C4d May Predict Treatment Failure and Disease Progression in Primary Focal Segmental Glomerulosclerosis

To investigate the prognostic significance of C4d, a stable tissue marker of complement activation, in primary focal segmental glomerulosclerosis (pFSGS).

Immunohistochemistry for C4d was performed on paraffin-embedded tissue in patients with pFSGS and only non-globally sclerosed glomeruli were evaluated for C4d. Based on the ratio of C4d-positive glomeruli/total number of glomeruli and number of C4d-positive non-sclerotic glomeruli and total number of non-sclerotic glomeruli, patients were stratified into two subgroups: < 50% or ≥ 50% of C4d-positive glomeruli. Association of C4d with disease progression (composite of kidney failure and > 50% reduction in baseline eGFR), renal survival and treatment failure was analysed.

A total of 58 patients were included. Patients with ≥ 50% of C4d-positive glomeruli had worse renal survival (p = 0.005) and higher rate of treatment failure (p = 0.002) and disease progression (p = 0.025). Patients with ≥ 50% of C4d-positive non-sclerotic glomeruli had worse renal survival (p = 0.034) and higher rate of treatment failure (p = 0.009) and disease progression (p = 0.046). C4d, either in all glomeruli (OR = 7.88, p = 0.013) or non-sclerotic glomeruli (OR = 4.97, p = 0.021), was independently associated with treatment failure. C4d deposits in ≥ 50% of all glomeruli and nonsclerotic glomeruli only were independently associated with progression to composite outcome (HR = 5.89, p = 0.011) and (HR = 3.93, p = 0.031), respectively, together with percentage of interstitial fibrosis and tubular atrophy.

C4d seems to be independently associated with treatment failure and disease progression in pFSGS. Beyond the influence on risk stratification in pFSGS, this study may prompt trials with complement interfering agents in pFSGS.