Slowly progressive anti-neutrophil cytoplasmic antibody-associated renal vasculitis: clinico-pathological characterization and outcome.

BACKGROUND: Although rapidly progressive glomerulonephritis is the main renal phenotype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), slow renal disease progression is sometimes observed. These forms have been rarely discussed; we analysed their prevalence, clinico-pathological characteristics and outcome. METHODS: We screened patients with microscopic  polyangiitis (MPA) and granulomatosis with polyangiitis followed at seven referral centres and selected those with estimated glomerular filtration rate (eGFR) reduction 25% as compared with diagnosis, while 4/34 (12%) had started RRT. CONCLUSIONS: AAV may present with slow renal disease progression; this subset is hallmarked by advanced age at diagnosis, positive MPO-ANCA, subclinical interstitial lung lesions and chronic damage at kidney biopsy. Partial renal recovery may occur following immunosuppression

Glomerular autoimmune multicomponents of human lupus nephritis in vivo: α-enolase and annexin AI

Renal targets of autoimmunity in human lupus nephritis (LN) are unknown. We sought to identify autoantibodies and glomerular target antigens in renal biopsy samples from patients with LN and determine whether the same autoantibodies can be detected in circulation. Glomeruli were microdissected from biopsy samples of 20 patients with LN and characterized by proteomic techniques. Serum samples from large cohorts of patients with systemic lupus erythematosus (SLE) with and without LN and other glomerulonephritides were tested. Glomerular IgGs recognized 11 podocyte antigens, with reactivity varying by LN pathology. Notably, IgG2 autoantibodies against α-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of α-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti-α-enolase (>15 mg/L) IgG2 and/or anti-annexin AI (>2.7 mg/L) IgG2 were detected in most patients with LN but not patients with other glomerulonephritides, and they identified two cohorts: patients with high anti-α-enolase/low anti-annexin AI IgG2 and patients with low anti-α-enolase/high anti-annexin AI IgG2. Serum levels of both autoantibodies decreased significantly after 12 months of therapy for LN. Anti-α-enolase IgG2 recognized specific epitopes of α-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human α-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against α-enolase and annexin AI predominate in the glomerulus and can be detected in serum

Anti-podocyte antibodies: coexistence and clinical correlations in membranous nephropathy patients

Negli ultimi anni, la ricerca sulla patogenesi della forma umana della nefropatia membranosa (NM) ha compiuto dei notevoli progressi, soprattutto grazie all’applicazione di nuove tecnologie quali la microdissezione laser e le metodiche di proteomica. Attualmente è noto che più di un anticorpo diretto contro antigeni podocitari è coinvolto nello sviluppo della forma idiopatica della malattia. Questi antigeni sono: il recettore della fosfolipasi A2 (PLA2r), l’aldoso reduttasi (AR), la superossido dismutasi 2 (SOD2) e l’alfa-enolasi (AENO). Questo ha portato ad ipotizzare l’utilizzo dei rispettivi anticorpi come potenziali biomarcatori di malattia o della sua attività. Al momento, l’evidenza del coinvolgimento patogenetico di tali anticorpi è abbastanza forte (soprattutto per gli anti-PLA2r), tuttavia è ancora poco noto il loro comportamento nel decorso della malattia e, soprattutto, dopo la terapia immunosoppressiva. Inoltre, nessun gruppo di ricerca ha ancora valutato l’escrezione urinaria di tali anticorpi: ulteriori e preziose valutazioni sulla patogenesi della NM potrebbero derivare da questa analisi. Lo studio si è basato su 22 pazienti affetti da NM, reclutati alla diagnosi e seguiti per due anni con titolazioni seriate su siero ed urine di tutto il pannello anticorpale noto, dopo essere stati trattati con uno schema immunosoppressivo largamente diffuso, il ciclo di Ponticelli. Alla diagnosi, tutti gli anticorpi sono risultati complessivamente elevati. Dopo la terapia, essi si sono complessivamente ridotti. Anche i livelli urinari sono risultati essere incrementati rispetto ai controlli normali, tuttavia non hanno mostrato una tendenza alla riduzione. Nessun singolo anticorpo è sembrato essere meglio legato all’andamento clinico. Gli anti-PLA2r urinari sono apparsi più correlati agli anticorpi sierici, tuttavia questi ultimi si sono ridotti anche nei pazienti perstentemente nefrosici. Nessun paziente che ha raggiunto la remissione completa è risultato essere invece positivo per anti-AR e/o anti-SOD2. I risultati di questo studio confermano sostanzialmente i risultati di precedenti pubblicazioni sull’argomento. Viene ancora una volta suggerito che, alla base della patogenesi della NM, vi sia la presenza di una complessa rete autoanticorpale. Non viene invece ancora chiarito se la valutazione del pannello anticorpale completo possa offrire dei reali vantaggi dal punto di vista clinico. Appare tuttavia evidente che ogni singola specificità possa essere utile nel completare il quadro clinico-anticorpale del singolo paziente.In recent years, research on human membranous nephropathy (MN) pathogenesis has made considerable progress, especially through the application of new technologies such as laser capture microdissection and proteomics techniques. Nowadays, it is known that more than one antibody directed against podocyte antigens is involved in the development of idiopathic MN. These antigens are: phospholipase A2 receptor (PLA2r), aldose reductase (AR), superoxide dismutase 2 (SOD2) and alpha-enolase (AENO). Therefore, there is a big interest to evaluate such antibodies as potential disease biomarkers. However, at the moment, it is still poorly known their behavior during the course of the disease, especially after immunosuppressive therapy. In addition, no research group has yet evaluated the urinary excretion of these antibodies: interesting data on MN pathogenesis of may arise from this analysis. This study was based on 22 patients with MN, recruited at diagnosis and followed for two years with lengthwise serum and urinary specimens collection. All patents were treated with the immunosuppressive Ponticelli’s schedule. At diagnosis, all serum antibodies were higher than normal. After therapy, they reduced in most patients. Although urinary levels were found to be increased if compared to normal controls, they did not show a decreasing trend. No single antibody appeared to be better linked to the clinical outcome. Urinary anti-PLA2r appeared particularly related to serum anti-PLA2r, but they decreased also in persistent nephrotic subjects. No patient in complete remission was found to be positive for anti-AR and / or anti-SOD2. This study essentially confirms the results of previous publications. Is once again suggested that, at the basis of MN pathogenesis, there is the presence of a complex autoantibody network. There is not yet clear whether the evaluation of the complete antibody panel could offer real benefits from the clinical point of view. However, every antibody specificity may be useful in completing the clinical picture of every single patient and in broadening our knowledge on MN

Mechanisms Limiting Renal Tissue Protection and Repair in Glomerulonephritis

Glomerulonephritis are renal disorders resulting from different pathogenic mechanisms (i.e., autoimmunity, complement, inflammatory activation, etc.). Clarifying details of the pathogenic cascade is basic to limit the progression from starting inflammation to degenerative stages. The balance between tissue injury, activation of protective systems and renal tissue repair determines the final outcome. Induction of an oxidative stress is part of glomerular inflammation and activation of protective antioxidant systems has a crucial role in reducing tissue effects. The generation of highly reactive oxygen species can be evaluated in vivo by tracing the inner-layer content of phosphatidyl ethanolamine and phosphatidyl serine in cell membranes. Albumin is the major antioxidant in serum and the level of oxidized albumin is another indirect sign of oxidative stress. Studies performed in Gn, specifically in FSGS, showed a high degree of oxidation in most contexts. High levels of circulating anti-SOD2 antibodies, limiting the detoxyfing activity of SOD2, have been detected in autoimmune Gn(lupus nephritis and membranous nephropathy) in association with persistence of proteinuria and worsening of renal function. In renal transplant, high levels of circulating anti-Glutathione S-transferase antibodies have been correlated with chronic antibody rejection and progressive loss of renal function. Annexins, mainly ANXA1 and ANXA2, play a general anti-inflammatory effect by inhibiting neutrophil functions. Cytosolic ANXA1 is decreased in apoptotic neutrophils of patients with glomerular polyangitis in association with delayed apoptosis that is considered the mechanism for polyangitis. High circulating levels of anti-ANXA1 and anti-ANXA2 antibodies characterize lupus nephritis implying a reduced anti-inflammatory effect. High circulating levels of antibodies targeting Macrophages (anti-FMNL1) have been detected in Gn in association with proteinuria. They potentially modify the intra-glomerular presence of protective macrophages (M2a, M2c) thus acting on the composition of renal infiltrate and on tissue repair

Coexistence of Different Circulating Anti-PodocyteAntibodies in Membranous Nephropathy

19openopenCorrado Murtas; Maurizio Bruschi; Giovanni Candiano; Gabriella Moroni; Riccardo Magistroni; Andrea Magnano; Francesca Bruno; Antonella Radice; Luciana Furci; Lucia Argentiero;| Maria Luisa Carnevali;| Piergiorgio Messa; Francesco Scolari; Renato Alberto Sinico; Loreto Gesualdo; Fernando C. Fervenza; Landino Allegri; Pietro Ravani; Gian Marco GhiggeriCorrado, Murtas; Maurizio, Bruschi; Giovanni, Candiano; Gabriella, Moroni; Riccardo, Magistroni; Andrea, Magnano; Francesca, Bruno; Antonella, Radice; Luciana, Furci; Lucia, Argentiero; | Maria Luisa, Carnevali; | Piergiorgio, Messa; Scolari, Francesco; Renato Alberto, Sinico; Loreto, Gesualdo; Fernando C., Fervenza; Landino, Allegri; Pietro, Ravani; Gian Marco, Ghigger

Clinical Features and Long-Term Outcome of Nephrotic Syndrome Associated with Heterozygous NPHS1 and NPHS2 Mutations

Background and objectives: Mutations in nephrin (NPHS1) and podocin (NPHS2) genes represent a major cause of idiopathic nephrotic syndrome (NS) in children. It is not yet clear whether the presence of a single mutation acts as a modifier of the clinical course of NS

Autoimmunity in Membranous Nephropathy Targets Aldose Reductase and SOD2

Glomerular targets of autoimmunity in human membranous nephropathy are poorly understood. Here, we used a combined proteomic approach to identify specific antibodies against podocyte proteins in both serum and glomeruli of patients with membranous nephropathy (MN). We detected specific anti–aldose reductase (AR) and anti–manganese superoxide dismutase (SOD2) IgG4 in sera of patients with MN. We also eluted high titers of anti-AR and anti-SOD2 IgG4 from microdissected glomeruli of three biopsies of MN kidneys but not from biopsies of other glomerulonephritides characterized by IgG deposition (five lupus nephritis and two membranoproliferative glomerulonephritis). We identified both antigens in MN biopsies but not in other renal pathologies or normal kidney. Confocal and immunoelectron microscopy (IEM) showed co-localization of anti-AR and anti-SOD2 with IgG4 and C5b-9 in electron-dense podocyte immune deposits. Preliminary in vitro experiments showed an increase of SOD2 expression on podocyte plasma membrane after treatment with hydrogen peroxide. In conclusion, our data support AR and SOD2 as renal antigens of human MN and suggest that oxidative stress may drive glomerular SOD2 expression