Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Effect of centre- and patient-related factors on uptake of haemodiafiltration in Australia and New Zealand: a cohort study using ANZDATA

Background: The use of haemodiafiltration (HDF) for the management of patients with end-stage kidney failure is increasing worldwide. Factors associated with HDF use have not been studied and may vary in different countries and jurisdictions. The aim of this study was to document the pattern of increase and variability in uptake of HDF in Australia and New Zealand, and to describe patient- and centre-related factors associated with its use. Methods: Using the Australian and New Zealand Dialysis and Transplant Registry, all incident patients commencing haemodialysis (HD) between 2000 and 2014 were included. The primary outcome was HDF commencement over time, which was evaluated using multivariable logistic regression stratified by country. Results: Of 27 433 patients starting HD, 3339 (14.4%) of 23 194 patients in Australia and 810 (19.1%) of 4239 in New Zealand received HDF. HDF uptake increased over time in both countries but was more rapid in New Zealand than Australia. In Australia, HDF use was more likely in males (odds ratio (OR) 1.13, 95% confidence interval (CI) = 1.03–1.24, P = 0.009) and less likely with older age (reference 70 years OR = 0.48; 95% CI = 0.41–0.56); higher body mass index (body mass index (BMI) 30 kg/m OR = 1.46; 95% CI = 1.33–1.61), chronic lung disease (OR = 0.84; 95% CI = 0.76–0.94; P < 0.001), cerebrovascular disease (OR = 0.76; 95% CI = 0.67–0.85; P < 0.001) and peripheral vascular disease (OR = 0.77; 95% CI = 0.70–0.85; P < 0.001). No association was identified with race. In New Zealand, HDF use was more likely in Maori and Pacific Islanders (OR = 1.32; 95% CI = 1.05–1.66) and Asians (OR = 1.75; 95% CI = 1.15–2.68) compared to Caucasians, and less likely in males (OR = 0.76; 95% CI = 0.62–0.94; P = 0.01). No association was identified with BMI or co-morbidities. In both countries, centres with a higher ratio of HD to peritoneal dialysis (PD) were more likely to prescribe HDF. Larger Australian centres were more likely to prescribe HDF (36–147 new patients/year OR = 26.75, 95% CI = 18.54–38.59; 17–35/year OR = 7.51, 95% CI = 5.35–10.55; 7–16/year OR = 3.00; 95% CI = 2.19–4.13; ≤6/year reference). Conclusion: Haemodiafiltration uptake is increasing, variable and associated with both patient and centre characteristics. Centre characteristics not explicitly captured elsewhere explained 36% of variability in HDF uptake in Australia and 48% in New Zealand

Patient survival on haemodiafiltration and haemodialysis: a cohort study using the Australia and New Zealand dialysis and transplant registry

Background: It is unclear if haemodiafiltration improves patient survival compared with standard haemodialysis. Observational studies have tended to show benefit with haemodiafiltration, while meta-analyses have not provided definitive proof of superiority. Methods: Using data from the Australia and New Zealand Dialysis and Transplant Registry, this binational inception cohort study compared all adult patients who commenced haemodialysis in Australia and New Zealand between 2000 and 2014. The primary outcome was all-cause mortality. Cardiovascular mortality was the secondary outcome. Outcomes were measured from the first haemodialysis treatment and were examined using multivariable Cox regression analyses. Patients were censored at permanent discontinuation of haemodialysis or at 31 December 2014. Analyses were stratified by country. Results: The study included 26 961 patients (4110 haemodiafiltration, 22 851 standard haemodialysis; 22 774 Australia, 4187 New Zealand) with a median follow-up of 5.31 (interquartile range 2.87-8.36) years. Median age was 62 years, 61% were male, 71% were Caucasian. Compared with standard haemodialysis, haemodiafiltration was associated with a significantly lower risk of all-cause mortality [adjusted hazard ratio (HR) for Australia 0.79, 95% confidence interval (95% CI) 0.72-0.87; adjusted HR for New Zealand 0.88, 95% CI 0.78-1.00]. In Australian patients, there was also an association between haemodiafiltration and reduced cardiovascular mortality (adjusted HR 0.78, 95% CI 0.64-0.95). Conclusion: Haemodiafiltration was associated with superior survival across patient subgroups of age, sex and comorbidity

Rationale and design of the Sodium Lowering In Dialysate (SoLID) trial: a randomised controlled trial of low versus standard dialysate sodium concentration during hemodialysis for regression of left ventricular mass

BACKGROUND: The current literature recognises that left ventricular hypertrophy makes a key contribution to the high rate of premature cardiovascular mortality in dialysis patients. Determining how we might intervene to ameliorate left ventricular hypertrophy in dialysis populations has become a research priority. Reducing sodium exposure through lower dialysate sodium may be a promising intervention in this regard. However there is clinical equipoise around this intervention because the benefit has not yet been demonstrated in a robust prospective clinical trial, and several observational studies have suggested sodium lowering interventions may be deleterious in some dialysis patients. METHODS/DESIGN: The Sodium Lowering in Dialysate (SoLID) study is funded by the Health Research Council of New Zealand. It is a multi-centre, prospective, randomised, single-blind (outcomes assessor), controlled parallel assignment 3-year clinical trial. The SoLID study is designed to study what impact low dialysate sodium has upon cardiovascular risk in dialysis patients. The study intends to enrol 118 home hemodialysis patients from 6 sites in New Zealand over 24 months and follow up each participant over 12 months. Key exclusion criteria are: patients who dialyse more frequently than 3.5 times per week, pre-dialysis serum sodium of <135 mM, and maintenance hemodiafiltration. In addition, some medical conditions, treatments or participation in other dialysis trials, which contraindicate the SoLID study intervention or confound its effects, will be exclusion criteria. The intervention and control groups will be dialysed using dialysate sodium 135 mM and 140 mM respectively, for 12 months. The primary outcome measure is left ventricular mass index, as measured by cardiac magnetic resonance imaging, after 12 months of intervention. Eleven or more secondary outcomes will be studied in an attempt to better understand the physiologic and clinical mechanisms by which lower dialysate sodium alters the primary end point. DISCUSSION: The SoLID study is designed to clarify the effect of low dialysate sodium upon the cardiovascular outcomes of dialysis patients. The study results will provide much needed information about the efficacy of a cost effective, economically sustainable solution to a condition which is curtailing the lives of so many dialysis patients. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry number: ACTRN1261100097599