The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression

Zhao, Na; Hou, Ping; Lv, Jicheng; Moldoveanu, Zina; Li, Yifu; Kiryluk, Krzysztof; Gharavi, Ali G.; Novák, Jan; Zhang, Hong

doi:10.1038/ki.2012.197

Cited by 187 publications

(151 citation statements)

References 45 publications

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“…The pattern of IgA1 glycosylation and the molecular mass of IgA1-containing immune complexes are important factors that determine the ability of IgA1 to activate the different complement pathways (27). It was recently shown that elevated serum levels of galactose-deficient IgA1 are associated with a poor prognosis in IgAN (28). Whether the IgA1 glycosylation pattern of patients who show a positive staining for C4d is different from that of C4d negative patients is unknown.…”

Section: Discussionmentioning

confidence: 99%

Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

Espinosa¹,

Ortega²,

Sánchez³

et al. 2014

Clinical Journal of the American Society of Nephrology

171

156

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Background and objectives Several studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-toperform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN.Design, setting, participants, & measurements This retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival.Results There were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P,0.001). Independent risk factors associated with ESRD were as follows: proteinuria (hazard ratio [HR] per every 1 g/d increase. 1.16; 95% confidence interval [95% CI], 1.03 to 1.31; P=0.01), eGFR (HR per every 1 ml/min per 1.73 m 2 increase, 0.96; 95% CI, 0.94 to 0.97; P,0.001), T2 Oxford classification (tubular atrophy/ interstitial fibrosis, .50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01).Conclusions C4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.

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Section: Discussionmentioning

confidence: 99%

Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

Espinosa¹,

Ortega²,

Sánchez³

et al. 2014

Clinical Journal of the American Society of Nephrology

171

156

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“…42,43 Briefly, F(ab') 2 fragments of goat anti-human IgA (Jackson ImmunoResearch Laboratories, West Grove, PA) were coated onto high-binding MaxiSorp 96-well plates (Nalge-Nunc, Rochester, NY) at 4°C overnight. After blocking with 1% BSA (Sigma-Aldrich, St. Louis, MO), 2-fold dilutions (from 1:2000 to 1:16,000) of serum samples and standards were added and incubated overnight at room temperature.…”

Section: Assay For Gd-iga1mentioning

confidence: 99%

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Zhu

Zhai

Wang

et al. 2015

Journal of the American Society of Nephrology

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Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q32 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1Δ) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations. Group 1 included 1178 subjects with IgAN and available genome-wide association study data. Group 2 included 365 subjects with IgAN and available clinical follow-up data. In group 1, rs6677604 was associated with mesangial C3 deposition by genotype-phenotype correlation analysis. In group 2, we detected a linkage between the rs6677604-A allele and CFHR3-1Δ and found that the rs6677604-A allele was associated with higher serum levels of CFH and lower levels of the complement activation split product C3a. Furthermore, CFH levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition. Moreover, serum levels of the pathogenic galactose-deficient glycoform of IgA1 were also associated with the degree of mesangial C3 deposition in patients with IgAN. Our findings suggest that genetic variants in CFH, CFHR3, and CFHR1 affect complement activation and thereby, predispose patients to develop IgAN.

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“…Hence the presence of abnormally glycosylated IgAs does not "per se" justify the mesangial lesions and that other factors should be associated. Recent studies suggest that auto antibodies recognizing the abnormally glycosylated IgA1s are essential in the pathogenesis of the disease [58,59] . These findings document that IgAN is an autoimmune disease due to the mesangial deposition of immunocomplexes containing GdpIgA1.…”

Section: Salvadori M Et Al Pathophysiology Of Nephropathymentioning

confidence: 99%

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

Salvadori

Rosso

2015

WJN

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Immunoglobulin A (IgA) nephropathy is one of the most common glomerulonephritis and its frequency is probably underestimated because in most patients the disease has an indolent course and the kidney biopsy is essential for the diagnosis. In the last years its pathogenesis has been better identified even if still now several questions remain to be answered. The genetic wide association studies have allowed to identifying the relevance of genetics and several putative genes have been identified. The genetics has also allowed explaining why some ancestral groups are affected with higher frequency. To date is clear that IgA nephropathy is related to auto antibodies against immunoglobulin A1 (IgA1) with poor O-glycosylation. The role of mucosal infections is confirmed, but which are the pathogens involved and which is the role of Toll-like receptor polymorphism is less clear. Similarly to date whether the disease is due to the circulating immunocomplexes deposition on the mesangium or whether the antigen is already present on the mesangial cell as a "lanthanic" deposition remains to be clarified. Finally also the link between the mesangial and the podocyte injury and the tubulointerstitial scarring, as well as the mechanisms involved need to be better clarified.

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The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression

Cited by 187 publications

References 45 publications

Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

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