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

Implementing core outcomes in kidney disease: report of the Standardized Outcomes in Nephrology (SONG) implementation workshop

There are an estimated 14,000 randomized trials published in chronic kidney disease. The most frequently reported outcomes are biochemical endpoints, rather than clinical and patient-reported outcomes including cardiovascular disease, mortality, and quality of life. While many trials have focused on optimizing kidney health, the heterogeneity and uncertain relevance of outcomes reported across trials may limit their policy and practice impact. The international Standardized Outcomes in Nephrology (SONG) Initiative was formed to identify core outcomes that are critically important to patients and health professionals, to be reported consistently across trials. We convened a SONG Implementation Workshop to discuss the implementation of core outcomes. Eighty-two patients/caregivers and health professionals participated in plenary and breakout discussions. In this report, we summarize the findings of the workshop in two main themes: socializing the concept of core outcomes, and demonstrating feasibility and usability. We outline implementation strategies and pathways to be established through partnership with stakeholders, which may bolster acceptance and reporting of core outcomes in trials, and encourage their use by end-users such as guideline producers and policymakers to help improve patient-important outcomes

Habitat Preferences, and Population Structure and Stability, in an Eastern Hellbender Population in the West Branch of the Susquehanna River

We collected habitat and population data over two field seasons (2012 and 2014) for an eastern hellbender (Cryptobranchus alleganiensis) population in a tributary of the West Branch of the Susquehanna River. Analyses of population data show that the population has been stable across the sample years, with no significant change in linear density. Analyses of habitat use show that hellbenders take up residency in or near the thalweg, where the majority of cover rocks are located. Peripheral cover rocks are only rarely used by hellbenders. We found a positive relationship between the size (total body length) of hellbenders and the size (length) of the cover rock. Population size/age structure and sex ratios were similar between the two sample years. During the second field season (2014), we observed American eels (Anguilla rostrata) beneath cover rocks, but in no case did we find eels and hellbenders beneath the same cover rock. We observed no eels in the study area in 2012. Recent eel introductions in the watershed likely explain the sudden appearance of eels in the study reach. The precipitous co-occurrence of eels and hellbenders raises the concern that eels may compete with hellbenders for rock cover and for a limited food resource that consists mainly of Allegheny crayfish (Orconectes obscurus). Significant competition for food and cover, and eel predation on hellbender eggs, larvae and juveniles, could potentially initiate a decline in an otherwise stable hellbender population

Use of Artificial Nest Boxes to Facilitate Egg Collection for an Eastern Hellbender Head-Starting Program

Population declines have been taking place throughout the entire geographic range of the eastern hellbender (Cryptobranchus alleganiensis) in North America. The declines and local extinctions have led to multiple head-starting programs to augment or restore hellbender populations. Once widespread throughout the Susquehanna River basin, the eastern hellbender is now restricted to several tributaries of the West Branch watershed. In order to establish a head-starting program for the Susquehanna River basin, we are collecting fertilized eggs to be transported to zoological facilities that are prepared to raise larval and juvenile hellbenders until they are of a size where they are unlikely to be subject to predation (3-5 years of age). To facilitate the collection of fertilized eggs, we installed 17 artificial nest boxes in the late summer of 2014. The boxes are distributed across three stream reaches occupied by hellbenders and within a single tributary of the West Branch watershed. The boxes are made of concrete and weigh 27 kg. By mid-September, no adult hellbenders had taken up residence in, nor had nested within, the concrete boxes. We now believe that the nest boxes should have been installed several months in advance of the nesting season so that adult hellbenders would have had more opportunities to find the boxes and take up residence. We plan to leave the boxes in place until the next nesting season, but will modify the boxes to darken the chamber, making it more suitable for permanent residency and egg deposition. In lieu of collecting eggs from the artificial nest chambers, we are currently searching for natural nests from which we hope to collect eggs to be transported to the head-start facility

The changes in maximal oxygen uptake (V̊O2MAX) induced by physical exertion during an Antarctic expedition depend on the initial V̊O2MAX of the individuals: a case study of the Brazilian expedition

Antarctic climate is challenging, since the cold, wind and sensory monotony are stressful stimuli to individuals. Moreover, camp activities and heavy clothes may contribute to increase physiological strain. Thus, we aimed to characterise the physiological demand of a 24-day period in the Antarctic field and then to evaluate the effect of this expedition on the aerobic fitness in individuals with heterogeneous initial aerobic fitness (as determined by estimating maximum oxygen consumption – V̊O2MAX). Before and after the 24-day period in Antarctica, 7 researchers and 2 mountaineers were subjected to incremental tests to estimate their V̊O2MAX. Field effort was characterised by measuring heart rate (HR). During the field trips, their HR remained 33.4% of the recording time between 50–60% HRMAX, 22.3% between 60–70% HRMAX, and only 1.4% between 80 and 90% HRMAX. The changes in estimated V̊O2MAX during the expedition depended on the pre-expedition aerobic fitness. The post-expedition V̊O2MAX increased by 5.9% and decreased by 14.3%in individuals with lower (researchers) and higher (mountaineers) initial V̊O2MAX, respectively. We concluded that physical effort in the Antarctic field is characterised as predominantly of low- to moderate-intensity. This effort represented an effective training load for individuals with lower initial V̊O2MAX, but not for those with higher V̊O2MAX

Perceptual responses during the 10 km self-paced run.

The following perceptual variables were measured under temperate (25°C) and hot (35°C) conditions: rating of perceived exertion (RPE; panel A) and thermal sensation (panel B). Data are expressed as means ± SD. # indicates a significant difference compared to the control trial at 25°C (main effect of ambient temperature), p < 0.05.</p

Timeline of the experimental trials.

Environmental heat stress impairs endurance performance by enhancing exercise-induced physiological and perceptual responses. However, the time course of these responses during self-paced running, particularly when comparing hot and temperate conditions, still needs further clarification. Moreover, monitoring fatigue induced by exercise is paramount to prescribing training and recovery adequately, but investigations on the effects of a hot environment on post-exercise neuromuscular fatigue are scarce. This study compared the time course of physiological and perceptual responses during a 10 km self-paced treadmill run (as fast as possible) between temperate (25°C) and hot (35°C) conditions. We also investigated the changes in countermovement jump (CMJ) performance following exercise in these two ambient temperatures. Thirteen recreational long-distance runners (11 men and 2 women), inhabitants of a tropical region, completed the two experimental trials in a randomized order. Compared to 25°C, participants had transiently higher body core temperature (TCORE) and consistently greater perceived exertion while running at 35°C (p p p CORE caused by environmental heat stress, post-exercise neuromuscular fatigue is similar between temperate and hot conditions. This finding suggests that the higher external load (faster speed) at 25°C compensates for the effects of more significant perceptual responses at 35°C in inducing neuromuscular fatigue.</div