Cluster of differentiation-44 as a novel biomarker of lupus nephritis and its role in kidney inflammation and fibrosis

Front Immunol. 2024 Oct 1:15:1443153. doi: 10.3389/fimmu.2024.1443153. eCollection 2024.

Abstract

Introduction: CD44 is a transmembrane glycoprotein implicated in tissue inflammation and fibrosis. We investigated its role in kidney inflammation and fibrosis in a murine model of lupus nephritis (LN), and the clinico-pathological association of serum CD44 level in patients with biopsy-proven Class III/IV ± V LN.

Methods: NZB/W F1 mice were treated with control IgG or anti-CD44 monoclonal antibody for 4 weeks and disease parameters assessed. Serum CD44 level in LN patients was determined by ELISA. Control groups included healthy subjects and patients with non-renal SLE or non-lupus renal disease.

Results: CD44 expression was absent in the normal kidney, but it was expressed in proximal and distal tubular epithelial cells and infiltrating cells in renal biopsies from patients with active proliferative LN. ScRNA-Seq datasets confirmed that CD44 was predominantly expressed in tubular cells and all immune cells identified in LN patients including tissue resident, inflammatory and phagocytic macrophages, Treg cells, effector and central memory CD4+ T cells, resident memory CD8+ T cells and naïve and activated B cells. Treatment of NZB/W F1 mice with anti-CD44 antibody preserved kidney histology and reduced proteinuria, tubulo-interstitial infiltration of CD3+, CD4+ and CD19+ immune cells, and mediators of kidney fibrosis compared to Control mice. Longitudinal studies showed that serum CD44 level increased prior to clinical renal flare by 4.5 months and the level decreased after treatment. ROC curve analysis showed that CD44 level distinguished patients with active LN from healthy subjects and patients with quiescent LN, active non-renal lupus, and non-lupus CKD (ROC AUC of 0.99, 0.96, 0.99 and 0.99 respectively). CD44 level correlated with leukocyte infiltration and interstitial inflammation scores in active LN kidney biopsies.

Discussion: Our findings suggest that CD44 plays a pathogenic role in renal parenchymal inflammation and fibrosis in active LN and monitoring CD44 may facilitate early diagnosis of flare.

Keywords: CD44; biomarker; kidney inflammation; lupus nephritis; tubulo-interstitial fibrosis.

MeSH terms

  • Adult
  • Animals
  • Biomarkers*
  • Biopsy
  • Disease Models, Animal
  • Female
  • Fibrosis*
  • Humans
  • Hyaluronan Receptors* / metabolism
  • Inflammation / immunology
  • Kidney* / immunology
  • Kidney* / metabolism
  • Kidney* / pathology
  • Lupus Nephritis* / diagnosis
  • Lupus Nephritis* / immunology
  • Lupus Nephritis* / metabolism
  • Lupus Nephritis* / pathology
  • Male
  • Mice
  • Mice, Inbred NZB
  • Middle Aged

Substances

  • Biomarkers
  • Hyaluronan Receptors
  • CD44 protein, human

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the RGC General Research Fund (grant numbers: HKU 761013, HKU 781208M and 17117522), Health and Medical Research Fund (06172656), UGC Research Matching Grant Schemes (207301144 and 207301229), the University of Hong Kong Small Project Funding (104006514 and 201409176201), Hong Kong Society of Nephrology Research Grant (HKSNRG2023 - B01), the Department of Medicine Academic Activities Fund; and kind donations from Mr C. S. Yung; Mr S. Ho; and Hui Hoy & Chow Sin Lan Charity Fund and the Family of Mr Hui Ming. SY is supported by the Endowment Fund established for the ‘Yu Chiu Kwong Professorship in Medicine’ awarded to TMC; the Wai Hung Charitable Foundation Limited; and Mr & Mrs Tam Wing Fan Edmund Renal Research Fund. LG was supported by the Li Shu Fan Master of Research in Medicine Scholarship, the Mr & Mrs SH Wong Foundation Scholarship for Master of Research in Medicine, the BL Wong Scholarship for Master of Research in Medicine, the Yu Chun Keung Memorial Scholarship for Master of Research in Medicine, and the Undergraduate Research Fellowship Programme Undergraduate Research Internship Award. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.