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

Modifications de la cinétique contractile dans la dystrophie musculaire de Duchenne

Séance des 5 et 6 décembre 1967.info:eu-repo/semantics/publishe

Disorder of muscle contraction processes in sex-linked (Duchenne) muscular dystrophy, with correlative electromyographic study of myopathic involvement in small hand muscles

The aim of this investigation is to develop the pathophysiologic analysis of the contractile disorder in muscular dystrophy. The adductor pollicis muscle was investigated by needle electromyography and by nerve stimulation methods in six normal boys serving as controls, and in seventeen hands of fifteen patients with Duchenne muscular dystrophy. Being involved later than proximal muscles by the disease, the small hand muscles allowed us to study a whole spectrum of changes, from the preclinical stage to advanced myogenic atrophy. The anomalies of the voluntary motor unit potentials disclosed by needle electromyography bear a unique relation to the disturbances of contractile processes in the same muscle. These combined features consistently reflect the peculiar dynamics of disease in the hand muscles but they cannot be predicted in any given patient from the over-all clinical data (age, gait disturbances, level of enzymes creatine phosphokinase and lactic dehydrogenase in blood, etc.).In the course of Duchenne dystrophy the disorder of contraction in the adductor pollicis muscle antedates any recordable anomaly in the electrical activity of the same muscle. Several changes indicate that the capability for tension development is decreased with respect to that of the muscle of normal boys of similar age: reduction of tetanic force (Po), of twitch force (Pt) and of the maximum rate of tension development in tetanus (Ro) and in twitch (Rt). Consistent changes are recorded in the staircase profiles of the isometric twitch during two per second stimulation of the motor nerve. They point to an anomaly in the process of activation of the myofilaments. The contraction kinetics are not grossly damaged by Duchenne dystrophy. The contraction time (CT) of the twitch does not appear to change significantly, which suggests that the myosin of the still excitable dystrophic muscle fibers has a normal ATPase activity. The maximum speed of relaxation per kg. St:Pt, is reduced from 10 to 6.5 in the patients. The relaxation time (T1/2R) is increased by +23 per cent. However, both the relaxation time and speed change to approximate normal values during two per second stimulation. The paper provides a quantitative reference base for correlative biochemical, pathophysiologic and electron microscopic studies of the still unknown etiology of this disorder.info:eu-repo/semantics/publishe

Individual sun exposure can be assessed using meteorological satellite measurements

International audienceThe work compares measurements of UVA and UVB exposure of children recorded with personal dosimeters with assessment through a detailed questionnaire and satellite measurements. Satellite measurements give a good estimate of individual UVA and UVB exposure, independently of exposure conditions and could be used to estimate actual exposure