Hiroki Hayashi

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.