Interventions for preventing the progression of autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading inherited cause of kidney disease. Clinical management has historically focused on symptom control and reducing associated complications. Improved understanding of the molecular and cellular mechanisms involved in kidney cyst growth and disease progression has resulted in new pharmaceutical agents targeting disease pathogenesis and preventing disease progression. However, the role of disease-modifying agents for all people with ADPKD is unclear. This is an update of a review first published in 2015. OBJECTIVES: We aimed to evaluate the benefits and harms of interventions to prevent the progression of ADPKD and the safety based on patient-important endpoints, defined by the Standardised Outcomes in NephroloGy-Polycystic Kidney Disease (SONG-PKD) core outcome set, and general and specific adverse effects. SEARCH METHODS: We searched the Cochrane Kidney and Transplants Register of Studies up to 13 August 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any interventions for preventing the progression of ADPKD with other interventions, placebo, or standard care were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risks of bias and extracted data. Summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included 57 studies (8016 participants) that investigated 18 pharmacological interventions (vasopressin 2 receptor (V2R) antagonists, antihypertensive therapy, mammalian target of rapamycin (mTOR) inhibitors, somatostatin analogues, antiplatelet agents, eicosapentaenoic acids, statins, kinase inhibitors, diuretics, anti-diabetic agents, water intake, dietary intervention, and supplements) in this review. Compared to placebo, the V2R antagonist tolvaptan probably preserves eGFR (3 studies, 2758 participants: MD 1.26 mL/min/1.73 m2, 95% CI 0.73 to 1.78; I2 = 0%) and probably slows total kidney volume (TKV) growth in adults (1 study, 1307 participants: MD -2.70 mL/cm, 95% CI -3.24 to -2.16) (moderate certainty evidence). However, there was insufficient evidence to determine tolvaptan's impact on kidney failure and death. There may be no difference in serious adverse events; however, treatment probably increases nocturia, fatigue and liver enzymes, may increase dry mouth and thirst, and may decrease hypertension and urinary and upper respiratory tract infections. Data on the impact of other therapeutic interventions were largely inconclusive. Compared to placebo, somatostatin analogues probably decrease TKV (6 studies, 500 participants: SMD -0.33, 95% CI -0.51 to -0.16; I2 = 11%), probably have little or no effect on eGFR (4 studies, 180 participants: MD 4.11 mL/min/1.73 m3, 95% CI -3.19 to 11.41; I2 = 0%) (moderate certainty evidence), and may have little or no effect on kidney failure (2 studies, 405 participants: RR 0.64, 95% CI 0.16 to 2.49; I2 = 39%; low certainty evidence). Serious adverse events may increase (2 studies, 405 participants: RR 1.81, 95% CI 1.01 to 3.25; low certainty evidence). Somatostatin analogues probably increase alopecia, diarrhoea or abnormal faeces, dizziness and fatigue but may have little or no effect on anaemia or infection. The effect on death is unclear. Targeted low blood pressure probably results in a smaller per cent annual increase in TKV (1 study, 558 participants: MD -1.00, 95% CI -1.67 to -0.33; moderate certainty evidence) compared to standard blood pressure targets, had uncertain effects on death, but probably do not impact other outcomes such as change in eGFR or adverse events. Kidney failure was not reported. Data comparing antihypertensive agents, mTOR inhibitors, eicosapentaenoic acids, statins, vitamin D compounds, metformin, trichlormethiazide, spironolactone, bosutinib, curcumin, niacinamide, prescribed water intake and antiplatelet agents were sparse and inconclusive. An additional 23 ongoing studies were also identified, including larger phase III RCTs, which will be assessed in a future update of this review. AUTHORS' CONCLUSIONS: Although many interventions have been investigated in patients with ADPKD, at present, there is little evidence that they improve patient outcomes. Tolvaptan is the only therapeutic intervention that has demonstrated the ability to slow disease progression, as assessed by eGFR and TKV change. However, it has not demonstrated benefits for death or kidney failure. In order to confirm the role of other therapeutic interventions in ADPKD management, large RCTs focused on patient-centred outcomes are needed. The search identified 23 ongoing studies, which may provide more insight into the role of specific interventions.

Unbalanced circulating Humanin levels and cardiovascular risk in chronic hemodialysis patients: a pilot, prospective study.

BACKGROUND: Mortality and cardiovascular (CV) risk prediction in individuals with end-stage kidney disease (ESKD) on chronic hemodialysis (HD) remains challenging due to the multitude of implicated factors. In a multicenter ESKD-HD cohort, we tested the prognostic yield of the assessment of circulating Humanin, a small mitochondrial-derived peptide involved in CV protection, on CV events and mortality. METHODS: We conducted a prospective, observational, pilot study on 94 prevalent HD patients. The prognostic capacity of circulating Humanin levels was tested on a primary composite (all-cause mortality + non-fatal CV events) and a secondary exploratory endpoint (all-cause mortality alone). RESULTS: Baseline Humanin level was comparable in patients reaching the primary or secondary endpoint as compared to others (p = 0.69 and 0.76, respectively). Unadjusted followed by multivariable Cox regression analyses adjusted for age, left ventricular mass index (LVMi), E/e', pulse pressure and diabetes mellitus indicated a non-linear relationship between Humanin levels and the composite outcome with the highest Hazard Ratio (HR) associated with very low (< 450.7 pg/mL; HR ranging from 4.25 to 2.49) and very high (> 759.5 pg/mL; HR ranging from 5.84 to 4.50) Humanin values. Restricted cubic splines fitting univariate and multivariate Cox regression analyses visually confirmed a curvilinear trend with an increasing risk observed for lower and higher Humanin values around the median, respectively. A similar, u-shaped association was also evidenced with the secondary endpoint. CONCLUSIONS: Altered Humanin levels may impart prognostic information in ESKD-HD patients at risk of death or CV events. Future investigations are needed to confirm whether Humanin measurement could improve CV and mortality risk prediction beyond traditional risk models.

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.

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.

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.

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

Background: Biomarkers development for prognostication or prediction of perioperative myocardial disease is critical for the evolution of treatment options in patients undergoing cardiac surgery. The aim of our prospective monocentric study was to investigate the role of selenoprotein 1 (SEEP 1) as a potential biomarker for assessing the risk of myocardial injury after cardiac surgery. 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); (3) Results: circulating SEPP-1 levels measured 4 h after surgery were strongly correlated with CK-MB levels measured at 48 h (R = 0.598, p < 0.0001) and at 72 h (R = 0.308, p = 0.05). Close correlations were also found between 4 h SEPP-1 and Hs-c troponin values measured at 24 h (R = 0.532, p < 0.0001), 48 h (R = 0.348, p = 0.01) and 72 h (R = 0.377, p = 0.02), as well as with cardiopulmonary bypass (CPB) (R = 0.389, p = 0.008) and cross-clamp time (R = 0.374, p = 0.001); (4) Conclusions: Early SEPP1 measurement after CPB may hold great potential for identifying cardiac surgery patients at risk of developing perioperative myocardial injury.

Kidney Fibrosis and Matrix Metalloproteinases (MMPs).

Chronic kidney disease (CKD) is a disorder that causes changes in both the structure and function of the kidneys, causing complications such as hypertension, edema, and oliguria. Renal fibrosis is also a common pathological feature of CKD. Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix (ECM) proteins. The proteinase domain consists of a zinc ion in the active site, which contributes to its stabilization with another zinc and three calcium structural ions. Many cellular processes are controlled by MMPs, such as cell-cell interactions and various signaling pathways, while they are also involved in degrading substrates on cell surfaces. Tissue inhibitors of metalloproteinases (TIMPs) are key regulators of metalloproteinases, and both are involved in regulating cell turnover, the regulation, and the progression of fibrosis and apoptosis in the tissue. MMPs play a role in renal fibrosis, such as the tubular cell epithelial-mesenchymal transition (TEM), activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT), and pericyte-myofibroblast transdifferentiation. This review aims to show the mechanisms through which MMPs contribute to renal fibrosis, paying particular attention to MMP-9 and the epithelial-mesenchymal transition.

Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: a clinical practice document by the European Renal Best Practice board of the European Renal Association.

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with poor long-term outcomes and quality of life. The use of supplemental iron, erythropoiesis-stimulating agents (ESAs) and blood transfusions has been the mainstay for treatment of anaemia in CKD for more than 3 decades. Despite available treatments, CKD patients with anaemia are undertreated and moderate-severe anaemia remains prevalent in the CKD population. Anaemia has consistently been associated with greater mortality, hospitalization, cardiovascular events and CKD progression in CKD patients, and the risk increases with anaemia severity. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitors have a novel mechanism of action by mimicking the body's response to hypoxia and have emerged as an alternative to ESAs for treatment of anaemia in CKD. Their efficacy in correcting and maintaining haemoglobin has been demonstrated in >30 phase 3 clinical trials. Additionally, HIF activation results in various pleiotropic effects beyond erythropoiesis, with cholesterol reduction and improved iron homeostasis and potential anti-inflammatory effects. The long-term safety of these agents, particularly with respect to cardiovascular and thromboembolic events, and their possible effect on tumour growth needs to be fully elucidated. This article presents in detail the effects of HIF-PH inhibitors, describes their mechanisms of action and pharmacologic properties and discusses their place in the treatment of anaemia in CKD according to the available evidence.

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.

Sleep apnoea syndrome prevalence in chronic kidney disease and end-stage kidney disease patients: a systematic review and meta-analysis.

Background: Several studies have examined the frequency of sleep apnoea (SA) in patients with chronic kidney disease (CKD), reporting different prevalence rates. Our systematic review and meta-analysis aimed to define the clinical penetrance of SA in CKD and end-stage kidney disease (ESKD) patients. Methods: Ovid-MEDLINE and PubMed databases were explored up to 5 June 2023 to identify studies providing SA prevalence in CKD and ESKD patients assessed by different diagnostic methods, either sleep questionnaires or respiration monitoring equipment [such as polysomnography (PSG), type III portable monitors or other diagnostic tools]. Single-study data were pooled using the random-effects model. The Chi2 and Cochrane-I2 tests were used to assess the presence of heterogeneity, which was explored performing sensitivity and/or subgroup analyses. Results: A cumulative analysis from 32 single-study data revealed a prevalence of SA of 57% [95% confidence interval (CI) 42%-71%] in the CKD population, whereas a prevalence of 49% (95% CI 47%-52%) was found pooling data from 91 studies in ESKD individuals. The prevalence of SA using instrumental sleep monitoring devices, including classical PSG and type III portable sleep monitors, was 62% (95% CI 52%-72%) and 56% (95% CI 42%-69%) in CKD and ESKD populations, respectively. Sleep questionnaires revealed a prevalence of 33% (95% CI 16%-49%) and 39% (95% CI 30%-49%). Conclusions: SA is commonly seen in both non-dialysis CKD and ESKD patients. Sleep-related questionnaires underestimated the presence of SA in this population. This emphasizes the need to use objective diagnostic tools to identify such a syndrome in kidney disease.

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.

Evaluation of arteriovenous fistula for hemodialysis with a new generation digital stethoscope: a pilot study.

BACKGROUND AND AIMS: The management of complications of arteriovenous fistula (AVF) for hemodialysis, principally stenosis, remains a major challenge for clinicians with a substantial impact on health resources. Stenosis not infrequently preludes to thrombotic events with the loss of AVF functionality. A functioning AVF, when listened by a stethoscope, has a continuous systolic-diastolic low-frequency murmur, while with stenosis, the frequency of the murmur increases and the duration of diastolic component decreases, disappearing in severe stenosis. These evidences are strictly subjective and dependent from operator skill and experience. New generation digital stethoscopes are able to record sound and subsequently dedicated software allows to extract quantitative variables that characterize the sound in an absolutely objective and repeatable way. The aim of our study was to analyze with an appropriate software sounds from AVFs taken by a commercial digital stethoscope and to investigate the potentiality to develop an objective way to detect stenosis. METHODS: Between September 2022 and January 2023, 64 chronic hemodialysis (HD) patients were screened by two blinded experienced examiners for recognized criteria for stenosis by Doppler ultrasound (DUS) and, consequently, the sound coming from the AVFs using a 3 M™ Littmann® CORE Digital Stethoscope 8570 in standardized sites was recorded. The sound waves were transformed into quantitative variables (amplitude and frequency) using a sound analysis software. The practical usefulness of the core digital stethoscope for a quick identification of an AVF stenosis was further evaluated through a pragmatic trial. Eight young nephrologist trainees underwent a simple auscultatory training consisting of two sessions of sound auscultation focusing two times on a "normal" AVF sound by placing the digital stethoscope on a convenience site of a functional AVF. RESULTS: In 48 patients eligible, all sound components displayed, alone, a remarkable diagnostic capacity. More in detail, the AUC of the average power was 0.872 [95% CI 0.729-0.951], while that of the mean normalized frequency was 0.822 [95% 0.656-0.930]. From a total of 32 auscultations (eight different block sequences, each one comprising four auscultations), the young clinicians were able to identify the correct sound (stenosis/normal AVF) in 25 cases, corresponding to an overall accuracy of 78.12% (95% CI 60.03-90.72%). CONCLUSIONS: The analysis of sound waves by a digital stethoscope permitted us to distinguish between stenotic and no stenotic AVFs. The standardization of this technique and the introducing of data in a deep learning algorithm could allow an objective and fast method for a frequent monitoring of AVF.

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.

Circulating miRNA 122-5p Expression Predicts Mortality and Cardiovascular Events in Chronic Hemodialysis Patients: A Multicentric, Pilot, Prospective Study.

BACKGROUND: Despite patients undergoing chronic hemodialysis (HD) being notoriously prone to adverse cardiovascular (CV) events, risk prediction in this population remains challenging. miRNA 122-5p, a short, non-coding RNA predominantly involved in lipid and carbohydrate metabolism, has recently been related to the onset and progression of CV disease. METHODS: We run a pilot, multicenter, longitudinal, observational study to evaluate the clinical significance and prognostic usefulness of circulating miRNA 122-5p in a multicentric cohort of 74 individuals on maintenance HD. RESULTS: Patients displayed lower circulating miRNA 122-5p as compared to healthy controls (p = 0.004). At correlation analyses, ALT (ß = 0.333; p = 0.02), E/e' (ß = 0.265; p = 0.02) and CRP (ß = -0.219; p = 0.041) were independent predictors of miRNA 122-5p levels. During a median follow-up of 22 months (range of 1-24), 30 subjects (40.5%) experienced a composite endpoint of all-cause mortality and fatal/non-fatal CV events. Baseline circulating miRNA 122-5p was higher in these subjects (p = 0.01) and it predicted a significantly higher risk of endpoint occurrence (Kaplan-Meier crude HR 3.192; 95% CI 1.529-6.663; p = 0.002; Cox regression adjusted HR 1.115; 95% CI 1.009-1.232; p = 0.03). CONCLUSIONS: Altered miRNA 122-5p levels in HD patients may reflect hepatic and CV damage and may impart important prognostic information for improving CV risk prediction in this particular setting.

Self-Reported Physical Inactivity and Mood Disturbances in End-Stage Kidney Disease (ESKD) Patients on Chronic Dialysis Treatment.

BACKGROUND: Physical inactivity and mood disturbances are key issues in individuals with end-stage kidney disease (ESKD) and may lead to poor clinical outcomes. METHODS: We performed a pilot, observational study to explore the possible relationships between the self-reported level of physical activity (IPAQ) and the severity of mood disturbances (BDI score) in a cohort of 58 ESKD patients undergoing chronic hemodialysis (HD; n = 30) or peritoneal dialysis (PD; n = 28). RESULTS: Overall, ESKD patients were severely inactive (median METs: 590 [460-1850]) and the intensity of overall and walking physical activity was mostly low to moderate. HD individuals appeared less active than PD (METs 550 [250-1600] vs. 1080 [750-1730]; p = 0.003) and were also less prone to walking (METs 180 ± 90 vs. 320 ± 100; p = 0.01), while a barely statistical difference was noticed for the time spent sitting. ESKD individuals displayed a median BDI score of 17 [12-21], which indicated, on average, the presence of borderline depression, which was apparently more evident among HD individuals. A strong, inverse correlation was found between self-reported METs and BDI scores (R = -0.78; p < 0.0001), while such scores paralleled the time spent sitting during a weekday (R = 0.45; p = 0.0004) and a weekend day (R = 0.40; p = 0.002). CONCLUSIONS: In ESKD patients on chronic dialysis, physical inactivity and mood disturbances might be significantly inter-connected, thereby amplifying their relative impact on quality of life, dysautonomia and long-term outcomes. Future studies on larger populations are recommended to confirm these preliminary observations. Promoting strategies to improve fitness, along with greater attention to physiological aspects, should be incorporated into the clinical management of ESKD patients.

Hyperkalemia in CKD: an overview of available therapeutic strategies.

Hyperkalemia (HK) is a life-threatening condition that often occurs in patients with chronic kidney disease (CKD). High serum potassium (sKsK) is responsible for a higher risk of end-stage renal disease, arrhythmias and mortality. This risk increases in patients that discontinue cardio-nephroprotective renin-angiotensin-aldosterone system inhibitor (RAASi) therapy after developing HK. Hence, the management of HK deserves the attention of the clinician in order to optimize the therapeutic strategies of chronic treatment of HK in the CKD patient. The adoption in clinical practice of the new hypokalaemic agents patiromer and sodium zirconium cyclosilicate (SZC) for the prevention and chronic treatment of HK could allow patients, suffering from heart failure and chronic renal failure, to continue to benefit from RAASi therapy. We have updated a narrative review of the clear variables, correct definition, epidemiology, pathogenesis, etiology and classifications for HK among non-dialysis CKD (ND CKD) patients. Furthermore, by describing the prognostic impact on mortality and on the progression of renal damage, we want to outline the strategies currently available for the control of potassium (K+) plasma levels.

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.

Chronic kidney disease: the missing concept in the 2019 EULAR/ERA-EDTA recommendations for lupus nephritis.

Chronic kidney disease (CKD) is diagnosed when glomerular filtration rate (GFR) falls below 60 ml/min/1.73 m2 or urinary albumin:creatinine ratio (UACR) reaches ≥30 mg/g, as these two thresholds indicate a higher risk of adverse health outcomes, including cardiovascular mortality. CKD is classified as mild, moderate or severe, based on GFR and UACR values, and the latter two classifications convey a high or very high cardiovascular risk, respectively. Additionally, CKD can be diagnosed based on abnormalities detected by histology or imaging. Lupus nephritis (LN) is a cause of CKD. Despite the high cardiovascular mortality of patients with LN, neither albuminuria nor CKD are discussed in the 2019 European League Against Rheumatism (EULAR)/European Renal Association-European Dialysis and Transplant Association recommendations for the management of LN or the more recent 2022 EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases. Indeed, the proteinuria target values discussed in the recommendations may be present in patients with severe CKD and a very high cardiovascular risk who may benefit from guidance detailed in the 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice. We propose that the recommendations should move from a conceptual framework of LN as an entity separate from CKD to a framework in which LN is considered a cause of CKD and evidence generated from large CKD trials applies unless demonstrated otherwise.

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.