Takashi Oda

IgA vasculitis (IgAV), formerly known as Henoch‐Schönlein purpura, is a small‐vessel vasculitis characterized by IgA‐dominant immune deposits in the skin, kidney, gastrointestinal tract, and joints, often following infections, particularly β‐hemolytic streptococci. Nephritis‐associated plasmin receptor (NAPlr), a streptococcal glyceraldehyde‐3‐phosphate dehydrogenase, has been identified as a nephritogenic protein in post‐streptococcal acute glomerulonephritis, binding plasmin and maintaining its proteolytic activity, thereby promoting tissue injury. However, the role of NAPlr in IgAV pathophysiology remains unclear. In this study, we investigated histological staining for NAPlr and plasmin activity in IgAV cutaneous lesions and evaluated circulating anti‐NAPlr antibodies. Skin specimens from patients with IgAV were analyzed by immunofluorescence and in situ zymography, and serum anti‐NAPlr antibodies (IgG, IgM, and IgA) were measured by enzyme‐linked immunosorbent assay in 21 patients with IgAV and 18 healthy donors. Positive staining for NAPlr and plasmin activity was observed in dermal lesions in 7 of 11 patients with IgAV, but was minimal in control skin. Patients with IgAV showed significantly elevated serum levels of anti‐NAPlr IgG and IgA antibodies compared with healthy donors. Anti‐NAPlr IgG levels positively correlated with serum creatinine and negatively correlated with CH50, with a nonsignificant inverse association with estimated glomerular filtration rate (eGFR). Serum galactose‐deficient IgA1 levels were also significantly increased in patients with IgAV, and were positively correlated with anti‐NAPlr IgA levels but negatively correlated with C4. These findings demonstrate the presence of a protein that is stained by anti‐NAPlr antibody in IgAV cutaneous lesions alongside elevated circulating anti‐NAPlr antibodies, suggesting that immune responses to NAPlr may contribute to IgA‐mediated vascular inflammation, potentially through complement activation.

Background: Estimating glomerular filtration rate (GFR) is challenging due to its dependence on age and body composition, especially in pediatric and elderly populations. Recently, d -serine and d -asparagine, rare amino acid enantiomers, have been identified as GFR biomarkers characterized by their ideal kidney clearance and minimal impacts of body size. We investigated the impact of age and sex on GFR estimation using these d -amino acids. Methods: We analyzed data from a cross-sectional observational cohort: 366 adult Japanese living kidney transplant donors and recipients. Using a dataset of 244 patients, we developed GFR estimation formulae based on blood levels of d -Ser and d -Asn using linear regression analyses, and validated the formulas’ performance in 122 patients. Results: The d -amino aci d- based equation was established as 60.4 x d -Ser ^-0.450 x d -Asn ^-0.304 x 0.916 (if female), in which age did not significantly improve model performance and the impact of sex was minor. The performance of the established equations was equivalent to that of creatinine-based equations: bias (absolute difference), 9.1 [8.0-11.2], precision (interquartile range of bias), 11.1 [8.8-14.2], and accuracy (ratios of 30% different from measured GFR [P ₃₀ ]), 0.82 [0.73-0.89]. Conclusions: d -Amino acid-based estimation of GFR exhibits minimal empirical association with age and sex, offering a distinct advantage over models dependent on these demographic variables. This stability may support its broad clinical utility as a reliable diagnostic tool across all age groups and diverse populations.

Circulating immune complexes (CICs) are frequently detected in the sera of patients with myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (MPO-AAGN) and their role in activating the classical complement pathway has been suggested. However, the precise composition and functional characteristics of CICs in AAGN remain poorly understood. We analyzed serum samples from four patients with MPO-AAGN and confirmed CICs. An immunoadsorbent column was prepared using a monoclonal rheumatoid factor antibody that binds to CICs, enabling extraction via immunoprecipitation. CICs were analyzed by Western blotting to detect MPO and IgG. Their capacity to activate complement was assessed in vitro by measuring complement activation products using the enzyme-linked immunosorbent assay following incubation with normal human serum. Western blotting revealed distinct bands for both MPO and IgG in all samples. Incubation of extracted CICs with normal human serum resulted in elevated levels of complement activation products, including C5a and C5b-9. This increase was completely inhibited by the addition of EDTA or EGTA. In conclusion, CICs in the serum of patients with MPO-AAGN contain MPO and IgG (presumably MPO-ANCA). These CICs can activate the complement system, likely through the classical pathway. Our findings support the hypothesis that CICs composed of MPO and MPO-ANCA contribute to complement activation via the classical pathway and play a significant role in AAGN pathogenesis.

Studies examining IgG subclasses within circulating immune complexes (CICs) in patients with IgG4-related disease remain scarce. A Japanese man in his 50s with a history of diabetes mellitus and chronic pancreatitis was referred to our department because of an increase in serum creatinine levels. Serum IgG and IgG4 levels were markedly high, accompanied by eosinophilia and elevated serum IgE levels. C3 hypocomplementemia and an increase in CICs were also noted, and imaging revealed swollen mediastinal lymph nodes. Renal biopsy revealed extensive tubulointerstitial nephritis with numerous IgG4-positive plasma cells and dense interstitial fibrosis. The patient was diagnosed with IgG4-related disease, and glucocorticoid therapy was initiated; renal function, serological abnormalities, and swelling of the mediastinal lymph nodes improved. Subsequent analyses revealed that the patient’s CICs mainly comprised IgG4 and that there was tubular deposition of complement components C1q, C4d, C3, and C5b-9 in the renal biopsy tissue, suggesting that immune complexes containing IgG4 activated the complement pathway in circulation and locally in the kidneys. Hypocomplementemia and CICs are observed in a subset of patients with IgG4-related diseases; however, the underlying mechanisms remain unclear. Further accumulation of IgG4-related disease cases is required to evaluate the possibility of IgG4-mediated complement activation.

Following the discovery of podocyte phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A, various potential target antigens for membranous nephropathy (MN) have been reported one after another. MN target antigens have now been identified in a significant proportion of patients, and a new classification framework classifies patients with MN based on the detected antigen and associated disease phenotype. A serology-based approach that does not require a histological diagnosis for patients suspected of having MN has also been proposed. However, there have been cases in which dual positivity for MN antigens and/or corresponding antibodies has been shown. Importantly, some of them showed a transition of the affected patient’s immune responses to MN antigens, suggesting that serological diagnosis changes depending on the timing of the analysis. In this review, we provide detailed information on these cases and present an overview of our recent understanding of their putative mechanisms involved in these cases. Greater awareness is required to adequately recognize and develop appropriate therapeutic strategies for this condition.

We report the histological changes over time for a patient with infection-related glomerulonephritis (IRGN) that developed in a transplanted kidney. A 47-year-old man had undergone renal transplantation 3 years ago for end-stage kidney disease (ESKD). After several episodes of acute rejection, the patient was in a stable CKD condition. The abrupt development of severe microscopic hematuria and renal dysfunction was observed approximately 2 weeks after the onset of a phlegmon in his right leg. An allograft biopsy showed prominent glomerular endocapillary proliferation on light microscopy, granular C3 deposition on immunofluorescent microscopy, and subepithelial electron-dense deposits on electron microscopy, suggesting IRGN accompanied by moderate interstitial fibrosis and tubular atrophy (IFTA). Positive glomerular staining for nephritis-associated plasmin receptor (NAPlr) and plasmin activity, which are biomarkers of bacterial IRGN, supported the diagnosis. Although the infection was completely cured with antibiotic therapy, renal dysfunction persisted. A re-biopsy of the allograft 2 months later revealed resolution of the glomerular endocapillary proliferation and negative staining for NAPlr/plasmin activity, with worsening IFTA. We showed, for the first time, the chronological changes in infiltrating cells and histological markers of IRGN in transplanted kidneys. Glomerular changes, including NAPlr/plasmin activity staining, almost disappeared after the cessation of infection, while interstitial changes continuously progressed, contributing to ESKD progression.

Hemophagocytic syndrome/macrophage activation syndrome (HPS/MAS) is a serious clinical condition that frequently leads to multiple organ failure, including acute kidney injury (AKI). Although the pathogenesis of AKI is not yet fully understood, it is believed to result from uncontrolled activation of the immune system involving macrophages and cytotoxic lymphocytes. Renal histology in HPS/MAS often presents with characteristic foamy glomerular lesions (glomerular lipidosis) with massive macrophage infiltration, known as histiocytic glomerulopathy. In this review, we introduce the recently proposed concept of renal-limited HPS/MAS as a novel etiology of histiocytic glomerular lipidosis. Patients with renal-limited HPS/MAS often develop AKI but do not fulfill the diagnostic criteria for HPS/MAS because their systemic manifestations are less severe. Therefore, the diagnosis largely depends on characteristic histological findings, that is, diffuse and global glomerular accumulation of foamy macrophages and cytotoxic lymphocytes accompanied by the interaction of these cells as well as the exclusion of various differential diseases. Although there are no established therapeutic regimens, these patients receive various types of therapies, including high-dose glucocorticoids, immunosuppressants, or anti-interleukin-1 drug, and generally achieve favorable outcomes. We summarized the concept, diagnostic challenges, and recent topics of this disease entity and discussed treatment options based on our own experiences.

Editorial: Pathogenic aspects of the innate immune system of the kidney