Urinary miRNA profile for the diagnosis of IgA nephropathy.
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ABSTRACT:
SUBMITTER: Szeto CC
PROVIDER: S-EPMC6399975 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objectives The activated complement profile in IgA nephropathy (IgAN) is still unclear. Our study investigated the profile of urinary complements in IgAN patients and their correlations with clinical and pathological characteristics. Methods Urinary protein abundance was detected by liquid chromatography-tandem mass spectrometry (LC‒MS/MS) in 50 IgAN, 50 membranous nephropathy (MN), and 68 healthy controls (HCs). Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify differentially expressed proteins in IgAN patients. Compared to HC and MN, differentially expressed complement proteins were screened in IgAN patients, and their correlations with laboratory or pathological parameters were analyzed. Then, 7 complement components were validated by enzyme-linked immunosorbent assay (ELISA) in the urine samples of 45 IgAN patients. Results There were 786 differentially expressed proteins between IgAN and HC. KEGG analysis showed that differentia
2022-11-28 | PXD038451 |
Project description:BACKGROUND:IgA 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. METHODS:In 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. RESULTS:A 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. CONCLUSIONS:Using 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.
| S-EPMC6295011 | biostudies-literature
Project description:Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic kidney disease, nephrolithiasis, and transplant rejection. This validation study uses the KIT Assay to investigate the clinical utility of the non-invasive detection of IgAN and predicting the progression of renal damage over time. The study design benefits from longitudinally collected urine samples from an investigator-initiated, multicenter, prospective study, evaluating the efficacy of corticosteroids versus Rituximab for preventing progressive IgAN. A total of 131 urine samples were processed for this study; 64 urine samples were collected from 34 IgAN patients, and urine samples from 64 demographically matched healthy controls were also collected; multiple urinary biomarkers consisting of cell-free DNA, methylated cell-free DNA, DMAIMO, MAMIMO, total protein, clusterin, creatinine, and CXCL10 were measured by the microwell-based KIT Assay. An IgA risk score (KIT-IgA) was significantly higher in IgAN patients as compared to healthy control (87.76 vs. 14.03, p < 0.0001) and performed better than proteinuria in discriminating between the two groups. The KIT Assay biomarkers, measured on a spot random urine sample at study entry could distinguish patients likely to have progressive renal dysfunction a year later. These data support the pursuit of larger prospective studies to evaluate the predictive performance of the KIT-IgA score in both screening for non-invasive diagnosis of IgAN, and for predicting risk of progressive renal disease from IgA and utilizing the KIT score for potentially evaluating the efficacy of IgAN-targeted therapies.
| S-EPMC6770813 | biostudies-literature
Project description:BACKGROUND:Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis in the world. Reliable biomarkers are required for the non-invasive diagnosis and monitoring of IgAN. This study aims to investigate the difference in urinary exosomal microRNA (miRNA) expression profiles between patients with IgA nephropathy (IgAN) and healthy controls, which may provide clues to identify novel potential non-invasive miRNA biomarkers for renal diseases. METHODS:Urine samples were collected from eighteen healthy controls and eighteen patients with IgAN. Differential centrifugation was performed to isolate exosomes from urine samples. High-throughput sequencing and real-time quantitative polymerase chain reaction (RT-qPCR) were sequentially used to screen and further validate miRNA expression profiles in urinary exosomes of patients with IgAN in two independent cohorts. RESULTS:Urinary exosomes were successfully isolated to obtain exosomal miRNAs. MiR-215-5p and miR-378i were significantly upregulated in urinary exosomes of patients with IgAN compared with healthy controls (P<.01), while miR-29c and miR-205-5p were significantly downregulated (P<.05). MiR-215-5p, miR-378i, miR-365b-3p and miR-135b-5p were found to have altered expression in patients with IgAN from validation cohorts, which was consistent with the high-throughput sequencing analysis. CONCLUSION:This study suggests that there is a significant difference in urinary exosomal miRNA profiles between patients with IgAN and healthy controls. These exosomal miRNAs, such as miR-29c, miR-146a and miR-205 may potentially serve as novel non-invasive biomarkers for IgAN.
| S-EPMC6816951 | biostudies-literature
Project description:Noninvasive biomarkers of disease activity are needed to predict disease remission status in patients with IgA nephropathy (IgAN). Soluble CD163 (sCD163), shed by monocytes and macrophages, is a potential biomarker in diseases associated with excessive macrophage activation. We investigated the association of urinary sCD163 (u-sCD163) with histopathological activity and clinical manifestations in 349 patients with biopsy-diagnosed IgAN. U-sCD163 was measured via enzyme-linked immunosorbent assay. In patients with IgAN, higher u-sCD163 levels were associated with histological lesions of greater severity, as well as more proteinuria and poorer renal function. Additionally, u-sCD163 was correlated with infiltration of tubulointerstitial CD163+ macrophages. High u-sCD163 levels (>3.57 ng/mg Cr) were associated with a 2.66-fold greater risk for IgAN remission failure in adjusted analyses. Adding u-sCD163 levels to the model containing clinical data at biopsy and MEST-C score significantly improved the risk prediction of IgAN remission status (AUC 0.788). Together, our results suggest that u-sCD163 may be a useful noninvasive biomarker to evaluate disease severity and remission status of IgAN.
| S-EPMC8733336 | biostudies-literature
Project description:The miRNAs in urinary sediment are easy to obtain, which provides a new approach to searching for non-invasive biomarkers of IgA nephropathy (IgAN). Compared with normal controls (n?=?3), 214 different miRNAs in the urinary sediment of IgAN (n?=?9) were found by miRNA chip assay. By quantitative PCR analysis, miR-25-3p, miR-144-3p and miR-486-5p were confirmed to be significantly higher in IgAN (n?=?93) than in the normal group (n?=?82) or disease control (n?=?40). These three miRNAs had good specificity and sensitivity for the diagnosis of IgAN by receiver operating characteristic curve analysis, in which the AUC value of miR-486-5p was the largest at 0.935. Urinary sediment miR-25-3p, miR-144-3p and miR-486-5p were demonstrated to be mainly derived from urinary erythrocytes, which were separated by CD235a magnetic beads. The increased expression of urinary erythrocyte miRNAs in IgAN patients was not associated with those in the blood erythrocytes. In addition, urinary supernatant microvesicles of miR-144-3p and miR-486-5p in the IgAN group were also significantly increased. This study showed that the miR-25-3p, miR-144-3p and miR-486-5p in urinary sediment were mainly derived from urinary erythrocytes, which could be non-invasive candidate biomarkers for IgA nephropathy.
| S-EPMC4802218 | biostudies-literature
Project description:Background and objectivesMegalin 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, & measurementsUrine 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.ResultsHistological 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.ConclusionsThe 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.
| S-EPMC4264761 | biostudies-literature
Project description:BackgroundRenal biopsy remains the golden standard for diagnosing and monitoring IgA nephropathy (IgAN). Vascular endothelial growth factor A (VEGFA) was crucial for the survival of glomerular cells. Our aim was to screen the expression pattern of urinary, circulating and renal VEGFA in IgAN patients to reveal their relationship with renal pathology and outcomes.MethodsBaseline VEGFA levels were determined with ELISA, real-time PCR and immunohistochemistry. Associations between VEGFA expression and clinical-pathological parameters, and renal outcomes were evaluated.ResultsCompared with healthy controls, urinary VEGFA level was obviously elevated in IgAN patients (76.19 ± 63.67 pg/mg Cr vs 146.67 ± 232.71 pg/mg Cr, p = 0.0291) and not correlated with serum VEGFA level. Baseline urinary VEGFA was significantly associated with gender and tubular atrophy/interstitial fibrosis by stepwise multivariate regression analysis. Urinary VEGFA was higher in male patients accompanied with higher serum creatinine, larger proportion of hypertension and recurrent hematuria than in female patients. In the kidney of IgAN patients, VEGFA were robustly expressed in the parietal epithelial cells, podocytes, mesangial cells and tubular epithelial cells. After a follow-up duration of 38.53 ± 27.14 months, IgAN patients with higher urinary VEGFA level were found to have a poorer renal outcome of renal replacement therapy (HR = 1.027, p = 0.037) or composite outcome (HR = 1.023, p = 0.039) after adjusting for confounders.ConclusionsIncreased urinary VEGFA might reflect certain renal pathology and, although not fully specific, still could be served as a valuable noninvasive indicator in predicting renal progression of IgAN.
| S-EPMC8551689 | biostudies-literature
Project description:Background. MicroRNAs (miRNAs) have been found in virtually all body fluids and used successfully as biomarkers for various diseases. Evidence indicates that miRNAs have important roles in IgA nephropathy (IgAN), a major cause of renal failure. In this study, we looked for differentially expressed miRNAs in IgAN and further evaluated the correlations between candidate miRNAs and the severity of IgAN. Methods. Microarray and RT-qRCR (real-time quantitative polymerase chain reaction) were sequentially used to screen and further verify miRNA expression profiles in urinary sediments of IgAN patients in two independent cohorts. The screening cohort consisted of 32 urine samples from 18 patients with IgAN, 4 patients with MN (membranous nephropathy), 4 patients with MCD (minimal changes disease) and 6 healthy subjects; the validation cohort consisted of 102 IgAN patients, 41 MN patients, 27 MCD patients and 34 healthy subjects. The renal pathological lesions of patients with IgAN were evaluated according to Lee's grading system and Oxford classification. Results. At the screening phase, significance analysis of microarrays analysis showed that no miRNA was differentially expressed in the IgAN group compared to all control groups. But IgAN grade I-II and III subgroups (according to Lee's grading system) shared dysregulation of two miRNAs (miR-3613-3p and miR-4668-5p). At the validation phase, RT-qPCR results showed that urinary level of miR-3613-3p was significantly lower in IgAN than that in MN, MCD and healthy controls (0.47, 0.44 and 0.24 folds, respectively, all P < 0.01 by Mann-Whitney U test); urinary level of miR-4668-5p was also significantly lower in IgAN than that in healthy controls (0.49 fold, P < 0.01). Significant correlations were found between urinary levels of miR-3613-3p with 24-hour urinary protein excretion (Spearman r = 0.50, P = 0.034), eGFR (estimated glomerular filtration rate) (r = - 0.48, P = 0.043) and Lee's grades (r = 0.57, P = 0.014). Similarly, miR-4668-5p was significantly correlated with eGFR (r = - 0.50, P = 0.034) and Lee's grades (r = 0.57, P = 0.013). For segmental glomerulosclerosis according to Oxford classification, patients scored as S0 had significantly lower levels of urinary miR-3613-3p and miR-4668-5p than those scored as S1 (0.41 and 0.43 folds, respectively, all P < 0.05). Conclusions. The expression profile of miRNAs was significantly altered in urinary sediments from patients with IgAN. Urinary expression of miR-3613-3p was down-regulated in patients with IgAN. Moreover, urinary levels of both miR-3613-3p and miR-4668-5p were correlated with disease severity. Further studies are needed to explore the roles of miR-3613-3p and miR-4668-5p in the pathogenesis and progression of IgA nephropathy.
| S-EPMC4458130 | biostudies-literature
Project description:In patients with IgA nephropathy (IgAN), circulatory IgA1 and IgA1 in mesangial deposits contain elevated amounts of galactose-deficient IgA1 (Gd-IgA1). We hypothesized that a fraction of Gd-IgA1 from the glomerular deposits and/or circulation may be excreted into the urine and thus represent a disease-specific biomarker. Levels of urinary IgA and Gd-IgA1 were determined in 207 patients with IgAN, 205 patients with other renal diseases, and 57 healthy controls, recruited in USA, Japan, and Italy. Urinary IgA was similarly elevated in patients with IgAN and renal-disease controls compared with healthy controls. However, urinary Gd-IgA1 levels were higher in patients with IgAN (IgAN, 28.0 ± 17.9; disease controls, 20.6 ± 17.4 units/mg urinary creatinine; P < 0.0001). Lectin western blotting data confirmed these results. In IgAN patients, levels of urinary Gd-IgA1 correlated with proteinuria (P < 0.001). When we purified IgA from serum and urine of an IgAN patient, the relative proportion of Gd-IgA1 to total IgA1 was higher in the urine compared with serum, suggesting selective excretion of Gd-IgA1 in IgAN. In summary, urinary excretion of Gd-IgA1 was elevated in patients with IgAN and the urinary Gd-IgA1 levels correlated with proteinuria. Urinary Gd-IgA1 may thus represent a disease-specific biomarker of IgAN.
| S-EPMC5018335 | biostudies-literature