Lotfi Chalabi

Plasma Osteoprotegerin Is Associated with Mortality in Hemodialysis Patients

Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Regulating molecules such as osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) could play a key role in bone-vascular calcification imbalance. This study investigated the contribution of these proteins as well as mineral metabolism disorders in hemodialysis (HD) patient outcome. A total of 185 HD patients were followed up prospectively for 2 yr. In addition to clinical characteristics, mineral metabolism markers as well as OPG and soluble RANKL (sRANKL) were measured at baseline. After 2 yr, survival rates were described with Kaplan-Meier and compared with Cox regression analyses; 50 patients died (27 from cardiovascular diseases). Calcium, phosphate, and calcium x phosphate product were not associated with mortality. Both hyperparathyroidism (parathyroid hormone > or =300 pg/ml) and hypoparathyroidism (parathyroid hormone <150 pg/ml) were poorly associated with all-cause and cardiovascular mortality. By contrast, elevated OPG levels predicted all-cause (relative risk [RR] 2.67; 95% confidence interval [CI] 1.32 to 5.41; P = 0.006) and cardiovascular mortality (RR 3.15; 95% CI 1.14 to 8.69; P = 0.03). Low levels of sRANKL were associated with a protective effect for all-cause mortality (RR 0.45; 95% CI 0.21 to 0.94; P = 0.03). The association of OPG with all-cause mortality was stronger in patients with C-reactive protein > or =12.52 mg/L. In this condition, both highest (RR 5.68; 95% CI 1.48 to 22.73; P = 0.01) and lowest tertiles (RR 5.37; 95% CI 147 to 1968; P = 0.01) significantly predicted poor outcome. These results show that regulating-bone molecules, especially OPG, are strong predictors of mortality in HD patients, suggesting that OPG is a vascular risk factor, in particular in patients who have high C-reactive protein levels. OPG determination therefore should be added to the biologic follow-up of these patients.

Biocompatibility of heparin-grafted hemodialysis membranes: Impact on monocyte chemoattractant protein-1 circulating level and oxidative status

This prospective observational study aimed at evaluating efficacy and biocompatibility performances of the new heparin‐coated Evodial dialyzers with/without systemic heparin reduction. After a 4‐week wash‐out period with reference polysulfone F70S dialyzers, 6 hemodialysis patients were sequentially dialyzed with Evodial, F70S, and Evodial dialyzers using 30% heparin reduction, each period of treatment was 4 weeks. Removal rates (RR) (urea, creatinine, and β2‐microglobulin), dialysis dose, and instantaneous clearances (urea and creatinine) were measured as well as inflammatory (C‐reactive protein, fibrinogen, interleukin 6, tumor necrosis factor α, and monocyte chemoattractant protein‐1) and oxidative stress (OS) (superoxide anion, homocysteine, and isoprostanes) parameters at the end of each study period. Patients treated with Evodial or F70S dialyzers for 4 weeks presented comparable dialysis efficacy parameters including urea and creatinine RR, dialysis dose and instantaneous clearances. By contrast, a significantly lower but reasonably good β2‐microglobulin RR was achieved with Evodial dialyzers. Regarding biocompatibility, no significant difference was observed with inflammation and OS except for postdialysis monocyte chemoattractant protein‐1 which significantly decreased with Evodial dialyzers. Thirty percent heparinization reduction with Evodial dialyzers did not induce any change in inflammation but led to an improvement in OS as demonstrated by a decrease in postdialysis superoxide production and predialysis homocysteine and isoprostane. This bioactive dialyzer together with heparin dose reduction represents a good trade‐off between efficacy and biocompatibility performance (improvement in OS with a weak decrease in efficacy) and its use is encouraging for hemodialysis patients not only in reducing OS but also in improving patient comorbid conditions due to lesser heparin side effects.

Creatinine Index as a Surrogate of Lean Body Mass Derived from Urea Kt/V, Pre-Dialysis Serum Levels and Anthropometric Characteristics of Haemodialysis Patients

Background and Objectives Protein-energy wasting is common in long-term haemodialysis (HD) patients with chronic kidney disease and is associated with increased morbidity and mortality. The creatinine index (CI) is a simple and useful nutritional parameter reflecting the dietary skeletal muscle protein intake and skeletal muscle mass of the patient. Because of the complexity of creatinine kinetic modeling (CKM) to derive CI, we developed a more simplified formula to estimate CI in HD patients. Design, Setting, Participants & Measurements A large database of 549 HD patients followed over more than 20 years including monthly CKM-derived CI values was used to develop a simple equation based on patient demographics, predialysis serum creatinine values and dialysis dose (spKt/V) using mixed regression models. Results The equation to estimate CI was developed based on age, gender, pre-dialysis serum creatinine concentrations and spKt/V urea. The equation-derived CI correlated strongly with the measured CI using CKM (correlation coefficient  = 0.79, p-value <0.001). The mean error of CI prediction using the equation was 13.47%. Preliminary examples of few typical HD patients have been used to illustrate the clinical relevance and potential usefulness of CI. Conclusions The elementary equation used to derive CI using demographic parameters, pre-dialysis serum creatinine concentrations and dialysis dose is a simple and accurate surrogate measure for muscle mass estimation. However, the predictive value of the simplified CI assessment method on mortality deserves further evaluation in large cohorts of HD patients.

FGF-23 removal is improved by on-line high-efficiency hemodiafiltration compared to conventional high flux hemodialysis.

BACKGROUND Reducing circulating levels of fibroblast growth factor-23 (FGF-23) in patients on renal replacement therapy (RRT) could appear as an appealing approach for cardiovascular events prevention. The purpose of our study was to compare the clearance of FGF-23 between high flux hemodialysis (HD) and on-line hemodiafiltration (OL-HDF) procedures. METHODS Fifty-three patients were included in the HD group while 32 patients were included in the OL-HDF group. Serum pre- and post-dialysis FGF-23 levels were measured using a 2nd generation Human FGF-23 (C-Term) ELISA kit. RESULTS Mean FGF-23 reduction rates were significantly higher in OL-HDF (55.7 ± 25.2%) versus HD (36.2 ± 28.6%) groups (P=.0001), as were calculated FGF-23 clearances (P=.015) and Kt/V-FGF-23 (P=.001). Overall, post-treatment FGF-23 levels were significantly lower than pre-treatment values in both groups (P<.01). CONCLUSIONS OL-HDF achieves higher FGF-23 removal over high flux HD.

Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly

Large cohort studies suggest that high convective volumes associated with online hemodiafiltration may reduce the risk of mortality/morbidity compared to optimal high-flux hemodialysis. By contrast, intradialytic tolerance is not well studied. The aim of the FRENCHIE (French Convective versus Hemodialysis in Elderly) study was to compare high-flux hemodialysis and online hemodiafiltration in terms of intradialytic tolerance. In this prospective, open-label randomized controlled trial, 381 elderly chronic hemodialysis patients (over age 65) were randomly assigned in a one-to-one ratio to either high-flux hemodialysis or online hemodiafiltration. The primary outcome was intradialytic tolerance (day 30-day 120). Secondary outcomes included health-related quality of life, cardiovascular risk biomarkers, morbidity, and mortality. During the observational period for intradialytic tolerance, 85% and 84% of patients in high-flux hemodialysis and online hemodiafiltration arms, respectively, experienced at least one adverse event without significant difference between groups. As exploratory analysis, intradialytic tolerance was also studied, considering the sessions as a statistical unit according to treatment actually received. Over a total of 11,981 sessions, 2,935 were complicated by the occurrence of at least one adverse event, with a significantly lower occurrence in online hemodiafiltration with fewer episodes of intradialytic symptomatic hypotension and muscle cramps. By contrast, health-related quality of life, morbidity, and mortality were not different in both groups. An improvement in the control of metabolic bone disease biomarkers and β2-microglobulin level without change in serum albumin concentration was observed with online hemodiafiltration. Thus, overall outcomes favor online hemodiafiltration over high-flux hemodialysis in the elderly.

Vitamin E-coated polysulfone membrane improved red blood cell antioxidant status in hemodialysis patients

BACKGROUND Oxidative stress has emerged as a strong pathogenic cofactor implicated in the development of long-term complications in hemodialysis (HD) patients, such as anemia, and as a major component of the malnutrition inflammation complex syndrome. This prospective multicenter study aimed at evaluating the short-term effects of the new vitamin E (vitE)-coated polysulfone (PS) membrane (VitabranE) on biocompatibility performances and anemia in HD patients. METHODS After a 3-month washout period with a high-flux synthetic dialyzer, 43 HD patients were switched to a vitE-PS dialyzer. Sampling was performed at baseline (corresponding to the end of the washout period) and after 1, 2 and 3 months of treatment. Oxidative stress status, as well as inflammatory parameters, was investigated at the end of each study period. Hemoglobin levels and administered doses of recombinant human erythropoietin or epoetin (EPO) were available in each center. RESULTS The use of vitE-coated membranes for 3 months was not associated with any change in inflammatory parameters. By contrast, vitE-PS dialyzer resulted in a progressive increase in red blood cell (RBC) vitE concentration and in RBC superoxide dismutase activity. A concomitant progressive significant decrease in advanced oxidation protein product concentration at 2 months was observed, suggesting a preventive effect on oxidative stress. Finally, a significant decrease of the erythropoietin resistance index was obtained after 3 months of treatment. CONCLUSIONS Use of the vitE-PS membrane during a short period improves erythrocyte antioxidant defense mechanisms and seems to lead to a reduction in EPO requirements in HD patients.

Cardiovascular risk stratification in hemodialysis patients in the era of highly sensitive troponins: should we choose between hs-troponin I and hs-troponin T?

Abstract Background: New highly sensitive (hs) assays have challenged the interpretation of cardiac troponins (cTn). The present study was designed to evaluate simultaneously conventional cTnT and cTnI together with their corresponding highly sensitive determinations in stable hemodialysis (HD) patients. Ability of cTn to stratify HD patient risk was assessed. Methods: A total of 224 stable HD patients was included in this observational study. cTnT and hs-cTnT were measured using Roche cTnT/hs-cTnT assays based on a Cobas e601® analyzer. cTnI and hs-cTnI were measured using Beckman AccuTnI/hs-TnI IUO assays on Access II system. Patients were followed up prospectively during 9 years. Relationship between cTn level and mortality was assessed through Cox survival analysis. Results: The median cTnT and cTnI concentrations were 38.5 ng/L (IQR, 18.8–76) and 10 ng/L (IQR, 10–20), respectively. The median hs-cTnT and hs-cTnI concentrations were 62.5 ng/L (IQR, 38.8–96.3) and 13.9 ng/L (IQR, 8.4–23.6), respectively. The prevalence of values above the 99th percentile was significantly more marked with cTnT (85.3 and 97.8% for conventional and hs cTnT, respectively) than with cTnI (7.6 and 67.4% for conventional and hs cTnI, respectively). During the follow-up, 167 patients died, mainly from cardiac cause (n=77). The optimized cut-off values, determined by bootstrap method, predicting mortality were 38, 69, 20 and 11 ng/L for cTnT, hs-cTnT, cTnI and hs-cTnI, respectively. After full adjustment, elevated plasma concentrations of all troponin were significant predictors of mortality. Conclusions: A large proportion of patients free of acute coronary syndrome (ACS) has hs-cTn I or T higher than the 99th percentile which could be seen as a limiting factor for ACS screening. However, all generation and type of troponin assays could be reliable indicators of prognosis risk in HD patients.

A combined index of cardiac biomarkers as a risk factor for early cardiovascular mortality in hemodialysis patients

Abstract Background: Cardiac biomarkers, including cardiac troponin-I (cTn-I) and N-terminal pro brain natriuretic peptide (NT-proBNP) have been associated with poor outcome in hemodialysis (HD) patients. The present study was designed to evaluate these biomarkers as biological risk factors for early and late mortality in HD patients. In addition, a multimarker approach including inflammatory index was performed in order to improve the cardiovascular risk assessment of these patients. Methods: cTnI, NT-proBNP and C-reactive protein (CRP) were measured at baseline (October through November 2002) in 130 HD patients [median age 69.0 (23.4–87.7) years old, 76 females, 54 males]. Patients were followed during 8 years. Adjusted hazard ratios (HRs) of death and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. Results: During the follow-up, 82 patients died, mainly from cardiac cause (63.4%). Elevated cTnI, NT-proBNP or CRP were all associated with increased early (death within 2 years of follow-up) but not late mortality. Moreover, the combination of all parameters (CRP ≥10.51 mg/L and cTnI ≥0.037 µg/L and NT-proBNP ≥10,204 pg/mL) dramatically increased the short-term mortality especially the cardiovascular mortality (HR 8.58, 95% CI 1.59–46.2; p=0.0007). Conclusions: A combined index of cardiovascular risk factors could provide supplementary risk stratification in HD patients for early cardiovascular mortality, strongly supporting the annual routine determination of these biomarkers.

Physical inactivity and protein energy wasting play independent roles in muscle weakness in maintenance haemodialysis patients

Background Muscle weakness is associated with increased mortality risk in chronic haemodialysis (CHD) patients. Protein energy wasting (PEW) and low physical activity could impair muscle quality and contribute to muscle weakness beyond muscle wasting in these patients. Aim of this study was to assess clinical and biological parameters involved in the reduction of muscle strength of CHD patients. Methods One hundred and twenty-three CHD patients (80 males, 43 females; 68,8 [57.9–78.8] y.o.) were included in this study. Maximal voluntary force (MVF) of quadriceps was assessed using a belt-stabilized hand-held dynamometer. Muscle quality was evaluated by muscle specific torque, defined as the strength per unit of muscle mass. Muscle mass was estimated using lean tissue index (LTI), skeletal muscle mass (SMM) assessed by bioelectrical impedance analysis and creatinine index (CI). Voorrips questionnaire was used to estimate physical activity. Criteria for the diagnosis of PEW were serum albumin, body mass index < 23 kg/m2, creatinine index < 18.82 mg/kg/d and low dietary protein intake estimated by nPCR < 0.80g/kg/d. Results MVF was 76.1 [58.2–111.7] N.m. and was associated with CI (β = 5.3 [2.2–8.4], p = 0.001), LTI (β = 2.8 [0.6–5.1], p = 0.013), Voorrips score (β = 17.4 [2.9–31.9], p = 0.02) and serum albumin (β = 1.9 [0.5–3.2], p = 0.006). Only serum albumin (β = 0.09 [0.03–0.15], p = 0.003), Voorrips score (β = 0.8 [0.2–1.5], p = 0.005) and CI (β = 0.2 [0.1–0.3], p<0.001) remained associated with muscle specific torque. Thirty patients have dynapenia defined as impaired MVF with maintained SMM and were younger with high hs-CRP (p = 0.001), PEW criteria (p<0.001) and low Voorrips score (p = 0.001), and reduced dialysis vintage (p<0.046). Conclusions Beyond atrophy, physical inactivity and PEW conspire to impair muscle strength and specific torque in CHD patients and could be related to muscle quality. Trial registration ClinicalTrials.gov NCT02806089