Serum PD-L1 and CTLA-4 levels as biomarkers of acute rejection and renal dysfunction in kidney transplant recipients

Purpose: Acute rejection in kidney transplantation is a critical barrier to long-term graft survival and the PD-1/PD-L1 and CTLA-4 molecules are crucial for the tolerance of alloreactive T cells against tubular epithelial cells. Our study aims to assess the role of these soluble PD-L1 and CTLA-4 molecules as biomarkers for non-invasive immunosurveillance after renal transplantation. Methods: Blood samples from 65 recipients were investigated for serum sPD-L1 and sCTLA-4 molecules at the time of kidney transplantation (baseline), in 3 time-points (15, 60 and 365 days) post-transplant, and when acute rejection (ACR) was suspected. Samples and standards were processed in duplicate using sandwich ELISA. Results: We revealed dynamic changes in serum expression over time, with a significant decrease from the time of kidney transplantation to the various monitoring points, except at the time of acute rejection when the levels increased. Multivariable logistic regression revealed that the sPD-L1 15-day post-transplant is an independent variable for ACR onset (AOR = 1.196 p = 0.020), and with a moderate discriminatory power (AUC = 0.717, p = 0.031), together with PD-L1 60 days, for the occurrence of rejection within 1 year from transplant. sPD-L1 after 15 days shows a predictive role also for DGF (AUC = 0.738, p = 0.001) and graft dysfunction at 60 days (AUC = 0.672, p = 0.022). Furthermore, a higher 15-day expression of sCTLA-4 in patients with ACR compared with those with stable graft (114.8 pg/mL vs. 67.8 pg/mL, p = 0.018) was reported. Conclusion: These analyses suggest the potential role of these serum molecules as dynamic biomarkers of inflammation and immunoregulation in AKI and acute rejection; they may indicate new immunotherapy targets, useful for modulating tolerance and assist the clinician in identifying patients at risk of rejection or kidney failure.