Myeloperoxidase-antineutrophil cytoplasmic antibody causes different renal diseases by immune-complex formation and pauci-immune mechanism: A case report.

Antineutrophil cytoplasmic antibody (ANCA) has been known to cause pauci-immune crescentic glomerulonephritis. In addition, several reports described membranous glomerulonephritis (MN) concurrent with ANCA-associated glomerulonephritis. Because the two glomerular diseases simultaneously appear in an ANCA-positive patient, the mechanisms whereby ANCA causes the two different glomerular diseases remain ambiguous. Herein, we report a case of 19-year-old man who presented with hematuria, pre-nephrotic proteinuria, and high titer of myeloperoxidase (MPO)-ANCA. The first renal biopsy revealed MN with chronic glomerular scar lesions of unknown etiology. Predominant immunoglobulin (Ig) G1 subclass and negative phospholipase-A2 receptor staining, together with granular-positive glomerular capillary co-localization of MPO and IgG staining, suggested secondary MN due to MPO-MPO-ANCA immune-complex. Five years later, the patient presented with fever, severe renal dysfunction, and alveolar hemorrhage with high titer of MPO-ANCA that indicated pulmonary renal syndrome due to ANCA-associated vasculitis. The second renal biopsy revealed pauci-immune crescentic glomerulonephritis without either apparent MN-lesion or glomerular IgG staining. This is the first reported case showing that MPO-ANCA caused two different glomerular diseases, MN and pauci-immune crescentic glomerulonephritis, in the same patient at the different time points. Our case indicated that common MPO-ANCA might cause different glomerular diseases by different immune mechanisms.

Manabe S ，Hatano M ，Nakano M ，Fujii T ，Nitta K ，Nagata M ... -  《-》

[Case of MPO-ANCA-associated vasculitis with membranous nephropathy].

Watanabe S ，Arimura Y ，Nomura K ，Kawashima S ，Yoshihara K ，Kaname S ，Yamada A ... -  《-》

Glomerular Immune Deposition in MPO-ANCA Associated Glomerulonephritis Is Associated With Poor Renal Survival.

Rapidly progressive glomerulonephritis caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is typically characterized as pauci-immune glomerulonephritis. However, immune complex (IC) deposition in the glomerulus has been reported in a growing number of studies. Here, we assess the presence of glomerular immune deposits alongside renal outcome in myeloperoxidase (MPO)-ANCA associated glomerulonephritis (MPO-ANCA GN). Clinical and histopathologic characteristics of 97 patients with MPO-ANCA GN classified by renal biopsy from January 2008 to December 2019 were extracted retrospectively from electronic medical records. The extent of immune deposits in the kidney (C3, C4, C1q, IgA, IgG, IgM) at diagnosis were analyzed by immunofluorescence (IF). Patients were followed up for a median period of 15 months. The response to treatment and outcomes of renal and histological lesion changes were also assessed. In our study, 41% (40/97) of patients showed positive IF (≥2+) for at least one of the six immunoglobulin or complement components tested. Patients with IC deposits showed higher levels of serum creatinine (p=0.025), lower platelet counts (p=0.009), lower serum complement C3 (sC3) (≤790 ml/L) (p=0.013) and serum IgG (p=0.018) than patients with pauci-immune (PI) deposition at diagnosis. End-stage renal disease was negatively associated with eGFR (HR 0.885, 95% CI 0.837 to 0.935, p<0.0001), platelet count (HR 0.996, 95% CI 0.992 to 1.000, p=0.046) and serum globulin (HR 0.905, 95% CI 0.854 to 0.959, p=0.001). Patients with lower sC3 levels showed a worse renal outcome than the patients with normal sC3 at diagnosis (p=0.003). Analysis of the components of the renal deposits found that patients with IgG deposits exhibited a poorer renal outcome compared to patients that were IgG negative (p=0.028). Moreover, Bowman's capsule rupture occurred less frequently in patients with IgM deposition compared with IgM negative counterparts (p=0.028). Vascular lesions and granuloma-like lesions had been seen more frequently in cases with IgA deposition than those without IgA deposition (p=0.03 and 0.015, respectively). In conclusion, patients with immune complex deposits in the kidney showed less platelet count, lower sC3 and sIgG levels, and higher serum creatinine levels. Patients with low sC3 at initial and with continued low sC3 during the treatment displayed a trend toward poorer kidney survival. Moreover, the IC group showed a worse renal outcome than the PI group, further enforcing the present strategy of introducing complement targeted therapies in AAV.

Lin W ，Shen C ，Zhong Y ，Ooi JD ，Eggenhuizen P ，Zhou YO ，Luo H ，Huang J ，Chen JB ，Wu T ，Meng T ，Xiao Z ，Ao X ，Peng W ，Tang R ，Yin H ，Xiao X ，Zhou Q ，Xiao P ... -  《Frontiers in Immunology》

Impact of anti-glomerular basement membrane antibodies and glomerular neutrophil activation on glomerulonephritis in experimental myeloperoxidase-antineutrophil cytoplasmic antibody vasculitis.

Antineutrophil cytoplasmic antibody (ANCA) and neutrophil interactions play important roles in ANCA-associated vasculitis (AAV) pathogenesis. However, mechanisms underlying the pathogenesis of crescent formation in ANCA-associated vasculitis have not been completely elucidated. To ascertain the involvement of these interactions in necrotizing crescentic glomerulonephritis (NCGN), we used an AAV rat model and investigated the effects of the anti-myeloperoxidase (MPO) antibody (Ab) titer, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF) and subnephritogenic anti-glomerular basement membrane (GBM) Abs, as proinflammatory stimuli. NCGN was induced in Wistar Kyoto rats by human MPO (hMPO) immunization. Renal function, pathology, and glomerular cytokine and chemokine expression were evaluated in hMPO-immunized rats with/without several co-treatments (TNF-α, G-CSF or subnephritogenic anti-GBM Abs). Rat neutrophils activation by IgG purified from rat serum in each group was examined in vitro. The hMPO-immunized rats had significantly higher level of anti-hMPO Ab production. The induced anti-hMPO Abs cross-reacted with TNF-α- or G-CSF-primed rat neutrophils secreting TNF-α and interleukin-1β in vitro. The reactivity of anti-MPO Abs against rat MPO, crescent formation with neutrophil extracellular traps and glomerular-activated neutrophil infiltration in the rat model were significantly enhanced by subnephritogenic anti-GBM Ab but not by TNF-α or G-CSF administration. The model rats injected with the subnephritogenic anti-GBM Abs showed increased urinary albumin excretion and serum TNF-α, chemokine (C-X-C) ligand 1 (CXCL1) and CXCL2 levels. TNF-α, CXCL1, CXCL2 and CXCL8 increased in the glomeruli with significant amounts of crescent formation. In addition, in vitro activated neutrophils decreased CXC chemokine receptor 1 (CXCR1) and CXCR2 expressions. The coexistence of subnephritogenic anti-GBM Abs leads to the inflammatory environment in glomeruli that is amplified by the interaction of ANCA and neutrophils. Development of NCGN in MPO-AAV may be necessary for not only the accumulation of neutrophils in glomeruli, but also the aberrant neutrophil activation on glomerulonephritis.

Kanzaki G ，Nagasaka S ，Higo S ，Kajimoto Y ，Kanemitsu T ，Aoki M ，Nagahama K ，Natori Y ，Tsuboi N ，Yokoo T ，Shimizu A ... -  《-》

Fatal pulmonary-renal syndrome manifested with immune complex crescentic glomerulonephritis in a patient with MPO-ANCA seropositivity.

Song JH ，Lee KJ ，Lee SW ，Han JY ，Kim MJ ... -  《YONSEI MEDICAL JOURNAL》