Hidekazu Ikeuchi

Aim: This study evaluated temporal changes in the clinical and histological features of lupus nephritis at first renal biopsy in Japan. Methods: This retrospective observational study used Japan Renal Biopsy Registry data. Patients undergoing their first renal biopsy in 2018–2021 were compared with a historical cohort from 2007 to 2012. Clinical characteristics and histological classes based on the International Society of Nephrology/Renal Pathology Society classification were compared. Results: The study included 331 patients in the historical cohort and 682 in the recent cohort. The recent cohort was older (median age, 42 vs. 37 years; p = 0.014), with a higher proportion aged 60 years or older (19.2% vs. 10.6%; p < 0.001). Histological class distribution differed significantly between cohorts. Class IV (±V) lesions were less frequent in the recent cohort (34.3% vs. 44.1%), whereas Class II and Class III (±V) lesions were numerically more frequent. The lower odds of Class IV (±V) lesions persisted after adjustment for age group (odds ratio, 0.676; 95% confidence interval, 0.516–0.886; p = 0.005). Amongst patients with Class III/IV lesions, pure Class III lesions were more frequent and pure Class IV lesions were less frequent in the recent cohort. Conclusion: The recent first‐biopsy cohort was older and had a lower proportion of Class IV (±V) lesions than the historical cohort, even after age adjustment. These findings suggest temporal changes in LN in Japan, although the greater proportion of missing histological classification data in the historical cohort should be considered when interpreting the histological differences.

Objectives: While recent guidelines recommend early glucocorticoid (GC) tapering for LN, supporting evidence for pure membranous LN remains limited. The present study investigated the impact of rapid GC tapering on renal outcomes in this population. Methods: We performed a multicentre retrospective study across 16 centres in Japan, including 67 patients with biopsy-proven pure membranous LN who initiated GC therapy between 2003 and 2023. Patients were classified into rapid tapering (GC dose ≤7.5 mg/day at 6 months) and conventional tapering (>7.5 mg/day at 6 months) groups. The primary endpoint was the partial renal response (PRR) at 12 months. Secondary endpoints included the complete renal response (CRR), relapse and severe adverse events (SAEs). Adjusted risk ratios (aRRs) were estimated using modified Poisson regression models for failure to achieve PRR/CRR. Results: Fifteen patients underwent rapid tapering and 52 conventional tapering. Baseline characteristics were generally comparable. At 12 months, PRR was achieved in 85.7% of the rapid group and 84.3% of the conventional group (aRR for failure 1.04; 95% CI 0.17–6.39). CRR rates at 12 months were 64.3% and 56.9%, respectively (aRR for failure 0.90; 95% CI 0.40–2.02). At 24 months, PRR and CRR did not differ statistically between groups. Relapse occurred in 20.0% versus 7.7% (P = 0.185). No SAEs were reported in the rapid group, while three occurred in the conventional group. Conclusions: Rapid GC tapering to ≤7.5 mg/day at 6 months appeared feasible in a subset of patients with pure membranous LN, but the findings are preliminary and should be interpreted cautiously because of the small rapid-taper group and imprecise estimates.

This study identifies atonal transcription factor 8 (ATOH8) as a previously unexplored regulator of podocyte function. We demonstrate that ATOH8 knockdown activates TGF-β signaling and increases extracellular matrix gene expression. Notably, ATOH8 deficiency alone does not cause renal injury but exacerbates glomerulosclerosis in an adriamycin-induced nephropathy model, accompanied by increased Tgfb1 mRNA expression in the renal cortex. These findings indicate that ATOH8 plays a protective role in podocyte function and limits glomerulosclerosis during kidney injury.

Objectives: Recent guidelines and recommendations for LN suggest rapid glucocorticoid (GC) reduction; however, robust supporting evidence remains limited. This study aimed to evaluate the impact of rapid GC reduction on renal outcomes in patients with proliferative LN. Methods: We conducted a multicentre retrospective chart review of patients with GC-naïve, biopsy-proven proliferative LN with available urinary protein-to-creatinine ratio (UPCR) data before and 52 weeks after GC treatment. Patients who reduced their prednisolone-equivalent dose to ≤7.5 mg/day within 6 months (rapid GC reducers) were compared with those who did not (conventional GC reducers) regarding partial renal response (PRR) at 12 months. Modified Poisson regression analysis was used to adjust for confounding factors. Results: A total of 344 patients from 17 centres were included: 50 rapid GC reducers and 294 conventional GC reducers. PRR at 12 months was achieved by 43/50 (86%) in the rapid GC group and 248/294 (84.4%) in the conventional group. After adjusting for age, initial UPCR, initial estimated glomerular filtration rate, the presence of a concomitant membranous lesion in the glomerulus, initial GC dose, use of methylprednisolone pulse therapy, strong immunosuppressants (mycophenolate mofetil, cyclophosphamide or rituximab) and hydroxychloroquine, no significant difference was observed in PRR at 12 months (adjusted risk ratio: 0.92, P = 0.758). Relapse rates and serious adverse events over 2 years of follow-up were also comparable between the groups. Conclusion: Rapid GC reduction to ≤7.5 mg/day within 6 months did not compromise renal outcomes or increase relapse in proliferative LN.

This study by miRNA microarray analysis demonstrated that miR-143-3p expression was upregulated in cultured human podocytes following exposure to transforming growth factor (TGF)-β1. Furthermore, we report that the miR-143/145 cluster contributes to decreased expression of Wilms’ tumor 1, which represents a possible mechanism for podocyte injury induced by TGF-β1. This study is important because it presents a novel mechanism for TGF-β-associated glomerular diseases, including diabetic kidney disease (DKD), and suggests potential therapeutic strategies targeting miR-143-3p/145-5p.

Autophagy is involved in the development of diabetic kidney disease (DKD), the leading cause of end-stage renal disease. The Fyn tyrosine kinase (Fyn) suppresses autophagy in the muscle. However, its role in kidney autophagic processes is unclear. Here, we examined the role of Fyn kinase in autophagy in proximal renal tubules both in vivo and in vitro. Phospho-proteomic analysis revealed that transglutaminase 2 (Tgm2), a protein involved in the degradation of p53 in the autophagosome, is phosphorylated on tyrosine 369 (Y369) by Fyn. Interestingly, we found that Fyn-dependent phosphorylation of Tgm2 regulates autophagy in proximal renal tubules in vitro, and that p53 expression is decreased upon autophagy in Tgm2-knockdown proximal renal tubule cell models. Using streptozocin (STZ)-induced hyperglycemic mice, we confirmed that Fyn regulated autophagy and mediated p53 expression via Tgm2. Taken together, these data provide a molecular basis for the role of the Fyn–Tgm2–p53 axis in the development of DKD.

Introduction Patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis and idiopathic interstitial lung diseases (IIPs) are positive for myeloperoxidase (MPO)–ANCA. MPO–ANCA-positive vasculitis mainly comprises microscopic polyangiitis (MPA) and unclassifiable vasculitis. These diseases are frequently complicated by interstitial lung disease (ILD). Few studies have reported the clinical differences between the subtypes of MPO–ANCA-positive ILD. Therefore, this study aimed to examine the clinical findings and courses of MPO–ANCA-positive ILD. Method This retrospective study enrolled 100 patients with MPO–ANCA-positive ILD who were categorized into three groups: MPA (n = 44), unclassifiable vasculitis (n = 29), and IIP (n = 27). Our study compared the clinical findings and prognosis of these patients and analyzed the poor prognostic factors. Furthermore, we assessed the association between the patients with and without acute exacerbation of ILD (AE-ILD). Results Our study found clinical differences in serum markers, clinical symptoms, and treatment regimens among the three groups. ILD complications, as the main cause of death, differed among the three groups (P = 0.04). Patients with unclassifiable vasculitis showed higher survival rates than those with IIP (P = 0.046). Patients with AE-ILD showed fewer general symptoms (P = 0.02) and lower survival rates (P < 0.01) than those without AE-ILD. In multivariate analysis, AE-ILD development was a strong poor prognostic factor for MPO–ANCA-positive ILD. Conclusions The subtypes of MPO–ANCA-positive ILD have different clinical features and prognoses. Patients who develop AE-ILD require careful evaluation of clinical courses. Key Points • In myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA)–positive interstitial lung disease (ILD), patients with unclassifiable vasculitis showed a better prognosis than those with idiopathic ILD.. • Development of acute exacerbation in ILD was a strong poor prognostic factor in patients with MPO–ANCA-positive ILD..

Excess lipid accumulation is associated with obesity-related chronic kidney disease, but the mechanisms of fatty acid (FA) uptake have been poorly understood. To this end, we investigated how FAs are taken up by tubular epithelial cells (TECs) in mice by using in vivo FA tracing and histological methods. Immunohistochemistry showed that CD36, which is a well-known FA transporter, was abundantly expressed on the basolateral side of proximal TECs (PTECs). The uptake of ¹²⁵ I-BMIPP (a radiolabeled FA tracer) was significantly reduced in CD36-knockout kidneys at 1 min after injection. In vivo imaging with multiphoton microscopy revealed that BODIPY-C ₁₂ (a fluorescence-labeled FA tracer) accumulated on both the basolateral and apical sides of PTECs. Numerous lipid droplets accumulated in PTECs after accelerated lipolysis. Furthermore, PTEC-specific injury via diphtheria toxin (DT) injection in transgenic mice expressing the DT receptor resulted in a compensatory increase in lipid accumulation in downstream TECs. Importantly, urinary FAs were undetectable, even in mice and humans with remarkable albuminuria. Our data demonstrate that renal TECs take up FAs from blood (CD36-dependent) and primary urine (CD36-independent) and can store excess FAs as neutral lipids. The results further show that renal tubules have hitherto largely unappreciated mechanisms by which the excretion of FAs into the urine is avoided.