journal ◽

10.1093/eurheartj/ehy565.p2499 ◽

2018 ◽

Vol 39 (suppl_1) ◽

Author(s):

M S Fernandez-Alfonso ◽

M Gil-Ortega ◽

E Vega ◽

M Martin-Ramos ◽

R Gonzalez-Blazquez ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Endothelial Dysfunction ◽

Kidney Disease ◽

Arterial Stiffness ◽

Rat Model ◽

Vascular Function

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Circulating Endothelial Cells and Chronic Kidney Disease

BioMed Research International ◽

10.1155/2014/364738 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Kunying Zhang ◽

Fang Yin ◽

Lin Lin

Keyword(s):

Chronic Kidney Disease ◽

Endothelial Cells ◽

Endothelial Dysfunction ◽

Kidney Disease ◽

Vascular Dysfunction ◽

Endothelial Damage ◽

Circulating Endothelial Cells ◽

Response To Treatment ◽

Term Outcome ◽

Long Term Outcome

Endothelial dysfunction may play a crucial role in initiation of the pathogenesis of vascular disease and atherosclerosis. The identification and quantification of circulating endothelial cells (CEC) have been developed as a novel marker of endothelial function. We describe, in great detail, mechanisms of endothelial dysfunction and CEC detachment. We also review the relationship between numbers of CEC and disease severity and response to treatment. In addition, we describe the possible clinical use of CEC in chronic kidney disease (CKD) and kidney transplantation. In summary, CEC have been developed as a novel approach to assess the endothelial damage. Measurement of the CEC level would provide an important diagnostic and prognostic value on the endothelium status and the long-term outcome of vascular dysfunction.

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Sex differences in endothelial function in chronic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00156.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. F33-F40

Author(s):

Nicholas T. Kruse ◽

Zhiying You ◽

Kerrie Moreau ◽

Jessica Kendrick ◽

Diana Jalal

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Sex Differences ◽

Kidney Disease ◽

Vascular Function ◽

Vascular Dysfunction ◽

Men And Women ◽

Younger Women ◽

Younger Men

Vascular dysfunction plays an important role in the etiology of chronic kidney disease (CKD) and is associated with cardiovascular diseases. Sex differences in vascular function are common in clinical and nonclinical populations. However, no data exist in individuals with CKD. The present study tested the hypothesis that sex and/or aging differences exist in vascular function in patients with CKD. Endothelium-dependent dilation (EDD; measured via brachial artery flow-mediated dilation) and endothelium-independent dilation (EID; measured via nitroglycerin-mediated dilation) were assessed. Analyses were adjusted for several variables that could influence vascular function (diabetes, cardiovascular disease, and blood pressure). Women, in general, had higher EDD values than men (6.5 ± 4.9% vs. 4.4 ± 3.4%); however, EID did not differ among these groups. In younger men and women (<55 yr old), EDD and EID were higher ( P < 0.05) than their older (≥55 yr old) counterparts (EDD: 7.0 ± 4.1% vs. 4.4 ± 3.8% and EID: 24.0 ± 9.6% vs. 18.3 ± 9.2%). Additionally, younger women exhibited higher ( P < 0.05) EDD and EID compared with younger men (EDD: 9.5 ± 6.4% vs. 5.1 ± 3.8%, P = 0.01, and EID: 24.0 ± 9.6% vs. 18.3 ± 9.2%). No differences in EDD and EID were present between older men and women with CKD. Diabetes independently predicted lower EID but not EDD in men and women. Blood pressure and cardiovascular disease did not predict EDD or EID. This is the first study to show significant sex differences in vascular function. Moreover, these differences are evident between younger men and women with CKD but are abolished with age. Additional studies are needed to better understand the mechanisms that may underlie sex differences in vascular dysfunction with CKD.

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Endothelial cell transfusion ameliorates endothelial dysfunction in 5/6 nephrectomized rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00132.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. H1256-H1264 ◽

Cited By ~ 5

Author(s):

Maricica Pacurari ◽

Dongqi Xing ◽

Rob H. P. Hilgers ◽

Yuan Yuan Guo ◽

Zhengqin Yang ◽

...

Keyword(s):

Nitric Oxide ◽

Chronic Kidney Disease ◽

Endothelial Dysfunction ◽

Nitric Oxide Synthase ◽

Kidney Disease ◽

Endothelial Nitric Oxide Synthase ◽

Vascular Function ◽

Vascular Reactivity ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Endothelial dysfunction is prevalent in chronic kidney disease. This study tested the hypothesis that transfusion of rat aortic endothelial cells (ECs) ameliorates endothelial dysfunction in a rat model of chronic kidney disease. Male Sprague-Dawley rats underwent sham surgery or 5/6 nephrectomy (Nx). Five weeks after Nx, EC (1.5 × 106 cells/rat) or vehicle were transfused intravenously. One week later, vascular reactivity of mesenteric artery was assessed on a wire myograph. Sensitivity of endothelium-dependent relaxation to acetylcholine and maximum vasodilation were impaired by Nx and improved by EC transfusion. Using selective pharmacological nitric oxide synthase isoform inhibitors, we demonstrated that the negative effect of Nx on endothelial function and rescue by EC transfusion are, at least in part, endothelial nitric oxide synthase mediated. Plasma asymmetric dimethylarginine was increased by Nx and decreased by EC transfusion, whereas mRNA expression of dimethylarginine dimethylaminohydrolases 1 (DDAH1) was decreased by Nx and restored by EC transfusion. Immunohistochemical staining confirmed that local expression of DDAH1 is decreased by Nx and increased by EC transfusion. In conclusion, EC transfusion attenuates Nx-induced endothelium-dependent vascular dysfunction by regulating DDAH1 expression and enhancing endothelial nitric oxide synthase activity. These results suggest that EC-based therapy could provide a novel therapeutic strategy to improve vascular function in chronic kidney disease.

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Mitochondrial Contributions to Vascular Endothelial Dysfunction, Arterial Stiffness and Cardiovascular Diseases

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00917.2020 ◽

2021 ◽

Author(s):

Danielle L. Kirkman ◽

Austin T. Robinson ◽

Matthew J. Rossman ◽

Douglas R. Seals ◽

David G. Edwards

Keyword(s):

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Vascular Function ◽

Vascular Dysfunction ◽

Current Evidence ◽

Vascular Endothelial ◽

Cvd Risk ◽

Important Player ◽

Related Mortality

Cardiovascular diseases (CVD) affect 1 in 3 adults and remain the leading causes of death in America. Advancing age is the major risk factor for CVD. Recent plateaus in CVD-related mortality rates in high income countries after decades of decline highlight a critical need to identify novel therapeutic targets and strategies to mitigate and manage the risk of CVD development and progression. Vascular dysfunction, characterized by endothelial dysfunction and large elastic artery stiffening, is independently associated with an increased CVD risk and incidence and is therefore an attractive target for CVD prevention and management. Vascular mitochondria have emerged as an important player in maintaining vascular homeostasis. As such, age and disease related impairments in mitochondrial function contribute to vascular dysfunction and consequent increases in CVD risk. This review outlines the role of mitochondria in vascular function and discusses the ramifications of mitochondrial dysfunction on vascular health in the setting of age and disease. The adverse vascular consequences of increased mitochondria derived reactive oxygen species, impaired mitochondrial quality control and defective mitochondrial calcium cycling are emphasized, in particular. Current evidence for both lifestyle and pharmaceutical mitochondrial-targeted strategies to improve vascular function is also presented.

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