A GLOMERULAR TYPE I INTERFERON SIGNATURE PREDICTS POOR CLINICAL OUTCOMES IN ANCA-ASSOCIATED GLOMERULONEPHRITIS PATIENTS WITH PRESERVED KIDNEY FUNCTION

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Abstract Title *

A GLOMERULAR TYPE I INTERFERON SIGNATURE PREDICTS POOR CLINICAL OUTCOMES IN ANCA-ASSOCIATED GLOMERULONEPHRITIS PATIENTS WITH PRESERVED KIDNEY FUNCTION

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Co-author 1

Nariaki Asada secretgardenrei@gmail.com University Medical Center Hamburg Eppendorf Nephrology Department Hamburg Germany *

Co-author 2

Jonas Engesser j.engesser@uke.de University Medical Center Hamburg Eppendorf Nephrology Department Hamburg Germany -

Co-author 3

Huiying Wang wanghuiying919@gmail.com University Medical Center Hamburg Eppendorf Nephrology Department Hamburg Germany -

Co-author 4

Pauline Ginsberg pauline.ginsberg@gmx.de University Medical Center Hamburg Eppendorf Nephrology Department Hamburg Japan -

Co-author 5

Kanako Watanabe-Kusunoki wata.kanako@gmail.com Hokkaido University Department of Rheumatology, Endocrinology and Nephrology Hokkaido Japan -

Co-author 6

Daigo Nakazawa daigo-na@med.hokudai.ac.jp Hokkaido University Department of Rheumatology, Endocrinology and Nephrology Hokkaido Germany -

Co-author 7

Victor Puelles vgpuelles@gmail.com University Medical Center Hamburg Eppendorf Department of Rheumatology, Endocrinology and Nephrology Hamburg Japan -

Co-author 8

Yusuke Okabayashi y.okabayashi0909@gmail.com The Jikei University School of Medicine Division of Nephrology and Hypertension Tokyo Japan -

Co-author 9

Co-author 10

Co-author 11

Co-author 12

Co-author 13

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Co-author 15

Introduction

ANCA-associated glomerulonephritis (ANCA-GN) is a rapidly progressive immune-mediated kidney disease. A significant proportion of patients fail to respond to treatment and progresses to end-stage kidney disease or death. Yet, the molecular mechanisms underlying treatment resistance remain poorly understood.

Methods

In this study, we performed genome-wide spatial transcriptomics on kidney biopsies from 28 ANCA-GN patients to identify gene signatures associated with poor clinical outcomes. In addition, we conducted high-resolution single-cell spatial transcriptomics and multicolor immunofluorescence staining in an independent cohort of 32 ANCA-GN patients to validate our findings and further investigate the molecular mechanisms underlying poor clinical outcomes in ANCA-GN.

Results

We compared treatment responders with non-responders, identifying a type I interferon (IFN-I) signature in the glomeruli associated with treatment resistance. Among patients with poor clinical outcomes, this glomerular IFN-I signature was particularly elevated in those with preserved kidney function. Using high-resolution single-cell spatial transcriptomics in an independent cohort of 32 ANCA-GN patients, we validated these findings and delved deeper into cellular responses to the IFN-I signaling. Our analysis revealed IFN-I-mediated inflammatory niches surrounding monocytes, parietal epithelial cells, and podocytes. Furthermore, we showed that IFN-I signaling was linked to reduced podocin expression and podocyte loss.

Conclusion

Our study identifies a distinct endotype of ANCA-GN defined by elevated IFN-I signaling in glomeruli, in which podocyte injury may drive disease progression alongside crescent formation for poor clinical outcomes.

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