Bernard Canaud

Protein-bound uraemic toxin removal in haemodialysis and post-dilution haemodiafiltration

BACKGROUNDnThe accumulation of larger and protein-bound toxins is involved in the uraemic syndrome but their elimination by dialysis therapy remains difficult. In the present study, the impact of the albumin permeability of recently introduced advanced high-flux dialysis membranes on the removal of such substances was tested in haemodialysis and online post-dilution haemodiafiltration.nnnMETHODSnTwo types of polyethersulfone membranes only differing in albumin permeability (referred as PU- and PU+) were compared in eight patients on maintenance dialysis in a prospective cross-over manner. Treatment settings were identical for individual patients: time 229 +/- 22 min; blood flow rate 378 +/- 33 mL/min; dialysate flow rate 500 mL/min; substitution flow rate in haemodiafiltration 94 +/- 9 mL/min. Removal of the protein-bound compounds p-cresyl sulfate (pCS) and indoxyl sulfate (IS) was determined by reduction ratios (RRs), dialytic clearances and mass in continuously collected dialysate. In addition, the elimination of the low-molecular weight (LMW) proteins beta(2)-microglobulin, cystatin c, myoglobin (myo), free retinol-binding protein (rbp) and albumin was measured.nnnRESULTSnPlasma levels of the protein-bound toxins were significantly decreased by all treatment forms. However, the decreases were comparable between dialysis membranes and between haemodialysis and haemodiafiltration. The RRs of total pCS ranged between 40.4 +/- 25.3 and 47.8 +/- 10.3% and of total IS between 50.4 +/- 2.6 and 54.6 +/- 8.7%. Elimination of free protein-bound toxins as assessed by their mass in dialysate closely correlated positively with the pre-treatment plasma concentrations being r = 0.920 (P < 0.001) for total pCS and r = 0.906 (P < 0.001) for total IS, respectively. Compared to haemodialysis, much higher removal of all LMW proteins was found in haemodiafiltration. Dialysis membrane differences were only obvious in haemodialysis for the larger LMW proteins myo and rbp yielding significantly higher RRs for PU+ (myo 46 +/- 9 versus 37 +/- 9%; rbp 18 +/- 5 versus 15 +/- 5%; P < 0.05). Additionally, the albumin loss varied between membranes and treatment modes being undetectable with PU- in haemodialysis and highest with PU+ in haemodiafiltration (1430 +/- 566 mg).nnnCONCLUSIONSnThe elimination of protein-bound compounds into dialysate is predicted by the level of pre-treatment plasma concentrations and depends particularly on diffusion. Lacking enhanced removal in online post-dilution haemodiafiltration emphasizes the minor significance of convection for the clearance of these solutes. Compared to LMW proteins, the highly protein-bound toxins pCS and IS are less effectively eliminated with all treatment forms. For a sustained decrease of pCS and IS plasma levels, alternative strategies promise to be more efficient therapy forms.

HDL Proteome in Hemodialysis Patients: A Quantitative Nanoflow Liquid Chromatography-Tandem Mass Spectrometry Approach

Aside from a decrease in the high-density lipoprotein (HDL) cholesterol levels, qualitative abnormalities of HDL can contribute to an increase in cardiovascular (CV) risk in end-stage renal disease (ESRD) patients undergoing chronic hemodialysis (HD). Dysfunctional HDL leads to an alteration of reverse cholesterol transport and the antioxidant and anti-inflammatory properties of HDL. In this study, a quantitative proteomics approach, based on iTRAQ labeling and nanoflow liquid chromatography mass spectrometry analysis, was used to generate detailed data on HDL-associated proteins. The HDL composition was compared between seven chronic HD patients and a pool of seven healthy controls. To confirm the proteomics results, specific biochemical assays were then performed in triplicate in the 14 samples as well as 46 sex-matched independent chronic HD patients and healthy volunteers. Of the 122 proteins identified in the HDL fraction, 40 were differentially expressed between the healthy volunteers and the HD patients. These proteins are involved in many HDL functions, including lipid metabolism, the acute inflammatory response, complement activation, the regulation of lipoprotein oxidation, and metal cation homeostasis. Among the identified proteins, apolipoprotein C-II and apolipoprotein C-III were significantly increased in the HDL fraction of HD patients whereas serotransferrin was decreased. In this study, we identified new markers of potential relevance to the pathways linked to HDL dysfunction in HD. Proteomic analysis of the HDL fraction provides an efficient method to identify new and uncharacterized candidate biomarkers of CV risk in HD patients.

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.

Direct determination of blood recirculation rate in hemodialysis by a conductivity method

Blood recirculation is one of the key factors of decreasing dialysis efficiency. Determination of recirculation rate (R) is necessary to optimize effective dialysis delivery and to monitor vascular access function. R can be directly measured by a conductivity method in paired filtration dialysis (PFD), a double-compartment hemodiafiltration system that permits direct access to plasma water via the ultrafiltration stream. Measurement of R, in this system, involves the first of two conductivity sensors integrated in a urea monitor (UMS, Bellco-Sorin, Mirandola, Italy), and two saline injections. The rise in conductivity (δC1) induced by a 2.7 ml bolus of hypertonic saline 20% (mg/dl) in the arterial line serves for calibration, and is followed by an equivalent injection into the venous line, giving rise to δC2. The ratio δC2/δC1 equals R. A comparison between R values obtained with this method and with the low-flow technique in 31 chronic dialysis patients during 138 PFD sessions is reported. Mean R ± SD by the conductivity method was 5.1 ± 2.0 and 5.7 ± 2.0% after 65 and 155 minutes of PFD (correlation coefficient, r = 0.75), whereas it was 6.4 ± 4.9% and 5.5 ± 4.6% after 30 sec of low blood pump flow for urea and creatinine markers, respectively (r = 0.35). After 120 sec of low flow, mean R increased to 9.0 ± 5.1 and 8.8 ± 4.6% for urea and creatinine, respectively (r = 0.45). Considerable discrepancies were found in R values measured simultaneously with the two blood markers. Statistically significant differences were found between the two measurement modalities (blood-side and conductivity); the correlation coefficients (r) varied between 0.28 and 0.41. The observed differences in mean R results do not seem considerable from a clinical perspective. The best agreement between blood-side and conductivity R measurements was obtained with Rcreat after 30 sec of low flow. Overall, a wider distribution was found in R values from blood-side determinations, most likely consequent to variability in the dosing method. The conductivity method appears more accurate and simple in assessing total R, and can be readily automated and integrated into the dialysis machine. The authors, therefore, recommend evaluation of R using methods not based on chemical blood concentration values.

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.

Endothelial progenitor cells in patients on extracorporeal maintenance dialysis therapy

BACKGROUNDnChronic renal failure patients have a high cardiovascular disease burden, low numbers and impaired function of endothelial progenitor cells (EPCs). We hypothesized that enhanced uraemic toxin removal restores EPCs in haemodialysis patients.nnnMETHODSnIn a prospective, randomized, cross-over trial, 18 patients were subjected to 4 weeks of each low-flux haemodialysis, high-flux haemodialysis and haemodiafiltration differing in uraemic toxin removal. EPCs were determined at baseline and at the end of each 4-week period. A cohort of 16 healthy volunteers served as control. EPCs were studied after culture on fibronectin (CFU-Hill) and collagen-1 (ECFC).nnnRESULTSnDialysis patients had a lower number of ECFCs than in healthy controls (P < 0.001) and a reduced fraction of vital ECFCs (P < 0.05), whereas the formation of endothelial cell colonies (ECCs) was increased (P < 0.05). Different middle molecular uraemic toxin removal had no effects on EPC numbers. The number of prototypical EPCs (CD34(u2009+)/VEGFR2-KDR(u2009+)/CD45(u2009-) ECFCs) was similar between patients and controls. Correlations of plasma C-reactive protein with ECC count, CFU-Hill colony count and CD34(u2009+)/VEGFR2-KDR(u2009+)/CD45(u2009-) subpopulation of both ECFC and CFU-Hill cells were observed.nnnCONCLUSIONSnDifferent middle molecule removal has no effect on EPCs. Reduced vitality and enhanced ECC formation suggest growth induction of impaired EPCs in chronic renal failure and are associated with inflammation.

Hemodiafiltration improves free light chain removal and normalizes κ/λ ratio in hemodialysis patients.

Background/AimsSerum free light chain (FLC) levels are correlated with chronic kidney disease (CKD) stages and are highest in patients on hemodialysis (HD). Aim of this study was to assess the FLC removal efficiency of Elisio™-210H dialyzer using either high-flux HD or on line high efficiency hemodiafiltration (HDF) modalities in CKD-5D patients.MethodsIn this prospective and comparative study, 20 CKD-5D patients free from multiple myeloma were randomized in two groups: HD versus on line HDF. All patients were dialyzed with Elisio™-210H dialyzer. Serum samples were collected before and after the midweek dialysis session, before randomization and at the end of the study to measure κ and λ FLC concentrations. Reduction ratios were corrected for net ultrafiltration.ResultsFor both HD and HDF mode, κ and λ FLC concentrations were significantly lower after dialysis than before but median reductions in κ and λ FLC levels were significantly higher in HDF versus HD groups (κ 73.5 vs. 65.5xa0%, pxa0=xa00.04 and λ 51.0 vs. 36.6xa0%, pxa0=xa00.07). After dialysis, all κ/λ ratio values were between 0.26 and 1.65 which is the reference range described in subjects with normal kidney function, for both HD and HDF groups (median κ/λ ratios were 0.80 [0.47–1.22] and 0.67 [0.50–0.79] respectively).ConclusionThis study shows the superiority of on line HDF compared with HD to remove both κ and λ FLC. Moreover, all post-dialysis κ/λ ratios reached normal reference range.

Management of mineral metabolism in haemodialysis patients: need for new strategies

Reply to Management of mineral metabolism in haemodialysis patients: need for new strategies’

On-Line Hemodialysis Monitoring: New Tools for Improving Safety, Tolerance and Efficacy

Hemodialysis adequacy is a complex concept that encompasses largely the dialysis dose appraisal based on monthly blood-based urea Kt/V measurement. Renal replacement therapies should provide an efficient way to clear adequately larger molecular weight solutes, to restore normal salt, electrolytes and fluid balance, to correct salt-dependent hypertension, to improve hemodynamic stability and to reduce bio-incompatibility of the hemodialysis system. Targeting such ambitious objective is obviously under the clinical supervision and judgment of nephrologists and care givers. Monitoring and achievement of these targets as a part of a continuous quality improvement process is necessary to attain dialysis adequacy goals. This review aims to provide an overview of available online hemodialysis technologies, their current applications in clinic, and the potential for future developments in improving care of chronic kidney disease patients. In order to facilitate understanding of readers we choose to classify online monitoring devices based on their clinical action.

Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints

Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.