#1486 Looking for a new role of known players: the additional value of plasmatic C3 and C4 in predicting IgA Nephropathy prognosis, an observational study
Authors: Tringali Edoardo , Vetrano Daniele , Tondolo Francesco , Maritati Federica , Fabbrizio Benedetta , Pasquinelli Gianandrea , Provenzano Michele , La Manna Gaetano , Baraldi Olga 
Published: May 2024

Abstract

Background and Aims
IgA Nephropathy (IgAN) is the most common glomerular disease worldwide [1]. Complement system activation through the alternative and lectin pathways is crucial in its pathogenesis and leads to worse outcome, eliciting the need for (new) biomarkers to assess risk of disease progression and potential response to new targeted treatments [2, 3]. Only few works have correlated serum C3 and C4 with disease activity and prognosis [4, 5]. Our work explores the potential advantages of incorporating serum C3 and C4 levels into a standardized prognostic model to assess kidney outcome in IgAN.

Method
This retrospective study, conducted at Sant'Orsola University Hospital in Bologna, investigated the prognostic value of serum complement C3 and C4 in patients with IgAN. The primary outcome was defined as a 40% decline in eGFR or the onset of kidney failure. The study aimed to evaluate whether the addition of serum C3 and C4 to an established predictive model, incorporating variables from the International IgA Prediction Tool (IntIgAPT), enhances the accuracy of outcome prediction. We computed the measures of goodness of fit for each model: Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), Nagelkerke R2 test (NR2) that depicts the% explained variation of the outcome based on the set of variables included, and Likelihood Ratio Test (LRT); discrimination with the c-index. Furthermore, we aimed to evaluate the characteristics of patients stratified by baseline serum C3 levels (Low &lt;90 mg/dl, Medium 90-140 mg/dl, High &gt;140 mg/dl).

Results
101 patients were included in the cohort. 90% were Caucasian and 65.3% were male with a mean age of 42.6 years. As reported in Table 1, mean eGFR and median proteinuria levels at baseline were 70.4 ml/min/1.73 m² and 1.04 g/24 h respectively. Mean serum C3 was 114.9 mg/dL. The Low group had lower values of eGFR at baseline (47.0 vs 75.67 and 68.64 ml/min/1.73 m², p = 0.015), while the Medium group had lower values of uProt (0.75 vs 1.81 and 1.46 g/24 h, p = 0.004). During a median 54.28 months follow-up, the Low group exhibited significantly higher primary outcome incidence (16.3 events vs 2.9 and 1.7 events x 100 pts/year, p = 0.003). We computed a first model (M1) based upon IntIgAPT variables and then a second model (M2) as the same of M1 plus serum C3 and C4 at baseline (Table 2). C3 showed a negative association with outcome (OR 0.88, CI 0.78 to 0.99, p = 0.05) whereas C4 had a positive one (OR 1.21, CI 1.02 to 1.48, p = 0.05). M2 had an improved prediction accuracy than M1, as evidenced by lower AIC (49.1 vs 53.8), higher c-index (0.74 vs 0.65), and NR2 (0.76 vs 0.65). Likelihood ratio test was significant between the two (p = 0.008).

Conclusion
The inclusion of serum C3 and C4 in a validated prognostic model enhances prediction accuracy and improves the percentage of events explained, highlighting complement's inherent informativeness. In our population lower C3 and higher C4 levels were associated with poorer prognosis in IgAN, characterizing a more ‘Complement-Pathic’ subset of patients. This result expands the current evidence, for the first time to our knowledge, in a Caucasian-prevalent study population.