The membrane attack complex drives thrombotic microangiopathy in complement mediated atypical hemolytic uremic syndrome

Smith-Jackson, Kate, Walsh, Patrick, Zelek, Wioleta M., Hoyler, Thomas, Martinic, Marianne M., Thompson, Gemma, Gibson, Beth, Connelly, Chloe, Pappworth, Isabel Y., Murphy, Mark J., Kavanagh, David and Marchbank, Kevin J. 2025. The membrane attack complex drives thrombotic microangiopathy in complement mediated atypical hemolytic uremic syndrome. Kidney International 10.1016/j.kint.2024.12.016

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Abstract

Introduction of complement (C) inhibition into clinical practice has revolutionized the treatment of patients with complement-mediated atypical hemolytic syndrome (aHUS). Our C3D1115N mouse model, engineered around a gain of function point mutation in C3, is associated with complement mediated aHUS in man, allowing us to study the clinical disease in a preclinical model. Backcrossing our model onto C7 deficient and C5aR1 deficient mice enabled further determination of the roles of the C5a-C5aR1 axis and C5b-9 (the membrane attack complex) on kidney disease. C7 deficiency completely abolished both clinical and histological evidence of disease. Removing C5aR1 (CD88) attenuated the risk of developing clinical disease, but mice still developed thrombotic microangiopathy. Therapeutic inhibition strengthened our genetic findings showing both anti-C7 therapy and an oral C5aR1 antagonist, when used before evidence of significant kidney injury, prevented mice from succumbing to disease. However, there was ongoing histological disease within mice treated with the C5aR1 antagonist. Our data suggest that both C5aR1 and C7 play a role in the development of the conditions required for thrombotic microangiopathy of the kidney. While disrupting the C5a-C5aR1 axis is beneficial, our genetic and therapeutic studies showed that thrombotic microangiopathy of the kidney can still develop and ultimately our data confirm that the membrane attack complex is required to develop thrombotic microangiopathy of the kidney. Overall, our study shows that in addition to requiring alternative pathway dysregulation, local generation of membrane attack complex within the kidney is also critical to drive disease pathology in complement-mediated aHUS.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0085-2538
Date of First Compliant Deposit:	5 February 2025
Date of Acceptance:	16 December 2024
Last Modified:	11 Feb 2025 11:45
URI:	https://orca.cardiff.ac.uk/id/eprint/175932

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