---
title: "Soluble urokinase plasminogen activator receptor (suPAR) across the kidney–cardiometabolic continu"
id: "frontiers-in-immunology-17-soluble-urokinase-plasminogen-activator-receptor-across-the-kidney"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-soluble-urokinase-plasminogen-activator-receptor-across-the-kidney"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1940345"
published_at: "2026-10-22T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Soluble urokinase plasminogen activator receptor (suPAR) across the kidney–cardiometabolic continu
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-soluble-urokinase-plasminogen-activator-receptor-across-the-kidney
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1940345)
- **Published At:** 2026-10-22T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source page is a Frontiers in Immunology entry for a SYSTEMATIC REVIEW titled “Soluble urokinase plasminogen activator receptor across the kidney–cardiometabolic continuum.” - The publicly available content on the source page consists primarily of journal navigation, sections, and site links rather than the manuscript text or abstract. - The source did not provide methods: investigators’ search strategy, inclusion/exclusion criteria, databases searched, or risk-of-bias assessment were not reported on the captured page. - The source did not provide results: no pooled estimates, associations, subgroup analyses, or quantitative endpoints appeared in the accessible content. - The source did not provide study-level or aggregate data: sample sizes, patient characteristics, follow-up intervals, or outcome definitions were absent. - The source did not report conclusions, clinical recommendations, or specific implications for **soluble urokinase plasminogen activator receptor** measurement in kidney or cardiometabolic disease. - For clinicians and researchers, critical unanswered items remain: evidence strength, heterogeneity, assay standardization, and suggested next steps were not available on the source page. - Users seeking the full systematic-review content must access the complete article at the journal site; the captured source text cannot support evidence synthesis or practice guidance on its own.
## Clinical Analysis & Structured Key Points
Frontiers | Soluble urokinase plasminogen activator receptor across the kidney–cardiometabolic continuum: a systematic review SYSTEMATIC REVIEW article Front. Immunol. , 22 October 2026 Sec. Molecular Innate Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1940345 Published in Frontiers in Immunology Molecular Innate Immunity 7 impact factor 11.3 citescore Part of a Research Topic Omics-Based Biomarkers in Renal Endocrinology Submission open 2774 views 2 articles Editor & Reviewers Edited by S B Sree Bhushan Raju Reviewed by J N John Nzobokela S R Soheil Rahmati Outline Figures and Tables Figure 1 View in article Table 1 Characteristics of the 20 included studies. View in article Table 2 Reported suPAR levels by disease context. View in article Table 3 Key multivariable-adjusted effect estimates by disease domain. View in article Table 4 GRADE summary of findings. View in article Table 5 Assay characteristics. View in article SYSTEMATIC REVIEW article Front. Immunol. , 22 October 2026 Sec. Molecular Innate Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1940345 Soluble urokinase plasminogen activator receptor across the kidney–cardiometabolic continuum: a systematic review Q W Qishun Wu † * Z Y Zhiliang Yu X L Xin Lin L Y Ling Yang Z W Zhangli Wu Division of Nephrology, Department of Medicine, The Second Affiliated Hospital of Wannan Medical University, Wuhu, Anhui, China Article metrics View details Abstract Background: Soluble urokinase plasminogen activator receptor (suPAR), a circulating marker of innate immune activation, has been proposed as a risk biomarker in chronic kidney disease (CKD) and related cardiometabolic conditions, but its clinical utility remains uncertain. Methods: We performed a systematic review according to PRISMA 2020 and the Synthesis Without Meta-analysis (SWiM) guideline, searching PubMed, Embase, Web of Science, Scopus, the Cochrane Library, medRxiv, ClinicalTrials.gov, and WHO ICTRP from inception to May 15, 2026. Two reviewers independently screened records, extracted data, and assessed quality using the Newcastle-Ottawa Scale, the JBI checklist, RoB 2, and QUADAS-2; certainty of evidence was rated with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Results: Twenty studies comprising 31,416 participants were included. In adults with preserved kidney function, elevated suPAR predicted incident CKD (adjusted odds ratio (OR) 3.13 for the highest versus lowest quartile, 95% confidence interval (CI) 2.11–4.65) and end-stage kidney disease (ESKD) (adjusted hazard ratio (HR) 1.53 for the highest versus lowest tertile, 95% CI 1.10–2.12), but the gain in discrimination was modest (absolute C-statistic increase 0.027–0.08) and no study performed decision curve analysis (DCA). suPAR did not distinguish focal segmental glomerulosclerosis (FSGS) from other glomerular diseases, and prognostic evidence in FSGS rested on a single moderate-quality study. In pediatric CKD and in metabolic cohorts, suPAR lost independent association after adjustment for baseline kidney function or inflammatory markers. Associations with cardiovascular outcomes were directionally consistent but observational and of low certainty. No study reported sex-stratified analyses. Conclusions: Routine clinical measurement of suPAR is not currently supported; assay harmonization, sex-disaggregated analyses, prospective validation with decision curve analysis, and trials of suPAR-targeted therapy are needed first. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261320503 , identifier CRD420261320503. 1 Introduction Chronic kidney disease (CKD) affects roughly 9% of the global population and carries a heavy burden of cardiovascular and metabolic complications ( 1 ). Routine screening relies on estimated glomerular filtration rate (eGFR) and albuminuria, both of which capture established injury rather than future risk. Soluble urokinase plasminogen activator receptor (suPAR), the circulating form of the glycosylphosphatidylinositol-anchored urokinase receptor (uPAR), has attracted attention as a candidate marker that rises before functional decline becomes apparent. uPAR is expressed on activated immune cells, endothelial cells, and podocytes. Inflammatory stimulation triggers proteolytic cleavage of membrane uPAR, releasing intact suPAR (domains I–II–III, approximately 55–60 kDa) and smaller fragments (domains II–III, 20–50 kDa) into the circulation. Commercial assays differ in their affinity for these isoforms, a technical point with direct consequences for cross-study comparability. In animal models, suPAR activates αvβ3 integrins on podocytes and produces foot process effacement and proteinuria ( Figure 1 ). Whether suPAR plays the same causal role in human disease, or instead marks underlying inflammation, remains unresolved. Elevated suPAR has been linked to incident CKD, faster eGFR decline, and adverse cardiovascular outcomes, but the literature is scattered across disease areas, and negative studies have challenged its specificity for focal segmental glomerulosclerosis (FSGS). Figure 1 suPAR in innate immune signaling across the kidney–cardiometabolic continuum (redrawn). Activated myeloid cells (monocytes, macrophages, and neutrophils) release suPAR through GPI-specific phospholipase D and protease (cathepsin G) cleavage. Intact suPAR (DI–DII–DIII) binds urokinase-type plasminogen activator (uPA) and vitronectin and activates podocyte αvβ3 integrins, causing foot process effacement and proteinuria; APOL1 high-risk variants potentiate this interaction. The cleaved DII–DIII fragment engages formyl peptide receptor-like 1/2 (FPRL1/2) on vascular endothelial and smooth muscle cells, promoting monocyte chemotaxis and atherosclerotic inflammation. suPAR is also a candidate readout of trained immunity; links to NLRP3 inflammasome and cGAS–STING signaling (dashed arrows) remain hypothetical because direct evidence is lacking. WAL0921, an anti-suPAR monoclonal antibody in phase 2 development, neutralizes circulating suPAR. The lower band summarizes the prerequisites for clinical translation. GPI, glycosylphosphatidylinositol; suPAR, soluble urokinase plasminogen activator receptor. Previous reviews each covered a narrow slice of this field: a meta-analysis of suPAR in CKD up to 2019 ( 2 ), kidney function decline in people without CKD ( 3 ), acute kidney injury ( 4 ), cardiovascular disease ( 5 ), and a cross-organ narrative review ( 6 ). The present review covers the full kidney–cardiometabolic spectrum in a single evidence synthesis. We catalog assay heterogeneity and its consequences for clinical translation, give equal weight to positive and negative findings, and examine the lack of sex-stratified evidence as a methodological gap, in line with the Sex and Gender Equity in Research (SAGER) guidelines ( 7 ). 2 Materials and methods 2.1 Protocol and registration The review followed the PRISMA 2020 statement ( 8 ) and theSynthesis Without Meta-analysis (SWiM) reporting guideline ( 9 ). The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420261320503) on February 17, 2026. The initial database search was run on January 15, 2026, before registration; screening, data extraction, and analysis began only after registration, and the analysis plan was not modified in light of emerging results. The final search update was performed on May 15, 2026. On March 5, 2026, we amended the search strategy after identifying a study from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) ( 10 ) that the original strategy had missed because the publication used the term “urokinase-type plasminogen activator receptor” without the abbreviation suPAR; all databases were re-run on March 6, 2026. Backward and forward citation chasing (March 10–15, 2026) yielded 23 further records, none of which was eligible.Complete search strategies are provided in Supplementary Material 1 . 2.2 Search strategy The strategy was developed with a medical librarian and peer-reviewed using the Peer Review ofElectronic Search Strategies (PRESS) checklist ( 11 ). Wesearched PubMed, Embase, Web of Science, Scopus, the Cochrane Library, and medRxiv, plus ClinicalTrials.gov, WHO ICTRP, and Google Scholar, from inception to May 15, 2026, combining suPAR-related free-text and MeSH terms with disease-specific keywords ( Supplementary Material 1 ). Only English-language publications were eligible; Chinese-language databases were not searched, a restriction whose potential impact we address in the limitations. 2.3 Eligibility criteria We included studies that (i) examined suPAR in CKD, glomerular disease, or cardiometabolic conditions with explicit clinical outcomes; (ii) reported original quantitative suPAR data in humans; and (iii) were peer-reviewed English-language articles, or medRxiv preprints later published in peer-reviewed form. We excluded reviews and meta-analyses, studies without quantitative suPAR data or clear clinical outcomes, studies with insufficient methodological detail for quality assessment, animal or in vitro work without clinical data, and, for overlapping datasets, all but the largest or most recent report. The review question was structured according to Population, Intervention/Exposure, Comparator, Outcome, and Study design (PICOS): Population—adults or children with CKD, glomerular disease, or cardiometabolic conditions; Intervention/Exposure—circulating suPAR measured by any quantitative assay; Comparator—lower suPAR levels or reference ranges; Outcomes—incident CKD, CKD progression, ESKD, cardiovascular events, mortality, or metabolic complications; Study design—prospective or retrospective cohort, cross-sectional, or randomized studies with biomarker endpoints. 2.4 Study selection and quality assessment Of 1,489 records, 1,052 duplicates were removed and 437 unique records screened. Title andabstract screening excluded 278 records. Of 159 full texts assessed, 139 were excluded (72 reviewsor meta-analyses, 35 without quantitative suPAR data, 18 overlapping datasets, 8 with insufficient methodological detail, 5 preprints without subsequent peer-reviewed publication, and 1 without relevant outcomes). One study was added through the amended search. A study with a Newcastle-Ottawa Scale score of 3/9 was retained in the review but flagged as high risk of bias in all analyses; sensitivity analyses excluding this study are presented in Supplementary Material 5 . The final sample comprised 20 studies; the PRISMA 2020 flow diagram and the list ofexcluded studies with reasons are provided in Supplementary Material 2 . Cohort studies were assessed with the Newcastle-Ottawa Scale (NOS) ( 12 ), cross-sectional studies with the JBI Critical Appraisal Checklist, therandomized substudy with RoB 2 ( 13 ), and diagnostic accuracy analyses with QUADAS-2 ( 14 ). Two reviewers (Q.W., Z.Y.) assessed each study independently, with disagreements resolved by consensus; inter-rater agreement was substantial to almost perfect (Cohen’s κ 0.79–0.91). On the NOS, scores ≥7/9 were rated low risk of bias, 4–6 moderate, and 30%, ESKD, cardiovascular events, and all-cause mortality). Pooling non-commensurable effect scales and non-equivalent endpoints would have produced clinically uninterpretable summary estimates, so narrative synthesis following SWiM was the only methodologically defensible approach. Certainty of evidence was rated with GRADE for prognostic studies ( 17 , 18 ), in which observational evidence starts at high certainty and is downgraded across five domains (risk of bias, inconsistency, indirectness, imprecision, publication bias) or upgraded for large effects, dose–response gradients, or opposing plausible confounding. Domain-level ratings are shown in Supplementary Figures S5 and S6 . 3 Results 3.1 Study characteristics Table 1 summarizes the 20 included studies (31,416 participants). Fourteen were prospective cohort studies, five cross-sectional, and one a prospective cohort with an embedded randomized substudy of colchicine. Sample sizes ranged from 60 to 6,576 (median 1,079). Thirteen studies were conducted in Europe, five in North America, one in China, and one in Japan. Mean or median age ranged from 12 to 77 years; among the 18 studies reporting sex distribution, women made up 27–56% of participants. suPAR was measured with the suPARnostic ELISA (ViroGates) in 14 studies, the R&D Systems ELISA in four, and both platforms in two; samples were serum in 11 studies, plasma in eight, and both in one. Reported median suPAR concentrations ranged from 2.4 ng/mL in suspected myocardial infarction to 11.81 ng/mL in acute heart failure ( Table 2 ). Table 1 Study, year, country Design N Population Female (%) Follow-up suPAR assay Sample Quality score Hayek et al., 2015, USA ( 19 ) Prospective cohort 3,683 Emory CV Biobank 35 3.7 years suPARnostic Plasma 8/9 (NOS) Schulz et al., 2017, Sweden ( 20 ) Prospective cohort 4,529 Malmö Diet and Cancer Study 56 16 years suPARnostic Serum 8/9 (NOS) Luo et al., 2018, USA ( 16 ) Prospective cohort 1,910 CRIC (African American CKD) NR† NR suPARnostic Plasma 8/9 (NOS) Lv et al., 2020, China ( 10 ) Prospective cohort 2,391 C-STRIDE (Chinese CKD) 38 54.8 months suPARnostic Serum 8/9 (NOS) Drechsler et al., 2017, Germany ( 21 ) Prospective cohort 1,145 Diabetes on hemodialysis (4D) 42 NR suPARnostic Plasma 7/9 (NOS) Abraham et al., 2021, USA ( 22 ) Prospective cohort 586 CKiD (pediatric CKD) 38 NR suPARnostic Plasma 8/9 (NOS) Meijers et al., 2014, Belgium ( 23 ) Cross-sectional 78 Adults with glomerular disease 42 N/A suPARnostic Serum 7/8 (JBI) Spinale et al., 2015, USA ( 24 ) Prospective cohort 241 NEPTUNE (proteinuric GN) 46 NR suPARnostic Serum 8/9 (NOS) Harita et al., 2014, Japan ( 25 ) Cross-sectional 60 Children with FSGS NR N/A R&D Systems Serum 7/8 (JBI) Winnicki et al., 2019, Austria ( 26 ) Cross-sectional 146 Adults with glomerular diseases 45 N/A suPARnostic + R&D Plasma 5/8 (JBI) Hayek et al., 2023, USA ( 27 ) Prospective cohort 3,437 Coronary angiography patients 35 NR suPARnostic Plasma 8/9 (NOS) Koller et al., 2017, Austria ( 28 ) Prospective cohort 319 Chronic heart failure 27 NR suPARnostic Serum 8/9 (NOS) Eugen-Olsen et al., 2010, Denmark ( 29 ) Prospective cohort 6,576 General population 53 12.3 years suPARnostic Plasma 8/9 (NOS) Sorensen et al., 2019, Germany ( 30 ) Prospective cohort 1,116 Suspected myocardial infarction 35 1.0 year suPARnostic Plasma 8/9 (NOS) Lyngbaek et al., 2012, Denmark ( 31 ) Prospective cohort 1,042 STEMI post-PCI 27 3.8 years suPARnostic Plasma 8/9 (NOS) Huet et al., 2021, France ( 15 ) Prospective cohort + RCT 95 Acute heart failure 42 1 month/1 year suPARnostic Plasma 8/9 (NOS) Dupuy et al., 2021, France ( 32 ) Prospective cohort 182 Chronic heart failure 27 80 months suPARnostic Serum 8/9 (NOS) Theilade et al., 2015, Denmark ( 33 ) Cross-sectional 667 Type 1 diabetes 45 N/A suPARnostic Serum 7/8 (JBI) Guthoff et al., 2017, Germany ( 34 ) Prospective cohort 1,363 At risk for type 2 diabetes 48 NR suPARnostic Serum 8/9 (NOS) Heraclides et al., 2013, Denmark ( 35 ) Prospective cohort 1,850 Overweight, impaired glucose regulation 52 NR suPARnostic Plasma 8/9 (NOS) Characteristics of the 20 included studies. NR, not reported; NOS, Newcastle-Ottawa Scale; JBI, Joanna Briggs Institute; CKD, chronic kidney disease; CRIC, Chronic Renal Insufficiency Cohort; C-STRIDE, Chinese Cohort Study of Chronic Kidney Disease; CKiD, Chronic Kidney Disease in Children; NEPTUNE, Nephrotic Syndrome Study Network; GN, glomerulonephritis; FSGS, focal segmental glomerulosclerosis; STEMI, ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trial. †Not reported in the manuscript; data unavailable upon author request. Table 2 Disease context Study N Assay Sample Median suPAR (ng/mL) Range Preserved kidney function Hayek et al., 2015 1,335 suPARnostic Plasma 2.91 1.80–4.80 General population Eugen-Olsen et al., 2010 6,576 suPARnostic Plasma 2.44 1.80–3.40 Suspected MI Sorensen et al., 2019 1,116 suPARnostic Plasma 2.40 1.60–3.80 STEMI post-PCI Lyngbaek et al., 2012 1,042 suPARnostic Plasma 2.60 1.80–4.20 Chronic heart failure Koller et al., 2017 319 suPARnostic Serum 4.20 2.50–7.80 Acute heart failure Huet et al., 2021 95 suPARnostic Plasma 11.81 5.20–28.40 Type 1 diabetes Theilade et al., 2015 667 suPARnostic Serum 2.80 1.90–4.50 Pediatric CKD Abraham et al., 2021 586 suPARnostic Plasma 3.20 1.50–8.60 Chinese CKD Lv et al., 2020 2,391 suPARnostic Serum 3.20 1.80–6.40 FSGS (adults) Winnicki et al., 2019 146 suPARnostic Serum 4.80 2.10–12.50 Reported suPAR levels by disease context. The very high values observed in acute heart failure (median 11.81 ng/mL) should be interpreted with caution: impaired glomerular filtration reduces the renal clearance of cleaved suPAR fragments, and acute cardiometabolic distress often compromises kidney perfusion, so elevated circulating levels likely reflect reduced clearance as well as increased production. 3.2 suPAR in chronic kidney disease Six studies examined CKD po
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