Endothelial dysfunction and cardiovascular disease in early-stage chronic kidney disease: Cause or association?

Moody, William E.; Edwards, Nicola C.; Madhani, Melanie; Chue, Colin D.; Steeds, Richard P.; Ferro, Charles J.; Townend, Jonathan N.

doi:10.1016/j.atherosclerosis.2012.01.043

Cited by 110 publications

(75 citation statements)

References 83 publications

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“…The mechanisms responsible for activation of the endothelium in chronic renal failure are multifactorial and include the presence of uremic toxins (particularly asymmetric dimethyl arginine), low-grade inflammation, and hypertension (3). One of the earliest changes on this endothelial activation has been postulated to be compositional and dimensional alterations of the endothelial surface layer (ESL) (4).…”

Section: Introductionmentioning

confidence: 99%

Association of Kidney Function with Changes in the Endothelial Surface Layer

Dane

Khairoun

Lee

et al. 2014

Clinical Journal of the American Society of Nephrology

113

104

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Background and objectives ESRD is accompanied by endothelial dysfunction. Because the endothelial glycocalyx (endothelial surface layer) governs interactions between flowing blood and the vessel wall, perturbation could influence disease progression. This study used a novel noninvasive sidestream-darkfield imaging method, which measures the accessibility of red blood cells to the endothelial surface layer in the microcirculation (perfused boundary region), to investigate whether renal function is associated with endothelial surface layer dimensions.Design, setting, participants, & measurements Perfused boundary region was measured in control participants (n=10), patients with ESRD (n=23), participants with normal kidney function after successful living donor kidney transplantation (n=12), and patients who developed interstitial fibrosis/tubular atrophy after kidney transplantation (n=10). In addition, the endothelial activation marker angiopoietin-2 and shed endothelial surface layer components syndecan-1 and soluble thrombomodulin were measured using ELISA.Results Compared with healthy controls (1.8260.16 mm), ESRD patients had a larger perfused boundary region (+0.23; 95% confidence interval, 0.46 to ,0.01; P,0.05), which signifies loss of endothelial surface layer dimensions. This large perfused boundary region was accompanied by higher circulating levels of syndecan-1 (+57.71; 95% confidence interval, 17.38 to 98.04; P,0.01) and soluble thrombomodulin (+12.88; 95% confidence interval, 0.29 to 25.46; P,0.001). After successful transplantation, the perfused boundary region was indistinguishable from healthy controls (without elevated levels of soluble thrombomodulin or syndecan-1). In contrast, however, patients who developed interstitial fibrosis and tubular atrophy showed a large perfused boundary region (+0.36; 95% confidence interval, 0.09 to 0.63; P,0.01) and higher levels of endothelial activation markers. In addition, a significant correlation between perfused boundary region, angiopoietin-2, and eGFR was observed (perfused boundary region versus GFR: Spearman's r=0.31; P,0.05; perfused boundary region versus angiopoietin-2: Spearman's r=20.33; P,0.05).Conclusion Reduced renal function is strongly associated with low endothelial surface layer dimensions. After successful kidney transplantation, the endothelial surface layer is indistinguishable from control.

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Section: Introductionmentioning

confidence: 99%

Association of Kidney Function with Changes in the Endothelial Surface Layer

Dane

Khairoun

Lee

et al. 2014

Clinical Journal of the American Society of Nephrology

113

104

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“…This is due to multiple disorders in CKD patients, among which cardiovascular disease (CVD) is the leading cause of death (4). In the past, the prevalence of cardiovascular events was mainly attributed to the vascular diseases, especially to atherosclerosis (71). However, more and more recent evidence demonstrates that arterial calcification (AC) is also an important and independent risk factor for cardiovascular mortality in CKD (92,93).…”

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confidence: 99%

MICS, an easily ignored contributor to arterial calcification in CKD patients

Zhang

Gao

Chen

et al. 2016

American Journal of Physiology-Renal Physiology

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In chronic kidney disease (CKD), simultaneous mineral and skeleton changes are prevalent, known as CKD-mineral bone disorder (CKD-MBD). Arterial calcification (AC) is a clinically important complication of CKD-MBD. It can increase arterial stiffness, which leads to severe cardiovascular events. However, current treatments have little effect on regression of AC, as its mechanisms are still unclear. There are multiple risk factors of AC, among which Malnutrition-Inflammation Complex Syndrome (MICS) is a new and crucial one. MICS, a combined syndrome of malnutrition and inflammation, generally begins at the early stage of CKD and becomes obvious in end-stage renal disease (ESRD). It was linked to reverse epidemiology and associated with increased cardiovascular mortality in ESRD patients. Recent data suggest that MICS can trigger CKD-MBD and accelerate the course of AC. In this present review, we summarize the recent understanding about the aggravating effects of MICS on AC and discuss the possible underlying mechanisms. A series of findings indicate that targeting MICS will provide a potential strategy for treating AC in CKD.

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“…Limited previous findings pointed to abnormal endothelial cell properties in CKD, contributing to cardiovascular complications in patients 3. Although the underlying mechanistic pathway that might explain the loss of endothelial barrier function in CKD has been unclear so far, it was suggested that vitamin D deficiency might participate in this uremia‐induced phenomenon 6, 32.…”

Section: Discussionmentioning

confidence: 99%

“…Impairment of endothelial function, which accompanies CKD,2 is recognized as a sentinel event in the development and progression of cardiovascular disease 3. As kidney function declines, there is a progressive decline of both plasma 25 hydroxyvitamin D (25(OH)D) and 1,25‐dihydroxyvitamin D (1,25(OH) 2 D) concentrations, and of the kidney‐derived protein α‐Klotho, accompanied by secondary hyperparathyroidism and increased fibroblast growth factor‐23 levels 4, 5.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Cuenca

Ferrantelli

Meinster

et al. 2018

JAHA

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BackgroundDysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (CKD). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD, not only by direct effects on the endothelium but also by an increment of α‐Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia‐induced endothelial damage and the extent to which this was dependent on increased α‐Klotho concentrations.Methods and ResultsIn a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial‐gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α‐Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real‐time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro‐permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial‐cadherin–based cell‐cell junctions and diminished F‐actin stress fiber organization, preventing the formation of endothelial intracellular gaps.ConclusionsOur results demonstrate that paricalcitol attenuates the CKD‐induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell‐cell interactions.

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Endothelial dysfunction and cardiovascular disease in early-stage chronic kidney disease: Cause or association?

Cited by 110 publications

References 83 publications

Association of Kidney Function with Changes in the Endothelial Surface Layer

Association of Kidney Function with Changes in the Endothelial Surface Layer

MICS, an easily ignored contributor to arterial calcification in CKD patients

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

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