High-tone external muscle stimulation in patients with acute kidney injury (AKI): beneficial effects on NO metabolism, asymmetric dimethylarginine, and endothelin-1.

OBJECTIVES: The aim of this study was to assess potential effects of high-tone external muscle stimulation (HTEMS) on parameters of endothelial dysfunction (ED) in patients with acute kidney injury (AKI). BACKGROUND: The bad outcome of AKI patients is markedly influenced by ED, microinflammation, oxidative stress and protein hypercatabolism. Recently, we have shown that intradialytic application of HTMS was associated with a faster resolution of AKI. Here, we investigated in the same cohort of patients whether parameters of ED such as nitric oxide (NO), asymmetric-dimethylarginine (ADMA), and endothelin 1 (ET-1) are modulated by HTEMS as compared to non-HTEMS-treated AKI patients. METHODS: In a post-hoc study we analyzed plasma samples of the 34 AKI patients stage 5, of whom 17 underwent intradialytic HTEMS treatment while the other 17 served as AKI dialysis controls. Measurements included plasma nitrate and nitrite (NOx), ADMA, ET-1 and were performed before and on days 3, 7, 14, 21, and 28 after start of daily dialysis. Additional 16 healthy volunteers served as controls. RESULTS: Initially, in both AKI groups NOx levels were markedly lower and ADMA and ET-1 levels were higher compared to the healthy controls. After initiation of daily hemodialysis the HTEMS group showed a faster improvement of NOx and ET-1 (after 1 week) and ADMA levels (after 2 weeks) compared to the No- HTEMS group. After 2 weeks, all parameters of the HTEMS group were not different from healthy controls, while the No-HTEMSAKI group needed 3 - 4 weeks. CONCLUSION: Our findings suggest for the first time that in AKI patients, application of HTEMS is associated with a faster normalization of lowered NOx and elevated ADMA and ET-1 plasma levels. We hypothesize that the more rapid amelioration of these parameters in the HTEMS group contributed to the accelerated recovery of AKI. With regard to the small study groups with different causes of AKI, investigations in a greater number of AKI patients is required.

Very low protein diet reduces indoxyl sulfate levels in chronic kidney disease.

BACKGROUND AND OBJECTIVES: High levels of indoxyl sulfate (IS) are associated with chronic kidney disease (CKD) progression and increased mortality in CKD patients. The aim of this pilot study was to assess whether a very low protein diet (VLPD; 0.3 g/kg bw/day), with a consequent low phosphorus intake, would reduce IS serum levels compared to a low protein diet (LPD; 0.6 g/kg bw/day) in CKD patients not yet on dialysis. MATERIAL AND METHODS: This is a post hoc analysis of a preceding cross-over study aimed to analyze FGF23 during VLPD. Here we performed a prospective randomized controlled crossover study in which 32 patients were randomized to receive either a VLPD (0.3 g/kg bw/day) supplemented with ketoanalogues during the first week and an LPD during the second week (group A, n = 16), or an LPD during the first week and a VLPD during the second week (group B, n = 16 patients). IS serum levels were measured at baseline and at the end of each study period. We compared them to 24 hemodialysis patients (HD) and 14 healthy subjects (control). RESULTS: IS serum concentration was significantly higher in the HD (43.4 ± 12.3 µM) and CKD (11.1 ± 6.6 µM) groups compared to the control group (2.9 ± 1.1 µM; p < 0.001). IS levels also correlated with creatinine values in CKD patients (R(2) = 0.42; p < 0.0001). After only 1 week of a VLPD, even preceded by an LPD, CKD patients showed a significant reduction of IS serum levels (37%). CONCLUSIONS: VLPD supplemented with ketoanalogues reduced IS serum levels in CKD patients not yet on dialysis.

Blood pressure variability and outcomes in chronic kidney disease.

BACKGROUND: We investigated the effects of visit-to-visit systolic blood pressure variability (SBPV) on both mortality and dialysis inception in a cohort of chronic kidney disease (CKD) patients not requiring dialysis therapy. Furthermore, we also explored the carry-over effect of visit-to-visit SBPV on mortality after dialysis initiation. METHODS: We conducted a longitudinal retrospective, observational, multi-centre study in three tertiary care nephrology outpatient clinics. All the ambulatory CKD patients admitted to the outpatient clinics from 1 January 2004 to 31 December 2005 were screened for study eligibility. We selected all consecutive patients older than 18 years of age with a mean estimated glomerular filtration rate of <60 mL/min/m(2), free from cardiovascular disease. SBPV was defined as the ratio of the SD to the mean SBP of five values recorded during a run-in phase of 4-5 months. Data on dialysis inception and mortality were recorded through 31 December 2010. RESULTS: Overall, we selected a cohort of 374 elderly (median age: 79 years) subjects. A total of 232 (62%) and 103 (29%) patients were male and had diabetes, respectively. A significant association between SBPV and the risk of death but not of CKD progression to dialysis was noted at univariate and after multivariable adjustments (hazard ratio for all-cause mortality per 1% increase in SBPV: 1.05; 95% confidence interval: 1.02-1.09; P = 0.001). Notably, no lethal event was recorded after dialysis initiation. CONCLUSIONS: Current findings suggest that SBPV may be of use for risk stratification in CKD patients.

Human mature adipocytes express albumin and this expression is not regulated by inflammation.

AIMS: Our group investigated albumin gene expression in human adipocytes, its regulation by inflammation and the possible contribution of adipose tissue to albumin circulating levels. METHODS: Both inflamed and healthy subjects provided adipose tissue samples. RT-PCR, Real-Time PCR, and Western Blot analysis on homogenates of adipocytes and pre-adipocytes were performed. In sixty-three healthy subjects and fifty-four micro-inflamed end stage renal disease (ESRD) patients circulating levels of albumin were measured by nephelometry; all subjects were also evaluated for body composition, calculated from bioelectrical measurements and an thropometric data. RESULTS: A clear gene expression of albumin was showed in pre-adipocytes and, for the first time, in mature adipocytes. Albumin gene expression resulted significantly higher in pre-adipocytes than in adipocytes. No significant difference in albumin gene expression was showed between healthy controls and inflamed patients. A significant negative correlation was observed between albumin levels and fat mass in both healthy subjects and inflamed ESRD patients. CONCLUSIONS: In the present study we found first time evidence that human adipocytes express albumin. Our results also showed that systemic inflammation does not modulate albumin gene expression. The negative correlation between albumin and fat mass seems to exclude a significant contributing role of adipocyte in plasma albumin.

A translational approach to micro-inflammation in end-stage renal disease: molecular effects of low levels of interleukin-6.

Inflammation plays a key role in the progression of cardiovascular disease, the leading cause of mortality in ESRD (end-stage renal disease). Over recent years, inflammation has been greatly reduced with treatment, but mortality remains high. The aim of the present study was to assess whether low (<2 pg/ml) circulating levels of IL-6 (interleukin-6) are necessary and sufficient to activate the transcription factor STAT3 (signal transducer and activator of transcription 3) in human hepatocytes, and if this micro-inflammatory state was associated with changes in gene expression of some acute-phase proteins involved in cardiovascular mortality in ESRD. Human hepatocytes were treated for 24 h in the presence and absence of serum fractions from ESRD patients and healthy subjects with different concentrations of IL-6. The specific role of the cytokine was also evaluated by cell experiments with serum containing blocked IL-6. Furthermore, a comparison of the effects of IL-6 from patient serum and rIL-6 (recombinant IL-6) at increasing concentrations was performed. Confocal microscopy and Western blotting demonstrated that STAT3 activation was associated with IL-6 cell-membrane-bound receptor overexpression only in hepatocytes cultured with 1.8 pg/ml serum IL-6. A linear activation of STAT3 and IL-6 receptor expression was also observed after incubation with rIL-6. Treatment of hepatocytes with 1.8 pg/ml serum IL-6 was also associated with a 31.6-fold up-regulation of hepcidin gene expression and a 8.9-fold down-regulation of fetuin-A gene expression. In conclusion, these results demonstrated that low (<2 pg/ml) circulating levels of IL-6, as present in non-inflamed ESRD patients, are sufficient to activate some inflammatory pathways and can differentially regulate hepcidin and fetuin-A gene expression.

SARS-CoV-2 Infections and COVID-19 Fatality: Estimation of Infection Fatality Ratio and Current Prevalence.

COVID-19 is one of the most important problems for public health, according to the number of deaths associated to this pathology reported so far. However, from the epidemiological point of view, the dimension of the problem is still unknown, since the number of actual cases of SARS-CoV-2 infected people is underestimated, due to limited testing. This paper aims at estimating the actual Infection Fatality Ratio (number of deaths with respect to the number of infected people) and the actual current prevalence (number of infected people with respect to the entire population), both in a specific population and all over the world. With this aim, this paper proposes a method to estimate Infection Fatality Ratio of a still ongoing infection, based on a daily estimation, and on the relationship between this estimation and the number of tests performed per death. The method has been applied using data about COVID-19 from Italy. Results show a fatality ratio of about 0.9%, which is lower than previous findings. The number of actual infected people in Italy is also estimated, and results show that (i) infection started at the end of January 2020; (ii) a maximum number of about 100,000 new cases in one day was reached at the beginning of March 2020; (iii) the estimated cumulative number of infections at the beginning of October 2020 is about 4.2 million cases in Italy (more than 120 million worldwide, if a generalization is conjectured as reasonable). Therefore, the prevalence at the beginning of October 2020 is estimated at about 6.9% in Italy (1.6% worldwide, if a generalization is conjectured).

A project to prevent renal diseases in the general population.

BACKGROUND: Early identification of subjects unaware of hypertension, diabetes and urinary abnormalities may prevent and/or reduce the onset and progression of kidney disease and ameliorate outcomes. In this study, the presence of hypertension, diabetes and urinary abnormalities was checked in subjects walking in a large square of Naples. METHODS: Data on age, habits and history of hypertension and/or diabetes were collected. Systolic and diastolic blood pressure were recorded. Protein, glucose, leukocytes and red blood cells were measured in urine. RESULTS: Participants numbered 698. Smoking (past or current smoking) was reported by 77%. Many of the participants with hypertension (35%) showed uncontrolled hypertension despite antihypertensive therapy. Hypertension was found for the first time in 154 subjects, and was confirmed in 28% of them afterwards; 23 participants (15% of hypertensive subjects) did not recheck blood pressure (BP) despite our summons. Proteinuria was found in 18% of new hypertensive participants. In 14 out of 17 diabetic participants without history of hypertension, hypertension was found for the first time and confirmed thereafter. Urinary abnormalities were present in more than one half of the participants, and were more prevalent in women and diabetics. Diabetics numbered 55 out of 698 subjects. In spite of therapy, glucosuria was present in almost one third of diabetics. Glucosuria was found in 6 participants with no history of diabetes (0.9% of all subjects). CONCLUSIONS: These data demonstrate that (a) many persons with hypertension are not aware of it; (b) control of hypertension is inadequate in most treated hypertensive patients and even worse in diabetics; (c) urinary abnormalities are frequently present in otherwise healthy subjects; (d) projects with the aim of raising awareness of hypertension, urinary abnormalities and diabetes in out-clinic subjects should be supported; (e) the use of a transportable clinic parked in residential areas of cities appears a suitable way for promoting evaluation of BP and urine test in subjects unaware of disease.

[Sudden cardiac death in patient with CKD].

Despite significant improvements in technology of dialysis delivery, cardiovascular disease remains the mayor cause of death in dialysis patients. Individuals with End Stage Renal Disease (ESRD( present an high incidence of coronary artery disease, arrhythmia and sudden cardiac death (SCD). This review summarizes the current available literature regarding the physiopathology, the risk factors and potential interventions to reduce the risk of SCD in dialysis patients, including medical therapy or defibrillators.

Very Low-Protein Diet (VLPD) Reduces Metabolic Acidosis in Subjects with Chronic Kidney Disease: The "Nutritional Light Signal" of the Renal Acid Load.

BACKGROUND: Metabolic acidosis is a common complication of chronic kidney disease; current guidelines recommend treatment with alkali if bicarbonate levels are lower than 22 mMol/L. In fact, recent studies have shown that an early administration of alkali reduces progression of CKD. The aim of the study is to evaluate the effect of fruit and vegetables to reduce the acid load in CKD. METHODS: We conducted a case-control study in 146 patients who received sodium bicarbonate. Of these, 54 patients assumed very low-protein diet (VLPD) and 92 were controls (ratio 1:2). We calculated every three months the potential renal acid load (PRAL) and the net endogenous acid production (NEAP), inversely correlated with serum bicarbonate levels and representing the non-volatile acid load derived from nutrition. Un-paired T-test and Chi-square test were used to assess differences between study groups at baseline and study completion. Two-tailed probability values ≤0.05 were considered statistically significant. RESULTS: At baseline, there were no statistical differences between the two groups regarding systolic blood pressure (SBP), diastolic blood pressure (DBP), protein and phosphate intake, urinary sodium, potassium, phosphate and urea nitrogen, NEAP, and PRAL. VLPD patients showed at 6 and 12 months a significant reduction of SBP (p < 0.0001), DBP (p < 0.001), plasma urea (p < 0.0001) protein intake (p < 0.0001), calcemia (p < 0.0001), phosphatemia (p < 0.0001), phosphate intake (p < 0.0001), urinary sodium (p < 0.0001), urinary potassium (p < 0.002), and urinary phosphate (p < 0.0001). NEAP and PRAL were significantly reduced in VLPD during follow-up. CONCLUSION: VLPD reduces intake of acids; nutritional therapy of CKD, that has always taken into consideration a lower protein, salt, and phosphate intake, should be adopted to correct metabolic acidosis, an important target in the treatment of CKD patients. We provide useful indications regarding acid load of food and drinks-the "acid load dietary traffic light".

Muscle stimulation in elderly patients with CKD and sarcopenia.

OBJECTIVES: Aim of our study was to assess the potential effects of high-tone external muscle stimulation (HTEMS) on improvement of endothelial dysfunction (ED) and kidney damage in elderly patients with chronic kidney disease (CKD), sarcopenia and/or serious physical disability with a high Multidisciplinary Prognostic Index (MPI). METHODS: We enrolled 12 consecutive CKD patients with MPI > 0,66 from January 1st, 2008 to December 31st, 2014. Six patients underwent a 2-hours HTEMS during the first day (group A) and the other six patients (group B) underwent a sham experiment with HTEMS without power supply. After 24 hours, patients of group A were shifted to group B and vice-versa. Nitrite/nitrate (NOx), endotheline-1 (ET-1) and urine creatinine concentration were measured in all patients. RESULTS: During HTEMS urine amount increased by 22% (p=0.049), so did urine creatinine that increased by 40%, (p=0.034) and creatinine clearance that increased by 26% (p=0.041). There was no statistical difference in urine nitrogen (that raised by 11%, p=0.526), urine sodium (that reduced by 42%, p=0.121) and urine potassium levels (p=0,491). At the same time, NOx changed from 44.15.1 to 38.45.3 M/L after 1 hour, to 36.44.8 M/L after 2 hours, to 41.15.7 M/L after 3 hours and to 46,95.0 M/L after 4 hours (p=0.008) during HTEMS, while it did not vary during the sham section of the experiment, respectively 43.66.1 M/L , 436.4 M/L, 42.85.5 M/L, 434.7 M/L, and 42.85.8 M/L (p=0.992). CONCLUSION: Our study showed that HTEMS may improve microcirculation and, through this mechanism, may reduce kidney damage in elderly patients with CKD and severe muscle atrophy.

[The devil teaches us his tricks... and also how to hide them]. / Quando il diavolo fa le pentole ma anche i coperchi.

Spontaneous ureteric ruptures is a rare condition [1]and bilateral ureteric rupture is even more uncommon. Few cases are described in the literature in which bilateral ureteric rupture is associated to dermatomyositis [2]or to intra-arterial contrast medium application for infrarenal aortic stent placement [3]. We discuss here a case of bilateral ureteric rupture in a 74-year-old man with bladder cancer, presenting oliguric acute kidney failure and a light abdominal pain.

[An unusual case of acute kidney insufficiency]. / Un caso insolito di Insufficienza renale acuta.

Acute aortic dissection (AAD) is a life-threatening condition with high morbidity and mortality, that involves renal arteries in at least 5-10% so leading to renal ischemia and insufficiency. AAD presenting with anuria and the necessity of renal replacement therapy occurs rarely. Here we describe a case of a hypertensive and obese patient presenting with anuria and acute kidney injury, who underwent to hemodialysis and later was diagnosed with aortic dissection. Through this case, we underline the importance of considering AAD as an important differential in patients with a long history of uncontrolled hypertension presenting with anuria.

Variability of blood pressure in dialysis patients: a new marker of cardiovascular risk.

BACKGROUND: Hemodialysis patients have a high cardiovascular mortality, and hypertension is the most prevalent treatable risk factor. We aimed to assess the predictive significance of dialysis-to-dialysis variability in blood pressure in hemodialysis patients. METHODS: We performed a historical cohort study in 1,088 prevalent hemodialysis patients, followed up for 5 years. The risk of cardiovascular death was determined in relation to dialysis-to-dialysis variability in blood pressure, maximum blood pressure and pulse pressure. RESULTS: Variability in blood pressure was a predictor of cardiovascular death (hazard ratio [HR] = 1.242; 95% confidence interval [95% CI], 1.004-1.537; p=0.046). Also age (HR=1.021; 95% CI, 1.011-1.048; p=0.049), diabetes (HR=1.134; 95% CI, 1.128-1.451; p=0.035), creatinine (HR=0.837; 95% CI, 0.717-0.977; p=0.024) and albumin (HR=0.901; 95% CI, 0.821-0.924; p=0.022) influenced mortality. Maximum blood pressure and pulse pressure did not show any effect on cardiovascular death. CONCLUSION: Dialysis-to-dialysis variability in blood pressure is a predictor of cardiovascular mortality in hemodialysis patients, and blood pressure variability may be used in managing hypertension and predicting outcomes in dialysis patients.

Daily dialysis reduces pulse wave velocity in chronic hemodialysis patients.

Pulse wave velocity (PWV) is a predictor of morbidity and mortality in patients with end-stage renal disease (ESRD). Dialysis patients show cyclic changes in PWV related to their hydration status and blood pressure. Our aim is to assess the impact of daily dialysis on PWV. We performed a randomized crossover study of 60 patients who underwent standard hemodialysis (HD) three times per week for at least 6 months. Patients were classified into three groups according to their PWV values before (pre-) and after (post-) HD, with a cutoff value of 12 m s(-1), as follows: the low-low (LL) group had normal pre-HD and post-HD PWV; the high-low (HL) group had high pre-HD PWV and normal post-HD PWV; and the high-high (HH) group had high pre- and post-HD PWV. All patients continued standard HD for 2 weeks. A total of 10 patients from each group were randomly assigned to continue standard HD for 1 week and then underwent daily dialysis for 1 week. The remaining 10 patients underwent daily dialysis for 1 week and then underwent standard HD for 1 week. PWV values were measured before and 1 h after each dialysis session. With daily dialysis treatment, 2 of 20 patients (10%) moved from the PWV-HH group to the PWV-HL group, whereas 18 of 20 patients (90%) moved from the PWV-HL group to the PWV-LL group (P = 0.030). Daily dialysis reduces PWV in the ESRD patients. As PWV is a strong predictor of mortality in ESRD and has cyclic variations in patients who are on standard HD, we believe that daily dialysis may be used in patients with high PWV levels to reduce their mortality risk.

Acute effects of very-low-protein diet on FGF23 levels: a randomized study.

BACKGROUND AND OBJECTIVES: High levels of fibroblast growth factor 23 are associated with mortality, CKD progression, and calcification in CKD patients. The aim of this pilot study is to assess whether a very-low-protein diet (0.3 g/kg per day) with a consequent low intake of phosphorus would reduce fibroblast growth factor 23 compared with a low-protein diet (0.6 g/kg per day) in CKD patients not yet on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective, randomized, controlled crossover study was performed in which 32 patients were randomized into two groups. Group A (16 patients) received a very-low-protein diet (0.3 g/kg body wt per day) supplemented with ketoanalogues during the first week and a low-protein diet during the second week, and group B (16 patients) received a low-protein diet during the first week and a very-low-protein diet during the second week. Fibroblast growth factor 23, seric, and urinary phosphate levels were measured at baseline and the end of each study period. RESULTS: After only 1 week of the very-low-protein diet, reductions in fibroblast growth factor 23 levels (33.5%), serum phosphate (12%), and urinary phosphate (34%) with the very-low-protein diet compared with the low-protein diet were observed. Serum and urinary phosphate levels and protein intake were significant determinants of fibroblast growth factor 23 (95% confidence interval=1.04-1.19, 1.12-1.37, and 1.51-2.23, respectively). CONCLUSIONS: A very-low-protein diet supplemented with ketoanalogues reduced fibroblast growth factor 23 levels in CKD patients not yet on dialysis.

Variability of pulse wave velocity and mortality in chronic hemodialysis patients.

We have already demonstrated that in chronic hemodialysis (HD) patients, the cyclic variations in both hydration status and blood pressure are responsible for changes in pulse wave velocity (PWV). The aim of this study is to verify whether the cyclic variation of PWV influences mortality in dialysis patients. We studied 167 oligoanuric (urinary output <500 mL/day) patients on chronic standard bicarbonate HD for at least 6 months. They performed 3 HD sessions of 4 hours per week. Patients were classified into 3 groups: normal PWV before and after dialysis (LL); high PWV before and normal PWV after dialysis (HL); and high PWV before and after dialysis (HH). The carotid-femoral PWV was measured with an automated system using the foot-to-foot method. Analysis of variance was used to compare the different groups. The outcome event studied was all-cause mortality and cardiovascular mortality. The PWV values observed were LL in 44 patients (26.3%); HL in 53 patients (31.8%); and HH in 70 patients (41.9%). The 3 groups of patients are homogenous for sex, age, and blood pressure. The HH group had a higher prevalence of (P<0.001) ASCVD. It is interesting that the distribution of patients in the 3 groups is correlated with the basal value of PWV. In fact, when the basal measure of PWV is elevated, there is a higher probability that an HD session cannot reduce PWV (<12 ms). A total of 53 patients (31.7%) died during the follow-up of 2 years: 5 patients in the LL group (11.4%); 16 in the HL group (30.2%); and 32 in the HH group (50.7%) (LL vs. HL, P=0.047; LL vs. HH, P<0.00001; HL vs. HH, P=0.034). We evidence for the first time that different behaviors of PWV in dialysis subjects determine differences in mortality.