Short-Term Outcomes of Infection-Related Glomerulonephritis in Diabetes Mellitus.

Background and objective Infection-related glomerulonephritis (IRGN) in adults, particularly the diabetic population, has a grave prognosis with many patients progressing to dialysis-dependent renal failure. Indian data on this entity are very scarce. This study attempts to correlate the clinicopathological factors related to diabetic IRGN and its short-term outcomes. Subjects and methods A retrospective analysis of all diabetic patients with biopsy-proven IRGN between January 2017 and August 2021 was conducted. Factors affecting outcomes such as clinical characteristics, urine examination, complete blood count, serum biochemistry, renal biopsy, and follow-up data were obtained and analyzed to determine the risk of progression to chronic kidney disease (CKD)/end-stage renal disease (ESRD). Univariate/multivariate analysis and receiver operating characteristic (ROC) curve were performed to identify independent risk factors affecting outcomes. Results A total of 40 diabetic patients with IRGN was included in the study, with a mean age of 53.08 ± 10 years, comprising predominantly males (60%). Infective foci were occult in majority (37.5%). Isolated low C3 levels were documented in the majority, while three patients (7.5%) had normal complement levels. Complete renal recovery was noted in 15 patients (37.5%), while 12 patients (30%) progressed to ESRD. Anuria or uremia at presentation, glomerulosclerosis >28.6%, interstitial fibrosis with tubular atrophy (IFTA) >17.5%, and diabetic nephropathy correlated to poor renal recovery. No correlation was observed between endocapillary proliferation, the pattern of deposits, the prevalence of crescents, and complement levels with the outcome. Conclusion IRGN is a common immune-mediated clinical entity among diabetics and often requires renal replacement therapy. Anuria or uremia at presentation, diabetic nephropathy, elevated glomerulosclerosis, and IFTA were associated with poor renal recovery. Complement levels and crescents had no impact on the outcome.

Glomerular injury induced by vinyl carbamate in A/J inbred mice: a novel model of membranoproliferative glomerulonephritis.

Ethyl carbamate (EC) is a process contaminant found in fermented foods and alcoholic beverages. Metabolic conversion of ethyl carbamate generates vinyl carbamate (VC), a carcinogenic metabolite. EC, as a Group 2A probable human carcinogen, and the more potent VC, are known to cause tumors in rodents. However, their effects on the kidney are unknown and were explored here. Female A/J inbred mice received an intraperitoneal injection of vehicle or VC. Beginning 5 weeks after VC injection, mice showed signs of moribund state. Mouse necropsies revealed renal glomerular injury that histopathologically recapitulated human membranoproliferative glomerulonephritis (MPGN), as evidenced by light microscopy, immunostaining for immunoglobulins and complements, and electron microscopy. To determine the molecular pathomechanisms, a post-hoc analysis was performed on a publicly available RNA-Seq transcriptome of kidneys from control rats and rats treated with fermented wine containing high concentrations of EC. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the differentially expressed genes revealed that the complement and coagulation cascades were a top predicted biological process involved. Furthermore, pathway-based data integration and visualization revealed that key regulators of complement activation were altered by high EC treatment. Among these, complement factors (CF) D and H, critical positive and negative regulators of the alternative pathway, respectively, were most affected, with CFD induced by 3.49-fold and CFH repressed by 5.9-fold, underscoring a hyperactive alternative pathway. Consistently, exposure of primary glomerular endothelial cells to EC or VC resulted in induction of CFD and repression of CFH, accompanied by increased fixation of C3 and C5b9. This effect seems to be mediated by Ras, one of the top genes that interact with both EC and VC, as identified by analyzing the chemical-gene/protein interactions database. Indeed, EC or VC-elicited complement activation was associated with activation of Ras signaling, but was abolished by the Ras inhibitor farnesyl thiosalicylic acid. Collectively, our findings suggest that VC, a metabolite of EC, induces glomerular injury in mice akin to human MPGN, possibly via perturbing the expression of complement regulators, resulting in an effect that favors activation of the alternative complement pathway.

Crescentic Glomerulonephritis in Association With Renal Cell Carcinoma: A Case Report.

Clear renal cell carcinoma (RCC) is the most common primary renal tumor originating within the renal cortex. It is responsible for 75% to 85% of all primary renal neoplasms. Multiple risk factors are associated with the development of RCC, the most common being smoking. On some occasions, RCC has been linked to some autoimmune conditions, but data is limited. Especially, its association with glomerulonephritis (GN) is rare in literature and not fully understood. In this case report, we discuss a presentation of RCC associated with crescentic GN.

A Rare Presentation of Cryoglobulinemic Vasculitis Associated with Primary Sjögren's Syndrome.

INTRODUCTION: Sjögren's syndrome is a chronic autoimmune disorder that results in dry eyes and mouth. It is rarely associated with cryoglobulinemia, the agglutination of cryoglobulins at cold temperatures that leads to systemic inflammation and organ damage. We have, herein, presented a case of Cryoglobulinemic Vasculitis (CryoVas), which presents as cryoglobulinemic glomerulonephritis and Central Nervous System (CNS) vasculitis and peripheral neuropathy. CASE REPORT: A 52-year-old woman with a past medical history of Sjögren's syndrome was admitted to the intensive care unit with severe hyponatremia, orthopnea, and progressive lower extremity weakness, and was found to have an intradural extramedullary hematoma with mass effect in the thoracic spine and diffuse hyperintense cord signal abnormality in thoracic spine suggestive of intermixed proteinaceous or hemorrhagic material. Further testing demonstrated that the patient experienced worsening neuropathy, proteinuria, hematuria, declining renal function, and the presence of cryoglobulins in the blood. After a thorough examination and a renal biopsy, the patient was diagnosed with cryoglobulinemic glomerulonephritis and cryoglobulinemic vasculitis of the spine. The patient was treated with rituximab and pulse-dose steroids, with which the patient exhibited improved renal function and resolution of a previously seen intradural hematoma on repeat MRI. CONCLUSION: We have, herein, discussed a rare case of cryoglobulinemic vasculitis that has led to a rare CNS manifestation and concomitant cryoglobulinemic glomerulonephritis. This suggests that clinicians should consider cryoglobulinemic vasculitis as the etiology that could manifest with multiorgan involvement, especially in patients with underlying rheumatic diseases.

Female With Hypertensive Emergency Later Found to Have ANCA-Associated Vasculitis: A Case Report.

Granulomatosis with polyangiitis (GPA) is a form of ANCA-associated vasculitis characterized by necrotizing vasculitis affecting small blood vessels. The clinical presentation varies based on organ involvement, commonly affecting the upper and lower respiratory tracts and kidneys. Typical GPA presents as recurrent sinus infection, otitis media, dyspnea, chest pain, and glomerulonephritis, which can present as hematuria, proteinuria, and elevated serum creatinine. ANCA tests positive in the majority of cases. Treatment strategies involve induction of remission and maintenance therapy. We report a case of a 48-year-old female presenting with a hypertensive emergency, a rarely reported manifestation of GPA. She initially presented with severe headache and cough, with systolic blood pressure exceeding 220 mmHg, necessitating hospital admission. The initial workup revealed elevated serum creatinine and CT chest findings suggestive of multi-lobar pneumonia, for which she received antibiotic treatment. Despite aggressive antihypertensive therapy, her blood pressure remained refractory, and she developed hematuria and anemia, requiring a blood transfusion. Further evaluation revealed a history of joint pain, recurrent sinus infections, and a pruritic skin rash, prompting suspicion of vasculitis. Further work-up included elevated erythrocyte sedimentation rate (ESR), normal IgE, absence of eosinophilia, and positive PR3 antibodies and c-ANCA. Prompted by clinical suspicion, treatment with steroids was initiated, and a kidney biopsy confirmed acute necrotizing pauci-immune glomerulonephritis consistent with GPA. Subsequently, rituximab therapy was initiated, resulting in significant improvement in her clinical symptoms and blood pressure, and the patient was successfully discharged home. This case highlights a rare presentation of GPA as a hypertensive emergency, possibly linked to renal involvement in the form of glomerulonephritis. Pulmonary manifestations mimicking infections posed diagnostic challenges. Cutaneous findings potentially associated with increased joint and renal involvement underscore the clinical complexity of GPA. The unusual presentation of hypertensive emergency in young patients underscores the need for heightened awareness of this potential manifestation in GPA. Early recognition and aggressive immunosuppressive therapy are crucial to mitigate irreversible renal damage in such atypical presentations.

Etiology, clinical profile, and outcomes of crescentic glomerulonephritis in children: a systematic review.

BACKGROUND: Crescentic glomerulonephritis, if not managed promptly, is associated with unsatisfactory outcomes. There are limited studies reporting the outcomes of crescentic glomerulonephritis in children. OBJECTIVES: This systematic review is aimed at synthesizing the data on etiology, clinical profile, and outcomes of crescentic glomerulonephritis in children. DATA SOURCES: We performed a literature search using PubMed, Embase, and Web of Science from inception to January 2024 without language or geographic restrictions. STUDY ELIGIBILITY CRITERIA: Cohort and cross-sectional studies with at least 10 participants reporting etiology, clinical features, and outcomes on crescentic glomerulonephritis in children were considered eligible. PARTICIPANTS AND INTERVENTIONS: Children aged less than 18 years with crescentic glomerulonephritis. STUDY APPRAISAL AND SYNTHESIS METHODS: We used a tool by Hoy et al. for assessing the quality of studies. We calculated pooled estimates using random effect meta-analyses. Primary outcome was the pooled proportion of patients progressing to kidney failure. RESULTS: From 1706 records, we included 36 studies (1548 participants) from 16 countries. Etiology was immune-complex glomerulonephritis in 76% (95% CI 67 to 85), pauci-immune in 19% (13 to 25), and anti-GBM disease in 5% (3 to 7) of patients. Gross hematuria, oliguria, edema, and hypertension were observed in 63% (41 to 82), 57% (34 to 79), 79% (65 to 90), and 64% (49 to 77), respectively. In-hospital mortality, reported in 11 studies, was 7% (4 to 11). Progression to kidney failure and chronic kidney disease was reported in 27% (21 to 33) and 50% (29 to 71) of patients, respectively. Risk factors for kidney failure included oliguria, dialysis requirement at onset, estimated GFR, proportion of fibrous crescents, and pauci-immune glomerulonephritis as the underlying etiology. LIMITATIONS: High heterogeneity in pooled estimates of the outcomes. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Immune-complex glomerulonephritis is the most common etiology in children, with edema, hypertension, gross hematuria, and oliguria being the chief presenting manifestations. Almost one in every four patients with crescentic glomerulonephritis progressed to kidney failure. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO registration number CRD42024500515.

Regulatory cell therapy for kidney transplantation and autoimmune kidney diseases.

Regulatory cell therapies, including regulatory T cells and mesenchymal stromal cells, have shown promise in early clinical trials for reducing immunosuppression burden in transplantation. While regulatory cell therapies may also offer potential for treating autoimmune kidney diseases, data remains sparse, limited mainly to preclinical studies. This review synthesises current literature on the application of regulatory cell therapies in these fields, highlighting the safety and efficacy shown in existing clinical trials. We discuss the need for further clinical validation, optimisation of clinical and immune monitoring protocols, and the challenges of manufacturing and quality control under Good Manufacturing Practice conditions, particularly for investigator-led trials. Additionally, we explore the potential for expanding clinical indications and the unique challenges posed in paediatric applications. Future directions include scaling up production, refining protocols to ensure consistent quality across manufacturing sites, and extending applications to other immune-mediated diseases.

Denovo glomerulonephritis associated with IgA anti-GBM alloantibodies after kidney transplantation in Alport syndrome: A case report with diagnostic implications.

Alport syndrome (AS) is a hereditary disorder caused by pathogenic variants in COL4A3, COL4A4, or COL4A5 genes expressing α3, α4, and α5 chains of basement membrane type IV collagen (COL4). The triple-helical α3α4α5(IV) protomer is a major component of the mature glomerular basement membrane (GBM) whose defective formation in AS leads to structural GBM disruption and kidney dysfunction, often resulting in kidney replacement therapy. A genetically intact renal graft exposes the immune system to a non-tolerized α3α4α5(IV) component and an alloimmune response eventually ensues. So far, only IgG alloantibodies reacting against COL4 have been reported in AS alloimmune responses. Here, we report alloimmune glomerulonephritis mediated by IgA antibodies against the non-collagenous C-terminal domain 1 of the α5(IV) chain in a patient with autosomal recessive AS following a second kidney transplantation. The patient presented a not previously described biallelic variant in the COL4A4 gene. Immunological, diagnostic, and clinical implications are discussed.

Clinicopathological characteristics of neural epidermal growth factor-like 1 protein-associated membranous glomerulonephritis.

Neural epidermal growth factor-like 1 protein (NELL1) is the second most common target antigen in membranous glomerulonephritis (MGN). However, data regarding the clinicopathological characteristics of NELL1-associated MGN are limited owing to its low prevalence. This study examined the prevalence and clinicopathological characteristics of NELL1-associated MGN in a Japanese cohort. Additionally, we compared the clinicopathological features of NELL1-positive MGN, phospholipase A2 receptor 1 (PLA2R1)-positive MGN, and MGN negative for all three antigens (NELL1, PLA2R1, and thrombospondin type-1 domain-containing 7A). Among 257 consecutive patients pathologically diagnosed with MGN at two centers in Japan, 24 (9.3%) were immunohistochemically positive for NELL1. Clinically, patients with NELL1-positive MGN were significantly older (p < 0.001) and had a higher frequency of bucillamine use (vs PLA2R1-positive MGN, p < 0.01). Histologically, NELL1-positive MGN exhibited significantly lower detection of spikes and crater formation (p < 0.001), higher prevalence of segmental spike distribution (vs PLA2R1-positive MGN: p < 0.001), and higher prevalence of stage I cases on electron microscopy (p < 0.01). There were no significant differences in the prognoses among the three groups. The characteristic histological feature of segmental distribution in NELL1-positive MGN may be related to bucillamine use and the early phase of the disease. Further investigations with larger numbers of patients may offer further insight into the prognosis of patients with NELL1-positive MGN.

Case report: membranoproliferative glomerulonephritis associated with Q fever causing chronic endocarditis.

BACKGROUND: Membranoproliferative glomerulonephritis is a rare entity which can be a result from autoimmune diseases, caused by various medications and infections. CASE PRESENTATION: We herein present the case of a 62-year-old male patient who presented with fatigue and was found to have severe anemia, impaired renal function, and nephrotic syndrome. A renal biopsy revealed membranoproliferative glomerulonephritis (MPGN) of the immune complex type with activation of the classical complement pathway. Further investigations led to the diagnosis of a chronic Coxiella burnetii-infection (Q fever), likely acquired during cycling trips in a region known for intensive sheep farming. Additionally, the patient was found to have a post endocarditic destructive bicuspid aortic valve caused by this pathogen. Treatment with hydroxychloroquine and doxycycline was administered for a duration of 24 months. The aortic valve was replaced successfully and the patient recovered completely. CONCLUSIONS: Early detection and targeted treatment of this life-threatening disease is crucial for complete recovery of the patient.

Targeting the epidermal growth factor receptor (EGFR/ErbB) for the potential treatment of renal pathologies.

Epidermal growth factor receptor (EGFR), which is referred to as ErbB1/HER1, is the prototype of the EGFR family of receptor tyrosine kinases which also comprises ErbB2 (Neu, HER2), ErbB3 (HER3), and ErbB4 (HER4). EGFR, along with other ErbBs, is expressed in the kidney tubules and is physiologically involved in nephrogenesis and tissue repair, mainly following acute kidney injury. However, its sustained activation is linked to several kidney pathologies, including diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, chronic kidney disease, and renal fibrosis. This review aims to provide a summary of the recent findings regarding the consequences of EGFR activation in several key renal pathologies. We also discuss the potential interplay between EGFR and the reno-protective angiotensin-(1-7) (Ang-(1-7), a heptapeptide member of the renin-angiotensin-aldosterone system that counter-regulates the actions of angiotensin II. Ang-(1-7)-mediated inhibition of EGFR transactivation might represent a potential mechanism of action for its renoprotection. Our review suggests that there is a significant body of evidence supporting the potential inhibition of EGFR/ErbB, and/or administration of Ang-(1-7), as potential novel therapeutic strategies in the treatment of renal pathologies. Thus, EGFR inhibitors such as Gefitinib and Erlinotib that have an acceptable safety profile and have been clinically used in cancer chemotherapy since their FDA approval in the early 2000s, might be considered for repurposing in the treatment of renal pathologies.

Preclinical Detection of Early Glomerular Injury in Children with Kidney Diseases-Independently of Usual Markers of Kidney Impairment and Inflammation.

Glomerular kidney diseases typically begin insidiously and can progress to end stage kidney failure. Early onset of therapy can slow down disease progression. Early diagnosis is required to ensure such timely therapy. The goal of our study was to evaluate protein biomarkers (BMs) for common nephropathies that have been described for children with Alport syndrome. Nineteen candidate BMs were determined by commercial ELISA in children with congenital anomalies of the kidneys and urogenital tract, inflammatory kidney injury, or diabetes mellitus. It is particularly essential to search for kidney disease BMs in children because they are a crucial target group that likely exhibits early disease stages and in which misleading diseases unrelated to the kidney are rare. Only minor differences in blood between affected individuals and controls were found. However, in urine, several biomarker candidates alone or in combination seemed to be promising indicators of renal injury in early disease stages. The BMs of highest sensitivity and specificity were collagen type XIII, hyaluronan-binding protein 2, and complement C4-binding protein. These proteins are unrelated to inflammation markers or to risk factors for and signs of renal failure. In conclusion, our study evaluated several strong candidates for screening for early stages of kidney diseases and can help to establish early nephroprotective regimens.

How Stem and Progenitor Cells Can Affect Renal Diseases.

Stem and progenitor cells have been observed to contribute to regenerative processes in acute renal failure and chronic kidney disease. Recent research has delved into the intricate mechanisms by which stem and progenitor cells exert their influence on kidney diseases. Understanding how these cells integrate with the existing renal architecture and their response to injury could pave the way for innovative treatment strategies aimed at promoting kidney repair and regeneration. Overall, the role of stem and progenitor cells in kidney diseases is multifaceted, with their ability to contribute to tissue regeneration, immune modulation, and the maintenance of renal homeostasis. Here, we review the studies that we have available today about the involvement of stem and progenitor cells both in regenerative therapies and in the causes of renal diseases, as well as in natural healing mechanisms, taking into account the main kidney disorders, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, C3 glomerulopathy, focal segmental glomerulosclerosis, idiopathic membranous nephropathy, anti-glomerular basement membrane glomerulonephritis, and ANCA-associated crescentic glomerulonephritis. Moreover, based on the comprehensive data available in the framework of the specific kidney diseases on stem cells and renal progenitors, we hypothesize a possible role of adult renal progenitors in exacerbating or recovering the illness.

Corrigendum: Genetic investigation of Nordic patients with complement-mediated kidney diseases.

[This corrects the article DOI: 10.3389/fimmu.2023.1254759.].

Therapeutic targets in membranous nephropathy: plasma cells and complement.

Membranous nephropathy (MN) is an antibody-mediated autoimmune disease and the most common cause of nephrotic syndrome in adults. The discovery of phospholipase A2 receptor 1 (PLA2R1) as the first target antigen in patients with MN 15 years ago has led to a paradigm shift in the pathobiological understanding of this disease. Autoantibodies against PLA2R1 as well as thrombospondin type-1 domain-containing 7A, the second identified antigen in adults, were shown to be disease-causing and act through local activation of the complement system, primarily via the classical and lectin pathways. These findings indicate that both plasma cells, the main source of antibodies and autoantibodies, as well as the complement system, the main pathogenic effector mechanism in MN, are rational and pathogenesis-based treatment targets in MN. This review summarizes pathomechanistic and clinical evidence for and against plasma cell- and complement-targeted treatments in MN.

Left ventricular thrombus in patient with nonischemic cardiomyopathy: A case report.

Left ventricular thrombus (LVT) is a severe consequence that typically follows acute myocardial infarction (MI) and can occur in nonischemic cardiomyopathies. In patients who have experienced an ST-segment elevation acute myocardial infarction (STEMI), LVT is seen up to 15% of the time; for patients without an ischemic cardiomyopathy, it is only 2% to 36% of the time. According to Virchow's triad, the cornerstone of LVT formation includes endothelial injury, blood stasis, and hypercoagulability. However, LVT increases morbidity and mortality in patients with both ischemic and nonischemic cardiomyopathies by increasing the risk of stroke or systemic embolism. Studies on nonischemic etiology are limited, and the majority of LVT case series concentrate on ischemic cardiomyopathies. We present this case with the nonischemic cardiomyopathies caused by LVT. Specifically, the patient underwent coronary artery assessment using photon-counting computed tomography, which is among the most advanced systems worldwide.

A scoping review on adult patients with de novo glomerular diseases following COVID-19 infection or vaccine.

BACKGROUND: There are increasing reports of glomerular disease (GD) following COVID-19 infection and vaccination. Current evidence on the possible link between COVID-19 infection or vaccination and GD is conflicting. OBJECTIVE: The present study undertakes a scoping review of research to describe the relationship between COVID-19 infection and vaccination with GD and the common management strategies and overall outcomes of the disease to identify knowledge gaps and guide further research. ELIGIBILITY CRITERIA: All original research studies published in English until 5th September 2022 were considered for inclusion in the review. Exclusion criteria were animal studies, autopsy studies, and data involving patients who were paediatric patients (< 16 years), were transplant recipients, had a recurrence of glomerular disease, had concomitant cancer or non-COVID-19 infection which may cause glomerular disease, or did not receive a renal biopsy. SOURCES OF EVIDENCE: The five electronic databases searched were MEDLINE, PubMed, Scopus, EMBASE, and Cochrane. METHODS: Two separate search strings related to COVID-19, and glomerular disease were combined using the Boolean operator 'AND'. Filters were used to limit publications to original research studies published in English. Search results from each database were imported into Covidence software ( www.covidence.org ) and used for de-duplication, article screening, and data extraction. Descriptive analyses were used to summarise demographics, diagnoses, and treatment outcomes. RESULTS: After removing duplicates, 6853 titles and abstracts were screened. Of the 188 studies included, 106 studies described 341 patients with GD following COVID-19 infection and 82 described 146 patients with GD following a COVID-19 vaccination. IgA nephropathy was the most common GD pathology reported following COVID-19 vaccination with GD most common following mRNA vaccines. Collapsing focal segmental glomerulosclerosis was the most common GD following COVID-19 infection. Immunosuppressive treatment of GD was more common in the vaccine cohort than in the infection cohort. CONCLUSION: Despite the significant number of COVID-19 infections and vaccinations around the world, our understanding of GD associated with COVID-19 infection and vaccination remains poor, and more research is needed to understand the possible relationship better.

Myeloperoxidase-ANCA IgG induces different forms of small vessel vasculitis based on type of synergistic immune stimuli.

Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis has diverse patterns of injury including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Necrotizing and crescentic glomerulonephritis (NCGN) occurs in all syndromes and as renal limited vasculitis (RLV). Single-dose intravenous ANCA IgG-specific for mouse myeloperoxidase (MPO) causes RLV in mice. Although multiple mouse models have elucidated ANCA-IgG induced necrotizing and crescentic glomerulonephritis (NCGN), pathogenesis of ANCA-induced granulomatosis and vasculitis outside the kidney has not been clarified. To investigate this, we used intravenous MPO-ANCA IgG in the same strain of mice to induce different patterns of lung disease mirroring patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Repeated intravenous MPO-ANCA IgG induced GPA with NCGN, lung capillaritis, arteritis and granulomatosis. Lung leukocyte phenotypes were evaluated by immunohistochemical image analysis and by flow cytometry. ANCA lung capillaritis and microabscesses began within one day and evolved into granulomas in under seven days. Influenza plus single-dose MPO-ANCA IgG induced MPA with NCGN, lung capillaritis and arteritis, but no granulomatosis. Allergic airway disease caused by house dust mites or ovalbumin plus single-dose intravenous MPO-ANCA IgG induced EGPA with eosinophilic bronchiolitis, NCGN, capillaritis, arteritis, and granulomatosis. Thus, our study shows that the occurrence and pattern of lung lesions are determined by the same ANCA IgG accompanied by different synergistic immune factors.

IgG subclass shifts occurring at acute exacerbations in autoimmune nodopathies.

BACKGROUND: Autoimmune nodopathy associated with anti-contactin1 (CNTN1) IgG4 antibodies frequently manifests as acute axonal degeneration in addition to detachment of the paranodal myelin loops. The acute destruction of myelinated nerve fibers does not match the function of IgG4, which cannot activate the complement pathway. IgG subclass switching from IgG1 or IgG3 to IgG4 has been observed in some patients with autoimmune diseases associated with IgG4 throughout their disease course. METHODS: Serial changes in IgG subclasses, clinico-neurophysiological features, and nerve and renal pathology were reviewed in three patients with anti-CNTN1-associated autoimmune nodopathy and one patient with anti-contactin-associated protein1 (Caspr1) autoimmune nodopathy. RESULTS: All four patients had predominantly IgG4 autoantibodies, whereas they showed evidence of acute axonal degeneration. The IgG1 subclass was present in all patients at their progressing stage but then disappeared at follow-up. Nerve pathology in the patients with anti-CNTN1 and anti-Caspr1 autoimmune nodopathies showed both structural changes in the paranodes and evidence of acute axonal degeneration. Renal biopsy specimens from two patients with membranous glomerulonephritis and anti-CNTN1 autoimmune nodopathy showed deposition of IgG1 and complement on the glomerular basement membrane, as well as IgG4. DISCUSSION: In patients with autoimmune nodopathies associated with anti-CNTN1 and anti-Caspr1 IgG4 antibodies, IgG1 subclass autoantibodies were present at their acute exacerbations and might have contributed to the axonal degeneration and glomerular injury. IgG1 disappeared with the cessation of disease progression, which indicates that the IgG1 subclass is a possible biomarker of disease activity.