Hélène Leray-Moragues

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.

Imbalance of Oxidants and Antioxidants in Haemodialysis Patients

Dialysis-related pathology (DRP) observed in long-term haemodialysis patients is increasingly reported. Among DRP manifestations, cardiovascular disease is the most frequent, being the first cause of mortality in haemodialysis patients. Alterations in lipid metabolism and oxidative stress are recognised as major risk factors that could be prevented or reduced by optimal therapy.In order to evaluate the rationale for preventive intervention against oxidative damage we review the factors that are implied and may be responsible for the imbalance between prooxidative and antioxidative mechanisms in haemodialysis patients. Oxidative stress resulting from this imbalance is responsible for increasing stress markers and enhancing susceptibility to LDL oxidation. Factors implied in this prooxidative state belong to four groups: (1) uremia and comorbid status of the end stage renal disease (ESRD) patient; (2) losses of antioxidant substances via the dialysis; (3) haemoincompatibility of the dialysis system; (4) adjuvant therapy. Such prooxidant status could have further deleterious consequences since it has been recently shown that antioxidant status could modulate cell functions such as reactive oxygen species (ROS) production, adhesive molecule expression and/or cell proliferation.Preventive modalities, including use of biocompatible membrane, ultrapure dialysate, exogenous supplementation of antioxidant vitamins, extracorporeal removal of ROS and oxidatively-modified substances, would appear highly desirable to reduce complications of long-term dialysis patients.

Overview of clinical studies in hemodiafiltration: What do we need now ?

Despite several technical advances in dialysis treatment modalities and a better patient care management including correction of anemia, suppression of secondary hyperparathyroidism, lipid and oxidative stress profiles improvement, the morbidity and the mortality of dialysis patients still remain still elevated. Recent prospective interventional trials in hemodialysis (HEMO study and 4D study) were not very conclusive in showing any significant improvement in dialysis patient outcomes. High‐efficiency convective therapies, such as online hemodiafiltration (HDF), are claimed to be superior to conventional diffusive hemodialysis (HD) in improving the dialysis efficacy and in reducing intradialytic morbidity and all‐cause and cardiovascular mortality in dialysis patients. The aim of this report was, first, to review the evidence‐based facts tending to prove the superiority of HDF vs. HD in terms of efficacy and tolerance, and, second, to analyze the needs to prove the clinical superiority of HDF in terms of reducing morbidity and all‐cause mortality of dialysis patients. A systematic review of studies comparing HDF and HD has been performed in the microbiological safety of online production, the solute removal capacity of small and medium‐size uremic toxins, and its implication in the reduction of the bioactive dialysis system vs. patient interaction. Major planned randomized international studies comparing HDF and HD in terms of morbidity and mortality have been reviewed. To conclude, it is thought that these long‐term prospective randomized trials will clarify on a scientific evidence‐based level the putative beneficial role of high‐efficiency HDF modalities on dialysis patient outcomes.

Analysis of Risk Factors for Catheter-Related Bacteremia in 2000 Permanent Dual Catheters for Hemodialysis

Background: Infection constitutes a leading cause of morbidity and mortality in hemodialysis (HD) patients. The type of vascular access is an important determinant of the risk of infection. Therefore, identification of risk factors leading to catheter-related bacteremia (CRB) is strongly required. The aim of this prospective large cohort study of HD patients using only catheters as vascular access was to isolate risk factors for CRB. Methods: 2,230 permanent silicone dual catheters implanted in 1,749 patients between November 1982 and November 2005 were studied. The following data were collected at the time of catheter implantation: presence of hypertension, diabetes mellitus, obesity, atherosclerosis, immunodepression, Wright-Khan index, site and side of catheter insertion, and history of bacteremia. Results: The site of catheter insertion was internal jugular (n = 2,133), subclavian (n = 79) and femoral (n = 17). Duration of catheter use was as follows: 30–90 days (n = 1,607) and >90 days (n = 1,054); 226 episodes of bacteremia occurred in 197 catheters. Microorganisms responsible were mainly Staphylococcus aureus, coagulase-negative staphylococci, Enterobacter spp. and Pseudomonas aeruginosa. The overall incidence of bacteremic episodes was 0.514/1,000 catheter days. Hypertension, atherosclerosis, diabetes mellitus, site of catheter implantation, duration of catheter use, Wright-Khan comorbidity index and previous history of CRB were significant risk factors associated with bacteremia in univariate analysis. Multivariate analysis revealed that a previous history of a bacteremic episode (odds ratio, OR = 2.70, 95% confidence interval, CI = 1.56–4.68), diabetes mellitus (OR = 2.37, 95% CI = 1.65–3.39), duration of catheter use >90 days (OR = 1.85, 95% CI = 1.35–2.55) and hypertension (OR = 1.49, 95% CI = 1.08–2.04) were still significant factors associated with bacteremia. Conclusion: Reducing CRB is still a challenge for nephrologists to reduce patient morbidity and mortality. Our study could demonstrate that diabetes, previous history of CRB, site of catheter implantation and duration of catheter use were the most important risk factors for bacteremia. Therefore, to prevent CRB, particular attention should be paid to patients with diabetes and a previous history of bacteremia following strict hygienic and aseptic rules for catheter handling associated with the regular use of antiseptic lock solutions.

Prohormone brain natriuretic peptide (proBNP), BNP and N-terminal-proBNP circulating levels in chronic hemodialysis patients. Correlation with ventricular function, fluid removal and effect of hemodiafiltration

Abstract Background: Brain natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP) and to a lesser extent prohormone proBNP are recognized as biochemical markers of left ventricular dysfunction. In renal failure, interpretation of natriuretic peptide remains unclear, as natriuretic peptide levels may be not only be dependent on cardiac function and dimensions but also on renal function, fluid volume and removal by dialysis procedure including hemodiafiltration (HDF). The purpose of this study was (i) to assess BNP, NT-proBNP and proBNP levels and their correlation with clinical and echocardiographic data in chronic hemodialysis patients, and (ii) to investigate basal level alteration following HDF. Methods: Baseline clinical and echocardiographic parameters were collected in 31 dialysis patients without evidence of cardiac failure. Pre- and post-HDF BNP, NT-proBNP and proBNP concentrations were measured. Correlations between echocardiographic measurements and basal circulating peptides, between changes in peptide values and changes in fluid volume after HDF were investigated. Results: Baseline plasmatic levels were elevated (BNP=517±840 pg/mL, NT-proBNP=5340±6132 pg/mL and proBNP=3569±4683 pg/mL) and correlated with left auricular diameter and left ventricular mass index. HDF session induced a significant decrease of 39%, 59% and 36% for BNP, NT-proBNP and proBNP levels, respectively. This decrease was not correlated to post-HDF fluid removal or weight decrease. Correlation between BNP and proBNP was stronger (r2=0.88) than between NT-proBNP and proBNP (r2=0.54). Conclusions: Despite their elimination, BNP, NT-proBNP and proBNP could be potential markers of left ventricular remodeling in chronic renal failure patients on hemodialysis. According to these results, their cut-off values, however, need to be re-evaluated. Clin Chem Lab Med 2008;46:1019–24.

Osteoprotegerin and sclerostin in chronic kidney disease prior to dialysis: potential partners in vascular calcifications

BACKGROUNDnOsteoprotegerin (OPG), sclerostin and DKK1 constitute opposite bone turnover inhibitors, OPG inhibiting osteoclastogenesis while sclerostin and DKK1 exerting their inhibitory effects on osteoblastogenesis. Both proteins have been recognized as strong risk factors of vascular calcifications in non-dialysis chronic kidney disease (ND-CKD) patients. The aim of this study was to investigate the relationships between these inhibitors and coronary artery calcifications (CAC) in this population.nnnMETHODSnA total of 241 ND-CKD patients [143 males; 69.0 (25.0-95.0) years; median estimated glomerular filtration rate using CKD-EPI 35.1 (6.7-120.1) mL/min/1.73 m(2)] were enrolled in this cross-sectional study. All underwent chest multidetector computed tomography for CAC scoring. OPG, sclerostin, DKK1 and mineral metabolism markers including PTH and bone alkaline phosphatase were measured. Logistic regression analyses were used to study the relationships between CAC and these markers.nnnRESULTSnDecline in renal function was associated with a significant increase in OPG and sclerostin while a slight but significant decrease in DKK1 was observed. The main crude associations with presence of CAC were a high level of OPG [OR = 2.55 95% confidence interval (95% CI) (1.35-4.82) for a level ranging from 6.26 to 9.15 pmol/L and OR = 5.74 95% CI (2.87-11.5) for a level ≥9.15 pmol/L; P < 0.0001] and a high level of sclerostin [OR = 2.64 95% CI (1.39-5.00) for a level ranging from 0.748 to 1.139 ng/mL and OR = 3.78 95% CI (1.96-7.31) for a level ≥1.139 ng/mL; P = 0.0002]. A logistic regression model clearly showed that the risk to present CAC was significantly increased when both OPG (≥6.26 pmol/L) and sclerostin (≥0.748 ng/mL) levels were high [crude model: OR = 11.47 95% CI (4.54-29.0); P < 0.0001; model adjusted for age, gender, diabetes, body mass index and smoking habits: OR = 5.69 95% CI (1.76-18.4); P = 0.02]. No association between DKK1 and presence of CAC was observed.nnnCONCLUSIONSnOur results strongly suggest that bone turnover inhibitors, OPG and sclerostin, are independently associated with CAC with potential additive effects in ND-CKD patients.

Fine-Tuning of the Prediction of Mortality in Hemodialysis Patients by Use of Cytokine Proteomic Determination

BACKGROUND AND OBJECTIVESnInflammation-induced atherosclerosis and enhanced susceptibility to infection are linked to immune dysfunction and account for an important part of mortality in hemodialysis patients. This 4-yr prospective study aimed to use cytokine proteomic determination for predicting cardiovascular and noncardiovascular mortality in hemodialysis patients.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnLevels of 12 cytokines were measured using a proteomic biochip system in 134 patients who were on stable hemodialysis and compared with a control group of 150 healthy volunteers. Cox proportional hazards regression analysis was used to determine the relationship between cytokine and clinical outcome.nnnRESULTSnA proinflammatory state characterized by decreased anti-/proinflammatory cytokine ratio was evidenced in hemodialysis patients compared with control subjects. After adjustment for age, gender, smoking, and high-sensitivity C-reactive protein levels, IL-6 and (IL-4+IL-10)/IL-6 ratio were associated with a significant and specific enhanced hazard ratio of cardiovascular mortality (hazard ratio 11.32 [95% confidence interval 2.52 to 50.90; P < 0.01] and hazard ratio 3.14 [95% confidence interval 1.20 to 8.22; P < 0.05], respectively, when comparing the third and first tertiles). It is interesting that (IL-4+IL-6+IL-10)/(IL-2+IFN-gamma) ratio, used as a marker of lymphocytes T helper subsets cytokine secretion, was associated only with noncardiovascular mortality (hazard ratio 4.93; 95% confidence interval 1.03 to 23.65; P < 0.05).nnnCONCLUSIONnBeyond the strong prediction of cardiovascular mortality by IL-6, determination of cytokine ratios can be useful to identify hemodialysis patients with increased noncardiovascular mortality risk.

Bone biomarkers help grading severity of coronary calcifications in non dialysis chronic kidney disease patients.

Background Osteoprotegerin (OPG) and fibroblast growth factor-23 (FGF23) are recognized as strong risk factors of vascular calcifications in non dialysis chronic kidney disease (ND-CKD) patients. The aim of this study was to investigate the relationships between FGF23, OPG, and coronary artery calcifications (CAC) in this population and to attempt identification of the most powerful biomarker of CAC: FGF23? OPG? Methodology/Principal Findings 195 ND-CKD patients (112 males/83 females, 70.8 [27.4–94.6] years) were enrolled in this cross-sectional study. All underwent chest multidetector computed tomography for CAC scoring. Vascular risk markers including FGF23 and OPG were measured. Logistic regression analyses were used to study the potential relationships between CAC and these markers. The fully adjusted-univariate analysis clearly showed high OPG (≥10.71 pmol/L) as the only variable significantly associated with moderate CAC ([100–400[) (ORu200a=u200a2.73 [1.03;7.26]; pu200a=u200a0.04). Such association failed to persist for CAC scoring higher than 400. Indeed, severe CAC was only associated with high phosphate fractional excretion (FEPO4) (≥38.71%) (ORu200a=u200a5.47 [1.76;17.0]; pu200a=u200a0.003) and high FGF23 (≥173.30 RU/mL) (ORu200a=u200a5.40 [1.91;15.3]; pu200a=u200a0.002). In addition, the risk to present severe CAC when FGF23 level was high was not significantly different when OPG was normal or high. Conversely, the risk to present moderate CAC when OPG level was high was not significantly different when FGF23 was normal or high. Conclusions Our results strongly suggest that OPG is associated to moderate CAC while FGF23 rather represents a biomarker of severe CAC in ND-CKD patients.

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 u200a=u200a0.79, 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.

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.