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Urine proteins reveal distinct coagulation and complement cascades underlying acute versus chronic lupus nephritis
Ting Zhang, … , Ramesh Saxena, Chandra Mohan
Ting Zhang, … , Ramesh Saxena, Chandra Mohan
Published October 1, 2025
Citation Information: J Clin Invest. 2025;135(19):e186143. https://doi.org/10.1172/JCI186143.
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Research Article Autoimmunity Immunology

Urine proteins reveal distinct coagulation and complement cascades underlying acute versus chronic lupus nephritis

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Abstract

The current gold standard for assessing renal pathology in lupus nephritis (LN) is invasive and cannot be serially repeated. To assess if urine can serve as a liquid biopsy for underlying renal pathology, urine obtained from patients with LN at the time of renal biopsy were interrogated for 1,317 proteins, using an aptamer-based proteomic screen. Levels of 57 urine proteins were significantly elevated and correlated with pathology activity index (AI), notably endocapillary hypercellularity, fibrinoid necrosis, and cellular crescents. These included proteins pertaining to leukocyte/podocyte activation, neutrophil activation, endothelial activation, and markers of inflammation/anti-inflammation. In contrast, complement and coagulation cascade proteins, and proteins related to the extracellular matrix (ECM) emerged as the strongest urinary readouts of concurrent renal pathology chonicity index (CI), notably tubular atrophy and interstitial fibrosis. In vitro mechanistic studies revealed that complement proteins C3a and C5a increased the expression of profibrotic ECM proteins in macrophages and proximal tubule epithelial cells. Thus, carefully assembled panels of urinary proteins that are indicative of high renal pathology AI and/or CI may help monitor the status of renal pathology after therapy in patients with LN, in a noninvasive manner, without the need for repeat renal biopsies.

Authors

Ting Zhang, Jessica Castillo, Anto Sam Crosslee Louis Sam Titus, Kamala Vanarsa, Vedant Sharma, Sohan Kureti, Ramesh Saxena, Chandra Mohan

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Figure 4

Proteins elevated in urine samples of patients with LN with high renal pathology CI.

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Proteins elevated in urine samples of patients with LN with high renal p...
(A) A volcano plot representation of all 1,317 proteins assayed in the aptamer-based screen; log-transformed data were used for analysis. In total, 112 proteins were significantly upregulated with an FC < 0.5 and P < 0.05. Of the 112 elevated proteins, 50 had a Spearman’s r > 0.6 with concurrent renal pathology CI (here, abbreviated CI). All these proteins had ROC AUC values of greater than 0.8, comparing patients with high CI with other patients with lupus. (B) A PCA plot of the 50 significantly elevated proteins in participants with high CI (FC > 2; P < 0.05; Spearman’s r > 0.6 with CI), with principal components (PCs) displayed on each axis. Concentration ellipses encompass each subject group, color coded as indicated. (C–E) The 50 proteins from the aptamer-based screen whose levels were elevated in individuals with high CI (FC > 2; P < 0.05; Spearman’s r > 0.6 with CI) were used for GO and KEGG pathway enrichment analysis. The implicated top 10 KEGG pathways (C), biological processes (D), and molecular functions (E) identified using the Database for Annotation, Visualization and Integrated Discovery are displayed. Annotation details are as listed in Figure 1. (F) The Cytoscape stringAPP was used to create protein-protein interaction networks for the significantly elevated proteins in individuals with high CI (FC > 2; P < 0.05; Spearman’s r > 0.6 with CI). Annotation details are as listed in Figure 1. Reactome pathways implicated include 2 dominant clusters: cluster 1, including formation of fibrin clot (clotting cascade) and hemostasis; and cluster 2, including complement cascade initial triggering of complement, and activation of C3 and C5.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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