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Lymphatic vessels in patients with crescentic glomerulonephritis: association with renal pathology and prognosis

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Abstract

Background

Various immune cells, including T cells, B cells, macrophages, and neutrophils contribute to the development of crescentic glomerulonephritis. Previous animal studies have suggested that lymphangiogenesis is involved in the migration of inflammatory cells and the activation of adaptive immunity. However, the extent of the association between lymphatic vessels and crescentic glomerulonephritis severity and prognosis remains unknown.

Methods and results

In this study, we assessed lymphatic vessel density in 71 patients with crescentic glomerulonephritis who underwent renal biopsies between June 2017 and June 2022. By immunohistochemistry and immunofluorescence, we identified increased lymphatic vessel density in the kidneys of patients with crescentic glomerulonephritis compared to controls. Lymphatic vessels were categorized as total, periglomerular, and interstitial. Spearman's rank correlation analysis showed a positive correlation between total and periglomerular lymphatic vessel density and glomerular crescent proportion. High lymphatic vessel density (total and periglomerular) correlated with declining kidney function, increased proteinuria, and severe glomerular and interstitial pathology. Interstitial lymphatic vessel density had minimal relationship with renal lesions. After a median duration of 13 months of follow-up, higher total and periglomerular lymphatic vessel density was associated with poorer prognosis. Transcriptomic analysis revealed increased immune cell activation and migration in crescentic glomerulonephritis patients compared to healthy controls. Periglomerular lymphatic vessels might play a significant role in immune cell infiltration and renal injury.

Conclusion

Elevated lymphatic vessel density in patients with crescentic glomerulonephritis is associated with poor prognosis and may serve as a predictive factor for adverse outcomes in these patients.

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Data availability

The corresponding author can provide the supporting data of this study upon reasonable request.

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Funding

This work was supported by the National Natural Sciences Foundation of China for General Programs (Grants No. 82070739, 82370699) and the Key Program of National Natural Science Foundation of China (Grant No. 82230021); the General Program of National Natural Sciences Foundation of China (Grant No.82170702); the National key research and development program (Grant No. 2021YFC2500204).

Author information

Authors and Affiliations

  1. Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China

    Danni Hu, Zheng Wang, Shujie Wang, Yueqiang Li, Guangchang Pei, Rui Zeng & Gang Xu

  2. Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, China

    Rui Zeng

  3. NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China

    Rui Zeng

  4. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China

    Rui Zeng

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  1. Danni Hu
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Contributions

Conceptualization: GP, RZ, and GX; Methodology: GP; Software: ZW; Validation: DG, and SW; Formal Analysis: GP, YL, RZ, and GX; Investigation: DH, ZW, and SW; Resources: GP, RZ, and GX; Data Curation: DH; Writing – Original Draft Preparation: GP, DH, and ZW; Writing – Review & Editing: DH; Visualization: DH, and ZW; Supervision: GP, RZ, and GX; Project Administration: GP, RZ, and GX.

Corresponding authors

Correspondence to Guangchang Pei, Rui Zeng or Gang Xu.

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Conflict of interest

The authors of this article declare no conflicts of interest. The findings presented in this paper have not been previously published in any form, except for abstracts.

Ethical approval

This study followed the principles of the Helsinki Declaration and received approval from the Research Ethics Committee of Tongji Hospital, Huazhong University of Science and Technology (TJ-IRB202303121).

Human and animal rights

The present study complies with the guidelines for human studies. No animals were used in this study.

Informed consent

Due to the nature of the study being observational, no interventions were implemented on the participants, and no identifiable patient information was included. This was done to ensure the patients’ confidentiality and privacy. Therefore, all individuals involved in the research were exempted from providing informed consent.

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Supplementary Information

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40620_2024_1903_MOESM1_ESM.pdf

SFigure1. The periglomerular LVs play a more significant role in immune cell infiltration and kidney injury in crescentic glomerulonephritis (cGN) patients compared to interstitial LVs. A. Enrichment pathways of DEGs between healthy controls and cGN patients’ renal biopsy samples based on Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Nor: Healthy controls; CGN: crescentic glomerulonephritis patients. B. Expression levels of LYVE1 in renal biopsy samples (periglomerular) from healthy controls and cGN patients. C. Expression levels of LYVE1 in the renal interstitial regions of patients with various kidney diseases. LD: Healthy Living Donor; HP: Arterial Hypertension; DN: Diabetic Nephropathy; FSGS: Focal Segmental Glomerulosclerosis; IgAN: IgA Nephropathy; LN: Lupus Nephritis; MN: Membranous Glomerulonephropathy; MCD: Minimal Change Disease; TBMD: Thin Basement Membrane Disease; CGN: Vasculitis. D. GSEA of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, indicating a significant enrichment of “Cell adhesion molecules”, “Chemokine signaling pathway”, “Cytokine-cytokine receptor interaction”, “JAK-STAT signaling pathway” and “PI3K-Akt signaling pathway” in cGN patients with high expression of LYVE1 compared to those with low expression. E. Correlation analysis between LYVE1 expression and immune infiltration. MDSC: Myeloid-derived suppressor cell; Act.DC: Activated dendritic cell; Mast: Mast cell; CD8+ Tem: Effector memeory CD8+ T cell; Tregs: Regulatory T cell; Macro: Macrophage; CD8+ Tcm: Central memory CD8+ T cell; CD4+ Tcm: Central memory CD4+ T cell; Bm: Memory B cell; γδ T: Gamma delta T cell; Act.CD4+ T: Activated CD4+ T cell; Th2: Type 2 T helper cell; Esoi: Eosinophil; Act.CD8+ T: Activated CD8+ T cell; CD4+ Tem: Effector memeory CD4+ T cell; Act. B: Activated B cell; Tfh: T follicular helper cell; Neutro: Neutrophil; NK: Natural killer cell; Th1: Type 1 T helper cell; Mono: Monocyte; Imm.B: Immature B cell; NKT: Natural killer T cell; Imm.DC: Immature dendritic cell; CD56bright NK: CD56bright natural killer cell; PDC: Plasmacytoid dendritic cell; CD56dim NK: CD56dim natural killer cell; Th17: Type 17 T helper cell. F. Analysis of the correlation between LYVE1 expression and different inflammatory cells. (Nor: Healthy controls; CGN: crescentic glomerulonephritis patients. ***P<0.001; ** P<0.01; * P<0.05). Supplementary file1 (PDF 786 KB)

Supplementary file2 (XLSX 27 KB)

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Hu, D., Wang, Z., Wang, S. et al. Lymphatic vessels in patients with crescentic glomerulonephritis: association with renal pathology and prognosis. J Nephrol (2024). https://doi.org/10.1007/s40620-024-01903-0

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