• IgG4
• allergen-specific immunotherapy (AIT)
• allergic disease
• autoimmune disease
• chronic infection
• immune tolerance
• tumor

• Humans
• Immunoglobulin G/immunology
• Autoimmune Diseases/immunology
• Animals
• Health
• Autoantibodies/immunology

• Chronic Kidney Disease
• Endothelial Heterogeneity
• Endothelial dysfunction
• Endothelial injury

• Humans
• Renal Insufficiency, Chronic/pathology
• Renal Insufficiency, Chronic/therapy
• Endothelial Cells/pathology
• Endothelial Cells/metabolism
• Disease Progression
• Endothelium, Vascular/pathology
• Kidney/pathology
• Kidney/blood supply
• Kidney/cytology
• Oxidative Stress
• Animals
• Glomerular Filtration Barrier/pathology

• Artificial Intelligence
• Glomerulonephritis
• IMMUNOLOGY
• Machine Learning
• Nephrology

• Humans
• Rituximab/administration & dosage
• Rituximab/therapeutic use
• Glomerulonephritis, Membranous/drug therapy
• Prospective Studies
• Multicenter Studies as Topic
• Randomized Controlled Trials as Topic
• Algorithms
• Artificial Intelligence
• Immunologic Factors/administration & dosage
• Immunologic Factors/therapeutic use
• Precision Medicine/methods
• Nephrotic Syndrome/drug therapy
• Male
• Adult
• Female
• France

• Ministère de la Santé

• clinical remission
• complement
• histopathology
• membranous nephropathy
• proteomics

• National Natural Science Foundation of China
• Department of Science and Technology of Sichuan Province

• complement
• coronavirus disease 2019
• factor H
• membranous nephropathy
• severe acute respiratory syndrome corona virus 2
• the alternative pathway

• Autoantibody
• Biomarker
• Membranous nephropathy
• Proteinuria
• Thrombospondin type-1 domain-containing 7A

• Humans
• Glomerulonephritis, Membranous/diagnosis
• Glomerulonephritis, Membranous/immunology
• Glomerulonephritis, Membranous/blood
• Thrombospondins/immunology
• Biomarkers/blood
• Autoantibodies/blood
• Autoantibodies/immunology
• Receptors, Phospholipase A2/immunology
• Prognosis
• Animals
• Podocytes/metabolism
• Podocytes/immunology

• Chronic kidney disease
• Complement
• Nephrology

• Animals
• Humans
• Mice
• Albumins
• Glomerulonephritis, Membranous/genetics
• Kidney Glomerulus/pathology
• Nephrotic Syndrome/pathology
• Podocytes/pathology

• R01 DK123234 NIDDK NIH HHS

• Membranous nephropathy
• integrated bioinformatics
• key biomarker
• molecular mechanism

• Exostosin ½
• Membranous nephropathy
• Neural cell adhesion molecule 1
• Neural epidermal growth factor like-1 protein
• Protocadherin 7
• Semaphorin 3B

Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ injury occurring due to endothelial cell damage and microthrombi formation in small vessels. TMA is primary when a genetic or acquired defect is identified, as in atypical hemolytic uremic syndrome (aHUS) or secondary when occurring in the context of another disease process such as infection, autoimmune disease, malignancy or drugs. Differentiating between a primary complement-mediated process and one triggered by secondary factors is critical to initiate timely treatment but can be challenging for clinicians, especially after a kidney transplant due to presence of multiple confounding factors. Similarly, primary membranous nephropathy is an immune-mediated glomerular disease associated with circulating autoantibodies (directed against the M-type phospholipase A2 receptor (PLA2R) in 70% cases) while secondary membranous nephropathy is associated with infections, drugs, cancer, or other autoimmune diseases. Complement activation has also been proposed as a possible mechanism in the etiopathogenesis of primary membranous nephropathy; however, despite complement being a potentially common link, aHUS and primary membranous nephropathy have not been reported together. Herein we describe a case of aHUS due to a pathogenic mutation in complement factor I that developed after a kidney transplant in a patient with an underlying diagnosis of PLA2R antibody associated-membranous nephropathy. We highlight how a systematic and comprehensive analysis helped to define the etiology of aHUS, establish mechanism of disease, and facilitated timely treatment with eculizumab that led to recovery of his kidney function. Nonetheless, ongoing anti-complement therapy did not prevent recurrence of membranous nephropathy in the allograft. To our knowledge, this is the first report of a patient with primary membranous nephropathy and aHUS after a kidney transplant.

• atypical hemolytic uremic syndrome
• complement factor I
• complement functional analysis
• kidney transplantation
• membranous nephropathy
• thrombotic microangiopathy

• KDIGO (Kidney Disease: Improving Global Outcomes)
• PLA2R1 autoantibodies
• autoimmunity
• immunomonitoring
• immunosuppressive therapy
• membranous nephropathy
• nephrotic syndrome
• rituximab

• Adult
• Antibodies/therapeutic use
• Autoimmune Diseases/drug therapy
• Glomerulonephritis, Membranous/drug therapy
• Humans
• Immunosuppressive Agents/therapeutic use
• Nephrotic Syndrome
• Receptors, Phospholipase A2
• Rituximab/therapeutic use

• IgA nephropathy
• immunosuppressant
• membranous nephropathy
• minimal change disease
• precision medicine

• Biomarkers
• Glomerulonephritis, IGA/drug therapy
• Glomerulonephritis, Membranous/drug therapy
• Humans
• Immunoglobulin A

• CMRPG6F0381-3 Chang Gung Memorial Hospital at Chiayi, Taiwan

Idiopathic membranous nephropathy (iMN) is a major cause of nephrotic syndrome. Atypical membranous nephropathy (aMN) is a new type of nephropathy in China, characterized by a ‘full-house’ on immunofluorescent examination, that is IgG, IgA, IgM, C3, C1q positive, but without clinical evidence of a secondary cause. Phospholipase A2 receptor (PLA2R) was the major target antigens in iMN patients. Activation of the mannose-binding lectin (MBL) pathway plays a vital role in the development of MN. Our objective was to investigate the role of PLA2R and MBL in the pathogenesis of iMN and aMN.

We conducted a retrospective observational study using propensity score matching by age, gender, and eGFR. All clinical, laboratory data, and follow-up data of the patients were collected. Serum levels of anti-PLA2R antibodies and MBL were tested.

Finally, 30 iMN patients and 30 aMN patients were included, and 20 healthy controls were retrospectively collected in this study. The 24 h proteinuria level was higher and serum albumin was lower in anti-PLA2R (+) patients than in anti-PLA2R (−) patients in both iMN and aMN groups. In aMN patients, MBL levels were significantly higher in anti-PLA2R (+) patients than in anti-PLA2R (−) patients (p = .045). The serum level of anti-PLA2R positively correlated with no-remission in both iMN and aMN groups.

The complement lectin pathway has an association with the development of MN, especially in patients with positive anti-PLA2R antibodies. Serum MBL cannot differentiate between the two diseases. Serum MBL levels are not associated with clinical manifestations, nor with prognosis.

• Idiopathic membranous nephropathy
• MBL
• PLA2R
• atypical membranous nephropathy
• complement

• C3 glomerulopathy
• Children
• Complement
• Glomerular disease

Defective complement activation has been associated with various types of kidney disease. This led to the hypothesis that specific urine complement fragments may be associated with kidney disease etiologies, and disease progression may be reflected by changes in these complement fragments. We investigated the occurrence of complement fragments in urine, their association with kidney function and disease etiology in 16,027 subjects, using mass spectrometry based peptidomics data from the Human Urinary Proteome/Peptidome Database. Twenty-three different urinary peptides originating from complement proteins C3, C4 and factor B (CFB) could be identified. Most C3-derived peptides showed inverse association with estimated glomerular filtration rate (eGFR), while the majority of peptides derived from CFB demonstrated positive association with eGFR. Several peptides derived from the complement proteins C3, C4 and CFB were found significantly associated with specific kidney disease etiologies. These peptides may depict disease-specific complement activation and could serve as non-invasive biomarkers to support development of complement interventions through assessing complement activity for patients’ stratification and monitoring of drug impact. Further investigation of these complement peptides may provide additional insight into disease pathophysiology and could possibly guide therapeutic decisions, especially when targeting complement factors.

Primary membranous nephropathy (pMN) is an autoimmune kidney disease and a common cause of nephrotic syndrome in adults. Rituximab is becoming a first line therapy for patients with persistent nephrotic syndrome with proven safety and efficacy, achieving remission in 60%–80% of cases. For the remaining 20%–40% of patients there is an urgent need to identify early biomarkers of resistance to rituximab to adapt therapeutic management. In nephrotic patients, rituximab is found in the blood more transiently than in other autoimmune diseases without proteinuria, due to rituximab wasting in the urine. However, rituximab immunomonitoring is not routinely performed. We evaluated the predictive value of serum rituximab levels in patients with pMN three months after rituximab injection (month-3) on clinical remission rates six months (month-6) and 12 months (month-12) after injection and investigated predictive factors for serum rituximab levels at month-3. Sixty-eight patients treated with rituximab between July 2015 and January 2020 from two French nephrology centers were included. We identified residual rituximab levels at month-3 as a novel early predictor of remission at month-6 (p <0.0001) and month-12 (p = 0.001). Reduced likelihood of remission in patients with undetectable rituximab at month-3 was associated with lower serum albumin and higher anti-PLA2R1 titers at baseline and with lower serum albumin, higher proteinuria, higher CD19⁺ counts and higher anti-PLA2R1 titers during follow-up. In multivariate analysis, high baseline proteinuria and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-6 and high baseline weight and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-12. We identified serum albumin at baseline as a predictive factor for serum rituximab levels at month-3. Patients with serum albumin below 22.5 g/L at baseline had an 8.66-fold higher risk of having undetectable rituximab levels at month-3. Therefore, rituximab immunomonitoring in pMN patients treated with rituximab would allow the detection of patients at risk of treatment failure as early as month-3. Studies are needed to assess whether patients with low residual rituximab levels at month-3 may benefit from an early additional course of rituximab.

• autoimmunity
• chronic kidney disease rituximab immunomonitoring in membranous nephropathy
• membranous nephropathy
• nephrotic syndrome
• rituximab

• chronic inflammatory demyelinating polyneuropathy
• contactin-1
• immunoglobulin G type 4
• membranous nephropathy
• nephrotic syndrome

• anti-PLA2R antibodies
• anti-THSD7A antibody
• membranous nephropathy
• outcome
• remission

• Animals
• Autoantibodies/blood
• Autoantibodies/immunology
• Autoantigens/immunology
• Autoimmunity
• Combined Modality Therapy/adverse effects
• Combined Modality Therapy/methods
• Disease Management
• Disease Susceptibility/immunology
• Glomerulonephritis, Membranous/diagnosis
• Glomerulonephritis, Membranous/immunology
• Glomerulonephritis, Membranous/therapy
• Humans
• Kidney Glomerulus/immunology
• Kidney Glomerulus/pathology
• Molecular Diagnostic Techniques
• Podocytes/immunology
• Podocytes/pathology
• Receptors, Phospholipase A2/immunology

Primary membranous nephropathy (MN) is characterized by the presence of antipodocyte antibodies, but studies describing phenotypic and functional abnormalities in circulating lymphocytes are limited.

We analyzed 68 different B- and T-cell subsets using flow cytometry in 30 MN patients (before initiating immunosuppression) compared with 31 patients with non–immune-mediated chronic kidney disease (CKD) and 12 healthy individuals. We also measured 19 serum cytokines in MN patients and in healthy controls. Lastly, we quantified the ex vivo production of phospholipase A2 receptor (PLA2R)-specific IgG by plasmablasts (measuring antibodies in culture supernatants and by the newly developed FluoroSpot assay [AutoImmun Diagnostika, Strasberg, Germany]) and assessed the circulating antibody repertoire by phage immunoprecipitation sequencing (PhIP-Seq).

After adjusting for multiple testing, plasma cells and regulatory B cells (B_REG) were significantly higher (P < 0.05) in MN patients compared with both control groups. The percentages of circulating plasma cells correlated with serum anti-PLA2R antibody levels (P = 0.042) and were associated with disease activity. Ex vivo–expanded PLA2R-specific IgG-producing plasmablasts generated from circulating PLA2R-specific memory B cells (mBCs) correlated with serum anti-PLA2R IgG antibodies (P < 0.001) in MN patients. Tumor necrosis factor-α (TNF-α) was the only significantly increased cytokine in MN patients (P < 0.05), whereas there was no significant difference across study groups in the autoantibody and antiviral antibody repertoire.

This extensive phenotypic and functional immune characterization shows that autoreactive plasma cells are present in the circulation of MN patients, providing a new therapeutic target and a candidate biomarker of disease activity.

• membranous nephropathy
• phospholipase A2 receptor
• plasma cells
• regulatory B cells
• regulatory T cells