林 宏樹

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.

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.

INTRODUCTION: Clinical epidemiological data on monoclonal gammopathy of renal significance (MGRS) are lacking. In this retrospective observational study, MGRS was compared with B-cell or plasma cell malignancies (BCM/PCM) with renal involvement to clarify differences in their clinical features. METHODS: Among the 1408 renal biopsies performed at our hospital, 25 MGRS and 18 BCM/PCM patients were identified. We investigated baseline characteristics and hematologic parameters of MGRS in reference to BCM/PCM using multivariable analysis. Cox proportional hazards analysis was performed for end-stage kidney disease (ESKD) and all-cause mortality. RESULTS: Comparing the MGRS with the BCM/PCM, mean differences in creatinine level, estimated glomerular filtration rate, and clonal bone marrow plasma cell percentage were - 2.76 mg/dL, 27.72 mL/min/1.73 m2, and - 18.86%, respectively (all P < 0.001). MGRS group had a predominance of glomerular lesions such as immunoglobulin-associated amyloidosis, cryoglobulinemic GN, and MIDD, and a lower risk of acute kidney injury/acute renal disease compared to BCM/PCM. During a median observation period of 23.7 months, clone-directed therapy was performed in 32.0% of patients in the MGRS group, compared to 83.3% of patients in the BCM/PCM group. Compared with BCM/PCM, MGRS had a hazard ratio of 0.66 (95% confidence interval (CI) 0.23-1.92, P = 0.45) for ESKD and 0.33 (95% CI 0.11-1.03, P = 0.06) for death in multivariate logistic regression analysis. CONCLUSIONS: The clinical characteristics of MGRS and BCM/PCM with monoclonal immunoglobulin-associated renal disease are disparate. Understanding these differences is crucial for developing tailored clinical approaches and therapeutic strategies to improve patient outcome.