Published papers

BACKGROUNDActive vitamin D metabolites, including 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), have potent immunomodulatory effects that attenuate acute kidney injury (AKI) in animal models.METHODSWe conducted a phase 2, randomized, double-blind, multiple-dose, 3-arm clinical trial comparing oral calcifediol (25D), calcitriol (1,25D), and placebo among 150 critically ill adult patients at high risk of moderate to severe acute kidney injury (AKI). The primary endpoint was a hierarchical composite of death, kidney replacement therapy (KRT), and kidney injury (baseline-adjusted mean change in serum creatinine), each assessed within 7 days following enrollment using a rank-based procedure. Secondary endpoints included new or progressive AKI and a composite of KRT or death. Hypercalcemia was the key safety endpoint. We also performed RNA-Seq on circulating CD14+ monocytes collected immediately prior to randomization and 2 days later.RESULTSThe global rank score for the primary endpoint was similar among calcifediol- (n = 51) versus placebo- (n = 49) treated patients (P = 0.85) and for calcitriol (n = 50) versus placebo-treated patients (P = 0.58). Secondary endpoints also occurred at similar rates across groups. Hypercalcemia occurred in 1 patient in the calcifediol group (1.7%), 1 patient in the calcitriol group (2.0%), and no patients in the placebo group. Compared with placebo, calcitriol upregulated more individual genes and pathways in circulating monocytes than did calcifediol, including pathways involving IFN-α, IFN-γ, oxidative phosphorylation, DNA repair, and heme metabolism.CONCLUSIONTreatment with calcifediol or calcitriol in critically ill adults upregulated multiple genes and pathways involving immunomodulation, DNA repair, and heme metabolism, but it did not attenuate AKI.TRIAL REGISTRATIONClinicalTrials.gov (NCT02962102)FUNDINGNIH/NIDDK grant K23DK106448 (to DEL) and NIH/NHLBI grant R01HL16687 (to EYK).

BACKGROUND: Renal dysfunction is associated with increased cardiovascular-related mortality, but its impact on outcome of out-of-hospital cardiac arrest (OHCA) remains unclear. We assessed whether post-OHCA outcome correlated with renal function early after OHCA. Methods and Results: Of the 16,452 registered patients in the SOS-KANTO 2012 Study, 5,112 cardiogenic OHCA adults with creatinine measurement (mean age, 72 years; male, 64%) were examined. First-obtained creatinine was used to assess eGFR. Associations between eGFR groups, ≥60 (n=997), 45-59 (n=1,311), 30-44 (n=1,441), and <30 mL/min/1.73 m2(n=1,363), and 3-month survival and neurological outcomes were examined. Favorable neurological outcome was defined as cerebral performance categories 1 or 2. Survival rate (15.1%, 9.7%, 3.9%, and 2.9%; P<0.001) and proportion of favorable neurological outcome (12.3%, 7.4%, 2.6%, and 2.2%; P<0.001) were determined for eGFR groups ≥60, 45-59, 30-44, and <30 mL/min/1.73 m2, respectively. The survival rate decreased with eGFR (<60 mL/min/1.73 m2), and survival adjusted OR were 0.74 (95% CI: 0.54-1.03), 0.42 (95% CI: 0.28-0.62), and 0.43 (95% CI: 0.28-0.68) for eGFR 45-59, 30-44, and <30 mL/min/1.73 m2, respectively. The adjusted OR for favorable neurological outcome also decreased with eGFR: 0.74 (95% CI: 0.52-1.06), 0.40 (95% CI: 0.25-0.64), and 0.48 (95% CI: 0.29-0.81), respectively. CONCLUSIONS: An independent and graded association was observed between decreased eGFR and 3-month survival and proportion of favorable neurological outcome in cardiogenic OHCA patients.

敗血症は感染症に対する制御不十分な生体反応により臓器障害を起こす致死的病態である．敗血症の予後の改善には，敗血症の早期認知と適切な治療介入が重要である．敗血症診療ガイドラインには国際版と日本版が存在する．両者とも最近改訂され，国際版は中低所得国を含む全世界での使用を念頭においた推奨，日本版は本邦の臨床に即した推奨を行っている．前版からの大きな変更点は，敗血症のスクリーニングにqSOFAスコア単独で用いないこと，敗血症の可能性が低いショックでない患者においては，敗血症であるかの評価を繰り返して抗菌薬投与を慎重に行うことである．多くの臨床研究から敗血症診療に関するエビデンスが蓄積されたが，単一で優れた診断法や特異的治療法は存在せず，バイタルサインを組み合わせた敗血症の早期認知，感染巣のコントロールと抗菌薬治療，呼吸循環管理を含む全身管理の連鎖が重要である．

OBJECTIVE: The Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During Post-Cardiac Arrest Care (HYBRID) II trial (jRCTs031180352) suggested that hydrogen inhalation may reduce post-cardiac arrest brain injury (PCABI). However, the combination of hypothermic target temperature management (TTM) and hydrogen inhalation on outcomes is unclear. The aim of this study was to investigate the combined effect of hydrogen inhalation and hypothermic TTM on outcomes after out-of-hospital cardiac arrest (OHCA). DESIGN: Post hoc analysis of a multicenter, randomized, controlled trial. SETTING: Fifteen Japanese ICUs. PATIENTS: Cardiogenic OHCA enrolled in the HYBRID II trial. INTERVENTIONS: Hydrogen mixed oxygen (hydrogen group) versus oxygen alone (control group). MEASUREMENTS AND MAIN RESULTS: TTM was performed at a target temperature of 32-34°C (TTM32-TTM34) or 35-36°C (TTM35-TTM36) per the institutional protocol. The association between hydrogen + TTM32-TTM34 and 90-day good neurologic outcomes was analyzed using generalized estimating equations. The 90-day survival was compared between the hydrogen and control groups under TTM32-TTM34 and TTM35-TTM36, respectively. The analysis included 72 patients (hydrogen [ n = 39] and control [ n = 33] groups) with outcome data. TTM32-TTM34 was implemented in 25 (64%) and 24 (73%) patients in the hydrogen and control groups, respectively ( p = 0.46). Under TTM32-TTM34, 17 (68%) and 9 (38%) patients achieved good neurologic outcomes in the hydrogen and control groups, respectively (relative risk: 1.81 [95% CI, 1.05-3.66], p < 0.05). Hydrogen + TTM32-TTM34 was independently associated with good neurologic outcomes (adjusted odds ratio 16.10 [95% CI, 1.88-138.17], p = 0.01). However, hydrogen + TTM32-TTM34 did not improve survival compared with TTM32-TTM34 alone (adjusted hazard ratio: 0.22 [95% CI, 0.05-1.06], p = 0.06). CONCLUSIONS: Hydrogen + TTM32-TTM34 was associated with improved neurologic outcomes after cardiogenic OHCA compared with TTM32-TTM34 monotherapy. Hydrogen inhalation is a promising treatment option for reducing PCABI when combined with TTM32-TTM34.

BACKGROUND: Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases. METHODS: We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. FINDINGS: Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. CONCLUSIONS: This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases. FUNDING: Grant from F. Hoffmann-La Roche (Roche) AG.

BACKGROUND: Inhaled molecular hydrogen gas (H2) has been shown to improve outcomes in animal models of cardiac arrest (CA). H2 inhalation is safe and feasible in patients after CA. We investigated whether inhaled H2 would improve outcomes after out-of-hospital CA (OHCA). METHODS: HYBRID II is a prospective, multicentre, randomised, double-blind, placebo-controlled trial performed at 15 hospitals in Japan, between February 1, 2017, and September 30, 2021. Patients aged 20-80 years with coma following cardiogenic OHCA were randomly assigned (1:1) using blinded gas cylinders to receive supplementary oxygen with 2% H2 or oxygen (control) for 18 h. The primary outcome was the proportion of patients with a 90-day Cerebral Performance Category (CPC) of 1 or 2 assessed in a full-analysis set. Secondary outcomes included the 90-day score on a modified Rankin scale (mRS) and survival. HYBRID II was registered with the University Hospital Medical Information Network (registration number: UMIN000019820) and re-registered with the Japan Registry for Clinical Trials (registration number: jRCTs031180352). FINDINGS: The trial was terminated prematurely because of the restrictions imposed on enrolment during the COVID-19 pandemic. Between February 1, 2017, and September 30, 2021, 429 patients were screened for eligibility, of whom 73 were randomly assigned to H2 (n = 39) or control (n = 34) groups. The primary outcome, i.e., a CPC of 1 or 2 at 90 days, was achieved in 22 (56%) and 13 (39%) patients in the H2 and control groups (relative risk compared with the control group, 0.72; 95% CI, 0.46-1.13; P = 0.15), respectively. Regarding the secondary outcomes, median mRS was 1 (IQR: 0-5) and 5 (1-6) in the H2 and control groups, respectively (P = 0.01). An mRS score of 0 was achieved in 18 (46%) and 7 (21%) patients in the H2 and control groups, respectively (P = 0.03). The 90-day survival rate was 85% (33/39) and 61% (20/33) in the H2 and control groups, respectively (P = 0.02). INTERPRETATION: The increase in participants with good neurological outcomes following post-OHCA H2 inhalation in a selected population of patients was not statistically significant. However, the secondary outcomes suggest that H2 inhalation may increase 90-day survival without neurological deficits. FUNDING: Taiyo Nippon Sanso Corporation. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

PURPOSE: To develop a new 4/6 infarct nephrectomy (INx) model rat mimicking moderate chronic kidney disease (CKD) and to evaluate its application. METHODS: We modified the conventional 5/6 INx rat model to create the 4/6 INx model by ligating the renal artery branch to induce infarction of one-third of the left kidney after right kidney removal and compared biochemically and histologically both models. To demonstrate the application of the 4/6 INx model, the effects of a supplementary compound containing calcium carbonate, chitosan, palm shell activated charcoal etc., that is effective for both CKD and its complications, were compared between both models. RESULTS: Impairment of renal function in the 4/6 INx group was significantly more moderate than in the 5/6 INx group (P < 0.05). The 4/6 INx group showed less histological damage in kidney than in the 5/6 INx group. The supplementary compound did not improve CKD in the 5/6 INx group, but ameliorated elevation of blood urea nitrogen in the 4/6 INx group. CONCLUSIONS: We developed the 4/6 INx model, which is more moderate than the conventional 5/6 INx model. This model could potentially demonstrate the effectiveness of drugs and supplements intended to prevent CKD and its progression.

STUDY OBJECTIVE: To elucidate the clinical utility of the Clinical Frailty Scale score for predicting poor neurologic functions in patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: This was a prospective, multicenter, observational study conducted between 2019 and 2021. The study included adults with nontraumatic OHCA admitted to the intensive care unit after return of spontaneous circulation (ROSC). Pre-arrest high Clinical Frailty Scale score was defined as 5 or more. Favorable neurologic outcomes defined as a Cerebral Performance Category score of 2 or less at 30 days after admission were compared between patients with and without high Clinical Frailty Scale scores. Multivariable logistic regression analyses fitted with generalized estimating equations were performed to adjust for patient characteristics, out-of-hospital information, and resuscitation content and account for within-institution clustering. RESULTS: Of 9,909 patients with OHCA during the study period, 1,216 were included, and 317 had a pre-arrest high Clinical Frailty Scale score. Favorable neurologic outcomes were fewer among patients with high Clinical Frailty Scale scores. The high Clinical Frailty Scale score group showed a lower percentage of favorable neurologic outcomes after OHCA than the low Clinical Frailty Scale score group (6.1% vs 24.4%; adjusted odds ratio, 0.45 [95% confidence interval 0.22 to 0.93]). This relationship remained in subgroups with cardiogenic OHCA, with ROSC after hospital arrival, and without a high risk of dying (Clinical Frailty Scale score of 7 or less), whereas the neurologic outcomes were comparable regardless of pre-arrest frailty in those with noncardiogenic OHCA and with ROSC before hospital arrival. CONCLUSIONS: Pre-arrest high Clinical Frailty Scale score was associated with unfavorable neurologic functions among patients resuscitated from OHCA. The Clinical Frailty Scale score would help predict clinical consequences following intensive care after ROSC.

BACKGROUND: To elucidate the association between blood glucose levels at the return of spontaneous circulation (ROSC) and neurological outcomes following out-of-hospital cardiac arrest (OHCA), a post hoc analysis was conducted using data from a prospective observational study involving 41 hospitals in Tokyo and its suburbs from 2019 to 2021. Adults with nontraumatic OHCA who achieved ROSC were included. METHODS: A total of 1533 patients were analyzed. A spline curve for estimating neurological outcomes (Cerebral Performance Category score ≤2 at 30 days) by blood glucose level at ROSC was generated. Patients were classified into low, moderate, and high blood glucose groups, defined as <100, 100-300, and ≥300 mg/dL, respectively. Neurological outcomes were compared using generalized estimating equations adjusted for patient and institutional characteristics. RESULTS: Favorable neurologic outcomes were fewer in the low and high blood glucose groups than in the moderate group (8/132 [6.1 %] and 62/485 [12.8 %] vs. 181/807 [22.4 %]). The adjusted model revealed that low and high glucose levels at ROSC were associated with fewer favorable outcomes (odds ratios, 0.43 [0.18-0.96] and 0.59 [0.42-0.84]). High blood glucose levels showed unfavorable effects in subgroups with cardiogenic or noncardiogenic etiology, age <65 years, and low-flow time ≤30 min, whereas low blood glucose levels showed unfavorable effects only in cardiogenic cases. CONCLUSIONS: Blood glucose levels <100 and ≥300 mg/dL were associated with unfavorable neurological outcomes, with a nonlinear inverted U-shaped relationship.

Macular edema (ME) can cause profound vision impairment and occurs in several prevalent retinal diseases, including diabetic retinopathy, choroidal neovascularization, retinal vein occlusion, and uveitis. Retinal edema typically results from dysfunction of the blood-retina barrier (BRB), which is associated with increased retinal expression of complement components. It is unclear whether the classical complement pathway has detrimental or protective roles in the context of BRB dysfunction. Here, we characterized Tspan12-KODBM (disrupted BRB maintenance) mice, a mouse model of cystoid edema generated by genetically and pharmacologically manipulating β-catenin–dependent norrin/frizzled-4 (FZD4) signaling. We assessed BRB function, cystoid edema, electroretinogram, and microglia activation outcomes in an aging study with WT, C1qa-KO, Tspan12-KODBM, and Tspan12-KODBM; C1qa-KO compound mutant mice. Phenotypic analyses and cell-based experiments indicated that C1QA contributes to maintaining basal β-catenin–dependent signaling and that the absence of C1QA exacerbates BRB dysfunction, cystoid edema, and neuroinflammation in Tspan12-KODBM; C1qa-KO compound mutant mice. Activation of β-catenin–dependent signaling by an anti-FZD4 and anti-LRP5 agonistic antibody modality achieved complete resolution of cystoid edema. This study shows that reducing or enhancing norrin/FZD4 signaling can increase or decrease cystoid edema, respectively, underscoring its potential as a therapeutic target in ME. Furthermore, this study provides insights into the contribution of C1QA to BRB maintenance.