Soluble Tie2 and Risk of Kidney Progression in a Longitudinal CKD Cohort

Background: Vascular instability contributes significantly to glomerular endothelial injury. Tie2, an endothelial-specific tyrosine kinase receptor, is essential for maintaining vascular integrity. Its soluble form (sTie2), which functions as a decoy receptor by inhibiting membrane-bound Tie2 activation, may reflect endothelial dysfunction. Although sTie2 may act as a biomarker in chronic kidney disease (CKD), its clinical relevance remains to be established. Methods: We analyzed patients with stage 1–3B CKD from the KNOW-CKD, a nationwide prospective longitudinal cohort, alongside kidney donors as healthy control. Serum levels of sTie2 and Angiopoietin 2 were measured using enzyme-linked immunosorbent assay. The kidney outcome was defined as a eGFR halving, serum creatinine doubling, or progress to kidney failure. Cox regression analysis assessed associations between biomarkers and outcome. Results: After excluding patients with polycystic kidney disease, glomerulonephritis, and major comorbidities, 400 CKD patients and 155 controls were included. CKD patients were older and had more diabetes and hypertension. Serum sTie2 levels were elevated in CKD and increased in a stage-dependent manner, whereas Ang2 levels did not. Over a mean follow-up of 9.12 ± 3.19 years, 104 (28.3%) kidney outcomes occurred, including 67 (18.2%) kidney failure. In tertile-based analysis, patients in higher sTie2 tertiles were older and had lower eGFR. After adjusting for age, sex, BMI, diabetes, hypertension, hemoglobin, albumin, calcium, phosphorus, and microalbuminuria, sTie2 tertiles showed dose-dependent associations with kidney outcomes (adjusted HR 1.74, P = 0.049; HR 2.31, P = 0.002). Conclusion: This study found that sTie2 levels increased with the CKD stage in a dose-responsive manner. Moreover, elevated baseline sTie2 was independently associated with poor renal prognosis, supporting its potential utility as a biomarker of endothelial dysfunction in CKD.