*3.2. Markers of Oxidative Stress, Tissue Remodeling, and Metabolism*

Myeloperoxidase (MPO) is a biomarker of oxidative stress that fosters nitic oxide consumption and which is associated with the development of atherosclerotic lesions, CV disease, and eGFR decline in CKD [42,43]. A recent observational analysis of the Chronic Renal Insufficiency Cohort (CRIC), which enrolled approximately 4000 patients with CKD in the United States (US), showed that serum MPO levels were associated with the risk of renal outcome, defined as initiation of RRT, 50% eGFR decline, or eGFR <sup>≤</sup> 15 mL/min/1.73 m<sup>2</sup> [44]. The key element of this analysis was that the effect of MPO was significant even after adjustment for main confounders, such as baseline eGFR and proteinuria levels. Matrix metalloproteinases (MMPs), endopeptidases involved in tissue development, and homeostasis through the regulation of cell differentiation, apoptosis, and angiogenesis were shown to intervene in inflammatory and fibrotic processes across the kidneys [45,46]. Blood and urine levels of MMPs were linked to renal and CV disease in previous clinical studies in humans. Serum and urine MMP-2, -8, and -9 levels are increased in patients with diabetic CKD, with MMP-9 being significantly associated with the severity of albuminuria [47,48]. Increased plasma levels of TIMP-1 (tissue inhibitor of metalloproteinases-1) predicted the incidence of CKD regardless of inflammatory markers such as C-reactive protein [49]. MMPs and TIMPs also play a role in accelerating the atherosclerotic process by increasing cell migration to the plaque fibrous cap that in turn determines plaque inflammation and rupture [50]. Indeed, the levels of several MMPs (MMP-1, -2, -8, -9) and TIMP-1 were found to be increased in patients with peripheral arterial disease, including those with aneurysms of the arterial wall [51]. Fibroblast growth factor-23 (FGF-23), a hormone involved in phosphorus metabolism

that increases progressively as kidney function declines, was significantly associated with mortality, atherosclerotic events, heart failure (HF), and ESKD in CKD patients [52,53].
