Urinary transcription factor 21 (TCF21) as a non-invasive biomarker of podocyte injury in preeclampsia: diagnostic performance and translational insights from a case–control study

Abstract

Early detection of preeclampsia may reduce maternal and fetal morbidity and mortality. While angiogenic biomarkers (sFlt-1 and PlGF) are clinically useful, their sensitivity is imperfect. Podocyte injury is implicated in preeclampsia; urinary transcription factor 21 (TCF21) may serve as a non-invasive marker of glomerular involvement. In this case-control study, 160 women with preeclampsia and 64 normotensive pregnant controls matched for age and gestational age were enrolled to evaluate the diagnostic utility of urinary TCF21 and its performance alongside angiogenic markers (sFlt-1, PlGF) at the time of clinical presentation for suspected preeclampsia. Preeclampsia cases were stratified into mild (n = 92) and severe (n = 68) disease, and each group was further stratified into early-onset and late-onset preeclampsia. Biomarker performance was assessed using logistic regression, receiver operating characteristic (ROC) analysis, and multivariable modeling. Compared with controls, women with preeclampsia had higher sFlt-1 (11.4-fold; p < 0.001), a higher sFlt-1/PlGF ratio (40.6-fold; p < 0.001), and higher urinary TCF21 (1.7-fold; p < 0.001), with lower PlGF (− 68%; p < 0.001). Urinary TCF21 demonstrated moderate discrimination for preeclampsia (AUC 0.769) and was inferior to the sFlt-1/PlGF ratio (AUC 0.812). At the prespecified cutoff of > 370 pg/mL, urinary TCF21 achieved 60.6% sensitivity and 90.6% specificity (LR + 6.45; LR − 0.43). Urinary TCF21 showed an exploratory inverse association with severity (r = − 0.258, p < 0.001) and diastolic blood pressure (r = − 0.244, p = 0.002). In multivariable analysis, urinary TCF21 remained independently associated with preeclampsia (adjusted odds ratio 2.83 per 50 pg/mL; 95% CI 1.49–5.59; p = 0.002), and combined models improved discrimination (AUC 0.87; 95% CI 0.82–0.91). Urinary TCF21 is a novel, non-invasive biomarker associated with preeclampsia and showed a hypothesis-generating inverse association with disease severity. In this case-control cohort, its high specificity suggests potential adjunct confirmatory performance at presentation when interpreted alongside angiogenic testing; however, cutoffs and probability thresholds are exploratory and require prospective external validation. Future studies should include creatinine-normalized reporting, assay standardization, and longitudinal sampling to evaluate predictive utility prior to symptom onset. First clinical evaluation of urinary TCF21 in preeclampsia: This is the first study to investigate urinary transcription factor 21 (TCF21) – a podocyte-specific transcription factor—as a non-invasive biomarker in preeclampsia. Independent signal beyond angiogenic imbalance: Urinary TCF21 remains significantly associated with preeclampsia after adjustment for established clinical factors and the sFlt-1/PlGF ratio, indicating a distinct renal/podocyte component not captured by angiogenic markers alone. High specificity suggests adjunct confirmatory potential at presentation: At a cutoff > 370 pg/mL, urinary TCF21 showed 90.6% specificity with a positive likelihood ratio (LR+) of 6.45 in this case-control cohort. These findings are hypothesis-generating and support consideration of urinary TCF21 as an adjunct to angiogenic testing pending prospective external validation. Novel, hypothesis-generating inverse association with disease severity: Unlike angiogenic biomarkers that typically track severity, urinary TCF21 showed an inverse relationship with preeclampsia severity, which may reflect dynamic biomarker kinetics, podocyte stress responses, altered shedding, or depletion in advanced disease and requires longitudinal validation. Improved discrimination using a multi-pathway panel: A multivariable model combining urinary TCF21, the sFlt-1/PlGF ratio, and clinical variables demonstrated significantly improved diagnostic discrimination (AUC 0.87, 95% CI 0.82–0.91) compared with models using either pathway alone, thereby integrating signals of placental dysfunction and glomerular injury into a single diagnostic framework. Translational feasibility for non-invasive stratification: Urine-based detection of TCF21 may offer a practical adjunct to reflect renal/podocyte involvement and refine phenotype characterization at presentation. Clinical implementation will require assay standardization, creatinine-normalized reporting, and validation in independent prospective cohorts. • Introduces a novel biomarker concept: Establishes urinary TCF21—a podocyte-specific transcription factor—as a new, non-invasive candidate biomarker for preeclampsia. • Connects placental and renal pathways: Provides clinical evidence that urinary TCF21 captures a renal/podocyte injury signal that is complementary to angiogenic imbalance (sFlt-1/PlGF), supporting a dual-pathway disease model. • Demonstrates independent diagnostic value: Shows that urinary TCF21 remains independently associated with preeclampsia after adjusting for clinical risk factors and angiogenic markers. • Identifies a distinctive, hypothesis-generating severity pattern: Urinary TCF21 showed an inverse association with disease severity, suggesting a dynamic podocyte-related signal distinct from the linear severity relationship seen with angiogenic biomarkers; this finding requires mechanistic and longitudinal validation. • Advances multi-marker risk modeling: Demonstrates improved discrimination when urinary TCF21 is integrated with the sFlt-1/PlGF ratio and clinical variables, supporting a multidimensional panel for diagnosis and stratification. • Highlights translational practicality: Proposes a feasible urine-based approach for adjunct testing and risk refinement at presentation, with performance and cutoffs requiring assay standardization and external validation before clinical use.