François Maurice

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.

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

BACKGROUND AND OBJECTIVES Inflammation-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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Levels 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. RESULTS A 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). CONCLUSION Beyond 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.

Association between novel indices of malnutrition–inflammation complex syndrome and cardiovascular disease in hemodialysis patients

Background:  Inflammation and malnutrition are recognized as important risk factors for cardiovascular disease (CVD) in hemodialysis (HD) patients. Owing to substantial short‐term variability of serum C‐reactive protein (CRP), more reliable markers of malnutrition–inflammation complex syndrome should be sought with stronger associations with the risk of CVD in HD patients. We therefore explored the clinical relevance of a composite inflammatory index (prognostic inflammatory and nutritional index [PINI]) and of muscle protein mass indicators, derived from creatinine kinetics.

Randomized Equivalence Study Evaluating the Possibility of Switching Hemodialysis Patients Receiving Subcutaneous Human Erythropoietin Directly to Intravenous Darbepoetin Alfa

Background: Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) used either intravenously or subcutaneously with no dose penalty; however, the direct switch from subcutaneous recombinant human erythropoietin (rHuEPO) to intravenous darbepoetin has barely been studied. Objective: To establish the equivalence of a direct switch from subcutaneous rHuEPO to intravenous darbepoetin versus an indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin in patients undergoing hemodialysis. Methods: In this open, randomized, 6-month, prospective study, patients with end-stage kidney disease who were on hemodialysis were randomized into 2 groups: direct switch from subcutaneous rHuEPO to intravenous darbepoetin (group 1) and indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin (group 2). A third, nonrandomized group (control), consisting of patients treated with intravenous rHuEPO who were switched to intravenous darbepoetin, was also studied to reflect possible variations of hemoglobin (Hb) levels due to change from one type of ESA to the other. The primary outcome was the proportion of patients with stable Hb levels at month 6. Secondary endpoints included Hb stability at month 3, dosage requirements for darbepoetin, and safety of the administration route. Results: Among 154 randomized patients, the percentages with stable Hb levels were equivalent in groups 1 and 2, respectively, at month 3 (86.0% vs 91.3%) and month 6 (82.1% vs 81.6%; difference –0.5 [90% CI –12.8 to 11.8]). Mean Hb levels between baseline and month 6 remained stable in both groups, with no variation in mean darbepoetin dose. Mean ferritin levels remained above 100 μg/L in the 3 groups during the whole study, and darbepoetin was well tolerated. Conclusions: This study has shown equivalent efficacy on Hb stability without the need for dosage increase in patients switched directly from subcutaneous rHuEPO to intravenous darbepoetin.

Early changes in body weight and blood pressure are associated with mortality in incident dialysis patients

Abstract Background While much research is devoted to identifying novel biomarkers, addressing the prognostic value of routinely measured clinical parameters is of great interest. We studied early blood pressure (BP) and body weight (BW) trajectories in incident haemodialysis patients and their association with all-cause mortality. Methods In a cohort of 357 incident patients, we obtained all records of BP and BW during the first 90 days on dialysis (over 12 800 observations) and analysed trajectories using penalized B-splines and mixed linear regression models. Baseline comorbidities and all-cause mortality (median follow-up: 2.2 years) were obtained from the French Renal Epidemiology and Information Network (REIN) registry, and the association with mortality was assessed by Cox models adjusting for baseline comorbidities. Results During the initial 90 days on dialysis, there were non-linear decreases in BP and BW, with milder slopes after 15 days [systolic BP (SBP)] or 30 days [diastolic BP (DBP) and BW]. SBP or DBP levels at dialysis initiation and changes in BW occurring in the first month or during the following 2 months were significantly associated with survival. In multivariate models adjusting for baseline comorbidities and prescriptions, higher SBP value and BW slopes were independently associated with a lower risk of mortality. Hazard ratios of mortality and 95% confidence intervals were 0.92 (0.85–0.99) for a 10 mmHg higher SBP and 0.76 (0.66–0.88) for a 1 kg/month higher BW change on Days 30–90. Conclusions BW loss in the first weeks on dialysis is a strong and independent predictor of mortality. Low BP is also associated with mortality and is probably the consequence of underlying cardiovascular diseases. These early markers appear to be valuable prognostic factors.

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.

Association of aminothiols with the clinical outcome in hemodialysis patients: comparison of chromatography and immunoassay for homocysteine determination

Abstract Background: Controversial results on hyperhomocysteinemia and cardiovascular risk in hemodialysis (HD) could be due in part to the methodology used for homocysteine (Hcy) determination. Objective: The aim of this study was to compare the influence of the method used for Hcy determination (chromatography or immunoassay) with regard to the association of Hcy with cardiovascular mortality rate in HD patients in a 3-year prospective study. Methods: A total of 162 patients undergoing HD were included in a cohort study. Baseline Hcy levels were measured by HPLC and fluorescence polarization immunoassay (FPIA). Cysteine and cysteinylglycine were determined simultaneously with Hcy measurement by HPLC. Results: Hcy levels obtained with both methods were highly correlated (r2=0.927, p<0.0001). An increased relative risk (RR) for cardiovascular mortality (n=31) was found between the highest against lowest tertile of Hcy for both HPLC (RR 2.74, 95% CI 1.07–7.02; p<0.05) and FPIA (RR 2.76, 95% CI 0.99–7.70; p=0.05). Interestingly, increased cysteine (≥452 μmol/L) and cysteinylglycine (≥36.6μmol/L) levels were associated with a decreased RR of non-cardiovascular death (n=26) (RR 0.27, 95% CI 0.09–0.79; p=0.02) for cysteine and (RR 0.28, 95% CI 0.09–0.90; p=0.03) for cysteinylglycine when compared to the first tertile. Conclusions: This study demonstrated an increased risk of cardiovascular mortality in HD patients with Hcy values in the third tertile, independent of the method used. HPLC offers the advantage of simultaneous determination of other aminothiols that appear to be associated with non-cardiovascular mortality. Clin Chem Lab Med 2006;44:949–54.