Arterial Stiffness In Chronic Kidney Disease Research Articles

Involvement of lysyl oxidase in the pathogenesis of arterial stiffness in chronic kidney disease.

Patients with chronic kidney disease (CKD) are at increased risk for adverse cardiovascular events. CKD is associated with increases in arterial stiffness, whereas improvements in arterial stiffness correlate with better survival. However, arterial stiffness is increased early in CKD, suggesting that there might be additional factors, unique to kidney disease, that increase arterial stiffness. Lysyl oxidase (LOX) is a key mediator of collagen cross linking and matrix remodeling. LOX is predominantly expressed in the cardiovascular system, and its upregulation has been associated with increased tissue stiffening and extracellular matrix remodeling. Thus, this study was designed to evaluate the role of increased LOX activity in inducing aortic stiffness in CKD and whether β-aminopropionitrile (BAPN), a LOX inhibitor, could prevent aortic stiffness by reducing collagen cross linking. Eight-week-old male C57BL/6 mice were subjected to 5/6 nephrectomy (Nx) or sham surgery. Two weeks after surgery, mice were randomized to BAPN (300 mg/kg/day in water) or vehicle treatment for 4 wk. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound. Aortic levels of LOX were assessed by ELISA, and cross-linked total collagen levels were analyzed by mass spectrometry and Sircol assay. Nx mice showed increased PWV and aortic wall remodeling compared with control mice. Collagen cross linking was increased in parallel with the increases in total collagen in the aorta of Nx mice. In contrast, Nx mice that received BAPN treatment showed decreased cross-linked collagens and PWV compared with that received vehicle treatment. Our results indicated that LOX might be an early and key mediator of aortic stiffness in CKD.NEW & NOTEWORTHY Arterial stiffness in CKD is associated with adverse cardiovascular outcomes. However, the mechanisms underlying increased aortic stiffness in CKD are unclear. Herein, we demonstrated that 1) increased aortic stiffness in CKD is independent of hypertension and calcification and 2) LOX-mediated changes in extracellular matrix are at least in part responsible for increased aortic stiffness in CKD. Prevention of excess LOX may have therapeutic potential in alleviating increased aortic stiffness and improving cardiovascular disease in CKD.

Clinical Factors Associated with Arterial Stiffness in Chronic Kidney Disease.

Arterial stiffness influences the prognosis of patients with end-stage kidney disease; however, the factors that promote arterial stiffness in chronic kidney disease (CKD) patients remain unknown. We aimed to explore the clinical factors associated with arterial stiffness in CKD. Between September 2017 and September 2022, all CKD patients treated at the Department of Nephrology, General Hospital of the Chinese People's Liberation Army, excluding dialysis patients, were screened and their medical records within the last month were collected. Arterial stiffness was measured by the augmentation index (AIx). The correlative clinical factors with arterial stiffness were explored in different linear regression models. 559 patients were included in the study. AIx@75 increased as the deterioration of CKDG1-CKDG5, with values of 1 (-9, 11), 5.5 (-4, 13.25), 9 (0, 16), 12 (1.5, 23.5), and 22 (13, 28), respectively (Z = 63.03, p < 0.001). Multivariate linear regression analysis showed that AIx@75 was positively associated with female sex (β = 8.926, 95% confidence interval (CI) 6.291, 11.562, p < 0.001), age (β = 0. 485, 95% CI 0.39, 0.58, p < 0.001), mean arterial pressure (MAP) (β = 0.255, 95% CI 0.159, 0.35, p < 0.001), and was negatively associated with ACEI/ARB (β = -4.466, 95% CI -6.963, -1.969, p < 0.001) and glucocorticoid (β = -3.163, 95% CI -6.143, -0.183, p = 0.038). Smoking, eGFR, hemoglobin, and cause of disease were associated with AIx@75 in multivariate linear regression models when considering factors partly. Female, age, smoking, MAP, eGFR, cause of disease, ACEI/ARB, and glucocorticoid were found to be associated with atherosclerosis in CKD patients.

Involvement of Lysyl Oxidase in the Pathogenesis of Arterial Stiffness in Chronic Kidney Disease

RationaleIncreased vascular stiffness is a key mediator of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Increased vascular stiffness in CKD is thought to be the consequence of long‐standing hypertension and vascular calcification. However, vascular stiffness is increased early in patients with CKD, even before metabolic complications develop. Lysyl Oxidase (LOX) is a key mediator of collagen crosslinking and matrix remodeling. Up‐regulation of LOX has been associated with increased tissue stiffness in cancer and wound healing. We hypothesize that increased LOX might be a key mechanism for increased vascular stiffness in CKD. β‐aminopropionitrile (BAPN), a LOX inhibitor, was used to test the hypothesis.Methods5/6 nephrectomy (Nx) or Sham surgery was performed in 8‐weeks old male C57BL/6 mice. 2‐weeks after Nx, mice were randomized to BAPN (300 mg/kg/day in water) or vehicle for 4‐weeks. Vascular stiffness was assessed by pulse wave velocity (PWV). LOX levels were measured by ELISA and qPCR. Collagen crosslinking was measured by mass spectrometry. Comparisons between groups were made using one‐way ANOVA, p‐Value &lt;0.05 was accepted as significant.ResultsNx resulted in decreased renal function at 8 weeks but no change in blood pressure or calcification. (~2‐3‐fold increase in creatinine, urea, and cystatin C) compared to control mice. Nx surgery resulted in increase in PWV (Con:179±32, Nx: 306 ± 47 cm/s, p&lt;0.001). This was associated with an increased LOX in aorta (Con:118±8, Nx: 311±13 pg/mg dry weight, p&lt;0.001). Mice with Nx surgery had an increased total collagen contents (183%, p&lt;0.001) as well as cross‐linked collagen (DPD; 83%, p&lt;0.05, PYD: 270% p&lt;0.01). BAPN treatment significantly attenuates PWV (211± 49 cm/s, p&lt;0.01), LOX (256±21 pg/mg dry weight, p&lt;0.05) and total collagen contents (23%, p&lt;0.01). BAPN treatment reduced the crosslinked collagens (DPD and PYD) but this did not reach statistical significance.ConclusionOur findings suggest: a) Increased vascular stiffness in CKD is independent of BP and calcification b) LOX mediated changes in extracellular matrix are at least in part responsible for the pathogenesis of arterial stiffness in CKD. Inhibition of excessive LOX may have therapeutic potential in alleviating increased vascular stiffness in CKD.

Pathophysiology and consequences of arterial stiffness in children with chronic kidney disease

Changes in arterial structure and function are seen early in the course of chronic kidney disease (CKD) and have been causally associated with cardiovascular (CV) morbidity. Numerous potential injuries encompassing both traditional and uremia-specific CV risk factors can induce structural arterial changes and accelerate arterial stiffening. When the buffering capacity of the normally elastic arteries is reduced, damage to vulnerable microcirculatory beds can occur. Moreover, the resultant increase to cardiac afterload contributes to the development of left ventricular hypertrophy and cardiac dysfunction. Adult studies have linked arterial stiffness with increased risk of mortality, CV events, cognitive decline, and CKD progression. Pulse wave velocity (PWV) is currently the gold standard of arterial stiffness assessment but its measurement in children is challenging due to technical difficulties and physiologic aspects related to growth and poor standardization between algorithms for calculating PWV. Nevertheless, studies in pediatric CKD have reported increased arterial stiffness in children with advanced CKD, on dialysis, and after kidney transplantation. Development of arterial stiffness in children with CKD is closely related to mineral-bone disease and hypertension, but other factors may also play a significant role. The clinical relevance of accelerated arterial stiffness in childhood on cardiovascular outcomes in adult life remains unclear, and prospective studies are needed. In this review we discuss mechanisms leading to arterial stiffness in CKD and its clinical implications, along with issues surrounding the technical aspects of arterial stiffness assessment in children.

Correlations between parameters of central hemodynamics and cytokine profile in chronic kidney disease in combination with cerebrovascular diseases

To study the relationship between central hemodynamics and arterial stiffness indicators with cystatin C, tumor necrosis factor-alpha (TNF-alpha) and interleukin-(IL)-10 in patients with chronic kidney disease (CKD) in combination with cerebrovascular diseases (CEV). One hundred and twenty patients, aged from 19 to 81 years, with signs of chronic renal dysfunction, including 73 with CKD (1st group) and 47 with CKD in combination with CEH (group 2), were examined. 'AngioScan' (Russia) was used to study indices of arterial rigidity. Blood plasma concentrations of TNF-alpha, IL-10 and cystatin C were determined by the enzyme immunoassay. There is a significant increase (p<0.05) in the systolic, diastolic, central levels of arterial pressure, augmentation index, the index of increase at a pulse rate of 75 per min, the age index, the age of the vascular system and cystatin C content in the patients with CKD in combination with CEV compared to the patients with CKD without accompanying CEH. In the group of patients with CKD in combination with CEV, a correlation was found between the level of TNF-alpha and arterial stiffness index on one side (r=0.318; p<0.05) and the augmentation index on the other (r=0.299; p<0.05). The results confirm the fact that there is a significant increase in the level of plasma cystatin C and a decrease in GFR in patients with CKD in combination with CEV. Correlations were found between the level of TNF-alpha, augmentation index and deterioration of parameters of central hemodynamics and arterial stiffness in CKD in combination with CEH.

Progression of arterial stiffness is associated with changes in bone mineral markers in advanced CKD

BackgroundArterial stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with chronic kidney disease (CKD). There are limited prospective data however on progression of arterial stiffness in CKD, including evaluating associations with bone mineral markers such as fibroblast growth factor 23 (FGF23) and soluble α-klotho (sKl).MethodsIn this prospective, single-center, observational study, arterial stiffness [measured by pulse wave velocity (PWV)] and hormones influencing mineral homeostasis, including serum FGF23 and sKl, were compared between non-dialysis CKD stages 4/5 and healthy controls at baseline and 12 months (12 m). Abdominal aortic calcification (AAC) was quantitated using lateral lumbar radiography at baseline.ResultsForty patients with CKD [mean estimated glomerular filtration rate (eGFR) 19.5 ± 6.7 mL/min/1.73m2] and 42 controls (mean eGFR 88.6 ± 12.9 mL/min/1.73m2) completed follow-up. There were no differences in age, gender and body mass index between groups. A significant increase in FGF23 [240.6 (141.9–1129.8) to 396.8 (160.3–997.7) pg/mL, p = 0.001] was observed in the CKD group but serum phosphate, corrected calcium, parathyroid hormone and sKl did not change significantly over 12 m. At baseline, CKD subjects had higher AAC prevalence [83.8% versus (vs.) 43.6%, p = 0.002] and higher aortic PWV [9.7(7.6–11.7) vs. 8.1 (7.2–9.7) m/s, p = 0.047] compared to controls. At 12 m, aortic PWV increased by 1.3 m/s (95% confidence interval, 0.56 to 2.08, p < 0.001) in the CKD cohort, with 30% of subjects showing progression from normal aortic elasticity to stiffening (PWV > 10 m/s). Serum FGF23 was associated with AAC, abnormal PWV and progression of PWV at 12 m.ConclusionsArterial stiffness and serum FGF23, both of which are associated with increased cardiovascular risk, increased over one year in individuals with CKD. Additionally, a significant association was found between serum FGF23 and arterial calcification and stiffness. Larger clinical studies and further experimental work are warranted to delineate the temporal relationship as well as the pathological mechanisms linking FGF23 and vascular disease.

Association of serum adiponectin concentration with aortic arterial stiffness in chronic kidney disease: from the KNOW-CKD study.

High serum adiponectin levels predict all-cause and cardiovascular mortality in chronic kidney disease (CKD). However, the relationship between serum adiponectin concentration and arterial stiffness in CKD is not well established. The aim of this study was to assess this relationship by measuring pulse wave velocity (PWV) in CKD patients. Serum adiponectin concentration was measured in 716 CKD patients in the prospective KoreaN cohort study for Outcome in patients With Chronic Kidney Disease. The study group consisted of 415 men and 301 women; mean age was 53.1years, and baseline estimated glomerular filtration rate (eGFR) was 51±29ml/min per 1.73m2. Heart to femoral PWV (hfPWV) and mean brachial to ankle PWV (baPWV) served as indicators of aortic artery stiffness and arterial stiffness, respectively. Increasing quartiles of serum adiponectin levels were associated with women, lower eGFRs and body mass indices, and higher urinary albumin-creatinine ratios. Serum adiponectin concentration also correlated with hfPWV and mean baPWV, even after adjusting for age and sex. It independently associated with hfPWV (B 0.028; 95% confidence interval, 0.004-0.051; P=0.020) but not mean baPWV in a multivariable linear regression analysis. In a multivariable logistic regression analysis, it correlated significantly with the highest quartile of hfPWVs but not mean baPWVs. The independent and significant correlation of serum adiponectin concentration with hfPWV in CKD patients implicates adiponectin in CKD-associated aortic stiffness.

Hypertension and chronic kidney disease: respective contribution of mean and pulse pressure and arterial stiffness.

Hypertension (HTN) in chronic kidney disease (CKD) is influenced by blood pressure (BP) and the progression of CKD, including hemodialysis and renal transplantation. To date, the efficacy of antihypertensive drug strategies has chiefly been assessed by measuring steady-state systolic, diastolic and mean arterial pressures (MAP). However, recently elucidated features of the BP curve have highlighted other important goals, that is, the specific roles of pulse pressure (PP), arterial stiffness, pulse wave velocity (PWV) and wave reflections as potentially deleterious factors affecting the progression of HTN and CKD. Pharmacological strategies to date have included progressive withdrawal of alpha-blocking agents; efficacy of beta-blockers for coronary prevention; use of angiotensin blockade in HTN with glomerular injury, using angiotensin-converting enzyme inhibition or receptor blockade, as mono but never double-blockade, to avoid major complications; development of combination therapies with diuretics and/or calcium channel blockers. Nowadays, most clinical trials show that SBP, DBP and MAP-lowering is an effective strategy, although results no longer show preference for any specific drug class.Studies of arterial stiffness in CKD have become crucial. In older individuals, PWV is considerably elevated. The 'stiffness gradient' disappears or is inverted (normally, aortic PWV is lower than brachial PWV). Despite BP-lowering, PP is insufficiently dampened, thus promoting microcirculatory damage, progression of arterial calcifications and disturbed wave reflections, which all increase the risk of mortality. In the absence of effective hemodialysis or graft, increased arterial stiffness is therefore a major cardiovascular risk factor in CKD.

Metabolic Syndrome-Associated Risk Factors and High-Sensitivity C-Reactive Protein Independently Predict Arterial stiffness in 9903 Subjects With and Without Chronic Kidney Disease.

Metabolic syndrome (MS), high-sensitivity C-reactive protein (hs-CRP), and chronic kidney disease (CKD) are related to cardiovascular diseases. Although MS is common in CKD subjects, the contribution of MS-associated risk factors and hs-CRP to arterial stiffness in CKD has not been well studied.In this cross-sectional cohort study, we enrolled 9903 subjects who underwent brachial-ankle pulse wave velocity (baPWV) measurements from our database of Health Care Center. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Comparing those grouped with and without CKD, multivariate linear regression analyses were used.Overall, baPWV was found to have an inverse relationship with eGFR (P for trend <0.001), which increased progressively with the presence of CKD, increasing number of MS-associated risk factors and hs-CRP (P for trend <0.001). In the non-CKD group, age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, triglyceride, high-density lipoprotein cholesterol, and hs-CRP independently predicted baPWV, whereas in CKD, eGFR, age, gender, body mass index, SBP, DBP, and fasting glucose remained predictors.The number of MS-associated risk factors and hs-CRP remains a determinant of arterial stiffness in both CKD and non-CKD groups. The decline of renal function contributes to arterial stiffness only in CKD but not in non-CKD. Our findings suggest that for CKD subjects, renal function, BP, and glycemic control are potential targets for further interventional studies of arterial stiffness.

Arterial stiffness and increased cardiovascular risk in chronic kidney disease.

Chronic kidney disease (CKD) is a global public health problem. Cardiovascular disease (CVD) is a common comorbidity and a major cause of mortality in CKD population. While CVD-related mortality is relatively uncommon in young population, it accounts for most deaths in young CKD adults. There are numerous risk factors for CVD in CKD patients including conventional (hypertension, diabetes, dyslipidemia) and nonconventional (oxidative stress, inflammation, anemia, mineral metabolism disorder) factors. Recent studies have placed great emphasis on the association of arterial stiffness (AS) and CVD. AS is traditionally known as an aging marker of the artery; however, increased AS is observed in young and even in pediatric CKD patients; it is also shown that AS progresses in consistent with kidney function decline. Unparallel AS in young CKD population and excessive risk of CVD in young CKD adults show an indication that AS probably offers one of the underlying mechanisms for linking CKD and CVD. AS in CKD patients has multifactorial causes. Comorbidities such as hypertension, diabetes, dyslipidemia, and mineral metabolism disorder which are risk factors for CVD also show great contribution to AS in CKD patients. Increased systolic blood pressure and decreased diastolic blood pressure resulting from AS cause elevated ventricular afterload, lead to impaired coronary perfusion, myocardial ischemia, and ventricular hypertrophy, and consequently develop into CVD event. In this review, we summarized the role of AS in CKD and CVD, aiming to explore the linkage of AS between CKD and CVD.

ARTERIAL STIFFNESS AND CHRONIC KIDNEY DISEASE: CAUSES AND CONSEQUENCES

Chronic kidney disease (CKD) is associated with increased cardiovascular risk. CKD is characterized by accelerated aging of vessels in which the age-related arterial stiffness increase is exacerbated by a number of uremia-related processes. Increased arterial stiffness is associated with structural and functional disorders, as well as with the increase in cardiovascular mortality in patients with CKD. Increased arterial stiffness is diagnosed at an early stage of CKD. Modern understanding of the mechanisms of increased risk of cardiovascular complications in CKD, the factors contributing to the loss of elasticity of the arteries, arterial stiffness increase consequences are analyzed. Data illustrating the twoway interaction between CKD and arterial stiffness and mechanisms of accelerated progression of arterial stiffness in CKD are presented.

Risk factors for metabolic syndrome independently predict arterial stiffness and endothelial dysfunction in patients with chronic kidney disease and minimal comorbidity.

OBJECTIVEMetabolic syndrome (MS) is common in patients with chronic kidney disease (CKD), but its contribution to arterial stiffness and endothelial dysfunction in CKD is not well defined. We hypothesized that risk factors for MS would independently predict arterial stiffness and endothelial dysfunction in CKD patients.RESEARCH DESIGN AND METHODSRisk factors for MS, carotid-femoral pulse wave velocity (CF-PWV) and flow-mediated dilation (FMD) as measures of arterial stiffness and endothelial dysfunction, respectively, were assessed in 113 minimally comorbid CKD patients and in 23 matched control subjects.RESULTSCF-PWV correlated with systolic blood pressure (SBP), waist circumference, and plasma glucose (r2 = 0.25, 0.09, and 0.09; P < 0.01 for all). FMD correlated with SBP (r2 = 0.09; P < 0.01) and waist circumference (r2 = 0.03; P < 0.05). CF-PWV increased progressively (r2 = 0.07; P < 0.01) with increasing number of risk factors for MS. In multiple linear regression, SBP and waist circumference were independent determinants of CF-PWV, whereas only SBP predicted FMD.CONCLUSIONSThe number of MS risk factors is an important determinant of arterial stiffness in CKD patients irrespective of the degree of renal impairment. Although BP remains the major determinant of arterial stiffness and endothelial dysfunction, waist circumference independently predicts arterial stiffness. MS risk factors, particularly abdominal girth, are potential targets for future interventional studies in patients with CKD.

Association between markers of collagen turnover, arterial stiffness and left ventricular hypertrophy in chronic kidney disease (CKD): the Renal Research Institute (RRI)-CKD Study

Markers of collagen turnover have not been well studied in the context of cardiovascular disease in patients with chronic kidney disease (CKD). We investigated the associations between serum markers of collagen turnover [N-terminal procollagen type 3 propeptide (PIIINP) and carboxy-terminal telopeptide (C1TP)] and both pulse wave velocity (PWV) and left ventricular mass index (LVMI) in a CKD cohort. The study included 242 patients (mean age 60 ± 15 years, 53% males, 80% Caucasian, CKD Stages 3-5) from the Renal Research Institute (RRI)-CKD Study. Serum PIIINP and C1TP levels were analyzed by radioimmunoassay. PWV was obtained by applanation tonometry from carotid and femoral pressure wave contours. LVMI was measured by echocardiography. Statistical analyses included Pearson's correlations and multiple linear regression. Both PIIINP and C1TP values were significantly higher in more advanced stages of CKD (P < 0.05). A positive correlation was demonstrated between PWV and LVMI (r = 0.25, P = 0.0018), persisting after adjustment for potential confounders (partial r = 0.27, P = 0.0009). PIIINP correlated with PWV (r = 0.16, p = 0.029) and LVMI (r = 0.16, P = 0.0018), while C1TP correlated with LVMI (r = 0.18, P = 0.013) but not with PWV (r = 0.12, P = 0.09). In multivariable analysis adjusting for race, diabetes, estimated glomerular filtration rate (eGFR) and renin-angiotensin-aldosterone system inhibitors, only PWV (β = 0.45, P = 0.0017) but not LVMI (P = 0.09) remained significantly associated with serum PIIINP. Our results demonstrate the association of PIIINP (but not C1TP), a circulating biomarker of collagen synthesis with arterial stiffness (but not with LVMI) in a CKD cohort, independent of eGFR. This suggests that altered collagen turnover may play a role in the pathogenesis of arterial stiffness in CKD.

A Newly Estimated Glomerular Filtration Rate Is Independently Associated with Arterial Stiffness in Japanese Patients

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease, and thus is a major worldwide public health problem. Recently, an estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation for Japanese patients was proposed by the Japanese Society of Nephrology. However, the role of eGFR in the assessment of atherosclerosis is not well understood in Japanese patients. We analyzed the relationship between eGFR and severity of arterial stiffness using brachial-ankle pulse wave velocity (baPWV) in 647 adult Japanese patients. baPWV correlated significantly and positively with age, hypertension, diabetes, prior cardiovascular disease, blood pressure, pulse pressure and heart rate, and negatively with eGFR (r=-0.405, p<0.0001). A multiple regression analysis revealed that baPWV correlated independently with eGFR. Furthermore, there was a stepwise increase in baPWV, corresponding to advances in CKD through stages 1 to 5. When CKD stage 3 was divided at eGFR 45 mL/min/1.73 m2, the baPWV of stage 3b (eGFR 30 to 44) was significantly higher than that of stage 3a (eGFR 45 to 59) independent of traditional risk factors, suggesting that an eGFR of 45 mL/min/1.73 m2 may be a critical cut off value to predict arterial stiffness in CKD. In conclusion, the newly proposed eGFR is significantly associated with arterial stiffness, independent of traditional risk factors for cardiovascular disease.