Hemodiafiltration to Address Unmet Medical Needs ESKD Patients.
ABSTRACT: Hemodiafiltration combines diffusive and convective solute removal in a single therapy by ultrafiltering 20% or more of the blood volume processed using a high-flux hemodialyzer and maintaining fluid balance by infusing sterile nonpyrogenic replacement fluid directly into the patient's blood. In online hemodiafiltration, the large volumes of replacement fluid required are obtained by online filtration of standard dialysate through a series of bacteria- and endotoxin-retaining filters. Currently available systems for online hemodiafiltration are on the basis of conventional dialysis machines with added features to safely prepare and infuse replacement fluid and closely control fluid balance. Hemodiafiltration provides greater removal of higher molecular weight uremic retention solutes than conventional high-flux hemodialysis, and recently completed randomized, controlled clinical trials suggest better patient survival with online hemodiafiltration compared with standard high-flux hemodialysis when a high convection volume is delivered. Hemodiafiltration is also associated with improvements in other clinical outcomes, such as a reduction in intradialytic hypotension, and it is now used routinely to treat >100,000 patients, mainly in Europe and Japan.
Project description:Online hemodiafiltration provides greater removal of higher molecular weight uremic retention solutes than conventional high-flux hemodialysis. However, online hemodiafiltration is used sparsely in the United States in part because of a paucity of delivery systems cleared for clinical use by the US Food and Drug Administration. Although a pathway for regulatory approval exists in the United States, concerns remain, particularly regarding online production of the large volumes of sterile, nonpyrogenic substitution fluid infused directly into the bloodstream to maintain fluid balance. Clearly defined testing protocols, acceptable to Food and Drug Administration, will be useful to show that an online hemodiafiltration system is capable of routinely achieving a sterility assurance level of 10<sup>-6</sup> and nonpyrogenic levels of endotoxin. Large-scale clinical experience has shown that systems providing this level of performance when combined with certain design features, such as redundancy, and an appropriate quality management process can routinely and safely produce substitution fluid for online hemodiafiltration.
Project description:In patients with ESRD, the effects of online hemodiafiltration on all-cause mortality and cardiovascular events are unclear. In this prospective study, we randomly assigned 714 chronic hemodialysis patients to online postdilution hemodiafiltration (n=358) or to continue low-flux hemodialysis (n=356). The primary outcome measure was all-cause mortality. The main secondary endpoint was a composite of major cardiovascular events, including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, therapeutic coronary intervention, therapeutic carotid intervention, vascular intervention, or amputation. After a mean 3.0 years of follow-up (range, 0.4-6.6 years), we did not detect a significant difference between treatment groups with regard to all-cause mortality (121 versus 127 deaths per 1000 person-years in the online hemodiafiltration and low-flux hemodialysis groups, respectively; hazard ratio, 0.95; 95% confidence interval, 0.75-1.20). The incidences of cardiovascular events were 127 and 116 per 1000 person-years, respectively (hazard ratio, 1.07; 95% confidence interval, 0.83-1.39). Receiving high-volume hemodiafiltration during the trial associated with lower all-cause mortality, a finding that persisted after adjusting for potential confounders and dialysis facility. In conclusion, this trial did not detect a beneficial effect of hemodiafiltration on all-cause mortality and cardiovascular events compared with low-flux hemodialysis. On-treatment analysis suggests the possibility of a survival benefit among patients who receive high-volume hemodiafiltration, although this subgroup finding requires confirmation.
Project description:Two dialysis patients developed recurrent restless legs syndrome. The clinical courses and the association between the ?1-microglobulin removal rate and the therapeutic effects of hemodiafiltration were analyzed. Case 1: a middle-aged woman was switched from predilution online hemodiafiltration to hemodialysis, following which the ?1-microglobulin removal rate decreased from 39.1 to 29.9%. A month later, the severe restless legs syndrome occurred. The treatment was then switched to high-efficiency hemodiafiltration and 2 weeks later, these symptoms were resolved. The ?1-microglobulin removal rate increased to 41.9%. Her symptoms recurred 5 years later with severity; thus, the hemodiafiltration treatment conditions were changed. Under revised conditions, the ?1-microglobulin removal rate was 42.6%, and her symptoms were alleviated. Continuation of high-efficiency hemodiafiltration led to the resolution of the syndrome at 1 month after recurrence. Case 2: a middle-aged man on hemodialysis developed the restless legs syndrome in the second year of treatment. The ?1-microglobulin removal rate was 23.8%. After switching to a month-long high-efficiency hemodiafiltration with a removal rate of???40%, his symptoms were resolved. However, the syndrome recurred after a year with severity. The symptoms were alleviated using various measures. The hemodiafilters were changed, and hemodiafiltration with an ?1-microglobulin removal rate of???40% was continued; 2 months later, his symptoms resolved. High-efficiency online hemodiafiltration is an effective therapeutic strategy for restless legs syndrome in dialysis patients. We found, for the first time, that target removal efficiency is an ?1-microglobulin removal rate of 40% or higher.
Project description:<h4>Background</h4>Myoglobin clearance in acute kidney injury requiring renal replacement therapy is important because myoglobin has direct renal toxic effects. Clinical data comparing different modalities of renal replacement therapy addressing myoglobin clearance are limited. This study aimed to compare two renal replacement modalities regarding myoglobin clearance.<h4>Methods</h4>In this prospective, randomized, single-blinded, single-center trial, 70 critically ill patients requiring renal replacement therapy were randomized 1:1 into an intervention arm using continuous veno-venous hemodialysis with high cutoff dialyzer and a control arm using continuous veno-venous hemodiafiltration postdilution with high-flux dialyzer. Regional citrate anticoagulation was used in both groups to maintain the extracorporeal circuit. The concentrations of myoglobin, urea, creatinine, ?2-microglobulin, interleukin-6 and albumin were measured before and after the dialyzer at 1 h, 6 h, 12 h, 24 h and 48 h after initiating continuous renal replacement therapy.<h4>Results</h4>Thirty-three patients were allocated to the control arm (CVVHDF with high-flux dialyzer) and 35 patients to the intervention arm (CVVHD with high cutoff dialyzer). Myoglobin clearance, as a primary endpoint, was significantly better in the intervention arm than in the control arm throughout the whole study period. The clearance values for urea and creatinine were higher in the control arm. There was no measurable albumin clearance in both arms. The clearance data for ?<sub>2</sub>-microglobulin and interleukin-6 were non-inferior in the intervention arm compared to those for the control arm. Dialyzer lifespan was 57.0 [38.0, 72.0] hours in the control arm and 70.0 [56.75, 72.0] hours in the intervention arm (p?=?0.029).<h4>Conclusions</h4>Myoglobin clearance using continuous veno-venous hemodialysis with high cutoff dialyzer and regional citrate anticoagulation is better than that with continuous veno-venous hemodiafiltration with regional citrate anticoagulation.<h4>Trial registration</h4>German Clinical Trials Registry (DRKS00012407); date of registration 23/05/2017. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00012407 .
Project description:<h4>Introduction</h4>Administration of low-molecular-weight heparins (LMWHs) is necessary for preventing extracorporeal circuit thrombosis during hemodialysis. A substantial amount of LMWH is removed with online hemodiafiltration (OL-HDF) when administered through the inlet site of the extracorporeal circuit. Consequently, administration of LMWH at the outlet site appears to be more efficient. In this study we aimed to compare the effects of nadroparin calcium (NAD) administered through the outlet versus the inlet port site in postdilution OL-HDF and assess the NAD dose reduction.<h4>Methods</h4>Forty-nine hemodialysis patients were included in 3 consecutive 6-week studies as follows: phase I, inlet port line; phase II, outlet port line; and phase III, outlet port line with reduced dose. We evaluated clotting in the hemodialyzer and venous bubble trap, the dialysis dose (<i>K</i> <i>t/V</i>), and substitution volume.<h4>Results</h4>Thirty four percent, 63%, and 66% were categorized as "white" during phases I, II, and III, respectively. During phases I, II, and III, 75%, 93%, and 95% of the venous bubble traps were "clean," and 9%, 0.6%, and 0.4% of the dialyzers clotted, respectively. Average NAD dose was 0.43 ml during phase I and 0.3 ml during phase II. During phase III, the LMWH dose was reduced by 33% to 50% in 15 patients. In phase III, <i>Kt/V</i> improved from 1.64 to 1.75 and substitution volume increased from 20.18 to 21.96 L.<h4>Conclusions</h4>When using OL-HDF, a single administration of NAD at the outlet port line allows for a significant dose reduction and was associated with improved dialysis performance.
Project description:<h4>Unlabelled</h4>Resistance to erythropoiesis stimulating agents (ESA) is common in patients undergoing chronic hemodialysis (HD) treatment. ESA responsiveness might be improved by enhanced clearance of uremic toxins of middle molecular weight, as can be obtained by hemodiafiltration (HDF). In this analysis of the randomized controlled CONvective TRAnsport STudy (CONTRAST; NCT00205556), the effect of online HDF on ESA resistance and iron parameters was studied. This was a pre-specified secondary endpoint of the main trial. A 12 months' analysis of 714 patients randomized to either treatment with online post-dilution HDF or continuation of low-flux HD was performed. Both groups were treated with ultrapure dialysis fluids. ESA resistance, measured every three months, was expressed as the ESA index (weight adjusted weekly ESA dose in daily defined doses [DDD]/hematocrit). The mean ESA index during 12 months was not different between patients treated with HDF or HD (mean difference HDF versus HD over time 0.029 DDD/kg/Hct/week [-0.024 to 0.081]; P?=?0.29). Mean transferrin saturation ratio and ferritin levels during the study tended to be lower in patients treated with HDF (-2.52% [-4.72 to -0.31]; P?=?0.02 and -49 ng/mL [-103 to 4]; P?=?0.06 respectively), although there was a trend for those patients to receive slightly more iron supplementation (7.1 mg/week [-0.4 to 14.5]; P?=?0.06). In conclusion, compared to low-flux HD with ultrapure dialysis fluid, treatment with online HDF did not result in a decrease in ESA resistance.<h4>Trial registration</h4>ClinicalTrials.gov NCT00205556.
Project description:BACKGROUND:Hypertension and cardiovascular disease are common in children undergoing dialysis. Studies suggest that hemodiafiltration (HDF) may reduce cardiovascular mortality in adults, but data for children are scarce. METHODS:The HDF, Heart and Height study is a nonrandomized observational study comparing outcomes on conventional hemodialysis (HD) versus postdilution online HDF in children. Primary outcome measures were annualized changes in carotid intima-media thickness (cIMT) SD score and height SD score. RESULTS:We enrolled 190 children from 28 centers; 78 on HD and 55 on HDF completed 1-year follow-up. The groups were comparable for age, dialysis vintage, access type, dialysis frequency, blood flow, and residual renal function. At 1 year, cIMT SD score increased significantly in children on HD but remained static in the HDF cohort. On propensity score analysis, HD was associated with a +0.47 higher annualized cIMT SD score compared with HDF. Height SD score increased in HDF but remained static in HD. Mean arterial pressure SD score increased with HD only. Factors associated with higher cIMT and mean arterial pressure SD-scores were HD group, higher ultrafiltration rate, and higher ?2-microglobulin. The HDF cohort had lower ?2-microglobulin, parathyroid hormone, and high-sensitivity C-reactive protein at 1 year; fewer headaches, dizziness, or cramps; and shorter postdialysis recovery time. CONCLUSIONS:HDF is associated with a lack of progression in vascular measures versus progression with HD, as well as an increase in height not seen in the HD cohort. Patient-related outcomes improved among children on HDF correlating with improved BP control and clearances. Confirmation through randomized trials is required.
Project description:Retrospective studies suggest that online hemodiafiltration (OL-HDF) may reduce the risk of mortality compared with standard hemodialysis in patients with ESRD. We conducted a multicenter, open-label, randomized controlled trial in which we assigned 906 chronic hemodialysis patients either to continue hemodialysis (n=450) or to switch to high-efficiency postdilution OL-HDF (n=456). The primary outcome was all-cause mortality, and secondary outcomes included cardiovascular mortality, all-cause hospitalization, treatment tolerability, and laboratory data. Compared with patients who continued on hemodialysis, those assigned to OL-HDF had a 30% lower risk of all-cause mortality (hazard ratio [HR], 0.70; 95% confidence interval [95% CI], 0.53-0.92; P=0.01), a 33% lower risk of cardiovascular mortality (HR, 0.67; 95% CI, 0.44-1.02; P=0.06), and a 55% lower risk of infection-related mortality (HR, 0.45; 95% CI, 0.21-0.96; P=0.03). The estimated number needed to treat suggested that switching eight patients from hemodialysis to OL-HDF may prevent one annual death. The incidence rates of dialysis sessions complicated by hypotension and of all-cause hospitalization were lower in patients assigned to OL-HDF. In conclusion, high-efficiency postdilution OL-HDF reduces all-cause mortality compared with conventional hemodialysis.
Project description:BACKGROUND:End stage renal disease (ESRD) patients require a renal replacement therapy (RRT) to filter accumulated toxins and remove excess water, which are associated with impaired physical function. Hemodialysis (HD) removes middle-molecular weight (MMW) toxins less efficiently compared to hemodiafiltration (HDF); we hypothesized HDF may improve physical function. We detailed the design and methodology of the HDFIT protocol that is testing whether changing from HD to HDF effects physical activity levels and various outcomes. METHODS:HDFIT is a prospective, multi-center, unblinded, randomized control trial (RCT) investigating the impact of dialysis modality (HDF verses HD) on objectively measured physical activity levels, self-reported quality of life, and clinical/non-clinical outcomes. Clinically stable patients with HD vintage of 3 to 24?months without any severe limitation ambulation were recruited from sites throughout southern Brazil. Eligible patients were randomized in a 1:1 ratio to either: 1) be treated with high volume online HDF for 6?months, or 2) continue being treated with high-flux HD. This study includes run-in and randomization visits (baseline), 3- and 6-month study visits during the interventional period, and a 12-month observational follow up. The primary outcome is the difference in the change in steps per 24?h on dialysis days from baseline to the 6-month follow up in patients treated with HDF versus HD. Physical activity is being measured over one week at study visits with the ActiGraph ( www.actigraphcorp.com ). For assessment of peridialytic differences during the dialysis recovery period, we will analyze granular physical activity levels based on the initiation time of HD on dialysis days, or concurrent times on non-dialysis days and the long interdialytic day. DISCUSSION:In this manuscript, we provide detailed information about the HDFIT study design and methodology. This trial will provide novel insights into peridialytic profiles of physical activity and various self-reported, clinical and laboratory outcomes in ESRD patients treated by high volume online HDF versus high-flux HD. Ultimately, this investigation will elucidate whether HDF is associated with patients having better vitality and quality of life, and less negative outcomes as compared to HD. TRIAL REGISTRATION:Registered on ClinicalTrials.gov on 20 April 2016 ( NCT02787161 ).
Project description:Hemodialysis (HD) patients have a high risk of infections. The uremic milieu has a negative impact on several immune responses. Online hemodiafiltration (HDF) may reduce the risk of infections by ameliorating the uremic milieu through enhanced clearance of middle molecules. Since there are few data on infectious outcomes in HDF, we compared the effects of HDF with low-flux HD on the incidence and type of infections.We used data of the 714 HD patients (age 64 ±14, 62% men, 25% Diabetes Mellitus, 7% catheters) participating in the CONvective TRAnsport STudy (CONTRAST), a randomized controlled trial evaluating the effect of HDF as compared to low-flux HD. The events were adjudicated by an independent event committee. The risk of infectious events was compared with Cox regression for repeated events and Cox proportional hazard models. The distributions of types of infection were compared between the groups.Thirty one percent of the patients suffered from one or more infections leading to hospitalization during the study (median follow-up 1.96 years). The risk for infections during the entire follow-up did not differ significantly between treatment arms (HDF 198 and HD 169 infections in 800 and 798 person-years respectively, hazard ratio HDF vs. HD 1.09 (0.88-1.34), P = 0.42. No difference was found in the occurrence of the first infectious event (either fatal, non-fatal or type specific). Of all infections, respiratory infections (25% in HDF, 28% in HD) were most common, followed by skin/musculoskeletal infections (21% in HDF, 13% in HD).HDF as compared to HD did not result in a reduced risk of infections, larger studies are needed to confirm our findings.ClinicalTrials.gov NCT00205556.