Relationship Between Serum C3/C4 Ratio and Prognosis of Immunoglobulin A Nephropathy Based on Propensity Score Matching
Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and a leading cause of end-stage renal disease (ESRD). Characterized by IgA deposition in the glomerular mesangium, IgAN exhibits highly variable clinical outcomes, ranging from mild proteinuria to rapid progression to ESRD. Despite established clinical risk factors such as hypertension, proteinuria, and impaired renal function, the role of complement system activation in IgAN pathogenesis and prognosis remains a subject of debate. This study investigates the prognostic value of the serum complement 3-to-complement 4 (C3/C4) ratio in IgAN, leveraging propensity score matching (PSM) to minimize confounding factors and clarify its association with clinical and histopathological features.
Study Design and Methodology
A retrospective cohort of 397 patients with biopsy-proven IgAN was analyzed. Participants were enrolled from January 2007 to December 2012 at the Chinese People’s Liberation Army General Hospital. Inclusion criteria mandated age ≥18 years, ≥8 glomeruli in biopsy specimens, and baseline estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m². Exclusion criteria encompassed secondary IgAN, coexisting glomerular diseases, immunosuppressive therapy within six months prior to biopsy, abnormal liver function, and insufficient follow-up data.
Clinical parameters recorded at biopsy included demographics, blood pressure, 24-hour urinary protein excretion (24h-Upre), serum creatinine (SCr), uric acid (UA), albumin, liver enzymes, lipid profiles, hemoglobin, and serum immunoglobulin and complement levels. Histopathological scoring followed the Oxford classification, assessing mesangial hypercellularity (M), endocapillary proliferation (E), segmental sclerosis (S), tubular atrophy/interstitial fibrosis (T), crescents (C), and global glomerulosclerosis (G). The primary endpoint was progression to ESRD, defined as eGFR <15 mL/min/1.73 m² or initiation of renal replacement therapy.
Statistical analyses evaluated correlations between the C3/C4 ratio and clinical-histopathological variables. Patients were stratified by C3/C4 quartiles, with the first quartile (C3/C4 <3.6) designated as the low-ratio group. Propensity score matching (1:1) balanced baseline characteristics between this group and controls (C3/C4 ≥3.6). Multivariate Cox regression and Kaplan-Meier survival analyses assessed renal outcomes.
Key Findings
Baseline Characteristics and Complement Profile
Among 397 patients, the median follow-up was 75 months, with 62 patients (15.6%) progressing to ESRD. Baseline serum C3 levels were normal in 80.3% of patients, while 4.3% exhibited elevated C4. The median C3/C4 ratio was 4.3 (interquartile range: 3.6–5.1). Patients with lower ratios (C3/C4 <3.6) demonstrated significantly higher SCr (104.9 vs. 88.5 µmol/L), UA (411.1 vs. 367.3 µmol/L), and 24h-Upre (1.8 vs. 1.1 g/24h) compared to higher-ratio groups (all P<0.05). Chronic histopathological lesions, notably severe tubular atrophy (T1+T2: 59.2% vs. 43.5%) and global glomerulosclerosis (G3+G4: 51.0% vs. 37.1%), were more prevalent in the low-ratio cohort (P<0.05).
Correlation Between C3/C4 Ratio and Disease Severity
The C3/C4 ratio inversely correlated with SCr (r=−0.251), UA (r=−0.158), 24h-Upre (r=−0.142), and histopathological markers of chronicity (G: r=−0.135; T: r=−0.162; P<0.01). Conversely, it positively correlated with eGFR (r=0.256), serum IgG (r=0.141), and albumin (r=0.163; P<0.01). These associations underscored the ratio’s reflection of both glomerular filtration capacity and chronic kidney injury.
Survival Analysis and Prognostic Value
Kaplan-Meier survival curves revealed stark outcome disparities across C3/C4 quartiles. Patients with C3/C4 <3.6 exhibited 10-year renal survival rates of 46.4%, compared to 83.7% in the highest quartile (C3/C4 ≥5.1). Unadjusted Cox regression identified the C3/C4 ratio as a significant predictor of ESRD (HR=0.700; 95% CI: 0.561–0.874; P=0.002). However, multivariate adjustment attenuated this association, with only SCr (HR=1.008), 24h-Upre (HR=1.226), and glomerulosclerosis (HR=1.859) retaining independence (P<0.01).
To address baseline imbalances, PSM yielded 88 matched pairs. Post-matching, the low-ratio group maintained a 25.0% ESRD incidence versus 6.8% in controls (P=0.002). Adjusted Cox models confirmed the C3/C4 ratio as an independent risk factor (HR=0.587; 95% CI: 0.329–0.880; P=0.010), alongside SCr, proteinuria, and histopathological damage.
Mechanistic and Clinical Implications
Complement activation via the lectin and alternative pathways is central to IgAN pathogenesis. While serum C3 and C4 levels often remain within normal ranges, their ratio may better capture dynamic shifts in complement consumption. A low C3/C4 ratio suggests disproportionate C4 elevation relative to C3, potentially indicating sustained classical pathway activation or impaired C3 synthesis. This imbalance correlates with advanced glomerulosclerosis and tubulointerstitial fibrosis, hallmarks of progressive disease.
The study’s propensity-matched analysis mitigates confounding by indication, reinforcing the C3/C4 ratio’s robustness as a prognostic marker. Clinically, integrating this ratio with established predictors (e.g., proteinuria, eGFR) could refine risk stratification and guide therapeutic decisions. For instance, patients with C3/C4 <3.6 may benefit from intensified immunosuppression or complement-targeted therapies, though prospective validation is needed.
Limitations and Future Directions
This single-center retrospective design limits generalizability, and unmeasured confounders (e.g., genetic factors, environmental exposures) may persist despite PSM. Serial complement measurements during follow-up could elucidate temporal trends, while mechanistic studies should clarify whether the C3/C4 ratio reflects complement consumption, synthesis, or alternative pathway regulation.
Conclusion
In IgAN, a reduced serum C3/C4 ratio signifies more severe clinical manifestations and chronic histological injury, independently predicting ESRD risk. This ratio offers incremental prognostic value beyond traditional markers, emphasizing the interplay between complement dysregulation and disease progression. Future studies should explore its utility in guiding personalized treatment and monitoring therapeutic responses.
doi.org/10.1097/CM9.0000000000000674
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