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Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin-Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H-Related Protein-5 (FHR5) Deposition.

ABSTRACT: Introduction:IgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury. Methods:To elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN. Results:M-ficolin, L-ficolin, mannan-binding lectin (MBL)-associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H-related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN. Conclusion:Our data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity.

SUBMITTER: Medjeral-Thomas NR

PROVIDER: S-EPMC5932138 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin-Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H-Related Protein-5 (FHR5) Deposition.

Medjeral-Thomas Nicholas R NR Troldborg Anne A Constantinou Nicholas N Lomax-Browne Hannah J HJ Hansen Annette G AG Willicombe Michelle M Pusey Charles D CD Cook H Terence HT Thiel Steffen S Pickering Matthew C MC

Kidney international reports 20171129 2

<h4>Introduction</h4>IgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury.<h4>Methods</h4>To elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN.<h4>Results</h4>M-ficolin, L-ficolin, ma ...[more]

PMID: 29725647

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Project description:ObjectiveWe aimed to explore the relationship between the presence and intensity of glomerular IgG deposition and the occurrence of kidney progression events in IgA nephropathy (IgAN).MethodsThis retrospective study encompassed a total of 1207 patients with IgAN spanning the period from 2010 to 2022, and complete follow-up data were accessible for 736 patients. The IgG intensity was categorized as follows: low-level, defined as IgG (±) and IgG (+), and high-level, defined as IgG (++) and IgG (+++).ResultsWe found that the IgG-positive deposited group (N = 113, 9.36%) had significantly higher levels of ESR, TC, LDL, uric acid, proteinuria, and blood glucose, and lower serum albumin level compared to the IgG-negative deposited group (N = 1094, 90.64%). In terms of pathology, the IgG-positive deposited group had a significantly higher percentage of T2 score compared to the IgG-negative deposited group (p = 0.002). At the end of the follow-up period, the IgG-positive deposited group had a higher eGFR decline (-5.7 ± 4.37 ml/year) compared to the IgG-negative deposited group (-4 ± 2.52 ml/year), however, there was not a statistically significant difference between the two groups (p = 0.096). We observed that the high-IgG group had significantly higher level of TG compared to the low-IgG group (p = 0.042). Further analysis revealed that the group of patients with high level of IgG deposition in the kidney experienced a higher incidence of composite kidney outcomes compared to the group with low level of IgG deposition (p = 0.009). Logistic regression analyses showed that high level IgG deposition was an independent risk factor for kidney progression of IgAN (HR 13.419; 95% CI 2.690-66.943, P = 0.029). Further analyses for a solid conclusion using Cox regression that we found high level IgG deposition (HR 115.277; 95% CI 2.299-5.779E3, P = 0.017), eGFR (HR 0.932; 95% CI 0.870-0.999, P = 0.047), and urine protein excretion (HR 1.001; 95% CI 1.000-1.002, P = 0.015) were independent risk factor for kidney progression of IgAN.ConclusionsThe intensity of IgG deposition has been found to be associated with the progression of IgAN. Future prospective studies should provide more robust evidence on the impact of IgG deposition on kidney outcomes in patients with IgAN.

Project description:BackgroundGlomerular deposition of C4d is a widely used biomarker for activation of the lectin pathway in the complement system and is reported to be associated with kidney progression in immunoglobulin A nephropathy (IgAN). The aim of this study was to evaluate whether glomerular C4d deposition, as a new biomarker, improves the prediction of kidney prognosis in IgAN.Study designSystematic review and meta-analysis.Setting & populationPatients with biopsy-proven primary IgAN without age limitations.Selection Criteria for Studies: Cross-sectional or cohort studies reporting the prevalence of glomerular C4d deposition or evaluating its association with IgAN progression.PredictorGlomerular C4d deposition.OutcomeComposite progression event of a >30% decline in estimated glomerular filtration rate or end-stage kidney disease.Results12 studies with 1,251 patients were included. The prevalence of glomerular C4d deposition was 34% (95% CI, 27%-41%), with large heterogeneity (I 2 = 86%; P < 0.001). Patients with C4d deposition had lower estimated glomerular filtration rates (mean difference [MD], -11.48; 95% CI, -18.27 to -4.70; P < 0.001) as well as higher urinary protein-creatinine ratios (MD, 0.87; 95% CI, 0.53-1.21; P < 0.001) or 24-hour urinary protein excretion (MD, 0.99; 95% CI, 0.50-1.47; P < 0.001) and higher risk for hypertension (relative risk [RR], 1.45; 95% CI, 1.06-1.99; P = 0.02) than patients without C4d deposition. Glomerular C4d deposition was associated with a high Oxford classification score, including M1, E1, S1, and T1/2 lesions (all P ≤ 0.006). Patients with C4d deposition had higher rates of use of renin-angiotensin system blockers and immunosuppressants. Glomerular C4d was found to be a risk factor for the composite kidney event (RR, 3.17; 95% CI, 2.29-4.40; P < 0.001; adjusted HR, 2.05; 95% CI, 1.53-2.76; P < 0.001) and end-stage kidney disease (RR, 4.37; 95% CI, 3.15-6.07; P < 0.001) without evidence of heterogeneity.LimitationsThe definition of positive C4d was not uniform and not all studies provided data about kidney outcomes.ConclusionsGlomerular C4d deposition is associated with an adverse prognosis and may be a useful biomarker of disease prediction in IgAN.

Dataset Information

Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin-Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H-Related Protein-5 (FHR5) Deposition.

Publications

Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin-Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H-Related Protein-5 (FHR5) Deposition.

Similar Datasets

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