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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 7

Coagulation and complement proteins associated with LN pathology.

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Coagulation and complement proteins associated with LN pathology.
(A) Th...
(A) The blood coagulation cascade, highlighting molecules whose levels in urine are significantly correlated with renal pathology AI (blue font), CI (CI) (red font), or both (purple font) in LN. Other proteins are listed in black font (interrogated but not significantly changed) or grey font (not interrogated by the proteomic screen). Uninterrupted arrows indicate activation, and interrupted arrows signify inhibition or cleavage of downstream protein or substrate. The yellow bubbles highlight only proteins significantly elevated in LN with high-CI versus low-CI (FC ≥ 2; P < 0.05) or higher in CI than in AI by at least 10%. The pink bubbles highlight proteins whose levels were significantly elevated only in patients with LN with high-AI versus low-AI (FC ≥ 2; P < 0.05) or higher in AI than in CI by at least 10% (in terms of correlation coefficient or FC). Also shown is a Spearman correlation heatmap displaying correlations among the 27 coagulation-related proteins and renal pathology metrics. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. (B) The complement activation pathway highlighting molecules whose levels in urine are significantly elevated with AI, CI, or both. See A for other annotation details. Also shown is a Spearman correlation heatmap displaying correlations among the 32 complement related proteins and their paired renal pathology metrics, as detailed in A. α2-AP, MG, α2-antiplasmin, α2-macroglobulin; APC, activated protein C; AT, antithrombin; B, factor B; BK, bradykinin; C1 INH, C1 esterase inhibitor; C4BP, C4 binding protein; CL-K1, collectin kidney 1; D, factor D; DAF, decay-accelerating factor; FDP, fibrin degradation products; H, factor H; I, factor I; MAP-1, MBL/ficolin-associated protein 1; MASP, mannan-binding lectin-associated serine protease; MBL, mannose-binding lectin; MCP, membrane cofactor protein; P, properdin; PK, prekallikrein; sMAP, small MBL-associated protein; TM, thrombomodulin; tPA, tissue plasminogen activator; uPA, urokinase.

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

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