Adding Serum C3 and C4 to Enhance Prediction Models for IgAN

Complement system (CS) activation is critical for the pathogenesis of IgA nephropathy (IgAN). However, the role of CS has primarily been examined through histological, genetic, and biochemical investigations, focusing on the byproducts of cascade activation and detectable metabolites, rather than correlating serum C3 and C4 fractions with IgAN activity and prognosis.

Therefore, Edoardo Tringali and colleagues conducted a retrospective, longitudinal study to investigate the prognostic value of serum complement at the time of IgAN diagnosis. Specifically, they sought to determine whether adding serum C3 and C4 levels to existing predictive models would improve their accuracy. The results appeared in Scientific Reports.

Data came from clinical records of patients with a histology-proven diagnosis of IgAN referred at Sant’Orsola University Hospital, Bologna, Italy, from January 2009 to December 2022. There were 101 participants in the study, of whom 90% were White and 65.3% were male. The mean age was 42.6 years. The patients were divided into low (< 90 mg/dl), medium (90–140 mg/dl), and high (>140 mg/dl) groups based on their baseline C3 levels.

The primary objective was to examine the prognostic value of serum C3 and C4 when added to existing prognostic IgAN models, including the International IgA Prediction Tool (IntIgAPT). The primary outcome used for model computation was a kidney composite outcome (50% decline in eGFR and/or onset of kidney failure). A secondary aim was to investigate the interaction of serum complement with other baseline clinical features on the primary endpoint.

Median follow-up was 54.28 months, during which the low group demonstrated a higher incidence of the primary outcome: 16.1 events (95% CI ,7.0-36.1 × 100 patients/year) compared to the medium (2.7 events; 95% CI, 1.3-6.0 × 100 patients/year) and high (1.7 events; 95% CI, 0.2-11.8 × 100 patients/year) groups, with a significant difference between rates (P=.003).

The reference prediction models used were Model-1 (M1), which includes CKD progression variables, and Model-3 (M3), which consists of IntIgANPT variables. The researchers implemented these models, respectively, with baseline C3 and C4 to create Model-2 (M2) and Model-4 (M4). M2 demonstrated better predicted outcomes and higher discrimination (lower Akaike information criterion and Bayesian information criterion, higher c-index and Nagelkerke R square) than M1. M4 performed better than M3, showing improved outcome prediction when C3 and C4 levels were incorporated.

In summary, implementing serum C3 and C4 into existing, validated prediction models can enhance their predictive accuracy for IgAN. Lower C3 and higher C4 levels were associated with poorer prognosis, highlighting a more “complement-pathic” subset of patients.

“Similarly to what has been suggested in other complement-mediated kidney diseases, such as membranoproliferative glomerulonephritis, adopting a ‘cluster-oriented’ pathophysiological approach in IgAN could aid in addressing the current unmet medical need for biomarkers and risk stratification,” the authors wrote.

Source: Scientific Reports