Menso J. Nubé

Effect of Online Hemodiafiltration on All-Cause Mortality and Cardiovascular Outcomes

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.

Online haemodiafiltration: definition, dose quantification and safety revisited

The general objective assigned to the EUropean DIALlysis (EUDIAL) Working Group by the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) was to enhance the quality of dialysis therapies in Europe in the broadest possible sense. Given the increasing interest in convective therapies, the Working Group has started by focusing on haemodiafiltration (HDF) therapies. Several reports suggest that those therapies potentially improve the outcomes for end-stage renal disease patients. Europe is the leader in the field, having introduced the concept of ultra-purity for water and dialysis fluids and with notified bodies of the European Community having certified water treatment systems and online HDF machines. The prevalence of online HDF-treated patients is steadily increasing in Europe, averaging 15%. A EUDIAL consensus conference was held in Paris on 13 October 2011 to revisit terminology, safety and efficacy of online HDF. This is the first report of the expert group arising from that conference.

Short-term Effects of Online Hemodiafiltration on Phosphate Control: A Result From the Randomized Controlled Convective Transport Study (CONTRAST)

BACKGROUND Hyperphosphatemia is an independent risk factor for all-cause and cardiovascular mortality in hemodialysis (HD) patients. Phosphate control often is unsuccessful using conventional dialysis therapies. STUDY DESIGN Short-term analysis of a secondary outcome of an ongoing randomized controlled trial. SETTING & PARTICIPANTS 493 (84%) consecutive patients from 589 patients included in the Convective Transport Study (CONTRAST) by January 2009 from 26 centers in 3 countries. INTERVENTION Online hemodiafiltration (HDF) versus continuation of low-flux HD. OUTCOMES Differences in change from baseline to 6 months in phosphate levels and proportion of patients reaching phosphate treatment targets (phosphate < or = 5.5 mg/dL). MEASUREMENTS Phosphate, use of phosphate-binding agents, and proportion of patients achieving treatment targets at baseline, 3 months, and 6 months. RESULTS Phosphate levels decreased from 5.18 +/- 0.10 (SE) mg/dL at baseline to 4.87 +/- 0.10 mg/dL at 6 months in HDF patients (P < 0.001) and were stable in HD patients (5.10 +/- 0.10 mg/dL at baseline and 5.03 +/- 0.10 mg/dL after 6 months; P = 0.5). The difference in change in phosphate levels between HD and HDF patients (B = -0.24; 95% CI, -0.52 to 0.03; P = 0.08) increased after adjustment for phosphate-binder use (B = -0.36; 95% CI, -0.65 to -0.06; P = 0.02). The proportion of patients reaching phosphate treatment targets increased from 64% to 74% in HDF patients and was stable in HD patients (66% and 66%); the difference between groups reached statistical significance (P = 0.04). Nutritional parameters and residual renal function were similar in both treatment groups. LIMITATIONS Only predialysis serum phosphate levels were measured; phosphate clearance could therefore not be calculated. CONCLUSION HDF may help improve phosphate control. Whether this contributes to improved clinical outcome remains to be established.

Effect of increased convective clearance by on-line hemodiafiltration on all cause and cardiovascular mortality in chronic hemodialysis patients - the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomised controlled trial [ISRCTN38365125]

BackgroundThe high incidence of cardiovascular disease in patients with end stage renal disease (ESRD) is related to the accumulation of uremic toxins in the middle and large-middle molecular weight range. As online hemodiafiltration (HDF) removes these molecules more effectively than standard hemodialysis (HD), it has been suggested that online HDF improves survival and cardiovascular outcome. Thus far, no conclusive data of HDF on target organ damage and cardiovascular morbidity and mortality are available. Therefore, the CONvective TRAnsport STudy (CONTRAST) has been initiated.MethodsCONTRAST is a Dutch multi-center randomised controlled trial. In this trial, approximately 800 chronic hemodialysis patients will be randomised between online HDF and low-flux HD, and followed for three years. The primary endpoint is all cause mortality. The main secondary outcome variables are fatal and non-fatal cardiovascular events.ConclusionThe study is designed to provide conclusive evidence whether online HDF leads to a lower mortality and less cardiovascular events as compared to standard HD.

Clinical evidence on hemodiafiltration: A systematic review and a meta-analysis

In this review, a systematic literature search and meta‐analysis were performed to assess the effects of hemodiafiltration (HDF) on clinical outcome, as compared with hemodialysis (HD). Furthermore, the relation between the convection volume in HDF and clinical outcome was studied. The literature search identified six randomized controlled trials (RCTs). In a meta‐analysis of these RCTs, HDF treatment was related to a decreased risk of mortality (RR: 0.84; 95% CI 0.73–0.96) and cardiovascular death (RR: 0.73; 95% CI 0.57–0.92). Post hoc analyses of the three largest RCTs suggested an inverse relation between the magnitude of convection volume and mortality risk. The evidence presented in this analysis supports a wider acceptance of HDF.

Role of Residual Renal Function in Phosphate Control and Anemia Management in Chronic Hemodialysis Patients

BACKGROUND AND OBJECTIVES There is increasing awareness that residual renal function (RRF) has beneficial effects in hemodialysis (HD) patients. The aim of this study was to investigate the role of RRF, expressed as GFR, in phosphate and anemia management in chronic HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Baseline data of 552 consecutive patients from the Convective Transport Study (CONTRAST) were analyzed. Patients with a urinary output≥100 ml/24 h (n=295) were categorized in tertiles on the basis of degree of GFR and compared with anuric patients (i.e., urinary output<100 ml/24 h, n=274). Relations between GFR and serum phosphate and erythropoiesis-stimulating agent (ESA) index (weekly ESA dose per kg body weight divided by hematocrit) were analyzed with multivariable regression models. RESULTS Phosphate levels were between 3.5 and 5.5 mg/dl in 68% of patients in the upper tertile (GFR>4.13 ml/min per 1.73 m2), as compared with 46% in anuric patients despite lower prescription of phosphate-binding agents. Mean hemoglobin levels were 11.9±1.2 g/dl with no differences between the GFR categories. The ESA index was 31% lower in patients in the upper tertile as compared with anuric patients. After adjustments for patient characteristics, patients in the upper tertile had significantly lower serum phosphate levels and ESA index as compared with anuric patients. CONCLUSIONS This study suggests a strong relation between RRF and improved phosphate and anemia control in HD patients. Efforts to preserve RRF in HD patients could improve outcomes and should be encouraged.

Haemodiafiltration and mortality in end-stage kidney disease patients: a pooled individual participant data analysis from four randomized controlled trials

BACKGROUND Mortality rates remain high for haemodialysis (HD) patients and simply increasing the HD dose to remove more small solutes does not improve survival. Online haemodiafiltration (HDF) provides additional clearance of larger toxins compared with standard HD. Randomized controlled trials (RCTs) comparing HDF with conventional HD on all-cause and cause-specific mortality in end-stage kidney disease (ESKD) patients reported inconsistent results and were at high risk of bias. We conducted a pooled individual participant data analysis of RCTs to provide the most reliable evidence to date on the effects of HDF on mortality outcomes in ESKD patients. METHODS Individual participant data were used from four trials that compared online HDF with HD and were designed to examine the effects of HDF on mortality endpoints. Bias by informative censoring of patients was resolved. Hazard ratios (HRs) and 95% confidence intervals (95% CI) comparing the effect of online HDF versus HD on all-cause and cause-specific mortality were calculated using the Cox proportional hazard regression models. The relationship between convection volume and the study outcomes was examined by delivered convection volume standardized to body surface area. RESULTS After a median follow-up of 2.5 years (Q1-Q3: 1.9-3.0), 769 of the 2793 participants had died (292 cardiovascular deaths). Online HDF reduced the risk of all-cause mortality by 14% (95% CI: 1%; 25%) and cardiovascular mortality by 23% (95% CI: 3%; 39%). There was no evidence for a differential effect in subgroups. The largest survival benefit was for patients receiving the highest delivered convection volume [>23 L per 1.73 m(2) body surface area (BSA) per session], with a multivariable-adjusted HR of 0.78 (95% CI: 0.62; 0.98) for all-cause mortality and 0.69 (95% CI: 0.47; 1.00) for cardiovascular disease mortality. CONCLUSIONS This pooled individual participant analysis on the effects of online HDF compared with conventional HD indicates that online HDF reduces the risk of mortality in ESKD patients. This effect holds across a variety of important clinical subgroups of patients and is most pronounced for those receiving a higher convection volume normalized to BSA.

Microbiological quality and quality control of purified water and ultrapure dialysis fluids for online hemodiafiltration in routine clinical practice

During online hemodiafiltration, patients are directly infused with sterile substitution solutions to maintain fluid balance. Adequate water treatment and a well-organized quality control process are essential to provide non-pyrogenic fluids with consistent optimal quality. We sought to assess water quality, the water treatment system, and the methods for surveillance of microbiological water quality in 10 Dutch dialysis centers that routinely treat patients with hemodiafiltration. Microbiological monitoring results (micro-organisms and endotoxins) were collected over a 1-year period representing 11,258 hemodiafiltration sessions covering 97 patients. In all centers, water purification was based on a reverse osmosis module in combination with a second reverse osmosis and/or an electrodeionizer. All centers regularly and routinely monitored the microbiological purity of the dialysis water with adequate analytical methods but with variable monitoring frequency. Microbiological assessments were compliant with reference quality levels in 3923 of 3961 samples. Our study suggests that non-pyrogenic substitution fluids can be produced online for a prolonged period of time. It is likely that the current Dutch Quality of Care Guideline has contributed to high-quality water treatment and a well-organized control process.

Role of Residual Kidney Function and Convective Volume on Change in β2-Microglobulin Levels in Hemodiafiltration Patients

BACKGROUND AND OBJECTIVES Removal of beta2-microglobulin (beta2M) can be increased by adding convective transport to hemodialysis (HD). The aim of this study was to investigate the change in beta2M levels after 6-mo treatment with hemodiafiltration (HDF) and to evaluate the role of residual kidney function (RKF) and the amount of convective volume with this change. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Predialysis serum beta2M levels were evaluated in 230 patients with and 176 patients without RKF from the CONvective TRAnsport STudy (CONTRAST) at baseline and 6 mo after randomization for online HDF or low-flux HD. In HDF patients, potential determinants of change in beta2M were analyzed using multivariable linear regression models. RESULTS Mean serum beta2M levels decreased from 29.5 +/- 0.8 (+/-SEM) at baseline to 24.3 +/- 0.6 mg/L after 6 mo in HDF patients and increased from 31.9 +/- 0.9 to 34.4 +/- 1.0 mg/L in HD patients, with the difference of change between treatment groups being statistically significant (regression coefficient -7.7 mg/L, 95% confidence interval -9.5 to -5.6, P < 0.001). This difference was more pronounced in patients without RKF as compared with patients with RKF. In HDF patients, beta2M levels remained unchanged in patients with GFR >4.2 ml/min/1.73 m2. The beta2M decrease was not related to convective volume. CONCLUSIONS This study demonstrated effective lowering of beta2M levels by HDF, especially in patients without RKF. The role of the amount of convective volume on beta2M decrease appears limited, possibly because of resistance to beta2M transfer between body compartments.

Higher convection volume exchange with online hemodiafiltration is associated with survival advantage for dialysis patients: the effect of adjustment for body size

Mortality remains high for hemodialysis patients. Online hemodiafiltration (OL-HDF) removes more middle-sized uremic toxins but outcomes of individual trials comparing OL-HDF with hemodialysis have been discrepant. Secondary analyses reported higher convective volumes, easier to achieve in larger patients, and improved survival. Here we tested different methods to standardize OL-HDF convection volume on all-cause and cardiovascular mortality compared with hemodialysis. Pooled individual patient analysis of four prospective trials compared thirds of delivered convection volume with hemodialysis. Convection volumes were either not standardized or standardized to weight, body mass index, body surface area, and total body water. Data were analyzed by multivariable Cox proportional hazards modeling from 2793 patients. All-cause mortality was reduced when the convective dose was unstandardized or standardized to body surface area and total body water; hazard ratio (95% confidence intervals) of 0.65 (0.51-0.82), 0.74 (0.58-0.93), and 0.71 (0.56-0.93) for those receiving higher convective doses. Standardization by body weight or body mass index gave no significant survival advantage. Higher convection volumes were generally associated with greater survival benefit with OL-HDF, but results varied across different ways of standardization for body size. Thus, further studies should take body size into account when evaluating the impact of delivered convection volume on mortality end points.