Crescentic glomerulonephritis due to linear IgA anti-glomerular basement membrane disease: report of a rare case.

Anti-glomerular basement membrane (GBM) disease is a rare and severe vasculitis that affects the glomerular and pulmonary capillaries and has an incidence of less than 2 cases per million individuals per year. Anti-GBM disease is mediated by autoantibodies against the α3 chain of type IV collagen. In the majority of cases, the autoantibodies are of the immunoglobulin G (IgG) class, with rare cases being mediated by immunoglobulin M (IgM) or immunoglobulin A (IgA); there are less than 15 IgA-mediated cases reported in the literature worldwide. The classic form of this disease manifests with rapidly progressive glomerulonephritis (RPGN), with or without pulmonary hemorrhage, and the diagnosis consists of identifying high titers of autoantibodies in the serum and/or deposited in the tissues. IgA antibodies are not identified in routine immunoassay tests, and renal biopsy with immunofluorescence is essential for diagnosis. We present a case of RPGN due to anti-GBM disease with linear IgA deposition, whose diagnosis was made exclusively by renal biopsy and with an unfavorable prognosis.

Clinical phenotype of AAV, anti-GBM disease and double-positive patients after SARS-CoV-2 vaccination.

The number of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), anti-glomerular basement membrane (GBM) disease and double-positive patients (DPPs) following the coronavirus disease 2019 (COVID-19) vaccine reported in the literature is increasing, we reviewed the reported cases of AAV, anti-GBM disease and DPPs subsequent to COVID-19 vaccination, and compared the disparities in DPPs who received the COVID-19 vaccination and those who did not. We did not observe any differences in clinical phenotype of AAV, anti-GBM disease and DPPs before and after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination.

Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis.

Anti-glomerular basement membrane (GBM) disease is a small-vessel vasculitis that represents the most aggressive form of autoimmune glomerulonephritis. The study aimed to investigate the prevalence, clinical characteristics, risk factors, and outcomes of anti-GBM disease through a systematic review and meta-analysis involving 47 studies with 2830 patients. The overall incidence of anti-GBM disease ranged from 0.60 to 1.79 per million population per annum. In rapidly progressive glomerulonephritis and crescentic glomerulonephritis, the pooled incidence rates were 8.0% and 12.8%, respectively. The pooled prevalence rates of anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and 32.6%, respectively. Patients with combined ANCA positivity demonstrated a prognosis comparable to those patients with only anti-GBM antibodies, though with differing clinical features. The pooled one-year patient and kidney survival rates were 76.2% and 30.2%, respectively. Kidney function on diagnosis and normal glomeruli percentage were identified as strong prognostic factors. This study represents the first comprehensive meta-analysis on anti-GBM disease, providing insights into its management. However, caution is warranted in interpreting some results due to the observational nature of the included studies and high heterogeneity.

Disease activity prediction and prognosis of anti-GBM nephritis based on T lymphocyte subset ratios.

INTRODUCTION: Cell-mediated autoimmunity, especially the autoreactivity of T cells, is known to underlie the initiation of anti-glomerular basement membrane disease. However, the T lymphocyte subsets that determine the disease activity, renal fibrosis, and prognosis of anti-GBM disease have not been clearly elucidated. METHODS: The T lymphocyte subsets (CD4+ and CD8+) were examined on peripheral blood and renal biopsy tissues from 65 patients with biopsy proven anti-GBM disease. Patients were divided into the high ratio group and low ratio group according to the cutoff values in the receiver operating characteristic curve analysis. The correlations of T lymphocyte subsets with clinical, pathological data, and renal outcome were analyzed. RESULTS: By the end of follow-up, 45 patients (69.2%) developed end-stage renal disease (ESRD). In peripheral blood, the CD4+/CD8+ ratio showed a predictive ability with a sensitivity and specificity of 91.3% and 52.9%, respectively, which gave rise to a cutoff value of 0.89. There was a significant difference in the activity index between these two groups (3.91 ± 1.38 vs. 2.89 ± 1.13, p = 0.007). In the renal tissues, the CD4+/CD8+ ratio had the optimal cutoff point of 0.82 with a sensitivity of 57.8% and specificity of 85%. The renal activity index was higher for the renal tissues with high CD4+/CD8+ ratios than that of tissues with low CD4+/CD8+ ratios (4.32 ± 1.55 vs. 3.37 ± 1.41, p = 0.016). Peripheral blood CD4+/CD8+ ratios of ≥0.89 or renal tissue CD4+/CD8+ ratios of < 0.82 positively correlated with poor renal prognosis in patients with anti-GBM nephritis. CONCLUSIONS: The CD4+/CD8+ ratio was associated with renal activity index both in peripheral blood and renal tissue and predicts the renal prognosis of patients with anti-GBM nephritis.

Anti-glomerular basement membrane disease mediated by IgG and IgA: a case report.

BACKGROUND: Anti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune condition responsible for rapidly progressive glomerulonephritis. This disease is usually mediated by IgG autoantibodies against the noncollagenous domain of the α3(IV) collagen chain. In rare cases, IgA or IgM anti-GBM antibodies are involved. This raises the question of whether there are different types of antibody-mediated anti-GBM disease at the same time. CASE REPORT: A 37-year-old woman with anti-GBM disease mediated by IgG and IgA. The patient developed rapidly progressive glomerulonephritis with nephrotic syndrome. Indirect immunofluorescence analysis indicated the presence of IgG and IgA antibodies reactive with a basement membrane component, identified by enzyme-linked immunoadsorbent assay and Western blotting as the α3(IV) collagen chain. After plasmapheresis and immunotherapy (steroids and cyclophosphamide), much improved the massive proteinuria and renal function. Follow up to date, she had normal renal function without proteinuria. CONCLUSIONS: This is the first case report of anti-GBM disease mediated by IgG and IgA. If the clinical presentation and histopathological findings are suggestive of atypical anti-GBM disease, alternative laboratory tests such as Western blotting analysis can be used to confirm the diagnosis.

Pediatric double positive anti-glomerular basement membrane antibody and anti-neutrophil cytoplasmic antibody glomerulonephritis-A case report with review of literature.

Anti-glomerular basement membrane (GBM) disease is a rarely described entity in the pediatric population, especially in those less than 3 years old. Even rarer, is double seropositive disease, consisting of anti-GBM antibody plus anti-neutrophil cytoplasmic antibodies. Both single and double antibody positive diseases are characterized by rapidly progressive glomerulonephritis, often without pulmonary involvement in the pediatric population. We report the case of a 2-year-old child with double seropositive anti-GBM disease, the youngest in the current literature, along with the role of therapeutic plasma exchange and rituximab in disease treatment.

The clinical and immunological features of the post-extracorporeal shock wave lithotripsy anti-glomerular basement membrane disease.

INTRODUCTION: Extracorporeal shock wave lithotripsy (ESWL) is a noninvasive modality to treat urolithiasis, with complications including tissue damage and hematoma of kidney parenchyma. Anti-glomerular basement membrane (GBM) disease is suggested to be a rare complication of ESWL since it was reported in several cases to occur after ESWL. However, the clinical and immunological features of the ESWL-associated anti-GBM disease have not been fully investigated so far. CASE PRESENTATION: Here, we present the clinical, pathological, and immunological characteristics of three patients with the post-ESWL anti-GBM disease in our hospital. Anti-GBM disease occurred within a median of 22 months after ESWL treatment. It presented with similar clinical features to the classic anti-GBM disease, including fever, gross hematuria, and rapidly progressive glomerulonephritis (RPGN) with poor renal prognosis. Sera from all patients recognized the α3(IV)NC1 in GBM, but with IgG2 and IgG4 as the dominant IgG subclasses. CONCLUSION: Although further exploration is required to prove the causal relationship in this rare condition, our study reminds physicians that patients developing acute renal insufficiency after ESWL should lead to the suspicion of anti-GBM disease and in-time diagnosis and treatment.

Concurrent Anti-Glomerular Basement Membrane Antibody Disease and Membranous Nephropathy: A Case Series.

RATIONALE & OBJECTIVE: Anti-glomerular basement membrane (GBM) disease is a rapidly progressive glomerulonephritis which, in some instances, occurs concurrently with other diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Rarely, it also occurs with membranous nephropathy (MN). We report a series of such patients, characterizing their long-term follow up. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Twelve patients referred to 1 medical center between 2001 and 2019 with anti-GBM disease and MN whose clinical characteristics and course were described. RESULTS: Patients' ages ranged from 20 to 81 years old, and all presented with severe acute kidney injury requiring dialysis on presentation or shortly thereafter. Only 1 patient had pulmonary findings on presentation. The predominant pathology was crescentic and necrotizing glomerulonephritis with linear staining for immunoglobulin G along the GBM associated with epimembranous electron-dense immune-type deposits. All 11 patients who were tested had significant titers of anti-GBM antibodies, but only 1 of the 5 tested for phospholipase A2 receptor (PLA2R) on biopsy was positive. Eight patients received therapy with cyclophosphamide, prednisone, and plasmapheresis; 2 patients with prednisone and plasmapheresis; and 2 with rituximab-based regimens. Progression to a requirement for kidney replacement therapy occurred in all 12 patients, but 2 patients later recovered kidney function. Recurrence of anti-GBM disease did not occur for any of the patients studied. LIMITATIONS: Incomplete testing for PLA2R in biopsy and serum, limited sample size, and lack of uniform treatment regimen. CONCLUSIONS: In this case series, the presentation of concurrent anti-GBM disease and MN was characterized by rapidly progressive glomerulonephritis and poor kidney outcomes. These findings suggest possible value from earlier diagnosis and the need for identification of more effective treatment regimens.

Anti-glomerular Basement Membrane Disease: What Have We Learned?

Since the first clinicopathologic description by Ernest Goodpasture of a patient whom he considered to have died of influenza in 1919, substantial progress has been made in our knowledge of anti-glomerular basement membrane disease. This has led to a significant decrease in the morbidity and mortality associated with this disease. In this paper, we aim to review the literature that has enhanced our understanding of classic anti-glomerular basement membrane disease and its clinic-pathologic variants in the key areas of immunopathogenesis and histopathology. We also summarize varied clinical presentations and therapeutic strategies.

Absence of Anti-Glomerular Basement Membrane Antibodies in 200 Patients With Systemic Lupus Erythematosus With or Without Lupus Nephritis: Results of the GOODLUPUS Study.

Introduction: Anti-glomerular basement membrane (GBM) antibodies are pathogenic antibodies first detected in renal-limited anti-GBM disease and in Goodpasture disease, the latter characterized by rapidly progressive crescentic glomerulonephritis combined with intra-alveolar hemorrhage. Studies have suggested that anti-GBM antibody positivity may be of interest in lupus nephritis (LN). Moreover, severe anti-GBM vasculitis cases in patients with systemic lupus erythematosus (SLE) have been described in the literature, but few studies have assessed the incidence of anti-GBM antibodies in SLE patients. Objective: The main study objective was to determine if positive anti-GBM antibodies were present in the serum of SLE patients with or without proliferative renal damage and compared to a healthy control group. Methodology: This retrospective study was performed on SLE patients' sera from a Franco-German European biobank, developed between 2011 and 2014, from 17 hospital centers in the Haut-Rhin region. Patients were selected according to their renal involvement, and matched by age and gender. The serum from healthy voluntary blood donors was also tested. Anti-GBM were screened by fluorescence enzyme immunoassay (FEIA), and then by indirect immunofluorescence (IIF) in case of low reactivity detection (titer >6 U/ml). Results: The cohort was composed of 100 SLE patients with proliferative LN (27% with class III, 67% with class IV, and 6% with class V), compared to 100 SLE patients without LN and 100 controls. Patients were mostly Caucasian and met the ACR 1997 criteria and/or the SLICC 2012 criteria. Among the 300 tested sera, no significant levels of anti-GBM antibodies were detected (>10 U/ml) by the automated technique, three sera were found "ambivalent" (>7 U/ml): one in the SLE with LN group and two in the SLE without LN group. Subsequent IIF assays did not detect anti-GBM antibodies. Conclusion: Anti-GBM antibodies were not detected in the serum of Caucasian patients with SLE, even in case of renal involvement, a situation favoring the antigenic exposure of glomerular basement membranes. Our results reaffirm the central role of anti-GBM antibodies as a specific diagnostic biomarker for Goodpasture vasculitis and therefore confirm that anti-GBM antibody must not be carried out in patients with SLE (with or without LN) in the absence of disease-suggestive symptoms.

Imlifidase: First Approval.

Imlifidase (IdefirixTM), a cysteine protease derived from the immunoglobulin G (IgG)­degrading enzyme of Streptococcus (S.) pyogenes is being developed by Hansa Biopharma AB for treatment of transplant rejection and rare IgG-mediated autoimmune conditions. In August 2020, intravenous imlifidase received its first global approval in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor. Imlifidase is currently undergoing clinical evaluation for the prevention of kidney transplant rejection in the USA, Australia, France and Austria, and clinical development is underway for anti-glomerular basement membrane disease, and for Guillain-Barre syndrome in France, the UK and the Netherlands. This article summarizes the milestones in the development of imlifidase leading to this first approval for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor.

Goodpasture syndrome manifesting as nephrotic-range proteinuria with anti-glomerular basement membrane antibody seronegativity: A case report.

RATIONALE: The Goodpasture syndrome is an extremely rare disease, with renal and pulmonary manifestations, and is mediated by anti-glomerular basement membrane (anti-GBM) antibodies. Renal pathological changes are mainly characterized by glomerular crescent formation and linear immunofluorescent staining for immunoglobulin G on the GBM. There are few reports on the atypical course of the syndrome involving serum-negative anti-GBM antibodies. Therefore, we present a case of Goodpasture syndrome that presented with nephrotic-range proteinuria and was seronegative for anti-GBM antibodies. PATIENT CONCERNS: A 38-year-old Chinese man presented with a lung lesion that was discovered by physical examination a month prior to presentation. The chief concern was occasional hemoptysis without fever, cough, chest pain, and edema. DIAGNOSES: Laboratory testing revealed that the urinary protein level and urine erythrocyte count were 7.4 g/24 hours and 144/high-power field (HPF), respectively. Serological testing for anti-GBM antibodies was negative. Chest computed tomography revealed multiple exudative lesions in both lungs, indicating alveolar infiltration and hemorrhage. Electronic bronchoscopy and pathological examination of the alveolar lavage fluid indicated no abnormalities. However, kidney biopsy suggested cellular crescent formation and segmental necrosis of the globuli, with linear IgG and complement C3 deposition on the GBM. These findings were consistent with the diagnosis of anti-GBM antibody nephritis. INTERVENTIONS: The patient underwent 7 sessions of double filtration plasmapheresis. He was also administered with intravenous methylprednisolone and cyclophosphamide. After renal function stabilization, he was discharged under an immunosuppressive regimen comprising of glucocorticoids and cyclophosphamides. OUTCOMES: Three months later, follow-up examination revealed that the 24-hour urine protein had increased to 13 g. Furthermore, the urine erythrocyte count was 243/HPF. After a 6-month follow-up, the patient achieved partial remission, with a proteinuria level of 3.9 g/24 hours and a urine erythrocyte count of 187/HPF. LESSONS: This extremely rare case of Goodpasture syndrome manifested with seronegativity for anti-GBM antibodies and nephrotic-range proteinuria. Our findings emphasize the importance of renal biopsy for the clinical diagnosis of atypical cases. Furthermore, because renal involvement achieved only partial remission despite therapy, early detection and active treatment of the Goodpasture syndrome is necessary to improve the prognosis of patients.

Nephrotic syndrome due to minimal-change disease superimposed on anti-glomerular basement membrane antibody positive glomerulonephritis; a case report.

BACKGROUND: The prognosis for renal function in anti-GBM glomerulonephritis (anti-GBM GN) is extremely poor, and when renal impairment progresses severely, it is difficult to expect improvement. In addition, it is also known that once the disease activity can be controlled by aggressive treatment, its recurrence is rare. We experienced an anti-GBM GN that improved from severe renal dysfunction and relapsed. A possible cause was the superimpose of nephrotic syndrome due to minimal change disease (MCD). CASE PRESENTATION: A 30-year-old man was admitted to our hospital because of general malaise, fever, oliguria and renal dysfunction. The patient's laboratory data showed serum creatinine as high as 6.6 mg/dl, and severe inflammation (C-reactive protein 20.6 mg/dl). Anti-glomerular basement membrane antibody (anti-GBM Ab) was detected in his serum, which led to the diagnosis of anti-GBM GN. Treatment was initiated with high-dose glucocorticoid (GC) and plasma exchange therapy (PE), and the patient's renal function and oliguria improved rapidly and he was discharged 40 days after admission. Renal biopsy findings showed cellular crescents associated with linear IgG depositions along the glomerular tufts compatible with anti-GBM GN, but only about one-third of the glomeruli was involved, suggesting that it still remains an early stage of the disease. However, 2 months after discharge, he had a relapse and was readmitted due to severe proteinuria with positive anti-GBM Ab. On the second admission, after high-dose GC and PE combined with intravenous cyclophosphamide, and remission was achieved. Despite the relatively minor renal biopsy findings, the patient showed rapid renal dysfunction and relatively rapid improvement with our treatment. Electron microscopy of the renal biopsy tissue showed significant foot process effacement on podocytes in the apparently normal glomeruli, without electron dense deposits. CONCLUSION: On the basis of clinical course and renal pathology, it is suggested that the present case was a rare complication of an early stage of anti-GBM GN and minimal change nephrotic syndrome. Although the simultaneous development of anti-GBM GN and MCD with anti-GBM antibody is unclear, it might have been precipitated by influenza infection or some unknown factor.

Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from Actinomyces.

BACKGROUND: Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α3127-148 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected. METHODS: To investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity. RESULTS: On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human α3127-148. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat α3127-148. B7 induced T cell activation from human α3127-148-immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7's pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in α3135-145-immunized mice. CONCLUSIONS: Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.

Anti-glomerular basement membrane disease complicated with posterior reversible encephalopathy syndrome and subcortical cerebral hemorrhage: a case report and review of the literature.

A 71-year-old woman was hospitalized for the treatment of fatigue, fever, and cough. On admission, she showed increased serum inflammation markers, severe anemia, pulmonary hemorrhage, and advanced acute kidney injury requiring hemodialysis. Her serum anti-glomerular basement membrane (GBM) antibody titer was found to be extremely high on the 7th hospital day. She was eventually diagnosed with anti-GBM disease. She was treated with a combination of corticosteroid pulse therapy, oral prednisolone and cyclophosphamide, and plasma exchange, but continued to require maintenance hemodialysis for end-stage kidney disease. During her treatment, she suddenly developed headache, blindness, seizure, and consciousness disturbance. She was diagnosed by magnetic resonance imaging with posterior reversible encephalopathy syndrome (PRES) with subcortical cerebral hemorrhage. Both the PRES and cerebral hemorrhage subsided soon after control of her hypertension and reinforcement of immunosuppressive treatment. PRES, particularly when accompanied by cerebral hemorrhage, may cause irreversible and lethal neurological abnormalities, and nephrologists should, therefore, be aware of the potential risk of PRES in patients with anti-GBM disease. We discuss the current case in the light of the previous literature.

IgA vasculitis and anti-GBM disease: two ends of a spectrum of immune complex vasculitis.

Two immune complex vasculitides, IgA vasculitis (IgAV) and anti-GBM disease, represent polar extremes with regard to our understanding of disease pathogenesis, standardized management protocols and outcomes. This report compares our current approach to these uncommon entities in adults. Both diseases demonstrate degrees of small vessel necrosis and glomerular crescent formation. IgAV has an antibody response directed against unknown antigens, is often treated conservatively and has poorly studied long term renal outcomes. By contrast, anti-GBM disease presents with rapidly progressive glomerulonephritis and often results in end stage renal failure, despite intensive immunosuppression. Rarely, some cases of anti-GBM disease may be IgA predominant and bind other α-chains present in the GBM, but their clinical course is as for other anti-GBM disease patients but not IgAV, suggesting that the antigenic target rather than the antibody subclass is the critical factor in determining disease outcome. However, both conditions are associated with increased mortality in adults and result in significant chronic kidney disease and hypertension.

[Successful rituximab treatment of recurrent glomerulonephritis associated with antibodies against the glomerular basement membrane]. / Erfolgreiche Rituximabtherapie des Rezidivs einer Glomerulonephritis assoziiert mit Antikörpern gegen die glomeruläre Basalmembran.

This article presents a case of recurrent anti-GBM disease (with antibodies against the glomerular basement membrane [GBM]) in a 17-year-old patient successfully treated with rituximab. Kidney biopsy with detection of linear deposition of immunoglobulin G (IgG) along the basement membrane is the diagnostic gold standard, which should be accompanied by serological testing. However, standard assays for the detection of anti-GBM antibodies have a high rate of false-negative results. In this particular case, an increase in proteinuria despite standard therapy (plasmapheresis, steroids, cyclophosphamide) was the clinical correlate of relapsing disease. The use of rituximab completely resolved the recurrent anti-GBM disease.

Impact of ANCA-Associated Vasculitis on Outcomes of Hospitalizations for Goodpasture's Syndrome in the United States: Nationwide Inpatient Sample 2003-2014.

Background and objectives: Goodpasture's syndrome (GS) is a rare, life-threatening autoimmune disease. Although the coexistence of anti-neutrophil cytoplasmic antibody (ANCA) with Goodpasture's syndrome has been recognized, the impacts of ANCA vasculitis on mortality and resource utilization among patients with GS are unclear. Materials and Methods: We used the National Inpatient Sample to identify hospitalized patients with a principal diagnosis of GS from 2003 to 2014 in the database. The predictor of interest was the presence of ANCA-associated vasculitis. We tested the differences concerning in-hospital treatment and outcomes between GS patients with and without ANCA-associated vasculitis using logistic regression analysis with adjustment for other clinical characteristics. Results: A total of 964 patients were primarily admitted to hospital for GS. Of these, 84 (8.7%) had a concurrent diagnosis of ANCA-associated vasculitis. Hemoptysis was more prevalent in GS patients with ANCA-associated vasculitis. During hospitalization, GS patients with ANCA-associated required non-significantly more mechanical ventilation and non-invasive ventilation support, but non-significantly less renal replacement therapy and plasmapheresis than those with GS alone. There was no significant difference in in-hospital outcomes, including organ failure and mortality, between GS patients with and without ANCA-associated vasculitis. Conclusions: Our study demonstrated no significant differences between resource utilization and in-hospital mortality among hospitalized patients with coexistence of ANCA vasculitis and GS, compared to those with GS alone.

A Modified Peptide Derived from Goodpasture Autoantigen Arrested and Attenuated Kidney Injuries in a Rat Model of Anti-GBM Glomerulonephritis.

BACKGROUND: In Goodpasture disease, the noncollagenous domain 1 of the α3 chain (α3NC1) of type IV collagen is the main target antigen of antibodies against glomerular basement membrane (GBM). We previously identified a nephritogenic epitope, P14 (α3127-148), that could induce crescentic nephritis in WKY rats, and defined its core motif. Designing a modified peptide, replacing critical pathogenic residues with nonpathogenic ones (on the basis of homologous regions in α1NC1 chain of type IV collagen, known to be nonpathogenic), might provide a therapeutic option for anti-GBM GN. METHODS: We synthesized a modified peptide, replacing a single amino acid, and injected it into α3-P14-immunized rats from day 0 (the early-treatment group) or a later-treatment group (from days 17 to 21). A scrambled peptide administrated with the same protocol served as a control. RESULTS: The modified peptide, but not the scrambled peptide, attenuated anti-GBM GN in both treatment groups, and halted further crescent formation even after disease onset. Kidneys from the modified peptide-treated rats exhibited reductions in IgG deposits, complement activation, and infiltration by T cells and macrophages. Treatment also resulted in an anti-inflammatory cytokine profile versus a proinflammatory profile for animals not receiving the modified peptide; it also reduced α3-P14-specific T cell activation, modulated T cell differentiation by decreasing Th17 cells and enhancing the ratio of Treg/Th17 cells, and inhibited binding of α3-P14 to antibodies and MHC II molecules. CONCLUSIONS: A modified peptide involving alteration of a critical motif in a nephritogenic T cell epitope alleviated anti-GBM GN in a rat model. Our findings may provide insights into an immunotherapeutic approach for autoimmune kidney disorders such as Goodpasture disease.