Catherine Fortier

Aortic-Brachial Stiffness Mismatch and Mortality in Dialysis Population

We hypothesized that increased aortic stiffness (central elastic artery) combined with a decrease in brachial stiffness (peripheral muscular artery) leads to the reversal of the physiological stiffness gradient (ie, mismatch), promoting end-organ damages through increased forward pressure wave transmission into the microcirculation. We, therefore, examined the effect of aortic-brachial stiffness mismatch on mortality in patients in need of dialysis. In a prospective observational study, aortic-brachial arterial stiffness mismatch (pulse wave velocity ratio) was assessed using carotid-femoral pulse wave velocity divided by carotid-radial pulse wave velocity in 310 adult patients on dialysis. After a median follow-up of 29 months, 146 (47%) deaths occurred. The hazard ratio (HR) for mortality related to PWV ratio in a Cox regression analysis was 1.43 (95% confidence interval [CI], 1.24–1.64; P<0.001 per 1 SD) and was still significant after adjustments for confounding factors, such as age, dialysis vintage, sex, cardiovascular disease, diabetes mellitus, smoking status, and weight (HR, 1.23; 95% CI: 1.02–1.49). The HRs for changes in 1 SD of augmentation index (HR, 1.35; 95% CI, 1.12–1.63), carotid-femoral pulse wave velocity (HR, 1.29; 95% CI, 1.11–1.50), and carotid-radial pulse wave velocity (HR, 0.80; 95% CI, 0.67–0.95) were statistically significant in univariate analysis, but were no longer statistically significant after adjustment for age. In conclusion, aortic-brachial arterial stiffness mismatch was strongly and independently associated with increased mortality in this dialysis population. Further studies are required to confirm these finding in lower-risk groups.

Aortic-Brachial Pulse Wave Velocity Ratio: A Blood Pressure-Independent Index of Vascular Aging.

Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV (R2=0.10 and 0.08; P<0.001 and P=0.003) and MAP and carotid–radial PWV (R2=0.22 and 0.12; P<0.001 and P<0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio (R2=0.0002 and 0.0001; P=0.8 and P=0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging.Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV ( R 2=0.10 and 0.08; P <0.001 and P =0.003) and MAP and carotid–radial PWV ( R 2=0.22 and 0.12; P <0.001 and P <0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio ( R 2=0.0002 and 0.0001; P =0.8 and P =0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging. # Novelty and Significance {#article-title-24}

Arterial Stiffness Gradient

Background: Aortic stiffness is a strong predictor of cardiovascular mortality in various clinical conditions. The aim of this review is to focus on the arterial stiffness gradient, to discuss the integrated role of medium-sized muscular conduit arteries in the regulation of pulsatile pressure and organ perfusion and to provide a rationale for integrating their mechanical properties into risk prediction. Summary: The physiological arterial stiffness gradient results from a higher degree of vascular stiffness as the distance from the heart increases, creating multiple reflective sites and attenuating the pulsatile nature of the forward pressure wave along the arterial tree down to the microcirculation. The stiffness gradient hypothesis simultaneously explains its physiological beneficial effects from both cardiac and peripheral microcirculatory points of view. The loss or reversal of stiffness gradient leads to the transmission of a highly pulsatile pressure wave into the microcirculation. This suggests that a higher degree of stiffness of medium-sized conduit arteries may play a role in protecting the microcirculation from a highly pulsatile forward pressure wave. Using the ratio of carotid-femoral pulse wave velocity (PWV) to carotid-radial PWV, referred to as PWV ratio, a recent study in a dialysis cohort has shown that the PWV ratio is a better predictor of mortality than the classical carotid-femoral PWV. Key Messages: Theoretically, the use of the PWV ratio seems more logical for risk determination than aortic stiffness as it provides a better estimation of the loss of stiffness gradient, which is the unifying hypothesis that explains the impact of aortic stiffness both on the myocardium and on peripheral organs.

Active vitamin D and accelerated progression of aortic stiffness in hemodialysis patients: a longitudinal observational study.

BACKGROUND We hypothesized that high-dose active vitamin D therapy in the form of alphacalcidol (α-calcidol), used to treat secondary hyperparathyroidism in chronic kidney disease, could lead to vascular calcification and accelerated progression of aortic stiffness. METHODS We conducted an observational study in 85 patients on chronic hemodialysis, among which 70 were taking a weekly dose of α-calcidol of <2 µg and 15 were taking a weekly dose of ≥2 µg (pharmacological dose). Parathyroid hormone, 25-hydroxyvitamin D, fibroblast growth factor 23, and α-klotho were determined. Aortic stiffness was assessed by determination of carotid-femoral pulse wave velocity (cf-PWV) at baseline and after a mean follow-up of 1.2 years. A multivariable regression model was used to evaluate the impact of pharmacological dose of α-calcidol on the progression of aortic stiffness. RESULTS At baseline, clinical, biological, and hemodynamic parameters were similar. At follow-up, cf-PWV increased more in patients with pharmacological dose of α-calcidol (0.583±2.291 m/s vs. 1.948±1.475 m/s; P = 0.04). After adjustment for changes in mean blood pressure and duration of follow-up, pharmacological dose of α-calcidol was associated with a higher rate of progression of cf-PWV (0.969 m/s; 95% confidence interval = 0.111-1.827; P = 0.03), and this association persisted after further adjustments for parameters of mineral metabolism. CONCLUSIONS In this study, pharmacological dose of α-calcidol was associated with accelerated progression of aortic stiffness. This study suggest that the vascular safety of active vitamin D posology may need to be specifically addressed in the treatment of chronic kidney disease-related bone mineral disorder.

Levels of Angiopoietin-Like-2 Are Positively Associated With Aortic Stiffness and Mortality After Kidney Transplantation

BACKGROUND Angiopoietin‐like‐2 (ANGPTL2) is a secreted proinflammatory glycoprotein that promotes endothelial dysfunction, atherosclerosis, and cardiovascular disease (CVD). Circulating ANGPTL2 is increased in chronic kidney disease (CKD), where the risk of CVD is amplified. The objectives of the present study were to (i) examine whether kidney transplantation (KTx) reduces ANGPTL2 levels, (ii) identify the determinants of ANGPTL2 after KTx, (iii) study the association of ANGPTL2 with aortic stiffness, and (iv) assess the impact of ANGPTL2 on mortality after KTx. METHODS In 75 patients, serum ANGPTL2 levels were measured at baseline and 3 months after KTx. Aortic stiffness was determined by carotid‐femoral pulse wave velocity, glomerular filtration rate was estimated by CKD‐EPI formula, and serum cytokines and endothlin‐1 levels were determined 3 months after KTx. Survival analysis was performed using Kaplan‐Meier and Cox regression after a median follow‐up of 90 months. RESULTS After 3 months of KTx, ANGPTL2 levels decreased from 71 ng/ml (53‐95) to 11 ng/ml (9‐15) (P < 0.001). In multivariate analysis, age, lower renal function, and endothelin‐1 were independently associated with higher post‐KTx ANGPTL2 levels. ANGPTL2 was positively associated with aortic stiffness after KTx, even when adjusted for mean blood pressure (standardized &bgr; = 0.314; P = 0.008). During follow‐up, 13 deaths occurred. The group of patients with higher post‐KTx ANGPTL2 levels had a hazard ratio for mortality of 3.9 (95% confidence interval: 1.07‐14.4; P = 0.039). CONCLUSION KTx significantly reduced serum ANGPTL2 levels. The positive association between post‐KTx ANGPTL2, aortic stiffness and mortality, suggests that ANGPTL2 may play a biological role in CKD‐related CVD.

Reduction of Arterial Stiffness After Kidney Transplantation: A Systematic Review and Meta‐Analysis

Background End‐stage kidney disease is associated with increased arterial stiffness. Although correction of uremia by kidney transplantation (KTx) could improve arterial stiffness, results from clinical studies are unclear partly due to small sample sizes. Method and Results We conducted a systematic review and meta‐analysis of before‐after design studies performed in adult KTx patients with available measures of arterial stiffness parameters (pulse wave velocity [PWV], central pulse pressure [PP], and augmentation index) before and at any time post‐KTx. Mean difference of post‐ and pre‐KTx values of different outcomes were estimated using a random effect model with 95% confidence interval. To deal with repetition of measurement within a study, only 1 period of measurement was considered per study by analysis. Twelve studies were included in meta‐analysis, where a significant decrease of overall PWV by 1.20 m/s (95% CI 0.67‐1.73, I2=72%), central PWV by 1.20 m/s (95% CI 0.16‐2.25, I2=83%), peripheral PWV by 1.17 m/s (95% CI 0.17‐2.17, I2=79%), and brachial‐ankle PWV by 1.21 m/s (95% CI 0.66‐1.75, I2=0%) was observed. Central PP (reported in 4 studies) decreased by 4.75 mm Hg (95% CI 0.78–10.28, I2=50%). Augmentation index (reported in 7 studies) decreased by 10.5% (95% CI 6.9‐14.1, I2=64%). A meta‐regression analysis showed that the timing of assessment post‐KTx was the major source of the residual variance. Conclusions This meta‐analysis suggests a reduction of the overall arterial stiffness in patients with end‐stage kidney disease after KTx.

Fracture Risk in Dialysis and Kidney Transplanted Patients: A Systematic Review: FRACTURE RISK IN DIALYSIS AND KIDNEY TRANSPLANTED PATIENTS

Chronic kidney disease is associated with an increased risk of fracture and cardiovascular mortality. The risk of fracture in hemodialysis (HD), peritoneal dialysis (PD) and kidney transplant (KT) patients is higher when compared with the general population. However, there exists a knowledge gap concerning which group has the highest risk of fracture. We aimed to compare the risk of fracture in HD, PD, and KT populations. We conducted a systematic review of observational studies evaluating the risk of fracture in HD, PD, or KT patients. Eligible studies were searched using MEDLINE, Embase, Web of Science, and Cochrane Library from their inception to January 2016, and in grey literature. Incidences (cumulative and rate) of fracture were described together using the median, according to fracture sites, the data source (administrative database or cohort and clinical registry), and fracture diagnosis method. Prevalence estimates were described separately. We included 47 studies evaluating the risk of fracture in HD, PD, and KT populations. In administrative database studies, incidence of hip fracture in HD (median 11.45 per 1000 person‐years [p‐y]), range: 9.3 to 13.6 was higher than in KT (median 2.6 per 1000 p‐y; range 1.5 to 3.8) or in PD (median 5.2 per 1000 p‐y; range 4.1 to 6.3). In dialysis (HD+PD), three studies reported a higher incidence of hip fracture than in KT. Prevalent vertebral fracture (assessed by X‐rays or questionnaire) reported in HD was in a similar range as that reported in KT. Incidence of overall fracture was similar in HD and KT, from administrative databases studies, but lower in HD compared with KT, from cohorts or clinical registry studies. This systematic review suggests an important difference in fracture risk between HD, PD, and KT population, which vary according to the diagnosis method for fracture identification.

Aortic-Brachial Pulse Wave Velocity Ratio: A Measure of Arterial Stiffness Gradient Not Affected by Mean Arterial Pressure

Background: Aortic stiffness, measured by carotid-femoral pulse wave velocity (cf-PWV), is used for the prediction of cardiovascular risk. This mini-review describes the nonlinear relationship between cf-PWV and operational blood pressure, presents the proposed methods to adjust for this relationship, and discusses a potential place for aortic-brachial PWV ratio (a measure of arterial stiffness gradient) as a blood pressure-independent measure of vascular aging. Summary: PWV is inherently dependent on the operational blood pressure. In cross-sectional studies, PWV adjustment for mean arterial pressure (MAP) is preferred, but still remains a nonoptimal approach, as the relationship between PWV and blood pressure is nonlinear and varies considerably among individuals due to heterogeneity in genetic background, vascular tone, and vascular remodeling. Extrapolations from the blood pressure-independent stiffness parameter β (β0) have led to the creation of stiffness index β, which can be used for local stiffness. A similar approach has been used for cardio-ankle PWV to generate a blood pressure-independent cardio-ankle vascular index (CAVI). It was recently demonstrated that stiffness index β and CAVI remain slightly blood pressure-dependent, and a more appropriate formula has been proposed to make the proper adjustments. On the other hand, the negative impact of aortic stiffness on clinical outcomes is thought to be mediated through attenuation or reversal of the arterial stiffness gradient, which can also be influenced by a reduction in peripheral medium-sized muscular arteries in conditions that predispose to accelerate vascular aging. Arterial stiffness gradient, assessed by aortic-brachial PWV ratio, is emerging to be at least as good as cf-PWV for risk prediction, but has the advantage of not being affected by operating MAP. Key Messages: The negative impacts of aortic stiffness on clinical outcomes are proposed to be mediated through attenuation or reversal of arterial stiffness gradient. Aortic-brachial PWV ratio, a measure of arterial stiffness gradient, is independent of MAP.

[OP.7C.12] IMPACT OF KIDNEY TRANSPLANTATION ON AORTIC PULSE WAVE VELOCITY AND AORTIC STIFFNESS INDEX B0

Objective: Patients with chronic kidney disease are at increased risk of aortic stiffness and cardiovascular disease. We have previously shown that aortic pulse wave velocity (PWV) improves as early as 3 months post-kidney transplantation (KTx). Arterial stiffness index &bgr;0 has been proposed to be an intrinsic blood pressure independent parameter of vascular wall property. The aim of this study is to examine 1) the early versus late changes in aortic PWV and stiffness index &bgr;0 and 2) to define the characteristics of patients with favorable and unfavorable trajectories of stiffness index &bgr;0. Design and method: In this longitudinal study, 79 patients who underwent KTx were enrolled and followed-up before, 3, 6 and 24 months after KTx. Aortic stiffness was determined non-invasively by the assessment of carotid-femoral pulse wave velocity (cf-PWV) (Complior) while central mean blood pressure was obtained from applanation tonometry (SphygmoCor). Aortic stiffness index &bgr;0 was calculated using the following formulae: &bgr;0 = (PWV2)*2&rgr;)/Pd-ln(Pd/Pref) in which Pref refers to reference pressure (Pref = 100mmHg), &rgr; to blood mass density (&rgr; = 1050 kg/m3) and Pd to brachial diastolic blood pressure (mmHg). Cytokines profile was measured in plasma by ELISA using a Multiplex array. Results: There was an early reduction of &bgr;0 3 months after KTx (from 29.0 ± 17.7 to 25.8 ± 10.6 (P = 0.014)) outweighed by an increase at 6 and 24 months (27.8 ± 12.0 to 28.2 ± 11.2). There were no late changes of aortic PWV at 6 and 24 months. The faster progression of &bgr;0 after an initial improvement was not related to renal function, age, comorbidities or kidney donor characteristics. Nonetheless, the accelerated progression of &bgr;0 was associated with higher levels of pro-inflammatory cytokines, such as interleukin-6 (P = 0.029), interleukine-8 (P = 0.040) and interleukin-10 (P = 0.032). Figure. No caption available. Conclusions: The early improvement of aortic stiffness index &bgr;0 after KTx suggests that KTx leads to an early improvement of the intrinsic mechanical properties of aorta. However, this improvement is followed by a later progression of &bgr;0, which is associated with increased pro-inflammatory cytokines, suggesting that activation if immune system may be involved in arterial wall remodelling in kidney transplant recipients.

[OP.3A.03] MINERAL, BONE METABOLISM MARKERS AND ARTERIAL STIFFNESS IN DIALYSIS POPULATION

Objective: Mineral and bone disorders in Chronic Kidney Disease (CKD) are associated with increased arterial stiffness, cardiovascular events, and mortality. This study aims to determine the association between new bone markers (Sclerostin, DKK1, &agr;-Klotho, FGF23) and parameters of arterial stiffness (central and peripheral) and mortality in a dialysis population. Design and method: Cross-sectional and retrospective study of hemodialysis patients that have been previously recruited for the study of arterial stiffness at CHU de Québec, Canada. Demographic, clinical, pharmacological, mineral, biochemical parameters and mortality were collected. Bone markers levels of Sclerostin, DKK1, &agr;-Klotho, FGF23, P1NP and TRAP5b were obtained by ELISA from pre-dialytic plasma. Carotid-femoral (CF) and carotid-radial (CR) pulse-wave velocity (PWV) and femoral/radial PWV ratio were measured in every patient as previously performed. Linear and Cox regression analysis were used to assess factors associated with arterial stiffness and mortality. Results: We included 130 hemodialysis patients with a median follow-up of 1290 (864) days. Population characteristics are presented in table 1. The population is composed of 47% male with a mean age of 72 (±14) years and a mean dialysis vintage of 545 (1171) days. 56% had coronary artery disease, 51% had diabetes and 89% suffered from hypertension. At the end of follow-up, 97 (75%) patients had died. Median CF-PWV was 13,5 (5,1) m/s, CR-PWV was 8,4 (2,0) m/s and PWV-ratio was 1,7 (0,7). In univariate analysis, as displayed in table 2, only FGF23 blood level was inversely associated with CF-PWV while &agr;-Klotho and Sclerostin were positively associated with CR-PWV. FGF23, &agr;-Klotho and Sclerostin levels were inversely associated with the PWV ratio. In multivariate models adjusting for demographic, biochemical and mineral parameters, &agr;-Klotho was positively associated with CR-PWV and inversely associated with the PWV ratio. Finally, only FGF23 levels were associated with an increased mortality in both univariate and multivariate models. Figure. No caption available. Conclusions: In a dialysis population, plasma levels of &agr;-Klotho and Sclerostin are associated with peripheral arterial stiffness and femoral/radial stiffness ratio. High levels of FGF23 are associated with increased mortality. These results suggest a central role of mineral parameters in arterial stiffness in CKD.