Serum Complement Levels Demonstrate Prognostic Value in IgA Nephropathy

Olga Baraldi, MD, PhD

Credit: Giornale Italiano di Nefrologia

Findings from a recent study are calling attention to the prognostic value of serum C3 and C4 in IgA nephropathy (IgAN), demonstrating enhanced outcome prediction accuracy with the addition of both levels into existing prognostic scores.¹

Compared to reference models without C3 and C4, those incorporating serum complement levels had more accurate outcome predictions, suggesting integration of these markers into existing prognostic scores could help optimize risk stratification in IgAN.¹

“Enhancing risk stratification is an urgent need in nephrology research,” Olga Baraldi, MD, PhD, senior assistant professor in the department of medical and surgical sciences at the University of Bologna in Italy, and colleagues wrote.¹ “Until now, the role of the complement system has primarily been explored through histological, genetic, and biochemical investigations, focusing on the byproducts of cascade activation and detectable metabolites in tissues, blood, and urine. To date, few studies have correlated serum C3 and C4 fractions with disease activity and prognosis.”

An autoimmune disease leading to inflammation and kidney damage, IgAN is a significant cause of chronic kidney disease and kidney failure. Its exact cause is unknown and clinical presentation varies greatly, with some patients experiencing more serious, rapid symptoms than others. Treatment seeks to delay kidney damage and eventual kidney failure, but a better ability to stratify patients by their risk of disease progression is important for improving outcomes.²

To investigate the prognostic value of serum C3 and C4, investigators conducted a retrospective, observational, single-center study in which they reviewed clinical records of patients with a histology-proven diagnosis of IgAN referred at Sant’Orsola University Hospital from January 2009-December 2022. For inclusion, patients were required to be ≥ 18 years of age at diagnosis and have a renal biopsy scored according to the Oxford MEST-C scoring system; available medical history, blood pressure measures, data related to renal function, urinary exams, serum protein profile, serum complement levels, and immunoglobulin levels of IgA, IgG, and IgM at the time of renal biopsy; and a follow-up duration of ≥ 12 months.¹

Treatment was administrated based on current clinical practice and guideline recommendations. Optimized first-line treatment included the management of blood pressure and other cardiovascular risk factors, lifestyle modification, and maximally tolerated dose of renin-angiotensin–aldosterone-system inhibitors and sodium/glucose cotransporter-2 inhibitors.¹

The primary outcome used for model computation was a kidney composite outcome, defined as a 50% decline in eGFR and/or the onset of kidney failure.¹

In total, 101 patients were included in the study. Among the cohort, 90% of patients were Caucasian and 65.3% were male with a mean age of 42.6 years. The mean eGFR and median proteinuria levels at baseline were 70.4 ml/min/1.73 m2 and 1.04 g/24 h, respectively, and mean serum C3 was 114.9 mg/dL.¹

During a median follow-up of 54.28 months, the low baseline C3 group had a greater incidence of the primary outcome (16.1 events; 95% CI, 7.0–36.1 × 100 pts/year) as compared with the medium (2.7 events; 95% CI, 1.3–6.0 × 100 pts/year) and high (1.7 events; 95% CI, 0.2–11.8 × 100 pts/year) groups, with a statistically significant difference between groups (P = .003).¹

Investigators used 2 reference models to construct new models incorporating baseline C3 and C4 values. Model 1 included the main clinical variables of CKD progression (age, gender, systolic blood pressure, eGFR, and 24-hour urine protein) while Model 3 included variables from the International IgA nephropathy prediction tool (age, systolic and diastolic blood pressure, eGFR, 24-hour urine protein, and MEST-score). Model 2 and Model 4 were built by adding baseline C3 and C4 to Model 1 and Model 3, respectively.¹

In Model 1, lower eGFR (Odds ratio [OR], 0.95; CI, 0.92–0.99; P = .006) and greater 24-hour urine protein (OR, 1.39; CI, 1.08–1.79; P = .008) were associated with a greater risk of the outcome, while there was no correlation with sex, age, and systolic blood pressure. In Model 2, higher 24-hour urine protein and lower eGFR still predicted a worse outcome, and both lower C3 (OR, 0.94; CI, 0.89–0.94; P = .029) and elevated C4 (OR, 1.12; CI, 1.01–1.25; P = .031) were also associated with the outcome. Comparison of the models revealed lower values of both akaike information criterion (54.9 vs 64.1) and bayesian information criterion (75.2 vs 81.3), higher discrimination (c-index 0.73 vs 0.63), and higher nagelkerke R square (67% vs 50%) with Model 2 compared to Model 1 (P = .003).¹

In Model 3, 24-hour urine protein (OR, 1.62; CI, 1.12–5.21; P = .018) was associated with the outcome. In Model 4, 24-hour urine protein (OR, 2.32; CI, 1.12–4.78; P = .022), age (OR, 1.30; CI, 1.01–1.56; P = .045), and C3 (OR, 0.91; CI, 0.83–0.99; P = .049) showed an association with outcome. Investigators noted C4 had a positive relation with the outcome, although it was not statistically significant (OR, 1.19; CI, 0.99–1.45; P = .058). Model 4 had a lower akaike information criterion (39.9 vs 44.8) and bayesian information criterion (66.0 vs 75.4) than Model 3, along with a higher c-index (0.77 vs 0.67) and nagelkerke R square (0.77 vs 0.68) (P = .009).¹

“At present, serum complement C3 and C4 levels could be useful as markers to screen the more ‘Complement-pathic’ subset of patients in IgAN,” investigators concluded.¹ “Integrating these markers into existing prognostic scores could enhance outcome prediction accuracy and optimize risk stratification in order to choose the best-tailored therapies for our patients."

References

1. ^{Tringali E, Vetrano D, Tondolo F, et al. Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy. Sci Rep 14, 16224 (2024). https://doi.org/10.1038/s41598-024-65857-w}
2. ^{National Institute of Diabetes and Digestive and Kidney Diseases. IgA Nephropathy. Health Information. September 2022. Accessed July 23, 2024. https://www.niddk.nih.gov/health-information/kidney-disease/iga-nephropathy}