Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare ANCA-associated small-vessel vasculitis that may involve the peripheral nervous system. Although peripheral neuropathy is a common manifestation, acute symmetric presentations may mimic Guillain-Barré syndrome (GBS), creating significant diagnostic challenges. We describe the case of a 71-year-old woman with a history of allergic asthma and hypertension who developed progressive distal paraesthesias and ascending weakness following a flu-like prodrome. Neurological examination showed symmetrical flaccid weakness and generalised areflexia. Cerebrospinal fluid analysis was normal, while nerve conduction studies demonstrated acute axonal polyneuropathy fulfilling the Brighton criteria for GBS. Intravenous immunoglobulin therapy (2 g/kg) initially resulted in transient clinical improvement, but neurological symptoms rapidly relapsed with painful lower-limb weakness. Subsequent investigations revealed acute kidney injury associated with proteinuria, microscopic haematuria and marked eosinophilia (30%). ANCA testing demonstrated strong MPO-ANCA positivity (> 134 U/mL). Kidney biopsy showed crescentic glomerulonephritis with eosinophilic interstitial infiltrates, supporting the diagnosis of EGPA-associated vasculitis. Treatment with corticosteroids followed by rituximab led to progressive neurological and renal recovery. This case highlights that EGPA may rarely present with a GBS-like phenotype and underscores the importance of considering vasculitic etiologies in patients with atypical or relapsing GBS presentations, particularly in the presence of eosinophilia or renal involvement. Given its favourable cost-benefit profile, ANCA testing may represent a valuable diagnostic tool in selected patients with suspected GBS to facilitate early diagnosis and timely initiation of immunosuppressive therapy.

BACKGROUND Granulomatosis with polyangiitis (GPA) is a small-to-medium vessel necrotizing vasculitis that affects multiple organ systems. It commonly manifests as glomerulonephritis and inflammation involving the respiratory tract. Rarely, ocular, cutaneous, neurological, and musculoskeletal manifestations occur. Mass lesions are uncommon in GPA. Our patient had a subcarinal mass and was diagnosed with GPA. In our literature review, we identified several reports of mediastinal masses; however, no specific cases of subcarinal masses were found. CASE REPORT A 22-year-old woman presented with syncope, chest pain, and weight loss. Imaging revealed a subcarinal mass. This was concerning for lymphoma or histoplasmosis. Extensive testing ensued, while treatment for histoplasmosis was initiated. Workup included a mediastinal mass biopsy that revealed granulomatous inflammation. While testing was ongoing, she developed purpuric rashes on her lower extremities and hematuria, and was subsequently found to have proteinuria of 274 mg per 24 hours. Autoimmune testing was initiated, and she was found to be positive for serine protease-3 antibody and antineutrophil cytoplasmic antibody (ANCA) indirect immunofluorescence assay with a cytoplasmic ANCA pattern and 1: 320 titer. The latter is highly specific for GPA and, along with granulomatous inflammation and clinical findings, confirmed the diagnosis. She was treated with prednisone and rituximab and had significant clinical improvement at the time of discharge. CONCLUSIONS Subcarinal masses are commonly caused by malignancies and infections. This case details an unusual presentation of GPA as a subcarinal mass. It highlights the importance of considering GPA as a possible diagnosis for patients with constitutional symptoms, mediastinal mass, and necrotizing granulomatous inflammation on pathology.

Idiopathic membranous nephropathy (IMN) presents a heterogeneous clinical course, with approximately 30% to 40% of patients experiencing spontaneous remission, while others respond poorly to treatment. This study aims to identify reliable biomarkers for risk stratification in IMN patients. We conducted a prospective observational study involving 187 patients with IMN from February 2022 to February 2024. Patients were categorized into remission and non-remission groups based on clinical outcomes one year post-treatment. Comparative analyses revealed that the non-remission group exhibited significantly higher incidences of hypertension, elevated 24-hour urinary protein, higher serum creatinine levels, and increased inflammatory markers, including the systemic immune inflammation index (SII), systemic inflammation response index (SIRI), and pan-immune inflammation value (PIV). Conversely, the estimated glomerular filtration rate (eGFR) and lymphocyte-to-monocyte ratio (LMR) were lower in non-remission patients. Spearman correlation identified hypertension, 24-hour urinary protein, and inflammatory indexes as positive correlates with non-remission, while eGFR showed a negative correlation. Multivariate logistic regression confirmed hypertension, high 24-hour urinary protein, SII, SIRI, and PIV as independent risk factors for non-remission; eGFR was a protective factor. Receiver operating characteristic analysis revealed that SII and PIV effectively predicted non-remission (AUC=0.743 and 0.759, respectively). These findings underscore the potential of these indicators in assessing disease severity and guiding personalized treatment strategies.

ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome is a rare, autosomal dominant autoinflammatory disorder caused by gain-of-function mutations in ALPK1. These mutations activate NF-κB signaling and drive development of a multisystemic disease. Beyond the hallmark features captured in the ROSAH acronym, affected individuals may experience recurrent low-grade fevers, deforming arthritis, and gastrointestinal inflammation. Prior to the identification of a unifying genetic cause, patients can be misdiagnosed with a range of immune-mediated conditions, such as systemic juvenile idiopathic arthritis, multiple sclerosis, and systemic lupus erythematosus. Here, we report a 44-year-old man who was given a diagnosis of lupus nephritis before being found to have ROSAH. He presented with mild chronic kidney disease and subnephrotic proteinuria. Renal biopsy revealed immune complex-mediated glomerulonephritis with minimal mesangial proliferation, resembling class II lupus nephritis, despite the absence of clinical or serological markers of systemic lupus erythematosus. In parallel, we leveraged the world's largest reported single-center ROSAH cohort to assess the prevalence of chronic kidney disease in this rare genetic syndrome.

Membranous nephropathy is an autoimmune disease associated with antibodies against podocyte proteins, and it is the main cause of nephrotic syndrome in adults. Rituximab has now become the first-line treatment for membranous nephropathy, with 80% of patients achieving remission. However, some patients develop drug resistance or experience relapse to rituximab. Potential resistance mechanisms include changes in bioavailability and pharmacokinetics, rituximab internalization by B cells, memory B cells escape from rituximab, generation of anti-rituximab antibodies, impact of phospholipase A2 receptor antibodies and epitope spreading, and chronic and irreversible kidney injury. Understanding these specific resistant mechanisms has driven the development of multiple therapies. Emerging treatments, including next-generation anti-CD20 monoclonal antibodies, B lymphocyte stimulator inhibitors, proteasome inhibitors, complement inhibitors, and plasma cell-targeted drugs, offer new hope for these patients. This review summarizes the potential mechanisms of rituximab resistance in membranous nephropathy and recent therapeutic advances, aiming to provide guidance for clinical management of membranous nephropathy.

BACKGROUND Infective endocarditis is challenging to diagnose when blood cultures are negative, and its symptoms are nonspecific. Bartonella species are fastidious intracellular bacteria that can cause culture-negative endocarditis and immune-mediated complications such as glomerulonephritis, often mimicking ANCA-associated glomerulonephritis. CASE REPORT A 25-year-old man who underwent a Ross procedure for congenital aortic stenosis performed in childhood presented with 1 month of night sweats, abdominal pain, and intermittent nausea. Initial evaluation revealed elevated creatinine, pancytopenia, proteinuria, microscopic hematuria, and splenomegaly. Serologies showed positive c-ANCA and elevated PR3 antibodies. A presumed diagnosis of ANCA-associated glomerulonephritis led to initiation of high-dose steroids and planned rituximab. Kidney biopsy demonstrated crescentic glomerulonephritis with C3-dominant immune complex deposition, atypical for pauci-immune disease, prompting discontinuation of steroids. Further infectious workup revealed high Bartonella henselae IgM and IgG titers. The patient met the criteria for possible infective endocarditis under the 2023 Duke-ISCVID criteria. Transesophageal echocardiography showed valvular abnormalities without definite vegetations, although only a prior transthoracic echocardiogram was available for comparison. The patient was treated with doxycycline and rifampin for 12 weeks, resulting in clinical and laboratory improvement. CONCLUSIONS This case demonstrates that Bartonella endocarditis can closely mimic ANCA-associated glomerulonephritis and rapidly progressive glomerulonephritis. In patients with systemic symptoms, positive ANCA serologies, and negative cultures, occult infection must be a key consideration, especially in patients at high risk for infective endocarditis. A careful exposure history, including pets, travel, and dental procedures, can provide crucial diagnostic clues. Early recognition and targeted antimicrobial therapy are essential to prevent irreversible organ damage and avoid inappropriate immunosuppression.

Ongoing phase 3 clinical trials are evaluating novel therapies for diverse manifestations of systemic lupus erythematosus, including cutaneous disease and lupus nephritis. Current investigational strategies predominantly target key immunopathogenic pathways, particularly type I interferon signaling and B cell activation, which reflects an evolving approach to management.

Concurrent anti-neutrophil cytoplasmic antibody (ANCA)-associated nephritis and immunoglobulin G4 (IgG4)-related nephritis is a rare clinical entity with incompletely understood pathogenesis and progression. We describe the case of a 56-year-old woman, without significant past medical history, who presented with a recurrent low-grade fever for over 3 months, occasional non-productive cough, and acute renal insufficiency, but without chills. Empirical anti-infective therapy was ineffective. Laboratory evaluation revealed moderate anemia and microscopic hematuria without proteinuria on urinalysis. Immunological testing was positive for anti-myeloperoxidase (MPO) antibodies, supporting a preliminary diagnosis of ANCA-associated vasculitis with renal involvement. Renal biopsy demonstrated crescentic glomerulonephritis coexisting with tubulointerstitial nephritis (TIN), with predominant infiltration by IgG4-producing plasma cells, despite a normal serum IgG4 concentration. Following confirmation of no therapeutic contraindications, the patient received corticosteroids in combination with rituximab. At a 2-week follow-up, renal function had improved, erythrocyte sedimentation rate and C-reactive protein were normalized, and urinalysis was negative for occult blood and protein, indicating effective disease control. Cases with concurrent ANCA-associated vasculitis and IgG4-related renal disease are exceedingly uncommon. Their clinical manifestations are often atypical, and routine laboratory assessments are insufficient for differentiation, typically requiring integrated histopathological analysis for definitive diagnosis. Further clinical observations and laboratory studies are needed to clarify the pathogenesis, improve diagnostic accuracy, and establish optimal treatment strategies for this complex condition.

IgA nephropathy (IgAN) is a common glomerulonephrites worldwide. We herein aimed to investigate the pathogenic mechanisms underlying IgAN and to identify hub targets. The IgAN-related datasets were derived from the Gene Expression Omnibus database. Hub targets were identified by integrating differentially expressed gene (DEG) analysis and multiple protein-protein interaction (PPI) network algorithms. Functional enrichment and immune landscape analyses were conducted to explore the functional impacts of the hub targets. An IgAN cell model was employed to confirm the hub gene expression and its effect on cell proliferation in vitro. Drugs targeting the hub gene were validated via molecular docking. By integrating DEG and multiple PPI network algorithms, NR1H4 was significantly downregulated in IgAN comparing to control samples, which was successfully validated in multiple datasets, clinical cohort, and IgAN cell model. A total of 48 pathways were significantly enriched in both NR1H4 low vs. high expression groups and IgAN vs. control groups. Moreover, NR1H4 overexpression significantly inhibited the abnormal cell proliferation of IgA1-induced HMCs in vitro. NR1H4 showed great clinical potential in IgAN, particularly in terms of diagnostic value (AUC > 0.7) and as a drug target (e.g., the promising drug like obeticholic acid). In conclusion, NR1H4 downregulation probably contributed to the development of IgAN by promoting abnormal cell proliferation, highlighting its considerable clinical potential in the management strategy of IgAN.

Focal segmental glomerulosclerosis (FSGS) is a progressive glomerular disease characterized by podocyte injury, proteinuria, and risk of kidney failure. Until recently, no medicines had been approved by the FDA or European Medicines Agency, with management focused on supportive care and proteinuria reduction. This supplement explores the burden of FSGS from a clinical, humanistic, and economic perspective, informed by the results of 3 systematic literature reviews. FSGS is associated with poorer quality of life and high health care costs, and these outcomes are correlated with disease severity. Kidney Disease: Improving Global Outcomes guidelines recommend monitoring estimated glomerular filtration rate (eGFR) for kidney function; however, it is acknowledged that given the variable decline in FSGS, eGFR is not an ideal trial end point. Consequently, proteinuria reduction has become the preferred surrogate efficacy end point, as supported by the International Society of Glomerular Disease's global Proteinuria and Other Biomarkers as Endpoints for Clinical Trials in Kidney Disease initiative and subsequent FDA endorsement. Available treatments, such as glucocorticoids or calcineurin inhibitors, are limited in efficacy and safety. Among emerging medicines, sparsentan, a dual endothelin and angiotensin receptor antagonist (DEARA), has demonstrated consistent and significant reductions in proteinuria among patients with primary and genetic FSGS resulting in its approval by the FDA to reduce proteinuria in adult and pediatric patients aged 8 years and older with FSGS without nephrotic syndrome. In the phase 2 DUET clinical trial (NCT01613118), those treated with sparsentan showed a urine protein-creatinine ratio reduction of -35.6% (95% CI, -46.3% to -24.6%) vs baseline at 240 weeks. Sparsentan also showed greater reductions in proteinuria vs irbesartan, a standard renin-angiotensin system agent, along with a comparable safety profile in the phase 3 DUPLEX trial (NCT03493685). In model-based projections among real-world registry cohorts, sustained reductions in proteinuria are associated with lower long-term risk of kidney failure. These findings align with the PARASOL-FSGS initiative, supporting the role of proteinuria reduction as a key end point, facilitating pragmatic trial designs to address the persistent treatment gap in FSGS.