梅田 良祐

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: Although the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification was proposed recently, until now, no reports have been made comparing the association of renal prognosis between the 2018 revised ISN/RPS classification and the 2003 ISN/RPS classification. The present study aimed to assess the usefulness, especially of activity and chronicity assessment, of the 2018 revised ISN/RPS classification for lupus nephritis (LN) in terms of renal prognosis compared to the classification in 2003. METHODS: We retrospectively collected medical records of 170 LN patients from the database of renal biopsy at Fujita Health University from January 2003 to April 2019. Each renal biopsy specimen was reevaluated according to both the 2003 ISN/RPS classification and the 2018 revised ISN/RPS classification. Renal endpoint was defined as a 30% decline of estimated glomerular filtration rate (eGFR). RESULTS: A total of 129 patients were class III/IV±V (class III, 44 patients; class IV, 35 patients; class III/IV+V, 50 patients). The mean age was 42 years, 88% were female, and the median observation period was 50.5 months. Renal prognosis was significantly different among the classes and significantly poor in the patients with higher modified National Institute of Health (mNIH) chronicity index (C index, ≥ 4) by a log-rank test (p = 0.05 and p = 0.02, respectively). By Cox proportional hazard models, only the C index was significantly associated with renal outcome (hazard ratio 1.32, 95% CI 1.11-1.56, p ≤ 0.01), while the classes, the 2003 activity and chronicity subdivision, and the mNIH activity index had no significant association with renal outcome. Each component of the C index was significantly associated with renal outcome in different models. CONCLUSION: This study demonstrates that the 2018 revised ISN/RPS classification was more useful in terms of association with renal prognosis compared to the 2003 ISN/RPS classification.