坪井 直毅

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.

Tryptophan (TRP) metabolism through the kynurenine pathway generates multiple biologically active metabolites with diverse immunomodulatory effects, but their roles in glomerulonephritis (GN), particularly in innate immunity, remain poorly understood. Using a nephrotoxic serum-induced GN (NTS-GN) model, we first analyzed mice deficient in key TRP-metabolizing enzymes of the kynurenine pathway: Indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2), and kynurenine 3-monooxygenase (KMO), and found that Ido1-deficient mice exhibited exacerbated kidney injury and glomerular neutrophil infiltration, whereas Ido2 deficiency had no significant impact. In contrast, Kmo-deficient mice showed reduced crescent formation. Unexpectedly, the concentration of kynurenic acid (KYNA), a downstream metabolite of IDO1, was elevated in the kidney cortex of Ido1-deficient mice. Exogenous KYNA administration improved survival, ameliorated renal injury, and reduced neutrophil infiltration in Ido1-deficient mice, indicating its protective effect against antibody-mediated injury. Moreover, KYNA suppressed immune complex-mediated neutrophil spreading, attenuated FcγR-dependent Syk phosphorylation, and reduced VEGF secretion in vitro. Our results position KYNA as a key modulator of neutrophil-driven inflammation in antibody-mediated GN. This study uncovers distinct roles for kynurenine pathway enzymes and highlights the TRP-KYNA pathway as a promising immunometabolic target for controlling innate immune responses in GN.

An 81-year-old man was treated with prednisolone, avacopan, and rituximab for microscopic polyangiitis and sulfamethoxazole/trimethoprim (SMX/TMP) and vonoprazan for prophylaxis. The liver enzyme levels were elevated 42 days after avacopan administration. Avacopan, SMX/TMP, and vonoprazan treatment were discontinued. A liver biopsy revealed vanishing bile duct syndrome. The patient was subsequently treated with ursodeoxycholic acid and glucocorticoid. Although vasculitis remained in remission, the patient ultimately died. Autopsy revealed persistent bile ductopenia and progressive liver cell injury confirmed by cytokeratin 7 positivity, severe cholestasis, and portal fibrosis. Further studies are required to elucidate associated mechanisms and risk factors.

BACKGROUND: Despite the widespread use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the management of chronic kidney disease, their role in autosomal dominant polycystic kidney disease (ADPKD) remains unclear. METHODS: This observational study evaluated the efficacy of the SGLT2i dapagliflozin in patients with ADPKD receiving tolvaptan. The primary outcome was the chronic estimated glomerular filtration rate (eGFR) slope, modeled using a multivariable linear mixed-effect model; a within-group analysis was also performed using an interrupted time series approach. RESULTS: A total of 48 patients receiving tolvaptan were analyzed (24 patients in the control group vs 24 patients in the dapagliflozin group). The mean follow-up duration was 649 ± 363 days across all patients. The chronic eGFR slope was -2.30 [95% confidence interval (CI) -3.47, -1.13] in the control group and -1.72 (95% CI -3.48, -0.03) mL/min/1.73 m2 per year in the dapagliflozin group (P = .595). In within-group analysis using an interrupted time series approach, the chronic eGFR slope changed from -2.34 (95% CI -3.39, -1.30) to -1.14 (95% CI -2.68, 0.40) mL/min/1.73 m2 per year following dapagliflozin initiation (P = .191). No serious adverse events were observed during the follow-up period. CONCLUSIONS: Although no statistically significant differences were observed, both between- and within-group analyses showed a numerically slower decline in eGFR with dapagliflozin. Importantly, no evidence of harm was observed. These findings may contribute to ongoing discussions regarding the potential role of SGLT2i in ADPKD.