Ultrasound Elastography in Children.

Ultrasound elastography is a novel ultrasound technique, being extensively researched in children in the last decade. It measures tissue elasticity with the observation of tissue response after an external stimulus. From research to clinical practice, ultrasound elastography has evolved significantly in liver fibrosis evaluation in children; however, several other applications of the technique are available in both clinical practice and research environments. Practically, in children any organ can be assessed, including the brain in early ages, along with muscle and connective tissue elasticity evaluation, spleen, kidney, skin, lymphatic tissue, etc. The elastography method, age, body mass index and technical points should be considered when performing ultrasound elastography. This review highlights its vast potential as a diagnostic tool in the pediatric population, where ultrasound is a dominant imaging tool; however, the indications and exam protocol for its clinical use in several fields in pediatrics have yet to be elucidated.

Liver and kidney ultrasound elastography in children and young adults with hypertension or chronic kidney disease.

BACKGROUND: Ultrasound elastography is a research method increasingly used to measure tissue elasticity. The aim of the study was to assess its usability in pediatric patients with either chronic kidney disease (CKD) or hypertension. METHODS: A total of 46 patients with CKD (group 1), 50 patients with hypertension (group 2), and 33 healthy participants as the control group were included. In all, we performed studies assessing their cardiovascular risk along with liver and kidney elastography. RESULTS: Liver elastography parameters were increased compared to those in the control group (1.49 m/s, p = 0.007, in group 1 and 1.52 m/s, p < 0.001, in group 2, vs. 1.41 m/s among controls). Kidney elastography parameters were significantly higher in group 2 (1.9 m/s, p = 0.001, and 1.9 m/s, p = 0.003, in each kidney) when compared to group 1 (1.79 m/s and 1.81 m/s). Additionally, all participants were divided according to overweight/obesity and normal weight status, where both liver (1.53 m/s vs. 1.45 m/s, p < 0.001) and kidney parameters (1.96 m/s and 1.92 m/s vs. 1.81 m/s and 1.84 m/s, p = 0.002) were significantly higher in the group of overweight/obese subjects. CONCLUSIONS: Ultrasound elastography of the liver and kidney is feasible in pediatric patients with either CKD or hypertension, showing increased liver stiffness parameters in both groups, further aggravated by obesity. In obese patients with CKD, kidney stiffness also increased indicating a negative effect of clustering cardiovascular risk factors leading to decreased kidney elasticity. Further research is warranted. A higher resolution version of the Graphical abstract is available as Supplementary information.

Epicardial Adipose Tissue: A Piece of The Puzzle in Pediatric Hypertension.

BACKGROUND AND PURPOSE: Epicardial adipose tissue (EAT) is a metabolically active tissue located on the surface of the myocardium, which might have a potential impact on cardiac function and morphology. The aim of this study was to evaluate whether EAT is associated with essential arterial hypertension (AH) in children and adolescents. METHODS: Prospective cardiovascular magnetic resonance (CMR) study and clinical evaluation were performed on 72 children, 36 of whom were diagnosed with essential AH, and the other 36 were healthy controls. The two groups were compared in volume and thickness of EAT, end-diastolic volume, end-systolic volume, stroke volume, left ventricular (LV) ejection fraction, average heart mass, average LV myocardial thickness, peak filling rate, peak filling time and clinical parameters. RESULTS: Hypertensive patients have a higher volume (16.5 ± 1.9 cm3 and 10.9 ± 1.5 cm3 (t = -13.815, p < 0.001)) and thickness (0.8 ± 0.3 cm and 0.4 ± 0.1 cm, (U = 65.5, p < 0.001)) of EAT compared to their healthy peers. The volume of EAT might be a potential predictor of AH in children. CONCLUSIONS: Our study indicates that the volume of EAT is closely associated with hypertension in children and adolescents.

Lipid Biomarkers and Atherosclerosis-Old and New in Cardiovascular Risk in Childhood.

Lipids are a complex group of molecules in the body, essential as structural, functional and metabolic components. When disbalanced, they are regarded as a cardiovascular risk factor, traditionally in cholesterol level evaluation. However, due to their complex nature, much research is still needed for a comprehensive understanding of their role in atherosclerosis, especially in the young. Several new lipid biomarkers are emerging, some already researched to a point, such as lipoproteins and apolipoproteins. Other lipid molecules are also being increasingly researched, including oxidized forms due to oxidative inflammation in atherosclerosis, and sphingolipids. For many, even those less new, the atherogenic potential is not clear and no clinical recommendations are in place to aid the clinician in using them in everyday clinical practice. Moreover, lipids' involvement in atherogenesis in children has yet to be elucidated. This review summarizes the current knowledge on lipids as biomarkers of cardiovascular risk in the paediatric population.

Association of multiple retinal nodular hamartomas and "confetti" skin lesions with end-stage renal disease in patients with tuberous sclerosis.

PURPOSE: The main purpose of this study is to explore characteristics of patients with chronic kidney disease in tuberous sclerosis (TSC) and to underline differences in clinical characteristics between end-stage renal disease (ESRD) patients and patients in earlier stages of chronic kidney disease. METHODS: This multicentric, retrospective study included data for 48 patients from seven South-Eastern European countries (Albania, Bosnia and Herzegovina, Croatia, Greece, Montenegro, Serbia, Slovenia) in the period from February to August 2020. Researchers collected data from local and national nephrological and neurological registries and offered clinical and laboratory results from medical histories in follow-up periods. RESULTS: This study enrolled 48 patients with a median age of 32.3 years (range, 18-46 years), and predominant female gender (60.45%). The percentage of patients with chronic kidney disease (CKD) diagnosis of the total number of patients was 66.90%, with end-stage renal disease development in 39.6%. The most prevalent renal lesions leading to chronic kidney disease were angiomyolipomas (AMLs) in 76.6%, while multiple renal cysts were present in 42.6% of patients. Nephrectomy was performed in 43% of patients, while the mTOR inhibitors were used in 18 patients (37.5%). The majority of patients had cutaneous manifestations of tuberous sclerosis-83.30% had hypomelanotic cutaneous lesions, and 68.80% had angiofibromas. Multiple retinal nodular hamartomas and "confetti" skin lesions were more frequent in end-stage renal disease (ESRD) than in patients with earlier stages of chronic kidney disease (p-0.033 and 0.03, respectively). CONCLUSION: Our study has also shown that retinal hamartomas and "confetti" skin lesions are more frequent in end-stage renal diseases (ESRD) patients than in other chronic kidney disease (CKD) patients. Usage of mTOR inhibitors can also reduce the number of complications and associated with tuberous sclerosis, such as dermatological manifestations and retinal hamartoma, which are more common in the terminal stage of chronic kidney disease.

Obesity and Body Composition in Relation to Liver and Kidney Ultrasound Elastography in Paediatric Patients with Either Hypertension or Chronic Kidney Disease.

(1) Background: Ultrasound elastography is a novel ultrasound technique for evaluating tissue elasticity. One of the key factors influencing the measurement in children is excess weight. This study aimed to evaluate the effect of body composition, namely, fat mass, on liver and kidney ultrasound elastography in paediatric patients. (2) Methods: 114 participants, in whom bioimpedance, along with liver and kidney ultrasound elastography, were performed, were included (37 patients with chronic kidney disease, 46 patients with hypertension, and 31 healthy subjects). (3) Results: Bioimpedance analysis showed a significant correlation between liver elastography parameters and the phase angle (p = 0.002), fat-free mass (p = 0.001), body cell mass (p = 0.001), total body water (p = 0.001), extracellular water (p = 0.006), and, to lesser extent, fat mass (p = 0.041). On the contrary, kidney elastography parameters strongly correlated only with fat mass (p < 0.001 for both kidneys). (4) Conclusions: Liver and kidney stiffness increased in overweight participants and showed significant correlation with fat mass, particularly in the case of kidney elastography.

The Impact of Lactobacillus Plantarum PCS26 Supplementation on the Treatment and Recurrence of Urinary Tract Infections in Children-A Pilot Study.

Urinary tract infections (UTI) are frequent bacterial infections in childhood. Considering the known beneficial effects of probiotics in the gastrointestinal field, they could also help to alleviate UTIs. In our clinical pilot study, we sought to verify the positive effects of the specific probiotic strain on the course and prevention of UTI in children. Thirty children with UTIs were enrolled and sequentially sampled into two groups (placebo/control and probiotic/test) in a double-blind, randomized, placebo-controlled clinical pilot study. We chose Lactobacillus plantarum PCS 26 (Lp26) derived from local Slovenian cheese in Pathogen Combat Project, which showed a good in vitro antimicrobial effect on Escherichia coli (E. coli). Several parameters were followed to look for differences between both groups in the acute phase of the UTI and after 6 months of taking probiotic or placebo supplementation. Our results showed no statistically significant differences between both groups; however, two children in the placebo group suffered a recurrence of febrile UTI within 6 months of the follow-up period, while there were no recurrences of UTI in the probiotic group. In the test group, the number of febrile days after the initiation of antibiotics with probiotics was shorter, although not reaching statistical significance (p = 0.084). According to our results, probiotics might be helpful in alleviating UTI symptoms and in UTI prevention. Further research with a larger sample size is warranted. Additionally, basic scientific studies for the selection of proper immunobiotic strains of probiotics should be performed.

Glomerular Filtration Rate Assessment in Children.

Glomerular filtration rate (GFR) measurement is a key tool for determining the degree of chronic kidney disease. The assessment of GFR is even more challenging in children than in adults with more variables in the equation than race and sex. Monitoring the progress of the kidney disease can therefore be difficult as in the initial stages of a decline in kidney function, there are no clinical signs. Due to children's growth and development, changes in muscle mass and growth impair GFR estimation based solely on serum creatinine values. More invasive methods of GFR measurement are more reliable, but techniques using ionising agents, requiring large volume blood samples or timed voiding, have limited application in children. This paper reviews the methods of measuring and determining glomerular filtration rate and kidney function in children.

Assessing 48 SNPs in Hypertensive Paediatric Patients and Young Adults with Review of Genetic Background of Essential Hypertension.

Essential hypertension in paediatric patients and young adults is rising, mostly on account of obesity-related hypertension. Clinically, the difference between obese hypertensive and non-obese hypertensive individuals is evident; yet, the pathophysiology of essential and obesity-related hypertension is multifactorial, complex and not fully understood. The aim of our study was to obtain a comprehensive view of the clinical differences between obesity-related hypertension and hypertension in non-obese paediatric patients and young adults and to do genetic tests to possibly highlight some of the pathophysiological differences with a review of their genetic backgrounds. Four hundred and thirty-six hypertensive paediatric patients and young adults were included in the study, and a study of 48 single-nucleotide polymorphisms, using Kompetitive allele specific PCR, was conducted. The subjects were divided into 243 non-obese participants with hypertension and 193 obese participants with hypertension. The data for the clinical comparison of both groups were collected as well. The differences in some clinical and biochemical parameters were confirmed. Genetic tests showed a significant difference in one allele frequency between both groups in five SNPs: rs6232, rs6235, rs12145833, rs59744560 and rs9568856. In rs6235 and rs59744560, a direct effect of different allele states could be implied. Obesity-related hypertension at a young age differs from essential hypertension in those non-obese. The reported genetic differences could be important in understanding the complex pathophysiology of early-onset obesity-related hypertension and should be further evaluated.

Transition of Chronic Pediatric Nephrological Patients to Adult Care Excluding Patients on Renal Replacement Therapy with Literature Review.

(1) Background: The transition of children with chronic kidney disease to adult care has become a well-handled issue. However, other patients with normal or mildly decreased renal function also requiring further management and transition are neglected. (2) Methods: A questionnaire was sent to patients with kidney pathology, aged 17 years and older.(3) Results: The patients were mostly high-school (55%) or college students (39%), living with their parents (94%). One third did not know how their disease affected their choice of profession and reproductive health. Furthermore, 46% of the respondents did not know who would continue with their care, and 44% still had a primary pediatrician. (4) Conclusions: A review of the literature on the topic was performed and summarized here. Regular education is the key for successful transfer, not only in chronic kidney and transplant patients, but also in others in whom a decline in renal function can be expected in the future.

Systemic Inflammation, Oxidative Stress and Cardiovascular Health in Children and Adolescents: A Systematic Review.

Recent studies indicate that cerebrovascular diseases and processes of atherosclerosis originate in the childhood era and are largely influenced by chronic inflammation. Some features of vascular dysfunction in adulthood may even be programmed prenatally via genetic influences and an unfavorable intrauterine milieu. Oxidative stress, defined by an imbalance between the production and generation of reactive oxygen species (ROS) in cells and tissues and the capability of an organism to scavenge these molecules via antioxidant mechanisms, has been linked to adverse cardiovascular health in adults, yet has not been systematically reviewed in the pediatric population. We performed a systematic search as per the PRISMA guidelines in PubMed/Medline and Cochrane Reviews and detected, in total, 1228 potentially eligible pediatric articles on systemic inflammation, oxidative stress, antioxidant use, cardiovascular disease and endothelial dysfunction. The abstracts and full-text manuscripts of these were screened for inclusion and exclusion criteria, and a total of 160 articles were included. The results indicate that systemic inflammation and oxidative stress influence cardiovascular health in many chronic pediatric conditions, including hypertension, obesity, diabetes mellitus types 1 and 2, chronic kidney disease, hyperlipidemia and obstructive sleep apnea. Exercise and diet may diminish ROS formation and enhance the total serum antioxidant capacity. Antioxidant supplementation may, in selected conditions, contribute to the diminution of the oxidative state and improve endothelial function; yet, in many areas, studies provide unsatisfactory results.

Body Composition and Cardiovascular Risk Factors in a Paediatric Population.

The aim of our study was to evaluate associations between body composition parameters and several clinical parameters. A total of 206 children and adolescents (120 male, 86 female) were prospectively included. Body impedance measurement was performed in all participants. During the hospital work-up, several clinical parameters such as anthropometric measurements and laboratory and ultrasound findings were obtained and correlated to body composition parameters. There was a significant association between body composition parameters and anthropometric measurements, systolic blood pressure, insulin levels, serum creatinine, urate, liver function tests, triglycerides, cholesterols and apolipoproteins, homocysteine, vitamin D and proteins in 24-h urine. Body composition differed by gender, between participants with and without hepatic steatosis and between patients with and without left ventricular hypertrophy. Interestingly, body composition did not correlate with diastolic blood pressure, pulse wave velocity and intima media thickness. This study showed that several clinical parameters are associated with body composition in children. Obesity and body composition play an important role in the development of other cardiovascular risk factors and are not dependent on fat mass alone, and the latter might be used for cardiovascular risk determination.

Development and Validation of a New Screening Tool with Non-Invasive Indicators for Assessment of Malnutrition Risk in Hospitalised Children.

There is no evidence of the most effective nutritional screening tool for hospitalized children. The present study aimed to develop a quick, simple, and valid screening tool for identifying malnutrition risk of hospital admission with non-invasive indicators. A cross-sectional study was conducted. Children`s nutritional baseline using a questionnaire, subjective malnutritional risk, and Subjective Global Nutritional Assessment were assessed on admission. Concurrent validity was assessed using American Society for Parenteral and Enteral Nutrition (ASPEN)and Academy of Nutrition and Dietetics assessment and Subjective Global Nutritional Assessment tool. A new screening tool Simple Pediatric Nutritional risk Screening tool (SPENS) was developed, and sensitivity, specificity and reliability were evaluated. A total of 180 children aged from 1 month to 18 years were included (142 in the development phase and 38 in the validation phase). SPENS consist of four variables and shows almost perfect agreement with subjective malnutritional risk assessment (κ = 0.837) with high sensitivity and specificity (93.3% and 91.3% respectively). Compared with Subjective Global Nutritional Assessment and ASPEN and Academy of Nutrition and Dietetics assessment, SPENS had sensitivity 92.9% and 86.7%, a specificity of 87.5% and 87.0%, and an overall agreement of 0.78 and 0.728, respectively. Due to the fast, simple, easy, and practical to use, screening the SPENS can be performed by nurses, physicians, and dieticians.

Novel Biomarkers of Heart Failure in Pediatrics.

Novel biomarkers of heart failure are the subject of numerous studies. Biomarkers of heart failure can be determined in the blood and in the urine. Seven groups of biomarkers of heart failure based on pathophysiological mechanisms are presented in this review, namely biomarkers of myocardial stretch, myocyte injury, myocardial remodeling, biomarkers of inflammation, renal dysfunction, neurohumoral activation, and oxidative stress. Studies of biomarkers in the pediatric population are scarce, therefore, further investigation is needed for reliable prognostic and therapeutic implications. The future of biomarker use is in multimarker panels that include a combination of biomarkers with different pathophysiological mechanisms in order to improve their diagnostic and prognostic predictive value.

The Role of Urate in Cardiovascular Risk in Adolescents and Young Adults With Hypertension, Assessed by Pulse Wave Velocity.

Background: Urate is increasingly recognized as a cardiovascular risk factor. It has been associated with hypertension, metabolic syndrome, obesity, chronic kidney disease and diabetes. Its prognostic role is less clear. The aim of our study was to evaluate the association between serum urate and pulse wave velocity, a measure of arterial stiffness in hypertensive adolescents and young adults. Methods: 269 adolescents and young adults with hypertension were included in the study. From all, anthropometric, blood pressure, pulse wave velocity and serum urate measurements were made. Variables were compared between sex, participants with or without obesity and with or without elevated urate. Results: In multiple regression analysis for urate as dependent variable gender and diastolic pressure were found to be statistically significant. The difference between urate levels were found between boys and girls (p < 0.001), obese and non-obese (p < 0.001); however, pulse wave velocity did not differ between hyper- and eu-uricemic group (p = 0.162). Conclusion: Associations between urate, gender, diastolic blood pressure and obesity were confirmed, however, no significant associations between pulse wave velocity and urate were detected.

Current Knowledge of Selected Cardiovascular Biomarkers in Pediatrics: Kidney Injury Molecule-1, Salusin-α and -ß, Uromodulin, and Adropin.

Cardiovascular diseases are the leading cause of morbidity and mortality in the modern world. Their common denominator is atherosclerosis, a process beginning in childhood. In pediatrics, the aim of preventive measures is to recognize children and adolescents at risk for accelerated atherosclerosis and possible premature cardiovascular events in adulthood. Several diagnostic procedures and biomarkers are available for cardiovascular risk assessment in adults. However, reliable markers in pediatrics are still insufficiently studied. In this contribution, we discuss five potential biomarkers of particular interest: kidney injury molecule-1, salusin-α and -ß, uromodulin, and adropin. Studies regarding the pediatric population are scarce, but they support the evidence from studies in the adult population. These markers might entail both a prognostic and a therapeutic interest.

Emerging Links between Microbiome Composition and Skin Immunology in Diaper Dermatitis: A Narrative Review.

Diaper dermatitis is a common type of irritant contact dermatitis occurring in infants and toddlers. Its occurrence is triggered by an unfavorable environment under the diaper, damage to skin integrity by fecal enzyme degradation, overhydration and disruption of the lipid bilayer structure facilitating the entry of irritants and microorganisms. In diaper dermatitis development, the central proinflammatory cytokines are IL-1α, IL-8 and TNF-α. The initial release of IL-1α and TNF-α starts a further cascade of pro-inflammatory chemo- and cytokines, resulting in inflammation and erythema of the skin. A recently recognized factor in diaper dermatitis is the composition of the skin microbiome; common pathogenic strains Candida albicans and Staphylococcus aureus are associated with skin irritation. The resulting impaired microbiome composition produces a local inflammatory response and may thus worsen the initial dermatitis clinical presentation and subsequent healing. Introduction of probiotics is an attractive treatment for microbiome modulation, which has shown success in other skin conditions in adults and children. Probiotics are thought to work as a protective shield against irritants, maintain low skin pH, secrete beneficial metabolites, and block pathogen invasion. There is preliminary evidence that certain probiotics given orally or topically could be used as a gentle intervention in diaper dermatitis.

Pulse Wave Velocity, Central Haemodynamic Parameters, and Markers of Kidney Function in Children.

OBJECTIVES: Chronic kidney disease (CKD) is a well-established risk factor for cardiovascular diseases. Studies in adults have demonstrated the association between mildly decreased kidney function or even normal values of markers of kidney function to pulse wave velocity (PWV), a measure of arterial stiffness and a predictor of cardiovascular events. Our study aimed to evaluate associations between markers of CKD, PWV, and central haemodynamic parameters in children and adolescents at risk of subclinical kidney damage. METHODS: 182 children and adolescents with hypertension, obesity, or hypercholesterolaemia (risk factors for subclinical kidney damage) were included in the study. The subjects were subdivided into 4 groups comprising children and adolescents with hypertension (group 1), obesity (group 2), hypercholesterolaemia (group 3), and a group with a combination of risk factors, such as obesity-related hypertension and metabolic syndrome (group 4). The study groups were compared to a group of healthy controls (group 5). PWV was measured by applanation tonometry (SphygmoCor, SCOR-Vx, Sydney, NSW, Australia) and laboratory parameters (serum creatinine, serum cystatin C, and microalbuminuria) were collected. RESULTS: Pearson's correlation coefficient demonstrated a statistically significant correlation between PWV and serum creatinine in group of all subjects (r = 0.220, p = 0.002). Further subdivision showed the correlation was significant in group 4 (r = 0.370, p = 0.002). In group 2 a correlation between PWV and cystatin C was found (r = -0.535, p = 0.009). In multiple regression analysis of all subjects with PWV as the dependent variable, age and diastolic blood pressure were statistically significant. Correlations between markers of kidney function and central haemodynamic parameters also showed significant correlations between serum creatinine and heart rate (HR) (r = -0.476, p < 0.001) as well as associated parameters (augmentation index, standardized at HR 75/min, ejection duration, and subendocardial viability ratio). CONCLUSIONS: Our study demonstrated a correlation between serum creatinine and PWV in children with combined risk factors for atherosclerosis and probable subclinical kidney damage. Further prospective research is needed to confirm the findings, and thus the preventive role of PWV determination in paediatric nephrology.

Obesogens in Children-An Uncharted Territory.

Obesogens are exogenous chemicals belonging to the group of endocrine-disrupting chemicals and are believed to interfere in obesity development. In children, several chemicals are under investigation, most commonly bisphenol A, phthalates, perfluorinated alkyl substances, and persistent organic pollutants, including organochlorinated pesticides, tributyltin, polychlorinated biphenyls and dioxins. Several associations have been studied between chemical exposure in utero and postnatally. Current opinion among researchers indicates that the obesogen theory is very likely; however, limited published studies show inconsistent support for the obesogenic effects of most substances in children and are limited by difficulty in providing the exact mechanisms of action, nor is their mutual effect in humans known, let alone in children. Existing data indicate that we have only scratched the surface and have much more to learn about obesogens. Hopefully, in the future, more information will provide an opportunity for policy makers to take action and protect public health.

Body composition obtained by bioelectrical impedance with a nutritional questionnaire in children with chronic kidney disease, obesity, or hypertension.

AIM: The purpose of the study was to determine body composition using bioimpedance (BIA), to obtain perinatal parameters and eating habits of a group of children with chronic kidney disease (CKD), children with obesity and arterial hypertension (AH), and children with normal weight and AH, and to compare results with a healthy population. MATERIALS AND METHODS: Body composition data were collected using Nutrilab Bioimpedance device (Akern 2016 with Biatrodes, Akern electrodes). The results, namely fat-free mass (FFM), total body water (TBW), extracellular water (ECW), body cell mass (BCM), fat mass (FM), phase angle (PA), and nutritional questionnaire have been statistically analyzed by SPSS software using independent samples t-test and Pearson's correlation test. RESULTS: 128 children were analyzed - 30 with CKD, 30 obese children with AH, 30 normal-weight children with AH, and 38 healthy children as a control group. Results showed significant differences in parameters between our control group and hypertensive patients and between our control group and obese patients with AH. There was a statistically significant difference for TBW and ECW between the control group and children with CKD, other parameters were in lower ranges compared to the control group. The questionnaire evaluation showed significant differences in perinatal parameters, food habits, and family history in all groups. CONCLUSION: Our pilot study confirmed that BIA parameters of some chronic pediatric patients differ significantly compared to the healthy pediatric population. The results give insight into the importance of monitoring the nutritional status of patients with presumed risk and thus preventing further complications.