Serum matrix metalloproteinase 7 and accelerated glomerular filtration rate decline in a general non-diabetic population

Abstract

Background: Age-related reduction of glomerular filtration rate (GFR) is a major contributor to the global chronic kidney disease (CKD) epidemic. We investigated whether baseline serum levels of the pro-fibrotic matrix metalloproteinase 2 (MMP2), MMP7 and their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP1), which mediates fibrosis development in aging animals, were associated with GFR decline in a general non-diabetic population.

Methods: In the Renal Iohexol Clearance Survey, we measured GFR using iohexol clearance in 1627 subjects aged 50-64 years without self-reported diabetes, kidney or cardiovascular disease. After a median of 5.6 years, 1324 had follow-up GFR measurements. Using linear mixed models and logistic regression analyses, we evaluated the association of MMP7, MMP2 and TIMP1 with the mean GFR decline rate, risk of accelerated GFR decline (defined as subjects with the 10% steepest GFR slopes: ≥1.8 mL/min/1.73 m2/year) and incident CKD [GFR <60 mL/min/1.73 m2 and/or urinary albumin to creatinine ratio (ACR) ≥3.0 mg/mmol].

Results: Higher MMP7 levels (per standard deviation increase of MMP7) were associated with steeper GFR decline rates [-0.23 mL/min/1.73 m2/year (95% confidence interval -0.34 to -0.12)] and increased risk of accelerated GFR decline and incident CKD [odds ratios 1.58 (1.30-1.93) and 1.45 (1.05-2.01), respectively, in a model adjusted for age, sex, baseline GFR, ACR and cardiovascular risk factors]. MMP2 and TIMP1 showed no association with GFR decline or incident CKD.

Conclusions: The pro-fibrotic biomarker MMP7, but not MMP2 or TIMP1, is associated with increased risk of accelerated GFR decline and incident CKD in middle-aged persons from the general population.

Keywords: MMP7; accelerated GFR decline; epidemiology; fibrosis; incident CKD.

Graphical Abstract

FIGURE 1

Flowchart: an overview of the RENIS cohort. Number (N) of invited participants, response rate (%) and number of participants excluded/missing due to different reasons.

FIGURE 2

The non-linear association between MMP7 concentration and risk of accelerated GFR decline based on Model 3 in Table 2. Baseline MMP7 concentration is on the x-axis, the ORs for accelerated decline are on the y-axis and dotted lines indicating the change point for each quartile of MMP7 concentration. The dashed lines indicate 95% CIs. MMP7 concentrations are shown as picogram per millilitre.

FIGURE 3

Interaction analysis (forest plot) of the adjusted ORs for accelerated decline by various groups per SD increase in MMP7 concentration. Adjusted for sex, age, baseline GFR, BMI, ever smoker, sBP, BP medication, ACR and fasting glucose. P-values for the interaction between MMP7 and the given variables are shown in addition to the P-values for the different subgroups.