cardiovascular risk in CKD. However, there are no vascular calcification biomarkers for later diagnostic and early therapeutic strategy implementation in CKD. Vascular calcification consists of calcium phosphate mineral deposition in the intima and media layers of the vessels, characterized by deregulation of endogenous calcification inhibitors, abnormal mineral metabolism and inflammation. Previous studies have described the circulating J. Clin. Med. 2020, 9, 813 3 of 4 vitamin K-dependent protein (VKDP), named Gla-rich protein (GRP), as a molecule with anti-calcifying and anti-inflammatory properties in the cardiovascular system, but there are no previous studies about its role in VC diagnostics. The study of Silva et al. [8] identified GRP as an early marker of vascular damage in CKD. In a cohort of 80 diabetic patients, authors demonstrated a close relationship between a decrease of serum GRP levels and the progression of renal damage from mild CKD (stage two) to moderate CKD (stage four) measured by estimated GFR. In addition, there was a negative correlation with markers of mineral metabolism (phosphate, Ca, CaxP, parathyroid hormone, Fibroblast growth factors-23), vascular calcification score, pulse pressure and IL-6 levels. They suggest the potential utility of GRP as an early marker of vascular damage in CKD. Recognized therapeutic strategies used in DN patients, including the strict control of glucose levels, blood pressure, and new anti-diabetic drugs, only retard renal damage progression, but there are no novel direct therapies for DN. In the original paper by Lee at al. [9] they evaluate the relationship between long-term use of Beta2-Adrenergic Receptor Agonists (β2AR) and diabetic vascular complications in a cohort of Korean patients. Authors indicate that macro- and micro-vascular complications in diabetic patients decreased with an increased duration of β2AR agonist administration, exercising a protective effect in this population. Increasing studies are evaluating novel therapies based in plants used in Chinese traditional medicine, with promising data. In this sense, Do et al. [10] discuss the therapeutic use of Lespedeza bicolor (a member of the leguminosae family) to prevent familiar diabetic nephropathy. In this study, they developed several in vitro studies and in vivo models of diabetic-induced renal damage, using a precursor in advanced glycation end-products (AGEs) formation, the methylglyoxal (MGO). Authors provide evidence of how Lespedeza bicolor recovers MGO-induced metabolic dysfunction and glucotoxicity, and its associated mechanisms that regulate the formation of AGEs and cellular oxidative stress response. Importantly, a barrier to progress in the knowledge of DN is the lack of animal models resembling the main features of human DN, making more studies necessary. In the paper of Lavoz et al. [11], authors used the model of leptin-deficient BTBR ob/ob mice, a mouse model characterized by a kidney disease that mimics key features of advanced human DN and showed evidence of the reversibility of glomerular lesions. Therefore, this model has been recommended as an excellent approach for carrying out preclinical studies of therapeutic interventions. Using this model, Lavoz et al. found that vascular endothelial growth factor receptor-2 (VEGFR2 kinase inhibition therapeutic treatment, starting after kidney disease developed, reversed the structural abnormalities of DN, including the amelioration of mesangial matrix accumulation and renal inflammation mitigation, and also improved renal function. This group and others have proposed the developmental gene GREMLIN as a DN therapeutic target. Lavoz et al. have previously described that GREMLIN acts via VEGFR2 in tubular epithelial cells. Now, they have found that GREMLIN expression levels, but not the canonical VEGF ligands, were upregulated coincidentally with the onset of renal damage, and remained elevated thereafter in BTBR ob/ob mice. They proposed that the VEGFR2 blockade could be a potential therapeutic option for DN, mainly by targeting GREMLIN. Funding: Editors are funding by Grants from the Instituto de Salud Carlos III(ISCIII) and Fondos FEDER European Union (PI17/00119 and Red de Investigación Renal (REDINREN): RD16/0009, to M.R-O), Comunidad de Madrid (“NOVELREN” B2017/BMD-3751 to M.R-O); the José Castillejo grant (CAS19/00133 to R.R.R-D); the “Juan de la Cierva Formacion” training program of the Ministerio de Economia, Industria y Competitividad (MINECO) supported the salary of SR-M (FJCI-2016-29050); Sociedad Española de Nefrologia (S.E.N. to M.R-O). Grants PAI 82140017 to C.L. of Chile; IMPROVE-PD project (“Identification and Management of Patients atRisk–Outcome and Vascular Events in Peritoneal Dialysis”) funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 812699 to M.R.O. Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. J. Clin. Med. 2020, 9, 813 4 of 4 References 1. Donate-Correa, J.; Luis-Rodríguez, D.; Martín-Núñez, E.; Tagua, V.G.; Hernández-Carballo, C.;