Differential excretion of urinary complement fragments in kidney diseases: a potential link to complement activation?

Defective complement activation has been associated with various types of kidney disease. This led to the hypothesis that specific urine complement fragments may be associated with kidney disease etiologies, and disease progression may be reflected by changes in these complement fragments. We investigated the occurrence of complement fragments in urine, their association with kidney function, proteinuria and disease etiology. Mass spectrometry based peptidomics data from the Human Urinary Proteome/Peptidome Database were extracted and the distribution of complement peptides in the different kidney disease etiologies and controls was investigated. All datasets with informations on disease/health status and detectable complement peptides were included (n=16027). Twenty-three different urinary peptides derived from complement proteins could be identified, originating from the complement proteins C3, C4 and complement factor B. For most C3-derived peptides an inverse association with eGFR was observed, while the majority of peptides derived from CFB demonstrated positive association with eGFR. Highest levels of significant C3 excretion relative to controls were seen in minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MGN), lupus nephritis (LN), diabetic kidney disease (DKD), IgAN, membranoproliferative glomerulonephritis (MPGN), and C3-glomerulonephritis. In conclusion, several peptides derived from the complement proteins C3, C4 and factor B are significantly associated with specific kidney disease etiologies. These peptides may depict disease-specific complement activation, as well as damage to the glomerular basement membrane. Further targeted investigation of these peptides may provide new insight into disease pathophysiology and could possibly guide therapeutic decisions, especially when targeting complement factors.