Claire H. den Hoedt

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.

Hepcidin-25 is related to cardiovascular events in chronic haemodialysis patients

BACKGROUND The development of atherosclerosis may be enhanced by iron accumulation in macrophages. Hepcidin-25 is a key regulator of iron homeostasis, which downregulates the cellular iron exporter ferroportin. In haemodialysis (HD) patients, hepcidin-25 levels are increased. Therefore, it is conceivable that hepcidin-25 is associated with all-cause mortality and/or fatal and non-fatal cardiovascular (CV) events in this patient group. The aim of the current analysis was to study the relationship between hepcidin-25 and all-cause mortality and both fatal and non-fatal CV events in chronic HD patients. METHODS Data from 405 chronic HD patients included in the CONvective TRAnsport STudy (NCT00205556) were studied (62% men, age 63.7 ± 13.9 years [mean ± SD]). The median (range) follow-up was 3.0 (0.8-6.6) years. Hepcidin-25 was measured with mass spectrometry. The relationship between hepcidin-25 and all-cause mortality or fatal and non-fatal CV events was investigated with multivariate Cox proportional hazard models. RESULTS Median (interquartile range) hepcidin-25 level was 13.8 (6.6-22.5) nmol/L. During follow-up, 158 (39%) patients died from any cause and 131 (32%) had a CV event. Hepcidin-25 was associated with all-cause mortality in an unadjusted model [hazard ratio (HR) 1.14 per 10 nmol/L, 95% CI 1.03-1.26; P = 0.01], but not after adjustment for all confounders including high-sensitive C-reactive protein (HR 1.02 per 10 nmol/L, 95% CI 0.87-1.20; P = 0.80). At the same time, hepcidin-25 was significantly related to fatal and non-fatal CV events in a fully adjusted model (HR 1.24 per 10 nmol/L, 95% CI 1.05-1.46, P = 0.01). CONCLUSION Hepcidin-25 was associated with fatal and non-fatal CV events, even after adjustment for inflammation. Furthermore, inflammation appears to be a significant confounder in the relation between hepcidin-25 and all-cause mortality. These findings suggest that hepcidin-25 might be a novel determinant of CV disease in chronic HD patients.

Online hemodiafiltration reduces systemic inflammation compared to low-flux hemodialysis

Online hemodiafiltration may diminish inflammatory activity through amelioration of the uremic milieu. However, impurities in water quality might provoke inflammatory responses. We therefore compared the long-term effect of low-flux hemodialysis to hemodiafiltration on the systemic inflammatory activity in a randomized controlled trial. High-sensitivity C-reactive protein and interleukin-6 were measured for up to 3 years in 405 patients of the CONvective TRAnsport STudy, and albumin was measured at baseline and every 3 months in 714 patients during the entire follow-up. Differences in the rate of change over time of C-reactive protein, interleukin-6, and albumin were compared between the two treatment arms. C-reactive protein and interleukin-6 concentrations increased in patients treated with hemodialysis, and remained stable in patients treated with hemodiafiltration. There was a statistically significant difference in rate of change between the groups after adjustments for baseline variables (C-reactive protein difference 20%/year and interleukin-6 difference 16%/year). The difference was more pronounced in anuric patients. Serum albumin decreased significantly in both treatment arms, with no difference between the groups. Thus, long-term hemodiafiltration with ultrapure dialysate seems to reduce inflammatory activity over time compared to hemodialysis, but does not affect the rate of change in albumin.

Hepcidin-25 in Chronic Hemodialysis Patients Is Related to Residual Kidney Function and Not to Treatment with Erythropoiesis Stimulating Agents

Hepcidin-25, the bioactive form of hepcidin, is a key regulator of iron homeostasis as it induces internalization and degradation of ferroportin, a cellular iron exporter on enterocytes, macrophages and hepatocytes. Hepcidin levels are increased in chronic hemodialysis (HD) patients, but as of yet, limited information on factors associated with hepcidin-25 in these patients is available. In the current cross-sectional study, potential patient-, laboratory- and treatment-related determinants of serum hepcidin-20 and -25, were assessed in a large cohort of stable, prevalent HD patients. Baseline data from 405 patients (62% male; age 63.7±13.9 [mean SD]) enrolled in the CONvective TRAnsport STudy (CONTRAST; NCT00205556) were studied. Predialysis hepcidin concentrations were measured centrally with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patient-, laboratory- and treatment related characteristics were entered in a backward multivariable linear regression model. Hepcidin-25 levels were independently and positively associated with ferritin (p<0.001), hsCRP (p<0.001) and the presence of diabetes (p = 0.02) and inversely with the estimated glomerular filtration rate (p = 0.01), absolute reticulocyte count (p = 0.02) and soluble transferrin receptor (p<0.001). Men had lower hepcidin-25 levels as compared to women (p = 0.03). Hepcidin-25 was not associated with the maintenance dose of erythropoiesis stimulating agents (ESA) or iron therapy. In conclusion, in the currently studied cohort of chronic HD patients, hepcidin-25 was a marker for iron stores and erythropoiesis and was associated with inflammation. Furthermore, hepcidin-25 levels were influenced by residual kidney function. Hepcidin-25 did not reflect ESA or iron dose in chronic stable HD patients on maintenance therapy. These results suggest that hepcidin is involved in the pathophysiological pathway of renal anemia and iron availability in these patients, but challenges its function as a clinical parameter for ESA resistance.

Effect of Hemodiafiltration on Quality of Life over Time

BACKGROUND AND OBJECTIVES It is unclear if hemodiafiltration leads to a better quality of life compared with hemodialysis. It was, therefore, the aim of this study to assess the effect of hemodiafiltration on quality of life compared with hemodialysis in patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study analyzed the data of 714 patients with a median follow-up of 2 years from the Convective Transport Study. The patients were enrolled between June of 2004 and December of 2009. The Convective Transport Study is a randomized controlled trial on the effect of online hemodiafiltration versus low-flux hemodialysis on all-cause mortality. Quality of life was assessed with the Kidney Disease Quality of Life-Short Form. This questionnaire provides data for a physical and mental composite score and describes kidney disease-specific quality of life in 12 domains. The domains have scales from 0 to 100. RESULTS There were no significant differences in changes in health-related quality of life over time between patients treated with hemodialysis (n=358) or hemodiafiltration (n=356). The quality of life domain patient satisfaction declined over time in both dialysis modalities (hemodialysis: -2.5/yr, -3.4 to -1.5, P<0.001; hemodiafiltration: -1.4/yr, -2.4 to -0.5, P=0.004). CONCLUSIONS Compared with hemodialysis, hemodiafiltration had no significant effect on quality of life over time.

Clinical Predictors of Decline in Nutritional Parameters over Time in ESRD

BACKGROUND AND OBJECTIVES Inflammation and malnutrition are important features in patients with ESRD; however, data on changes in these parameters over time are scarce. This study aimed to gain insight into changes over time in serum albumin, body mass index, high-sensitivity C-reactive protein, and IL-6 in patients with ESRD and aimed to identify clinical risk factors for deterioration of these parameters. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data were analyzed from the Convective Transport Study, a randomized controlled trial conducted from June 2004 to January 2011, in which 714 patients with chronic ESRD were randomized to either online hemodiafiltration or low-flux hemodialysis. Albumin and body mass index were measured up to 6 years and predialysis C-reactive protein and IL-6 were measured up to 3 years in a subset of 405 participants. Rates of change in these parameters over time were estimated across strata of predefined risk factors with linear mixed-effects models. RESULTS Albumin and body mass index decreased and C-reactive protein and IL-6 increased over time. For every incremental year of age at baseline, the yearly excess decline in albumin was 0.003 g/dl (-0.004 to -0.002; P<0.001) and the excess decline in body mass index was 0.02 kg/m(2) per year (-0.02 to -0.01; P<0.001). In patients with diabetes mellitus, there was a yearly excess decline of 0.05 g/dl in albumin (-0.09 to -0.02; P=0.002). Compared with women, men had an excess decline of 0.03 g/dl per year in albumin (-0.06 to -0.001; P=0.05) and an excess increase of 11.6% per year in IL-6 (0.63%-23.6%; P=0.04). CONCLUSIONS Despite guideline-based care, all inflammatory and nutritional parameters worsened over time. The deterioration of some of these parameters was more pronounced in men, older patients, and patients with diabetes mellitus. Special focus on the nutritional status of at-risk patients by individualizing medical care might improve their prognosis.

The cost–utility of haemodiafiltration versus haemodialysis in the Convective Transport Study

BACKGROUND Despite the growing interest in haemodiafiltration (HDF), there is no information on the costs and cost-utility of this dialysis modality yet. It was therefore our objective to study the cost-utility of HDF versus haemodialysis (HD). METHODS A cost-utility analysis was performed using a Markov model. It included data from the Convective Transport Study (CONTRAST), a randomized controlled trial that compared online HDF with low-flux HD. Costs were estimated using a societal perspective. Probabilistic sensitivity analyses were performed to study uncertainty. RESULTS Total annual costs for HDF and HD were €88 622±19,272 and €86,086±15,945, respectively (in 2009 euros). When modelled over a 5-year period, the incremental cost per quality-adjusted life year (QALY) of HDF versus HD was €287,679. Sensitivity analyses revealed that this amount will not fall below €140,000, even under the most favourable assumptions like a high-convection volume (>20.3 L). CONCLUSIONS Based on accepted societal willingness-to-pay thresholds, HDF cannot be considered a cost-effective treatment for patients with end-stage renal disease at present. Apparently, minor additional costs of HDF are not counterbalanced by a relevant QALY gain.

Clinical performance targets and quality of life in hemodialysis patients

Background/Aims: Patients value health-related quality of life (HRQOL) over survival. It was our aim to study the relation between attainment of widely accepted performance targets and HRQOL in hemodialysis patients. Methods: This study included baseline data from 715 hemodialysis patients from 29 dialysis centers. Six clinical performance targets, as recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI), were evaluated: single-pool Kt/V (≧1.2), hemoglobin (11–13 g/dl), vascular access (fistula), phosphorus (2.3–4.5 mg/dl), parathyroid hormone (150–300 pg/ml), and blood pressure (predialysis <140/90 and postdialysis <130/ 80 mm Hg). Results: After correction for case-mix and multiple comparisons, no association was found between the 6 KDOQI clinical performance targets and the 14 HRQOL domains, or between the number of performance targets reached and HRQOL. Conclusion: Attainment with widely accepted clinical performance targets was not related to the HRQOL of hemodialysis patients. Hence, in clinical guidelines, HRQOL should be adopted as an explicit treatment goal for these individuals.

Effect of GFR on Plasma N-Terminal Connective Tissue Growth Factor (CTGF) Concentrations

BACKGROUND Connective tissue growth factor (CTGF) has a key role in the pathogenesis of renal and cardiac fibrosis. Its amino-terminal fragment (N-CTGF), the predominant form of CTGF detected in plasma, has a molecular weight in the middle molecular range (18 kDa). However, it is unknown whether N-CTGF is a uremic retention solute that accumulates in chronic kidney disease (CKD) due to decreased renal clearance and whether it can be removed by hemodiafiltration. STUDY DESIGN 4 observational studies in patients and 2 pharmacokinetic studies in rodents. SETTING & PARTICIPANTS 4 single-center studies. First study (cross-sectional): 88 patients with CKD not receiving kidney replacement therapy. Second study (cross-sectional): 23 patients with end-stage kidney disease undergoing low-flux hemodialysis. Third study: 9 kidney transplant recipients before and 6 months after transplant. Fourth study: 11 low-flux hemodialysis patients and 12 hemodiafiltration patients before and after one dialysis session. PREDICTOR First, second, and third study: (residual) glomerular filtration rate (GFR). Fourth study: dialysis modality. OUTCOMES & MEASUREMENTS Plasma (N-)CTGF concentrations, measured by enzyme-linked immunosorbent assay. RESULTS In patients with CKD, we observed an independent association between plasma CTGF level and estimated GFR (β = -0.72; P < 0.001). In patients with end-stage kidney disease, plasma CTGF level correlated independently with residual kidney function (β = -0.55; P = 0.046). Successful kidney transplant resulted in a decrease in plasma CTGF level (P = 0.008) proportional to the increase in estimated GFR. Plasma CTGF was not removed by low-flux hemodialysis, whereas it was decreased by 68% by a single hemodiafiltration session (P < 0.001). Pharmacokinetic studies in nonuremic rodents confirmed that renal clearance is the major elimination route of N-CTGF. LIMITATIONS Observational studies with limited number of patients. Fourth study: nonrandomized, evaluation of the effect of one session; randomized longitudinal study is warranted. CONCLUSION Plasma (N-)CTGF is eliminated predominantly by the kidney, accumulates in CKD, and is decreased substantially by a single hemodiafiltration session.

Left Ventricular Mass in Dialysis Patients, Determinants and Relation with Outcome. Results from the COnvective TRansport STudy (CONTRAST)

Background and Objectives Left ventricular mass (LVM) is known to be related to overall and cardiovascular mortality in end stage kidney disease (ESKD) patients. The aims of the present study are 1) to determine whether LVM is associated with mortality and various cardiovascular events and 2) to identify determinants of LVM including biomarkers of inflammation and fibrosis. Design, Setting, Participants, & Measurements Analysis was performed with data of 327 ESKD patients, a subset from the CONvective TRAnsport STudy (CONTRAST). Echocardiography was performed at baseline. Cox regression analysis was used to assess the relation of LVM tertiles with clinical events. Multivariable linear regression models were used to identify factors associated with LVM. Results Median age was 65 (IQR: 54–73) years, 203 (61%) were male and median LVM was 227 (IQR: 183–279) grams. The risk of all-cause mortality (hazard ratio (HR) = 1.73, 95% CI: 1.11–2.99), cardiovascular death (HR = 3.66, 95% CI: 1.35–10.05) and sudden death (HR = 13.06; 95% CI: 6.60–107) was increased in the highest tertile (>260grams) of LVM. In the multivariable analysis positive relations with LVM were found for male gender (B = 38.8±10.3), residual renal function (B = 17.9±8.0), phosphate binder therapy (B = 16.9±8.5), and an inverse relation for a previous kidney transplantation (B = −41.1±7.6) and albumin (B = −2.9±1.1). Interleukin-6 (Il-6), high-sensitivity C-reactive protein (hsCRP), hepcidin-25 and connective tissue growth factor (CTGF) were not related to LVM. Conclusion We confirm the relation between a high LVM and outcome and expand the evidence for increased risk of sudden death. No relationship was found between LVM and markers of inflammation and fibrosis. Trial Registration Controlled-Trials.com ISRCTN38365125