Checkpoint Imbalance in IGA Nephropathy: Unraveling the Immune Dysregulation Driving Glomerular Injury

Abstract

Introduction: IgA nephropathy (IgAN), also known as Berger disease, is the most common form of primary glomerulonephritis and a leading cause of chronic kidney disease and end-stage renal failure worldwide. It is characterized by the deposition of IgA in the glomerular mesangium and subsequent immune-mediated renal injury.

Objectives: This review aims to summarize current insights into the immunopathogenesis of IgAN, with particular emphasis on the role of galactose-deficient IgA1 (Gd-IgA1) and the regulatory function of the PD-1/PD-L1 immune checkpoint pathway, as well as its therapeutic implications.

Methods: A narrative review of recent experimental and clinical literature was conducted, focusing on mechanisms of immune complex formation, complement activation, and immune checkpoint modulation in IgAN, including evidence from patients receiving immune checkpoint inhibitors.

Results: Current evidence indicates that patients with IgAN frequently produce galactose-deficient IgA1 (Gd-IgA1), which is inadequately cleared and recognized as autoantigenic. This leads to the generation of anti-Gd-IgA1 autoantibodies and formation of circulating immune complexes. Deposition of these complexes in the glomerular mesangium triggers complement activation, chronic inflammation, and progressive fibrosis, ultimately contributing to renal failure. Dysregulation of the PD-1/PD-L1 axis—particularly during immune checkpoint inhibitor therapy in cancer patients—can exacerbate autoimmune responses, resulting in disease flare-ups or de novo IgAN. The PD-1/PD-L1 pathway plays a critical role in limiting T-cell–mediated inflammation.

Conclusions: The PD-1/PD-L1 axis represents a double-edged sword in IgAN pathogenesis. While inhibition may increase the risk of autoimmune renal injury, therapeutic enhancement of this pathway may reduce excessive immune activation and kidney damage. Targeted immunomodulatory strategies involving PD-1/PD-L1 signaling therefore hold promise as future treatment approaches in IgAN management.