Dataset Information

Significance of urinary full-length megalin in patients with IgA nephropathy.

ABSTRACT:

Background and objectives

Megalin is highly expressed at the apical membranes of proximal tubular epithelial cells. A urinary full-length megalin (C-megalin) assay is linked to the severity of diabetic nephropathy in type 2 diabetes. This study examined the relationship between levels of urinary C-megalin and histological findings in adult patients with IgA nephropathy (IgAN).

Design, setting, participants, & measurements

Urine samples voided in the morning on the day of renal biopsy were obtained from 73 patients with IgAN (29 men and 44 women; mean age, 33 years) and 5 patients with membranous nephropathy (MN). Renal pathologic variables were analyzed using the Oxford classification of IgAN, the Shigematsu classification and the Clinical Guidelines of IgAN in Japan. The levels of urinary C-megalin were measured by sandwich ELISA.

Results

Histological analysis based on the Oxford classification revealed that the levels of urinary C-megalin were correlated with mesangial hypercellularity in IgAN patients (OR?=?1.76, 95% CI: 1.04-3.27, P<0.05). There was a significant correlation between the levels of urinary C-megalin and the severity of chronic extracapillary abnormalities according to the Shigematsu classification in IgAN patients (??=?0.33, P?=?0.008). The levels of urinary C-megalin were significantly higher in all risk levels of IgAN patients requiring dialysis using the Clinical Guidelines of IgAN in Japan than in the control group. The levels of urinary C-megalin were significantly higher in the high risk and very high risk grades than in the low risk grade (P<0.05). The levels of urinary C-megalin were significantly higher in MN patients compared to the control group.

Conclusions

The levels of urinary C-megalin are associated with histological abnormalities in adult IgAN patients. There is a possibility that urinary C-megalin is an independent predictor of disease progression of IgAN. In addition, our results suggest that urinary C-megalin is a marker of glomerular abnormalities in various glomerular diseases as well as IgAN.

SUBMITTER: Seki T

PROVIDER: S-EPMC4264761 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Significance of urinary full-length megalin in patients with IgA nephropathy.

Seki Takuto T Asanuma Katsuhiko K Asao Rin R Nonaka Kanae K Sasaki Yu Y Oliva Trejo Juan Alejandro JA Kurosawa Hiroyuki H Hirayama Yoshiaki Y Horikoshi Satoshi S Tomino Yasuhiko Y Saito Akihiko A

PloS one 20141212 12

<h4>Background and objectives</h4>Megalin is highly expressed at the apical membranes of proximal tubular epithelial cells. A urinary full-length megalin (C-megalin) assay is linked to the severity of diabetic nephropathy in type 2 diabetes. This study examined the relationship between levels of urinary C-megalin and histological findings in adult patients with IgA nephropathy (IgAN).<h4>Design, setting, participants, & measurements</h4>Urine samples voided in the morning on the day of renal bio ...[more]

PMID: 25502002

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Project description:Subepithelial deposits are observed in rare adult IgA nephropathy (IgAN) cases and are a key diagnostic finding in IgA-dominant infection-related glomerulonephritis (IgA-IRGN). Sometimes, it is difficult to distinguish IgA-IRGN from IgAN without a precise clinical history. We hypothesized that some IgA-IRGN cases might be diagnosed as IgAN with subepithelial deposits (IgAN-SD) and aimed to clarify the significance of subepithelial deposits in patients diagnosed with IgAN. We examined 464 patients diagnosed with IgAN at Nagasaki University Hospital and affiliated hospitals between 1996 and 2013. The differences in clinicopathological findings between IgAN-SD and IgAN with no subepithelial deposits (IgAN-NSD) were investigated. In addition to clinical data and typical IgAN pathological features, we analyzed complement levels, immunoglobulin localization, light chain staining patterns, and intramembranous deposits. There were 214 men and 250 women with a mean age of 38.8 ± 18.3 years. Subepithelial deposition was observed in 51 patients (11%). Compared to patients with IgAN-NSD, those with IgAN-SD had significantly lower mean serum protein (6.4 g/dL vs. 6.7 g/dL; p = 0.02), albumin (3.7 g/dL vs. 3.9 g/dL; p = 0.02), and complement (C3) (94 mg/dL vs. 103 mg/dL; p = 0.02) levels. Diffuse mesangial hypercellularity (M) (65% vs. 45%; p<0.01), endocapillary hypercellularity: (E) (43% vs. 28%; p = 0.03), and IgA staining in the glomerular capillary wall (22% vs. 8%; p<0.01) were more common in patients with IgAN-SD. The incidence of light chain lambda predominance was lower in patients with IgAN-SD (47% vs. 63%; p = 0.03). Hump-shaped subepithelial deposits and intramembranous deposits were observed in nine and 17 patients with IgAN-SD, respectively. Patients with IgAN-SD tended to have the characteristics of IgA-IRGN rather than IgAN-NSD. Since the therapeutic strategies for IgA-IRGN differ from those for IgAN, we should review the clinical history and pay careful attention to the clinical course in cases with atypical findings, such as subepithelial deposits.

Project description:IntroductionGalactose-deficient IgA1 (Gd-IgA1) is a critical pathogenic factor for IgA nephropathy (IgAN), but its value as a disease-specific biomarker remains controversial. We aimed to clarify the clinical significance of Gd-IgA1 in patients with IgAN.MethodsWe retrospectively reviewed 111 patients who were diagnosed with IgAN based on the findings of renal biopsies (RB) at Showa University Hospital since 2007. Serum Gd-IgA1 (s-Gd-IgA1) at the time of RB was compared among 111 IgAN patients, 18 Henoch-Schönlein purpura nephritis (HSPN) patients, 29 lupus nephritis (LN) patients, 28 ANCA-associated vasculitis (AAV) patients, and 13 minimal change disease (MCD) patients using ELISA with an anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for mesangial Gd-IgA1 (m-Gd-IgA1) deposition using KM55.ResultsAlthough levels of s-Gd-IgA1 were comparable among IgAN and HSPN, s-Gd-IgA1 levels were significantly elevated in patients with IgAN compared with LN, AAV and MCD (IgAN vs. HSPN, LN, AAV, and MCD: 16.2 ± 9.1 vs. 14.2 ± 10.8, p = 0.263; 12.7 ± 9.4, p = 0.008; 13.1 ± 7.3, p = 0.059; and 8.2 ± 4.8 μg/mL, p<0.001, respectively). Mesangial-Gd-IgA1 deposition was specifically detected in IgAN or HSPN. The increase in s-Gd-IgA1 significantly correlated with m-Gd-IgA1 positivity in patients with IgAN, and s-Gd-IgA1 elevation and m-Gd-IgA1 deposition were evident in patients with histopathologically advanced IgAN. Moreover, s-Gd-IgA1 levels were significantly higher in IgAN patients with glomerular sclerosis and tubulo-interstitial lesions. Mesangial-Gd-IgA1 intensity negatively correlated with eGFR in IgAN. Multivariate analysis selected s-Gd-IgA1 elevation as a significant risk factor for a 30%-reduction in eGFR in IgAN (HR, 1.37; 95% CI, 1.02-1.89; p = 0.038).ConclusionsAlthough IgAN and HSPN remain difficult to differentiate, s-Gd-IgA1 elevation and m-Gd-IgA1 deposition are reliable diagnostic factors that reflect IgAN severity. Serum-Gd-IgA1 could serve as a predictor of renal outcomes in IgAN. Thus, Gd-IgA1 could be significant biomarker for patients with IgAN.

Project description:BackgroundIgA nephropathy (IgAN) is one of the most common forms of idiopathic glomerular diseases and might lead to end-stage kidney disease. Accurate and non-invasive biomarkers for early diagnosis are required for early intervention and consequent therapy for IgAN patients. Because variance in the disease incidence and predisposing genes of IgAN has been detected among different ethnicities, the ethnicity factor should be considered in IgAN biomarker discovery. The differences in the protein profiles and pathological mechanisms of IgAN in patients of Uygur ethnicity need to be clearly illustrated.MethodsIn this study, we used urinary proteomics to discover candidate biomarkers of IgAN in patients of Uygur ethnicity. The urinary proteins from Uygur normal control and Uygur IgAN patients were extracted and analyzed using 2D-LC-MS/MS and isobaric tags for relative and absolute quantitation (iTRAQ) analysis.ResultsA total of 277 proteins were found to be differentially represented in Uygur IgAN compared with the respective normal controls. The bioinformatics analysis revealed that the immune response, cell survival, and complement system were activated in Uygur IgAN. Many differentially expressed proteins were found to be related to nephropathy and kidney injuries. Four candidate biomarkers were validated by Western blot, and these results were consistent with the iTRAQ results. ICAM1, TIMP1, SERPINC1 and ADIPOQ were upregulated in Uygur IgAN. Bioinformatic analysis revealed that the increase of ICAM1 and TIMP1 might be caused by IgAN, but the increase of SERPINC1 and ADIPOQ might be caused by proteinuria. SERPINC1 and ICAM1 were identified as the candidate biomarkers with excellent area-under-the-curve (AUC) values (0.84) for distinguishing Uygur IgAN from normal controls.ConclusionsUsing urinary proteomic analysis, we identified several candidate biomarkers for IgAN in patients of Uygur ethnicity. These results will prove helpful for exploring the pathological mechanism of IgAN in patients of Uygur ethnicity and for developing better treatments for these patients.

Dataset Information

Significance of urinary full-length megalin in patients with IgA nephropathy.

Background and objectives

Design, setting, participants, & measurements

Results

Conclusions

Publications

Significance of urinary full-length megalin in patients with IgA nephropathy.

Similar Datasets

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