Association of Urinary Matrix Metalloproteinase 7 Levels With Incident Renal Flare in Lupus Nephritis

Abstract

Objective Flares of lupus nephritis (LN) are frequent and associated with impaired renal prognosis. One major management obstacle in LN flare is the lack of effective methods to identify at‐risk patients earlier in their disease course. This study was undertaken to test the utility of measurement of urinary matrix metalloproteinase 7 (MMP‐7) for the dynamic surveillance of renal disease activity and prediction of renal flares in LN. Methods A prospective, 2‐stage cohort study was performed in patients with LN. Urinary MMP‐7 levels at the time of biopsy were evaluated in 154 patients with newly diagnosed LN in 2 independent cohorts. Urinary MMP‐7 levels were assessed for correlation with renal histologic activity. Furthermore, after a minimum period of 12 months of renal disease remission, urinary MMP‐7 levels were monitored bimonthly for 2 years in 65 patients with LN. The association between urinary MMP‐7 levels and development of LN flare was analyzed. Results Urinary MMP‐7 levels were elevated in patients with LN. A higher urinary MMP‐7 level in LN was associated with greater renal histologic activity. As a marker for identifying LN patients with more severe renal histologic activity (i.e., a histologic activity index of ≥7), the level of urinary MMP‐7 outperformed other clinical markers and improved their predictive performance, thus linking urinary MMP‐7 levels to renal disease activity. Furthermore, among patients who had follow‐up measurements of urinary MMP‐7 after achievement of long‐term remission of renal disease activity, an elevated urinary MMP‐7 level during follow‐up was independently associated with an increased risk of LN flare. This elevation in the urinary MMP‐7 level hinted at the risk of an LN flare at an earlier time point prior to indications using conventional laboratory measures. Thus, use of the urinary MMP‐7 level in conjunction with other clinical measures improved the prognostic value for prediction of an LN flare. Conclusion Urinary MMP‐7 levels in LN are correlated with renal histologic activity. An elevated urinary MMP‐7 level detected after achievement of long‐term renal disease remission is associated with a higher risk of incident renal flare in patients with LN.

Flares in Lupus Nephritis: Risk Factors and Strategies for Their Prevention

“…Treatment of LN should be viewed as a longlasting battle, and patients should be informed upfront about the benefit of maintaining treatment for several years, while of course, accounting for their preferences and needs. We anticipate that intensive research in the field of biomarkers, including plasma [69] and urine [70][71][72][73][74][75][76][77] mediators such as TWEAK, VCAM-1, CD163, and matrix metalloproteinases, will be fruitful and provide novel non-invasive tools to monitor renal disease activity, thus enabling prognostication and treatment tailoring in patients with LN.…”

A serum proteomic study of two case-control cohorts identifies novel biomarkers for bipolar disorder

“…Altered tubular cell turnover is also believed to induce the tubular microcyst formation seen with long-term lithium exposure [ 64 ]. Interestingly, serum and urinary levels of MMP-7 can predict progression across multiple kidney disease states [ 65 – 67 ] and reflect the renal fibrotic stage [ 54 , 68 ]. Moreover, fibrotic development can be mitigated by both inhibition of MMP-7 activity [ 50 , 69 ] and blockage of lithium reabsorption in tubules [ 70 ].…”

IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis

“…TGF-b1 regulates the expression of MMP-9 (44); the main function of MMPs is to degrade ECM components, so it seems that TGF-b1 enhances matrix degradation. However, a large number of studies have shown that the levels of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in serum, urine and glomerulus of LN patients are increased, accompanied by the deposition of mesangial matrix (78,(175)(176)(177)(178)(179). Overexpressed MMPs interact with TIMPs, changing matrix composition to promote mesangial matrix expansion (178).…”