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Matrix Metalloproteinase-2 and CKD Progression: The Chronic Renal Insufficiency Cohort (CRIC) Study
Robin L Baudier1,2, Paula F Orlandi3, Wei Yang4
1Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA.
Rationale & Objective:
Matrix metalloproteinase 2 (MMP-2) plays an important role in the development of fibrosis, the final common pathway of chronic kidney disease (CKD). This study aimed to assess the relationship between repeated measures of MMP-2 and CKD progression in a large, diverse prospective cohort.
Study Design:
In a prospective cohort of Chronic Renal Insufficiency Cohort (CRIC) participants (N = 3,827), MMP-2 was measured at baseline. In a case-cohort design, MMP-2 was additionally measured at year 2 in a randomly selected subcohort and cases of estimated glomerular filtration rate (eGFR) halving or kidney replacement therapy (KRT) (N = 1,439).
Setting & Participants:
CRIC is a multicenter prospective cohort of adults with CKD.
Exposure:
MMP-2 measured in plasma at baseline and at year 2.
Outcomes:
A composite kidney endpoint (KRT/eGFR halving).
Analytical Approach:
Weighted Cox proportional hazards models for case-cohort participants.
Results:
Participants were followed for a median of 4.6 years from year 2 and 6.9 years from the baseline. Persistently elevated MMP-2 (≥300 ng/mL at both baseline and year 2) increased the hazard of the composite kidney endpoint (HR, 1.61; 95% CI, 1.07-2.42; P = 0.09) after adjusting for covariates. The relationship of persistently elevated MMP-2 was modified by levels of inflammation, with a 2.6 times higher rate of the composite kidney endpoint in those with high-sensitivity C-reactive protein < 2.5 g/dL at study entry. Heterogeneity of effect was found with proteinuria, with a baseline MMP-2 level of ≥300 ng/mL associated with an increased risk of the composite kidney endpoint (HR, 1.30; 95% CI, 1.09-1.54) only with proteinuria ≥ 442 mg/g.
Limitations:
The observational study design limits causal interpretation.
Conclusions:
Elevated MMP-2 is associated with CKD progression, particularly among those with low inflammation and those with proteinuria. Future investigations are warranted to confirm the reduction in risk of CKD progression among these subgroups of patients with CKD.
Insights
Persistently elevated Matrix Metalloproteinase 2 (MMP-2) is linked to chronic kidney disease progression. This risk is higher in patients with low inflammation and significant proteinuria, suggesting targeted interventions.
Area of Science:
- Nephrology and Urology
- Biomarkers in Disease Progression
- Fibrosis Research
Background:
- Matrix metalloproteinase 2 (MMP-2) is implicated in fibrosis, a key factor in chronic kidney disease (CKD) progression.
- Understanding the role of MMP-2 in CKD progression is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the association between repeated measurements of MMP-2 and the progression of CKD.
- To explore potential modifying effects of inflammation and proteinuria on this association.
Main Methods:
- A case-cohort study design was employed within the Chronic Renal Insufficiency Cohort (CRIC) study.
- MMP-2 levels were measured at baseline and year 2 in 3,827 participants.
- Weighted Cox proportional hazards models were used to analyze the association with a composite kidney endpoint (kidney replacement therapy or eGFR halving).
Main Results:
- Persistently elevated MMP-2 (≥300 ng/mL at baseline and year 2) was associated with an increased hazard of the composite kidney endpoint (HR, 1.61).
- The association was modified by inflammation levels; a 2.6-fold higher rate was observed in those with low hs-CRP.
- A baseline MMP-2 level ≥300 ng/mL increased risk only in patients with proteinuria ≥442 mg/g (HR, 1.30).
Conclusions:
- Elevated MMP-2 is a significant predictor of CKD progression.
- The risk associated with MMP-2 is particularly pronounced in patients with low inflammation and significant proteinuria.
- Further research is needed to validate these findings and explore therapeutic strategies for these subgroups.
