Ercan Ok

Mortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results from the Turkish OL-HDF Study

BACKGROUND Online haemodiafiltration (OL-HDF) is considered to confer clinical benefits over haemodialysis (HD) in terms of solute removal in patients undergoing maintenance HD. The aim of this study was to compare postdilution OL-HDF and high-flux HD in terms of morbidity and mortality. METHODS In this prospective, randomized, controlled trial, we enrolled 782 patients undergoing thrice-weekly HD and randomly assigned them in a 1:1 ratio to either postdilution OL-HDF or high-flux HD. The mean age of patients was 56.5 ± 13.9 years, time on HD 57.9 ± 44.6 months with a diabetes incidence of 34.7%. The follow-up period was 2 years, with the mean follow-up of 22.7 ± 10.9 months. The primary outcome was a composite of death from any cause and nonfatal cardiovascular events. The major secondary outcomes were cardiovascular and overall mortality, intradialytic complications, hospitalization rate, changes in several laboratory parameters and medications used. RESULTS The filtration volume in OL-HDF was 17.2 ± 1.3 L. Primary outcome was not different between the groups (event-free survival of 77.6% in OL-HDF versus 74.8% in the high-flux group, P = 0.28), as well as cardiovascular and overall survival, hospitalization rate and number of hypotensive episodes. In a post hoc analysis, the subgroup of OL-HDF patients treated with a median substitution volume >17.4 L per session (high-efficiency OL-HDF, n = 195) had better cardiovascular (P = 0.002) and overall survival (P = 0.03) compared with the high-flux HD group. In adjusted Cox-regression analysis, treatment with high-efficiency OL-HDF was associated with a 46% risk reduction for overall mortality {RR = 0.54 [95% confidence interval (95% CI) 0.31-0.93], P = 0.02} and a 71% risk reduction for cardiovascular mortality [RR = 0.29 (95% CI 0.12-0.65), P = 0.003] compared with high-flux HD. CONCLUSIONS The composite of all-cause mortality and nonfatal cardiovascular event rate was not different in the OL-HDF and in the high-flux HD groups. In a post hoc analysis, OL-HDF treatment with substitution volumes over 17.4 L was associated with better cardiovascular and overall survival.

Effect of Fluid Management Guided by Bioimpedance Spectroscopy on Cardiovascular Parameters in Hemodialysis Patients: A Randomized Controlled Trial

BACKGROUND Fluid overload is the main determinant of hypertension and left ventricular hypertrophy in hemodialysis patients. However, assessment of fluid overload can be difficult in clinical practice. We investigated whether objective measurement of fluid overload with bioimpedance spectroscopy is helpful in optimizing fluid status. STUDY DESIGN Prospective, randomized, and controlled study. SETTING & PARTICIPANTS 156 hemodialysis patients from 2 centers were randomly assigned to 2 groups. INTERVENTION Dry weight was assessed by routine clinical practice and fluid overload was assessed by bioimpedance spectroscopy in both groups. In the intervention group (n = 78), fluid overload information was provided to treating physicians and used to adjust fluid removal during dialysis. In the control group (n = 78), fluid overload information was not provided to treating physicians and fluid removal during dialysis was adjusted according to usual clinical practice. OUTCOMES The primary outcome was regression of left ventricular mass index during a 1-year follow-up. Improvement in blood pressure and left atrial volume were the main secondary outcomes. Changes in arterial stiffness parameters were additional outcomes. MEASUREMENTS Fluid overload was assessed twice monthly in the intervention group and every 3 months in the control group before the mid- or end-week hemodialysis session. Echocardiography, 48-hour ambulatory blood pressure measurement, and pulse wave analysis were performed at baseline and 12 months. RESULTS Baseline fluid overload parameters in the intervention and control groups were 1.45 ± 1.11 (SD) and 1.44 ± 1.12 L, respectively (P = 0.7). Time-averaged fluid overload values significantly decreased in the intervention group (mean difference, -0.5 ± 0.8 L), but not in the control group (mean difference, 0.1 ± 1.2 L), and the mean difference between groups was -0.5 L (95% CI, -0.8 to -0.2; P = 0.001). Left ventricular mass index regressed from 131 ± 36 to 116 ± 29 g/m(2) (P < 0.001) in the intervention group, but not in the control group (121 ± 35 to 120 ± 30 g/m(2); P = 0.9); mean difference between groups was -10.2 g/m(2) (95% CI, -19.2 to -1.17 g/m(2); P = 0.04). In addition, values for left atrial volume index, blood pressure, and arterial stiffness parameters decreased in the intervention group, but not in the control group. LIMITATIONS Ambulatory blood pressure data were not available for all patients. CONCLUSIONS Assessment of fluid overload with bioimpedance spectroscopy provides better management of fluid status, leading to regression of left ventricular mass index, decrease in blood pressure, and improvement in arterial stiffness.

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.

Magnesium reduces calcification in bovine vascular smooth muscle cells in a dose-dependent manner

Background. Vascular calcification (VC), mainly due to elevated phosphate levels, is one major problem in patients suffering from chronic kidney disease. In clinical studies, an inverse relationship between serum magnesium and VC has been reported. However, there is only few information about the influence of magnesium on calcification on a cellular level available. Therefore, we investigated the effect of magnesium on calcification induced by β-glycerophosphate (BGP) in bovine vascular smooth muscle cells (BVSMCs). Methods. BVSMCs were incubated with calcification media for 14 days while simultaneously increasing the magnesium concentration. Calcium deposition, transdifferentiation of cells and apoptosis were measured applying quantification of calcium, von Kossa and Alizarin red staining, real-time reverse transcription–polymerase chain reaction and annexin V staining, respectively. Results. Calcium deposition in the cells dramatically increased with addition of BGP and could be mostly prevented by co-incubation with magnesium. Higher magnesium levels led to inhibition of BGP-induced alkaline phosphatase activity as well as to a decreased expression of genes associated with the process of transdifferentiation of BVSMCs into osteoblast-like cells. Furthermore, estimated calcium entry into the cells decreased with increasing magnesium concentrations in the media. In addition, higher magnesium concentrations prevented cell damage (apoptosis) induced by BGP as well as progression of already established calcification. Conclusions. Higher magnesium levels prevented BVSMC calcification, inhibited expression of osteogenic proteins, apoptosis and further progression of already established calcification. Thus, magnesium is influencing molecular processes associated with VC and may have the potential to play a role for VC also in clinical situations.

Comparison of 4- and 8-h dialysis sessions in thrice-weekly in-centre haemodialysis A prospective, case-controlled study

BACKGROUND Longer dialysis sessions may improve outcome in haemodialysis (HD) patients. We compared the clinical and laboratory outcomes of 8- and 4-h thrice-weekly HD. METHODS Two-hundred and forty-seven HD patients who agreed to participate in a thrice-weekly 8-h in-centre nocturnal HD (NHD) treatment and 247 age-, sex-, diabetes status- and HD duration-matched control cases to 4-h conventional HD (CHD) were enrolled in this prospective controlled study. Echocardiography and psychometric measurements were performed at baseline and at the 12th month. The primary outcome was 1-year overall mortality. RESULTS Overall mortality rates were 1.77 (NHD) and 6.23 (CHD) per 100 patient-years (P = 0.01) during a mean 11.3 ± 4.7 months of follow-up. NHD treatment was associated with a 72% risk reduction for overall mortality compared to the CHD treatment (hazard ratio = 0.28, 95% confidence interval 0.09-0.85, P = 0.02). Hospitalization rate was lower in the NHD arm. Post-HD body weight and serum albumin levels increased in the NHD group. Use of antihypertensive medications and erythropoietin declined in the NHD group. In the NHD group, left atrium and left ventricular end-diastolic diameters decreased and left ventricular mass index regressed. Both use of phosphate binders and serum phosphate level decreased in the NHD group. Cognitive functions improved in the NHD group, and quality of life scores deteriorated in the CHD group. CONCLUSIONS Eight-hour thrice-weekly in-centre NHD provides morbidity and possibly mortality benefits compared to conventional 4-h HD.

Relations between malnutrition–inflammation–atherosclerosis and volume status. The usefulness of bioimpedance analysis in peritoneal dialysis patients

BACKGROUND Chronic fluid overload (FO) is frequently present in peritoneal dialysis (PD) patients and is associated with hypertension and left ventricular hypertrophy and dysfunction, which are important predictors of death in dialysis patients. In the present study, we investigated the relationship between nutrition, inflammation, atherosclerosis and body fluid volumes measured by multi-frequency bioimpedance analysis (m-BIA) in PD patients. In addition, we analysed the relationship of extracellular volume values by m-BIA to echocardiographic parameters in order to define its usefulness as a measure of FO. METHODS Ninety-five prevalent PD patients (mean age 50 ± 13 years, 10 of them diabetic) were enrolled. Extracellular water (ECW), total body water (TBW), dry lean mass (DLM) and phase angle (PA) were measured by m-BIA. Volume status was determined by measuring left atrium diameter (LAD) and left ventricular end-diastolic diameter (LVEDD). Measurement of carotid artery intima-media thickness (CA-IMT) was used to assess the presence of subclinical atherosclerosis. Serum albumin was used as a nutritional marker, and serum C-reactive protein (CRP) was used as an inflammatory marker. RESULTS Mean ECW/height was 10.0 ± 1.0 L/m for whole group and 9.3 ± 0.6 L/m in patients with normal clinical hydration parameters. In correlation analysis, markers of nutrition, inflammation and atherosclerosis correlated well with m-BIA parameters. When we used echographically measured LAD (> 40 mm) or LVEDD (> 55 mm) as a confirmatory parameter, a cut-off value of 10.48 L/m ECW/height (78% specificity, with a sensitivity of 77% for LAD and 72% specificity, with a sensitivity of 70% for LVEDD) was found in ROC analysis for the diagnosis of FO. Patients with FO were older and had higher systolic blood pressure, cardiothoracic index, serum CRP level and mean CA-IMT than patients without FO. Patients with inflammation had higher CA-IMT values. In multivariate analysis, only two factors-low urine output and ECW/height-were independently associated with the presence of inflammation. CONCLUSIONS FO defined by m-BIA is significantly correlated with markers of malnutrition, inflammation and atherosclerosis in PD patients. The indices obtained from m-BIA, especially ECW/height, correlated well with volume overload as assessed by echocardiography and might be a measure worth testing in a properly designed clinical study.

Carbamylated Low-Density Lipoprotein Induces Monocyte Adhesion to Endothelial Cells Through Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1

Objective—Carbamylated low-density lipoprotein (LDL), the most abundant modified LDL isoform in human blood, has been recently implicated in causing the atherosclerosis-prone injuries to endothelial cells in vitro and atherosclerosis in humans. This study was aimed at testing the hypothesis that carbamylated LDL acts via inducing monocyte adhesion to endothelial cells and determining the adhesion molecules responsible for the recruitment of monocytes. Methods and Results—Exposure of human coronary artery endothelial cells with carbamylated LDL but not native LDL caused U937 monocyte adhesion and the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 adhesion molecules as measured by cell enzyme-linked immunosorbent assay. Silencing of intercellular adhesion molecule-1 by siRNA or its inhibition using neutralizing antibody resulted in decreased monocyte adhesion to the endothelial cells. Similar silencing or neutralizing of vascular cell adhesion molecule-1 alone did not have an effect but was shown to contribute to intercellular adhesion molecule-1 when tested simultaneously. Conclusions—Taken together, these data provide evidence that intercellular adhesion molecule-1 in cooperation with vascular cell adhesion molecule-1 are essential for monocyte adhesion by carbamylated low-density lipoprotein-activated human vascular endothelial cells in vitro.

CRYPTOSPORIDIOSIS AND BLASTOCYSTOSIS IN RENAL TRANSPLANT RECIPIENTS

Some intestinal parasitic infections are frequently seen in renal transplant recipients. Parasites such as Cryptosporidium spp. and Blastocystis hominis are often asymptomatic or responsible for limited infections in normals, but may cause prolonged and heavy infections with gastrointestinal complaints, mainly diarrhea, in immunocompromised patients. Such infections can often not be detected by routine diagnostic procedures, but special concentration and staining methods are needed. We investigated 115 fecal specimens from 69 renal transplant recipients and 42 fecal specimens from 42 control cases. Of the 69 recipients, 27 (39.1%) had B. hominis and 13 (18.8%) had Cryptosporidium spp. in at least one fecal specimen. Prevalence of symptomatic Cryptosporidium infections was significantly higher in the renal transplant recipients, when compared with the control group (p < 0.05). Special parasitological procedures must be performed in immunocompromised patients with chronic gastrointestinal complaints. Disappearance of symptoms after antiparastic drugs in some of 16 symptomatic patients are described, suggesting that these infections are more pathogenic in transplant recipients.

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.

Endogenous Testosterone and Mortality in Male Hemodialysis Patients: Is It the Result of Aging?

BACKGROUND AND OBJECTIVES Low serum testosterone levels in hemodialysis (HD) patients have recently been associated with cardiovascular risk factors and increased mortality. To confirm this observation, we investigated the predictive role of serum total testosterone levels on mortality in a large group of male HD patients from Turkey. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS A total of 420 prevalent male HD patients were sampled in March 2005 and followed up for all-cause mortality. Serum total testosterone levels were measured by ELISA at baseline and studied in relation to mortality and cardiovascular risk profile. RESULTS Mean testosterone level was 8.69 ± 4.10 (0.17 to 27.40) nmol/L. A large proportion of patients (66%) had testosterone deficiency (<10 nmol/L). In univariate analysis, serum testosterone levels were positively correlated with creatinine and inversely correlated with age, body mass index, and lipid parameters. During an average follow-up of 32 months, 104 (24.8%) patients died. The overall survival rate was significantly lower in patients within the low testosterone tertile (<6.8 nmol/L) compared with those within the high tertile (>10.1 nmol/L; 64 versus 81%; P = 0.004). A 1-nmol/L increase in serum testosterone level was associated with a 7% decrease in overall mortality (hazard ratio 0.93; 95% confidence interval 0.89 to 0.98; P = 0.01); however, this association was dependent on age and other risk factors in adjusted Cox regression analyses. CONCLUSIONS Testosterone deficiency is common in male HD patients. Although testosterone levels, per se, predicted mortality in this population, this association was largely dependent on age.