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

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Nationwide surveillance of bacterial respiratory pathogens conducted by the Japanese Society of Chemotherapy in 2007: general view of the pathogens’ antibacterial susceptibility

AbstractFor the purpose of a nationwide surveillance of the antimicrobial susceptibility of bacterial respiratory pathogens in patients in Japan, the Japanese Society of Chemotherapy conducted their second year survey, during the period from January to August, 2007. A total of 1178 strains were collected from clinical specimens obtained from adult patients with well-diagnosed respiratory tract infections. Susceptibility testing was evaluable for 1108 strains (226 Staphylococcus aureus, 257 Streptococcus pneumoniae, 6 Streptococcus pyogenes, 206 Haemophilus influenzae, 120 Moraxella catarrhalis, 122 Klebsiella pneumoniae, and 171 Pseudomonas aeruginosa). A total of 44 antibacterial agents, including 26 β-lactams (four penicillins, three penicillins in combination with β-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), three aminoglycosides, four macrolides (including ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standards Institute (CLSI). The incidence of methicillinresistant Staphylococcus aureus (MRSA) was high, at 59.7%, and the incidences of penicillin-intermediateresistant and -resistant Streptococcus pneumoniae (PISP and PRSP) were 30.4% and 5.1%, respectively. Among Haemophilus influenzae strains, 19.9% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately-resistant (BLNAI), 29.1% to be β-lactamasenon-producing ABPC-resistant (BLNAR), and 6.7% to be β-lactamase-producing ABPC-resistant (BLPAR) strains. Extended-spectrum β-lactamase-producing Klebsiella pneumoniae was not isolated. Two isolates (1.2%) of Pseudomonas aeruginosa were found to be metallo-β-lactamase-producing strains, including one (0.6%) suspected multidrug-resistant strain showing resistance to imipenem, amikacin, and ciprofloxacin. These data will be a useful reference for future periodic surveillance studies and for investigations to control resistant infections as well. Continued surveillance is required to prevent the further spread of these antimicrobial resistances

Observation of Coulomb-Assisted Nuclear Bound State of Ξ\Xi−^−–14^{14}N System

In an emulsion-counter hybrid experiment performed at J-PARC, a $\Xi^-$ absorption event was observed which decayed into twin single-$\Lambda$ hypernuclei. Kinematic calculations enabled a unique identification of the reaction process as $\Xi^{-} + ^{14}$N$\ \rightarrow\ ^{10}_\Lambda$Be + $^5_\Lambda$He. For the binding energy of the $\Xi^{-}$ hyperon in the $\Xi^-$-$^{14}$N system a value of $1.27 \pm 0.21$ MeV was deduced. The energy level of $\Xi^-$ is likely a nuclear $1p$ state which indicates a weak ${\Xi}N$-$\Lambda\Lambda$ coupling

Observation of a Be double-Lambda hypernucleus in the J-PARC E07 experiment

A double-$\Lambda$ hypernucleus, ${}_{\Lambda\Lambda}\mathrm{Be}$, was observed by the J-PARC E07 collaboration in nuclear emulsions tagged by the $(K^{-},K^{+})$ reaction. This event was interpreted as a production and decay of ${}_{\Lambda\Lambda}^{\;10}\mathrm{Be}$, ${}_{\Lambda\Lambda}^{\;11}\mathrm{Be}$, or ${}_{\Lambda\Lambda}^{\;12}\mathrm{Be}^{*}$ via $\Xi^{-}$ capture in ${}^{16}\mathrm{O}$. By assuming the capture in the atomic 3D state, the binding energy of two $\Lambda$ hyperons$\,$($B_{\Lambda\Lambda}$) of these double-$\Lambda$ hypernuclei are obtained to be $15.05 \pm 0.11\,\mathrm{MeV}$, $19.07 \pm 0.11\,\mathrm{MeV}$, and $13.68 \pm 0.11\,\mathrm{MeV}$, respectively. Based on the kinematic fitting, ${}_{\Lambda\Lambda}^{\;11}\mathrm{Be}$ is the most likely explanation for the observed event.Comment: 11 pages, 3 figure