Immune Deposits, Complement Activation, and APOL1 Risk Variants in Focal Segmental Glomerulosclerosis

The role of immune deposits and complement activation in APOL1-mediated focal segmental glomerulosclerosis (FSGS) remains unclear. Using the CureGN cohort, we examined the associations between APOL1 renal risk variants (RRVs), glomerular immune deposits, and urinary complement activation.

We analyzed glomerular IgG, IgM, and C3 deposition, kidney biopsy findings, urinary membrane attack complex (sC5b9) levels, and clinical data in FSGS patients, regardless of race. Study participants were categorized as high-risk (two RRVs) or low-risk (zero to one RRV).

Of 175 participants, 148 (84%) had genetic testing, among whom 31 were high-risk and 117 were low-risk participants. High-risk participants had a higher prevalence of collapsing FSGS (45% vs. 11%, p < 0.001) and mesangial IgG deposition (intensity >0) (32% vs. 3%, p < 0.001). Incident participants enrolled within 6 months of biopsy showed a trend toward higher urinary sC5b9-to-protein ratio in high-risk participants (0.15 [0.08-0.31] vs. 0.03 [0-0.20] μg/g, p = 0.09). IgG staining correlated with urinary sC5b9 levels (r = 0.34, p = 0.008), suggesting a link between IgG deposition and urinary membrane attack complex excretion.

APOL1 high-risk FSGS is associated with mesangial IgG deposition and increased urinary membrane attack complex levels, implicating immune-mediated mechanisms in FSGS pathogenesis.