DOI: 10.25934/pr00007518
title: Role of persistent and isolated reduced serum complement 3 (C3) in lupus nephritis

description: Lupus nephritis (LN) occurs when lupus autoantibodies affect structures in the kidney that filter out waste. This causes kidney inflammation and may lead to blood in the urine, protein in the urine, high blood pressure, impaired kidney function or even kidney failure. It is a common complication of systemic lupus erythematosus (SLE), an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs. LN would leads to end-stage renal disease (ESRD) in 17% to 25% of the cases. ESRD is the final, permanent stage of chronic kidney disease, where kidney function has declined to the point that the kidneys can no longer function on their own.
A number of clinical and serological factors have been identified as biomarkers of disease activity in LN but only few of them are reliable predictors of renal outcome. The complement system is a group of nearly 60 proteins that are in blood plasma or on the surface of some cells. C3 and C4 are important proteins in the blood and in lupus, both C3 and C4 levels are usually low. A serum level reduction of C3 and C4 is usually associated with active renal disease; however, their prognostic significance is still unclear.
One of the main limitations of the studies on prognostic biomarkers in LN- and on complement levels in particular- is that they often consider only baseline variables (i.e., taken at diagnosis or at the beginning of therapy) or variables taken at the time of relapse. Conversely, assessing their dynamic behaviour over time can be even more important since persistent abnormalities may reflect refractoriness to treatment and thus portend a poor prognosis.
This would be consistent with data regarding other immune-mediated renal diseases, such as atypical forms of post-infectious glomerulonephritis, a kidney infammation resulting from immunological events triggered by a variety of bacterial, viral, and protozoal infections, where persistent low sC3 levels causes a more severe and chronic disease and antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis,a group of disorders involving severe, systemic, small vessel inflammation characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA), where low sC3 (but not sC4) levels were associated with an increased risk of ESRD.

We would explore if persistently reduced serum complement 3 (sC3) is a marker of renal prognosis and of treatment failure in patients affected by Lupus Nephritis (LN). The proposed post-hoc analysis will be performed on data from the LUNAR (The Lupus Nephritis assessment With Rituximab Study) study, that evaluated efficacy and safety of Rituximab in a randomized, double blid placebo controlled phase III trial in patients with LN treated concomitantly with Mofetil Mycofenolate (MMF) and steroids. 
The trial evaluated as secondary end-points changes from baseline to week 52 in sC3 values. The regularly repeated doses of serum complement levels (sC3 and sC4) associated to renal outcome would offer an answer to our research question.