A Prospective Study on Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease

Abstract

IntroductionMinimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are related podocytopathies with distinct kidney outcomes. Surprisingly, elevated urinary activation fragments have been found in FSGS despite little complement deposition on immunofluorescence staining. Whether complement activation distinguishes FSGS from MCD, participating in the development of segmental lesions, remains unknown. MethodsWe performed an observational study in subjects with MCD and FSGS, and proteinuria ≥ 1 g/g of creatinine. We included both primary and secondary or unknown causes. We compared urinary fragments of terminal pathway activation, sC5b9 and C5a expressed as creatinine ratios, between MCD and FSGS. ResultsPatients with FSGS (n=41) had a serum albumin of 31±10 g/L and proteinuria of 5.1 (2.6-9.1) g/g at sampling, while those with MCD (n=15) had a lower serum albumin (22±9 g/L, p=0.002), and a proteinuria of 3.8 (1.9-7.7) g/g (p=0.40). Urinary sC5b9 and C5a were 8.7 (1.7-52.3) and 1.26 (0.45-1.84) μg/mmol of creatinine, respectively in FSGS subjects, compared to 0.8 (0.0-1.5) and 0.06 (0.01-0.15) μg/mmol of creatinine in MCD (p<0.001), respectively. We found no association between urinary complement fragments and age, eGFR, or chronic kidney lesions. When analyzing samples with proteinurias ≥ 3 g/g, the c-statistics for urinary sC5b9 and C5a were 0.96 and 1.00, respectively, in differentiating FSGS from MCD. ConclusionWe found no urinary complement activation fragments in MCD, in comparison to FSGS, despite similar levels of proteinuria. This suggests a role for complement activation in the pathogenesis of FSGS and provides an additional tool for distinguishing these two entities.