The Mitochondrial-Derived Peptide MOTS-c May Refine Mortality and Cardiovascular Risk Prediction in Chronic Hemodialysis Patients: A Multicenter Cohort Study.

INTRODUCTION: Uremic patients exhibit remarkably increased rates of mortality and cardiovascular (CV) events, but risk prediction in this setting remains difficult. Systemic mitochondrial dysfunction is pervasive in end-stage kidney disease and may contribute to CV complications. We tested the clinical significance of circulating MOTS-c, a small mitochondrial-derived peptide, as a biomarker for improving mortality and CV risk prediction in hemodialysis (HD) patients. METHODS: We conducted a prospective, observational, multicenter study on 94 prevalent HD patients. The study endpoint was a composite of all-cause mortality and non-fatal CV events. The diagnostic and prognostic capacities of predictive models based on cohort-related risk factors were tested before and after the inclusion of MOTS-c. RESULTS: MOTS-c levels were higher in HD patients than in controls (p < 0.001) and even more elevated (p = 0.01) in the 53 individuals experiencing the combined endpoint during follow-up (median duration: 26.5 months). MOTS-c was independently associated with the endpoint at either multivariate logistic (OR 1.020; 95% CI: 1.011-1.109; p = 0.03) or Cox regression analyses (HR 1.004; 95% CI: 1.000-1.025; p = 0.05) and the addition of this biomarker to prognostic models including the other cohort-related risk predictors (age, left ventricular mass, evidence of diastolic dysfunction, diabetes, pulse pressure) significantly improved the calibration, risk variability explanation, discrimination (receiver operating characteristic area under the curve from 0.727 to 0.743; C-index from 0.658 to 0.700), and particularly, the overall reclassification capacity (NRI 15.87%; p = 0.01). CONCLUSIONS: In HD patients, the mitochondrial-derived peptide MOTS-c may impart significant information to refine CV risk prediction, beyond cohort-related risk factors. Future investigations are needed to generalize these findings in larger and more heterogeneous cohorts.

Spice Up Your Kidney: A Review on the Effects of Capsaicin in Renal Physiology and Disease.

Capsaicin, the organic compound which attributes the spicy flavor and taste of red peppers and chili peppers, has been extensively studied for centuries as a potential natural remedy for the treatment of several illnesses. Indeed, this compound exerts well-known systemic pleiotropic effects and may thus bring important benefits against various pathological conditions like neuropathic pain, rhinitis, itching, or chronic inflammation. Yet, little is known about the possible biological activity of capsaicin at the kidney level, as this aspect has only been addressed by sparse experimental investigations. In this paper, we aimed to review the available evidence focusing specifically on the effects of capsaicin on renal physiology, as well as its potential benefits for the treatment of various kidney disorders. Capsaicin may indeed modulate various aspects of renal function and renal nervous activity. On the other hand, the observed experimental benefits in preventing acute kidney injury, slowing down the progression of diabetic and chronic kidney disease, ameliorating hypertension, and even delaying renal cancer growth may set the stage for future human trials of capsaicin administration as an adjuvant or preventive therapy for different, difficult-to-treat renal diseases.

Selenoprotein-P1 (SEPP1) Expression in Human Proximal Tubule Cells after Ischemia-Reperfusion Injury: An In Vitro Model.

Background and Objectives: Selenium deficiency represents a risk factor for the occurrence of severe diseases, such as acute kidney injury (AKI). Recently, selenoprotein-p1 (SEPP1), a selenium transporter, mainly released by the liver, has emerged as a promising plasmatic biomarker of AKI as a consequence of cardio-surgery operations. The aim of the present study was to investigate, on an in vitro model of hypoxia induced in renal tubular cells, HK-2, the effects of sodium selenite (Na2SeO3) and to evaluate the expression of SEPP1 as a marker of injury. Materials and Methods: HK-2 cells were pre-incubated with 100 nM Na2SeO3 for 24 h, and then, treated for 24 h with CoCl2 (500 µM), a chemical hypoxia inducer. The results were derived from an ROS assay, MTT, and Western blot analysis. Results: The pre-treatment determined an increase in cells' viability and a reduction in reactive oxygen species (ROS), as shown by MTT and the ROS assay. Moreover, by Western blot an increase in SEPP1 expression was observed after hypoxic injury as after adding sodium selenite. Conclusions: Our preliminary results shed light on the possible role of selenium supplementation as a means to prevent oxidative damage and to increase SEPP1 after acute kidney injury. In our in vitro model, SEPP1 emerges as a promising biomarker of kidney injury, although further studies in vivo are necessary to validate our findings.

Perioperative Marinobufagenin (MBG) Measurement May Improve Acute Kidney Injury Risk Assessment in Patients Undergoing Major Cardiac Surgery: A Proof-of-Concept Study.

Background and Objectives: Acute kidney injury (AKI) remains a significant complication following major cardiac surgery. Marinobufagenin (MBG), a cardiotonic steroid involved in sodium balance and blood pressure regulation, has been linked to organ damage after ischemia-reperfusion events. This pilot, prospective study investigates the utility of circulating MBG to improve AKI risk assessment in cardiac surgery patients as a stand-alone biomarker and after inclusion in a validated risk model (STS-AKI score). Materials and Methods: We included 45 patients undergoing elective cardiac surgery. The MBG levels were measured preoperatively and at 4, 8, and 12 h post-surgery. The AKI was defined according to the KDIGO guidelines. Statistical analyses assessed the diagnostic and prognostic utility of MBG and its integration with the STS-AKI score. Results: An AKI occurred in 26.7% of the patients. The STS-AKI score performed well in this cohort (AUC: 0.736). The MBG levels displayed a decreasing trend in the whole population after surgery (p = 0.02). However, in the AKI patients, MBG increased at 4 and 8 h before decreasing at 12 h post-surgery. The MBG changes from the baseline to 8 h and from 8 to 12 h post-surgery showed a remarkable diagnostic accuracy for an AKI (AUCs: 0.917 and 0.843, respectively). Integrating these MBG changes with the STS-AKI score significantly improved the model performance, including discrimination, calibration, and risk reclassification. Conclusions: The MBG measurement, particularly any dynamic changes post-surgery, enhances AKI risk stratification in cardiac surgery patients. Integrating MBG with the STS-AKI score offers more accurate risk predictions, potentially leading to better patient management and outcomes.

Urinary Post-Translationally Modified Fetuin-A (uPTM-FetA) in Chronic Kidney Disease Patients with and without Diabetic Kidney Disease.

Background and Objectives: A novel post-translational modification (PTM) fragment derived from the cleavage of Fetuin-A (PTM-FetA) has recently emerged as a sensitive biomarker for kidney damage in diabetic patients, but evidence in other chronic renal diseases is lacking. In this pilot study, we aimed at evaluating the clinical significance of urinary PTM-FetA (uPTM-FetA) in a mixed cohort of patients with non-advanced chronic kidney disease (CKD) secondary to diabetic kidney disease (DKD) or other causes. Materials and Methods: We enrolled 47 adult patients with CKD (mean CKD-Epi 40.10 ± 16.5 mL/min/1.73 m2) due to DKD (n = 34) or other etiology (n = 13). uPTM-FetA was measured in the urine using a commercially available ELISA kit. Fifteen healthy individuals served as controls. Results: Collectively, all CKD patients displayed remarkably higher levels of uPTM-FetA than controls (0.84 [0.10-1.15] vs. 29.68 [2.50-55.16] ng/mL p = 0.0005), but values were lower in non-DKD than in DKD patients (1.66 [0.09-4.19] vs. 13.9 [0.01-45.02] ng/mL; p = 0.01). uPTM-FetA showed a great diagnostic capacity at ROC analyses to identify the presence of CKD (AUC 0.776; p < 0.001) and, within CKD patients, to discriminate the diabetic and non-diabetic etiology (AUC 0.673; p = 0.02). At multivariate correlation analyses, proteinuria (ß = 0.442; p = 0.02) and BMI (ß = -0.334; p = 0.04) were the sole independent predictors of uPTM-FetA in this study population. Conclusions: uPTM-FetA could be a novel sensitive biomarker at the crossroad of chronic renal damage and metabolic dysfunction. Additionally, this biomarker could also represent a non-invasive, complementary tool for discriminating among different CKD etiologies (DKD vs. non-DKD) in difficult cases or when renal biopsy is not available.

miRNAs in Uremic Cardiomyopathy: A Comprehensive Review.

Uremic Cardiomyopathy (UCM) is an irreversible cardiovascular complication that is highly pervasive among chronic kidney disease (CKD) patients, particularly in End-Stage Kidney Disease (ESKD) individuals undergoing chronic dialysis. Features of UCM are an abnormal myocardial fibrosis, an asymmetric ventricular hypertrophy with subsequent diastolic dysfunction and a complex and multifactorial pathogenesis where underlying biological mechanisms remain partly undefined. In this paper, we reviewed the key evidence available on the biological and clinical significance of micro-RNAs (miRNAs) in UCM. miRNAs are short, noncoding RNA molecules with regulatory functions that play a pivotal role in myriad basic cellular processes, such as cell growth and differentiation. Deranged miRNAs expression has already been observed in various diseases, and their capacity to modulate cardiac remodeling and fibrosis under either physiological or pathological conditions is well acknowledged. In the context of UCM, robust experimental evidence confirms a close involvement of some miRNAs in the key pathways that are known to trigger or worsen ventricular hypertrophy or fibrosis. Moreover, very preliminary findings may set the stage for therapeutic interventions targeting specific miRNAs for ameliorating heart damage. Finally, scant but promising clinical evidence may suggest a potential future application of circulating miRNAs as diagnostic or prognostic biomarkers for improving risk stratification in UCM as well.

New Insights on the Role of Marinobufagenin from Bench to Bedside in Cardiovascular and Kidney Diseases.

Marinobufagenin (MBG) is a member of the bufadienolide family of compounds, which are natural cardiac glycosides found in a variety of animal species, including man, which have different physiological and biochemical functions but have a common action on the inhibition of the adenosine triphosphatase sodium-potassium pump (Na+/K+-ATPase). MBG acts as an endogenous cardiotonic steroid, and in the last decade, its role as a pathogenic factor in various human diseases has emerged. In this paper, we have collated major evidence regarding the biological characteristics and functions of MBG and its implications in human pathology. This review focused on MBG involvement in chronic kidney disease, including end-stage renal disease, cardiovascular diseases, sex and gender medicine, and its actions on the nervous and immune systems. The role of MBG in pathogenesis and the development of a wide range of pathological conditions indicate that this endogenous peptide could be used in the future as a diagnostic biomarker and/or therapeutic target, opening important avenues of scientific research.

Childhood Obesity: Insight into Kidney Involvement.

This review examines the impact of childhood obesity on the kidney from an epidemiological, pathogenetic, clinical, and pathological perspective, with the aim of providing pediatricians and nephrologists with the most current data on this topic. The prevalence of childhood obesity and chronic kidney disease (CKD) is steadily increasing worldwide, reaching epidemic proportions. While the impact of obesity in children with CKD is less pronounced than in adults, recent studies suggest a similar trend in the child population. This is likely due to the significant association between obesity and the two leading causes of end-stage renal disease (ESRD): diabetes mellitus (DM) and hypertension. Obesity is a complex, systemic disease that reflects interactions between environmental and genetic factors. A key mechanism of kidney damage is related to metabolic syndrome and insulin resistance. Therefore, we can speculate about an adipose tissue-kidney axis in which neurohormonal and immunological mechanisms exacerbate complications resulting from obesity. Adipose tissue, now recognized as an endocrine organ, secretes cytokines called adipokines that may induce adaptive or maladaptive responses in renal cells, leading to kidney fibrosis. The impact of obesity on kidney transplant-related outcomes for both donors and recipients is also significant, making stringent preventive measures critical in the pre- and post-transplant phases. The challenge lies in identifying renal involvement as early as possible, as it is often completely asymptomatic and not detectable through common markers of kidney function. Ongoing research into innovative technologies, such as proteomics and metabolomics, aims to identify new biomarkers and is constantly evolving. Many aspects of pediatric disease progression in the population of children with obesity still require clarification. However, the latest scientific evidence in the field of nephrology offers glimpses into various new perspectives, such as genetic factors, comorbidities, and novel biomarkers. Investigating these aspects early could potentially improve the prognosis of these young patients through new diagnostic and therapeutic strategies. Hence, the aim of this review is to provide a comprehensive exploration of the pathogenetic mechanisms and prevalent pathological patterns of kidney damage observed in children with obesity.

Urinary Marinobufagenin in Patients with Non-Advanced Chronic Kidney Disease: A Cross-Sectional Study.

Background and Objectives: The global prevalence of chronic kidney disease (CKD) is on the rise, posing important challenges for healthcare systems. Thus, the search for new factors potentially involved in the pathogenesis, progression and complications of early CKD remains urgent. Marinobufagenin (MBG) is a natriuretic endogenous cardiotonic steroid, and increased circulating levels of it may accelerate kidney damage. In this study, we explored the possible clinical significance of measuring urinary marinobufagenin (uMBG) in patients with non-advanced CKD. Materials and Methods: One hundred and eight adult CKD patients (mean age 71.6 ± 10 years, 70.4% male; mean eGFR 40.54 ± 17 mL/min/1.73 m2) were enrolled in this cross-sectional study. uMBG was measured together with a series of clinical, anthropometric, laboratory and instrumental analyses. Twenty-five healthy matched subjects served as controls for the uMBG measurement. Results: The uMBG values were lower in the patients with CKD as compared to those of the controls (0.37 [IQR: 0.25-0.45] vs. 0.64 [0.46-0.78] nmol/L. p = 0.004), and a significant trend in eGFR levels was noticed across the decreasing uMBG tertiles (p = 0.03). Regarding the correlation analyses, the uMBG values remained robustly associated with the eGFR in multivariate models employing either uMBG or eGFR as the dependent variable (ß = 0.248; p = 0.01 and ß = 0.139; p = 0.04, respectively). Besides the eGFR, the independent predictors of uMBG values in this population were the use of statins (ß = -0.326; p = 0.001), the presence of diabetes (ß = 0.243; p = 0.009) and urine sodium (ß = 0.204; p = 0.01). Conclusions: Reduced uMBG excretion may reflect impaired renal clearance, which may contribute to the detrimental effects attributed to this hormone due to systemic accumulation. Future studies are needed to clarify the biological mechanisms placing uMBG at the crossroad of sodium intake and the presence of diabetes in CKD-suffering individuals and to verify whether a statin treatment may somewhat limit the detrimental effects of MBG in the presence of impaired renal function.

Autosomic dominant polycystic kidney disease and metformin: Old knowledge and new insights on retarding progression of chronic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common congenital kidney disorder, generally caused by mutations in the PKD1 and PKD2 genes, coding for polycystins 1 and 2. Its pathogenesis is accompanied by alterations of the cAMP, mTOR, MAPK/ERK, and JAK/STAT pathways. ADPKD is clinically characterized by the formation of many growing cysts with kidney enlargement and a progressive damage to the parenchyma, up to its complete loss of function, and the onset of end-stage renal disease (ESRD). The current aim of ADPKD therapy is the inhibition of cyst development and retardation of chronic kidney disease progression. Several drugs have been recently included as potential therapies for ADPKD including metformin, the drug of choice for the treatment of type 2 diabetes mellitus, according to its potential inhibitory effects on cystogenesis. In this review, we summarize preclinical and clinical evidence endorsing or rejecting metformin administration in ADPKD evolution and pathological mechanisms. We explored the biology of APDKD and the role of metformin in slowing down cystogenesis searching PubMed and Clinical Trials to identify relevant data from the database inception to December 2020. From our research analysis, evidence for metformin as emerging cure for ADPKD mainly arise from preclinical studies. In fact, clinical studies are still scanty and stronger evidence is awaited. Its effects are likely mediated by inhibition of the ERK pathway and increase of AMPK levels, which are both linked to ADPKD pathogenesis.

Decreased Cathepsin-K Mirrors the Severity of Subclinical Atherosclerosis in Kidney Transplant Recipients.

Background: In kidney transplantation (Ktx) recipients, cardiovascular (CV) disease remains the leading cause of death. Abnormal carotid intima-media thickness (IMT) represents a valid indicator of incipient atherosclerosis also in this setting. Cathepsin-K (CatK) is a cysteine protease involved in vascular remodelling, as well as in progressive atherosclerosis. In this study we evaluated clinical predictors of CatK in Ktx recipients, with a particular focus on its possible relationships with subclinical atherosclerosis. Methods: Circulating CatK was measured in 40 stable Ktx recipients together with several laboratory, clinical and echocardiography parameters. 30 healthy subjects and 30 hemodialysis (HD) patients served as controls for CatK values. Carotid IMT was measured in Ktx and these subjects were then categorized according to age-gender reference cut-offs of normal IMT. Results: CatK levels were similar in Ktx recipients and healthy subjects but significantly reduced as compared to HD (p = 0.0001). In Ktx, at multivariate analyses CatK was associated with the LV end-diastolic volume (LVEDVi) ( ß = 0.514; p = 0.05), Ktx vintage ( ß = -0.333; p = 0.05) and mean IMT ( ß = -0.545; p = 0.05); this latter robust inverse association was confirmed also in another multivariate model with IMT as the dependent variable. Logistic regression analyses confirmed the beneficial meaning of CatK increase towards subclinical atherosclerosis [Odds Ratio (OR) 0.761; 95% Confidence Interval (CI) 0.569-0.918, p = 0.04]. At Receiver Operating Characteristics (ROC) analyses, CatK held a remarkable discriminatory power in identifying Ktx patients with abnormally increased IMT [Area Under the Curve (AUC) 0.763; 95% CI 0.601-0.926; p = 0.001]). Conclusions: In Ktx recipients, reduced CatK levels reflect the time-dependent improvement in the uremic milieu, cardiac adaptations and, above all, the severity of subclinical atherosclerosis. CatK measurement in Ktx may therefore hold significance for improving early CV risk stratification.

Selenoprotein P-1 (SEPP1) as an Early Biomarker of Acute Kidney Injury in Patients Undergoing Cardiopulmonary Bypass.

Background: Acute Kidney Injury (AKI) is a frequent, dangerous complication in patients undergoing cardiopulmonary bypass (CPB) with oxidative stress playing a crucial role. In this pilot study we evaluated the possible role of the selenoprotein-p1 (SEPP1), a circulating, anti-oxidant selenium transporter, as a predictive biomarker of AKI in this population setting. Methods: Circulating SEPP1 was measured in the blood of 45 patients before surgery and at 4 h, 8 h and 12 h after CPB by Enzyme-Linked Immunosorbent Assay (ELISA). Results: SEPP1 increased from 69 [IQR 39-85] to 3263 [IQR 1886.2-5042.7] ng/mL (p for trend < 0.0001). AKI occurred in 26.7% of patients. In these individuals, an earlier and more prominent increase in SEPP1 was observed at 4 h and 8 h, as compared with those not experiencing AKI (difference between trends p < 0.0001). Logistic regression analyses evidenced 4 h and 8 h SEPP1 as significantly associated with AKI (OR 1.035; 95% CI 1.002-1.068; p = 0.03 and 1.011; 95% CI 1.002-1.021; p = 0.02, respectively). ROC analyses displayed a remarkable discriminatory capacity of early SEPP1 measurements in identifying AKI (AUCs ranging from 0.682 to 0.854; p from 0.04 to < 0.0001). In addition, 12 h-SEPP1 showed diagnostic capacity to identify patients reaching a secondary composite endpoint including major adverse kidney events (MAKEs). Conclusions: Findings from this pilot, exploratory study suggest that early SEPP1 measurement after CPB may hold great potential for improving renal risk stratification in cardiac surgery patients. Further studies in wider and more heterogeneous cohorts are needed to generalize these findings and to evaluate a possible applicability in daily practice.

Role of Vitamin K in Chronic Kidney Disease: A Focus on Bone and Cardiovascular Health.

Chronic kidney disease (CKD) is commonly associated with vitamin K deficiency. Some of the serious complications of CKD are represented by cardiovascular disease (CVD) and skeletal fragility with an increased risk of morbidity and mortality. A complex pathogenetic link between hormonal and ionic disturbances, bone tissue and metabolism alterations, and vascular calcification (VC) exists and has been defined as chronic kidney disease-mineral and bone disorder (CKD-MBD). Poor vitamin K status seems to have a key role in the progression of CKD, but also in the onset and advance of both bone and cardiovascular complications. Three forms of vitamin K are currently known: vitamin K1 (phylloquinone), vitamin K2 (menaquinone), and vitamin K3 (menadione). Vitamin K plays different roles, including in activating vitamin K-dependent proteins (VKDPs) and in modulating bone metabolism and contributing to the inhibition of VC. This review focuses on the biochemical and functional characteristics of vitamin K vitamers, suggesting this nutrient as a possible marker of kidney, CV, and bone damage in the CKD population and exploring its potential use for promoting health in this clinical setting. Treatment strategies for CKD-associated osteoporosis and CV disease should include vitamin K supplementation. However, further randomized clinical studies are needed to assess the safety and the adequate dosage to prevent these CKD complications.

Circulating Omentin-1, Sustained Inflammation and Hyperphosphatemia at the Interface of Subclinical Atherosclerosis in Chronic Kidney Disease Patients on Chronic Renal Replacement Therapy.

Background and Objectives: Subclinical atherosclerosis, reflected by abnormal carotid intima-media thickness (cIMT), is pervasive among chronic kidney disease patients on chronic renal replacement therapy (RRT), being mostly influenced by uremia-related rather than traditional risk factors. Materials and Methods: In this pilot study, we measured circulating levels of Omentin-1, a recently discovered adipokine with strong anti-atherogenic properties, in a heterogeneous cohort of 77 asymptomatic RRT individuals (40 chronic kidney transplant recipients, Ktx; and 37 chronic hemodialysis patients, HD) and in 30 age-matched controls. Results: Omentin-1 was increased in RRT individuals as compared with controls (p = 0.03). When stratifying for renal replacement modality, we found Ktx patients to have significantly lower Omentin-1 than HD patients (p = 0.01). Lower Omentin-1 levels were also found among RRT individuals with pathological cIMT (168.7 [51.1-457.8] vs. 474.9 [197.2-1432.1]; p = 0.004). Our multivariate correlations analysis revealed Omentin-1 as the most robust independent predictor of carotid atherosclerosis (ß-0.687; p = 0.03), even more than total cholesterol, diastolic BP and age, and this adipokine was at the crossroad of a complex interplay with sustained inflammation (high CRP and ferritin) and hyperphosphatemia in predicting higher cIMT values. Conclusion: The findings reported extend to renal patients with advanced disease, with the possible involvement of Omentin-1 in the pathogenesis of atherosclerosis. This may set the stage for future interventional studies of Omentin-1 replacement to retard atherosclerosis progression, as it is currently being investigated in other disease settings.

Antecedent ACE-inhibition, inflammatory response, and cardiac surgery associated acute kidney injury.

Cardiopulmonary bypass (CPB) may trigger organs damage, including kidney injury, due to a massive cytokine release. In this observational, prospective study, we analyzed the possible impact of chronic treatment with ACE-Inhibitors (ACE-I) on the inflammatory response and renal function after CPB. Sixty-nine patients undergoing major cardiac surgery with CPB were enrolled. Patients were stratified according to long-term (> 6 mo.) ACE-I use (n = 38) or not (n = 31). The primary endpoint was the change in IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, TNF alpha, EGF and VEGF plasma levels. Secondary (renal) endpoints were postoperative acute kidney injury (AKI), recovery of baseline GFR values and the absolute changes in renal function indexes. After CPB, IL-1alpha, IL-1beta, IL-4 and TNF-alpha remained stable over time while a significant decrease in IL-2 levels was noticed in the ACE-I group (p = 0.01). IL-6 and IL-8 increased after surgery and tended to decrease after 48 h. IL-10 levels showed a similar variation, but both their rise and decrease were more pronounced in patients under ACE-I treatment (p = 0.007). Finally, VEGF and EGF showed a marked initial decrease with a tendency to normalization 10 days after surgery (p for trend ranging from 0.01 to 0.001). The occurrence of AKI within 2 days after surgery, the rate of GFR recovery and the absolute changes in renal function indexes were not statistically different between groups. Chronic, long-term ACE-I treatment may influence the inflammatory response following CPB. On the other hand, this drug class apparently has neutral impact on perioperative renal outcomes.

Altered circulating marinobufagenin levels and recurrent intradialytic hypotensive episodes in chronic hemodialysis patients: a pilot, prospective study.

Intradialytic hypotension (IDH) is a sudden and often serious complication of chronic hemodialysis (HD). In this prospective study, we aimed at evaluating the clinical predictors of IDH in a homogeneous cohort of chronic HD patients, with a particular focus on marinobufagenin (MBG), an endogenous cardiotonic steroid which alterations have previously been involved in various cardiovascular disorders. MBG levels in HD patients were significantly higher than in controls (p = 0.03), remained unchanged throughout a single HD session and were not correlated with the absolute or partial fluid loss achieved. During a 30-day follow-up, 19 patients (65.5%) experienced at least one IDH (73 total episodes). An inverse correlation was found between baseline MBG and the number of IDH (R = -0.55; p = 0.001). HD patients experiencing IDH presented remarkably lower baseline MBG as compared to others (p = 0.008) with a statistically significant trend during HD (p = 0.02). At Kaplan-Meier analyses, HD patients with lower MBG manifested a four-to-six fold increased risk of IDH during follow-up (crude Hazard Ratio ranging from 4.37 to 6.68). At Cox regression analyses, MBG measurement at different time points resulted the strongest time-dependent predictors of IDH among all the variables considered (HR ranging from 0.068 to 0.155; p: 0.002 to <0.0001). Findings obtained suggest that differently altered MBG in chronic HD patients may reflect a diverse vascular and hemodynamic tolerance to HD stress, eventually leading to recurrent IDH episodes. Further studies are needed to confirm the prognostic capacity of MBG for identifying HD patients at high risk of IDH, particularly those with apparently optimal fluid status.

Renal denervation for resistant hypertension.

BACKGROUND: Resistant hypertension is highly prevalent among the general hypertensive population and the clinical management of this condition remains problematic. Different approaches, including a more intensified antihypertensive therapy, lifestyle modifications or both, have largely failed to improve patients' outcomes and to reduce cardiovascular and renal risk. As renal sympathetic hyperactivity is a major driver of resistant hypertension, in the last decade renal sympathetic ablation (renal denervation) has been proposed as a possible therapeutic alternative to treat this condition. OBJECTIVES: We sought to evaluate the short- and long-term effects of renal denervation in individuals with resistant hypertension on clinical end points, including fatal and non-fatal cardiovascular events, all-cause mortality, hospital admissions, quality of life, blood pressure control, left ventricular hypertrophy, cardiovascular and metabolic profile and kidney function, as well as the potential adverse events related to the procedure. SEARCH METHODS: For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to 3 November 2020: Cochrane Hypertension's Specialised Register, CENTRAL (2020, Issue 11), Ovid MEDLINE, and Ovid Embase. The World Health Organization International Clinical Trials Registry Platform (via CENTRAL) and the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov were searched for ongoing trials. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that compared renal denervation to standard therapy or sham procedure to treat resistant hypertension, without language restriction. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed study risk of bias. We summarised treatment effects on available clinical outcomes and adverse events using random-effects meta-analyses. We assessed heterogeneity in estimated treatment effects using Chi² and I² statistics. We calculated summary treatment estimates as a mean difference (MD) or standardised mean difference (SMD) for continuous outcomes, and a risk ratio (RR) for dichotomous outcomes, together with their 95% confidence intervals (CI). Certainty of evidence has been assessed using the GRADE approach. MAIN RESULTS: We found 15 eligible studies (1416 participants). In four studies, renal denervation was compared to sham procedure; in the remaining studies, renal denervation was tested against standard or intensified antihypertensive therapy. Most studies had unclear or high risk of bias for allocation concealment and blinding.  When compared to control, there was low-certainty evidence that renal denervation had little or no effect on the risk of myocardial infarction (4 studies, 742 participants; RR 1.31, 95% CI 0.45 to 3.84), ischaemic stroke (5 studies, 892 participants; RR 0.98, 95% CI 0.33 to 2.95), unstable angina (3 studies, 270 participants; RR 0.51, 95% CI 0.09 to 2.89) or hospitalisation (3 studies, 743 participants; RR 1.24, 95% CI 0.50 to 3.11). Based on moderate-certainty evidence, renal denervation may reduce 24-hour ambulatory blood pressure monitoring (ABPM) systolic BP (9 studies, 1045 participants; MD -5.29 mmHg, 95% CI -10.46 to -0.13), ABPM diastolic BP (8 studies, 1004 participants; MD -3.75 mmHg, 95% CI -7.10 to -0.39) and office diastolic BP (8 studies, 1049 participants; MD -4.61 mmHg, 95% CI -8.23 to -0.99). Conversely, this procedure had little or no effect on office systolic BP (10 studies, 1090 participants; MD -5.92 mmHg, 95% CI -12.94 to 1.10). Moderate-certainty evidence suggested that renal denervation may not reduce serum creatinine (5 studies, 721 participants, MD 0.03 mg/dL, 95% CI -0.06 to 0.13) and may not increase the estimated glomerular filtration rate (eGFR) or creatinine clearance (6 studies, 822 participants; MD -2.56 mL/min, 95% CI -7.53 to 2.42).  AUTHORS' CONCLUSIONS: In patients with resistant hypertension, there is low-certainty evidence that renal denervation does not improve major cardiovascular outomes and renal function. Conversely, moderate-certainty evidence exists that it may improve 24h ABPM and diastolic office-measured BP. Future trials measuring patient-centred instead of surrogate outcomes, with longer follow-up periods, larger sample size and more standardised procedural methods are necessary to clarify the utility of this procedure in this population.

Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: "Can the Promise Be Kept?"

Anemia is a common complication of chronic kidney disease (CKD). The prevalence of anemia in CKD strongly increases as the estimated Glomerular Filtration Rate (eGFR) decreases. The pathophysiology of anemia in CKD is complex. The main causes are erythropoietin (EPO) deficiency and functional iron deficiency (FID). The administration of injectable preparations of recombinant erythropoiesis-stimulating agents (ESAs), especially epoetin and darbepoetin, coupled with oral or intravenous(iv) iron supplementation, is the current treatment for anemia in CKD for both dialysis and non-dialysis patients. This approach reduces patients' dependence on transfusion, ensuring the achievement of optimal hemoglobin target levels. However, there is still no evidence that treating anemia with ESAs can significantly reduce the risk of cardiovascular events. Meanwhile, iv iron supplementation causes an increased risk of allergic reactions, gastrointestinal side effects, infection, and cardiovascular events. Currently, there are no studies defining the best strategy for using ESAs to minimize possible risks. One class of agents under evaluation, known as prolyl hydroxylase inhibitors (PHIs), acts to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. Several randomized controlled trials showed that HIF-PHIs are almost comparable to ESAs. In the era of personalized medicine, it is possible to envisage and investigate specific contexts of the application of HIF stabilizers based on the individual risk profile and mechanism of action.

Antiproteinuric effect of DPP-IV inhibitors in diabetic and non-diabetic kidney diseases.

Diabetes Mellitus (DM) is a chronic and severe metabolic disease, characterized by chronic hyperglycemia due to insulin resistance and/or reduced insulin secretion. Concerning the non-insulin glucose-lowering therapy for diabetes, Dipeptidyl-peptidase-4 (DPP-4) inhibitors, members of the incretin family, represent new agents, capable of a glycemic control improvement with an advantageous safety profile, given the absence of weight gain, the low incidence of hypoglycemia and the good renal tolerance in patients suffering from chronic renal failure. In addition to demonstrating efficacy in glycemic control through inhibition of GLP-1 degradation, DPP-4 inhibitors (DPP-4is) seem to demonstrate pleiotropic effects, which also make them interesting in both diabetic and non-diabetic nephropathies, especially for their capacity of reducing proteinuria. Several studies about diabetic nephropathy on patients' cohorts and murine models have demonstrated a solid direct relationship between DPP-4 activity and urinary albumin excretion (UAE), thus confirming the capacity of DPP-4is to reduce proteinuria; the mechanism responsible for that effect was studied to assess if it was the result of a direct action on renal impairment or a secondary consequence of the better glycemic control related to these agents. As a result of these more in-depth studies, DPP-4is have demonstrated an improvement of renal inflammation markers and consequent proteinuria reduction, regardless of glucose concentrations. Considering the nephroprotective effects of DPP-4is might be glycemic independent, several studies were conducted to prove the validity of the same effects in non-diabetic nephropathies. Among these studies, DPP-4is demonstrated an improvement of various renal inflammatory markers on several models of non-diabetes dependent renal impairment, confirming their capacity to reduce proteinuria, independently from the action on glucose metabolism. The objective of this review is to present and discuss the so far demonstrated antiproteinuric effect of DPP-4is and their effects on diabetic and non-diabetic nephropathies.

Erythropoiesis and chronic kidney disease-related anemia: From physiology to new therapeutic advancements.

Erythropoiesis is triggered by hypoxia and is strictly regulated by hormones, growth factors, cytokines, and vitamins to ensure an adequate oxygen delivery to all body cells. Abnormalities in one or more of these factors may induce different kinds of anemia requiring different treatments. A key player in red blood cell production is erythropoietin. It is a glycoprotein hormone, mainly produced by the kidneys, that promotes erythroid progenitor cell survival and differentiation in the bone marrow and regulates iron metabolism. A deficit in erythropoietin synthesis is the main cause of the normochromic normocytic anemia frequently observed in patients with progressive chronic kidney disease. The present review summarizes the most recent findings about each step of the erythropoietic process, going from the renal oxygen sensing system to the cascade of events induced by erythropoietin through its own receptor in the bone marrow. The paper also describes the new class of drugs designed to stabilize the hypoxia-inducible factor by inhibiting prolyl hydroxylase, with a discussion about their metabolism, disposition, efficacy, and safety. According to many trials, these drugs seem able to simulate tissue hypoxia and then stimulate erythropoiesis in patients affected by renal impairment. In conclusion, the in-depth investigation of all events involved in erythropoiesis is crucial to understand anemia pathophysiology and to identify new therapeutic strategies, in an attempt to overcome the potential side effects of the commonly used erythropoiesis-stimulating agents.