Circulating Soluble Thrombomodulin Is Elevated in Early-Stage CKD and Is Associated with Renal Dysfunction: A Transcriptomic and Retrospective Cohort Study

Chronic kidney disease (CKD) is characterized by progressive renal dysfunction and endothelial injury. Thrombomodulin (TM), encoded by the THBD gene, is released into the circulation as soluble TM (sTM) following endothelial damage; however, its clinical significance in CKD remains unclear. To address this question, public bulk and single-cell transcriptomic datasets were analyzed to characterize THBD expression and cellular localization in kidney injury, and a retrospective cohort of 278 hospitalized patients was used to evaluate circulating sTM levels across CKD stages and their associations with renal function, coagulation, and cardiac biomarkers. The transcriptomic analyses showed that THBD was upregulated in injured kidneys, positively correlated with a fibrosis-related transcriptional signature, and predominantly expressed in renal endothelial cells. Consistent with these findings, circulating sTM was elevated as early as stage 1 CKD and increased progressively with advancing disease stage. Higher sTM levels were positively associated with serum creatinine, serum urea, and urinary albumin-to-creatinine ratio (UACR), and inversely associated with estimated glomerular filtration rate (eGFR). In addition, sTM showed weak-to-modest associations with coagulation, fibrinolytic, and cardiac biomarkers. Multivariable analysis showed that eGFR remained independently associated with log-transformed sTM after adjustment for major clinical covariates (β = −0.0116, 95% CI −0.0141 to −0.0090, p < 0.001). ROC analysis showed that sTM discriminated CKD from non-CKD (AUC = 0.971) and early-stage CKD from non-CKD (AUC = 0.854), outperforming eGFR (AUC 0.920 and 0.565, respectively) and performing comparably to UACR. Collectively, these findings support sTM as a candidate biomarker associated with CKD severity whose interpretation should integrate endothelial injury and reduced renal elimination and prospective validation is warranted.