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.

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.

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.

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.

NFKB1 promoter polymorphism: A new predictive marker of cytomegalovirus infection after kidney transplantation.

INTRODUCTION: Cytomegalovirus (CMV) infection represents a common cause of morbidity and mortality in kidney transplant recipients (KTR). The NF-kB signaling pathway is highly involved in the pathogenesis of CMV infection. The -94ins/delATTG functional polymorphism in the promoter of NFKB1 has been associated with low intracellular levels of the protein and high incidence of inflammatory and autoimmune disease. In this study, we evaluated the association of this NFKB1 polymorphism with the risk of CMV infection. METHODS: CMV infection was defined as virus isolation or detection of viral antigens or nucleic acid in any body fluid or tissue specimen. Using Cox regression and survival analysis, we analyzed the association between the polymorphism and CMV infection as well as recurrence in the first 12 months after transplantation. RESULTS: We analyzed the -94ins/delATTG NFKB1 polymorphism of 189 KTRs. The 65% of CMV infections occurred in ins/ins group. Survival free from CMV infection was 54.7% for ins/ins group and 79.4% for deletion carriers one year after transplantation (P < 0.0001). At multivariate regression, deletion carriers showed a lower risk of CMV infection and recurrence with respect to ins/ins KTRs (HR = 0.224 P = 0.0002; HR = 0.307, P = 0.012, respectively). CONCLUSIONS: In conclusion, pretransplantation screening for NFKB1 -94ins/delATTG polymorphism may predict CMV infection and improve the management of patients at higher risk of infection in the post-transplant period.

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.

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.

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.

Marinobufagenin, Left Ventricular Hypertrophy and Residual Renal Function in Kidney Transplant Recipients.

BACKGROUND: Left ventricular hypertrophy (LVH), which is a pervasive complication of end-stage kidney disease (ESKD), persists in some uremic individuals even after kidney transplantation (Ktx), contributing to worsening CV outcomes. Marinobufagenin (MBG), an endogenous steroid cardiotonic hormone endowed with natriuretic and vasoconstrictive properties, is an acknowledged trigger of uremic cardiomyopathy. However, its clinical significance in the setting of Ktx remains undefined. METHODS: In a cohort of chronic Ktx recipients (n = 40), we assessed circulating MBG together with a thorough clinical and echocardiographic examination. Forty matched haemodialysis (HD) patients and thirty healthy subjects served as controls for MBG measurements. Patients were then prospectively followed up to 12 months and the occurrence of an established cardio-renal endpoint (death, CV events, renal events, graft rejection) was recorded. RESULTS: Median MBG plasma levels were lower in Ktx as compared with HD patients (p = 0.02), but higher as compared with healthy controls (p = 0.0005). Urinary sodium (ß = 0.423; p = 0.01) and eGFR (ß = -0.324; p = 0.02) were the sole independent predictors of MBG in this cohort, while a strong correlation with left ventricular mass index (LVMi), found in univariate analyses (R = 0.543; p = 0.0007), gained significance only in multivariate models not including eGFR. Logistic regression analyses indicated MBG as a significant predictor of the combined endpoint (OR 2.38 [1.10-5.12] per each 1 nmoL/L increase; p = 0.01), as well as eGFR, LVMi, serum phosphate and proteinuria. CONCLUSIONS: Ktx recipients display altered MBG levels which are influenced by sodium balance, renal impairment and the severity of LVH. Thus, MBG might represent an important missing link between reduced graft function and pathological cardiac remodelling and may hold important prognostic value for improving cardio-renal risk assessment.

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.

A small circulating miRNAs signature predicts mortality and adverse cardiovascular outcomes in chronic hemodialysis patients.

Background: Chronic hemodialysis (HD) patients exhibit severe morpho-functional cardiac alterations, putting them at a high risk of death and adverse cardiovascular (CV) outcomes. Despite the fact that an unbalanced expression of various microRNAs (miRNAs) has been related to pathological cardiac remodeling and worse CV outcomes, scarce evidence exists on their role in this setting. Methods: We evaluated circulating levels of a selected miRNAs panel (30a-5p, 23a-3p, 451a and let7d-5p) in 74 chronic HD patients together with a thorough clinical and echocardiography assessment. Individuals were then prospectively followed (median 22 months). The primary endpoint was a composite of all-cause and CV mortality and non-fatal CV events. Results: Circulating levels of all miRNAs were lower in HD patients as compared with healthy controls and independently correlated to the severity of cardiac dysfunction. miRNA 30a-5p, 23a-3p and 451a expression was even lower in 30 subjects (40.5%) reaching the composite endpoint (P < .001), while no differences were reported for let7d-5p. The predictive value of these miRNAs was supported by univariate followed by multivariate Cox regression analyses [hazard ratio (HR) ranging from 0.943 to 0.995; P = .05 to .02] while Kaplan-Meier analyses confirmed a faster progression to the endpoint in individuals displaying miRNA levels below an optimal receiver operating characteristic-derived cut-off value (P ranging from .001 to <.0001; crude HRs 7.95 to 8.61). Conclusions: Lower circulating levels of miRNA 30-5p, 23a-3p and 451a in HD patients may reflect cardiac abnormalities and predict a higher risk of worse clinical outcomes in the short mid-term. Future studies on larger HD populations are needed to generalize these findings.

Acquisition of optical coherence tomography angiography metrics during hemodialysis procedures: A pilot study.

Background and aims: The observation of optical microcirculation gives us an extraordinary way to directly assess in vivo the responses of human circulation to stress stimuli. We run a pilot study to analyze optical coherence tomography angiography (OCT-A) metrics at determined time-points during a hemodialysis (HD) session to understand how these metrics gradually change and to evaluate possible correlations with patients' characteristics. Methods: After the eligibility screening, 15 patients (23 eyes) were included in the study. OCT-A parameters were collected at established time-points: Before treatment (t0), at first hour (t1), at second hour (t2), at third hour (t3), and finally at the end of HD treatment (t4). Patients were finally shared in hypotensive group if they occurred in a hypotensive episode during subsequent month methods or no hypotensive group. The instrument software automatically segmented OCT-A scans into four en-face slabs: The superficial capillary plexus (SCP), the deep capillary plexus (DCP), the outer retinal plexus and the choriocapillaris plexus. In this study we focus on SCP, DCP plexuses. Results: Overall, the majority of ophthalmic parameters remained unaffected and comparable at dialysis end; a significant reduction being observed at the end vs. starting of HD only for deep capillary plexus (DCP: Whole, fovea, and parafovea) and for central choroid thickness (CCT) (p < 0.05). An overall trend during the session showed in general a decrease with a significance in particular for DCP (whole, fovea, and parafovea) and for CCT (P = 0.006). In the hypotension group, Superficial capillary plexus (SCP: Fovea and parafovea) significantly increased comparing post vs. pre-dialysis values while CCT significantly decreased. Analyzing the trend during treatment only CCT maintained a significant trend (p for trend = 0.002). In the no-hypotension group, neither pre- vs. post-analysis and trend analysis showed a statistical significance. Conclusion: Main achievement of our study was to measure, for the first time in literature, single parameters at different time-points of a HD session. As a result of this process we did not notice a brusque decreasing or increasing of OCT-A metrics but we can characterize the different effect of HD on the two distinct areas distinguishing ocular vessels: Retinal and choroidal circulation. As interesting sub-analysis, Hypotensive group showed for CCT a decreasing trend with a difference statistically significant respect to the group with no-hypotension maintaining a constant trend. In our opinion, these results suggest the role of autonomic system on vessel control in patients affected by uremia.

Circulating Omentin-1 levels and altered iron balance in chronic haemodialysis patients.

BACKGROUND: Iron deficiency is highly prevalent among patients undergoing chronic haemodialysis (HD) but its correct identification is often problematic as common biomarkers of iron status, such as transferrin saturation (TSAT) and ferritin, can be altered by inflammation or malnutrition. METHODS: In this pilot multicentre study, we aimed at evaluating circulating levels of Omentin-1, a novel fat depot-specific adipokine that is also involved in iron regulation, in a cohort of 85 chronic HD patients with relation to their iron status. RESULTS: Omentin-1 levels in HD were statistically higher than in healthy controls (P = 0.03) and there was a significant, growing trend in all iron parameters across Omentin-1 tertiles (P < 0.001). Compared with patients with optimal iron status, Omentin-1 levels were lower in subjects categorized according to TSAT ≤20% or serum ferritin ≤200 µg/L (both P < 0.001) and even more reduced in 19 patients (22%) simultaneously displaying low levels of both markers (P < 0.001). In this latter group, Omentin-1 levels increased in parallel to all other iron markers after iron correction by i.v. supplementation. At multivariate regression analyses, ferritin (ß = 0.71; P < 0.001) and TSAT (ß = 0.32; P = 0.03) remained the sole independent predictors of Omentin-1 levels. This biomarker also showed a remarkable diagnostic capacity at receiver operating characteristic analyses in identifying iron-depleted HD patients according to a criterion of TSAT ≤20% [area under the curve (AUC) 0.827], ferritin ≤200 µg/L (AUC 0.863) or low levels of both parameters (AUC 0.907). CONCLUSIONS: Findings obtained indicate that Omentin-1 is somewhat involved in iron balance regulation and might be a candidate biomarker for diagnosing and managing altered iron conditions in HD patients.

Marinobufagenin, left ventricular geometry and cardiac dysfunction in end-stage kidney disease patients.

PURPOSE: Left ventricular hypertrophy (LVH) is remarkably prevalent among end-stage kidney disease (ESKD) on chronic dialysis and has a strong prognostic value for adverse outcomes. In experimental models, the endogenous cardiotonic steroid Marinobufagenin (MBG) promotes cardiac hypertrophy and accelerates uremic cardiomyopathy. In this study, we investigated the possible relationships between MBG, LV geometry and cardiac dysfunction in a clinical setting of ESKD. METHODS: Plasmatic MBG was measured in 46 prevalent ESKD patients (n = 30 HD, n = 16 PD) together with a thorough laboratory, clinical, bioimpedance and echocardiography assessment. Different patterns of LV geometry were defined by left ventricular mass index (LVMi) and ventricular morphology. Diastolic dysfunction was diagnosed by the ASE/EACVI criteria. RESULTS: MBG levels were significantly higher in ESKD patients than in healthy controls (p = 0.001) and more elevated in PD than in HD (p = 0.02). At multivariate analyses, E/e' (ß = 0.38; p = 0.009) and LVMi (ß = 0.42; p = 0.02) remained the sole independent predictors of MBG. A statistically significant trend in MBG levels (p = 0.01) was noticed across different patterns of LV geometry, with the highest values found in eccentric LVH. MBG levels were higher in the presence of diastolic dysfunction (p = 0.01) and this substance displayed a remarkable diagnostic capacity in distinguish patients with normal LV geometry, LV hypertrophy and, particularly, eccentric LVH (AUC 0.888; p < 0.0001) and diastolic dysfunction (AUC 0.79; p = 0.001). CONCLUSIONS: Deranged plasma MBG levels in ESKD patients on chronic dialysis reflect alterations in LV structure and function. MBG may, thus, candidate as a novel biomarker for improving cardiac assessment in this high-risk population.

Nephrosclerosis impacts time trajectory of renal function and outcomes in elderly individuals with chronic kidney disease.

Despite hypertension ranks among the leading causes of chronic kidney disease (CKD), the impact of chronic hypertensive nephropathy, the so-called 'nephrosclerosis' (NS), on CKD progression is often unpredictable, particularly in elderly population. We have conducted a prospective, observational study to define renal function patterns and outcomes in elderly CKD individuals with or without NS. Three hundred four individuals with an already established CKD were categorized according to the etiology of CKD. NS was defined as the presence of CKD associated with long-term essential hypertension, hypertensive retinopathy, left ventricular hypertrophy and minimal proteinuria. Time trajectories in estimated glomerular filtration rate (eGFR) (CKD-Epi) were computed over a 4-year follow-up. In addition, we analyzed the occurrence of a composite outcome of doubling of serum creatinine levels, eGFR reduction ≥25% and/or the need of chronic renal replacement therapy. CKD was secondary to nephrosclerosis (CKD-NS) in 220 (72.3%). In the whole cohort, the average estimated annual GFR slope was 1.8 mL/min/1.73 m2 eGFR decline was slower in CKD-NS as compared with others (1.4 vs 3.4 mL/min/1.73 m2; p<0.001). The composite renal outcome during follow-up occurred less frequently among elderly with CKD-NS (16/204 vs 14/70; p=0.01, crude HR 0.43, 95% CI 0.22 to 0.85) and was associated at logistic analyses with the etiology of CKD, background cardiovascular disease, total and low density lipoproteins (LDL) cholesterol, and glycemia levels (p value was ranging from 0.01 to 0.05). Despite being highly prevalent in the elderly, NS is associated with a more favorable renal disease course as compared with other conditions.

Retarding Progression of Chronic Kidney Disease in Autosomal Dominant Polycystic Kidney Disease with Metformin and Other Therapies: An Update of New Insights.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent single-gene disorder leading to renal failure. Current therapies are aimed to treat renal and extrarenal complications of ADPKD, but improved knowledge of the pathophysiological mechanisms leading to the generation and growth of cysts has permitted the identification of new drug candidates for clinical trials. Among these, in this review, we will examine above all the role of metformin, hypothesized to be able to activate the AMP-activated protein kinase (AMPK) pathway and potentially modulate some mechanisms implicated in the onset and the growth of the cysts.