Preoperative Serum Alkaline Phosphatase Predicts Arteriovenous Fistula Maturation Failure

Arteriovenous fistula (AVF) maturation failure remains a major obstacle for hemodialysis, yet its underlying molecular drivers are poorly characterized. The identification of key regulatory genes and clinically applicable biomarkers is critical for improving preoperative risk assessment.

We employed an integrative multiomics approach to unbiasedly identify hub genes. Transcriptomic datasets (GSE220796 and GSE119296) were analyzed using weighted gene coexpression network analysis (WGCNA) and machine learning. Cellular localization was defined via single-cell RNA-sequencing (GSE250469). Findings were validated in a prospective clinical cohort (n = 55) and through functional tube formation assays with human umbilical vein endothelial cells.

The tissue-nonspecific alkaline phosphatase (ALPL) gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP), was identified as a core hub gene upregulated in failed AVFs, predominantly in PLA2G2A ⁺ fibroblasts. In the clinical cohort, tissue TNSALP protein levels were higher in failed AVFs and correlated with preoperative serum alkaline phosphatase (ALP) levels (r = 0.38, P = 0.018). Higher preoperative serum ALP was independently associated with lower odds of successful AVF maturation (adjusted odds ratio [OR]: 0.75 per 10 units per liter (U/l) increase, 95% confidence interval (CI): 0.55-0.98, P = 0.048). Functionally, recombinant human TNSALP protein dose-dependently suppressed human umbilical vein endothelial cells tube formation in vitro (P < 0.05).

Our study identifies ALPL as a candidate mediator associated with AVF maturation failure and suggests that serum ALP, a routine clinical test, may serve as a practical biomarker for preoperative risk stratification.