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

Improved electrical-properties of Silicon dioxide films for MOS gate dielectrics grown in an inductively coupled RF plasma

The effects of growth conditions on properties of silicon dioxide grown in oxygen/argon plasma are described. An inductively coupled r.f. plasma anodization system was designed in which various experimental parameters could be varied and monitored. Its design is described first and then we examine the effects of some experimental conditions on the electrical properties of MOS capacitors fabricated with the plasma oxides. A qualitative model of the growth mechanism of SiO2 in oxygen plasma has been described. The data obtained in this investigation in addition to our work reported earlier on dependence of electrical properties on the anodization current density and the gas pressure in the plasma, is helpful in optimizing the growth conditions to produce device grade oxide films

GROWTH-KINETICS OF SILICON DIOXIDE ON SILICON IN AN INDUCTIVELY COUPLED RF PLASMA AT CONSTANT ANODIZATION CURRENTS

The kinetics of plasma oxidation of silicon at constant anodization current have been investigated. Oxidation was performed in an inductively coupled rf plasma anodization setup. The oxidation model is based on the assumption that the oxidant from the plasma is neutral atomic oxygen which captures an electron inside the oxide and forms a negative oxygen ion (O-). The O- ion then hops through interstitial sites in the oxide due to the high drift field during the anodization. A photon-assisted oxidation mechanism is assumed to occur at the SiO2/Si interface in which the energy to break Si-Si bonds at the interface is supplied by UV photons which are generated in the plasma. Based on these assumptions an analytical model was developed that successfully explains the dependence of oxidation rate on the gas pressure in the plasma, which was not explained by previous investigators. It has been shown that during constant current anodization, the space-charge effects inside the oxide are negligible. It was found that the oxidation rate shows a weak temperature dependence with a thermal activation energy of 0.04 eV. The data on oxide thickness versus the oxidation time were found to be in good agreement with the theory

ELECTRICAL-PROPERTIES OF SILICON DIOXIDE FILMS GROWN BY INDUCTIVELY COUPLED RF PLASMA ANODIZATION

The effect of growth conditions on the electrical properties of silicon dioxide grown in oxygen/argon plasma at 500-degrees-C are described. The two process parameters whose effects were studied in detail were: gas pressure in plasma and anodization current density. MOS capacitors were fabricated with these oxides. These were subjected to a post oxidation anneal at 800-degrees-C for 20 min and a post-metallization anneal at 450-degrees-C for 30 min. Measurements on these capacitors indicated that the growth parameters have a marked effect on the density of interface states, fixed oxide charge and the electron trap density in plasma oxides. A qualitative model based on the mechanism of plasma oxidation is presented which explains the dependence of oxide properties over process conditions. Measurements on the thickness of oxides grown at various distances from the plasma have also been presented. It has been pointed out that our oxidation data are not in agreement with various growth kinetics models existing in literature. Hence, a suitable mechanism of plasma oxidation is required which must explain the dependence of electrical properties of plasma oxides on growth parameters