| Background and ObjectiveIgA nephropathy(IgAN),is the most common form of primary glomerular disease in our country,20%-40%patients will gradually progress to end-stage renal disease(ESRD)within 10～20 years,finally these ESRD patients all need maintainous renal replacement therapy.How to identify the high risk patients with IgAN at the early stage,and make effective interventions,postpone them to ESRD,is always an urgent key issue.The traditional clinical variables,such as eGFR,proteinuria,hyperten--tion have many delays to predict progression of IgAN.Searching biomarkers can be used to predict progression of IgAN at the early stage is extremely urgent.Urine kideny injury molecule-1(uKIM-1)and urine angiotensinogen(uAGT)have been tested for predicting progression of IgAN.But,their predictive ability are moderate,it is still need to find other better biomarker to improve the predictive ability of predicting progression of IgAN.Tubulointerstitial fibrosis plays important role in progression of IgAN,the pathway of Wnt/β-catenin plays important role in the tubulointerstitial fibrosis induced by injury of tubulointerstitial.Matrix metalloproteinase-7(MMP-7)is the important target of the downstream pathway of Wnt/β-catenin.Detecting urine MMP-7(uMMP-7)from mouse and human can give a good response of the activity of Wnt/β-catenin.We hypothesize that uMMP-7 might be used as one good and potential biomarker for predicting progression of IgAN.The aim of this study is to investigate whether urine matrix metalloproteinase-7 can be used as one biomarker for predicting progression of IgAN,and compare with uKIM-1 and uAGT,make one optimized combined model that combined biomarker with clinical model for predicting progression of IgAN.MethodWe prospectively enrolled patients with IgAN who were admitted to the five hospitals(Nanfang Hospital,the affiliated Hospital of Guilin medical university,the second Hospital of Dalian medical university,Guizhou provincial people’s Hospital,and Haikou people’s Hospital),whose eGFR range from 30 to 120 ml/min/1.73m2 from April 2012 to August 2017.The spot urine from patients were collected at admission,using enzyme linked immunosorbent assay(ELISA)to test uMMP-7,uKIM-1,uAGT,adjusted by urine creatinine,collected clinical history and tested laboratory routine parameters,including hemoglobin,serum potassium,serum calcium,serum phosphorus,serum albumin,fasting blood glucose,blood lipid,serum creatinine,serum uric acid,24-hours proteinuria,etc.The end point was composite event,was defined as a>40%decrease in eGFR;or end-stage renal disease.Using logistic regression model analysis to make one multivariate clinical risk model;Cox proportional hazards regression model was used to analyze different level(tertile level)of uMMP-7,uKIM-1 and uAGT for predicting progression of IgAN.Receiver operating characteristic(ROC)curve was used to analyze the area under the curve of each urine biomarker for predicting progression of IgAN.Risk reclassification method was used to analyze biomarkers to improve risk stratification of clinical model.Kaplan-Meier method was used to analyze the cumulative incidence of biomarkers for predicting progression of IgAN.ResultsThere were 537 patients enrolled,follow-up and analyzed renal end point in our cohort,median follow-up time was 38 months,51 patients(9.5%)were in progression group,486 patients(90.5%)were in non-progression group.The levels of uMMP-7(4.95 vs 2.69 ng/mg Cr),uKIM-1(0.89 vs 0.55 ng/mg Cr)and uAGT(74.16 vs 9.16ng/mg Cr)were significantly higher in progression group than those in the non-progression group(P all<0.01).The results of the Cox regression model adjusted for clinical multivariates showed that compared with the low uMMP-7 level group,HR of uMMP-7 for predicting progression of IgAN in the high uMMP-7 level group was 13.90(95%CI:3.01,64.27,P=0.001),each increased standard deviation(SD),hazard risk(HR)of uMMP-7 for predicting progression of IgAN was 3.68(95%CI:1.90,7.12,P=0.000).ROC curve analysis showed that AUC of the clinical model for predicting progression of IgAN was:0.78,AUC of uMMP-7 for predicting progression of IgAN was 0.76;compared with the clinincal model,AUC of uMMP-7 in combination with clinical model for predicting progression of IgAN was:0.84(P<0.01).The results of risk reclassification analysis showed that compared with the clinincal model,category-free NRI and IDI of uMMP-7 in combination with clinical model for predicting progression of IgAN were:0.48 and 0.07(P all<0.01).ConclusionUrine MMP-7 can significantly enhance the ability of clinical model for predicting progression of IgAN,improve risk stratification of clinical model for predicting progression of IgAN,can be used as one new and novel biomarker for predicting progression of IgAN. |
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