Yoshihito Nihei

IgA nephropathy is the most common primary glomerular nephritis worldwide and remains one of the leading causes of kidney failure. Although IgA nephropathy is a heterogeneous disease, glomerular deposition of galactose-deficient IgA1 (Gd-IgA1) is considered a pathological feature shared across the disease. This pathological hallmark underpins the multihit hypothesis of IgA nephropathy and has driven the development of therapies targeting Gd-IgA1 production, several of which have recently demonstrated clinical efficacy and received regulatory approval. These advances provide a timely opportunity to re-evaluate the role of Gd-IgA1 in the pathogenesis of IgA nephropathy. Notably, analysis of longitudinal changes in serum Gd-IgA1 levels and proteinuria reported in recent therapeutic trials raises the possibility that only a subset of circulating Gd-IgA1, rather than the entire circulating Gd-IgA1 pool, may drive glomerular inflammation leading to hematuria and/or proteinuria in IgA nephropathy. In this review, we propose the concept of “pathogenic Gd-IgA1” to describe this disease-relevant subset and highlight three potential features: a mucosal origin, molecular properties that promote selective mesangial deposition, and the capacity to form immune complexes and activate the complement system. This conceptual framework may deepen our understanding of IgA nephropathy pathogenesis, help optimize the use of emerging therapies, and facilitate the development of novel therapies that selectively target pathogenic Gd-IgA1.

This study evaluates the dynamic clinical reasoning of 4 leading large language models in complex nephrology cases, demonstrating that while Gemini 2.5 Pro achieved the highest reasoning scores and computational efficiency, all tested models excelled at static data synthesis but shared vulnerabilities in formulating nuanced differential diagnoses and in prospective clinical planning.

Key Points: Serum IgM-free apoptosis inhibitor of macrophage reflects disease activity in human IgA nephropathy. Glomerular apoptosis inhibitor of macrophage deposition was colocalized with mesangial IgA and reflected the acute glomerular injuries by complement activation. Multivariate Cox regression analysis revealed serum IgM-free apoptosis inhibitor of macrophage as an independent predictor of hematuria remission in patients. Background: IgA nephropathy is characterized by mesangial deposits of IgA1-containing immune complex with complement 3. Our previous study demonstrated that apoptosis inhibitor of macrophage (AIM) plays a critical role in in situ IgA-containing immune complex formation and subsequent complement activation in murine IgA nephropathy. We further evaluated the clinicopathologic role of AIM in human IgA nephropathy. Methods: We enrolled 77 patients with IgA nephropathy, five patients with thin basement membrane disease as disease controls, and 40 age-matched healthy individuals as healthy controls. We analyzed the association between serum IgM-free AIM (sAIM)/glomerular AIM (gAIM) deposition area and clinicopathologic features. Results: sAIM level was higher in patients with IgA nephropathy at diagnosis than in disease and healthy controls (1.02±0.49 versus 0.56±0.19 versus 0.57±0.20 µ g/ml), significantly decreased to 0.67±0.44 µ g/ml after tonsillectomy and steroid pulse therapy, and was associated with serum IgA ( r ² =0.23) and IgA–IgG immune complex levels ( r ² =0.12). gAIM was colocalized with mesangial IgA and high intensity of gAIM was associated with the degree of hematuria (30–49 versus 10–19 per high-power field) and acute lesions, including those with Oxford classification scores of endocapillary hypercellularity (E1 3% versus E0 2%) and crescent formation (C1 3% versus C0 2%). Furthermore, gAIM deposition was positively correlated with glomerular complement 3 deposition ( r ² =0.54). Multivariate Cox regression analysis revealed sAIM as an independent predictor of hematuria remission (hazard ratio, 1.86; 95% confidence interval, 1.03 to 3.15). According to Kaplan–Meier analysis, patients with larger reduction of sAIM (≥0.45 µ g/ml) after tonsillectomy and steroid pulse therapy showed a significantly improved hematuria (6 versus 9 months). Conclusions: We suggest that IgA nephropathy patients with high sAIM levels have high disease activity and patients with high intensity of gAIM deposition have acute glomerular injuries leading to hematuria.

Aim: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, yet its pathogenesis remains incompletely understood. B cell activating factor (BAFF), a TNF family member involved in B cell activation and IgA class switching, has been proposed as a potential pathogenic factor in IgAN. However, its role in disease progression is unclear. This study aimed to investigate the pathological role of BAFF in IgAN using grouped ddY (gddY) mice, a spontaneous murine model of IgAN. Methods: gddY mice were treated with anti‐BAFF monoclonal antibody (anti‐BAFF Ab) or PBS via intraperitoneal injection twice a week for 4 weeks. Urinary albumin, serum immunoglobulins, and IgA‐IgG immune complex were measured pre‐ and post‐treatment. Serum levels of aberrantly glycosylated IgA were quantified using specific lectin‐based assays. Glomerular IgA and C3 depositions were evaluated by immunofluorescence, and B cell populations in spleen and bone marrow were analysed by flowcytometry. Results: Anti‐BAFF Ab treatment significantly reduced serum IgA, IgG, and IgM levels as compared with PBS treatment ( p < 0.001, p = 0.003, and p = 0.002, respectively). However, it did not affect serum aberrantly glycosylated IgA, IgA‐IgG immune complex, and urinary albumin excretion. Glomerular depositions of IgA and C3 as well as B cell population in the spleen and bone marrow were also not affected by anti‐BAFF Ab treatment. Conclusion: BAFF inhibition reduces general immunoglobulin levels but does not impact nephritogenic IgA production or disease progression in murine IgAN. These findings suggest that BAFF‐dependent IgA production may not be involved in the pathogenesis of IgAN.

Aim: Glomerular IgA deposition is incidentally observed in asymptomatic individuals; however, it remains unclear whether these cases represent a preclinical stage of IgA nephropathy (IgAN). We aimed to address this question by staining kidney samples from autopsy cases with the anti‐galactose‐deficient IgA1 (Gd‐IgA1: the key effector molecule in the pathogenesis of IgAN) antibody, KM55. Methods: Kidney samples from 192 autopsy cases in Japan were stained with anti‐IgA antibody and KM55. The deposition of complement C3, IgG and IgM in glomeruli, as well as the histological findings and clinical data were analysed in cases positive for glomerular IgA. Results: Glomerular IgA deposition was detected in 13 cases (6.8%), all of which were stained with KM55. Of 10 cases with available urinary data prior to admission, six did not have abnormal urinary findings. 7 of 13 were positive for glomerular Gd‐IgA1 alone without obvious histological changes. Glomerular IgG and IgM were detected in 1 of 13 and 5 of 13 cases, respectively. 2 of 13 were positive for glomerular C3, with one showing mesangial proliferation. Conclusion: Our results indicate that asymptomatic cases with glomerular IgA deposition may frequently include subclinical IgAN, characterised by glomerular deposition of Gd‐IgA1 (KM55‐positive) without prominent histopathological changes or obvious clinical symptoms.

Aim: Minimal change disease (MCD) is one of the causes of idiopathic nephrotic syndrome, and 40% of patients have allergic diseases. About 30% of MCD patients become resistant to steroid after a long period of steroid therapy; however, the mechanism of steroid resistance is unclear. Thymic stromal lymphopoietin (TSLP), an epithelial cytokine, is known to be associated with steroid‐resistant allergic disease. Experiments using mouse models of asthma suggest that TSLP‐mediated phosphorylation of signal transducer and activator of transcription 5 (STAT5) binds to corticosteroid receptors, resulting in steroid resistance. In the present study, we aim to investigate whether TSLP is involved in steroid resistance in patients with MCD. Methods: We compared serum TSLP levels in patients with MCD ( n = 26) and healthy controls ( n = 13). The cultured podocytes were used to investigate whether TSLP attenuates the podocyte‐protective effect of dexamethasone (DEX) and whether the administration of a TSLP‐neutralising antibody abolishes TSLP‐induced steroid resistance. Results: The level of serum TSLP in patients with MCD was significantly higher than that in healthy controls ( p < 0.05). Of note, in patients with MCD, serum TSLP levels significantly elevated at recurrence ( p < 0.05). In vitro, DEX protected podocytes from Adriamycin‐induced injury. The protective effect of DEX on podocytes was attenuated by co‐culture with TSLP ( p < 0.01). However, treatment with TSLP neutralising antibody improved TSLP‐induced steroid resistance ( p < 0.001). We also found that TSLP induces STAT5 activation in podocytes, which is blocked by TSLP‐neutralising antibodies. Conclusion: TSLP may be involved in steroid resistance via the STAT5 pathway in podocytes.

Key Points: Little is known about the clinicopathological characteristics and renal outcomes in the patients with gross hematuria (GH) after the vaccination. To fill a clinicopathological knowledge gap regarding vaccination and GH, we conducted a nationwide multicenter prospective cohort study. GH is more likely to occur in patients with IgA nephropathy, with a female bias, but without progressive exacerbation of renal function. Background: In the past 3 years, cases of gross hematuria (GH) after the vaccination for coronavirus disease 2019 in patients with IgA nephropathy (IgAN) have been frequently reported worldwide. However, the postevent renal prognosis of these patients, their clinical backgrounds, and underlying mechanisms remain unknown. Therefore, we conducted a nationwide multicenter prospective cohort study in Japan. Methods: We analyzed laboratory findings at the time of the first presentation to the hospital and 3 and 6 months after in patients with GH after the vaccination and histopathological findings in their kidney biopsy specimens. Moreover, changes in pathological biomarkers of IgAN such as galactose-deficient IgA1 (Gd-IgA1) and its immune complexes were also evaluated. Results: During the study period, 127 newly presenting patients with GH after the vaccination were enrolled, with a clear female bias (73.2%). GH was observed after the second or subsequent vaccinations in most patients (92.9%). Of the 37 patients undergoing kidney biopsy before the vaccination, 36 patients had been diagnosed with IgAN/IgA vasculitis (IgAV). In the remaining 90 patients, 69 of the 70 who newly underwent kidney biopsy were diagnosed with IgAN (n=67)/IgAV (n=2). Their histopathology did not show a high incidence of acute lesions such as endocapillary hypercellularity and crescentic lesions. Most cases showed a temporary increase in proteinuria, but no sustained worsening in renal function. Among the biomarkers measured, serum Gd-IgA1 and immune complexes were comparable throughout the observation period; however, only urinary Gd-IgA1 was increased at the time of GH. Conclusions: We found that GH after the vaccination is more likely to occur in patients with IgAN/IgAV, with a female bias, but without progressive exacerbation of renal function. Although further investigation is needed regarding causal relationship between vaccination and GH, this study provides many insights into the molecular mechanisms of GH.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including βII-spectrin. Most patients with IgAN also have serum anti–βII-spectrin IgA. As in patients with IgAN, IgA ⁺ plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to βII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous βII-spectrin exposed on the surface of embryonic kidney–derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.