Proteomics-based immune activation signatures are associated with kidney allograft rejection

Introduction Biopsy-based diagnostics for the detection of kidney allograft rejection are invasive and imperfect, highlighting the need for non-invasive biomarkers. However, the potential of plasma proteomics for assessing alloimmune injury remains unclear. Methods Therefore, proteomic profiling was performed in 88 kidney transplant recipients undergoing indication biopsy using the Olink Target 96 Inflammation panel. Differential protein expression analyses compared biopsy-proven rejection with no rejection. A composite proteomic score derived from the three most discriminatory proteins was evaluated in relation to histopathology, donor-derived cell-free DNA (dd-cfDNA), and graft outcomes. Results Among 92 analyzed proteins, TNFRSF9 showed the strongest association with rejection, followed by CXCL9 and IL-12B. The composite proteomic score discriminated rejection from no rejection (AUC 0.85, 95% CI 0.72–0.95), while integration with dd-cfDNA improved discrimination (AUC 0.88, 95% CI 0.78–0.99). Signals from the predefined inflammation-related protein panel increased progressively from no rejection to borderline changes and overt rejection ( P < 0.001). The score correlated with histopathological indices of activity, antibody-mediated rejection/microvascular inflammation, T-cell-mediated rejection/tubulointerstitial inflammation, and chronicity. Patients with borderline changes displayed heterogeneous proteomic signatures, with most overlapping the no-rejection group and a smaller subset exhibiting rejection-like signatures. The score correlated moderately with dd-cfDNA ( ρ =0.32, P = 0.009) and remained independently associated with death-censored graft failure (HR 2.67, 95% CI 1.31–5.42). Conclusion Together, these exploratory findings suggest that plasma proteomic signatures may reflect aspects of alloimmune injury across the rejection spectrum and are associated with chronic histological damage and graft failure. These findings support further investigation of plasma proteomics as a complementary approach for non-invasive assessment of kidney allograft injury while potentially also offering insights into mechanisms driving progressive allograft dysfunction.