Transcription factor Nrf2 activation regulates NETosis, endothelial injury, and kidney disease in myeloperoxidase-positive antineutrophil cytoplasmic antibody-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease pathologically characterized by vascular necrosis with inflammation. During AAV development, activated neutrophils produce reactive oxygen species (ROS), leading to the aberrant formation of neutrophil extracellular traps (NETs) via NETosis and subsequent fibrinoid vascular necrosis. Nuclear factor-erythroid 2-related factor 2 (Nrf2) functions as an intracellular defense system to counteract oxidative stress by providing antioxidant properties. Herein, we explored the role of Nrf2 in the pathogenesis of AAV. The role and mechanism of Nrf2 in ANCA-stimulated neutrophils and subsequent endothelial injury were evaluated in vitro using Nrf2 genetic deletion and Nrf2 activator treatment. In corresponding in vivo studies, the role of Nrf2 in ANCA-transfer AAV and spontaneous AAV murine models was examined. Pharmacological activation of Nrf2 in vitro suppressed ANCA-induced NET formation via the inhibition of ROS. In contrast, NET formation was enhanced in Nrf2-deficient neutrophils. Furthermore, Nrf2 activation protected endothelial cells from ANC-induced NETs-mediated injury. In vivo, Nrf2 activation ameliorated glomerulonephritis in two AAV models by upregulating antioxidants and inhibiting ROS-mediated NETs. Furthermore, Nrf2 activation restrained the expansion of splenic immune cells, including T lymphocytes and limited the infiltration of Th17 cells into the kidney. In contrast, Nrf2 genetic deficiency exacerbated vasculitis in a spontaneous AAV model. Thus, the pathophysiological process in AAV may be downregulated by Nrf2 activation, potentially leading to a new therapeutic strategy by regulating NETosis.

Successful initiation of hemodialysis for a hemophilia A patient with factor VIII inhibitor: a case report and literature review.

We report the first case of hemophilia A with factor VIII (FVIII) inhibitor who received hemodialysis via an arteriovenous (AV) fistula. Hemophilia A is a congenital deficiency of blood coagulation FVIII that is characterized by prolonged bleeding. Approximately 30% of patients with hemophilia develop allogeneic antibodies of FVIII. The inhibitors decrease the hemostatic effect of replacement therapy; thus, the prophylaxis strategy should be well designed. Prophylactic treatment with invasive procedures is needed to prevent excessive bleeding in patients with hemophilia undergoing hemodialysis. On the contrary, hemodialysis requires attention to the development of intracircuit coagulation during dialysis. Peritoneal dialysis or hemodialysis with a long-term tunneled central venous catheter has mainly been selected as the dialysis modality for patients with hemophilia and end-stage renal disease requiring renal replacement therapy because hemodialysis with an arteriovenous fistula may result in bleeding from the puncture site after each hemodialysis session. In our patient, hemodialysis was safely performed without any anticoagulant agents, and replacement therapy with FVIII concentrates prevented bleeding after puncture of the AV fistula.