Muriel P.C. Grooteman

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.

Protein-Energy Nutritional Status and Kidney Disease-specific Quality of Life in Hemodialysis Patients

OBJECTIVE Health-related quality of life (HRQOL) is an important outcome in dialysis care. Previous research has related protein-energy nutritional status to generic HRQOL domains, but it is still not clear as to how it relates to HRQOL domains that are unique to hemodialysis patients. Therefore, our aim was to study the relation between protein-energy nutritional status and kidney disease-specific HRQOL domains in hemodialysis patients. DESIGN This was a cross-sectional study. SETTING This study was performed at multiple centers. PATIENTS OR OTHER PARTICIPANTS We evaluated the first 590 hemodialysis patients who had enrolled in the Convective Transport Study. DETERMINANTS We measured protein-energy nutritional status by using the Subjective Global Assessment, albumin, normalized nitrogen appearance, creatinine, body mass index, and cholesterol. MAIN OUTCOME MEASURE HRQOL was assessed by using the Kidney Disease Quality Of Life-Short Form. RESULTS In all, 83% of the cohort was found to be well-nourished on the basis of the Subjective Global Assessment. Multiple nutritional parameters were positively related to the physical summary of generic HRQOL and to the following kidney disease-specific HRQOL scales: the effects of the kidney disease on daily life, the burden of the kidney disease, and overall health. CONCLUSIONS This study showed that, even in predominantly well-nourished hemodialysis patients, protein-energy nutritional status was significantly related to kidney disease-specific HRQOL.

Effect of Hemodiafiltration on Mortality, Inflammation and Quality of Life

Online hemodiafiltration may improve clinical outcome in end-stage kidney disease. The supposed mechanism is the improved clearance of uremic toxins by the convective transport which is added to the standard diffusive transport. This review summarizes the effects of hemodiafiltration on mortality, inflammation and health-related quality of life.

Should We Still Focus That Much on Cardiovascular Mortality in End Stage Renal Disease Patients? The CONvective TRAnsport STudy

Background We studied the distribution of causes of death in the CONTRAST cohort and compared the proportion of cardiovascular deaths with other populations to answer the question whether cardiovascular mortality is still the principal cause of death in end stage renal disease. In addition, we compared patients who died from the three most common death causes. Finally, we aimed to study factors related to dialysis withdrawal. Methods We used data from CONTRAST, a randomized controlled trial in 714 chronic hemodialysis patients comparing the effects of online hemodiafiltration versus low-flux hemodialysis. Causes of death were adjudicated. The distribution of causes of death was compared to that of the Dutch dialysis registry and of the Dutch general population. Results In CONTRAST, 231 patients died on treatment. 32% died from cardiovascular disease, 22% due to infection and 23% because of dialysis withdrawal. These proportions were similar to those in the Dutch dialysis registry and the proportional cardiovascular mortality was similar to that of the Dutch general population. cardiovascular death was more common in patients <60 years. Patients who withdrew were older, had more co-morbidity and a lower mental quality of life at baseline. Patients who withdrew had much co-morbidity. 46% died within 5 days after the last dialysis session. Conclusions Although the absolute risk of death is much higher, the proportion of cardiovascular deaths in a prevalent end stage renal disease population is similar to that of the general population. In older hemodialysis patients cardiovascular and non-cardiovascular death risk are equally important. Particularly the registration of dialysis withdrawal deserves attention. These findings may be partly limited to the Dutch population.

The Effect of Online Hemodiafiltration on Infections: Results from the CONvective TRAnsport STudy

Background 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. Patients and Methods 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. Results 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). Conclusions HDF as compared to HD did not result in a reduced risk of infections, larger studies are needed to confirm our findings. Trial Registration ClinicalTrials.gov NCT00205556

Is there clear evidence that middle molecule removal is important in renal replacement therapies

ples to measure plasma sodium, reducing the actual plasma sodium concentration, which tends to cancel out the Gibbs-Donnan effect and the difference in plasma and dialysate water content [19,20]. Even though direct ionometry in undiluted samples is used for plasma sodium measurements in clinical practice, these results are adjusted and reported as values obtained in diluted samples to avoid clinical misinterpretation [21]. In conclusion, predialysis plasma sodium is stable over time and is an individual characteristic ofHDpatients. It can be used as a reference for dialysate sodium prescription andmaybe amarker of a population at risk.