Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment

Introduction: Therapeutic agents that target complement are increasingly available for glomerular diseases. However, the mechanisms linking glomerular complement deposition with inflammation and damage are incompletely understood. Complement factor H-related protein 5 (FHR5) interacts with complement C3 and is considered to promote activation. Circulating and glomerular FHR5 associates with IgA nephropathy and abnormal FHR5 associates with familial C3 glomerulopathy (C3G). We characterized glomerular FHR5 staining in C3G and assessed its relationships with histological features of glomerular injury and clinical outcome.

Methods: We developed FHR5 staining protocols for formalin-fixed paraffin-embedded (FFPE) renal tissue and applied them to surplus biopsy sections from a C3G cohort.

Results: Glomerular FHR5 was highly prevalent in native and transplant C3G and correlated with glomerular C3 and C5b-9 staining. Glomerular FHR5 staining correlated negatively with estimated glomerular filtration rate (eGFR) (P = 0.04, difference of medians 19.7 ml/min per 1.73 m²; 95% confidence interval [CI] 1.1-43.0) and positively with a membranoproliferative glomerulonephritis pattern at diagnostic biopsy (odds ratio 18; 95% CI 1.6-201; P = 0.049). Glomerular FHR5 staining intensity positively correlated with glomerular complement C3b/iC3b/C3c (Pearson's correlation coefficient [R] = 0.59; P = 0.0008), C3dg (R = 0.47; P = 0.02) and C5b9 (R = 0.44, P = 0.02).

Conclusions: Glomerular FHR5 is highly prevalent in C3G, interacts with glomerular C3, and is associated with markers of disease severity. Glomerular FHR5 likely exacerbates complement-mediated glomerular damage in C3G and its interaction with glomerular complement might be exploited to target complement therapeutic agents.