[Therapeutic options to reduce arterial stiffness in chronic kidney disease].

Chronic kidney disease is associated with an increased cardiovascular risk. Several uremic toxins are also vascular toxins and may contribute to the increase of the cardiovascular risk through the development of aortic stiffening. In this process, oxidative stress and endothelial dysfunction play an important role. Considering that aortic stiffness is a known cardiovascular risk factor and a vascular biomarker involved in the development of chronic cardiac dysfunction, and that the reduction of aortic stiffness is associated with an improved survival of patients with end-stage kidney disease, we aim at reviewing the therapeutic options to reduce aortic stiffness and potentially the cardiovascular risk.

Reducing salt intake by urine chloride self-measurement in non-compliant patients with chronic kidney disease followed in nephrology clinics: a randomized trial.

BACKGROUND: Adherence to low salt diets and control of hypertension remain unmet clinical needs in chronic kidney disease (CKD) patients. METHODS: We performed a 6-month multicentre randomized trial in non-compliant patients with CKD followed in nephrology clinics testing the effect of self-measurement of urinary chloride (69 patients) as compared with standard care (69 patients) on two primary outcome measures, adherence to a low sodium (Na) diet (<100 mmol/day) as measured by 24-h urine Na (UNa) excretion and 24-h ambulatory blood pressure (ABPM) monitoring. RESULTS: In the whole sample (N = 138), baseline UNa and 24-h ABPM were143 ± 64 mmol/24 h and 131 ± 18/72 ± 10 mmHg, respectively, and did not differ between the two study arms. Patients in the active arm of the trial used >80% of the chloride strips provided to them at the baseline visit and at follow-up visits. At the third month, UNa was 35 mmol/24 h (95% CI 10.8-58.8 mmol/24 h; P = 0.005) lower in the active arm than the control arm, whereas at 6 months the between-arms difference in UNa decreased and was no longer significant [23 mmol/24 h (95% CI -5.6-50.7); P = 0.11]. The 24-h ABPM changes as well as daytime and night-time BP changes at 3 and 6 months were similar in the two study arms (Month 3, P = 0.69-0.99; Month 6, P = 0.73-0.91). Office BP, the use of antihypertensive drugs, estimated Glomerular Filtration Rate (eGFR) and proteinuria remained unchanged across the trial. CONCLUSIONS: The application of self-measurement of urinary chloride to guide adherence to a low salt diet had a modest effect on 24-h UNa and no significant effect on 24-h ABPM.

[Vascular dysfunction in Cardiorenal Syndrome type 4].

The Cardiorenal Syndrome type 4 (CRS-4) defines a pathological condition in which a primary chronic kidney disease (CKD) leads to a chronic impairment of cardiac function. The pathophysiology of CRS-4 and the role of arterial stiffness remain only in part understood. Several uremic toxins, such as uric acid, phosphates, advanced glycation end-products, asymmetric dimethylarginine, and endothelin-1, are also vascular toxins. Their effect on the arterial wall may be direct or mediated by chronic inflammation and oxidative stress. Uremic toxins lead to endothelial dysfunction, intima-media thickening and arterial stiffening. In patients with CRS-4, the increased aortic stiffness results in an increase of cardiac workload and left ventricular hypertrophy whereas the loss of elasticity results in decreased coronary artery perfusion pressure during diastole and increased risk of myocardial infarction. Since the reduction of arterial stiffness is associated with an increased survival in patients with CKD, the understanding of the mechanisms that lead to arterial stiffening in patients with CRS4 may be useful to select potential approaches to improve their outcome. In this review we aim at discussing current understanding of the pathways that link uremic toxins, arterial stiffening and impaired cardiac function in patients with CRS-4.

Arteriovenous fistula and pre-surgery mapping: Potential role of physical exercise on endothelial function.

BACKGROUND: The success of the construction of an arteriovenous fistula for haemodialysis is related to the vascular function of the vessels involved in the anastomosis, with particular reference to radial artery distensibility after reactive hyperaemia test and to the fall of resistance index. Only few studies have evaluated the impact of exercise protocols on the endothelial and morphological characteristics of the vessels of the upper limb with inconclusive results. In this pilot longitudinal study, we aimed to evaluate the impact of a standardized exercise protocol on the haemodynamic and resistive index of the arteries of the upper limb of uraemic patients. METHODS: A total of 17 uraemic patients planned to construct arteriovenous fistula at the distal third of the forearm were enrolled and followed up for 30 days. All patients performed repeated handgrips for 30 min/day. The arterial parameters were detected before and after an ischaemic stress of 5 min and radial and brachial artery flow-mediated dilation was evaluated as well as radial artery resistance index. RESULTS: Pre-exercise measurements of radial artery diameter and resistance index and brachial artery diameter were not modified by 30 days hand physical exercise, whereas the post-exercise haemodynamic were improved. Consequently, flow-mediated dilation of the radial artery was improved (21% ± 14% vs 30% ± 19%; p = 0.03) and resistance index of the radial artery was reduced (p = 0.02). CONCLUSION: Exercise has beneficial effects on endothelial function of the radial artery by resistive index and, potentially, on the outcome of the arteriovenous fistula. Further studies with larger sample size are needed to confirm our preliminary data.

Renal haemodynamics and coronary atherosclerotic burden are associated in patients with hypertension and mild coronary artery disease.

Intrarenal hemodynamic alterations are independent predictors of cardiovascular events in different populations. It has been hypothesized that there is an association between renal hemodynamics and coronary atherosclerotic burden in patients with hypertension. Therefore, the present study examined the associations between renal hemodynamics, coronary atherosclerotic burden and carotid atherosclerotic disease. A total of 130 patients with hypertension aged between 30-80 years who had been referred for an elective coronary angiography were enrolled in the present study. A duplex ultrasound of the intrarenal vasculature was performed to evaluate the resistive index (RI), pulsatility index (PI) and acceleration time (AT). The carotid intima-media thickness was additionally assessed. A coronary angiography was performed to detect the atherosclerotic burden using the Gensini Score (GS). Based on the GS values, subjects were divided into quintiles (I: ≤9; II: 9-17; III: 17-30; IV: 30-44; and V: GS >44) as well as in subjects with mild (GS ≤30) or severe coronary disease (GS >30). A weak significant difference in PI was identified among quintiles (P=0.041), whereas, RI and AT did not differ significantly. PI was associated with GS in the group with low coronary atherosclerotic burden (GS ≤30; P=0.047), whereas, no association was detected in subjects with GS >30. This association remained following adjustment for age and left ventricular ejection fraction (P=0.025). In conclusion, renal vascular alterations were associated with coronary atherosclerotic burden in patients with hypertension with mild coronary disease.

Inflammation and Aortic Pulse Wave Velocity: A Multicenter Longitudinal Study in Patients With Inflammatory Bowel Disease.

Background Inflammatory bowel disease ( IBD ) is characterized by a low prevalence of traditional risk factors, an increased aortic pulse-wave velocity ( aPWV ), and an excess of cardiovascular events. We have previously hypothesized that the cardiovascular risk excess reported in these patients could be explained by chronic inflammation. Here, we tested the hypothesis that chronic inflammation is responsible for the increased aPWV previously reported in IBD patients and that anti-TNFa (anti-tumor necrosis factor-alpha) therapy reduce aPWV in these patients. Methods and Results This was a multicenter longitudinal study. We enrolled 334 patients: 82 patients with ulcerative colitis, 85 patients with Crohn disease, and 167 healthy control subjects matched for age, sex, and mean blood pressure, from 3 centers in Europe, and followed them for 4 years (range, 2.5-5.7 years). At baseline, IBD patients had higher aPWV than controls. IBD patients in remission and those treated with anti-TNFa during follow-up experienced an aortic destiffening, whereas aPWV increased in those with active disease and those treated with salicylates ( P=0.01). Disease duration ( P=0.02) was associated with aortic stiffening as was, in patients with ulcerative colitis, high-sensitivity C-reactive protein during follow-up ( P=0.02). All these results were confirmed after adjustment for major confounders. Finally, the duration of anti-TNFa therapy was not associated with the magnitude of the reduction in aPWV at the end of follow-up ( P=0.85). Conclusions Long-term anti-TNFa therapy reduces aPWV , an established surrogate measure of cardiovascular risk, in patients with IBD . This suggests that effective control of inflammation may reduce cardiovascular risk in these patients.

Para-perirenal distribution of body fat is associated with reduced glomerular filtration rate regardless of other indices of adiposity in hypertensive patients.

Obesity is a well-known risk factor for the development and progression of chronic kidney disease. Recently, para-perirenal ultrasonographic fat thickness (PUFT) has shown to correlate with both total and visceral fat better than body mass index (BMI), waist circumference (WC), and other indices of obesity. Moreover, a local paracrine and mechanical action of the PUFT on kidney has been described in recent studies. Aim of our study was to assess the relationship between glomerular filtration rate (GFR) and PUFT in comparison with other anthropometric and ultrasonographic indices of adiposity. Two hundred and ninety-six hypertensive patients were enrolled. PUFT, cutis-rectis thickness and rectis-aorta thickness were obtained by ultrasonography. Anthropometric measures of adiposity were also measured. Estimated GFR was calculated using the CKD-EPI equation. Higher PUFT values were observed in patients with impaired renal function (P < 0.001), whereas no differences in BMI and WC were shown between groups divided by GFR. PUFT significantly correlated with GFR in all patients (r = -0.284; P < 0.001), with no differences in groups divided by sex, diabetes, or BMI. This association held in multivariate analyses also after correction for confounding factors, including other adiposity indices (P < 0.001). When receiver operating characteristic curves were built to detect a eGFR < 60 mL/minutes per 1.73 m2 , a PUFT value ≤3.725 cm showed a negative predictive value of 94.0%, with the largest area under the curve (AUC: 0.700) among the variables considered. In conclusion, the relationship between PUFT and GFR seems to be more accurate and less influenced by the bias affecting traditional indices of adiposity.

Stroke volume variation and serum creatinine changes during abdominal aortic aneurysm surgery: a time-integrated analysis.

BACKGROUND: Patients undergoing abdominal aortic aneurysm (AAA) surgery with suprarenal clamping are at high risk for acute kidney injury (AKI) and major cardiac and cerebrovascular events (MACCE). We aimed to assess whether the stroke volume variation (SVV), a measure of hemodynamic instability, is associated with AKI in hypertensive patients undergoing elective AAA surgery with suprarenal clamping. METHODS: In a cohort of 51 hypertensive patients, we performed serial measurements of SVV (n = 459) and serum creatinine (sCr) (n = 255). AKI was defined according to the KDIGO clinical practice guidelines. Data were analyzed by repeated-measures ANOVA and regression analysis of time-integrated changes of both SVV and sCr. RESULTS: AKI developed in 45% of patients (stage 1: 31%; stage 2: 10%; stage 3: 2%). The diuresis during surgery (beta - 0.29 Z-score 95% [CI - 0.54, - 0.05]; p = 0.02), clamp time (beta 0.29 Z-score [0.05-0.52]; p = 0.02), and time-integrated changes in SVV from baseline to 12 h after surgery (beta 0.31 Z-score [0.03-0.60]; p = 0.03) were independent predictors of the time-integrated changes in sCr from baseline to 48 h after the end of surgery. In a model adjusted for age and sex, patients with AKI had an increased risk for MACCE during a mean follow-up of 3.5 ± 1.1 years (HR 5.53 [1.52-20.06]; p = 0.004). CONCLUSIONS: SVV increases progressively during and after AAA surgery in subjects who will develop AKI. The increase of SVV precedes and predicts the rise in sCr and is a good discriminator of the development of AKI. AKI is associated with an increased long-term risk for MACCE.

Pulse wave velocity differs between ulcerative colitis and chronic kidney disease.

BACKGROUND: We hypothesized that a reversal of the physiological stiffness gradient, previously reported in end-stage renal disease, begins in the early stages of chronic kidney disease (CKD) and that chronic inflammation produces a different arterial phenotype in patients with ulcerative colitis (UC). OBJECTIVES: To assess the extent of arterial stiffening in the central (carotid-femoral pulse wave velocity, cf.-PWV) and peripheral arteries (carotid-radial pulse wave velocity, cr-PWV) and to explore the determinants of the stiffness gradient in UC and in CKD. METHODS: We enrolled 45 patients with UC, 45 patients with stage 3-4 CKD and 45 matched controls. RESULTS: Despite the comparable cf.-PWV, the cr-PWV was higher in patients with UC than in those with CKD (median: 8.7 vs. 7.5m/s; p<0.001) and, consequently, the PWV ratio was lower (median: 0.97 vs. 1.12; p<0.001). In patients with CKD a stiffness mismatch was reported starting from stage 3B. The PWV ratio was associated with age and C-reactive protein (beta: 0.08 z-score, 95%CI 0.02-0.14; p=0.01) or active disease (beta: 0.43 z-score, 95%CI 0.003-0.857; p=0.048) in patients with UC and with age and glomerular filtration rate (beta: -0.56 z-score, 95%CI -1.05 to -0.07; p=0.02) in patients with CKD. CONCLUSIONS: The arterial phenotype differed between UC and CKD. The reversal of the arterial stiffness gradient is evident in CKD patients starting from stage 3B but not in patients with UC and comparable cf.-PWV. In patients with UC, the stiffness of both elastic and muscular arteries is increased as a consequence of inflammation.

Digoxin and Hypermagnesuria.

In a recent issue of Nephron, Abu-Amer et al.[1] reported the presence of hypermagnesuria in patients following acute intravenous administration of digoxin and suggested that the Na+/K+-ATPase γ-subunit, which is the pharmacological target of digoxin, can play a role in this process. Hypermagnesuria induced by digoxin may have important clinical consequences, particularly in the presence of inherited and acquired conditions associated with hypermagnesuria and hypomagnesemia. Moreover, the co-administration of digoxin with other drugs that reduce gastrointestinal absorption (i.e., proton pump inhibitors) or increase urinary excretion (i.e., loop diuretics) may increase the likelihood of developing hypomagnesemia. In this article, we reviewed the main causes of hypermagnesuria and discussed potential drug interactions that can enhance the magnesuric effect of digoxin. We suggest that during the administration of digoxin, clinicians should consider the presence of other causes of hypomagnesemia and hypermagnesuria that could enhance the magnesuric effect of digoxin, monitor the urinary and serum levels of magnesium and prescribe an oral supplementation of magnesium.

Inflammation and Aortic Stiffness: An Individual Participant Data Meta-Analysis in Patients With Inflammatory Bowel Disease.

BACKGROUND: The recent finding that aortic pulse wave velocity (aPWV) is increased in patients with inflammatory bowel disease may explain why the cardiovascular risk is increased despite the low prevalence of traditional cardiovascular risk factors. We aimed to test whether inflammation is associated with aortic stiffening in this setting after adjustment for major confounders and to perform subgroup analyses. METHODS AND RESULTS: A systematic literature search for aPWV in inflammatory bowel disease was performed using PubMed, Scopus, Web of Science, and Google Scholar databases (last accessed May 7, 2017). Inclusion criterion was peer-reviewed publications on clinical studies reporting original data. This study followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data 2015 guidelines. Data were provided for 4 cohorts in 3 countries (151 participants with ulcerative colitis, 159 with Crohn's disease, and 227 control patients). Using aPWV, cohort-specific z scores were calculated after loge-transform and combined in meta-analysis to form pooled effects using a random-effects model. Compared with controls, aPWV was increased in patients with Crohn's disease (mean difference 0.78 z score; 95% confidence interval, 0.56-1.00 z score [P<0.001]) and ulcerative colitis (mean difference 0.75 z score; 95% confidence interval, 0.52-0.97 z score [P<0.001]). In an outlier-robust multivariate linear regression model adjusted for prespecified confounders, aPWV was associated with disease duration (years, ß=0.05 z score; 95% confidence interval, 0.02-0.08 z score [P<0.001]) and white blood cell count (billion cells/L, ß=0.07 z score; 95% confidence interval, 0.02-0.11 z score [P=0.002]) but not with markers of acute inflammation (C-reactive protein and erythrocyte sedimentation rate), cardiovascular risk factors, and therapy. CONCLUSIONS: The increased aPWV reported in patients with inflammatory bowel disease is associated with inflammation. CLINICAL TRIAL REGISTRATION: URL: http://www.crd.york.ac.uk. Unique identifier: PROSPERO 2016: CRD42016053070.

[Renal diseases related to MYH9 disorders].

Mutations in MYH9 gene encoding the nonmuscle myosin heavy chain IIA (NMMHC-IIA) are related to a number of rare autosomal-dominant disorders which has been known as May-Hegglin disease, Sebastian syndrome, Fechtner syndrome and Epstein syndrome. Their common clinical features are congenital macrothrombocytopaenia and polymorphonuclear inclusion bodies, in addition to a variable risk of developing proteinuria, chronic kidney disease progressing toward end stage, sensorineural deafness and presenile cataracts. The term MYH9 related disease (MYH9-RD) describes the variable expression of a single illness encompassing all previously mentioned hereditary disorders. Renal involvement in MYH9- RD has been observed in 30% of patients. Mutant MYH9 protein, expressed in podocytes, mesangial and tubular cells, plays a main role in foot process effacement and in development of nephropathy. Interestingly, the MYH9 gene is currently under investigation also for his possible contribution to many other non-hereditary glomerulopathies such as focal global glomerulosclerosis (hypertensive nephrosclerosis), idiopathic focal segmental glomerulosclerosis, C1q nephropathy and HIV-associated nephropathy. In this review we are aimed to describe renal diseases related to MYH9 disorders, from the hereditary disease to the acquired disorders, in which MYH9-gene acts as a "renal failure susceptibility gene".

Comparison of the CBA-H and SF-36 for the screening of the psychological and behavioural variables in chronic dialysis patients.

The aim of the study was to perform an analysis of the emotional reactions, perception of stressful life and behavioural changes related to Haemodialysis (HD) in order to identify those variables that can improve lifestyle and the adherence to treatment. Some psychometric assessment, such as the Cognitive Behavioural Assessment, Hospital Form, (CBA-H) and the Health Survey (SF-36), which provides two indexes: the Physical Component Score (PCS) and the Mental Component Score (MCS), are suitable to assess a patient's psychological and behavioural style and their health-related quality of life. The study involved 37 Italian out-patients with end-stage renal disease under HD therapy. We calculated the Spearman correlation between variables of CBA-H, SF-36, age and time on HD. We also performed a multivariate linear regression using the CBA-H variables as predictors and PCS and MCS as dependent variables. From the CBA-H, 95% of participants self-reported psychological characteristics comparable to Type A personality, which identifies an anxious, hyperactive and hostile subject. Physical limitations were found to be directly proportional to the time on dialysis (rs = -0.42). The condition of perceived stress worsens the state of mental health (rs = -0.68) and general health perception (rs = -0.44). The condition of vital exhaustion correlates both the PCS and the MCS (p<0.01) with possible outcomes of physical and mental illness. The psychological wellbeing of a dialyzed patient could be due to the combination of several factors, including life parameters, the positive perception of psychosocial outcomes, and the perceived quality of life. A multidisciplinary team (neurologists, psychiatrists, psychologists, and nurses) is essential to plan effective psychological and psychotherapeutic interventions to improve a mind-body integration.

A systematic review of arterial stiffness, wave reflection and air pollution.

Arterial stiffening is associated with increased cardiovascular risk. Whether exposure to relatively high levels of air pollution is associated with arterial stiffening is unclear. We aimed to assess the association between exposure to major air pollutants and arterial stiffening. PubMed, SCOPUS and Web of Science databases (through 31 January 2017) were searched using a combination of terms related to exposure to gaseous [nitrogen dioxide (NO2), nitrogen oxides (NOx) and sulphur dioxide (SO2)] or particulate matter pollutants (PM2.5, PM10 and PM10-2.5), arterial stiffness (pulse wave velocity) and reflected waves (augmentation index, augmentation pressure). Pertinent information were extracted from selected studies. In this systematic review were included 8 studies with available data on air pollution and arterial stiffness/reflected waves parameters (8 studies explored the effects of exposure to particulate matter pollutants, 3 studies the effects of exposure to gaseous pollutants); seven of them reported increased arterial stiffness/reflected waves after exposure to air pollution (6 of 8 studies after particulate matter pollutants; 2 of 3 studies after gaseous pollutants). Arterial stiffness and reflected waves were increased in the majority of the studies after both short- and long-term exposure to air pollutants. In conclusion, available evidence supports an association of main air pollutants with increased arterial stiffness and reflected waves. This finding may have implications for population-based strategies for the reduction of arterial stiffness, a vascular biomarker and an intermediate endpoint for cardiovascular disease.

Exercise in Patients on Dialysis: A Multicenter, Randomized Clinical Trial.

Previous studies have suggested the benefits of physical exercise for patients on dialysis. We conducted the Exercise Introduction to Enhance Performance in Dialysis trial, a 6-month randomized, multicenter trial to test whether a simple, personalized walking exercise program at home, managed by dialysis staff, improves functional status in adult patients on dialysis. The main study outcomes included change in physical performance at 6 months, assessed by the 6-minute walking test and the five times sit-to-stand test, and in quality of life, assessed by the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire. We randomized 296 patients to normal physical activity (control; n=145) or walking exercise (n=151); 227 patients (exercise n=104; control n=123) repeated the 6-month evaluations. The distance covered during the 6-minute walking test improved in the exercise group (mean distance±SD: baseline, 328±96 m; 6 months, 367±113 m) but not in the control group (baseline, 321±107 m; 6 months, 324±116 m; P<0.001 between groups). Similarly, the five times sit-to-stand test time improved in the exercise group (mean time±SD: baseline, 20.5±6.0 seconds; 6 months, 18.2±5.7 seconds) but not in the control group (baseline, 20.9±5.8 seconds; 6 months, 20.2±6.4 seconds; P=0.001 between groups). The cognitive function score (P=0.04) and quality of social interaction score (P=0.01) in the kidney disease component of the KDQOL-SF improved significantly in the exercise arm compared with the control arm. Hence, a simple, personalized, home-based, low-intensity exercise program managed by dialysis staff may improve physical performance and quality of life in patients on dialysis.

[miRNAs in main renal diseases: a new frontier for the nephrologist]. / I microRNA nelle principali patologie renali: una nuova frontiera per il nefrologo.

miRNAs are short non-coding RNAs that play a key role in the homeostasis and in the onset of many diseases. Different studies on nephropathies have identified miRNAs that are differentially expressed in nephropathic subjects compared to healthy controls. An important goal of these studies is to give the nephrologist the possibility to diagnose different nephropathies based on liquid biopsies that are less invasive for the patient than solid ones. The present review focalizes on the function of miRNAs in human physiology and renal diseases and analyzes the potential role that, in the near future, they may have in the diagnosis and treatment of acute and chronic kidney diseases.

[Metformin and kidney]. / Metformina e rene.

Metformin is the first choice among drugs used for the treatment of type II diabetes mellitus mainly because of several advantages: proven hypoglycemic effect, good safety profile, virtually no risk of hypoglycemia, body weight reduction, lipid-lowering effect, efficacy in preventing micro- and macrovascular complications as well as adverse cardiac and cerebrovascular events and reduced cost. Previous reports had shown an increased risk of lactic acidosis in patients receiving metformin. However, the current Guidelines have greatly limited this risk to certain categories of patients, such as those with severe chronic renal failure, particularly when predisposing risk factors such as administration of iodinated contrast are present. In this review, we reported the main data of the literature on the use of metformin in patients with chronic renal failure and both highly expected benefits and high potential risks.