Expanding the phenotype of Brunner syndrome from childhood to adulthood: Description of the second pediatric patient and his mother.

Brunner syndrome is a recessive X-linked disorder caused by pathogenic variants in the monoamine oxidase A gene (MAOA). It is characterized by distinctive aggressive behavior, mild intellectual disability, sleep disturbances, and typical biochemical alterations deriving from the impaired monoamine metabolism. We herein describe a 5-year-old boy with developmental delay, autistic features, and myoclonic epilepsy, and his mother, who had mild intellectual disability and recurrent episodes of palpitations, headache, abdominal pain, and abdominal bloating. Whole exome sequencing allowed detection of the maternally-inherited variant c.410A>G, (p.Glu137Gly) in the MAOA gene. The subsequent biochemical studies confirmed the MAOA deficiency both in the child and his mother. Given the serotonergic symptoms associated with high serotonin levels found in the mother, treatment with a serotonin reuptake inhibitor and dietary modifications were carried out, resulting in regression of the biochemical abnormalities and partial reduction of symptoms. Our report expands the phenotypic spectrum of Brunner disease, bringing new perspectives on the behavioral and neurodevelopmental phenotype from childhood to adulthood.

Fate of melatonin orally administered in preterm newborns: Antioxidant performance and basis for neuroprotection.

Preterm infants cannot counteract excessive reactive oxygen species (ROS) production due to preterm birth, leading to an excess of lipid peroxidation with malondialdehyde (MDA) production, capable of contributing to brain damage. Melatonin (ME), an endogenous brain hormone, and its metabolites, act as a free radical scavenger against ROS. Unfortunately, preterms have an impaired antioxidant system, resulting in the inability to produce and release ME. This prospective, multicenter, parallel groups, randomized, double-blind, placebo-controlled trial aimed to assess: (i) the endogenous production of ME in very preterm infants (gestational age ≤ 29 + 6 WE, 28 infants in the ME and 26 in the placebo group); (ii) the exogenous hormone availability and its metabolization to the main metabolite, 6-OH-ME after 15 days of ME oral treatment; (iii) difference of MDA plasma concentration, as peroxidation marker, after treatment. Blood was collected before the first administration (T1) and after 15 days of administration (T2). ME and 6-OH-ME were detected by liquid chromatography tandem mass spectrometry, MDA was measured by liquid chromatograph with fluorescence detection. ME and 6-OH-ME were not detectable in the placebo group at any study time-point. ME was absent in the active group at T1. In contrast, after oral administration, ME and 6-OH-ME resulted highly detectable and the difference between concentrations T2 versus T1 was statistically significant, as well as the difference between treated and placebo groups at T2. MDA levels seemed stable during the 15 days of treatment in both groups. Nevertheless, a trend in the percentage of neonates with reduced MDA concentration at T2/T1 was 48.1% in the ME group versus 38.5% in the placebo group. We demonstrated that very preterm infants are not able to produce endogenous detectable plasma levels of ME during their first days of life. Still, following ME oral administration, appreciable amounts of ME and 6-OH-ME were available. The trend of MDA reduction in the active group requires further clinical trials to fix the dosage, the length of ME therapy and to identify more appropriate indexes to demonstrate, at biological and clinical levels, the antioxidant activity and consequent neuroprotectant potential of ME in very preterm newborns.

Serum and Hepatic Autofluorescence as a Real-Time Diagnostic Tool for Early Cholestasis Assessment.

While it is well established that various factors can impair the production and flow of bile and lead to cholestatic disease in hepatic and extrahepatic sites, an enhanced assessment of the biomarkers of the underlying pathophysiological mechanisms is still needed to improve early diagnosis and therapeutic strategies. Hence, we investigated fluorescing endogenous biomolecules as possible intrinsic biomarkers of molecular and cellular changes in cholestasis. Spectroscopic autofluorescence (AF) analysis was performed using a fiber optic probe (366 nm excitation), under living conditions and in serum, on the livers of male Wistar rats submitted to bile duct ligation (BDL, 24, 48, and 72 h). Biomarkers of liver injury were assayed biochemically. In the serum, AF analysis distinctly detected increased bilirubin at 24 h BDL. A continuous, significant increase in red-fluorescing porphyrin derivatives indicated the subversion of heme metabolism, consistent with an almost twofold increase in the serum iron at 72 h BDL. In the liver, changes in the AF of NAD(P)H and flavins, as well as lipopigments, indicated the impairment of mitochondrial functionality, oxidative stress, and the accumulation of oxidative products. A serum/hepatic AF profile can be thus proposed as a supportive diagnostic tool for the in situ, real-time study of bio-metabolic alterations in bile duct ligation (BDL) in experimental hepatology, with the potential to eventually translate to clinical diagnosis.

Fatty liver oxidative events monitored by autofluorescence optical diagnosis: Comparison between subnormothermic machine perfusion and conventional cold storage preservation.

AIMS: Livers with moderate steatosis are currently recruited as marginal organs to face donor shortage in transplantation, even though lipid excess and oxidative stress increase preservation injury risk. Sensitive, real-time detection of liver metabolism engagement could help donor selection and preservation procedures, ameliorating the graft outcome. Hence, we investigated endogenous biomolecules with autofluorescence (AF) properties as biomarkers supporting the detection of liver oxidative events and the assessment of metabolic responses to external stimuli. METHODS: Livers from male Wistar rats fed a 12-day methionine/choline-deficient (MCD) diet were subjected to AF spectrofluorometric analysis (fiber-optic probe, 366-nm excitation) before and after organ isolation, and following preservation (cold storage or 20°C machine perfusion) and reperfusion. RESULTS: Innovative dynamic AF results on lipid oxidation to lipofuscin-like lipopigments, correlating with biochemical oxidative damage (thiobarbituric acid reactive substances) and antioxidant defense (glutathione) parameters, suggested lipid engagement in MCD livers counteracting reactive oxidizing species. The maintained MCD liver functionality was supported by limited changes in bilirubin AF spectral profile, reflecting bile composition balance, despite their intrinsic mitochondrial weakness, confirmed by adenosine 5'-triphosphate levels, and regardless of different preservation effects on energy metabolism revealed by conventional reduced forms of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate and flavin AF data. CONCLUSION: Autofluorescence showed that, after a relatively short time on an MCD diet, livers are still able to face oxidizing events and maintain a functional balance. These results strengthen AF as a supportive diagnostic tool in experimental hepatology, to characterize marginal livers in real time, monitor their response to ischemia/reperfusion, and investigate protective therapeutic agents.

Liver Graft Susceptibility during Static Cold Storage and Dynamic Machine Perfusion: DCD versus Fatty Livers.

We compared static preservation (cold storage, CS, 4 °C) with dynamic preservation (machine perfusion, MP, 20 °C) followed by reperfusion using marginal livers: a model of donation after cardiac death (DCD) livers and two models of fatty livers, the methionine-choline deficient (MCD) diet model, and obese Zucker (fa/fa) rats. CS injury in DCD livers was reversed by an oxygenated washout (OW): hepatic damage, bile flow, and the ATP/ADP ratio in the OW + CS group was comparable with the ratio obtained with MP. Using fatty livers, CS preservation induced a marked release in hepatic and biliary enzymes in obese Zucker rats when compared with the MCD group. The same trend occurred for bile flow. No difference was found when comparing MP in MCD and obese Zucker rats. Fatty acid analysis demonstrated that the total saturated (SFA)/polyunsaturated fatty acid (PUFA) ratio was, respectively, 1.5 and 0.71 in obese Zucker and MCD rats. While preservation damage in DCD livers is associated with the ATP/ADP recovered with OW, injury in fatty livers is linked to fatty acid constituents: livers from obese. Zucker rats, with greater content in saturated FA, might be more prone to CS injury. On the contrary, MCD livers with elevated PUFA content might be less susceptible to hypothermia.

MCD diet-induced steatohepatitis is associated with alterations in asymmetric dimethylarginine (ADMA) and its transporters.

Using an experimental model of NASH induced by a methionine-choline-deficient (MCD) diet, we investigated whether changes occur in serum and tissue levels of asymmetric dimethylarginine (ADMA). Male Wistar rats underwent NASH induced by 8-week feeding with an MCD diet. Serum and hepatic biopsies at 2, 4 and 8 weeks were taken, and serum enzymes, ADMA and nitrate/nitrite (NOx), were evaluated. Hepatic biopsies were used for mRNA and protein expression analysis of dimethylarginine dimethylaminohydrolase-1 (DDAH-1) and protein methyltransferases (PRMT-1), enzymes involved in ADMA metabolism and synthesis, respectively, and ADMA transporters (CAT-1, CAT-2A and CAT-2B). Lipid peroxides (TBARS), glutathione, ATP/ADP and DDAH activity were quantified. An increase in serum AST and ALT was detected in MCD animals. A time-dependent decrease in serum and tissue ADMA and increase in mRNA expression of DDAH-1 and PRMT-1 as well as higher rates of mRNA expression of CAT-1 and lower rates of CAT-2A and CAT-2B were found after 8-week MCD diet. An increase in serum NOx and no changes in protein expression in DDAH-1 and CAT-1 and higher content in CAT-2 and PRMT-1 were found at 8 weeks. Hepatic DDAH activity decreased with a concomitant increase in oxidative stress, as demonstrated by high TBARS levels and low glutathione content. In conclusion, a decrease in serum and tissue ADMA levels in the MCD rats was found associated with a reduction in DDAH activity due to the marked oxidative stress observed. Changes in ADMA levels and its transporters are innovative factors in the onset and progression of hepatic alterations correlated with MCD diet-induced NASH.

Selective blockade of mGlu5 metabotropic glutamate receptors is protective against hepatic mitochondrial dysfunction in 6-OHDA lesioned Parkinsonian rats.

Non-motor symptoms including those involving the splanchnic district are present in Parkinson's disease (PD). The authors previously reported that PD-like rats, bearing a lesion of the nigrostriatal pathway induced by the injection of 6-hydroxydopamine (6-OHDA), have impaired hepatic mitochondrial function. Glutamate intervenes at multiple levels in PD and liver pathophysiologies. The metabotropic glutamate receptor 5 (mGluR5) is abundantly expressed in brain and liver and may represent a pharmacological target for PD therapy. This study investigated whether and how chronic treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a well-characterized mGluR5 antagonist, may influence hepatic function with regard to neuronal cell loss in PD-like rats. Chronic treatment with MPEP was started immediately (Early) or 4 weeks after (Delayed) intrastriatal injection of 6-OHDA and lasted 4 weeks. Early MPEP treatment significantly prevented the decrease in adenosine triphosphate (ATP) production/content and counteracted increased reactive oxygen species (ROS) formation in isolated hepatic mitochondria of PD-like animals. Early MPEP administration also reduced the toxin-induced neurodegenerative process; improved survival of nigral dopaminergic neurons correlated with enhanced mitochondrial ATP content and production. ATP content/production, in turn, negatively correlated with ROS formation suggesting that the MPEP-dependent improvement in hepatic function positively influenced neuronal cell survival. Delayed MPEP treatment had no effect on hepatic mitochondrial function and neuronal cell loss. Antagonizing mGluR5 may synergistically act against neuronal cell loss and PD-related hepatic mitochondrial alterations and may represent an interesting alternative to non-dopaminergic therapeutic strategies for the treatment of PD.

Adenine phosphoribosyltransferase (APRT) deficiency: identification of a novel nonsense mutation.

BACKGROUND: Adenine phosphoribosyltransferase deficiency (APRTD) is an under estimated genetic form of kidney stones and/or kidney failure, characterized by intratubular precipitation of 2,8-dihydroxyadenine crystals (2,8-DHA). Currently, five pathologic allelic variants have been identified as responsible of the complete inactivation of APRT protein. CASE PRESENTATION: In this study, we report a novel nonsense mutation of the APRT gene from a 47- year old Italian patient. The mutation, localized in the exon 5, leads to the replacement of a cytosine with a thymine (g.2098C > T), introducing a stop codon at amino acid position 147 (p.Gln147X).This early termination was deleterious for the enzyme structural and functional integrity, as demonstrated by the structure analysis and the activity assay of the mutant APRT protein. CONCLUSION: These data revealed that the p.Gln147X mutation in APRT gene might be a new cause of APRT disease.

Lung matrix metalloproteinase activation following partial hepatic ischemia/reperfusion injury in rats.

PURPOSE: Warm hepatic ischemia-reperfusion (I/R) injury can lead to multiorgan dysfunction. The aim of the present study was to investigate whether acute liver I/R does affect the function and/or structure of remote organs such as lung, kidney, and heart via modulation of extracellular matrix remodelling. METHODS: Male Sprague-Dawley rats were subjected to 30 min partial hepatic ischemia by clamping the hepatic artery and the portal vein. After a 60 min reperfusion, liver, lung, kidney, and heart biopsies and blood samples were collected. Serum hepatic enzymes, creatinine, urea, Troponin I and TNF-alpha, and tissue matrix metalloproteinases (MMP-2, MMP-9), myeloperoxidase (MPO), malondialdehyde (MDA), and morphology were monitored. RESULTS: Serum levels of hepatic enzymes and TNF-alpha were concomitantly increased during hepatic I/R. An increase in hepatic MMP-2 and MMP-9 activities was substantiated by tissue morphology alterations. Notably, acute hepatic I/R affect the lung inasmuch as MMP-9 activity and MPO levels were increased. No difference in MMPs and MPO was observed in kidney and heart. CONCLUSIONS: Although the underlying mechanism needs further investigation, this is the first study in which the MMP activation in a distant organ is reported; this event is probably TNF-alpha-mediated and the lung appears as the first remote organ to be involved in hepatic I/R injury.

Testing the reported long-term advantages of protein-fortified human milk in very low birth weight neonates.

Preterm infants are at-risk for extrauterine growth restriction and downward percentile-crossing between birth and discharge. Increased energy and protein intake through fortification of human milk during the first weeks of life has been associated with improved short-term growth and better developmental outcomes. The aim of this study was to evaluate whether these benefits persist up to children school age. The study was designed as an observational study. During hospitalization, 22 very low birth weight preterm infants were fed with increasing protein fortification of human milk (protein supplemented group, PSG). As a control group (CG), 11 preterm infants were fed with standard nutrition regimen. At children school age (9-11 years), we assessed anthropometric data (weight, height, BMI), global health (renal function), and specific psychological outcomes (Child Behavior Checklist 6-18). A global homogeneity between CG and PSG groups emerged: we found no significant differences in weight, height, and BMI, nor in internalizing symptom outcomes (all ps > 0.05). However, mothers reported significantly higher externalizing symptoms for the PSG infants compared to CG infants. Therefore, neonatal enteral protein supplementation in very low birth weight preterm infants leads to no positive nor adverse consequences in long-term assessment, suggesting that benefits are restricted to the neonatal term and first years of age.

Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: a self-perpetuating crosstalk?

In Parkinson's disease (PD), aside from the central lesion, involvement of visceral organs has been proposed as part of the complex clinical picture of the disease. The issue is still poorly understood and relatively unexplored. In this study we used a classic rodent model of nigrostriatal degeneration, induced by the intrastriatal injection of 6-hydroxydopamine (6-OHDA), to investigate whether and how a PD-like central dopaminergic denervation may influence hepatic functions. Rats received an intrastriatal injection of 6-OHDA or saline (sham), and blood, cerebrospinal fluid, liver and brain samples were obtained for up to 8 weeks after surgery. Specimens were analyzed for changes in cytokine and thyroid hormone levels, as well as liver mitochondrial alterations. Hepatic mitochondria isolated from animals bearing extended nigrostriatal lesion displayed increased ROS production, while membrane potential (ΔΨ) and ATP production were significantly decreased. Reduced ATP production correlated with nigral neuronal loss. Thyroid hormone levels were significantly increased in serum of PD rats compared to sham animals while steady expression of selected cytokines was detected in all groups. Hepatic enzyme functions were comparable in all animals. Our study indicates for the first time that in a rodent model of PD, hepatic mitochondria dysfunctions arise as a consequence of nigrostriatal degeneration, and that thyroid hormone represents a key interface in this CNS-liver interaction. Liver plays a fundamental detoxifying function and a better understanding of PD-related hepatic mitochondrial alterations, which might further promote neurodegeneration, may represent an important step for the development of novel therapeutic strategies.

Endogenous Catecholamine Release in COVID-19 Related Acute Respiratory Distress Syndrome: Link between Enhanced Sympathetic Stimulation, Cardiac Dysfunction and Outcome.

The aim of this study was to measure the serum levels of catecholamines in patients admitted to intensive care unit (ICU) with COVID-19-related acute respiratory distress syndrome (ARDS) and describe their relation with clinical, inflammatory and echocardiographic parameters. Serum levels of endogenous catecholamines (norepinephrine, epinephrine and dopamine) were measured at ICU admission. We enrolled 71 patients consecutively admitted to ICU due to moderate to severe ARDS. 11 patients (15.5%) died during the admission in ICU. Serum levels of endogenous catecholamines were significantly elevated. Norepinephrine levels were higher in those with RV and LV systolic dysfunction, higher CRP, and higher IL-6. Patients with higher mortality rate were those with norepinephrine values ≥ 3124 ng/mL, CRP ≥ 17.2 mg/dL and IL-6 ≥ 102 pg/mL. Univariable analysis by Cox proportional hazards regression modelling showed that norepinephrine, IL-6 and CRP had the highest risk of acute mortality. Multivariable analysis showed that only norepinephrine and IL-6 retained in the model. Marked increase of serum catecholamine levels is present during acute phase of critically ill COVID-19 and it is associated with inflammatory and clinical parameters.

Lumbar Puncture and Meningitis in Infants with Proven Early- or Late-Onset Sepsis: An Italian Prospective Multicenter Observational Study.

Background: To evaluate the rates of lumbar puncture (LP) in infants with culture-proven sepsis. Study design: We prospectively enrolled 400 infants with early- or late-onset sepsis due to Group B streptococcus (GBS) or Eschericha coli, diagnosed within 90 days of life. Rates of LP and potential variables associated with LP performance were evaluated. Moreover, cerebrospinal fluid (CSF) characteristics and results of the molecular analysis were investigated. Results: LP was performed in 228/400 (57.0%) infants; 123/228 LPs (53.9%) were performed after antibiotic initiation, hampering the ability to identify the pathogen in the CSF culture. However, polymerase chain reaction increased the probability of positive results of CSF analysis compared to microbiological culture (28/79, 35.4% vs. 14/79, 17.7%, p = 0.001). Severe clinical presentation and GBS infection were associated with higher LP rates. The rate of meningitis was 28.5% (65/228). Conclusions: Rates of LP are low in culture-proven neonatal sepsis and antibiotics are frequently given before LP is carried out. Thus meningitis may be underestimated, and the chances of giving an effective therapy to the newborn are reduced. LP should be performed before the start of antibiotics when there is a clinical suspicion of infection.

Timing of Symptoms of Early-Onset Sepsis after Intrapartum Antibiotic Prophylaxis: Can It Inform the Neonatal Management?

The effectiveness of "inadequate" intrapartum antibiotic prophylaxis (IAP administered < 4 h prior to delivery) in preventing early-onset sepsis (EOS) is debated. Italian prospective surveillance cohort data (2003-2022) were used to study the type and duration of IAP according to the timing of symptoms onset of group B streptococcus (GBS) and E. coli culture-confirmed EOS cases. IAP was defined "active" when the pathogen yielded in cultures was susceptible. We identified 263 EOS cases (GBS = 191; E. coli = 72). Among GBS EOS, 25% had received IAP (always active when beta-lactams were administered). Most IAP-exposed neonates with GBS were symptomatic at birth (67%) or remained asymptomatic (25%), regardless of IAP duration. Among E. coli EOS, 60% were IAP-exposed. However, IAP was active in only 8% of cases, and these newborns remained asymptomatic or presented with symptoms prior to 6 h of life. In contrast, most newborns exposed to an "inactive" IAP (52%) developed symptoms from 1 to >48 h of life. The key element to define IAP "adequate" seems the pathogen's antimicrobial susceptibility rather than its duration. Newborns exposed to an active antimicrobial (as frequently occurs with GBS infections), who remain asymptomatic in the first 6 h of life, are likely uninfected. Because E. coli isolates are often unsusceptible to beta-lactam antibiotics, IAP-exposed neonates frequently develop symptoms of EOS after birth, up to 48 h of life and beyond.

Lobe-specific heterogeneity and matrix metalloproteinase activation after ischemia/reperfusion injury in rat livers.

Studies assessing the effects of partial-hepatic ischemia/reperfusion (I/R) injury focused on the damage to the ischemic-lobe, whereas few data are available on non-ischemic lobe. This study investigated whether acute liver I/R does affect non-ischemic lobe function via modulation of extracellular matrix remodeling. Male Sprague-Dawley rats underwent left lateral- and median-lobe ischemia for 30 min and reperfusion for 60 min or sham operation. After reperfusion, blood samples and hepatic biopsies from both the ischemic (left-lobe, LL) and the non-ischemic lobe (right-lobe, RL) were collected. Serum hepatic enzymes and TNF-alpha, tissue matrix metalloproteinases (MMP-2, MMP-9), liver morphology, malondialdehyde (MDA), and myeloperoxidase (MPO) were evaluated. Liver I/R injury was confirmed by altered increased hepatic enzymes and TNF-alpha. I/R induced an altered morphology and an increase in MMP-2 and MMP-9 activity not only in left-ischemic lobe (LL) but also in the right-non-ischemic (RL) lobe. A lobar difference was detected for MDA formation and MPO activity in both sham and I/R submitted rats, with higher levels in the left lobe for both groups. This study indicates that an increase in MMPs, which may be TNF-alpha-mediated, occurs in both the ischemic- and the non-ischemic lobes; the heterogeneous lobe concentrations of MDA and MPO suggest that the random sampling of liver tissue should be avoided.

Escherichia coli Is Overtaking Group B Streptococcus in Early-Onset Neonatal Sepsis.

The widespread use of intrapartum antibiotic prophylaxis (IAP) to prevent group B streptococcus (GBS) early-onset sepsis (EOS) is changing the epidemiology of EOS. Italian prospective area-based surveillance data (from 1 January 2016 to 31 December 2020) were used, from which we identified 64 cases of culture-proven EOS (E. coli, n = 39; GBS, n = 25) among 159,898 live births (annual incidence rates of 0.24 and 0.16 per 1000, respectively). Approximately 10% of E. coli isolates were resistant to both gentamicin and ampicillin. Five neonates died; among them, four were born very pre-term (E. coli, n = 3; GBS, n = 1) and one was born full-term (E. coli, n = 1). After adjustment for gestational age, IAP-exposed neonates had ≥95% lower risk of death, as compared to IAP-unexposed neonates, both in the whole cohort (OR 0.04, 95% CI 0.00-0.70; p = 0.03) and in the E. coli EOS cohort (OR 0.05, 95% CI 0.00-0.88; p = 0.04). In multi-variable logistic regression analysis, IAP was inversely associated with severe disease (OR = 0.12, 95% CI 0.02-0.76; p = 0.03). E. coli is now the leading pathogen in neonatal EOS, and its incidence is close to that of GBS in full-term neonates. IAP reduces the risk of severe disease and death. Importantly, approximately 10% of E. coli isolates causing EOS were found to be resistant to typical first-line antibiotics.

Machine perfusion at 20°C reduces preservation damage to livers from non-heart beating donors.

We previously reported that machine perfusion (MP) performed at 20°C enhanced the preservation of steatotic rat livers. Here, we tested whether rat livers retrieved 30 min after cardiac arrest (NHBDs) were better protected by MP at 20°C than with cold storage. We compared the recovery of livers from NHBDs with organs obtained from heart beating donors (HBDs) preserved by cold storage. MP technique: livers were perfused for 6h with UW-G modified at 20°C. Cold storage: livers were perfused in situ and preserved with UW solution at 4°C for 6h. Both MP and cold storage preserved livers were reperfused with Krebs-Heinselet buffer (2h at 37°C). AST and LDH release and mitochondrial glutamate dehydrogenase (GDH) levels were evaluated. Parameters assessed included: bile production and biliary enzymes; tissue ATP; reduced and oxidized glutathione (GSH/GSSG); protein-SH group concentration. Livers preserved by MP at 20°C showed significantly lower hepatic damage at the end of reperfusion compared with cold storage. GDH release was significantly reduced and bile production, ATP levels, GSH/GSSG and protein-SH groups were higher in livers preserved by MP at 20°C than with cold storage. The best preserved morphology and high glycogen content was obtained with livers submitted to MP at 20°C. Liver recovery using MP at 20°C was comparable to recovery with HBDs. MP at 20°C improves cell survival and gives a better-quality of preservation for livers obtained from NHBDs and may provide a new method for the successful utilization of marginal livers.

Association between the uremic toxins indoxyl-sulfate and p-cresyl-sulfate with sarcopenia and malnutrition in elderly patients with advanced chronic kidney disease.

BACKGROUND: in patients with chronic kidney disease (CKD) indoxyl sulfate (IS) and p-cresyl sulfate (PCs) may induce sarcopenia either directly or via systemic inflammation. We evaluated whether IS and PCs were associated with: sarcopenia, systemic inflammation and nutritional status. METHODS: we examined cross sectionally 93 patients with advanced CKD. Sarcopenia was identified according to EWGSOP2 definition. Malnutrition was assessed by Malnutrition Inflammation Score (MIS) and Protein Energy Wasting syndrome (PEW). Inflammatory status was assessed by dosing: CRP, IL6, TNFα, MCP1, IL10, IL17, IL12p70. RESULTS: we did not find any association of sarcopenia with IS and PCs. IS was associated with LogTNFα and LogMCP-1 in the overall cohort (r = 0.30, p = 0.0043; r = 0.22 p = 0.047) and in not sarcopenic patients (r = 0.32, p = 0.0077; r = 0.25, p = 0.041). PCs was associated with LogIL10 and LogIL12p70 in sarcopenic patients (r = 0.58, p = 0.0042; r = 0.52, p = 0.013). IS was higher in patients without PEW (p = 0.029), while PCs was higher in patients with PEW (p = 0.0040). IS and PCs were not different in patients with normal or increased MIS. CONCLUSIONS: IS and PCs were not associated with sarcopenia, although they were both associated with some inflammatory pathways. Notably, we found a positive association of PCs with PEW syndrome.

Association of Sarcopenia and Gut Microbiota Composition in Older Patients with Advanced Chronic Kidney Disease, Investigation of the Interactions with Uremic Toxins, Inflammation and Oxidative Stress.

Sarcopenia is a prevalent condition in chronic kidney disease (CKD). We determined gut microbiota (gMB) composition in CKD patients with or without sarcopenia. Furthermore, we investigated whether in these patients, there was any association between gMB, uremic toxins, inflammation and oxidative stress. We analyzed gMB composition, uremic toxins (indoxyl sulphate and p-cresyl sulphate), inflammatory cytokines (interleukin 10, tumor necrosis factor α, interleukin 6, interleukin 17, interleukin 12 p70, monocyte chemoattractant protein-1 and fetuin-A) and oxidative stress (malondialdehyde) of 64 elderly CKD patients (10 < eGFR < 45 mL/min/1.73 m2, not on dialysis) categorized as sarcopenic and not-sarcopenic. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 criteria. Sarcopenic patients had a greater abundance of the Micrococcaceae and Verrucomicrobiaceae families and of Megasphaera, Rothia, Veillonella, Akkermansia and Coprobacillus genera. They had a lower abundance of the Gemellaceae and Veillonellaceae families and of Acidaminococcus and Gemella genera. GMB was associated with uremic toxins, inflammatory cytokines and MDA. However, uremic toxins, inflammatory cytokines and MDA were not different in sarcopenic compared with not-sarcopenic individuals, except for interleukin 10, which was higher in not-sarcopenic patients. In older CKD patients, gMB was different in sarcopenic than in not-sarcopenic ones. Several bacterial families and genera were associated with uremic toxins and inflammatory cytokines, although none of these latter substantially different in sarcopenic versus not-sarcopenic patients.