Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy

Wu, Jianzhong; Hu, Zhizhi; Wang, Yuxi; Hu, Danni; Yang, Qian; Li, Yueqiang; Dai, Wei; Zhu, Fan; Yang, Juan; Wang, Meng; Zhu, Han; Liu, Liu; He, Xiaofeng; Han, Min; Yao, Ying; Pei, Guangchang; Zeng, Rui; Xu, Gang

doi:10.1111/his.14318

Cited by 23 publications

(17 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The genotype–phenotype analysis in this study showed that patients with IgAN with the rs12614-T allele presented with high serum C3 levels and less intense mesangial C3 deposition, which were indicators of mild complement activation. Similarly, several studies found that decreased serum C3 levels and intense mesangial C3 deposition could predict the poor prognosis of IgAN ( 32 , 33 ), suggesting that the complement activation may be an essential player in the pathogenesis of IgAN. However, no association was observed between rs12614 and the renal outcome of IgAN, and a longer follow-up time may be needed for further elucidation.…”

Section: Discussionmentioning

confidence: 90%

Functional variant rs12614 in CFB confers a low risk of IgA nephropathy by attenuating complement alternative pathway activation in Han Chinese

et al. 2022

View full text Add to dashboard Cite

Activation of the alternative pathway (AP) of complement is thought to play an important role in Immunoglobin A nephropathy (IgAN). Our previous study showed that rs4151657 within the complement factor B (CFB) gene increased the risk of IgAN. The protein encoded by the CFB gene is an initial factor that promotes AP activation. The aim of this study was to investigate whether other variants of CFB confer susceptibility to IgAN and elucidate their potential roles in AP activation. A total of 1,350 patients with IgAN and 1,420 healthy controls were enrolled and five tag single-nucleotide polymorphisms were selected for genotyping. The levels of key AP components, such as CFB, complement factor H and complement split product C3a, were measured by enzyme-linked immunosorbent assay. Molecular docking and molecular dynamic simulation were carried out to characterize the mutation of residues in the protein structure and the dynamic properties of wide type and mutation models of CFB protein. The allele-specific effect on CFB expression and its binding affinity to C3b were investigated through cell transfection and surface plasmon resonance analysis, respectively. We found that rs12614 significantly reduced the risk of IgAN (OR = 0.69, 95% CI = 0.52–0.91, P = 0.009), and the rs12614-T (R32W mutation) was correlated with lower CFB levels, higher serum C3 level, and less mesangial C3 deposition in patients with IgAN. The structural model showed that the R32W mutation reduced the structural stability of CFB protein. Furthermore, in vitro study revealed that rs12614-T decreased the expression of CFB and reduced its binding affinity to C3b by four-fold compared with rs12614-C. In conclusion, the rs12614-T in CFB was associated with low risk of IgAN probably by attenuating AP activation.

show abstract

Section: Discussionmentioning

confidence: 90%

Functional variant rs12614 in CFB confers a low risk of IgA nephropathy by attenuating complement alternative pathway activation in Han Chinese

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In addition to MPGN, C3 may be deposited in IgAN or MN. When C3 deposition was accompanied by IgAN and MN, the renal outcome was worse in cases with above-moderate C3 dominance [17][18][19]. Therefore, it is necessary to review and reclassify the primary diagnosis; due to practical problems, this should be considered a limitation of the present study.…”

Section: Discussionmentioning

confidence: 87%

Comparison of dominant and nondominant C3 deposition in primary glomerulonephritis

Ryu¹,

Baek²,

Son³

et al. 2023

Kidney Res Clin Pract

View full text Add to dashboard Cite

Background: Alternative complement pathway dysregulation plays a key role in glomerulonephritis (GN) and is associated with C3 deposition. Herein, we examined pathological and clinical differences between cases of primary GN with C3-dominant (C3D-GN) and nondominant (C3ND-GN) deposition. Methods: We extracted primary GN data from the Korean GlomeruloNEphritis sTudy (KoGNET). C3D-GN was defined as C3 staining two grades greater than C1q, C4, and immunoglobulin via immunofluorescence analysis. To overcome a large difference in the number of patients between the C3D-GN and C3ND-GN groups (50 vs. 13,070), permutation testing was used for analysis.Results: The C3D-GN group exhibited higher serum creatinine (p ≤ 0.001), a greater prevalence of estimated glomerular filtration rate of <60 mL/min/1.72 m2 (p ≤ 0.001), higher (but not significantly so) C-reactive protein level, and lower serum C3 level (p ≤ 0.001). Serum albumin, urine protein/creatinine ratio, number of patients who progressed to end-stage renal disease, and all-cause mortality were comparable between groups. Interstitial fibrosis and mesangial cellularity were greater in the C3D-GN group (p = 0.04 and p = 0.01, respectively) than in the C3ND-GN group. C3 deposition was dominant in the former group (p < 0.001), in parallel with increased subendothelial deposition (p ≤ 0.001). Conclusion: Greater progression of renal injury and higher mortality occurred in patients with C3D-GN than with C3ND-GN, along with pathologic differences in interstitial and mesangial changes.

show abstract

“…In IgA nephropathy, complement activation is widespread, as evidenced by approximately 90% patients with glomerular C3 deposition. 7,38 Recent novel therapies targeting complement activation showed promising effects in IgA nephropathy. 11,39,40 Glomerular complement activation in IgA nephropathy is also influenced by multiple factors and mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Mesangial C3 Deposition, Complement-Associated Variant, and Disease Progression in IgA Nephropathy

Kang,

Xu,

Shi

et al. 2023

CJASN

View full text Add to dashboard Cite

Background: IgA nephropathy is the most common primary glomerulonephritis worldwide, with dominant deposition of IgA and co-deposits of complement component 3 (C3). Phenotypes and progression of IgA nephropathy varies among different ethnic populations, while IgA nephropathy patients from Asian showed more severe clinical phenotypes, active kidney lesions, and rapid progression. Our previous genome-wide association study identified complement factor H variant rs6677604, tightly linked with the deletion of complement factor H-related protein 3 and complement factor H-related protein 1 genes (ΔCFHR3-1), as IgA nephropathy susceptible variant, and additionally revealed its effect on complement regulation in IgA nephropathy. Methods: To further explore the effect of rs6677604 on IgA nephropathy progression, here we enrolled a Chinese IgA nephropathy cohort of 1781 patients with regular follow-up for analysis. The rs6677604 genotype was measured, and the genotype-phenotype correlation was analyzed using t-test, Chi-squared test, or nonparametric test, as well as the association between rs6677604 genotype or mesangial C3 deposition and IgA nephropathy prognosis was analyzed using Kaplan–Maier analysis and Cox regression. Results: We found that patients with rs6677604-GG genotype had a stronger intensity of mesangial C3 deposition than those with the rs6677604-AA/AG genotype. Patients with IgA nephropathy who had stronger intensity of C3 deposition manifested with more severe clinical and pathological manifestations, including lower eGFR and higher Oxford-M/S/T/C scores. In the survival analysis, stronger intensity of mesangial C3 deposition, but not rs6677604-GG genotypes, was associated with poor long-term kidney outcome in IgA nephropathy. Conclusions: We found that in Chinese patients with IgA nephropathy, variant rs6677604 was associated with mesangial C3 deposition, and mesangial C3 deposition, but not rs6677604, was associated with IgA nephropathy severity and progression.

show abstract

Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy

Cited by 23 publications

References 36 publications

Functional variant rs12614 in CFB confers a low risk of IgA nephropathy by attenuating complement alternative pathway activation in Han Chinese

Functional variant rs12614 in CFB confers a low risk of IgA nephropathy by attenuating complement alternative pathway activation in Han Chinese

Comparison of dominant and nondominant C3 deposition in primary glomerulonephritis

Mesangial C3 Deposition, Complement-Associated Variant, and Disease Progression in IgA Nephropathy

Contact Info

Product

Resources

About