C3 Staining, Serum IgA/C3 May Aid Treatment, Prediction of Renal Outcomes in IgAN

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Findings from a recent study are highlighting the importance of considering both the serum IgA/C3 ratio and glomerular C3 staining when predicting renal outcomes and guiding treatment decisions for adult patients with IgA nephropathy (IgAN).¹

Results showed patients with serum IgA/C3 ≥ 2.806 and C3 staining ≥ 2 had worse outcomes, further identifying hypertension, serum creatinine, chronic kidney disease (CKD) stage, T1/2, and C3 staining as independent predictive factors of renal survival, all of which may inform an improved prognostic model for IgAN patients and allow for personalized treatment approaches.¹

One of the leading causes of glomerulonephritis and renal failure, IgAN is an autoimmune disease causing antibody-mediated destruction of the glomerular basement membrane. Its pathophysiology is poorly understood, and although some patients experience a benign disease course, others progress to end-stage renal disease (ESRD). Stratification and treatment are difficult due to its broad clinical presentation, highlighting the need for a viable prognostic tool for predicting outcomes.²

“The serum IgA/C3 ratio and glomerular C3 staining may have a likely impact on adult IgAN patients, but no study has proven this,” Dandan Yang, of West China Hospital at Sichuan University in China, and colleagues wrote.¹ “Thus, we speculated that this study could provide more exact evidence for the predictive outcomes of IgAN by using a combination of the serum IgA/C3 ratio and glomerular C3 staining.”

To assess the predictive value of the serum IgA/C3 ratio and glomerular C3 deposits in kidney biopsy in adult IgAN, investigators respectively enrolled adult patients with newly diagnosed, biopsy-proven IgAN at West China Hospital from December 2007 - February 2020. For inclusion, patients were required to have ≥ 12 months of follow-up data; predominance of IgA deposits in the glomerular mesangium by renal biopsy pathology; and complete serum IgA, serum C3, and pathological glomerular C3 staining data.¹

A total of 718 eligible patients were included in the study. Among the cohort, the majority (57%) were female and the mean age was 34.04±11.09 years. Investigators divided patients into 2 groups based on their proteinuria range: proteinuria >3.5 g and proteinuria ≤3.5 g.¹

Additionally, serum IgA and C3 were measured using the immunoturbidimetry method at baseline, and the serum IgA/C3 ratio was calculated to apply a receiver operating characteristic curve (ROC)-based cutoff ratio, 2.806, which had optimal sensitivity (63.9%) and specificity (58.7%) for both proteinuria groups. The composite endpoint was a renal function decline of >50% in estimated glomerular filtration rate (eGFR), ESRD, and/or death.¹

Upon analysis, the difference in prognosis between the serum IgA/C3 ≥2.806 group and the serum IgA/C3 <2.806 group was not statistically significant (P = .656). Similar results were also found between the C3 staining ≥2 group and the C3 staining <2 group (P = .582), suggesting the serum IgA/C3 ratio or C3 staining is not an independent protective factor for the prognosis of IgAN.¹

All 718 patients were classified into 4 groups according to serum IgA/C3 ratio and glomerular C3 staining in order to better understand the relationship between the risk factors C3 staining and serum IgA/C3 ratio: Group 1 (serum IgA/C3 ≥2.806 and C3 staining ≥2) (n = 250), Group 2 (serum IgA/C3 ≥2.806 and C3 staining <2) (n = 174), Group 3 (serum IgA/C3 <2.806 and C3 staining ≥2) (n = 128) and Group 4 (serum IgA/C3 <2.806 and C3 staining <2) (n = 166).¹

Investigators noted when the serum IgA/C3 ratio was at the same level, patients with a glomerular C3 staining score ≥2 always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis. When glomerular C3 staining was at the same level, proteinuria was significantly increased in patients with serum IgA/C3 <2.806. Investigators also pointed out serum creatinine was significantly lower and eGFR was higher in Group 4 compared to Group 1.¹

Further analysis revealed patients with serum IgA/C3 ≥2.806 and C3 staining ≥2 seemed to have worse outcomes (Group 1 vs Group 2; P = .083). Additionally, male IgAN patients in Group 2 had statistically significantly better outcomes as opposed to females in Group 2, who had significantly poorer outcomes compared to Group 4 (P = .027). Investigators pointed out the renal survival rate also significantly differed between Group 2 and Group 3 in IgAN patients with CKD stage 1-2 and receiving support treatments.¹

Further renal survival analysis indicated serum IgA/C3 ≥2.806 and glomerular C3 staining ≥2 (Group 1) may be correlated with a poorer prognosis, especially in different clinicopathological characteristics of IgAN patients. Multivariate Cox analysis revealed hypertension, serum creatinine, CKD stage, T1/2, and C3 staining were independent predictive factors of renal survival.¹

“The combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease,” investigators concluded.¹

References:

1. ^{Yang D, Pei G, Wang S, Qin A, Tang Y, Qin W. Combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in adult IgA nephropathy. Kidney Blood Press Res. Published online February 21, 2024. doi:10.1159/000536114}
2. ^{Rawla P, Limaiem F, Hashmi MF. IgA Nephropathy (Berger Disease). StatPearls. July 7, 2023. Accessed March 20, 2024. https://www.ncbi.nlm.nih.gov/books/NBK538214/}