253. Targeting atheroma formation in crescentic glomerulonephritis
Creators: name: Antonelou1, Marilina
name: Salama1, Alan D
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Crescentic glomerulonephritis (CGN) as is frequently found in Antineutrophil Cytoplasmic Antibody (ANCA)- associated vasculitis, represents a severe form of glomerular inflammation characterised by abnormal or excessive glomerular neutrophil and monocyte activation with evidence of release of leukocyte proteases, such myeloperoxidase (MPO), and neutrophil extracellular traps (NETs) inducing kidney damage. Diseases associated with CGN are almost uniformly treated with glucocorticoids (GC), and both disease and treatment can lead to severe morbidity. Recent data suggest that even modest GC doses are associated with markedly increased rates of cardiovascular disease, translating to a significant cause of premature mortality in these patient cohorts. We have previously shown that MPO inhibition attenuates disease severity in preclinical nephrotoxic nephritis. We established a combined preclinical model of non-accelerated nephrotoxic nephritis (NTN) and atheroma to investigate the effect of renal inflammation on atheroma formation. We subsequently, used this model to investigate the effect of MPO inhibition, using the selective MPO inhibitor AZM198, and glucocorticoid therapy on atheroma formation in the presence of nephritis. <strong>Methods:</strong> Thirty-seven ApoE<sup>-/-</sup>, 5 C57BL/6 and 5 MPO<sup>-/-</sup>ApoE<sup>-/- </sup>mice were immunised with sheep nephrotoxic serum mixed 1:1 with Lipopolysaccharide. Six ApoE<sup>-/- </sup>mice were immunised with saline solution to act as a control. During the first two weeks post immunisation all groups received the same high fat diet. From week 3 until week 10 the ApoE<sup>-/-</sup> animals were divided in three treatment groups and the following compounds were incorporated in their high fat diet: vehicle control ( high fat diet alone), MPO inhibition (AZM198; 500mol/kg/day) and Prednisolone (5mg/kg/day). Weekly weights, urine protein and urine glucose were recorded. At the beginning of week 11, animals were sacrificed, blood and 16-hour urine were collected, and aortas, hearts and kidneys harvested. Aortas were dissected and stained with Red O and kidney sections were stained for haematoxylin and eosin and Periodic Acid-Schiff stain. Percentage atheromatous plaque area was quantified using Image J software and histological renal severity was assessed using a red cell cast (0-4) and glomerular thrombosis score (0-4). <strong>Results:</strong> ApoE<sup>-/- </sup> mice with NTN had increased atheroma formation compared to ApoE<sup>-/-</sup> animals without NTN (p =0.04) (Figure 1). There was no significant difference in plaque area between the vehicle control group and the group treated with MPO inhibition (p=0.87)as well as the MPO deficient (MPO<sup>-/-</sup>ApoE<sup>-/- </sup>mice) (p=0.46). The animals treated with prednisolone had significant atheroma formation, which was significantly higher than all other groups (p &lt; 0.001). There was significant mortality associated with the prednisolone group compared to both vehicle (p=0.001) and MPO inhibition group (0.01) but no significant difference in mortality between the vehicle group and the MPO inhibition group ( p=0.09). There was no significant difference in weekly urine proteinuria (p &gt;0.2) and glycosuria levels (p &gt;0.4) amongst the three treatment groups throughout the study. There was no significant difference in terminal serum creatinine (p&gt;0.16) , blood glucose (p&gt;0.75) and 16- hour proteinuria (p&gt;0.26) as well as histological disease severity amongst the three treatment groups (p&gt;0.28). C57BL/6 animals with NTN did not develop atheroma formation compared to the ApoE<sup>-/- </sup>mice with NTN (p=0.04). <strong>Conclusions:</strong> Renal inflammation significantly accelerates atheroma formation in susceptible animals. Treatment with glucocorticoids led to significant atheroma formation and mortality compared to treatment with myeloperoxidase inhibition. <strong>Disclosures:</strong> MA received funding from Medical Research Council Grant MR/P001777/1