Characterization of a Rat Model of Myeloperoxidase-Anti-Neutrophil Cytoplasmic Antibody-Associated Crescentic Glomerulonephritis

Nephron ◽  
2021 ◽  
pp. 1-17
Author(s):  
Domenico Cerullo ◽  
Daniela Rottoli ◽  
Daniela Corna ◽  
Paola Rizzo ◽  
Mauro Abbate ◽  
...  
Keyword(s):  
Crescentic Glomerulonephritis ◽  
Neutrophil Infiltration ◽  
Double Positive ◽  
Ki 67 ◽  
Necrotizing Crescentic Glomerulonephritis ◽  
Neural Cell Adhesion ◽  
Current Therapies ◽  
Wistar Kyoto ◽  
Set Up ◽  
Parietal Epithelial Cells

<b><i>Background/Aim:</i></b> Necrotizing crescentic glomerulonephritis (GN) associated with anti-neutrophil cytoplasmic antibodies (ANCA) against myeloperoxidase (MPO) is a devastating disease that quickly progresses to kidney failure. Current therapies are broadly immunosuppressive and associated with adverse effects. We wanted to set up a model that could be suitable for testing narrowly targeted therapies. <b><i>Methods:</i></b> The model was constructed in male Wistar Kyoto rats through injections of human MPO (hMPO) and pertussis toxin, followed by a sub-nephritogenic dose of sheep anti-rat glomerular basement membrane (GBM) serum to boost the disease. Rats were monitored for 35 days. Rats given hMPO alone, saline, or human serum albumin with or without anti-GBM serum were also studied. <b><i>Results:</i></b> Rats receiving hMPO developed circulating anti-hMPO and anti-rat MPO antibodies. Challenging hMPO-immunized rats with the anti-GBM serum led to more glomerular neutrophil infiltration and MPO release, and severe haematuria, heavy proteinuria, and higher blood urea nitrogen than hMPO alone. Pauci-immune GN developed with crescents, affecting 25% of glomeruli. The majority of crescents were fibrocellular. Necrotizing lesions and Bowman capsule ruptures were detected. Cells double positive for claudin-1 (a marker of parietal epithelial cells [PECs]) and neural cell adhesion molecule (NCAM; progenitor PECs) were present in crescents. Double staining for NCAM and Ki-67 established proliferative status of progenitor PECs. Podocyte damage was associated with endothelial and GBM changes by electron microscopy. Monocyte/macrophages and CD4<sup>+</sup> and CD8<sup>+</sup> T cells accumulated in glomeruli and the surrounding area and in the tubulointerstitium. Lung haemorrhage also manifested. <b><i>Conclusion:</i></b> This model reflects histological lesions of human ANCA-associated rapidly progressive GN and may be useful for investigating new therapies.

Tissue Ki67 proliferative index expression and pathological changes in hemodialysis arteriovenous fistulae: Preliminary single-center results

2021 ◽  
pp. 112972982110154
Author(s):  
Raffaella Mauro ◽  
Cristina Rocchi ◽  
Francesco Vasuri ◽  
Alessia Pini ◽  
Anna Laura Croci Chiocchini ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Hot Spot ◽  
Wall Thickening ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Group A ◽  
The Mean ◽  
Set Up ◽  
Group B

Background: Arteriovenous fistula (AVF) for hemodialysis integrates outward remodeling with vessel wall thickening in response to drastic hemodynamic changes. Aim of this study is to determine the role of Ki67, a well-established proliferative marker, related to AVF, and its relationship with time-dependent histological morphologic changes. Materials and methods: All patients were enrolled in 1 year and stratified in two groups: (A) pre-dialysis patients submitted to first AVF and (B) patients submitted to revision of AVF. Morphological changes: neo-angiogenesis (NAG), myointimal thickening (MIT), inflammatory infiltrate (IT), and aneurysmatic fistula degeneration (AD). The time of AVF creation was recorded. A biopsy of native vein in Group A and of arterialized vein in Group B was submitted to histological and immunohistochemical (IHC) analysis. IHC for Ki67 was automatically performed in all specimens. Ki67 immunoreactivity was assessed as the mean number of positive cells on several high-power fields, counted in the hot spots. Results: A total of 138 patients were enrolled, 69 (50.0%) Group A and 69 (50.0%) Group B. No NAG or MIT were found in Group A. Seven (10.1%) Group A veins showed a mild MIT. Analyzing the Group B, a moderate-to-severe MIT was present in 35 (50.7%), IT in 19 (27.5%), NAG in 37 (53.6%); AD was present in 10 (14.5%). All AVF of Group B with the exception of one (1.4%) showed a positivity for Ki67, with a mean of 12.31 ± 13.79 positive cells/hot spot (range 0–65). Ki67-immunoreactive cells had a subendothelial localization in 23 (33.3%) cases, a myointimal localization in SMC in 35 (50.7%) cases. The number of positive cells was significantly correlated with subendothelial localization of Ki67 ( p = 0.001) and with NA ( p = 0.001). Conclusions: Native veins do not contain cycling cells. In contrast, vascular cell proliferation starts immediately after AVF creation and persists independently of the time the fistula is set up. The amount of proliferating cells is significantly associated with MIT and subendothelial localization of Ki67-immunoreactive cells, thus suggesting a role of Ki-67 index in predicting AVF failure.

scholarly journals Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052199331
Author(s):  
Chun-Yang Zhang ◽  
Ran Miao ◽  
Wei Li ◽  
Hao-Yong Ning ◽  
Xiang-En Meng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Histological Examination ◽  
Crescentic Glomerulonephritis ◽  
Elevated Serum ◽  
Pulmonary Nodules ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Necrotizing Crescentic Glomerulonephritis ◽  
Transthoracic Biopsy ◽  
Nasal Inflammation ◽  
The Relationship

The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.

scholarly journals Rare case of atypical crescentic glomerulonephritis and interstitial lung disease with negative anti-GBM antibody and positive anti-MPO antibody

2019 ◽  
Vol 12 (8) ◽  
pp. e229256 ◽  
Author(s):  
Alexander Hanna ◽  
Jenny Ross ◽  
Fernanda Heitor
Keyword(s):  
Hepatitis B ◽  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Rare Case ◽  
Crescentic Glomerulonephritis ◽  
Kidney Biopsy ◽  
Flank Pain ◽  
Antineutrophil Cytoplasmic Antibodies ◽  
Hepatitis B Infection ◽  
Double Positive

A 70-year-old man presented with 1 month of haematuria and mild right-sided flank pain with no other symptoms. Diagnostic workup included serum studies which showed the presence of antimyeloperoxidase antibodies, a kidney biopsy which demonstrated necrotising crescentic glomerulonephritis with linear immunofluorescence of the basement membrane, and electron microscopy which exhibited thickening of the glomerular basement membrane. Incidentally, the patient was discovered to have a latent hepatitis B infection, which complicated immunosuppressive therapy. He was treated with a course of plasmapheresis and methylprednisolone, followed by entecavir for hepatitis B prophylaxis, and finally by rituximab. This case of glomerulonephritis was notable for its resemblance to the better known Goodpasture’s disease. Typically, Goodpasture’s syndrome exists on a spectrum from seronegative disease to double-positive disease that presents with both anti–glomerular basement membrane (anti-GBM) and cytoplasmic-antineutrophil cytoplasmic antibodies/antiproteinase 3 antibodies (c-ANCA/anti-PR3). However, this patient’s glomerulonephritis was unique because he presented negative for anti-GBM antibodies and positive for perinuclear-antineutrophil cytoplasmic antibodies/antimyeloperoxidase antibodies (p-ANCA/anti-MPO).

Subepithelial neutrophil infiltration as a predictor of the surgical outcome of chronic rhinosinusitis with nasal polyps

2020 ◽  
Vol 0 (0) ◽  
pp. 0-0
Author(s):  
D-K. Kim ◽  
H-S. Lim ◽  
K.M. Eun ◽  
Y. Seo ◽  
J.K. Kim ◽  
...  
Keyword(s):  
Machine Learning ◽  
Random Forest ◽  
Decision Tree ◽  
Chronic Rhinosinusitis ◽  
Surgical Outcomes ◽  
Nasal Polyps ◽  
Human Neutrophil Elastase ◽  
Immunofluorescence Analysis ◽  
Double Positive ◽  
Ki 67

BACKGROUND: Neutrophils present as major inflammatory cells in refractory chronic rhinosinusitis with nasal polyps (CRSwNP), regardless of the endotype. However, their role in the pathophysiology of CRSwNP remains poorly understood. We investigated factors predicting the surgical outcomes of CRSwNP patients with focus on neutrophilic localization. METHODS: We employed machine-learning methods such as the decision tree and random forest models to predict the surgical outcomes of CRSwNP. Immunofluorescence analysis was conducted to detect human neutrophil elastase (HNE), Bcl-2, and Ki-67 in NP tissues. We counted the immunofluorescence-positive cells and divided them into three groups based on the infiltrated area, namely, epithelial, subepithelial, and perivascular groups. RESULTS: On machine learning, the decision tree algorithm demonstrated that the number of subepithelial HNE-positive cells, Lund-Mackay (LM) scores, and endotype (eosinophilic or non-eosinophilic) were the most important predictors of surgical outcomes in CRSwNP patients. Additionally, the random forest algorithm showed that, after ranking the mean decrease in the Gini index or the accuracy of each factor, the top three ranking factors associated with surgical outcomes were the LM score, age, and number of subepithelial HNE-positive cells. In terms of cellular proliferation, immunofluorescence analysis revealed that Ki-67/HNE-double positive and Bcl-2/HNE-double positive cells were significantly increased in the subepithelial area in refractory CRSwNP. CONCLUSION: Our machine-learning approach and immunofluorescence analysis demonstrated that subepithelial neutrophils in NP tissues had a high expression of Ki-67 and could serve as a cellular biomarker for predicting surgical outcomes in CRSwNP patients.

scholarly journals New Insights into Glomerular Parietal Epithelial Cell Activation and Its Signaling Pathways in Glomerular Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Hua Su ◽  
Shan Chen ◽  
Fang-Fang He ◽  
Yu-Mei Wang ◽  
Philip Bondzie ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Signaling Pathways ◽  
Membranous Nephropathy ◽  
Cell Activation ◽  
Crescentic Glomerulonephritis ◽  
Diabetic Glomerulopathy ◽  
Glomerular Diseases ◽  
The Past ◽  
Parietal Epithelial Cell ◽  
Parietal Epithelial Cells

The glomerular parietal epithelial cells (PECs) have aroused an increasing attention recently. The proliferation of PECs is the main feature of crescentic glomerulonephritis; besides that, in the past decade, PEC activation has been identified in several types of noninflammatory glomerulonephropathies, such as focal segmental glomerulosclerosis, diabetic glomerulopathy, and membranous nephropathy. The pathogenesis of PEC activation is poorly understood; however, a few studies delicately elucidate the potential mechanisms and signaling pathways implicated in these processes. In this review we will focus on the latest observations and concepts about PEC activation in glomerular diseases and the newest identified signaling pathways in PEC activation.

scholarly journals De novo expression of podocyte proteins in parietal epithelial cells during experimental glomerular disease

2010 ◽  
Vol 298 (3) ◽  
pp. F702-F711 ◽  
Author(s):  
Takamoto Ohse ◽  
Michael R. Vaughan ◽  
Jeffrey B. Kopp ◽  
Ronald D. Krofft ◽  
Caroline B. Marshall ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Basement Membrane ◽  
Transforming Growth Factor ◽  
Wilms Tumor ◽  
Glomerular Disease ◽  
Double Positive ◽  
Specific Proteins ◽  
Parietal Epithelial Cells ◽  
Tgf Β1 ◽  
Glomerular Tuft

Studies have shown that certain cells of the glomerular tuft begin to express proteins considered unique to other cell types upon injury. Little is known about the response of parietal epithelial cells (PEC) to injury. To determine whether PECs change their phenotype upon injury to also express proteins traditionally considered podocyte specific, the following four models of glomerular disease were studied: the transforming growth factor (TGF)-β1 transgenic mouse model of global glomerulosclerosis, the adriamycin model of focal segmental glomerulosclerosis (FSGS), the anti-glomerular basement membrane (GBM) model of crescentic glomerulonephritis, and the passive Heymann nephritis model of membranous nephropathy. Double immunostaining was performed with antibodies to podocyte-specific proteins (synaptopodin and Wilms' tumor 1) and antibodies to PEC specific proteins (paired box gene 8 and claudin-1). No double staining was detected in normal mice. In contrast, the results showed a statistical increase in the number of cells attached to Bowman basement membrane that were double-positive for both podocyte/PEC proteins in TGF-β;1 transgenic, anti-GBM, and membranous animals. Double-positive cells for both podocyte and PEC proteins were also statistically increased in the glomerular tuft in TGF-β1 transgenic, anti-GBM, and FSGS mice. These results are consistent with glomerular cells coexpressing podocyte and PEC proteins in experimental glomerular disease, but not under normal circumstances.

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