Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Vorhersagbarkeit und Beurteilung der aquatischen Toxizitaet von Stoffgemischen - Binaere Kombinationen von unaehnlich wirkenden Substanzen unter Bedingungen akuter und chronischer Exposition

Die Belastungssituation in Gewaessern ist durch eine Exposition aquatischer Organismen gegenueber einer Vielzahl von Substanzen gekennzeichnet. Da die Zahl moeglicher Stoffkombinationen unuebersehbar ist, wird im Rahmen der Riskikoabschaetzung die Toxizitaet von Gemischen auf Grundlage der Einzelstoffoxizitaeten abgeschaetzt. In diesem Vorhaben wurde die Toxizitaet binaerer Gemische unaehnlich wirkender Substanzen im akuten und chronischen Daphnientest untersucht. Auf der Basis der ermittelten Konzentrations-Wirkungsbeziehungen der Einzelstoffe wurde die Toxizitaet der Gemische nach den Konzepten Konzentrations-Additivitaet und Unabhaengige Wirkung prognostiziert und mit den experimentell ermittelten Mischungstoxitaeten verglichen. Die akute und chronische Toxizitaet der untersuchten binaeren Gemische wurde von beiden Konzepten gut vorhergesagt. Unter akuter Exposition unterschieden sich die Vorhersagen beider Konzepte hinsichtlich Genauigkeit nicht. Im chronischen Daphnientest erbrachte jedoch das Konzept der Unabhaengigen Wirkung eine bessere Vorhersagegenauigkeit. Die vorliegende Studie hat gezeigt, dass der Effekt binaerer Mischungen unaehnlich wirkender Substanzen unter akuter und chronischer Exposition auf Daphnia magna meist groesser ist als der Effekt der jeweilig wirksamsten Einzelsubstanz und durch beide Konzepte angemessen vorhersagbar ist. Daher sollten Kombinationswirkungen unter Vorsorgegesichtspunkten in umweltpolitischen Regelungen zum Schutz aquatischer Systeme beruecksichtigt werden. (orig.)Aquatic organisms in surface waters are exposed towards a multitude of chemical substances. As the number of possible combinations is incalculable, the prediction of mixture toxicities bases on the toxicities of the single components. In this study the toxicity of binary mixtures of dissimilarly acting chemicals under acute and long-term exposure on Daphnia magna was investigated. The mixture toxicity predicted by the concepts Concentration Addition and Independent Action bases on the toxicities of the individual components. Experimental data were compared with both concepts. The observed toxicities under acute and long-term exposure were in good agreement with the predicted toxicity by both concepts. Under long-term exposure the predictive accuracy of Independent Action was higher. This study shows, that almost all toxicities of binary mixtures of dissimilarly acting chemicals under acute and long-term exposure on Daphnia magna was higher than the toxicity of the most effective single component. The mixture toxicities predicted by both concepts were in good agreement to the observed toxicities. For establishing environmental standards mixture toxicities should be taken into account for the future. (orig.)Available from TIB Hannover: F98B1952+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Bestimmung der Schadwirkung von Stoffkombinationen mit mehreren Schadstoffkomponenten im Vergleich aquatischer Bioteste

In tests with luminous bacteria, algae and daphnes as representatives of different trophic stages, the combination effect of heavy metals (Cd, Cr) and organic pollutants (p-chloroaniline, 1,2,3-trichlorobenzene, Na_3-NTA) in aquatic ecosystems is exemplarily tested with subsequent comparison of the results with models of the combination effect. The author differentiates between the principles of action ''similar joint action'' = ''concentration addition'', ''independent action'' = ''response addition'' and ''synergistic action'' and employs mathematical models juxtaposing a ''simple similar action'', and ''independent action'' to a ''complex similar action'' and ''dependent action'', respectively, as well as the ''toxic unit model'', which translates the concentration of a substance into the corresponding toxicological efficacy. Most, but not all of the investigated binary mixtures of substances exhibited additive effects, but some of the combination effects depended on the proportions in the mixture. Further combination effects found were less-than-additive, more-than-additive (Cd/Cr) and antagonistic ones. (uWA)In Tests mit Leuchtbakterien, Algen und Daphnen als Repraesentanten verschiedener trophischer Stufen wird die Kombinationswirkung von Schwermentallen (Cd,Cr) und organischen Schadstoffen (p-Chloranilin, 1,2,3-Trichlorbenzol, Na_3-NTA) in aquatischen Oekosystemen exemplarisch getestet und die Ergebnisse mit Modellen der Kombinationswirkung verglichen. Dabei unterscheidet die Autorin zwischen den Wirkprinzipien ''similar joint action'' = ''concentration addition'', ''independent addition'' = ''response addition'' und ''synergistic action'' sowie mathematische Modelle, die eine ''simple similr action'' bzw. ''independent action'' einer ''complex similar action'' bzw. ''dependent action'' gegenueberstellen und das ''Toxic Unit''-Modell, das die Konzentration eines Stoffes in die entsprechende toxikologische Wirksamkeit umsetzt. Die meisten, aber nicht alle der untersuchten binaeren Stoffgemische verhielten sich additiv, jedoch waren einige Kombinationswirkungen abhaengig von den Proportionen im Gemisch. Es traten auch geringere als additive, mehr als additive (Cd/Cr) und antagonistische Kombinationswirkungen auf. (UWA)Available from TIB Hannover: RN 8908(89-127) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman

Interlaboratory comparison of a standardized toxicity test using the nematode Caenorhabditis elegans (ISO 10872)

Höss S, Ahlf W, Bergtold M, et al. Interlaboratory comparison of a standardized toxicity test using the nematode Caenorhabditis elegans (ISO 10872). Environmental Toxicology and Chemistry. 2012;31(7):1525-1535

Screening and risk management solutions for steroidal estrogens in surface and wastewater

Background: The European Commission Implementing Decision EU 2015/495 included three steroidal estrogens, namely 17α-ethinyl estradiol, 17β-estradiol, and estrone, in the so-called “watch list” of the EU Water Framework Directive (WFD). The monitoring of these compounds is difficult because the detection limits of the majority of the available analytical methods cannot achieve the very low target concentrations required to meet proposed environmental quality criteria. In 2014, a combined Science-Policy Interface/Chemical Monitoring of Emerging Pollutants project was launched to meet this monitoring challenge. The project involved 24 research organizations and environmental agencies from 12 different countries. Methods: Sixteen surface water (SW) and 17 wastewater (WW) samples were collected across Europe and analysed using five in vitro effect-based and three chemical analytical methods. A general description of the project and data evaluation is provided by Könemann and colleagues in the companion publication 2018. In our study, we compared bioanalytical and chemical analytical results with regard to their application for aquatic status assessment. Therefore we considered the potential to predict population-relevant risks for aquatic organisms and the specificity and sensitivity of the various methods used in both approaches. Finally, we tested and discussed the applicability and relevance of previously suggested effect-based trigger values (EBT). Results and discussion: Results of the risk assessment based on chemical analytical data correlated highly with estrogenic activities (expressed as 17β-estradiol equivalents (EEQ) determined using effect-based methods), demonstrating the ability of the bioassays to predict the mixture risk caused by steroidal estrogens. For about 15% of SW and 40% of WW samples detection limits of chemical-analytical methods were too high to allow a status assessment, while detection limits of all effect-based methods were below proposed EBT. This demonstrates that effect-based methods are suitable for status assessment of surface waters. The in vitro effect-based methods were quite specific for steroidal estrogens and highly sensitive, meaning they have a low probability to detect false positive or negative results. After testing of three alternative EBT proposals, we concluded to use preliminary 400 pg/L EEQ as screening EBT corresponding to the AA-EQS of E2. Further test specific refinements in the application of this value are not excluded. Conclusions: We conclude that water quality assessment can progress from a purely analytical approach to effect-based monitoring, from single substance to known and unknown mixture assessment and from in vitro screening to population-relevant risk assessment. Despite a few limitations, effect-based in vitro methods are recommendable for monitoring steroidal estrogens under the WFD because they, a) are able to sensitively quantify the activity of steroidal estrogens in all surface and wastewater samples, b) are able to detect the combined effect of estrogen mixtures including unknown chemicals with estrogen receptor activating properties, c) allow an ecotoxicological status assessment using EBT to calculate risk quotients. This approach is similar to the risk ratio used in regulatory environmental risk assessments, but allows for an integrated mixture assessment. Outlook: The results of this study support the introduction of a holistic approach for the regulation of chemicals in the aquatic environment under the EU WFD, as proposed recently by EU Water Directors. An ecotoxicological status assessment for one of the most relevant modes of action of endocrine disruption will allow authorities responsible for water quality assessment to focus available monitoring resources and to improve the ecological status of EU waterbodies

Knowledge Sharing in a Coopetition Project Team: An Institutional Logics Perspective

Cooperation between firms is often addressed from the perspective of relationship organizing; however, we know little about people’s working-level engagement in collective action during interfirm projects. Focusing on cooperation between rival firms (coopetition), this paper explores how knowledge can be shared among participants. We conduct a case study of a joint-project team composed of staff from rival firms. Using the principles of grounded theory, we identify four distinct modes of knowledge sharing. By interpreting these modes in terms of temporalities and influential social structures, we develop an understanding of how individual engagement promotes knowledge sharing in an inter-firm coopetitive project. The study reexamines emerging orientations (cooperation and competition) according to institutional logics (market, corporation, and community) and temporalities. It also offers insight into the management of inter-organizational projects that are viewed as temporary organizations