Monitoring Immune Responses in IgA Nephropathy: Biomarkers to Guide Management

Abstract

IgA nephropathy (IgAN) is the commonest biopsy-reported primary glomerulonephritis worldwide. It has an incidence which peaks among young adults, and 30 to 40% of patients' progress to end stage kidney disease within twenty years of diagnosis. Ten-year kidney survival rates have been reported to be as low as 35% in some parts of the world. The successful management of IgAN is limited by an incomplete understanding of the pathophysiology of IgAN and a poor understanding of how pathophysiology may vary both from patient to patient and between patient groups, particularly across races. This is compounded by a lack of rigorously designed and delivered clinical trials in IgAN. This is slowly changing, with a number of Phase 2 and 3 clinical trials of novel therapies targeting a number of different putative pathogenic pathways in IgAN due to report in the next 5 years. From our current, albeit limited, understanding of the pathophysiology of IgAN it is unlikely a single therapy will be effective in all patients with IgAN. The successful management of IgAN in the future is, therefore, likely to be reliant on targeted therapies, carefully selected based on an individualized understanding of a patient's risk of progression and underlying pathophysiology. The potential role of biomarkers to facilitate personalization of prognostication and treatment of IgAN is immense. Here we review the progress made over the past decade in identifying and validating new biomarkers, with a particular focus on those that reflect immunological responses in IgAN.

Keywords: Berger’s disease; IgA nephropathy; biomarkers; management biomarkers in IgA nephropathy; treatment.

Figure 1

Features of the ideal biomarker.

Figure 2

Utility of traditional and suggested utility for novel IgAN-specific biomarkers. Traditional biomarkers are shown in yellow. Proposed novel IgAN-specific biomarkers with the greatest number of associated publications are shown in white, with those in parentheses being regularly reported as useful biomarkers in the literature but with very low quality evidence for sensitivity and specificity in IgAN.

Figure 3

The “four hit” hypothesis of IgA nephropathy. Hit 1: Appearance in the circulation of increased levels poorly O-galactosylated IgA1 (gd-IgA1). Hit 2: Generation of IgG and IgA autoantibodies directed against gd-IgA1. Hit 3: Formation of anti-gd-IgA1-gd-IgA1 immune complexes. Hit 4: Deposition of IgA immune complexes in the glomerular mesangium and consequent development of inflammatory and fibrotic processes in the kidney.