Boehringer Ingelheim (Japan)

Here, we present a protocol for describing the generation of a proximal tubule-on-chip model using human induced pluripotent stem cell (hiPSC)-derived kidney organoids for renal transporter analysis. We describe steps for hiPSC differentiation into kidney organoids, proximal tubule cell isolation, and microfluidic chip seeding. The hiPSC-derived model enhances transporter expression and polarization, with improved uptake and efflux functions compared to conventional immortalized cell-based models. This protocol serves as a platform to assess renal transporter function, nephrotoxicity, and drug-drug interactions. For complete details on the use and execution of this protocol, please refer to Ma et al.1.

Epidemiological and outcome studies on patients in Japan with heart failure (HF) categorized by left ventricular ejection fraction (LVEF) are currently limited. The aim of this non-interventional database study was to provide further information on these patients. Administrative claims data and electronic medical records from hospitals participating in the Voluntary Hospitals in Japan (VHJ) organization were used. Patients hospitalized with a primary diagnosis of HF between 1 April 2017 and 30 March 2020 were categorized by baseline LVEF on echocardiogram: HF with reduced EF (HFrEF, LVEF <40%); HF with preserved EF (HFpEF, LVEF ≥50%); and HF with mildly reduced EF (HFmrEF, 40% to <50% LVEF). Patients were evaluated for baseline characteristics, pre-admission diagnosis, prescription drugs, length of hospitalization, HF treatment cost, overall cost of hospitalization, and in-hospital prescription. An exploratory analysis compared post-hospitalization mortality and re-hospitalization rates. In total, 10646 hospitalized patients from 17 VHJ hospitals were enrolled. Of these, 7212 were included in the analysis set and categorized into HFpEF (3183, 44.1%), HFmrEF (1280, 17.7%), and HFrEF (2749, 38.1%) groups based on baseline LVEF. Beta-blocker use increased during hospitalization, with a mean (95% confidence interval [CI]) of 23.3% (22.3-24.3) of patients receiving these agents before admission versus 69.4% (68.3-70.5) at discharge. Administration of diuretics, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) showed a similar trend. Differences in treatments were observed between HF categories at discharge, with a higher proportion (95% CI) of ACE inhibitor use in the HFrEF group (40.6% [38.7-42.4]) versus HFmrEF (27.5% [25.1-30.0]) and HFpEF (20.6% [19.2-22.1]) groups (P<0.0001), and more ARB use in the HFmrEF and HFpEF groups (32.5% [29.9-35.1] and 31.2% [29.6-32.9], respectively) versus HFrEF (25.1% [23.5-26.8]; P<0.0001). Mean (standard deviation [SD]) length of hospitalization was 22.2 (23.3) days, and the median (interquartile range) was 17 (11-25) days. Estimated average cost of HF treatment per patient during index hospitalization was 300090 yen with HFrEF treatment costing the most. Average total healthcare expenditure during hospitalization was 1225650 yen per index hospitalization per patient, with HFrEF also the most expensive. During a mean (SD) observation period of 324 (304) days, ~21% of patients in each group required re-hospitalization for HF, and 625 patients (8.7%) died. The proportion of patients in each HF category was largely consistent with existing data. Discharge medications indicated high prescription of guideline-directed therapy. This study provides real-world data on patients with HF in Japan that can help inform future clinical decision-making.

Despite advancements in antifibrotic therapy, idiopathic pulmonary fibrosis (IPF) remains a medical condition with unmet needs. Single-cell RNA sequencing (scRNA-seq) has enhanced our understanding of IPF but lacks the cellular tissue context and gene expression localization that spatial transcriptomics provides. To bridge this gap, we profiled IPF and control patient lung tissue using spatial transcriptomics, integrating the data with an IPF scRNA-seq atlas. We identified three disease-associated niches with unique cellular compositions and localizations. These include a fibrotic niche, consisting of myofibroblasts and aberrant basaloid cells, located around airways and adjacent to an airway macrophage niche in the lumen, containing SPP1+ macrophages. In addition, we identified an immune niche, characterized by distinct lymphoid cell foci in fibrotic tissue, surrounded by remodeled endothelial vessels. This spatial characterization of IPF niches will facilitate the identification of drug targets that disrupt disease-driving niches and aid in the development of disease relevant in vitro models.

Sodium-glucose cotransporter-2 inhibitors are recommended treatment for adults with CKD, but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk–benefit profile in a post hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. The EMPA-KIDNEY trial randomized 6609 patients with CKD (eGFR ≥20 to <45 ml/min per 1.73 m2, or ≥45 to <90 ml/min per 1.73 m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed them for 2 years (median). Additional characteristics analyzed in subgroups were multimorbidity, polypharmacy, and health-related quality of life at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility, and diabetes and then eGFR and other comorbidities. Empagliflozin was generally well tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio, 0.72; 95% confidence interval, 0.64 to 0.82) and all-cause hospitalization by 14% (hazard ratio, 0.86; 95% confidence interval, 0.78 to 0.95), with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy, or health-related quality of life. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. These findings support the use of sodium-glucose cotransporter-2 inhibitors in CKD, irrespective of frailty, multimorbidity, or polypharmacy.

Empagliflozin, a sodium-glucose co-transporter 2 inhibitor, was shown to be effective in patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial. The present study aims to evaluate the cost-effectiveness of empagliflozin among Japanese patients with HFpEF. A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin added to standard of care (SoC) compared with SoC alone in patients with HFpEF from the perspective of the Japanese healthcare system and with a lifetime horizon. In addition to clinical events, the progression of disease severity was modelled based on the migration of Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (KCCQ-CSS). Model inputs, including risk of clinical events, costs, and utilities/disutilities, were derived from EMPEROR-Preserved trial data, a claims database and published literature. The generalizability of model results was investigated by applying various subgroups including age, body mass index (BMI), and region Asia, based on the subgroup analysis of EMPEROR-Preserved data. In the base-case analysis, empagliflozin yielded additional quality-adjusted life years (QALYs; 0.11) with an incremental cost of $1408 per patient for Japanese patients with HFpEF. Incremental cost, mainly derived from drug acquisition cost ($1963 per patient), was largely offset by reduced cost in hospitalization for heart failure (HHF) and cardiovascular death (-$537 per patient and -$166 per patient, respectively). Treatment of empagliflozin provided incremental 0.11 QALYs and 0.08 life years compared with SoC alone. The incremental cost-effectiveness ratio (ICER) was $12772 (¥1662689)/QALY, which was below the Japanese willingness-to-pay (WTP) threshold of $38408 (¥5000000)/QALY. The results were consistent across all the subgroups considered, and empagliflozin was dominant over SoC alone in the region Asia and BMI<25kg/m2 subgroups. ICERs for the remaining subgroups ranged from $7520/QALY (¥978972/QALY, patients with baseline age≥75years) to $31049/QALY (¥4041896/QALY, patients with baseline New York Heart Association class III/IV). Deterministic sensitivity analysis result showed that the treatment effect on HHF is the biggest driver of the cost-effectiveness analysis, while the ICER will be still under the threshold even if no effect of empagliflozin on HHF was assumed. The probabilistic sensitivity analysis result showed that 64% of simulations were cost-effective based on the Japanese WTP threshold. Empagliflozin was demonstrated to be cost-effective for patients with HFpEF in Japan based on EMPEROR-Preserved trial data.