Sarcopenic Obesity Versus Nonobese Sarcopenia in Hemodialysis Patients: Differences in Nutritional Status, Quality of Life, and Clinical Outcomes.

OBJECTIVE: Sarcopenia and sarcopenic obesity (SO) are linked to unfavorable prognosis in maintenance hemodialysis (MHD) populations. We tested whether nonobese sarcopenia and SO, as different stages of extreme protein-energy wasting, have different prognoses. METHODS: In this prospective observational study, 261 MHD patients were recruited from October 2010 to April 2012 and followed until October 2020. Two definitions were used to diagnose sarcopenia: the European Working Group on Sarcopenia in Older People consensus and the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium criteria. Obesity was determined as the percentage of total body fat, ≥27% for men and ≥38% for women. Data for all-cause and cardiovascular morbidity and mortality, baseline nutrition markers, inflammation and oxidative stress, adipokines, body composition parameters, handgrip strength, and quality of life (QoL) scores were measured. RESULTS: According to European Working Group on Sarcopenia in Older People, 115 (44.1%) patients were sarcopenic and 120 (46.0%) according to FNIH definitions. Of them, 28.4% and 34.5% were SO, respectively. Higher levels of albumin, creatinine, uric acid, leptin, phase angle, better nutritional scores, and lower adiponectin levels characterized SO patients compared with nonobese sarcopenic patients regardless of indexing method. Better QoL scores were noted in SO compared with nonobese sarcopenic patients using the FNIH sarcopenia criteria. The hazard of all-cause death, cardiovascular death, and first cardiovascular event for patients with SO was lower compared with the nonobese patients after multivariate adjustments. Statistical significance of these associations disappeared after including fat mass in multivariate models. CONCLUSIONS: MHD patients with SO have better nutritional status and prognosis for cardiovascular events, all-cause and cardiovascular disease mortality, and possibly better QoL compared with nonobese sarcopenic MHD patients. The better prognosis appears to be entirely due to the excess fat, which is protective in sarcopenic MHD patients similar to that described in the entire MHD population.

Quantitative Analysis of Vertical Transmission of Maternal SARS-CoV-2 Antibodies to Neonates and Young Infants Following Immunization During Pregnancy.

Serum antibody levels to SARS-CoV-2 in infants born to mothers who had received 2 doses of the BNT2b2 vaccine during pregnancy correlated positively with increasing gestational age at vaccination (P < .01) and negatively with increasing time from vaccination (P < .01), with a significant drop in infants aged >60 days (P = .045).

Population differences in antibody response to SARS-CoV-2 infection and BNT162b2 vaccination.

The concentration of SARS-CoV-2-specific serum antibodies, elicited by vaccination or infection, is a primary determinant of anti-viral immunity, which correlates with protection against infection and COVID-19. Serum samples were obtained from 25 897 participants and assayed for anti-SARS-CoV-2 spike protein RBD IgG antibodies. The cohort was composed of newly vaccinated BNT162b2 recipients, in the first month or 6 months after vaccination, COVID-19 patients and a general sample of the Israeli population. Antibody levels of BNT162b2 vaccine recipients were negatively correlated with age, with a prominent decrease in recipients over 55 years old, which was most significant in males. This trend was observable within the first month and 6 months after vaccination, while younger participants were more likely to maintain stable levels of serum antibodies. The antibody concentration of participants previously infected with SARS-CoV-2 was lower than the vaccinated and had a more complex, non-linear relation to age, sex and COVID-19 symptoms. Taken together, our data supports age and sex as primary determining factors for both the magnitude and durability of humoral response to SARS-CoV-2 infection and the COVID-19 vaccine. Our results could inform vaccination policies, prioritizing the most susceptible populations for repeated vaccination.

Safety and humoral responses to BNT162b2 mRNA vaccination of SARS-CoV-2 previously infected and naive populations.

Since COVID-19 risk of reinfection is of great concern, the safety and efficacy of the mRNA-based vaccines in previously infected populations should be assessed. We studied 78 individuals previously infected with SARS-CoV-19, who received a single dose of BNT162b2 mRNA COVID-19 vaccine, and 1:2 ratio matched infection-naïve cohort who received two injections. The evaluation procedure included symptom monitoring, and serological tests. Among the post-infected population, the median IgG-S response after the first vaccine dose was 3.35 AU, compared to 2.38 AU after the second vaccine injection in the infection naive group. A strong correlation was demonstrated between IgG-S level before vaccination, and the corresponding responses after a single vaccine dose (r = 0.8, p < 0.001) in the post infected population. Short-term severe symptoms that required medical attention were found in 6.8% among the post-infected individuals, while none were found in the infection naïve population. Our data suggest that a single vaccine dose is sufficient to induce an intense immune response in post-infected population regardless of seropositivity. Although some short-term safety issues were observed compared to the infection naïve population, a single dose regimen can be considered safe in post-infected populations.

Aluminum Content of Human Milk and Antiperspirant Use.

Background: Aluminum exposure may originate from numerous sources, including antiperspirants. Aluminum toxicity can cause a wide range of neurological impairments. Infants are exposed to aluminum through human milk (HM), formulas, total-parenteral-nutrition and vaccines. Due to potential risk of toxicity to both infants and women, it has been advised that lactating women decrease their use of aluminum-based products and antiperspirants. Our study aimed to determine whether the use of aluminum-based antiperspirants (ABA) affects aluminum levels in HM. Methods: This cross-sectional study included healthy mothers who exclusively breastfed infants (1 week to 5 months). Questionnaires were used to collect data on demographics, antiperspirant use and aluminum exposure. Mothers were instructed to express HM during the morning at first breastfeeding session. Aluminum levels were measured by atomic absorption spectrometry with a 5 ppb limit of detection. Results: Fifteen of the 58 (26%) recruited mothers used an aluminum-free antiperspirant (AFA) and 43 (74%) used an ABA. The range of aluminum concentration in HM was 0-100.8 µg/L (mean 11.4 ± 17.4 µg/L). The median aluminum level (Q1-Q3) was 6.5 µg/L (5.2-11.9) and 5.2 µg/L (3.46-9.4) in the AFA and ABA groups, respectively (p = 0.19). The aluminum levels were not affected by maternal age, education, diet, number of children, infant age, lactation stage or self-reported aluminum exposure. Conclusion: The data from this preliminary study demonstrate that the use of an ABA by lactating mothers does not increase their HM aluminum content. Additional studies with a larger cohort are warranted to confirm these findings.

Effect of anti-C5 antibody on recuperation from ischemia/reperfusion-induced acute kidney injury.

AbstractAim: The complement system is activated in acute kidney injury (AKI). Anti-C5 antibody targets the common terminal portion of the complement cascade that generate the terminal complex C5b-9 and has a renal-protective effect in paroxysmal nocturnal hemoglobinuria. However, the anti-C5 antibody's role in ischemia/reperfusion (I/R)-induced AKI has not been fully investigated. We therefore evaluated its effect on the pathophysiological cascade of I/R-induced AKI.Methods: Sprague-Dawley rats underwent unilateral right kidney nephrectomies with simultaneous clamping of the contralateral hilum for 60 min (ischemia), followed by reperfusion. In addition to a placebo, two treatment groups received either high or low doses of anti-C5 monoclonal antibody. After 48 h, the rats were euthanized, blood was drawn to evaluate systemic inflammation and to estimate glomerular filtration rate (GFR). The remaining kidney was removed for pathological evaluation and intra-renal complement activation.Results: I/R induced significant intra-renal complement activation and systemic inflammation compared with unilateral nephrectomy group. The anti-C5 antibody ameliorated the intra-renal complement activation (intra-renal C3 and C6), reduced systemic inflammation (C-reactive protein, and systemic C3), decreased intra-renal acute tubular necrosis damage and improved GFR (seen by the sensitive marker, serum cystatin C; 1.63 mg/L (I/R + placebo), 1.36 mg/L (I/R + low dose) and 1.21 mg/L (I/R + high dose), p = .08 and .03 compared with I/R + placebo).Conclusion: In I/R-induced AKI, the monoclonal anti-C5 complement factor ameliorates intra renal complement activation, decreases local and systemic inflammation and may improve GFR.

Human mesenchymal stromal cells ameliorate complement induced inflammatory cascade and improve renal functions in a rat model of ischemia-reperfusion induced acute kidney injury.

INTRODUCTION: The primary rational for using mesenchymal stromal cells (MSCs) to rejuvenate damaged tissue is mostly based on their capacity to trans-differentiate and repair injured organs. However, previous studies have demonstrated that MSCs are beneficial even at very early stages, before differentiation and proliferation can be expected. The aim of the current study was to investigate the multifaceted immunological effects of systemically administrating MSCs in the setting of acute kidney injury (AKI) induced by ischemic-reperfusion (I/R). METHODS: A rat model of I/R induced AKI was used. The rats underwent a unilateral nephrectomy with simultaneously clamping the contralateral kidney for 60 minutes. Four treatment groups received intravenously, increasing doses of human MSCs and after 48 hours, the rats were sacrificed. Blood was taken to evaluate renal functions and to measure systemic inflammatory markers. Kidneys were taken for histopathologic examinations and evaluations of intra-renal complement activation and inflammatory mediators. RESULTS: Renal functions improved in U shaped dose dependent manner. Mean serum creatinine levels were 4.5, 2.9, 2.6, 1.7 and 4.1 mg/dL in I/R + placebo, I/R + 150x103 cells, I/R + 250x103 cells, I/R + 500x103 cells and I/R + 1,000x103 cells respectfully (p-values<0.05). Urea demonstrated consistent results with the same U shape improvement manner. The extensive activation of the complement system was ameliorated in the MSCs treatment groups. In addition, MSCs significantly decreased intra-renal levels of IL-1ß and TNF-α. It should be noted that the highest doses of MSCs induced renal hypoxia, marked by the Hypoxy-probe staining. CONCLUSIONS: The early beneficial effect of MSCs in the setting of AKI may be attributed to their immunomodulatory effects. Safe treatment with MSCs can block the deleterious activation of the complement cascade and alleviate the hazardous inflammatory mediator-related cascade.

Abdominal obesity in normal weight versus overweight and obese hemodialysis patients: Associations with nutrition, inflammation, muscle strength, and quality of life.

OBJECTIVE: The biological basis of abdominal obesity leading to more severe outcomes in patients with normal body mass index (BMI) on maintenance hemodialysis (MHD) is unclear. The aim of this study was to compare the properties of abdominal obesity in different BMI categories of patients on MHD. METHODS: We performed a cross-sectional study of 188 MHD patients (52.7% women; mean age, 69.4 ± 11.5 y) with abdominal obesity in different BMI groups using criteria from the World Health Organization. Appetite and dietary intake, body composition, handgrip strength, malnutrition inflammation score (MIS), inflammatory biomarkers, adipokines, and health-related quality-of-life (QoL) questionnaires were studied. RESULTS: According to multivariable analyses, abdominally obese patients with normal BMIs consumed less protein per day (P = 0.04); had lower measurements of surrogates of lean (P < 0.001) and fat mass (P < 0.001); and had higher total cholesterol, tumor necrosis factor-α (P < 0.05), and ratios of adiponectin to leptin (P = 0.003) than overweight and obese patients with abdominal obesity. Multivariable analyses showed no differences in handgrip strength among the study groups.The abdominally obese study participants with normal weight had significantly lower scores in role physical (P = 0.003) and pain (P = 0.04) scales after multivariable adjustments. CONCLUSIONS: Normal-weight MHD patients with abdominal obesity exhibited a more proatherogenic profile in terms of inflammatory markers and adipokine expression, lower body composition reserves, and lower physical ability than patients with abdominal obesity with overweight and obesity. This at least partially explains the abdominal obesity paradox in the MHD population in which worse clinical outcomes are seen in abdominally obese patients with normal BMIs, as opposed to overweight and obese patients who are also abdominally obese.

Response of Renal Podocytes to Excessive Hydrostatic Pressure: a Pathophysiologic Cascade in a Malignant Hypertension Model.

BACKGROUND/AIMS: Renal injuries induced by increased intra-glomerular pressure coincide with podocyte detachment from the glomerular basement membrane (GBM). In previous studies, it was demonstrated that mesangial cells have a crucial role in the pathogenesis of malignant hypertension. However, the exact pathophysiological cascade responsible for podocyte detachment and its relationship with mesangial cells has not been fully elucidated yet and this was the aim of the current study. METHODS: Rat renal mesangial or podocytes were exposed to high hydrostatic pressure in an in-vitro model of malignant hypertension. The resulted effects on podocyte detachment, apoptosis and expression of podocin and integrinß1 in addition to Angiotensin-II and TGF-ß1 generation were evaluated. To simulate the paracrine effect podocytes were placed in mesangial cell media pre-exposed to pressure, or in media enriched with Angiotensin-II, TGF-ß1 or receptor blockers. RESULTS: High pressure resulted in increased Angiotensin-II levels in mesangial and podocyte cells. Angiotensin-II via the AT1 receptors reduced podocin expression and integrinß1, culminating in detachment of both viable and apoptotic podocytes. Mesangial cells exposed to pressure had a greater increase in Angiotensin-II than pressure-exposed podocytes. The massively increased concentration of Angiotensin-II by mesangial cells, together with increased TGF-ß1 production, resulted in increased apoptosis and detachment of non-viable apoptotic podocytes. Unlike the direct effect of pressure on podocytes, the mesangial mediated effects were not related to changes in adhesion proteins expression. CONCLUSIONS: Hypertension induces podocyte detachment by autocrine and paracrine effects. In a direct response to pressure, podocytes increase Angiotensin-II levels. This leads, via AT1 receptors, to structural changes in adhesion proteins, culminating in viable podocyte detachment. Paracrine effects of hypertension, mediated by mesangial cells, lead to higher levels of both Angiotensin-II and TGF-ß1, culminating in apoptosis and detachment of non-viable podocytes.

Effect of Peripheral Electrical Stimulation (PES) on Nocturnal Blood Glucose in Type 2 Diabetes: A Randomized Crossover Pilot Study.

BACKGROUND: Regulation of hepatic glucose production has been a target for antidiabetic drug development, due to its major contribution to glucose homeostasis. Previous pre-clinical study demonstrated that peripheral electrical stimulation (PES) may stimulate glucose utilization and improve hepatic insulin sensitivity. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM). METHODS: Twelve patients with T2DM were recruited for an open label, interventional, randomized trial. Eleven patients underwent, in a crossover design, an active, and a no-intervention control periods, separated with a two-week washout phase. During the active period, the patients received a daily lower extremity PES treatment (1.33Hz/16Hz burst mode), for 14 days. Study endpoints included changes in glucose levels, number of hypoglycemic episodes, and other potential side effects. Endpoints were analyzed based on continuous glucose meter readings, and laboratory evaluation. RESULTS: We found that during the active period, the most significant effect was on nocturnal glucose control (P < 0.0004), as well as on pre-meal mean glucose levels (P < 0.02). The mean daily glucose levels were also decreased although it did not reach clinical significance (P = 0.07). A reduction in serum cortisol (P < 0.01) but not in insulin was also detected after 2 weeks of treatment. No adverse events were recorded. CONCLUSIONS: These results indicate that repeated PES treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production. This effect may be mediated via hypothalamic-pituitary-adrenal axis modulation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02727790.

Renoprotective Effects of DNAse-I Treatment in a Rat Model of Ischemia/Reperfusion-Induced Acute Kidney Injury.

BACKGROUND: Massive DNA destruction/accumulation of cell-free DNA debris is a sensitive biomarker of progressive organ/tissue damage. Deleterious consequences of DNA debris accumulation are evident in cardiac ischemia, thrombosis, auto-inflammatory diseases, SLE-induced lupus nephritis and cystic fibrosis. In case of renal pathologies, degradation and elimination of DNA debris are suppressed, due to downregulated DNAse-I activity within the diseased kidneys. The aim of the current study was to evaluate whether exogenous DNAse-I administration might exert renoprotective effects in the setting of acute kidney injury (AKI or acute renal failure). METHODS: Sprague-Dawley rats underwent unilateral nephrectomy, with simultaneous clamping of contralateral kidney artery. The treated group received DNAse-I injection before discontinuing anesthesia. Positive (ischemic) controls received saline injection. Negative (non-ischemic) controls were either non-operated or subjected to surgery of similar duress and duration without ischemia. Renal perfusion was evaluated using the Laser-Doppler technique. Blood was procured for evaluating DNAse-I activity, renal functioning, renal perfusion. The kidneys were allocated for histopathologic examinations and for the evaluation of renal hypoxia, intra-renal apoptosis and proliferation. RESULTS: Contrary to the situation in untreated ischemic rats, renal perfusion was significantly improved in DNAse-treated animals, concomitantly with significant amelioration of damage to renal functioning and tissue integrity. Treatment with DNAse-I significantly decreased the ischemia-induced renal hypoxia and apoptosis, simultaneously stimulating renal cell proliferation. Exogenous DNAse-I administration accelerated the clearance of intra-renal apoptotic DNA debris. CONCLUSION: Functional/histologic hallmarks of renal injury were ameliorated, renal functioning improved, intra-renal hypoxia decreased and intra-renal regeneration processes were activated. Thus, DNAse-I treatment protected the kidney from deleterious consequences of ischemia-induced AKI.

Mesangial cells are responsible for orchestrating the renal podocytes injury in the context of malignant hypertension.

AIM: Two populations of renal cells fully possess functional contractile cell apparatus: mesangial cells and podocytes. Previous studies demonstrated that in the context of malignant hypertension overproduction of Angiotensin-II by the contracting mesangial cells aggravated hypercellularity and apoptosis of adjacent cell populations. The role of podocytes in pathogenesis of malignant hypertension is unclear. We investigated responsiveness of normal vs. hyperglycaemic podocytes to pressure in a model of malignant hypertension. METHODS: Rat renal podocytes and mesangial cells were subjected to high hydrostatic pressure, using an in vitro model of malignant hypertension. Part of them was pre-exposed to hyperglycaemic medium. Alternatively, the cells were cultured in conditioned medium collected from mesangial cells pre-exposed to pressure. RESULTS: Angiotensin-II was significantly increased in normoglycaemic mesangial cells subjected to pressure, triggering enhanced proliferation and apoptosis. No augmented Angiotensin-II, proliferation or apoptosis were evident in pressure-exposed normoglycaemic podocytes. In hyperglycaemic mesangial cells, but not podocytes, basal Angiotensin-II and apoptosis were augmented, along with abrogated proliferation. Challenge with exogenous Angiotensin-II or Angiotensin-II-containing conditioned medium, induced apoptosis both in podocytes and mesangial cells. CONCLUSIONS: 1. Unlike mesangial cells, podocytes do not respond to high pressure or hyperglycaemia per se. Resultantly, neither high pressure nor hyperglycaemia, trigger apoptosis of podocytes in vitro. However, surplus of Angiotensin-II, amply produced in vivo by the adjacent mesangial cells, would seem to be sufficient for initiating apoptosis of both mesangial cells and podocytes. 2. Hyperglycaemia abrogates cell replication. Resultantly, in diabetic patients regeneration of renal tissue damaged by the incidence of malignant hypertension may become compromised or completely lost.

Effect of N-acetylcysteine on residual renal function in chronic haemodialysis patients treated with high-flux synthetic dialysis membranes: a pilot study.

Background. Preservation of residual renal function in chronic dialysis patients has proven to be a major predictor of survival. The aim of the present study was to investigate an ability of the combined use of N-acetylcysteine and high-flux biocompatible haemodialysis membranes to improve residual renal function in haemodialysis patients. Patients and Methods. Chronic haemodialysis patients with a residual urine output of at least 100 mL/24 h were administered oral an N-acetylcysteine 1200 mg twice daily for 2 weeks. Treatment group included patients treated with dialysers using high-flux synthetic biocompatible membranes. Control group included patients treated with dialysers using low-flux semisyntetic triacetate haemodialysis membranes. Results. Eighteen patients participated in the study. The residual glomerular filtration rate showed a nonsignificant trend for increase in both groups. The magnitude of GFR improvement after N-acetylcysteine administration was less pronounced in the group treated with high-flux biocompatible membranes: +0.17 ± 0.56 mL/min/1.73 m(2) in treatment group and +0.65 ± 0.53 mL/min/1.73 m(2) in control group (P < 0.05). Conclusion. In this study of favorable effect of N-acetylcysteine on residual renal function in chronic haemodialysis patients may be less pronounced when using high-flux biocompatible, rather than low-flux semisyntetic, HD membranes.

Hyperglycaemia, inflammation, RAS activation: three culprits to blame for acute kidney injury emerging in healthy rats during general anaesthesia.

AIM: Major surgery under general anaesthesia might evoke acute kidney injury (AKI), sometimes culminating in end stage renal disease. We investigated the roles of hyperglycaemia, inflammation and renin-angiotensin system (RAS) activation in induction of AKI following anaesthesia by different anaesthetic drugs and/or regimens. METHODS: Ninety-four Sprague-Dawley rats underwent 1 h-anaesthesia by various protocols, including repeated blood glucose and insulin measurements. Blood samples and kidneys were allocated at sacrifice, for evaluation of renal function, inflammatory status and Angiotensin-II availability. RESULTS: Hyperglycaemia emerged in unconscious rats irrespective of anaesthetic drug choice or anaesthesia regimen. Insulin increase correlated with hyperglycaemia levels. Levels of Cystatin-C, as well as serum and urine neutrophil gelatinase-associated lipocain (NGAL), were significantly augmented. Serum transforming growth factor beta (TGF-ß) and interleukins (IL)-1ß, -4, -6, and -10 were significantly increased. Intra-renal Angiotensin-II, TGF-ß, IL-6 and-10 were significantly increased. IL-1 was decreased. IL-4 remained unaltered. CONCLUSIONS: Acute hyperglycaemia, systemic and intra-renal inflammation and RAS activation were independently triggered by induction of anaesthesia. Each confounder aggravated the impacts of the others, bringing about concomitant deterioration of renal function. Increased insulin secretion attenuated but did not abolish hyperglycaemia. Systemic inflammation was counterforced by anti-inflammatory cytokines, whereas intra-renal inflammation persisted, so that AKI progressed unopposed.

N-3 fatty acid supplementation to routine statin treatment inhibits platelet function, decreases patients' daytime blood pressure, and improves inflammatory status.

OBJECTIVES: N-3 fatty acids reduce the risks of cardiovascular morbidity and mortality. Administration of N-3 fatty acids to patients treated with statins may potentiate the treatment effects. We examined the operating mechanisms underlying such a combination. METHODS: Thirty-two hypercholesterolemic patients aged 30-70 years with hypercholesterolemia controlled by statins, received sequential treatments with placebo followed by 1.9 g/day of N-3 fatty acids for 23 weeks. Scheduled clinical visits included physical examination, 24-h blood pressure measurement, endothelial function evaluated by pulse wave analysis, analyses for platelet function, inflammation markers [interleukin (IL)-6, plasminogen activator inhibitor-1 (PAI-1)] and oxidative stress parameters (STAT-8-Isoprostane) were undertaken at baseline, after placebo treatment, and after 6 and 20 weeks of N-3 fatty acid intake. RESULTS: Platelets functions were significantly inhibited, whereas endothelial function parameters were unaltered. IL-6 significantly decreased whereas PAI-1and STAT-8-Isoprostane levels remained unaffected. Daytime blood pressure significantly decreased; however, nighttime pressure and heart rate remained unchanged. No evidence of lipid-profile improvement was observed following combined treatment with statins and N-3 fatty acids. CONCLUSIONS: In hypercholesterolemic patients, combination of statins and N-3 fatty acid inhibits platelet aggregation, alters inflammatory status, and positively affects daytime blood pressure. Close long-term follow-up might reveal additional beneficial effects of N-3 fatty acids in this patient population.