Simon Desmeules

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.

Impact of age on glomerular filtration estimates

BACKGROUND Glomerular filtration decreases progressively with age in adults. Predictive equation should have proper modelling to adequately account for normal senescence. METHODS Corrected 24-h creatinine clearances (CCLs) were measured in a cohort of 773 outpatients from 18 to 90 years old. Multiple linear regression was used to model the effect of age on glomerular filtration. Comparisons were made with the simplified MDRD and the MAYO equations. Impact of the derived equation was tested in a second cohort of 7551 patients with normal serum creatinine. RESULTS While all equations show declining function with age, our results suggest that the GFR reduction is progressive after the age of 30 and continue to decline steadily after the age of 60. This leads to a convex curve in the multiple regression analysis that is best fitted by an equation including the quadratic term (age(2)). In contrast, the MDRD equation produces a faster decrease in early adulthood and a flatter curve after the age of 60 while the MAYO equation produces a more linear effect. MDRD results in the normal range are lower than those estimated by the MAYO equation. These equations, as applied on an independent cohort of 7551 normal outpatients from 18 to 102 years, produce different profile of evolution of GFR with age. CONCLUSIONS Inclusion of a quadratic term for age in the formula estimating GFR results in better modelling of the natural decline of renal function associated with ageing. Furthermore, as GFR steadily declines after the age of 30, a single cut-off value of GFR normality for all ages leads to underdiagnosis of young adults and over diagnosis of elderly individuals. Guidelines should take into account the observed reduction of kidney function with age in normal population for optimal evaluation of eGFR.

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.

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.

Principles and Operational Parameters to Optimize Poison Removal with Extracorporeal Treatments

A role for nephrologists in the management of a poisoned patient involves evaluating the indications for, and methods of, enhancing the elimination of a poison. Nephrologists are familiar with the various extracorporeal treatments (ECTRs) used in the management of impaired kidney function, and their respective advantages and disadvantages. However, these same skills and knowledge may not always be considered, or applicable, when prescribing ECTR for the treatment of a poisoned patient. Maximizing solute elimination is a key aim of such treatments, perhaps more so than in the treatment of uremia, because ECTR has the potential to reverse clinical toxicity and shorten the duration of poisoning. This manuscript reviews the various principles that govern poison elimination by ECTR (diffusion, convection, adsorption, and centrifugation) and how components of the ECTR can be adjusted to maximize clearance. Data supporting these recommendations will be presented, whenever available.

Linezolid-Associated Acute Interstitial Nephritis and Drug Rash With Eosinophilia and Systemic Symptoms (DRESS) Syndrome

Linezolid is a recent addition to the antibiotic armamentarium against Gram-positive bacteria, including multiresistant staphylococci and enterococci. Linezolid is relatively well tolerated and is not believed to be nephrotoxic. However, we report the case of an 88-year-old woman who was treated for prosthetic joint infection and methicillin-resistant Staphylococcus aureus bacteremia with vancomycin followed by linezolid therapy. On day 7 of linezolid treatment, the patient developed severe pruritus, macular rash, facial edema, eosinophilia, marked increase in serum creatinine level, and mild hepatitis. Renal biopsy showed acute interstitial nephritis with eosinophilic cells. Discontinuation of linezolid and a short course of prednisone led to rapid improvement of renal function. This case of linezolid-associated acute interstitial nephritis within the context of a drug rash with eosinophilia and systemic symptoms (DRESS) syndrome in a patient treated with linezolid raises concerns about the presumed renal safety of this drug. Clinicians should be aware of this potential life-threatening adverse reaction and monitor kidney function while patients are using linezolid.

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.

Vascular access for hemodialysis

Vascular access (VA) is the prerequisite and mainstay of extra-corporeal renal replacement therapy. VA gives access to the ‘internal milieu’ of the endstage renal disease (ESRD) patient via the blood stream permitting blood purification. Blood access is required at least three times a week with high blood flow (300–400 ml/min) to deliver a minimal ‘dialysis dose’. Patency of VA is of vital importance for the ESRD patient since it represents his/her lifeline. For this reason VA was soon recognized as the Achilles’ heel of ESRD patients for successful hemodialysis therapy. Long-term maintenance of VA is therefore of paramount importance to guarantee continuity of renal replacement therapy in the long-term dialysis patient.