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. 2025 Sep 26;26(1):530.
doi: 10.1186/s12882-025-04457-w.

The carbonic anhydrase 3 protein in urine: a potential biomarker to monitor atherosclerotic renal artery stenosis

Xiufeng Li  1   2 , Na Liu  3 , Tianci Liu  3 , Guowei Liang  1 , Changgang Shao  4 , Teng Ma  5 , Man Zhang  6   7
Affiliations

The carbonic anhydrase 3 protein in urine: a potential biomarker to monitor atherosclerotic renal artery stenosis

Xiufeng Li et al. BMC Nephrol. .

Abstract

Background: Atherosclerotic renal artery stenosis (ARAS) represents the predominant etiology of renal artery stenosis. Current diagnostic modalities—including renal arteriography, Doppler ultrasonography (DUS), computed tomography angiography (CTA), and magnetic resonance angiography (MRA)—are limited by invasiveness or technical constraints. The development of noninvasive biomarkers for ARAS detection is therefore clinically imperative. We hypothesize that ischemic renal injury in ARAS induces pathological alterations that generate unique urinary protein signatures.

Methods: A total of ​138 subjects​ were enrolled and ​randomly divided into the discovery cohort and the validation cohort. Urinary proteins from the discovery cohort were profiled using ​data-independent acquisition mass spectrometry (DIA-MS)​​ to identify differentially expressed proteins. Candidate biomarkers were subsequently validated in the validation cohort via ​quantitative ELISA. Diagnostic performance was assessed by ​receiver operating characteristic (ROC) curve analysis, and associations between target protein levels and clinical parameters were evaluated using ​Spearman correlation​.

Results: As a result of DIA-MS indicated in the discovery cohort, 485 up-regulated urinary proteins and 177 down-regulated urinary proteins were identified in ARAS patients compared to disease controls. The top three proteins CA3, ORM2, and ART3 in AUC were selected as the potential urinary markers for further validation in the validation cohort. The uCA3/Cr level was significantly higher in both ARAS and disease controls than in healthy controls, and the uCA3/Cr level in patients with ARAS was significantly higher than in disease controls. There was no statistical difference in the uCA3/Cr level in subgroups with different severity of ARAS. Taking healthy controls as control values, the ROC area of uCA3/Cr was 0.9649(95%CI: 0.9200-1.000). We evaluated the area under the uCA3/Cr curve with the values of the disease control group as the control, the areas of ROC were 0.7391(95%CI: 0.6154–0.8628). Correlation analysis demonstrated that there was a strong positive correlation between uCA3/Cr concentration and urinary a1-microglobulin(a1MG) in ARAS and disease controls.

Conclusion: CA3 in urine may be related to renal interstitial injury, it could be used as a non-invasive biomarker for ARAS. However, large cohort studies and mechanistic investigations are required for further validation.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12882-025-04457-w.

Keywords: Atherosclerosis renal artery stenosis; Biomarker; Carbonic anhydrase 3; Diagnosis; Urine proteomics.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was conducted in compliance with the declaration of Helsinki principles and followed the recommendations of Medical Ethics Committee of Aerospace Center. Hospital (20201113-QTKT-01) and all subjects provided written consent before inclusion. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Analysis of differentially expressed proteins. (A) Volcano plots analysis of all DEPs compared to disease controls. (B) Hierarchical clustering of top 10 DEPs in different groups. (C) Gene Ontology (GO) enrichment analysis of up-expressed top 10 DEPs: Biological Process (BP), Cellular Component (CC) and Molecular Function (MF). (D) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of up-expressed top 10 DEPs. (E) Protein interaction networks of top 10 up-expressed proteins
Fig. 2
Fig. 2
Expressions and AUCs of CA3, ORM2 and ART3 in proteomics. (A) Expressions of CA3 in ARAS and DC. (B) Expressions of ART3 in ARAS and DC. (C) Expressions of ORM2 in ARAS and DC. (D) ROC curves of CA3 for the discrimination of ARAS vs. DC groups. (E) ROC curves of ART3 for the discrimination of ARAS vs. DC groups. (F) ROC curves of ORM2 for the discrimination of ARAS vs. DC groups
Fig. 3
Fig. 3
Urinary CA3/Cr, ART3/Cr and ORM2/Cr levels in different groups. (A) uCA3/Cr levels in ARAS, DC and HC groups. (B) uART3/Cr levels in ARAS, DC and HC groups. (C) uORM2/Cr levels in ARAS, DC and HC groups. (D) uCA3/Cr levels in mild and severe ARAS, DC and HC groups. (E) uART3/Cr levels in mild and severe ARAS, DC and HC groups. (F) uORM2/Cr levels in mild and severe ARAS, DC and HC groups
Fig. 4
Fig. 4
ROC curves of the DEPs. (A) ROC curves of uCA3/Cr for the discrimination of ARAS vs. HC groups. (B) ROC curves of uART3/Cr for the discrimination of ARAS vs. HC groups. (C) ROC curves of uCA3/Cr for the discrimination of ARAS vs. DC groups
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