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Abstract Background Haemodialysis results in a left ventricular hypertrophic response. It is unclear whether tight blood pressure control or particular medications might attenuate this response. We sought to determine, in a pre-dialysis cohort on atenolol, whether Losartan might attenuate left ventricular hypertrophy post arteriovenous fistula creation in end stage kidney disease. Materials and methods Placebo controlled double blind randomisation of 26 patients to fixed dose atenolol plus fixed dose losartan or placebo occurred 1 day prior to fistula creation. Pre-randomisation echocardiography was repeated at 1 week and 1-month. Measurement was undertaken of blood pressure, heart rate, brain natriuretic peptide, serum creatinine and estimated glomerular filtration rate. The primary pre-specified endpoint was the change in left ventricular mass at 1 month. Non-parametric statistical comparison was performed within and between groups. Results There was no difference in left ventricular mass between our groups 1-month post fistula creation. In the entire cohort, change in left ventricular mass was driven by changes in blood pressure and volume loading. Blood pressure changes correlated with left ventricular mass changes seen shortly post arteriovenous fistula creation, suggesting blood pressure control during this time period may be an important part of the management of end stage kidney disease. Conclusions We did not see an advantage with the use of losartan with respect to diminution of the LVM response. However, our demonstrated change in LVM was relatively small compared to previous literature and suggests a possible role for beta blockade as a neurohormonal modulator around the time of arteriovenous fistula creation. Trial registration Clinical trials.gov (NCT00602004).

Abstract Background The main hypothesis of this study is that Oxpentifylline administration will effectively treat erythropoietin- or darbepoietin-resistant anaemia in chronic kidney disease patients. Methods/design Inclusion criteria are adult patients with stage 4 or 5 chronic kidney disease (including dialysis patients) with significant anaemia (haemoglobin ≤ 110 g/L) for at least 3 months for which there is no clear identifiable cause and that is unresponsive to large doses of either erythropoietin (≥ 200 IU/kg/week) or darbepoetin (≥ 1 μg/kg/week). Patients will be randomized 1:1 to receive either placebo (1 tablet daily) or oxpentifylline (400 mg daily) per os for a period of 4 months. During this 4 month study period, haemoglobin measurements will be performed monthly. The primary outcome measure will be the difference in haemoglobin level between the 2 groups at the end of the 4 month study period, adjusted for baseline values. Secondary outcome measures will include erythropoiesis stimulating agent dosage, Key's index (erythropoiesis stimulating agent dosage divided by haemoglobin concentration), and blood transfusion requirement. Discussion This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their chronic kidney disease patients determine whether oxpentifylline represents a safe and effective strategy for treating erythropoiesis stimulating agent resistance in chronic kidney disease. Trial Registration Australian New Zealand Clinical Trials Registry Number ACTRN12608000199314.

Objectives: To develop a population pharmacokinetic (PK) model for vancomycin in adults receiving high-flux haemodialysis (HFHD) in an effort to optimize vancomycin dosing in this population.Methods: A population PK model using NONMEM was developed using retrospective data collected from 48 vancomycin courses administered to patients (n = 37) receiving HFHD. Fixed-dose [1.5 g loading dose (LD), 1 g maintenance dose (MD)], literature-adapted weight-based (WBL; 20 mg/kg LD, 10 mg/kg MD) and hospital-adapted weight-based (WBH; 25-30 mg/kg LD, 20-25 mg/kg MD) dosage regimens were then simulated using the Monte Carlo method. The PTA was an AUC24/MIC ≥400 with success being a PTA ≥90%.Results: The data were best described using a two-compartment model. It was observed that fixed-dose and WBL dosage regimens resulted in a PTA ≤90% for most days. The WBH dosing achieved a PTA ≥90% on most days, but there were supratherapeutic concentrations with repeated dosing of vancomycin. If HFHD was delayed by 48-72 h after the LD, the PTA would fall below 90%. A dose-optimized regimen was developed: 30 mg/kg LD and 10 mg/kg MD given on HFHD days. An additional dose of 500 mg or 1 g was administered 24 h after the LD if HFHD occurred 48-72 h post-LD. This dose-optimized regimen afforded a PTA ≥90% on all days of therapy and achieved clinically acceptable pre-haemodialysis concentrations.Conclusions: Current vancomycin dosage regimens used clinically do not achieve a PTA ≥90% for most days of therapy for people receiving HFHD. A dose-optimized regimen was developed, which could be implemented in clinical practice. [ABSTRACT FROM AUTHOR]

Background/Aims: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. Methods: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. Results: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman's rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. Conclusions: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo. [ABSTRACT FROM AUTHOR]

Background Pentoxifylline has been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the Handling Erythropoietin Resistance with Oxpentifylline multicentre double-blind, randomized controlled trial. The present sub-study evaluated the effects of pentoxifylline on the iron-regulatory hormone hepcidin in patients with ESA-hyporesponsive CKD. Methods This sub-study included 13 patients in the pentoxifylline arm (400 mg daily) and 13 in the matched placebo arm. Hepcidin-25 was measured by ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry following isolation from patient serum. Serum hepcidin-25, serum iron biomarkers, haemoglobin and ESA dosage were compared within and between the two groups. Results Hepcidin-25 concentration at 4 months adjusted for baseline did not differ significantly in pentoxifylline versus placebo treated patients (adjusted mean difference (MD) −7.9 nmol, P = 0.114), although the difference between the groups mean translated into a >25% reduction of circulating hepcidin-25 due to pentoxifylline compared with the placebo baseline. In paired analysis, serum hepcidin-25 levels were significantly decreased at 4 months compared with baseline in the pentoxifylline group (−5.47 ± 2.27 nmol/l, P < 0.05) but not in the placebo group (2.82 ± 4.29 nmol/l, P = 0.24). Pentoxifylline did not significantly alter serum ferritin (MD 55.4 mcg/l), transferrin saturation (MD 4.04%), the dosage of ESA (MD −9.93 U/kg per week) or haemoglobin concentration (MD 5.75 g/l). Conclusion The reduction of circulating hepcidin-25 due to pentoxifylline did not reach statistical significance; however, the magnitude of the difference suggests that pentoxifylline may be a clinically and biologically meaningful modulator of hepcidin-25 in dialysis of patients with ESA-hyporesponsive anaemia. [ABSTRACT FROM AUTHOR]

Objective: Pentoxifylline has previously been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the HERO multi-centre double-blind, randomized controlled trial. The present study evaluated the effects of pentoxifylline on oxidative stress in ESA-hyporesponsive CKD patients. Methods: This sub-study of the HERO trial compared 15 patients in the pentoxifylline arm (400 mg daily) and 17 in the matched placebo arm on oxidative stress markers: plasma total F2-isoprostanes, protein carbonyls, glutathione peroxidase (GPX), and superoxide dismutase (SOD) activities. Results: Pentoxifylline did not significantly alter total F2-isoprostanes (adjusted mean difference (MD) 35.01 pg/ml,P = 0.11), SOD activity (MD 0.82 U/ml,P = 0.07), GPX activity (MD −6.06 U/l,P = 0.09), or protein carbonyls (MD −0.04 nmol/mg,P = 0.52). Replicating results from the main study, pentoxifylline significantly increased haemoglobin concentration compared with controls (MD 7.2 g/l,P = 0.04). Conclusions: Pentoxifylline did not alter oxidative stress biomarkers, suggesting that alternative mechanisms may be responsible for the agent's ability to augment haemoglobin levels in CKD patients with ESA-hyporesponsive anaemia. [ABSTRACT FROM AUTHOR]

Background: Phosphate binders' constituents have alkalotic or acidotic properties and may contribute to acid base balance in haemodialysis patients. This study aimed to investigate the differential effects of phosphate binders on pre-dialysis serum bicarbonate in End Stage Kidney Disease patients on maintenance haemodialysis. Methods: Stable out-patients having satellite haemodialysis for at least 3 months were retrospectively studied for 18 months, excluding those with other medical causes for metabolic acidosis. Blood results were censored for inpatient episodes, at the time of death, renal transplant or dialysis modality change. Multivariable multilevel mixedeffects linear regression was used and five groups of phosphate binders were compared: Group A(Calcium (Ca) and/or Aluminium (Al) binders); B(Sevelamer hydrochloride (SH) alone); C(lanthanum carbonate (LC) alone); D(SH and Ca/Al), E(LC and Ca/Al). Results: Of 320 patients, 292 were eligible for analysis with a mean follow-up of 15.54 (standard deviation, SD 3.98) months. Similar mean pre-dialysis serum levels of bicarbonate were observed at all 6 month-interval analyses. At 18th months, observed mean serum bicarbonate levels in mmol/L were Group B: 21.58 (SD 2.82, P<0.001), C: 23.29 (SD 2.80, P=0.02), D: 21.56 (SD 3.00, P<0.001), and E: 21.29 (SD 3.62, P=0.92) compared with Group A: 22.98 (SD 2.77). Mean serum bicarbonate was related to total SH dose in mmol/L: 22.34 (SD 2.56) for SH <2.5 g/day, 21.61 (SD 2.62) for SH 2.5-4.8 g/day, 21.04 (SD 3.31) for SH >4.8 g/day compared with 22.85 (SD 2.91) for non-users; P-trend<0.001. Conclusions: Phosphate binders' constituents may contribute to/protect against a predisposition to pre-dialysis metabolic acidosis. This may be dose dependant in patients taking Sevelamer Hydrochloride. [ABSTRACT FROM AUTHOR]

A response by Gavin Becker and colleagues to a letter to the editor about their article "Phosphate Levels--Time for a Rethink?" in a 2009 issue is presented.