Peripheral blood level alterations of MMP-2 and MMP-9 in patients with chronic kidney disease on conservative treatment and on hemodialysis

doi:10.1016/j.clinbiochem.2011.03.143

Clinical Biochemistry

Volume 44, Issues 10–11, July 2011, Pages 838-843

https://doi.org/10.1016/j.clinbiochem.2011.03.143 Get rights and content

Abstract

Objectives

Data concerning the levels of metalloproteinase-2 (MMP-2) and MMP-9 in uremia and dialysis are conflicting and incomplete.

Design and methods

We measured the serum MMP levels in patients with chronic kidney disease (CKD) and undergoing maintenance hemodialysis (HD), and we tried to identify factors that could affect their levels.

Results

MMP-2 and the high sensitivity C-reactive protein (hsCRP) were inversely correlated with hematological parameters in the whole CKD group. CKD patients with stages 3 + 4 showed a significant increase in the MMP-9 levels compared to the other studied groups; this metalloproteinase was inversely correlated with lymphocyte count, and positively correlated with the hsCRP. The MMP-2 levels were higher in pre and post HD patients compared to the control group and CKD stage 1 + 2. In contrast, there was no difference in the MMP-9 levels. Both MMP-2 and MMP-9 were associated with the leukocyte count in pre HD group.

Conclusions

This study suggests a connection between an inflammatory state, biochemical response and the MMP levels in uremic and dialysis patients.

Introduction

Patients with chronic kidney disease (CKD) and on hemodialysis (HD) treatment are at significantly higher cardiovascular risk than the general population [1]. Even mild kidney dysfunction should be considered a medical condition predisposing to increased cardiovascular risk [2]. Atherosclerotic cardiovascular disease (CVD) is further accelerated by long-term HD treatment and appears to increase mortality and morbidity of these patients [3].

Matrix metalloproteinases (MMPs) are involved in the process of atherosclerosis. MMPs, such as MMP-2 and 9 degrade the type IV collagen, the major structural component of basement membrane. There has been an emphasis on these two MMPs because their elevated expression were demonstrated within plaques. They play a part in plaque rupture by weakening it [4]. In previous study, Chang et al. [5] suggested that increased MMP-2 and decreased MMP-9 levels contribute to the pathogenesis of CKD. More recent studies found that increased MMP-2 levels correlates with proteinuria, oxidative stress, CVD prevalence and the atherosclerosis marker — intima media thickness (IMT) both in CKD patients [6], [7] and in dialyzed population [8], [9]. In the case of MMP-9, its reduced levels were observed in CKD patients [5]. Moreover, Ebihara et al. [10] showed that chronic dialysis induced expression of the mRNA MMP-9 in peripheral blood monocytes, without significant elevation of serum MMP-9. In our previous studies [8], [9] we also did not observed the differences in the MMP-9 levels between the dialyzed patients and healthy controls and we could not find the correlation between this metalloproteinase and oxidative stress markers, CVD prevalence or atherosclerosis.

Inflammation in patients with end-stage renal disease is associated with malnutrition, cardiovascular morbidity and death [11]. Inflammatory stimuli leads to release of cytokines that are involved in many systemic changes, including increased synthesis and release of acute-phase proteins, such as C-reactive protein (CRP), and the suppression of other acute-phase proteins such as albumin [12]. MMP gene expression is regulated by inflammatory cytokines, and their excessive or inappropriate synthesis has been associated with the pathogenesis of many tissue destructive processes in uremia such as atherosclerotic CVD [4], [6], [7], [8], [9].

MMP-2 and MMP-9 are the important factors participating in progression of atherosclerosis in CKD and HD patients [6], [7], [8], [9]; however the results from data concerning their blood levels in these populations of patients are conflicting and incomplete. The purpose of the current study was to measure the serum MMP-2 and MMP-9 concentrations in CKD stages from 1 + 2 to 5, as well before and after the HD session, and also to identify potential factors that may affect their levels in these patients.

Section snippets

Subjects

The study involved 58 adult patients with different stages of CKD and 23 patients on HD treatment; they were clinically stable and free of active infection and autoimmune diseases. None of the patients received immunosuppressive treatment, lipid-lowering agents, non-steroidal anti-inflammatory drugs or antioxidants such as vitamin E, C or allopurinol at the time of the study. Eighteen healthy subjects who were receiving no drugs or vitamin supplements at the time of the study volunteered as

Demographic data

Detailed characteristics of subjects are shown in Table 1. In patients with CKD from stage 3 we noted the decrease in erythrocyte count, hemoglobin concentration (both p < 0.01), iron levels (p < 0.05), whereas creatinine and leukocyte count were increased (both p < 0.05) compared to controls. We noted in patients with CKD from stage 3 the decrease in erythrocyte count, hemoglobin concentration (both p < 0.01), iron levels (p < 0.05), whereas creatinine and leukocyte count were increased (both p < 0.05).

Discussion

According to our knowledge, this is the first study that demonstrates the parallel alteration of the MMP-2 and MMP-9 serum concentrations in patients with different CKD stages, as well before and after the HD session. Moreover, we have tried to find the factors that affect these MMP levels in the studied groups of uremic patients.

In the present investigation, we did not observed the differences in the MMP-2 levels in different stages of CKD patients compared to the controls. Starting from stage

Acknowledgments

This work was supported by a grant no. 3-28568F provided by the Medical University in Bialystok.

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This study indicates the association with declining renal function and mortality in patients undergoing PCI. Whilst renal disease was not associated with increased TVR in non-dialysis patients, dialysis-dependence was a strong independent predictor for increased TVR.
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However, serum MMP-2 was independent of proteinuria and albumin in CKD patients [215]. In another study, serum MMP-2 and MMP-9 correlated with inflammatory parameters in patients with CKD on conservative treatment and HD patients [216]. Increased TIMP-1 served as a pro-inflammatory biomarker in CKD [217].
Matrix metalloproteinases (MMPs) are a group of zinc and calcium endopeptidases which cleave extracellular matrix (ECM) proteins. They are also involved in the degradation of cell surface components and regulate multiple cellular processes, cell to cell interactions, cell proliferation, and cell signaling pathways. MMPs function in close interaction with the endogenous tissue inhibitors of matrix metalloproteinases (TIMPs), both of which regulate cell turnover, modulate various growth factors, and participate in the progression of tissue fibrosis and apoptosis. The multiple roles of MMPs and TIMPs are continuously elucidated in kidney development and repair, as well as in a number of kidney diseases. This chapter focuses on the current findings of the significance of MMPs and TIMPs in a wide range of kidney diseases, whether they result from kidney tissue changes, hemodynamic alterations, tubular epithelial cell apoptosis, inflammation, or fibrosis. In addition, the potential use of these endopeptidases as biomarkers of renal dysfunction and as targets for therapeutic interventions to attenuate kidney disease are also explored in this review.
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MMP-2 levels were higher in the CKD compared to the diabetes and control groups (p < 0.05). MMP-9 levels did not differ among groups. In hypertensive individuals logMMP-2 independently associated with PWV z score (β = 0.744, 95%CI 0.105 to 2.921, p < 0.05) after adjustment for age, sex, GRF, and phosphate levels. Creatinine levels correlated positively with MMP-2 in the CKD (r = 0.39, p < 0.05) and negatively in the diabetes group (r = −0.72, p < 0.05). Cholesterol levels correlated with MMP-2 in the diabetes group (r = 0.70, p < 0.05). Phosphate levels correlated with MMP-2 level in the control group (r = 0.67, p < 0.05). In multivariate regression model adjusted for age and sex, including phosphate and GRF as covariates, only phosphate predicted logMMP-2 levels (β = 0.333, 95%CI 0.060 to 0.671, p < 0.05).
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Peripheral blood level alterations of MMP-2 and MMP-9 in patients with chronic kidney disease on conservative treatment and on hemodialysis

Abstract

Objectives

Design and methods

Results

Conclusions

Introduction

Section snippets

Subjects

Demographic data

Discussion

Acknowledgments

Kidney Int

Kidney Int

Kidney Int

Atherosclerosis

Clin Chim Acta

Atherosclerosis

Kidney Int

J Orthop Res

J Biol Chem

Clin Biochem

Clin Biochem

Circulating matrix metalloproteinase-2 is an independent correlate of proteinuria in patients with chronic kidney disease

Am J Nephrol