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      The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel?

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          Abstract

          Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles.

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          Most cited references102

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          KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease

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            Mortality over a period of 10 years in patients with peripheral arterial disease.

            Previous investigators have observed a doubling of the mortality rate among patients with intermittent claudication, and we have reported a fourfold increase in the overall mortality rate among subjects with large-vessel peripheral arterial disease, as diagnosed by noninvasive testing. In this study, we investigated the association of large-vessel peripheral arterial disease with rates of mortality from all cardiovascular diseases and from coronary heart disease. We examined 565 men and women (average age, 66 years) for the presence of large-vessel peripheral arterial disease by means of two noninvasive techniques--measurement of segmental blood pressure and determination of flow velocity by Doppler ultrasound. We identified 67 subjects with the disease (11.9 percent), whom we followed prospectively for 10 years. Twenty-one of the 34 men (61.8 percent) and 11 of the 33 women (33.3 percent) with large-vessel peripheral arterial disease died during follow-up, as compared with 31 of the 183 men (16.9 percent) and 26 of the 225 women (11.6 percent) without evidence of peripheral arterial disease. After multivariate adjustment for age, sex, and other risk factors for cardiovascular disease, the relative risk of dying among subjects with large-vessel peripheral arterial disease as compared with those with no evidence of such disease was 3.1 (95 percent confidence interval, 1.9 to 4.9) for deaths from all causes, 5.9 (95 percent confidence interval, 3.0 to 11.4) for all deaths from cardiovascular disease, and 6.6 (95 percent confidence interval, 2.9 to 14.9) for deaths from coronary heart disease. The relative risk of death from causes other than cardiovascular disease was not significantly increased among the subjects with large-vessel peripheral arterial disease. After the exclusion of subjects who had a history of cardiovascular disease at base line, the relative risks among those with large-vessel peripheral arterial disease remained significantly elevated. Additional analyses revealed a 15-fold increase in rates of mortality due to cardiovascular disease and coronary heart disease among subjects with large-vessel peripheral arterial disease that was both severe and symptomatic. Patients with large-vessel peripheral arterial disease have a high risk of death from cardiovascular causes.
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              Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts.

              Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors.
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                Author and article information

                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                17 January 2020
                January 2020
                : 10
                : 1
                : 154
                Affiliations
                [1 ]Department of Health Sciences, Renal Unit, “Magna Graecia” University, 88100 Catanzaro, Italy; michiprov@ 123456hotmail.it (M.P.); andreucci@ 123456unicz.it (M.A.); teresa_faga@ 123456yahoo.it (T.F.); ashourmichael@ 123456yahoo.com (A.M.)
                [2 ]Division of Nephrology, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy; carlo.garofalo@ 123456hotmail.it
                [3 ]Interuniversity Center of Phlebolymphology (CIFL), “Magna Graecia” University, 88100 Catanzaro, Italy; infermierenicola@ 123456hotmail.it (N.I.); defranci@ 123456unicz.it (S.d.F.)
                [4 ]Department of Public Health and Infectious Disease, “Sapienza” University of Rome, 00185 Rome, Italy
                [5 ]Department of Radiology, Vibo Valentia Hospital, 89900 Vibo Valentia, Italy
                [6 ]Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, 00161 Rome, Italy; raffaele.grandeprospero@ 123456gmail.com (R.G.); paolo.sapienza@ 123456uniroma1.it (P.S.)
                [7 ]Department of Medical and Surgical Sciences, “Magna Graecia” University, 88100 Catanzaro, Italy
                [8 ]Department of Experimental and Clinical Medicine, “Magna Graecia” University, 88100 Catanzaro, Italy; mastroroberto@ 123456unicz.it
                Author notes
                [* ]Correspondence: rserra@ 123456unicz.it
                Author information
                https://orcid.org/0000-0002-2168-702X
                https://orcid.org/0000-0002-0198-7930
                https://orcid.org/0000-0002-3060-0520
                Article
                biomolecules-10-00154
                10.3390/biom10010154
                7022805
                31963569
                3fe6aca4-d663-4ff5-b80c-4b78705362de
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 December 2019
                : 14 January 2020
                Categories
                Review

                metalloproteinases,mmps,timps,ckd,peripheral vascular disease,biomarkers,proteinuria,egfr,pad.

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