Annie Rodriguez

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

BACKGROUND The 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. METHODS Two 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. RESULTS Plasma 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). CONCLUSIONS The 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.

Bisphenol A in Chronic Kidney Disease: Bisphenol A in CKD

The estrogenic endocrine-disrupting substance bisphenol A (BPA) is extensively used as a starting material for a variety of consumer plastic products including dialyzer materials. The present study was performed to explore plasma BPA levels in patients with impaired renal function and to investigate if dialyzers differing in elutable BPA influence plasma levels in patients on maintenance hemodialysis. In vitro BPA was eluted from high-flux polyethersulfone (PUREMA H, referred as PUR-H), high-flux polysulfone (referred as HF-PSu), and low-flux polysulfone (referred as LF-PSu) dialyzers by recirculation with water for 180 min. In a cross-sectional clinical study, plasma BPA levels of outpatients with different stages of chronic kidney disease (CKD) from four different centers were determined. Furthermore, in a prospective, randomized, and crossover setting, 18 maintenance dialysis patients were subjected successively to 4 weeks of thrice-weekly hemodialysis with each LF-PSu, HF-PSu, and PUR-H. In addition, the fractions of protein-bound and free BPA were determined in a subset of dialysis patients. The mass of BPA eluted from the blood compartments in vitro under aqueous conditions varied for the three dialyzers being very low for PUR-H (6.2 ± 2.5 ng; P < 0.001), intermediate for HF-PSu (48.1 ± 7.7 ng), and highest for LF-PSu (140.8 ± 38.7 ng; P < 0.01). In 152 prevalent patients with CKD enrolled in the cross-sectional trial, plasma BPA started to rise after stage 3. Maintenance hemodialysis patients had more than six times higher BPA concentrations than patients with CKD stage 5 not yet on dialysis (10.0 ± 6.6 vs. 1.6 ± 1.8 ng/mL; P < 0.001). The BPA concentrations highly and inversely correlated with renal function. In the randomized controlled study, the plasma BPA concentrations were highly elevated compared with healthy controls (range 9.1 ± 4.5-12.0 ± 6.0 ng/mL vs. ≤0.2 ± 0.1 ng/mL; P < 0.001), but no change of the plasma levels was observed during hemodialysis with any of the three dialyzers in the course of a single treatment and over a period of 4 weeks. The protein-bound fraction of plasma BPA in the dialysis patients was 74 ± 5%. Renal function and, most likely, the total quantity of ingested BPA are essential parameters affecting plasma BPA concentrations. Dialyzers are one additional source of BPA, but differences in the elutable BPA content are not associated with a significant effect on BPA plasma levels in Western European maintenance dialysis patients. Due to high protein binding, the removal of BPA by hemodialysis is limited.

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.

Whole-blood viscosity increases significantly in small arteries and capillaries in hemodiafiltration. Does acute hemorheological change trigger cardiovascular risk events in hemodialysis patient?

Whole‐blood viscosity is increasingly being recognized as a factor implicated in the vascular disease progression in high‐risk chronic kidney disease patients. Intermittent hemodialysis and hemodiafiltration sessions, characterized by rapid volume changes and anemia correction by erythropoietin stimulating agents, are favorable conditions for enhancing whole‐blood viscosity changes and consequently triggering cardiovascular events. To evaluate whole‐blood viscosity changes induced by hemodiafiltration, a cross‐sectional study has been performed in a group of 28 stable patients. In order to assess the impact of vessel size on whole‐blood viscosity changes, we performed a dynamic whole viscosity analysis on a wide spectrum of shear rates reproducing vasculature hemorheologic conditions. Blood viscosity changes are dependent on patient characteristics, hemoglobin, and total plasma protein concentrations. Whole blood viscosity increases significantly during hemodiafiltration over the complete spectrum of shear rates. Dynamic whole‐blood viscosity (WBV) increases up to 60%, predominantly at low shear rates in small arterioles and capillary beds. This observation underlines the potential pathogenic contribution of WBV increase in capillaries triggering cardiovascular events in the postdialysis period. Eight patients died from cardiovascular events. Higher WBV increase was noted in this group but did not reach statistical significance due to the insufficient power of the study. Hemorheological changes associated with WBV increase in capillary beds may contribute to aggravate silent tissue hypoxemia and precipitate cardiovascular events in chronic kidney disease patients. Prospective studies specifically designed and powered to evaluate the impact of WBV changes on cardiovascular events in dialysis patients are required.

Monthly reference change value of cardiac troponin in hemodialysis patients as a useful tool for long-term cardiovascular management.

PURPOSE OF RESEARCH Circulating cardiac troponin (cTn) has been identified as a risk factor for cardiovascular and overall mortality in patients undergoing hemodialysis. However, its interpretation remains difficult due to the high prevalence of patients with cTn level beyond the 99th percentile. Determining the cTn reference change value (RCV) may help in assessing a clinically significant change of cTn during regular follow-up of patients. We aimed to determine the long-term RCV of cTn in such patients and to calculate the perdialytic reduction rate of cTn. DESIGN AND METHODS To calculate RCV, high-sensitivity (hs)-cTnT (Roche), hs-cTnI (Abbott), and cTnI-ultra (Siemens) were determined every month before the midweek dialysis session over a 3-month period in 36 stable hemodialysis patients. cTn was also measured after the midweek dialysis session to calculate the cTn removal rate. RESULTS The mean RCV (95% confidence interval) was 22% (18-26) for hs-cTnT versus 53% (34-73) for hs-cTnI versus 65% (45-84) for cTnI-ultra. Log-normal RCV (%) was -19/+25 for hs-cTnT, -33/+96 for hs-cTnI, and -39/+115 for cTnI-ultra. The index of individuality was <0.6 regardless of the cTn assay used. A significantly greater reduction rate was observed for hs-cTnT (48%) than for hs-cTnI (30%, p<0.001) and cTnI-ultra (29%, p<0.05). CONCLUSIONS These results underline the need to use the RCV approach rather than cutoff points to identify the critical change in long-term serial cTn levels. In addition, RCV should be determined for each available assay due to significant differences between assays. Removal of cTn during hemodialysis sessions should also be considered if acute coronary syndrome is suspected during a session.

Does hemodiafiltration improve the removal of homocysteine

High prevalence of hyperhomocysteinemia is common in hemodialysis (HD) patients and could contribute to worsen the cardiovascular risk. Beyond vitamin B status, dialysis modality itself could influence homocysteine (Hcy) levels. The objective was compare the reduction rate (RR) of Hcy and cysteine in stable dialyzed patients treated by standard HD or hemodiafiltration (HDF). Seventy‐five patients undergoing stable dialysis through standard high‐flux HD (n = 35) or HDF (n = 40) were included. Biological parameters were determined before and after a midweek dialysis session. Urea percent reduction per session and Kt/V index (K, body urea clearance, T, time of dialysis, and V, urea distribution volume), defined as a marker of dialysis efficacy, were similar between HD and HDF groups. By contrast, higher RR of beta2 microglobulin (β2m) was observed in HDF compared with HD (78.6 vs. 72.0%, respectively; P < 0.001). Likewise, higher RR of Hcy was obtained with HDF compared to HD (46.0 vs. 41.5%, respectively; P < 0.05), whereas the RR of cysteine was similar in both groups. Interestingly, a positive correlation between Hcy RR and urea Kt/V index was observed (r = 0.29, P < 0.05) and between Hcy RR and β2m RR (r = 0.45, P < 0.001). Time‐averaged concentration (TAC) of Hcy was lower with HDF compared with HD (17.8 vs. 19.1 μmol/L, respectively), although not significant. There was no difference in median Hcy according to dialysis modality for neither pre‐ nor postdialysis levels. Significant higher removal of Hcy was observed with HDF compared with standard HD, although urea Kt/V index was similar. Enhanced removal of middle molecules, such as β2m, could be involved in Hcy RR improvement with HDF.

Comment évaluer l'apport protidique d'un patient hémodialysé ? Quelles formules utiliser en pratique ?

Resume Les formules simplifiees de calculs du taux de catabolisme protidique, et de leur equivalent l’apport protidique journalier, etablies a partir de la cinetique de l’uree sont d’excellents outils pour evaluer la qualite du traitement de suppleance extra-renal administre et ses consequences nutritionnelles proteiques. Ces formules s’inscrivent dans le cadre du controle permanent de qualite du patient hemodialyse. Elles ne peuvent pas se substituer au jugement clinique du nephrologue et ne peuvent en aucun cas remplacer les indicateurs conventionnels d’efficacite de dialyse (controle de la pression arterielle, controle du metabolisme mineralo-osseux, correction de l’anemie…) ou d’evaluation nutritionnelle (anthropometrique, proteines somatiques, evaluation subjective globale, bioimpedance…). Ces formules offrent un moyen commode et peu onereux de quantifier l’efficacite instantanee de l’hemodialyse en mesurant la « dose de dialyse » et en calculant « l’apport protidique equivalent » a partir de parametres simples bases sur l’uree. Elles apportent ainsi un moyen complement necessaire mais non suffisant au suivi complexe de l’efficacite du traitement de suppleance d’un patient dialyse.

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