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      Gla-Rich Protein (GRP) as an Early and Novel Marker of Vascular Calcification and Kidney Dysfunction in Diabetic Patients with CKD: A Pilot Cross-Sectional Study

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          Abstract

          Vascular calcification (VC) is one of the strongest predictors of cardiovascular risk in chronic kidney disease (CKD) patients. New diagnostic/prognostic tools are required for early detection of VC allowing interventional strategies. Gla-rich protein (GRP) is a cardiovascular calcification inhibitor, whose clinical utility is here highlighted. The present study explores, for the first time, correlations between levels of GRP in serum with CKD developmental stage, mineral metabolism markers, VC and pulse pressure (PP), in a cohort of 80 diabetic patients with mild to moderate CKD (stages 2–4). Spearman’s correlation analysis revealed a positive association of GRP serum levels with estimated glomerular filtration rate (eGFR) and α-Klotho, while a negative correlation with phosphate (P), fibroblast growth factor 23 (FGF-23), vascular calcification score (VCS), PP, calcium (x) phosphate (CaxP) and interleukin 6 (IL-6). Serum GRP levels were found to progressively decrease from stage 2 to stage 4 CKD. Multivariate analysis identified low levels of eGFR and GRP, and high levels of FGF-23 associated with both the VCS and PP. These results indicate an association between GRP, renal dysfunction and CKD-mineral and bone disorder. The relationship between low levels of GRP and vascular calcifications suggests a future, potential utility for GRP as an early marker of vascular damage in CKD.

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          Relation between kidney function, proteinuria, and adverse outcomes.

          Brenda R. Hemmelgarn, Braden J. Manns, Anita Lloyd … (2010)
          The current staging system for chronic kidney disease is based primarily on estimated glomerular filtration rate (eGFR) with lower eGFR associated with higher risk of adverse outcomes. Although proteinuria is also associated with adverse outcomes, it is not used to refine risk estimates of adverse events in this current system. To determine the association between reduced GFR, proteinuria, and adverse clinical outcomes. Community-based cohort study with participants identified from a province-wide laboratory registry that includes eGFR and proteinuria measurements from Alberta, Canada, between 2002 and 2007. There were 920 985 adults who had at least 1 outpatient serum creatinine measurement and who did not require renal replacement treatment at baseline. Proteinuria was assessed by urine dipstick or albumin-creatinine ratio (ACR). All-cause mortality, myocardial infarction, and progression to kidney failure. The majority of individuals (89.1%) had an eGFR of 60 mL/min/1.73 m(2) or greater. Over median follow-up of 35 months (range, 0-59 months), 27 959 participants (3.0%) died. The fully adjusted rate of all-cause mortality was higher in study participants with lower eGFRs or heavier proteinuria. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria measured by urine dipstick and eGFR of 60 mL/min/1.73 m(2) or greater, as compared with those with eGFR of 45 to 59.9 mL/min/1.73 m(2) and normal protein excretion (rate, 7.2 [95% CI, 6.6-7.8] vs 2.9 [95% CI, 2.7-3.0] per 1000 person-years, respectively; rate ratio, 2.5 [95% CI, 2.3-2.7]). Similar results were observed when proteinuria was measured by ACR (15.9 [95% CI, 14.0-18.1] and 7.0 [95% CI, 6.4-7.6] per 1000 person-years for heavy and absent proteinuria, respectively; rate ratio, 2.3 [95% CI, 2.0-2.6]) and for the outcomes of hospitalization with acute myocardial infarction, end-stage renal disease, and doubling of serum creatinine level. The risks of mortality, myocardial infarction, and progression to kidney failure associated with a given level of eGFR are independently increased in patients with higher levels of proteinuria.
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            Vascular calcification: the killer of patients with chronic kidney disease.

            Eduardo Slatopolsky, Dwight Towler, Masahide Mizobuchi (2009)
            Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Vascular calcification is a common complication in CKD, and investigators have demonstrated that the extent and histoanatomic type of vascular calcification are predictors of subsequent vascular mortality. Although research efforts in the past decade have greatly improved our knowledge of the multiple factors and mechanisms involved in vascular calcification in patients with kidney disease, many questions remain unanswered. No longer can we accept the concept that vascular calcification in CKD is a passive process resulting from an elevated calcium-phosphate product. Rather, as a result of the metabolic insults of diabetes, dyslipidemia, oxidative stress, uremia, and hyperphosphatemia, "osteoblast-like" cells form in the vessel wall. These mineralizing cells as well as the recruitment of undifferentiated progenitors to the osteochondrocyte lineage play a critical role in the calcification process. Important transcription factors such as Msx 2, osterix, and RUNX2 are crucial in the programming of osteogenesis. Thus, the simultaneous increase in arterial osteochondrocytic programs and reduction in active cellular defense mechanisms creates the "perfect storm" of vascular calcification seen in ESRD. Innovative clinical studies addressing the combined use of inhibitors that work on vascular calcification through distinct molecular mechanisms, such as fetuin-A, osteopontin, and bone morphogenic protein 7, among others, will be necessary to reduce significantly the accrual of vascular calcifications and cardiovascular mortality in kidney disease. In addition, the roles of oxidative stress and inflammation on the fate of smooth muscle vascular cells and their function deserve further translational investigation.
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              Cardiovascular disease in dialysis patients

              Mario Cozzolino, Michela Mangano, Andrea Stucchi … (2018)
              Abstract Cardiovascular disease (CVD) is a highly common complication and the first cause of death in patients with end-stage renal disease (ESRD) on haemodialysis (HD). In this population, mortality due to CVD is 20 times higher than in the general population and the majority of maintenance HD patients have CVD. This is likely due to ventricular hypertrophy as well as non-traditional risk factors, such as chronic volume overload, anaemia, inflammation, oxidative stress, chronic kidney disease–mineral bone disorder and other aspects of the ‘uraemic milieu’. Better understanding the impact of these numerous factors on CVD would be an important step for prevention and treatment. In this review we focus non-traditional CVD risk factors in HD patients.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Med
                Journal ID (iso-abbrev): J Clin Med
                Journal ID (publisher-id): jcm
                Title: Journal of Clinical Medicine
                Publisher: MDPI
                ISSN (Electronic): 2077-0383
                Publication date (Electronic): 27 February 2020
                Publication date Collection: March 2020
                Volume: 9
                Issue: 3
                Electronic Location Identifier: 635
                Affiliations
                [1 ]Department of Nephrology, Centro Hospitalar Universitário do Algarve, 8000-386 Faro, Portugal; anapassionara@ 123456gmail.com (A.P.S.); filipabritomendes@ 123456gmail.com (F.M.); pleaon@ 123456hotmail.com (P.L.N.)
                [2 ]Department of Biomedical Sciences and Medicine, Universidade do Algarve, 8005-139 Faro, Portugal; amacedo@ 123456keypoint.pt (A.M.); Heycarol.5@ 123456gmail.com (C.D.)
                [3 ]Centre of Marine Sciences (CCMAR), Universidade do Algarve, 8005-139 Faro, Portugal; caviegas@ 123456ualg.pt
                [4 ]GenoGla Diagnostics, Centre of Marine Sciences (CCMAR), Universidade do Algarve, 8005-139 Faro, Portugal
                [5 ]Keypoint Group, 1495-190 Miraflores, Portugal
                [6 ]Department of Cardiology, Centro Hospitalar Universitário do Algarve, 8000-386 Faro, Portugal; cpguilherme@ 123456gmail.com (P.G.); nelson.tavares63@ 123456gmail.com (N.T.)
                [7 ]Pathology Clinic, Centro Hospitalar Universitário do Algarve, 8000-386 Faro, Portugal; fatima.rato@ 123456gmail.com (F.R.); neliofilipe.santos@ 123456gmail.com (N.S.); marilia.faisca@ 123456synlab.pt (M.F.)
                [8 ]Faculdade de Medicina da Universidade de Lisboa, 1600-190 Lisboa, Portugal; edealmeida@ 123456mail.telepac.pt
                Author notes
                [* ]Correspondence: dsimes@ 123456ualg.pt ; Tel.: +351-289-800-100; Fax: +351-289-800-069
                [†]

                Both authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-0329-8805
                https://orcid.org/0000-0002-1388-7822
                https://orcid.org/0000-0003-0702-4569
                https://orcid.org/0000-0002-5145-4753
                Article
                Publisher ID: jcm-09-00635
                DOI: 10.3390/jcm9030635
                PMC ID: 7141108
                PubMed ID: 32120910
                SO-VID: e19b6e44-9fee-47da-ace2-0260db48fa35
                Copyright © © 2020 by the authors.
                License:

                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
                Date received : 04 February 2020
                Date accepted : 24 February 2020
                Categories
                Subject: Article

                Keywords: chronic kidney disease,cardiovascular disease,cardiovascular calcification,cardiovascular risk assessment,gla-rich protein,vascular calcification inhibitors
                Data availability:
                Keywords: chronic kidney disease, cardiovascular disease, cardiovascular calcification, cardiovascular risk assessment, gla-rich protein, vascular calcification inhibitors

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