Immune Checkpoint Signatures in Minimal Change Disease and Membranous Nephropathy: Divergent Pathways of a Shared Imbalance

Primary glomerulopathies share common immune dysregulation but differ in their predominant pathways. We compared immune checkpoint profiles in minimal change disease (MCD) and membranous nephropathy (MN) with those in healthy volunteers (HV). In a cohort of 90 individuals (MCD, <i>n</i> = 30; MN, <i>n</i> = 30; HV, <i>n</i> = 30), we performed multiparameter flow cytometry of PBMCs to assess the expression of PD-1/PD-L1, CTLA-4/CD86, and CD200/CD200R on CD4+and CD8+ T cells, CD19+ B cells, and natural killer cells (NK cells). ELISA measured serum soluble checkpoint concentrations, and transcript levels in PBMCs were measured by qPCR. Nonparametric statistics and ROC analysis were used. In MCD, a skewed T cell pattern was observed, characterized by dominant expression of PD-1 and CTLA-4, whereas in MN, a humoral predominance was observed with higher PD-L1 expression and attenuated CD200/CD200R axis. Across diseases, expression profiles and correlations between markers differed between HV and between MCD and MN. Soluble checkpoints (sPD-1, sPD-L1, sCD200, sCD200R) showed potential discriminatory value for GN compared to HV and for differentiating MCD from MN in ROC analyses. These findings indicate that the mechanisms maintaining immune tolerance in primary GN are standard but pathway-specific, consistent with the dominant immunological component of each disease. A significant implication of this study is the need to conduct tissue-level studies to confirm clinical utility and provide insights into personalized immunomodulatory strategies targeting PD-1/PD-L1, CTLA-4/CD86, and CD200/CD200R.