C4d Independently Predicts Disease Progression in Primary IgA Nephropathy

Nikola Zagorec, MD

Credit: Dubrava Clinical Hospital

C4d may be an independent predictor of disease progression in patients with primary IgA nephropathy (IgAN), according to findings from a recent study.¹

Results suggest that as a tissue marker of complement activation in patients with primary IgAN, C4d can be used as an additional marker of progressive disease course, as it is associated with worse renal survival and disease progression to kidney failure.¹

“Exploring the role of the complement system in the pathogenesis of IgAN is crucial for the development of new therapeutic targets,” Nikola Zagorec, MD, a nephrologist at Dubrava University Hospital in Croatia, and colleagues wrote.¹ “The need for new therapeutic agents is unmet, and soon, this gap could be bridged by complement system-interfering agents. Some of them are already being tested in clinical trials with promising results. However, there are still many unknowns regarding the role of the complement system in the pathogenesis of IgAN and its prognostic implications.”

Among the most active therapeutic pipelines of any rare disease in recent years is that of IgAN, with the latest development being the full FDA approval of sparsentan (Filspari) for reducing the loss of kidney function, making it the second IgAN therapeutic to receive full approval in the US.² With an increased focus on IgAN drug development, interest in the prognostic significance of complement components in IgAN has also grown.¹

To investigate the prevalence and prognostic significance of C4d in primary IgAN, investigators conducted a monocentric cohort study of patients recruited from a hospital register of kidney biopsies from the department of nephrology and dialysis at Dubrava University Hospital from January 2007 to December 2017. For inclusion, patients were required to be registered with a diagnosis of IgA nephropathy/vasculitis; have ≥ 8 glomeruli available for light microscopy; and lack known secondary causes of IgAN.¹

Investigators used the CKD-EPI 2021 equation to estimate patients’ kidney function, defining kidney failure as a permanent decline in eGFR < 15 mL/min/1.73 m2 or the initiation of kidney replacement therapy. Additional immunohistochemistry staining for C4d was performed on paraffin-embedded kidney tissue, and based on these results, patients were classified as being C4d-positive or C4d-negative.¹

After kidney biopsy, patients were treated and followed up in an outpatient clinic. The primary outcome was defined as kidney failure, and predictor variables of kidney failure and renal survival were analyzed.¹

Of 255 patients within the registry with a leading diagnosis of IgAN or IgA vasculitis, 95 satisfied the inclusion criteria and were ultimately included in the final analysis. Among this cohort, the median age at diagnosis (kidney biopsy) was 44.6 (interquartile range [IQR], 32–52.2) years, 71.6% of patients were male, and 45.3% were C4d-positive.¹

Investigators noted C4d-positive patients had significantly higher values of systolic blood pressure (135 vs 130 mmHg; P = .039) and diastolic blood pressure (90 vs 80 mmHg; P = .006) at diagnosis, additionally pointing out greater 24 h proteinuria (2.7 vs 1.5 g/day; P = .018) and serum uric acid levels (P = .033) but lower values of serum IgG (P = .034) and kidney function (53 vs 79 mL/min/1.73 m2; P <.001).¹

During a median follow-up of 102.2 (IQR, 72.1–138.2) months, 17 (17.9%) patients reached kidney failure, including 2 C4d-negative and 15 C4d-positive patients (P <.001). Of those who did not reach kidney failure, C4d-positive patients had greater 24 h proteinuria (1 vs 0.35 g/day; P <.001) and lower eGFR (52 vs 81 mL/min/1.73 m2; P <.001) at the last follow-up.¹

Overall renal survival without kidney failure was 174.9 (143.3 in the C4d-positive group vs 197.9 in the C4d-negative group; log-rank, χ2 = 17; P <.001). Further analysis revealed glomerular C4d was an independent predictor of disease progression to kidney failure (Hazard ratio [HR], 5.87; 95% CI, 1.06–32.44; P = .032).¹

“The presence of C4d in IgAN is associated with worse renal survival and disease progression to kidney failure,” investigators concluded.¹ “Why the lectin pathway of the complement system is activated in only particular patients with IgAN remains to be clarified in further investigations as well as the therapeutic implications of such lectin pathway activation in IgAN.”

References

1. ^{Zagorec N, Horvatić I, Kasumović D, et al. C4d Is an Independent Predictor of the Kidney Failure in Primary IgA Nephropathy. J. Clin. Med. https://doi.org/10.3390/jcm13175338}
2. ^{Brooks, A. FDA Approves Travere Therapeutics’ Sparsentan to Slow Kidney Function Decline in Adult Primary IgAN. HCPLive. September 5, 2024. Accessed September 19, 2024. https://www.hcplive.com/view/fda-approves-travere-therapuetics-sparsentan-for-proteinuria-reduction-in-adult-primary-igan}