Urinary Matrix Metalloproteinase 7 and Prediction of IgA Nephropathy Progression

Abstract

A major challenge in the management of immunoglobulin A nephropathy (IgAN) is the inability to identify patients at high risk for disease progression at an early stage. Our objective was to determine whether urinary matrix metalloproteinase 7 (MMP-7) is a promising predictor for IgAN progression and whether its addition to clinical data at the time of biopsy improves risk prediction. Prospective observational cohort study in China. 946 Chinese patients with IgAN followed up for a median of 40 months in 1 clinical center serving as the training set (n=554) and for 28 months in a second clinical center serving as the validation set (n= 392). Urinary MMP-7 and 7 previously reported biomarkers measured at the time of kidney biopsy and a score of histologically defined disease severity (MEST-C). IgAN progression was defined as a composite of >40% loss of estimated glomerular filtration rate, kidney failure, or death. Cox proportional hazard models adjusted for clinical characteristics, kidney function, relevant medications, and MEST-C score. Risk classification statistics were calculated for IgAN progression at 3 years, including C statistic, net reclassification index, and integrated discrimination index. High levels (>3.9μg/g of creatinine) of urinary MMP-7 were associated with a 2.7-fold higher risk for IgAN progression in adjusted analyses. Urinary MMP-7 level outperformed (C statistic, 0.78) levels of urinary angiotensinogen (C statistic, 0.75), epidermal growth factor (C statistic, 0.75), kidney injury molecule 1 (C statistic, 0.68), and serum galactose-deficient IgA1 (C statistic, 0.59) for predicting IgAN progression. The addition of urinary MMP-7 level to a model with clinical data from the time of biopsy (estimated glomerular filtration rate, mean arterial blood pressure, and proteinuria) and MEST-C score significantly improved the C statistic from 0.79 to 0.85, improved the 3-year risk prediction of IgAN progression (from 0.84 to C statistic of 0.90), and improved risk reclassification (category-free net reclassification improvement, 0.60). The predictive performance of urinary MMP-7 level, alone or combined with clinical data, was consistent in the external validation set. Lack of validation in other ethnic populations. In this study cohort, urinary MMP-7 level is an independent predictor of IgAN progression. The addition of urinary MMP-7 level to MEST-C score and clinical data at the time of biopsy significantly improved risk prediction of IgAN progression.