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The use of high-quality antigen-specific immunoassays for detecting anti-neutrophil cytoplasmic antibodies (ANCA) and anti-glomerular basement membrane (GBM) autoantibodies is recommended in patients with suspected ANCA vasculitis and/or anti-GBM disease. We analysed the diagnostic performance of a semi-quantitative and rapid immunoblot (EUROIMMUN AG, Lubeck, Germany) in two settings. Patient sera from different cohorts (ANCA vasculitis n = 187, anti-GBM disease n = 19, and disease controls n = 51) were used. The diagnostic performance of the immunoblot was assessed when used as a confirmatory test for the presence of ANCA in suspected ANCA vasculitis and when evaluating the presence of ANCA and/or anti-GBM antibodies in AAV and/or anti-GBM disease patients with a rapidly progressive glomerulonephritis (RPGN). In a confirmatory test setting, the immunoblot had an optimal sensitivity and specificity of 97.4 and 98.1% for PR3-ANCA and 98.5 and 96.4% for MPO-ANCA, respectively. With increasing test result ranges, a higher interval likelihood ratio (LR) was found for both ANCA entities. When evaluating for ANCA in patients with RPGN, the highest diagnostic accuracy (sensitivity 92.9% and specificity 100%) was obtained by using different cut-off values of positivity for PR3- (>5) and MPO-ANCA (>10). Also, the diagnostic performance for detecting anti-GBM was good (sensitivity 100% and specificity 100%). There are advantages over other assays in terms of time, costs, and interpretation of results. The immunoblot is a useful addition to current guidelines, particularly when a rapid diagnosis is necessary.

Patients with renopulmonary syndrome who have both anti-neutrophil cytoplasmic and anti-glomerular basement membrane antibodies have been described since 1989.The aim of the authors was to analyse the data of "double positive" patients diagnosed in their department, and compare these with previous studies.During the last 16 years, 87 anti-neutrophil cytoplasmic antibody positive and 11 anti-glomerular basement membrane antibody positive patients were diagnosed. Four patients with anti-glomerular basement membrane antibodies (36%) had detectable anti-neutrophil cytoplasmic antibodies, 2 patients were positive for anti-myeloperoxidase and 2 patients for anti-proteinase 3.In comparison with patients having anti-glomerular basement membrane antibodies, the double-positive patients were characterized by older age (median of 46 vs. 24 years), lack of male dominance (50% vs. 71%), more frequent presence of previous extrarenal symptoms (50% vs. 0%), and lower anti-glomerular basement membrane antibody levels (100EU/ml: 100% vs. 29%). The double-positive patients had more favourable 1-year survival (100% vs. 71%), despite their older age and similar treatment regimen (immunosuppression 100% in both groups, plasmapheresis in 75% vs. 86%), but 1-year renal survival was not different (25% vs. 14%).In agreement with literature data, about one third of patients with anti-glomerular basement membrane antibodies had detectable anti-neutrophil cytoplasmic antibodies, and the coexistence of the two antibodies may have clinical consequences.Bevezetés: A világirodalomban 1989 óta számolnak be olyan renopulmonalis szindrómás betegekről, akiknél mind az antiglomeruláris bazálmembrán, mind az antineutrofil citoplazmatikus antitest kimutatható. Célkitűzés: A szerzők célja az volt, hogy az intézetükben előfordult „kettős pozitív” eseteket felkutassák, adataikat feldolgozzák és összehasonlítsák az irodalomban leírtakkal. Módszer: Az elmúlt 16 évben 87 antineutrofil citoplazmatikus antitest pozitív vasculitises és 11 antiglomeruláris bazálmembrán antitest pozitív beteget kezeltek, közülük négy betegben (36%) volt az antineutrofil citoplazmatikus antitest is kimutatható (két antimieloperoxidáz-, két antiproteináz-3-pozitivitás). Eredmények: A csak antiglomeruláris bazálmembrán antitest pozitív betegekkel szemben a kettős pozitív betegekre magasabb átlagéletkor (46 vs. 24 év), a férfi dominancia hiánya (50% vs. 71%), megelőző extrarenalis tünetek gyakoribb jelenléte (50% vs. 0%), alacsonyabb antiglomeruláris bazálmembrán antitest szintek (100 EU/ml: 100% vs. 29%) voltak jellemzőek. A kettős pozitívak között jobb volt az egyéves betegtúlélés (100% vs. 71%) az idősebb kor és a hasonló kezelés ellenére (immunszuppresszió mindkét csoportban 100%, plazmaferézis 75%, illetve 86%), az egyéves vesetúlélés nem különbözött (25%, illetve 14%). Következtetések: A nemzetközi tapasztalatokhoz hasonlóan az antiglomeruláris bazálmembrán antitest pozitív hazai betegek harmadában antineutrofil citoplazmatikus antitest pozitivitás is észlelhető, ami eltérésekkel társul a renopulmonalis szindróma klinikai megjelenésében. Orv. Hetil., 2013, 154, 1696–1701.

Background/Aims: Patients with anti-glomerular basement membrane diseases produce pathogenic autoantibodies (autoAb) that deposit in the kidney and initiate severe inflammation. Restricted antigenic specificity of the autoAb against 2 regions (with related sequences) within α3(IV)NC1, along with shared idiotypes (i.e. structural determinants), among pathogenic human autoAb suggested that common genetic elements encode the autoAb. The aim of this study was to determine whether the idiotypic relatedness of the autoAb was due to the fact that unique and similar genes were used to encode them, divergent genes were used to produce Ab with similar Ag-binding properties and conformation, or if other mechanisms were operative. Methods: The encoding V gene sequences of pathogenic human anti-α3(IV)NC1 Ab, derived following immunization of XenoMice® which produce human but not murine IgG, with α3(IV)NC1 were determined. Predicted conformations of autoAb–α3(IV)NC1 interactions were derived using the Ab sequences and molecularmodels of the α3(IV)NC1 structure. Results: The pathogenic Ab were encoded by multiple, common VH and VL gene families indicating that they were not encoded by a unique subset of genes and that normal individuals have the capacity to produce them. However, modeling of the Ag–Ab interactions suggested that although the contact regions varied for individual Ab, the optimized energy constraints facilitate interaction of both Ab-binding regions with pathogenically relevant epitopes on α3(IV)NC1. Conclusions: The results suggest that the repetitive nature and relatedness of the α3(IV)NC1 antigenic epitopes facilitate cross-linking of pathogenic Ab, in vivo, by allowing both IgG Fab to bind to the basement membrane. This most likely accounts for the high-affinity Ab binding we and others observed among human anti-α3(IV)NC1 Ab. Based on these observations, we postulate that this interaction provides for the stability of the Ab interaction, resulting in a high-affinity interaction that serves as an ideal scaffold for optimal FcR engagement and complement activation, thereby accelerating inflammation and contributing to the rapidly progressive nature of this disease.

Fig 2. Early segmental fibrinoid necrosis with early cellular crescent formation without endocapillary proliferation or evidence of immune complexes in the remaining glomerular tuft. This light microscopic finding is that of a pauci-immune necrotizing glomerulonephritis, with a specific diagnosis of anti-GBM antibody-mediated glomerulonephritis made by immunofluorescence (see Fig 3) (Jones silver stain; original magnification 3400).

There is evidence derived from both experimental studies and from observation of human nephritis that platelets are important in the glomerular injury of chronic soluble-complex disease. It is not yet clear if platelets are involved in the events initiating endothelial damage, in perpetuating and amplifying injury, or both. Antiplatelet agents appear to have a role in the treatment of chronic forms of glomerulonephritis; but more knowledge of platelet involvement in nephritis and more readily available tests for platelet involvement are necessary before this suggestion can be tested intelligently.

The influence of HLA-linked genes on anti-GBM antibody-mediated nephritis. Thirty-nine Caucasian patients with glomerulonephritis caused by autoantibodies to glomerular basement membrane (GBM) were studied. They were segregated into three groups depending on presentation: Group 1 (19 patients) were anuric or oliguric, group 2 (13 patients) had rapidly deteriorating renal function but were not oliguric, and group 3 (seven patients) had stable renal function. The incidence of HLA-DR2 was greatly increased; it was present in 34 of 38 patients in whom DR antigens were identified compared to 43 of 154 controls (Pc = 0.63 × 10 -8 , relative risk 36, etiological fraction 0.86). The incidence of HLA-B7 was also increased; present in 23 of 39 patients and 43 of 193 controls (Pc = 0.26 × 10 -4 , relative risk 5.0, etiological fraction 0.43). These data were analyzed for a third order association between HLA-DR2, HLA-B7, and anti-GBM disease. Such an association was probable for patients in group 1 (P = 0.27 × 10 -6 ), likely for those in group 2 (P = 0.024) but unlikely for patients in group 3 (P = 0.62) suggesting HLA-B7-associated genes influence severity. Clinical results from a subset of the patients referred directly on presentation showed that patients who inherited HLA-B7 together with DR2 had significantly higher plasma creatinines, a greater proportion of glomeruli surrounded by crescents and a worse prognosis. Despite this there was little difference in severity of their lung disease. Influence des genes lies a HLA sur la severite de la nephrite mediee par un anticorps anti-GMB. Trente-neuf malades blancs atteints de glomerulonephrite due a des anticorps diriges contre la membrane basale glomerulaire (GBM) ont ete etudies. Ils ont ete divises en trois groupes en fonction du tableau: ceux du groupe 1 (19 malades) etaient anuriques ou oliguriques, ceux du groupe 2 (13 malades) avaient une fonction renale se deteriorant rapidement mais n'etaient pas oliguriques, et ceux du groupe 3 (sept malades) avaient une fonction renale stable. L'incidence de HLA-DR2 etait tres augmentee; il etait present chez 34 des 38 malades chez qui les antigenes DR avaient ete identifies, par rapport a 43 de 154 controles (Pc = 0,63 × 10 -8 , risque relatif 36, fraction etiologique 0,86). L'incidence de HLA-B7 etait egalement augmentee; il etait present chez 23 des 39 malades et 43 de 193 controles (Pc = 0,26 × 10 -4 , risque relatif 5,0, fraction etiologique 0,43). Ces donnees ont ete analysees pour une association du troisieme ordre entre HLA-DR2, HLA-B7, et la maladie anti-GBM. Une telle association etait probable pour les malades du groupe 1 (P = 0,27 × 10 -6 ), possible pour ceux du groupe 2 (P = 0,024), mais improbable pour ceux du groupe 3 (P = 0,62), suggerant que les genes associes a HLA-B7 influencent la severite. Les resultats cliniques d'un sous-groupe de malades adresses directement au debut ont montre que ceux qui avaient herite de HLA-B7 et de DR2 avaient des creatininemies significativement plus elvees, une plus grande proportion de glomerules entoures de croissants et un pronostic plus mauvais. Malgre cela, il y avait peu de difference de severite de leur maladie pulmonaire.

Glomerulonephritis induced by antibodies to the glomerular basement membrane is a well recognized cause of renal disease and is responsible for 5% to 15% of all glomerular disease. The patients usually present with an acute nephritic syndrome followed by rapidly progressive renal failure. We report two patients who presented with the nephrotic syndrome and anti-GBM glomerulonephritis, and who exhibited differing clinical courses not characteristic of "rapidly progressive glomerulonephritis" or Goodpasture's syndrome.

The effect of anti-GBM antibody on protein excretion was studied in isolated rat kidneys perfused with 20 mg of sheep anti-rat GBM (experimental) or nonantibody sheep IgG (control). Six control kidneys excreted 176 +/- 31 micrograms/min of BSA initially, rising to 296 +/- 111 micrograms/min at 2 h. Fractional clearance of BSA rose from 0.51 to 1.70%. Eight experimental kidneys excreted 211 +/- 56 micrograms/min of BSA, increasing to 1,924 +/- 804 micrograms/min at 2 h. Fractional BSA clearance increased from 0.56 to 11.49%. After 60 min, BSA excretion in anti-GBM-perfused kidneys exceeded controls by a factor of 6.5-7.9 (P less than 0.05) and fractional BSA clearance exceeded controls by a factor of 5.8-7.1 (P less than 0.05). Studies with fluorescent markers indicated proteinuria to be of glomerular origin in antibody-perfused kidneys. There were no significant differences between anti-GBM-perfused and control kidneys in perfusion pressures, perfusate flow rates, urine flow rates, inulin clearance, or sodium reabsorption. Antibody to GBM can induce a marked increase in glomerular permeability to BSA and IgG without participation of other systemic humoral or cellular mediation systems.