High-volume online haemodiafiltration improves erythropoiesis-stimulating agent (ESA) resistance in comparison with low-flux bicarbonate dialysis: results of the REDERT study.

BACKGROUND: In haemodialysis (HD) patients, anaemia is associated with reduced survival. Despite treatment with erythropoiesis-stimulating agents (ESAs), a large number of patients with chronic kidney disease show resistance to this therapy and require much higher than usual doses of ESAs in order to maintain the recommended haemoglobin (Hb) target, and recent studies suggest that hepcidin (HEP) may mediate the ESA resistance index (ERI). High-volume online haemodiafiltration (HV-OL-HDF) has been shown to improve anaemia and to reduce the need for ESAs in HD patients; this effect is associated with a reduced inflammatory state in these patients. The aim of the REDERT study (role of haemodiafiltration on ERI) was to investigate the effect of different dialysis techniques on ERI and HEP levels in chronic dialysis patients. METHODS: A single cross-over, randomized, multicentre study (A-B or B-A) was designed. Forty stable HD patients from seven different dialysis units (male 65%, mean age 67.6 ± 14.7 years and mean dialytic age 48 ± 10 months) were enrolled. Patients were randomized to the standard bicarbonate dialysis (BHD) with low-flux polysulfone (PS) membrane group or to the HV-OL-HDF group with high-flux PS membranes and exchange volume of >20 L/session. After 6 months, patients were shifted to the other dialytic group for a further 6 months. Clinical data, Hb, ESA doses and iron metabolism were recorded every month. HEP, beta2-microglobulin (b2MG) and C-reactive protein (CRP) were determined every 3 months, and ERI was calculated monthly as the weekly ESA dose per kilogram of body weight divided by Hb level. Data were analysed using paired-samples t-test, Wilcoxon signed-rank test and Spearman's correlation coefficient. RESULTS: Dialysis efficiency for small molecules assessed as Kt/V was significantly increased in HV-OL-HDF from 1.47 ± 0.24 to 1.49 ± 0.16; P < 0.01. A significant reduction of b2MG was obtained in HV-OL-HDF from month 3 whereas CRP values were not significantly changed during the study period either in BHD or HV-OL-HDF.ERI was significantly reduced in HV-OL-HDF at month 3 and 6 (from 9.1 ± 6.4 UI/weekly/Kg/Hb to 6.7 ± 5.3 UI/weekly/Kg/Hb; P < 0.05) due to a higher ESA consumption in BHD in spite of similar Hb levels. HEP levels were reduced in HV-OL-HDF with respect to BHD after 3 and 6 months. Iron consumption was not significantly different during BHD or HV-OL-HDF treatment as well as transferrin, ferritin and TSAT levels. A significant positive linear correlation between HEP and ERI (r(2) = 0.258, P < 0.001) was observed. CONCLUSIONS: In a uraemic patient population with low-grade inflammation treated with HV-OL-HDF, we observed a significant reduction of ERI values as well as HEP levels. The positive correlation between these two parameters supports a role for HEP in the development of ERI in the dialytic population. Moreover, the lower b2MG and the higher Kt/V achieved in HV-OL-HDF confirms the better depurative effect of this technique in comparison with BHD with respect to middle molecules and small-molecular-weight molecules.

Post-dilution on line haemodiafiltration with citrate dialysate: first clinical experience in chronic dialysis patients.

BACKGROUND: Citrate has anticoagulative properties and favorable effects on inflammation, but it has the potential hazards of inducing hypocalcemia. Bicarbonate dialysate (BHD) replacing citrate for acetate is now used in chronic haemodialysis but has never been tested in postdilution online haemodiafiltration (OL-HDF). METHODS: Thirteen chronic stable dialysis patients were enrolled in a pilot, short-term study. Patients underwent one week (3 dialysis sessions) of BHD with 0.8 mmol/L citrate dialysate, followed by one week of postdilution high volume OL-HDF with standard bicarbonate dialysate, and one week of high volume OL-HDF with 0.8 mmol/L citrate dialysate. RESULTS: In citrate OL-HDF pretreatment plasma levels of C-reactive protein and ß 2-microglobulin were significantly reduced; intra-treatment plasma acetate levels increased in the former technique and decreased in the latter. During both citrate techniques (OL-HDF and HD) ionized calcium levels remained stable within the normal range. CONCLUSIONS: Should our promising results be confirmed in a long-term study on a wider population, then OL-HDF with citrate dialysate may represent a further step in improving dialysis biocompatibility.

Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study.

BACKGROUND: Resistance to erythropoiesis-stimulating agents (ESAs) is often associated with chronic inflammation. Here, we investigated how anaemia, ESA resistance and the plasma levels of biological markers of inflammation could influence all-cause and cardiovascular disease morbidity and mortality. METHODS: Seven hundred and fifty-three haemodialysis (HD) patients (mean age 66 ± 14.2 years, mean dialytic age 70 ± 77 months and diabetes 18.8%) were enrolled and followed-up for 36 months. Demographic, clinical and laboratory data, co-morbidity conditions, administered drugs, all-cause mortality and fatal/non-fatal cardiovascular (CV) events were recorded. We measured ESA resistance index, C-reactive protein (CRP) and interleukin-6 (IL-6). RESULTS: Six hundred and fifty-one patients (86.4%) received ESAs. Patients with haemoglobin level <11 g/dL (n = 225) showed increased risk of CV [relative risk (RR) 1.415, 95% confidence interval (CI) 1.046-1.914] and overall mortality (RR 1.897, 95% CI 1.423-2.530) versus patients with haemoglobin levels >11 g/dL. ESA resistance values categorized into quartiles (Quartile I <5.6, Quartile II 5.7-9.6, Quartile III 9.7-15.4 and Quartile IV >15.4) correlated with all-cause mortality and fatal/non-fatal CV events (RR 1.97, 95% CI 1.392-2.786; RR 1.619, 95% CI 1.123-2.332, respectively). Furthermore, albumin was significantly reduced versus reference patients and correlated with all-cause mortality and CV events; CRP levels were higher in hyporesponders (Quartile IV) (P < 0.001) and predicted all-cause mortality and CV events. IL-6 but not CRP was a strong predictor of ESA resistance. CONCLUSIONS: ESA responsiveness can be considered a strong prognostic factor in HD patients and seems to be tightly related to protein-energy wasting and inflammation.

Soluble CD40 ligand is predictive of combined cardiovascular morbidity and mortality in patients on haemodialysis at a relatively short-term follow-up.

BACKGROUND: We tested the hypothesis that soluble CD40 ligand (sCD40L), a biomarker of proatherogenic inflammation, may be predictive of cardiovascular (CV) events in a subgroup of patients from the RISCAVID study, an observational and prospective study in patients on haemodialysis (HD). METHODS: Plasma sCD40L levels were assessed at the time of the enrollment in 300 HD patients (mean age: 65 ± 15 years), recruited in five different centres. During a follow-up of 24 months, overall mortality, CV mortality and CV major nonfatal events (acute myocardial infarction, congestive heart failure and stroke) were registered. Cox proportional hazards regression assessed adjusted differences in CV morbidity and mortality risk. RESULTS: Stratifying patients according to plasma sCD40L levels in those with levels lower or equal to (sCD40L-) and greater than (sCD40L+) the median value of 7.6 ng/mL, no significant difference was observed at baseline between the two groups in age, gender, blood pressure values and previous CV events. At 24-month follow-up, a significant (P < 0.01) lower incidence of the combined end point of CV morbidity and mortality was observed in the sCD40L- group (29%) as compared to the sCD40L+ group (36%). In the multivariate Cox proportional hazards regression model, the presence of sCD40L above the median value is associated with a significant increase in the risk of CV morbidity and mortality (hazard ratio: 1.61, 95% confidence interval 1.03-3.11). CONCLUSIONS: These observational results support the prognostic value of sCD40L in end-stage renal disease, thus providing a useful tool to better stratify CV prognosis in these patients.

A vitamin E-coated polysulfone membrane reduces serum levels of inflammatory markers and resistance to erythropoietin-stimulating agents in hemodialysis patients: results of a randomized cross-over multicenter trial.

BACKGROUND: Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anemia. Vitamin E is a fat-soluble antioxidant that plays a central role in reducing lipid peroxidation and inhibiting the generation of reactive oxygen species. The aim of this cross-over randomized study was to compare the effects of a vitamin E-coated polysulfone (Vit E PS) membrane and a non-vitamin E-coated polysulfone (PS) membrane on inflammatory markers and resistance to erythropoietin-stimulating agents (ESAs). METHODS: After a 1-month run-in period of standard bicarbonate dialysis with a synthetic membrane, 62 patients of both genders, and older than 18 years, dialysis vintage 48 ± 27 months, BMI 22 ± 3 (from 13 different dialysis units) were randomized (A-B or B-A) in a cross-over design to Vit E PS (treatment A) and to PS (treatment B) both for 6 months. C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations were determined by a sandwich enzyme immunoassay at baseline and every 2 months; red blood cell count, ESA dose and ESA resistance index (ERI) were assessed monthly. RESULTS: Hemoglobin (Hb) levels significantly increased in the Vit E PS group from 11.1 ± 0.6 g/dl at baseline to 11.5 ± 0.7 at 6 months (p < 0.001) and remained unchanged in the PS group. Although ESA dosage remained stable during the observation periods in both groups, ERI was significantly reduced in the Vit E PS group from 10.3 ± 2.2 IU-dl/kg/g Hb week at baseline to 9.2 ± 1.7 at 6 months (p < 0.001). No significant variation of ERI was observed in the PS group. A significant reduction in plasma CRP and IL-6 levels was observed in the Vit E PS group: CRP from 6.7 ± 4.8 to 4.8 ± 2.2 mg/l (p < 0.001) and IL-6 from 12.1 ± 1.4 to 7.5 ± 0.4 pg/ml (p < 0.05). In the PS group, CRP varied from 6.2 ± 4.0 to 6.4 ± 3.7, and IL-6 from 10.6 ± 2.1 to 9.6 ± 3.5 (p = n.s.). CONCLUSIONS: Treatment with Vit E PS membranes seems to lead to a reduction in ESA dosage in HD patients; in addition, a low chronic inflammatory response may contribute to a sparing effect on exogenous ESA requirements.

Impact of calcium, phosphate, PTH abnormalities and management on mortality in hemodialysis: results from the RISCAVID study.

BACKGROUND: Despite substantial progress in medical care, the mortality rate remains unacceptably high in dialysis patients. Evidence suggests that bone mineral dismetabolism (CKD-MBD) might contribute to this burden of death. However, to date only a few papers have investigated the clinical relevance of serum mineral derangements and the impact of different therapeutic strategies on mortality in a homogeneous cohort of south European dialysis patients. METHODS: The RISCAVID study was a prospective, observational study in which all patients receiving hemodialysis (HD) in the north-western region of Toscany in June 2004 were enrolled (N=757) and followed up for 24 months. RESULTS: At study entry, only 71 (9%) patients of the entire study cohort exhibited an optimal control of serum phosphorous (Pi), calcium (Ca), calciumX-phosphorous product (CAXPi) and intact parathyroidhormone (iPTH) according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical guidelines. Despite a similar prevalence, the severity of CKD-MBD appeared different to the results reported in the USA. Interestingly, none of the serum biomarkers or number of serum biomarkers within KDOQI targets was independently associated with all-cause and cardiovascular (CV) mortality. Among treatments, Sevelamer was the only drug independently associated with lower all-cause and cardiovascular mortality (p<0.001). CONCLUSION: The RISCAVID study highlights the difficulty of controlling bone mineral metabolism in HD patients and lends support to the hypothesis that a carefully chosen phosphate binder might impact survival in HD patients.

Estimate of body water compartments and of body composition in maintenance hemodialysis patients: comparison of single and multifrequency bioimpedance analysis.

OBJECTIVE: The goal of this study was to compare the adequacy of single and multifrequency bioimpedance analysis (BIA) to evaluate body water compartments, body composition, and nutritional status in maintenance hemodialysis patients. DESIGN: Cross-sectional study. SETTING: University-based hemodialysis unit. PATIENTS: Nineteen patients (12 male, 7 female), ages 28 to 82 years (mean, 58.9), treated with maintenance hemodialysis (MHD) for 0.5 to 15 years (mean, 7.3). INTERVENTION: This was a noninterventional study. Patients gave their informed consent to the diagnostic procedures performed. MAIN OUTCOME MEASURES: Total body water (TBW), extracellular water (ECW), fat-free mass (FFM), and body cell mass (BCM) volumes were estimated with single-frequency (sf BIA) and multifrequency (mf BIA) plethysmographs before and after a midweek dialytic session. Predialysis TBW also was estimated from anthropometric data (e TBW). Serum albumin, prealbumin and myoglobin, and creatinine index were determined as indicators of nutritional status and muscle mass. RESULTS: Sf BIA and mf BIA gave very similar results for TBW volumes. A high linear correlation was also found between e TBW values and both sf TBW and mf TBW; however, a statistically significant difference was found between e TBW and sf and mf TBW. Sf BIA and mf BIA gave quite different results for ECW, particularly when measured predialysis. The results obtained for FFM indicate a poor agreement between sf and mf BIA. The agreement was better when FFM was measured postdialysis. The values of BCM, either measured predialysis or postdialysis, indicate a significant difference between sf and mf BIA. FFM and BCM estimated with mf BIA had a closer correlation with creatinine index than sf BIA. mf BCM had also a higher correlation with serum myoglobin, which is produced by muscle cells. CONCLUSIONS: TBW can be estimated with enough confidence from either sf or mf BIA at any time. On the contrary, the results of ECW are significantly different with sf and mf BIA when measured predialysis. Thus, it seems more convenient to perform BIA after dialysis, in particular when assessing the "ideal" body weight. The measurements of FFM and BCM, obtained with either sf or mf BIA, are correlated with different indicators of nutritional status. In particular, mf BCM seems more appropriate than sf BCM for estimating muscle mass.