Abstract
BackgroundRecent pre-clinical studies have shown that complement activation contributes to glomerular and tubular injury in experimental FSGS. Although complement proteins are detected in the glomeruli of some patients with FSGS, it is not known whether this is due to complement activation or whether the proteins are simply trapped in sclerotic glomeruli. We measured complement activation fragments in the plasma and urine of patients with primary FSGS to determine whether complement activation is part of the disease process.Study DesignPlasma and urine samples from patients with biopsy-proven FSGS who participated in the FSGS Clinical Trial were analyzed.Setting and ParticipantsWe identified 19 patients for whom samples were available from weeks 0, 26, 52 and 78. The results for these FSGS patients were compared to results in samples from 10 healthy controls, 10 patients with chronic kidney disease (CKD), 20 patients with vasculitis, and 23 patients with lupus nephritis.OutcomesLongitudinal control of proteinuria and estimated glomerular filtration rate (eGFR).MeasurementsLevels of the complement fragments Ba, Bb, C4a, and sC5b-9 in plasma and urine.ResultsPlasma and urine Ba, C4a, sC5b-9 were significantly higher in FSGS patients at the time of diagnosis than in the control groups. Plasma Ba levels inversely correlated with the eGFR at the time of diagnosis and at the end of the study. Plasma and urine Ba levels at the end of the study positively correlated with the level of proteinuria, the primary outcome of the study.LimitationsLimited number of patients with samples from all time-points.ConclusionsThe complement system is activated in patients with primary FSGS, and elevated levels of plasma Ba correlate with more severe disease. Measurement of complement fragments may identify a subset of patients in whom the complement system is activated. Further investigations are needed to confirm our findings and to determine the prognostic significance of complement activation in patients with FSGS.
Highlights
Focal segmental glomerulosclerosis (FSGS) is an important cause of glomerular disease in children and adolescents
The complement system is activated in patients with primary FSGS, and elevated levels of plasma Ba correlate with more severe disease
We found that the levels of Ba and C4a in plasma from patients with FSGS were significantly higher than levels in patients with lupus nephritis, anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, and healthy controls (Fig 1)
Summary
Focal segmental glomerulosclerosis (FSGS) is an important cause of glomerular disease in children and adolescents. 50% of affected patients who fail to achieve remission of their proteinuria will progress to end stage kidney disease over a 5–10 year period. Mutations in podocyte proteins have been identified as monogenic causes of disease in nearly 30% of patients with steroid resistant FSGS [2]. Complement proteins are detected in the glomeruli of some patients with FSGS, it is not known whether this is due to complement activation or whether the proteins are trapped in sclerotic glomeruli. We measured complement activation fragments in the plasma and urine of patients with primary FSGS to determine whether complement activation is part of the disease process
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