Advancement in CKD Stages Leads to Increased Levels of Soluble PD-L1 in Serum

Background: Programmed death-ligand 1 (PD-L1) and its receptor, programmed death-1 (PD-1), play crucial roles in immune tolerance through their interactions. PD-L1, expressed on antigen-presenting cells, cancer cells, placental tissue, vascular endothelial cells, and tubular epithelial cells, suppresses T-cell activation when it binds to PD-1 on T cells. Recent studies indicate that soluble PD-L1 (sPD-L1) also induces immunotolerance, with levels varying in clinical conditions such as cancer and pregnancy. However, data on sPD-L1 levels in chronic kidney disease (CKD), including hemodialysis (HD) patients, are lacking. This study aims to compare serum sPD-L1 levels among individuals without CKD and patients with CKD stages 1 to 5. Methods: Serum sPD-L1 levels were measured using ELISA in samples from three cohorts (n=2,816): healthy individuals who received the SARS-CoV-2 mRNA vaccine (n=1,781) with or without underlying conditions such as hypertension and diabetes; cancer patients without CKD and with CKD stages 1 to 4 (n=402); and HD patients (n=633). Results: sPD-L1 levels increased with worsening CKD stages. Median sPD-L1 levels were higher in HD patients compared to those with stage 4 CKD. In a 1:1 matched case-control study of 394 HD patients with age- and sex-matched healthy controls, HD patients exhibited significantly higher median sPD-L1 levels than non-HD individuals (231.7 pg/mL vs. 85.0 pg/mL, p<0.0001). This finding remained consistent after excluding and re-matching patients with hypertension, diabetes, and cancer. Furthermore, longer HD vintage was associated with higher sPD-L1 levels. Conclusion: Serum sPD-L1 levels increase with CKD progression, reaching the highest levels in HD patients, particularly those with longer treatment duration. Future research will focus on elucidating the mechanisms behind the increase in sPD-L1 levels due to declining renal function and investigating whether elevated sPD-L1 levels heighten the risk of cancer or infections in dialysis patients.