Recently, we found a strict bone association between Fibroblast growth factor 23 (FGF23) and Fetuin-A, both involved in cardiovascular and mineral bone disorders. In this study, an uninvestigated bone marrow positivity for both was found. Though the role of exogenous FGF23 on mesenchymal cells (MSCs) was reported, no information is as yet available on the possible production of this hormone by MSCs. To further analyze these uninvestigated aspects, we studied human primary cells and mouse and human cell lines by means of immunostaining, qRT-PCR, enzyme linked immunosorbent assays, chromatin immunoprecipitation, transfection, and a streamlined approach for the FGF23⁻Fetuin-A interaction called Duolink proximity ligation assay. Mesenchymal cells produce but do not secrete FGF23 and its expression increases during osteo-differentiation. Fibroblast growth factor 23 is also involved in the regulation of Fetuin-A by binding directly to the Fetuin-A promoter and then activating its transcription. Both FGF23 overexpression and addition induced an upregulation of Fetuin-A in the absence of osteo-inducer factors. Fibroblast growth factor 23 and Fetuin-A promoter were increased by osteo-inducer factors with this effect being abolished after FGF23 silencing. In conclusion, both FGF23 and Fetuin-A are present and strictly linked to each other in MSCs with FGF23 driving Fetuin-A production. This mechanism suggests a role for these two proteins in the osteoblast differentiation.

coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-is an ongoing pandemic with high morbidity and mortality rates. Preliminary evidence suggests that acute kidney injury (AKI) is uncommon in patients with COVID-19 and associated with poor outcomes. Study aims and design: we performed a systematic review of the literature with a meta-analysis of clinical studies to evaluate the frequency of AKI and dialysis requirement in patients who underwent hospitalization due to COVID-19. The incidence of AKI according to the death risk was calculated in these patients. The random-effects model of DerSimonian and Laird was adopted, with heterogeneity and stratified analyses.

Background: Acute kidney injury (AKI) is a common complication among SARS-CoV-2-positive patients who undergo hospitalization. Abundant evidence exists concerning the epidemiology of AKI in patients hospitalized in the ICU for COVID-19 but limited data are available about the occurrence of AKI in SARS-CoV-2-positive patients being hospitalized in a non-ICU setting. Aim and Methods: We have carried out a retrospective study to evaluate frequency and risk factors for AKI among patients consecutively admitted at a third-level university hospital starting from February 2020 (the beginning of the first wave of the SARS-CoV-2 pandemic); all patients were hospitalized outside the ICU. Results: A total of 387 SARS-CoV-2-positive patients were included in the current study; 372 (96.1%) had SARS-CoV-2-related pneumonia. In-hospital AKI onset was recorded in 119 (30.7%) patients, mainly with AKI stage 1 (n = 74, 62.2%); eighteen (4.6%) patients reported AKI stage 3 and six (1.5%) patients had HD-dependent AKI. There were 235 (60.7%) patients with severe COVID-19, and this was more common in patients developing AKI, 94.5% (86/119) vs. 86.1% (149/268), p = 0.02. Multivariate regression model (n = 144 patients) reported an independent and significant relationship between AKI occurrence and greater levels of ferritin (p = 0.036), IL-6 (p = 0.032), and azotemia at admission (p = 0.0001). A total of 69 (17.8%) SARS-CoV-2-positive patients died and strong predictors of in-hospital death resulted from age (p < 0.0001), serum ferritin (p < 0.0001) and white blood cells (p < 0.001). According to multivariable analysis (n = 163 patients), there was a consistent link between in-hospital death and AKI stage (1) (p = 0.021) and -stage (2) (p = 0.009). Our results support the notion that AKI occurs frequently among hospitalized COVID-19 patients even in a non-ICU setting and plays a pivotal role in the mortality of this population. Further studies are ongoing in order to clearly establish the frequency of AKI in patients with COVID-19; the mechanisms underlying kidney injury in this population are an area of active investigation. These data provide solid evidence to support close monitoring of COVID-19 patients for the development of AKI and measures taken to prevent this.

Recently it has been demonstrated that Fetuin-A, an anti-inflammatory protein synthesized by the liver, is produced also in bone by an FGF23-regulated pathway. FGF23 has been also demonstrated to induce inflammatory cytokine production in the liver. This study aimed to explore if FGF23 plays a role in the Fetuin-A production in the liver cells too and the possible relationships with FGF23 pro-inflammatory effects. FGF23 and Fetuin-A were studied in liver, kidney and in plasma with immunochemistry, immunoprecipitation, western blot, chromatin immunoprecipitation, duolink, ELISA, qrtPCR methodology. FGF23 is produced, but not secreted by the liver cells. In hepatocytes and circulation, FGF23 was present only strictly linked to Fetuin-A, while Fetuin-A was found also in unbounded form. No link was observed in the kidney. FGF23 up to 600 pg/ml stimulates, while, at higher concentrations, reduces Fetuin-A expression. Notably, overall the range of concentrations, FGF23 stimulates Fetuin-A promoter, TNFα and IL6 expression. In the nucleus, FGF23 seems to act as a direct transcription factor of Fetuin-A promoter. These results suggest that FGF23 played a direct regulatory role in Fetuin-A expression in liver cells with a biphasic effect: Fetuin-A progressively increases when FGF23 increases up to 400-600 pg/mL, and declines at higher FGF23 concentrations. These results lead us to hypothesize: a) a possible epigenetic post-transcriptional regulation; b) a possible counter-regulatory effect of FGF23 induced inflammatory cytokines (TNFα/ NF-κB mechanism). This study could add an additional key for the interpretation of the possible mechanisms linking FGF23, Fetuin-A and inflammation in CKD patients and suggests a role for FGF23 as transcription factor.

Hepatitis C virus (HCV) is still common in patients with chronic kidney disease. It has been recently discovered that chronic HCV is a risk factor for increased incidence of CKD in the adult general population. According to a systematic review with a meta-analysis of clinical studies, pooling results of longitudinal studies (n = 2,299,134 unique patients) demonstrated an association between positive anti-HCV serologic status and increased incidence of CKD; the summary estimate for adjusted HR across the surveys was 1.54 (95% CI, 1.26; 1.87), (p < 0.0001). The introduction of direct-acting antiviral drugs (DAAs) has caused a paradigm shift in the management of HCV infection; recent guidelines recommend pan-genotypic drugs (i.e., drugs effective on all HCV genotypes) as the first-choice therapy for HCV, and these promise to be effective and safe even in the context of chronic kidney disease.