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

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Practical synthesis of methyl 7-(3-hydroxy-5-oxocyclopent-1-en-1-yl)-heptanoate

The key intermediate of misoprostol, methyl 7-(3-hydroxy-5-oxocyclopent-1-en-1-yl)-heptanoate was prepared from commercially available suberic acid in 40% yield over five steps. The key step involved a ZnCl2 catalyzed Friedel-Crafts reaction between furan and 2,9-oxonanedione. Sulfuric acid catalyzed methylation of 8-(furan-2-yl)-8-oxooctanoic acid followed by sequential reduction and ZnCl2 catalyzed Piancatelli rearrangement resulted in the formation of the key intermediate of misoprostol

The Feasibility of Maintaining Biological Phosphorus Removal in A-Stage via the Short Sludge Retention Time Approach: System Performance, Functional Genus Abundance, and Methanogenic Potential

The increasing concerns on resource and energy recovery call for the modification of the current wastewater treatment strategy. This study synthetically evaluates the feasibility of the short sludge retention time approach to improve the energy recovery potential, but keeping steady biological phosphorus removal and system stability simultaneously. SBRS-SRT and SBRcontrol that simulated the short sludge retention time and conventional biological phosphorus removal processes, respectively, were set up to treat real domestic sewage for 120 d. SBRS-SRT achieved an efficient COD (91.5 &plusmn; 3.5%), PO43&minus;-P (95.4 &plusmn; 3.8%), and TP (93.5 &plusmn; 3.7%) removal and maintained the settling volume index around 50 mL/gSS when the sludge retention time was 3 d, indicating steady operational stability. The poor ammonia removal performance (15.7 &plusmn; 7.7%) and a few sequences detected in samples collected in SBRS-SRT indicated the washout of nitrifiers. The dominant phosphorus accumulating organisms Tetrasphaera and Hydrogenophaga, which were enriched with the shortened sludge retention time, was in line with the excellent phosphorus performance of SBRS-SRT. The calculated methanogenic efficiency of SBRS-SRT increased significantly, which was in line with the higher sludge yield. This study proved that the short sludge retention time is a promising and practical approach to integrate biological phosphorus removal in A-stage when re-engineering a biological nutrient removal process

Synthesis of Vinyl Chloride Monomer over Carbon-Supported Tris-(Triphenylphosphine) Ruthenium Dichloride Catalysts

A series of catalysts, including Ru/AC, Ф-P-Ru/AC, Ф-P-Ru/AC-HCl, and Ф-P-Ru/AC-HNO3, were prepared and evaluated for the hydrochlorination reaction of acetylene. The test results reveal that the Ф-P-Ru/AC-HNO3 catalyst shows superior catalytic performance with an initial acetylene conversion of 97.2% and a relative increment of 87.0% within 48 h in comparison with that of the traditional RuCl3 catalyst. The substitution of inorganic RuCl3 precursor by organic Ф-P-Ru complex species in the catalysts results in more active species and tends to confine them in the micro-pores; the modification of carbon support by nitric acid in Ф-P-Ru catalyst may produce an interaction between the functional groups on modified support and Ru species, which is favorable to anchor and then reduce the loss of active species during the reaction, further increasing the amount of dominating Ru species, and greatly improving the reactants adsorption ability on the catalysts, thus enhancing the performance of the resultant catalysts. The as-prepared Ф-P-Ru catalysts are shown to be promising mercury-free candidates for the synthesis of vinyl chloride monomer

Activated Carbon-Supported Tetrapropylammonium Perruthenate Catalysts for Acetylene Hydrochlorination

The Ru-based catalysts, including Ru/AC (activated carbon), TPAP (tetrapropylammonium perruthenate)/AC, TPAP/AC-HNO3, and TPAP/AC-HCl, were prepared and assessed for the direct synthesis of vinyl chloride monomer. The results indicate that the TPAP/AC-HCl catalyst exhibits the best performance with the conversion falling from 97% to 91% in 48 hours’ reaction under the conditions of 180 °C, a GHSV(C2H2) of 180 h−1, and the feed ratio VHCl/VC2H2 of 1.15. The substitution of RuCl3 precursor with high valent TPAP species leads to more ruthenium oxides active species in the catalysts; the acidification treatment of carrier in TPAP/AC catalyst can produce an enhanced interaction between the active species and the modified functional groups on the carrier, and it is beneficial to inhibit the carbon deposition and sintering of ruthenium species in the reaction process, greatly increase the adsorption ability of reactants, and further increase the amount of dominating active species in the catalysts, thus improving the catalytic performance. This also provides a promising strategy to explore high efficient and economic mercury-free catalysts for the hydrochlorination of acetylene

Insights into removal of sulfonamides in anaerobic activated sludge system: Mechanisms, degradation pathways and stress responses

The fate of antibiotics in activated sludge has attracted increasing interests. However, the focus needs to shift from concerning removal efficiencies to understanding mechanisms and sludge responding to antibiotic toxicity. Herein, we operated two anaerobic sequencing batch reactors (ASBRs) for 200 days with sulfadiazine (SDZ) and sulfamethoxazole (SMX) added. The removal efficiency of SMX was higher than that of SDZ. SDZ was removed via adsorption (9.91-21.18%) and biodegradation (10.20-16.00%), while biodegradation (65.44-86.26%) was dominant for SMX removal. The mechanisms involved in adsorption and biodegradation were investigated, including adsorption strength, adsorption sites and the roles of enzymes. Protein-like substance (tryptophan) functioned vitally in adsorption by forming complexes with sulfonamides. P450 enzymes may catalyze sulfonamides degradation via hydroxylation and desulfurization. Activated sludge showed distinct responses to different sulfonamides, reflected in the changes of microbial communities and functions. These responses were related to sulfonamides removal, corresponding to the stronger adsorption capacity of activated sludge in ASBRSDZ and degradation capacity in ASBR-SMX. Furthermore, the reasons for different removal efficiencies of sulfonamides were analyzed according to steric and electronic effects. These findings propose insights into antibiotic removal and broaden the knowledge for self-protection mechanisms of activated sludge under chronic toxicities of antibiotics