Naotake Tsuboi

BACKGROUND: Differences in chest HRCT findings between myeloperoxidase (MPO)- antineutrophil cytoplasmic antibody (ANCA) and proteinase 3 (PR3)-ANCA in Japanese patients with ANCA-associated vasculitis (AAV) remain unclear. METHODS: We reviewed chest HRCT findings at diagnosis in 195 patients with AAV enrolled in the Remission Induction Therapy in Japanese Patients with ANCA-associated Vasculitis and Rapidly Progressive Glomerulonephritis (RemIT-JAV-RPGN) observational cohort study (2011-2013). Findings were classified by ANCA subtype and compared. RESULTS: Abnormal chest HRCT findings were observed in 172 of 195 patients. Main findings included ground-glass opacity (n = 92, 47%), reticulation (n = 79, 41%), traction bronchiectasis (n = 67, 34%), and honeycombing (n = 4 9, 25%). Honeycombing (n = 46, 29%) and reticulation (n = 70, 43%) predominated in patients with positive MPO-ANCA, whereas nodules (n = 4, 44%) and cavities (n = 3, 33%) were more frequent in those with positive PR3-ANCA. Interstitial pneumonia (IP) was diagnosed in 89 patients, with HRCT patterns of definite usual interstitial pneumonia (UIP) in 31 (35%), possible UIP in 22 (25%), and inconsistent with UIP in 36 (40%). IP was more frequent in patients with positive MPO-ANCA than in those with positive PR3-ANCA (47% vs 11%, respectively; p = 0.003). Definite UIP was more common in MPO-ANCA positivity than in other subtypes (41% vs 0%, respectively; p = 0.023). CONCLUSIONS: In Japanese patients with AAV, IP with a definite UIP pattern was more frequent in patients with MPO-ANCA positivity while nodules and cavities were more frequent in patients with positive PR3-ANCA.

BACKGROUND: Cisplatin-induced nephrotoxicity (CIN) is a major dose-limiting adverse event that can lead to both acute and chronic kidney injury. The formation of thiol-cisplatin conjugates within renal tubular cells has been implicated as a key mechanism underlying CIN. Flopropione is an inhibitor of cysteine conjugate β-lyase 1, an enzyme that catalyzes the formation of the thiol-cisplatin conjugate, which might prevent CIN. OBJECTIVE: We designed a clinical trial to evaluate the safety of flopropione in patients receiving cisplatin-based chemotherapy and explore its efficacy in preventing CIN. METHODS: This is a phase 1 and 2a, single-center, randomized, open-label trial conducted in patients undergoing cisplatin therapy. Participants are randomized in a 5:2 ratio per cohort to receive either flopropione or no treatment. On the day of cisplatin administration, the flopropione group receives oral flopropione twice daily (80 mg in cohort 1, 160 mg in cohort 2, and 240 mg in cohort 3). On the following day, all cohorts receive 3 doses of 80 mg of oral flopropione. A step-up dose escalation design is adopted, progressing from cohort 1 to 3 after confirming safety at each level. The primary end point is the safety of flopropione use in combination with cisplatin; the secondary end points include changes in the levels of urinary biomarkers of nephrotoxicity such as neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and kidney injury molecule-1. Blood and urine samples are collected within 48 hours before cisplatin administration and at 24 hours, 48 hours, and 1 week after its initiation for safety and efficacy assessments. RESULTS: The first participant was registered in July 2024. As of January 2026, participant registration is ongoing. The final participant will complete the study by March 2026. Publication of results is expected by March 2027. CONCLUSIONS: This study is expected to contribute to advances in preventive strategies for CIN by providing evidence that inhibition of cysteine conjugate β-lyase 1 by flopropione may attenuate CIN. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs041220021; https://jrct.mhlw.go.jp/en-latest-detail/jRCTs041220021. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/87907.

UNLABELLED: Neutrophils are key effector cells in the pathogenesis of acute kidney injury (AKI), where neutrophil extracellular traps (NETs) play a critical role. Mac-1 (CD11b/CD18), a leukocyte surface integrin, is known to mediate inflammation. We hypothesized that Mac-1 regulates NETs formation and exacerbates ischemic AKI. The expression of Mac-1 and NETs was analyzed in peripheral blood and renal tissues from patients with kidney diseases. Mac-1 knockout (Mac-1⁻/⁻) mice were used to establish a bilateral renal ischemia-reperfusion injury (IRI) model and compared with wild-type (WT) controls. Primary neutrophils were isolated from bone marrow in vitro to investigate the mechanisms underlying NETs formation. CD11b and NETs were both implicated in patients with either AKI following cardiac surgery or interstitial nephritis. In a murine bilateral renal IRI model, NETs formation was detected in WT kidneys at 24 h, and DNase I treatment significantly alleviated renal injury. Compared to WT mice, Mac-1⁻/⁻ mice exhibited reduced dysfunction, inflammation, and NETs infiltration. In vitro, Mac-1⁻/⁻ neutrophils showed decreased PMA-induced NETs formation and reduced ERK phosphorylation. Furthermore, treatment with anti-Mac-1 antibody (M1/70) in the murine IRI model significantly attenuated kidney inflammation and injury. Mac-1 exacerbates kidney inflammation and dysfunction in ischemic AKI by mediating NETs formation through an ERK phosphorylation-dependent mechanism. Blockade of Mac-1 using the antibody M1/70 effectively ameliorates this injury, highlighting its potential as a therapeutic target. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10753-025-02327-z.

IgA nephropathy (IgAN) is characterized by glomerular deposits of IgA-containing immune complexes (IgA-ICs), which are suspected to originate from circulation. However, the composition of these ICs is not fully understood. To address this gap in knowledge, we performed label-free quantitative mass-spectrometry analyses of glomerular and circulatory IgA-ICs with a focus on complement proteins. Glomeruli of patients with IgAN compared to healthy glomeruli had greater amounts of several complement-system proteins associated with classical, alternative, and terminal pathways, including complement factor H-related (CFHR) proteins 1, 2, 3, and 5, C1q chains B and C, and properdin. Circulatory IgA-ICs of patients with IgAN vs. healthy controls had a greater abundance of complement proteins CFHR1, C1q chains A, B, and C, and properdin. Furthermore, levels of several complement proteins in circulatory IgA-ICs of IgAN patients were reduced after immunosuppressive therapy (i.e., tonsillectomy combined with pulse steroid therapy) but not in patients on comprehensive supportive therapy. CFHR1 exhibited the greatest decrease (Fold change = 48.16, P < 0.0001). These data together revealed the complexity of complement proteome in glomerular and circulatory IgA-ICs and suggested an association of complement regulatory proteins, such as CFHR1, with pathogenic IgA-ICs.

Artificial intelligence for rare pathological lesion detection faces dual challenges: expert annotation scarcity and domain shifts across institutions. Using multi-institutional kidney biopsies from 22 hospitals with 3 scanner types (NDPI, VSI, SVS), we demonstrate that model performance decreases dramatically across domains, with up to 70.3% reduction in detection precision for rare lesions such as crescents and segmental sclerosis (comprising only 2-3% of annotations). We present an approach integrating semi-supervised learning with residual CycleGAN-based domain adaptation, reducing mean Fréchet inception distance between institutions from 55.9 to 20.2 while preserving diagnostic morphology. We identified context-dependent optimal strategies: semi-supervised learning with 50% confidence threshold excelled in same-hospital scenarios (15.2-17.7% improvement for rare lesions), while our combined GAN-Semi-Supervised approach demonstrated superior performance in cross-scanner scenarios between NDPI and VSI formats (up to 63.4% improvement for crescents). This methodology enables robust performance across diverse healthcare settings with minimal expert annotation.