Long-term effects of citric acid-based bicarbonate haemodialysis on patient outcomes: a survival propensity score-matched study in western France.

BACKGROUND: Citric acid-based bicarbonate haemodialysis (CIT-HD) has gained more clinical acceptance over the last few years in France and is a substitute for other acidifiers [e.g. acetic acid (CH3COOH) and hydrochloric acid (HCl)]. This trend was justified by several clinical benefits compared with CH3COOH as well as the desire to avoid the consequences of the corrosive action of HCl, but a nationwide clinical report raised concerns about the long-term safety of CIT-HD. The aim of this study was to assess the long-term effects of CIT-HD exposure on patient outcomes in western France. METHODS: This is a population-based retrospective multicentre observational study performed in 1132 incident end-stage kidney disease patients in five sanitary territories in western France who started their renal replacement therapy after 1 January 2008 and followed up through 15 October 2018. Relevant data, collected prospectively with the same medical software, were anonymously aggregated for the purposes of the study. The primary goal of this study was to investigate the effects of citrate exposure on all-cause mortality. To provide a control group to CIT-HD one, propensity score matching (PSM) at 2:1 was performed in two steps: the first analysis was intended to be exploratory, comparing patients who received citrate ≤80% of the time (CIT-HD ≤80) versus those who received citrate >80% of the time (CIT-HD >80), while the second analysis was intended to be explanatory in comparing patients with 0% (CIT-HD0) versus 100% citrate time exposure (CIT-HD100). RESULTS: After PSM, in the exploratory part of the analysis, 432 CIT-HD ≤80 patients were compared with 216 CIT-HD >80 patients and no difference was found for all-cause mortality using the Kaplan-Meier model (log-rank 0.97), univariate Cox regression analysis {hazard ratio [HR] 1.01 [95% confidence interval (CI) 0.71-1.40]} and multivariate Cox regression analysis [HR 1.11 (95% CI 0.76-1.61)] when adjusted for nine variables with clinical pertinence and high statistical relevance in the univariate analysis. In the explanatory part of the analysis, 316 CIT-HD0 patients were then compared with 158 CIT-HD100 patients and no difference was found using the Kaplan-Meier model (log-rank 0.06), univariate Cox regression analysis [HR 0.69 (95% CI 0.47-1.03)] and multivariate Cox regression analysis [HR 0.87 (95% CI 0.57-1.33)] when adjusted for seven variables with clinical pertinence and high statistical relevance in the univariate analysis. CONCLUSIONS: Findings of this study support the notion that CIT-HD exposure ≤6 years has no significant effect on all-cause mortality in HD patients. This finding remains true for patients receiving high-volume online haemodiafiltration, a modality most frequently prescribed in this cohort.

Clinical Performance Assessment of CorDiax Filters in Hemodialysis and Hemodiafiltration.

In this study, we evaluate the in vivo clinical performances of CorDiax FX 100 and CorDiax FX 1000 filters incorporating a high-flux membrane (Helixone Plus) designed for use in high-flux hemodialysis (HD) as well as in hemodiafiltration (HDF) in 6 stable end-stage kidney disease patients. In the HDF mode, various substitution modalities (post-, pre-, and mixed) were compared. In addition to conventional markers of efficacy of dialysis dose (urea, ionic dialysance, Kt/V), several additional middle- and large-size solute (ß2-microglobulin, myoglobin, serum-free light-chain kappa and lambda, α1-microglobulin, and FGF23) compounds were explored in order to cover the spectrum of uremic toxins that are involved in uremia. A precise quantitative assessment of solute removal was performed in this study mimicking solute kinetic complexity during patient/dialysis interaction (hemoconcentration due to volume contraction, postdialysis rebound due to compartmentalization effect) in order to fit better with clinical reality and to provide clinicians more realistic estimates of solute mass transfer. The study confirms that effective solute body clearances achieved in vivo both in HD and in HDF are significantly lower than instantaneous clearances reported by manufacturers. Among dialysis modalities assessed in this study, postdilution HDF offers the most efficient modality both in terms of solute removal capacity and substitution volume used. The predilution HDF mode provides slightly but significantly lower body clearances than the postdilution mode over the spectrum of solutes assessed, a dilution factor that can be compensated for by increasing the substitution rate adequately. The clinical performance of CorDiax FX filters featuring the same highly permeable membrane engineered in 2 different configurations, one facilitating internal convective transport in HD (high internal resistance) and the other favoring high-volume on-line HDF (low internal resistance), offers interesting and effective options for enhancing removal of middle- and larger-size uremic compounds. High-volume HDF relying on different fluid substitution modes remains the more efficient modality across a large spectrum of uremic compounds tested.

Are all dialyzers compatible with the convective volumes suggested for postdilution online hemodiafiltration?

INTRODUCTION: The recent analysis of 4 randomized controlled trials has confirmed the lower mortality risk for postdilution online hemodiafiltration (OL-HDF) compared to hemodialysis, and above all for patients with the highest delivered body surface area standardized convective volume (CV/BSA >23 L/1.73 m²/session). Since the impact of the dialyzers used in these trials has never been studied, we retrospectively analyzed clinical tests carried out with 19 commonly used dialyzers. The aim was to provide information on their performances and behavior to aid in an objective choice for therapies associated with OL-HDF. METHODS: "Efficiency" was evaluated by measuring the reduction ratio of beta-2 microglobulin (RRß2M) and myoglobin (RRmyo) for a CV/BSA between 0 and 30 L, extrapolating them at CV/BSA = 23 L. "Safety" was defined by the safe CV (CVsafe), corresponding to the CV/BSA above which albumin loss is >5 g/session. RESULTS: With CV/BSA = 23 L, all the dialyzers ensure an optimal ß2M extraction (RRß2M: 76%-84.5%). For myoglobin, efficiency disparities are bigger (RRmyo: 40%-85%). Above all, 4/19 dialyzers lose more than 5 g albumin and should not be used under these conditions. CONCLUSIONS: It is recommended to prescribe dialyzers that are above all safe. Moreover, if one considers that the removal of middle molecule solutes prevails over the CV necessary for their transmembrane transport, some dialyzers that are more efficient with CV/BSA <23 L than others with CV/BSA >= 23 L might then be prescribed when the conditions do not permit the suggested CV/BSA goal to be achieved.

Glutathione S Transferases Polymorphisms Are Independent Prognostic Factors in Lupus Nephritis Treated with Cyclophosphamide.

OBJECTIVE: To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST). METHODS: We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria ≤0.33g/day and serum creatinine ≤124 µmol/l. Partial remission (PR) was defined as proteinuria ≤1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline. RESULTS: Most patients were women (84%) and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile→105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile→105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95% CI [1.02-24.51]) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064-10.58]). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed. CONCLUSION: This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.

Hemodialysis in satellite dialysis units: incidence of patient fallback to the in-center dialysis unit.

BACKGROUND: Patient fallbacks occur when a patient treated in a satellite dialysis unit (SDU) must be transferred to an in-center dialysis unit. Fallbacks have an impact on the in-center dialysis unit organization. This study was carried out to estimate the incidence and risk factors of patient fallback. METHODS: Between 01/01/2006 and 31/12/2010 there were 193 patients starting dialysis in SDUs in one French region. The primary outcome was the incidence of temporary and permanent fallbacks with or without hospitalization. A survival analysis and binomial negative regression were used for the statistical analysis. RESULTS: Among the 193 patients, 117 (60.6%; 95% confidence interval [CI]: 53.3-67.6) had at least one fallback, which occurred within a median of 249 days (interquartile range [IQR]: 71-469) after the first session in the SDU. The median number of fallbacks by subject was 1 (IQR: 0-4). The median duration of the fallback period was 4 days (IQR: 1-8) and median number of dialysis sessions during the fallback time was 1 (IQR: 1-3). Of the 494 temporary fallbacks, 210 were due to patient hospitalization, the main cause of which was cardiovascular disease. At univariate analysis, patients permanently transferred to in-center hemodialysis units were older, had more peripheral arteriopathy, cancer and arrhythmia. At multivariate analysis, peripheral arteriopathy (relative risk [RR] 2.06, 95% CI 1.05-4.09) and the center (center 2: RR 0.42, 95% CI 0.21-0.84; center 3: RR 2.88, 95% CI 1.20-6.91) were significantly associated with the number of fallbacks. CONCLUSION: Fallback is a common event in hemodialysis patients treated in SDUs. Yet, the SDU system operates well since a third of patients treated in these units are still in SDUs at 2 years of follow-up. Factors associated with patient fallback are the center and cardiovascular disease.

[Extracellular hydration status and residual urinary sodium excretion in chronic hemodialysis patients: a cross-sectional multicenter study]. / Statut d'hydratation extracellulaire et natriurèse résiduelle en hémodialyse chronique : une étude transversale multicentrique.

BACKGROUND: In dialysis patients, a misevaluation of dry weight may lead to an increased morbidity and mortality. The aim of this cross-sectional multicenter study was to evaluate the association between residual urinary sodium excretion and extracellular volume status in chronically treated hemodialysis patients. PATIENTS AND METHODS: Dry weight was determined clinically and by whole-body bioimpedance spectroscopy (Body Composition Monitor, Fresenius Medical Care) prior to a mid-week session in 40 chronic hemodialysis patients with significant residual diuresis (more than 250 mL per day) and receiving treatment in four dialysis centers. Regarding their hydration status assessed by the Body Composition Monitor and in comparison to a healthy reference population, patients were assigned to 1 of the 3 categories: overhydrated, normohydrated and dehydrated. Urine output, urinary sodium excretion and residual renal function were measured for all patients within 30 days before dry weight assessment. RESULTS: The median post-HD session FO was of-0.40 L (IQR: from-1.95 to+0.90) and the median residual urinary sodium excretion was of 64 mmol/L (IQR: 46-79). Among these patients, 16 were normohydated, 16 were dehydrated and 8 were overhydrated. There was a linear relationship between the hydration status after HD session and the urinary sodium excretion (estimate: 5.6±1.5; p<0.001). Compared with normohydrated patients, overhydrated patients had a higher residual urinary sodium excretion (estimate: 26±10; p<0.01). CONCLUSION: In this study, urinary sodium excretion is associated with the hydration status evaluated by whole-body bioimpedance spectroscopy.

Elevated removal of middle molecules without significant albumin loss with mixed-dilution hemodiafiltration for patients unable to provide sufficient blood flow rates.

BACKGROUND: We examined the hypothesis that mixed-dilution online hemodiafiltration (MIXED) rather than predilution online hemodiafiltration (PRE) could enable patients with low blood flow rate (Qb) to benefit from advantages of convective therapies. METHODS: Thirty-eight patients were included in a prospective, randomized, crossover and multicenter study conducted with a view to comparing the equilibrated Kt/V, reduction ratio (RR) of phosphates, ß2-microglobulin (ß2-M) and myoglobin (myo) between PRE and MIXED, each at two Qb values of 250 and 300 ml/min during 4 h sessions with a FX1000HDF dialyzer. Albumin losses (Alb) were also measured in 12 patients. RESULTS: MIXED was always found to be more efficient compared to PRE notably for middle molecules (MM). RRß2-M: MIX250: 81.3 ± 3.6 vs. PRE250: 75.2 ± 5.9; MIX300: 82.7 ± 3.6 vs. PRE300: 78.1 ± 5.4; RRmyo: MIX250: 70.2 ± 3.6 vs. PRE250: 42.6 ± 2.6; MIX300: 70.6 ± 3.6 vs. PRE300: 45.7 ± 3.6 and with Alb <3.0 g/session. CONCLUSION: MIXED allows patients unable to provide sufficiently high Qb to achieve high levels of MM removal.

[Estimation of urea distribution volume in hemodialysis patients]. / Estimation du volume de distribution de l'urée chez le patient hémodialysé.

BACKGROUND: On-line urea clearance estimation, currently available on some dialysis monitors, makes it possible to calculate the dialysis dose Kt and thus allows to estimate Kt/V for each session, providing an estimation of urea distribution volume (V) at equilibrium assumed equal to total body water. METHODS: Three methods suitable for routinely estimating V, using the anthropometric Watson formula (V(Wat)), the body composition monitor (BCM) device (Fresenius Medical Care) based on bio-impedance analysis (V(imp)) and the indirect estimation (V(Daug)) obtained from measurement of Kt/(Kt/V)(sp) ratio respectively are compared during 25 dialysis sessions in 15 patients to a direct estimation (V(DDQ)) obtained by direct quantification of dialysis (DDQ) considered as the gold standard in hemodialysis patient.. RESULTS: V(Watson) overestimates V(DDQ) by about 20%. The values of V(imp) (29.1±5.6 L) and V(Daug) (29.5±4.6 L) are in agreement with V(DDQ) (29.9±5.2 L). Correlation coefficient with V(DDQ) is better for V(imp) (r=0.94) than for V(Daug) (r=0.85). CONCLUSION: Bio-impedancemetry using BCM and indirect method using the second generation Daugirdas equation are two methods of clinical interest for estimating V. Bio-impedancemetry does not require blood sample, but it needs to have a specific device at disposal.

[Feasibility between AN69 and hemodiafiltration online]. / Utilisation de l'AN69 en hémodiafiltration "online".

Removal of the middle molecules (MM) weight toxins, and particularly of beta-2-microglobuline (b2M) is made first by convection technique with membranes habitually used in hemodiafiltration online (HDFOL). AN69 was in standard hemodialysis (HD) the reference membrane for the removal of b2M mostly (60%) by adsorption. Its use with convective methods is generally restricted to low efficiency modalities with low substitution rates (Qs), either with continuous HF or HDF for acute renal failure, or with acetate free biofiltration (AFB) for chronic renal failure. So-called adsorptive membranes do not have, at the present time, a well-defined indication for high efficiency HDFOL, which necessitates substitution rates (Qs) higher than 15 litres per session. The objective of this study is to demonstrate the feasibility of such an association between polyethyleneimine (PEI) surface treated AN69 and HDFOL both in qualitative and quantitative terms. Five patients were dialysed, respectively, with Nephral 500ST (AN69, PEI, surface 2.15m(2), Hospal France) in HD (HDNEP), postdilution HDF (PostNEP), predilution HDF (PreNEP) and as a reference, with FX80 (Helixone, surface 1,8m(2), Fresenius) in PostD (PostFX). For the small molecules (SM), equilibrated Kt/V (Kt/VEq) and the phosphorus (Ph) reduction ratio (RR)Ph have been measured. Considering the predominating adsorption of b2M by AN69, the removal of MM - b2M and myoglobine (Myo) - was also assessed by their RR (RRb2M and RRMyo). Results are convincing in terms of behaviour in relation to convective techniques, the 2.15m(2) membrane used during 4 hour sessions accepting Qs up to 25 litres with PostD and up to 59 litres with PreD, without any alarm of transmembrane pressure (TMP) or any fiber coagulation incident, proving without any ambiguity the absence of deleterious membrane plugging and its compatibility with high efficiency HDFOL. The behaviour of AN69 in HDFOL in relation to SM does not differ from HDNEP or FXPost. For MM, results for b2M are significantly lower (P=0.01) for PostNEP (RR=71.4%) in comparison with PostFX (RR=79.3%), but the behaviour of AN69 is above all particular for higher molecular weight substances since results are significantly reversed (P=0.03) for Myo (PM=17,800Da) in favour of PostNEP (RR=73.6%) compared to PostFX (RR=65.7%). These results open up new horizons for HDFOL and encourage us to focus future studies on the consequences of an optimized removal, mainly by absorption, of high molecular weight toxins, such as factor D, C3a, C3b and cytokines (IL-1 and TNF). The expected beneficial consequences concern complications linked to inflammation and oxidative stress, which could account notably, beyond the mere quantitative removal of b2M, for the quasi disappearance of any clinical expression of dialysis-related amyloidosis.

Mid-dilution: an innovative high-quality and safe haemodiafiltration approach.

Mid-dilution (MidD) is a new concept allowing post- and predilution in the same dialyser (Olpur MD 190). The aim of the study was to compare, in 6 patients, MidD with post and predilution wird regard to purification tests, such as reduction ratios and instantaneous whole-blood clearances, of urea, creatinine and phosphorus as examples of low-weight molecules and of Beta2-microglobulin as an example of a middle molecule (MM). The aim was also to indicate directions for the use of this new dialyser, taking into account our own experience and the few observations already published. It was concluded that MidD, under excellent safety conditions, in spite of increased intradialyser pressures, offers a very high purification performance, particularly for MM, because of high convective volumes exceeding the recommended objectives for a better survival in dialysis.

A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors.

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P=.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.