Roles Of Urinary MiRNAs And Protein Biomarkers In IgA Nephropathy To Assess Kidney Injury And Disease Progression

Background and objectives：Immunoglobulin A nephropathy (IgAN) is the mostcommon glomerulonephritis worldwide. IgAN is a heterogeneous disease with differentclinical and pathological phenotypes. Repeated renal biopsy is not practical as aninvasive technique. The aim of this study is to investigate some urinary biomarkers, andwhether they can assess kidney injury and disease progression of IgAN.Methods: We studied the urinary miRNA levels of52biopsy-proven IgAN patients and25healthy controls. Urinary expressions of miR-34a, miR-205, miR-21, miR-146a andmiR-155were quantified by RT-PCR（real-time polymerase chain reaction）. Urinayexpressions of sIgA、PDGF-DD、TGF-β1、MCP-1、TNF-α and IL-1β1were measuredby ELISA method. ROC (receiver operating characteristic curve) was used to assess thesensitivity and specificity of the urine biomarkers in patients with IgAN. Logsticregression analysis was used to find risk factors related to IgAN. Furthermore, patientswith IgAN were followed up; urine biomarkers reflecting efficacy and diseaseprogression were analyzed.Results:1. The IgAN group had significantly lower urinary miR-34a，miR-205, miR-155buthigher miR-21levels than controls. Urinary miR-146a and miR-155were of nodifference. Urinary levels of miR-205were correlated with serum creatinine（Scr）andproteinuria，and inversely correlated with Glomerular filtration rate（GFR）. Urinarylevels of miR-21were correlated with Scr and U-Prot, but inversely correlated withGFR. The levels of urinary miR-205were signifcantly higher in Lee grade II than thosein grade III and grade IV-V，the levels of urinary miR-21were signifcantly higher inLee grade IV-V than those in grade II and grade III. Urinary miR-205levels inverselycorrelated with ratio of global sclerosis. Urinary miR-21levels correlated with ratio of global sclerosis and total crescents. The levels of urinary miR-205were downregulatedand miR-21were upregulated in patients with higher scores of tubular atrophy andinterstitial fbrosis. The levels of urinary miR-21were signifcantly higher in patientswith interstitial infammatory cell infltration score1and2than those with scores0.2. The levels of urinary sIgA、PDGF-DD、TGF-β1, and MCP-1were higher in IgANgroup than in healthy controls, and were correlated with Scr, U-prot but inverselycorrelated with GFR in patients with IgAN. What’s more, they were upgruateated inpatients with higher Lee grade. The levels of urinary IL-1β and TNF-α were of nodifference between two groups. The levels of urinary sIgA、PDGF-DD、TGF-β1、MCP-1and TNF-α were signifcantly higher in patients with mesangial proliferation score2than those with score0. Urinary sIgA、TGF-β1and MCP-1levels were correlated withratio of global sclerosis, total crescents and the severity of tubular atrophy. The levels ofurinary sIgA、MCP-1and TNF-α were elevated in patients with higher scores ofinterstitial fbrosis and interstitial infammatory cell infltration.3. Logistic regression analysis showed that urinary PDGF-DD≥16.95pg/mg Cr andMCP-1≥237.00pg/mg Cr were independent risk factors of IgAN. The combination ofurinary miRNAs and protein biomarkers may help to better evaluate the histologicalcharacteristics of IgAN. Urinary miR-205、miR-21、sIgA、PDGF-DD、TGF-β1、MCP-1were related to Scr, U-Prot and eGFR. sIgA、PDGF-DD、TGF-β1and MCP-1reflect the mesangial proliferation. Urinary miR-21、sIgA、MCP-1were correlated withinterstitial fbrosis and interstitial infammatory cell infltration.4. After4months therapy, the average U-Prot was significantly decreased（p＜0.0001）, and GFR was signifcantly higher（p=0.026）. In patients acceptingsteroid/immunosuppressive agent treatment, the rate of GFR decline(ml/min/1.73m2/month) was correlated with baseline urinary PDGF-DD, and inverselycorrelated with MCP-1. The decrease of U-Prot（g/24h/month）was correlated withbaseline urinary sIgA, and inversely correlated with miR-205. In patients who acceptedACEI/ARB, the rate of GFR decline was inversely correlated with baseline urinaryPDGF-DD. The decrease of U-Prot was correlated with baseline urinary TGF-β1. Conclusions: Some urianary miRNAs and protein biomarkers can reflect the renalfunction and histological characteristics of IgAN. What’s more, baseline levels of someurinary biomarkers may be predictors of disease progression. However, long-termprospective follow-up was needed to further investigate urine biomarkers that cansequentially assess the efficacy and disease prognosis of IgAN.