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.
View: Text | PDF
Research Article Autoimmunity Immunology

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

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

×

Figure 1

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

Options: View larger image (or click on image) Download as PowerPoint
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 the analysis. In total, 64 proteins were identified as being significantly upregulated with an FC of greater than 2 and a P value of less than 0.05 (red dots). An additional 22 proteins were identified as being significantly downregulated, with a FC of less than 0.5 and a P value of less than 0.05 (blue dots). Among the 64 upregulated proteins, 57 proteins (high-AI proteins, or Hi.AI in the figure) had the strongest Spearman correlation with renal pathology AI (r > 0.6); all these proteins also had ROC AUC values of greater than 0.775 when comparing patients with LN with Hi.AI with patients with LN with non-Hi.AI. (B) A PCA plot of the 57 significantly elevated proteins in participants with Hi.AI (FC > 2; P < 0.05; Spearman’s r > 0.6 with AI). The principal components (PCs) are displayed on each axis of the plot. Concentration ellipses encompass each subject group, color coded as indicated. (C–E) The 57 proteins from the aptamer-based screen whose levels were elevated in participants with Hi.AI with a FC of greater than 2, a P value of less than 0.05, and a Spearman’s r of greater than 0.6 with AI were used for GO and KEGG pathway enrichment analyses. The implicated top 10 KEGG pathways (C), biological processes (D), and molecular functions (E) identified using the Database for Annotation, Visualization and Integrated Discovery (DAVID) are displayed. Each annotation was identified by P value significance and are ordered by the protein ratio percentage within that annotation term. The color of each annotation dot is representative of the –log10FDR value, and the size corresponds to the number of proteins belonging to the annotation term. (F) The Cytoscape stringAPP was used to create protein-protein interaction networks for the significantly elevated proteins in participants with Hi.AI (FC > 2, P < 0.05, and Spearman’s r > 0.6 with AI). MCODE clustering identified the highly interconnected nodes in the networks. The colors are continuously mapped and increasing FC corresponds to a deeper red color.