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Persistent Chronic Thrombo-Inflammation in Anti–Glomerular Basement Membrane Disease Despite Immune Complex Removal

Douté, Mélodie ; Tyrberg, Linnéa LU orcid ; Youssfi, Younès ; Bajema, Ingeborg ; Mölne, Johan ; Nicoletti, Antonino ; Caligiuri, Giuseppina ; Segelmark, Mårten LU orcid and Clement, Marc (2025) In Kidney International Reports 10(9). p.3138-3149
Abstract

Introduction: Anti–glomerular basement membrane (anti-GBM) disease is a severe autoimmune disease characterized by autoantibody-mediated glomerular damage, leading to a rapid decline in kidney function and end-stage renal disease. The stimulation of megakaryopoiesis (Mkpoiesis) and platelet production, driven by kidney-derived hematopoietic growth factors (HGFs) such as thrombopoietin (TPO), exacerbates chronic thrombosis and inflammation. Activated platelets release bioactive molecules able to promote microvascular dysfunction, cell proliferation, and excessive extracellular matrix deposition in injured glomeruli. Understanding the molecular mechanisms driving persistent thrombo-inflammation during anti-GBM disease will enhance... (More)

Introduction: Anti–glomerular basement membrane (anti-GBM) disease is a severe autoimmune disease characterized by autoantibody-mediated glomerular damage, leading to a rapid decline in kidney function and end-stage renal disease. The stimulation of megakaryopoiesis (Mkpoiesis) and platelet production, driven by kidney-derived hematopoietic growth factors (HGFs) such as thrombopoietin (TPO), exacerbates chronic thrombosis and inflammation. Activated platelets release bioactive molecules able to promote microvascular dysfunction, cell proliferation, and excessive extracellular matrix deposition in injured glomeruli. Understanding the molecular mechanisms driving persistent thrombo-inflammation during anti-GBM disease will enhance therapeutic improvements. The hypothesis of this study was that anti-GBM disease could stimulate the production of kidney-derived HGFs and proinflammatory mediators. In addition, immobilized anti-GBM antibodies in glomeruli could directly activate FcγRIIA expressing platelets, thereby promoting chronic platelet activation during anti-GBM disease. Methods: In the GOOD-IDES-01 trial, patients received, in addition to standard care, imlifidase (the IgG-degrading enzyme, IdeS). In plasma samples collected from patients with anti-GBM disease, before and after imlifidase treatment, and from healthy blood donors (HBDs), we analyzed plasma HGFs, proinflammatory and platelet activation markers, and platelet-derived products. Results: Anti-GBM disease significantly elevated plasma proinflammatory and platelet activation markers, and HGFs (TPO and stem cell factor [SCF]). Plasma TPO correlated with anti-GBM titers. Standard care and imlifidase treatment only reduced TPO levels and platelet counts. Platelet activation markers (CD62P and Tlt1) strongly correlated with platelet-derived products (PDGF, CCL5, PF4, and TGFβ) during the active phase of the disease, but remained elevated despite the treatment. Conclusion: Circulating HGFs, proinflammatory cytokines, and platelet activation markers are important biomarkers of anti-GBM disease activity. Chronic platelet activation, persists independently of anti-GBM antibody integrity, highlighting the need for therapies targeting thrombo-inflammation.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
anti-GBM disease, hematopoietic growth factors, imlifidase, platelet activation, thrombo-inflammation
in
Kidney International Reports
volume
10
issue
9
pages
12 pages
publisher
Elsevier
external identifiers
  • pmid:40980667
  • scopus:105010303480
ISSN
2468-0249
DOI
10.1016/j.ekir.2025.06.014
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 International Society of Nephrology
id
cfd0440f-14ad-491b-98d6-bc0f15a38387
date added to LUP
2026-01-21 16:42:27
date last changed
2026-01-22 14:09:47
@article{cfd0440f-14ad-491b-98d6-bc0f15a38387,
  abstract     = {{<p>Introduction: Anti–glomerular basement membrane (anti-GBM) disease is a severe autoimmune disease characterized by autoantibody-mediated glomerular damage, leading to a rapid decline in kidney function and end-stage renal disease. The stimulation of megakaryopoiesis (Mkpoiesis) and platelet production, driven by kidney-derived hematopoietic growth factors (HGFs) such as thrombopoietin (TPO), exacerbates chronic thrombosis and inflammation. Activated platelets release bioactive molecules able to promote microvascular dysfunction, cell proliferation, and excessive extracellular matrix deposition in injured glomeruli. Understanding the molecular mechanisms driving persistent thrombo-inflammation during anti-GBM disease will enhance therapeutic improvements. The hypothesis of this study was that anti-GBM disease could stimulate the production of kidney-derived HGFs and proinflammatory mediators. In addition, immobilized anti-GBM antibodies in glomeruli could directly activate FcγRIIA expressing platelets, thereby promoting chronic platelet activation during anti-GBM disease. Methods: In the GOOD-IDES-01 trial, patients received, in addition to standard care, imlifidase (the IgG-degrading enzyme, IdeS). In plasma samples collected from patients with anti-GBM disease, before and after imlifidase treatment, and from healthy blood donors (HBDs), we analyzed plasma HGFs, proinflammatory and platelet activation markers, and platelet-derived products. Results: Anti-GBM disease significantly elevated plasma proinflammatory and platelet activation markers, and HGFs (TPO and stem cell factor [SCF]). Plasma TPO correlated with anti-GBM titers. Standard care and imlifidase treatment only reduced TPO levels and platelet counts. Platelet activation markers (CD62P and Tlt1) strongly correlated with platelet-derived products (PDGF, CCL5, PF4, and TGFβ) during the active phase of the disease, but remained elevated despite the treatment. Conclusion: Circulating HGFs, proinflammatory cytokines, and platelet activation markers are important biomarkers of anti-GBM disease activity. Chronic platelet activation, persists independently of anti-GBM antibody integrity, highlighting the need for therapies targeting thrombo-inflammation.</p>}},
  author       = {{Douté, Mélodie and Tyrberg, Linnéa and Youssfi, Younès and Bajema, Ingeborg and Mölne, Johan and Nicoletti, Antonino and Caligiuri, Giuseppina and Segelmark, Mårten and Clement, Marc}},
  issn         = {{2468-0249}},
  keywords     = {{anti-GBM disease; hematopoietic growth factors; imlifidase; platelet activation; thrombo-inflammation}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{3138--3149}},
  publisher    = {{Elsevier}},
  series       = {{Kidney International Reports}},
  title        = {{Persistent Chronic Thrombo-Inflammation in Anti–Glomerular Basement Membrane Disease Despite Immune Complex Removal}},
  url          = {{http://dx.doi.org/10.1016/j.ekir.2025.06.014}},
  doi          = {{10.1016/j.ekir.2025.06.014}},
  volume       = {{10}},
  year         = {{2025}},
}