Mihai S. Utescu

Determinants of Progression of Aortic Stiffness in Hemodialysis Patients A Prospective Longitudinal Study

Aortic stiffness is associated with increased cardiovascular mortality in patients with chronic kidney disease. However, the rate of progression of arterial stiffness and the role of cardiovascular risk factors in the progression of arterial stiffness has never been established in a longitudinal study. In a prospective, longitudinal, observational study, carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were assessed in 109 hemodialysis patients at baseline and after a mean follow-up of 1.2 years. We examined the impact of age, atherosclerotic cardiovascular disease, diabetes mellitus, dialysis vintage, and pentosidine (a well-characterized, advanced glycation end products) on the rate of progression of aortic stiffness. The annual rate of changes in carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were 0.84 m/s per year (95% confidence interval, 0.50–1.12 m/s per year) and −0.66 m/s per year (95% confidence interval, −0.85 to −0.47 m/s per year), respectively. Older subjects, and patients with diabetes mellitus or atherosclerotic cardiovascular disease had higher aortic stiffness at baseline, however, the rate of progression of aortic stiffness was only determined by plasma pentosidine levels (P=0.001). The degree of baseline aortic stiffness was a significant determinant of the regression of brachial stiffness (P<0.001) suggesting that the regression of brachial stiffness occurs in response to central aortic stiffness. These findings suggest that traditional cardiovascular risk factors may play some role in the progression of aortic stiffness before development of advanced chronic kidney disease, and that the enhanced rate of progression of aortic stiffness in chronic kidney disease patients on dialysis are probably determined by more specific chronic kidney disease–related risk factors such as advanced-glycation end products.

Age-related and blood pressure-independent reduction in aortic stiffness after kidney transplantation.

Objectives Aortic stiffness is a novel cardiovascular risk factor in patients with chronic kidney disease (CKD). The purpose of the present study is to examine whether there is a blood pressure-independent improvement in aortic stiffness 3 months after successful kidney transplantation (KTx), and whether this improvement is age-dependent. Method In this prospective, longitudinal observational study, we studied hemodynamic and biological parameters prior to and 3 months after a KTx in 52 stage 5 CKD patients. Aortic stiffness was measured by carotido-femoral pulse wave velocity (c-f PWV) and enhanced central wave reflection was evaluated by the heart rate-adjusted central augmentation index (AIx) by means of arterial tonometry. Endothelin-1, L-arginine, asymmetric dimethylarginine (biomarkers of endothelial dysfunction), pentosidine (advanced glycation end-products) and mineral metabolism parameters were also measured. Results After adjusting for the reduction in mean blood pressure, c-f PWV decreased significantly from 12.1 ± 3.3 to 11.6 ± 2.3 m/s (P < 0.05). In an analysis stratified by age, this improvement was only present in patients older than 50 years of age as compared with patients younger than 50 years of age (−5.5 ± 2.2 vs. 2.1 ± 1.9%, P < 0.05). AIx decreased from 22 ± 11 to 14 ± 13% (P < 0.01), but this reduction was not age-dependent. We also observed a similar degree of improvement in the biomarker levels of endothelial dysfunction and pentosidine in both groups. Conclusion This study shows for the first time that there is an age-dependent improvement in aortic stiffness after KTx. These observations suggest that older patients may have an added cardiovascular risk reduction after a successful KTx.

Effects of acute variation of dialysate calcium concentrations on arterial stiffness and aortic pressure waveform

Background. Abnormal mineral metabolism in chronic kidney disease plays a critical role in vascular calcification and arterial stiffness. The impact of presently used dialysis calcium concentration (DCa) on arterial stiffness and aortic pressure waveform has never been studied. The aim of the present study is to evaluate, in haemodialysis (HD) patients, the impact of acute modification of DCa on arterial stiffness and central pulse wave profile (cPWP). Method. A randomized Latin square cross-over study was used to evaluate the three different concentrations of DCa (1.00, 1.25 and 1.50 mmol/L) during the second HD of the week for 3 consecutive weeks. Subjects returned to their baseline DCa for the following two treatments, allowing for a 7-day washout period between each experimental HD. cPWP, carotido-radial (c-r) and carotido-femoral (c-f) pulse wave velocities (PWV), plasma level of ionized calcium (iCa) and intact parathyroid hormone (PTH) were measured prior to and immediately after each experimental HD session. Data were analysed by the general linear model for repeated measures and by the general linear mixed model. Results. Eighteen patients with a mean age of 48.9 ± 18 years and a median duration of HD of 8.7 months (range 1–87 months) completed the study. In post-HD, iCa decreased with DCa of 1.00 mmol/L (−0.14 ± 0.04 mmol/L, P < 0.001), increased with a DCa of 1.50 mmol/L (0.10 ± 0.06 mmol/L, P < 0.001) but did not change with a DCa of 1.25 mmol/L. Tests of within-subject contrast showed a linear relationship between higher DCa and a higher post-HD Δc-f PWV, Δc-r PWV and Δmean BP (P < 0.001, P = 0.008 and P = 0.002, respectively). Heart rate-adjusted central augmentation index (AIx) decreased significantly after HD, but was not related to DCa. The timing of wave refection (Tr) occurred earlier after dialysis resulting in a linear relationship between higher DCa and post-HD earlier Tr (P < 0.044). In a multivariate linear-mixed model for repeated measures, the percentage increase in c-f PWV and c-r PWV was significantly associated with the increasing level of iCa, whereas the increasing level of ΔMBP was not significant. In contrast, the percentage decrease in Tr (earlier wave reflection) was determined by higher ΔMBP and higher ultrafiltration, whereas the relative change in AIx was inversely determined by the variation in the heart rate and directly by ΔMBP. Conclusion. We conclude that Dca and acute changes in the serum iCa concentration, even within physiological range, are associated with detectable changes of arterial stiffness and cPWP. Long-term studies are necessary to evaluate the long-term effects of DCa modulation on arterial stiffness.

The impact of warfarin on the rate of progression of aortic stiffness in hemodialysis patients: a longitudinal study

BACKGROUND Accelerated progression of aortic stiffness in patients with advanced chronic kidney disease is not well explained by the traditional cardiovascular risk factors. We hypothesized that vitamin K deficiency may result in an accelerated progression of aortic stiffness in the pro-calcifying uremic milieu. METHOD Eighteen hemodialysis (HD) patients on warfarin were matched to 54 HD patients without warfarin (control). Aortic stiffness was determined by carotid-femoral pulse wave velocity (cf-PWV) at baseline and after a mean follow-up of 1.2 years. In the control group, spontaneous vitamin K deficiency was defined as proteins induced by vitamin K deficiency/absence-II >median. RESULTS At baseline, clinical characteristics and cf-PWV were similar. Adjusted cf-PWV increased by 0.86 ± 1.87 m/s in control and by 2.24 ± 2.68 m/s in warfarin group (P = 0.024). After adjustments for confounders, warfarin therapy was independently associated with progression of aortic stiffness (P = 0.016). The rate of progression of aortic stiffness showed a linear trend in response to vitamin K status and warfarin therapy, suggesting that at least part of the effects are mediated through reduced availability of vitamin K. The unadjusted and adjusted hazard ratio (HR) of warfarin therapy on mortality were, respectively, 2.40 (P = 0.006) and 2.53 (P = 0.006). In a forward conditional Cox regression analysis, age, albumin, augmentation index (AIx) and a cf-PWV > 13.8 m/s at the time of follow-up (HR: 2.11, P = 0.05) were independent determinants of mortality, whereas warfarin use was not retained as an independent factor. Finally, control patients with poor vitamin K status had an intermediate survival as compared with controls with better vitamin K status and patients with warfarin (P = 0.01). CONCLUSION This is the first study to show a temporal association between warfarin, functional vitamin K deficiency and progression of aortic stiffness in HD patients. These findings suggest that the net cardiovascular benefit of long-term warfarin therapy may need to be reevaluated in this population.

Impact of dialysate calcium concentration on the progression of aortic stiffness in patients on haemodialysis

BACKGROUND Higher dialysate calcium (DCa) can result in an acute and transient increase in arterial stiffness. The aim of the present study is to evaluate the impact of DCa on the progression of arterial stiffness, calcium balance and bone metabolism in haemodialysis (HD) patients over a 6-month period. Method. We randomly assigned 30 patients on chronic HD to be dialysed with a DCa of 1.12 or 1.37 mmol/L for a period of 6 months. Aortic stiffness and brachial stiffness were respectively measured by carotid-femoral pulse wave velocities (cf-PWV) and carotid-radial pulse wave velocity (cr-PWV) at baseline and at 3 and 6 months. Central pulse pressure (PP) and augmentation index were determined by radial artery tonometry. Dialysis calcium balance and parathyroid hormone (PTH) were measured monthly. Procollagen type-1 amino-terminal propeptide (P1NP) and C-terminal telopeptide of type-I collagen (CTX) were measured as markers of bone formation and resorption, respectively. Data was analysed by linear mixed model. RESULTS Twenty-seven patients (66 ± 13 years old) with a mean duration of HD of 5.8 ± 3.6 months completed the study. At baseline, the groups were similar with respect to age, serum levels of calcium, phosphate and PTH, blood pressure (BP), cf-PWV and cr-PWV. The cf-PWV at baseline and 3 and 6 months were, respectively, 13.4 ± 4.2, 14.7 ± 3.31 and 13.6 ± 2.5 m/s in the DCa 1.12 group and 14.6 ± 5.9, 15.8 ± 7.8 and 17.0 ± 7.0 m/s in the DCa 1.37 group. After correction for mean BP, cf-PWV increased with DCa 1.37 as compared to DCa 1.12 (Time-DCa interaction P = 0.002). However, there were no significant effects of DCa on progression of cr-PWV, central PP or augmentation index. During the intervention period, the mean PTH was slightly higher in the DCa 1.12 group as compared to the DCa 1.37 group (325 ± 185 versus 211 ± 128 ng/L, P = 0.054), and dialysis calcium balance was -8.1 ± 4.4 versus -0.2 ± 4.7 mmol/session, respectively, in groups with DCa 1.12 and DCa 1.37 (P = 0.0001). Treatment with DCa 1.12 mmol/L resulted in increasing levels of CTX as compared to DCa 1.37 (P = 0.02), whereas the P1NP levels did not change significantly in either group. CONCLUSIONS In this study, aortic stiffness progressed with DCa 1.37, while it remained stable with DCa 1.12 over a 6-month period. These results suggest that higher DCa concentrations could be a risk factor for the progression of aortic stiffness in HD patients. In the context of limited oral calcium, the long-term safety of DCa 1.12 on bone metabolism remains to be established.

The impact of arteriovenous fistulas on aortic stiffness in patients with chronic kidney disease

BACKGROUND The creation of arteriovenous fistulas (AVF) in patients with advanced chronic kidney disease (CKD) has been shown to have adverse effects on their central pulse wave profile suggesting a likely increase in arterial stiffness. The aim of the present study was to directly evaluate the effect of AVF on arterial stiffness. Method. Thirty-one stage-5 CKD patients underwent haemodynamic assessment prior to and 3 months after creation of AVF. Haemodynamic assessment included measurement of blood pressure (BP), central and carotidal pulse wave profile analysis, and carotido-femoral and carotido-radial pulse wave velocities (PWV). Pre-AVF and post-AVF haemodynamic parameters were compared using the Wilcoxon signed-rank test or the paired Student t-test as appropriate. Pearson correlations, single and multiple linear regressions, were used to determine the association between variables. RESULTS After creation of AVF, peripheral and central BPs decreased without significant change in heart rate (HR) or pulse pressure. Carotido-femoral PWV ((c-f)PWV) fell from 13.2 +/- 4.1 to 11.7 +/- 3.1 m/s (P < 0.001). There was an increase in the central augmentation index (20.8% +/- 11.5 versus 23.7% +/- 11.6, P = 0.07) of borderline significance, and a significant reduction in the subendocardial viability ratio (153% +/- 34 versus 143% +/- 32, P < 0.05), which was mainly the result of a decrease in the diastolic pressure time index (DPTI) without any significant change in the diastolic duration. The reduction of (c-f)PWV was explained by changes in mean BP and HR (R(2) = 0.29). The reduction in DPTI was related to changes in central diastolic BP and changes in end-systolic BP (adjusted R(2) = 0.87). The significant improvement in aortic stiffness was mostly the result of the relative reduction of (c-f)PWV in the subgroup of patients with baseline (c-f)PWV above the median value of 13 m/s. CONCLUSION The creation of AVF is associated with a passive improvement of aortic stiffness especially in patients with stiffer arteries. This improvement in arterial stiffness could potentially be beneficial to the cardiovascular system despite an associated deterioration in the aortic pulse wave profile.

Determinants of Progression of Aortic Stiffness in Hemodialysis Patients

Aortic stiffness is associated with increased cardiovascular mortality in patients with chronic kidney disease. However, the rate of progression of arterial stiffness and the role of cardiovascular risk factors in the progression of arterial stiffness has never been established in a longitudinal study. In a prospective, longitudinal, observational study, carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were assessed in 109 hemodialysis patients at baseline and after a mean follow-up of 1.2 years. We examined the impact of age, atherosclerotic cardiovascular disease, diabetes mellitus, dialysis vintage, and pentosidine (a well-characterized, advanced glycation end products) on the rate of progression of aortic stiffness. The annual rate of changes in carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were 0.84 m/s per year (95% confidence interval, 0.50–1.12 m/s per year) and −0.66 m/s per year (95% confidence interval, −0.85 to −0.47 m/s per year), respectively. Older subjects, and patients with diabetes mellitus or atherosclerotic cardiovascular disease had higher aortic stiffness at baseline, however, the rate of progression of aortic stiffness was only determined by plasma pentosidine levels (P=0.001). The degree of baseline aortic stiffness was a significant determinant of the regression of brachial stiffness (P<0.001) suggesting that the regression of brachial stiffness occurs in response to central aortic stiffness. These findings suggest that traditional cardiovascular risk factors may play some role in the progression of aortic stiffness before development of advanced chronic kidney disease, and that the enhanced rate of progression of aortic stiffness in chronic kidney disease patients on dialysis are probably determined by more specific chronic kidney disease–related risk factors such as advanced-glycation end products.

Determinants of Progression of Aortic Stiffness in Hemodialysis PatientsNovelty and Significance

Aortic stiffness is associated with increased cardiovascular mortality in patients with chronic kidney disease. However, the rate of progression of arterial stiffness and the role of cardiovascular risk factors in the progression of arterial stiffness has never been established in a longitudinal study. In a prospective, longitudinal, observational study, carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were assessed in 109 hemodialysis patients at baseline and after a mean follow-up of 1.2 years. We examined the impact of age, atherosclerotic cardiovascular disease, diabetes mellitus, dialysis vintage, and pentosidine (a well-characterized, advanced glycation end products) on the rate of progression of aortic stiffness. The annual rate of changes in carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were 0.84 m/s per year (95% confidence interval, 0.50–1.12 m/s per year) and −0.66 m/s per year (95% confidence interval, −0.85 to −0.47 m/s per year), respectively. Older subjects, and patients with diabetes mellitus or atherosclerotic cardiovascular disease had higher aortic stiffness at baseline, however, the rate of progression of aortic stiffness was only determined by plasma pentosidine levels (P=0.001). The degree of baseline aortic stiffness was a significant determinant of the regression of brachial stiffness (P<0.001) suggesting that the regression of brachial stiffness occurs in response to central aortic stiffness. These findings suggest that traditional cardiovascular risk factors may play some role in the progression of aortic stiffness before development of advanced chronic kidney disease, and that the enhanced rate of progression of aortic stiffness in chronic kidney disease patients on dialysis are probably determined by more specific chronic kidney disease–related risk factors such as advanced-glycation end products.

Determinants of Progression of Aortic Stiffness in Hemodialysis PatientsNovelty and Significance: A Prospective Longitudinal Study

Aortic stiffness is associated with increased cardiovascular mortality in patients with chronic kidney disease. However, the rate of progression of arterial stiffness and the role of cardiovascular risk factors in the progression of arterial stiffness has never been established in a longitudinal study. In a prospective, longitudinal, observational study, carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were assessed in 109 hemodialysis patients at baseline and after a mean follow-up of 1.2 years. We examined the impact of age, atherosclerotic cardiovascular disease, diabetes mellitus, dialysis vintage, and pentosidine (a well-characterized, advanced glycation end products) on the rate of progression of aortic stiffness. The annual rate of changes in carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were 0.84 m/s per year (95% confidence interval, 0.50–1.12 m/s per year) and −0.66 m/s per year (95% confidence interval, −0.85 to −0.47 m/s per year), respectively. Older subjects, and patients with diabetes mellitus or atherosclerotic cardiovascular disease had higher aortic stiffness at baseline, however, the rate of progression of aortic stiffness was only determined by plasma pentosidine levels (P=0.001). The degree of baseline aortic stiffness was a significant determinant of the regression of brachial stiffness (P<0.001) suggesting that the regression of brachial stiffness occurs in response to central aortic stiffness. These findings suggest that traditional cardiovascular risk factors may play some role in the progression of aortic stiffness before development of advanced chronic kidney disease, and that the enhanced rate of progression of aortic stiffness in chronic kidney disease patients on dialysis are probably determined by more specific chronic kidney disease–related risk factors such as advanced-glycation end products.