A Population-Based Epidemiologic Study of Symptomatic SARS-CoV-2 Infections and Fatalities in Brazilian Children over 3 Years.

OBJECTIVE: To provide a comprehensive overview of the epidemiologic characteristics, outcomes, and risk factors of COVID-19-related deaths in children and adolescents in Brazil. STUDY DESIGN: We conducted a population-based, retrospective cohort study that included all patients aged <18 years with laboratory-confirmed, symptomatic SARS-CoV-2 infection as registered in official Brazilian national surveillance systems for COVID-19 between February 2020 and February 2023. The primary outcome was COVID-19-related deaths. Odds ratios (ORs) of risk factors associated with death were estimated using multivariable logistic regression. RESULTS: Over a 3-year period, 2 855 704 pediatric patients with symptomatic SARS-CoV-2 infection were registered in Brazil. Of these, 59 179 (2.1%) were hospitalized, 13 844 (0.48%) were admitted to the intensive care unit, and 4943 (0.17%) received mechanical ventilation. A total of 4740 (0.17%) patients had fatal outcomes. The case fatality rate increased to 7.9% among patients who required hospitalization; 2102 (44.3%) patients who died did not receive advanced critical support. Notably, 2 (65%, 95% CI 58-71) or 3 doses (86%, 95% CI 81-89) of the vaccine provided strong protection against death. The following adjusted covariates were significantly associated with increased odds of death: age (0-4 and 11-17 years), ethnicity (Brown and Indigenous), region (Northeast or North), dyspnea, nosocomial infection, and comorbidities. Conversely, living in the South or Central-West regions, admission in the later period of the pandemic, and receiving a vaccine were all associated with protection against death. CONCLUSIONS: Our findings suggest that a complex interplay between individual factors and social inequities has shaped the impact of COVID-19 on Brazilian children and adolescents.

Leptin signalling altered in infantile nephropathic cystinosis-related bone disorder.

BACKGROUND: The CTNS gene mutation causes infantile nephropathic cystinosis (INC). Patients with INC develop Fanconi syndrome and chronic kidney disease (CKD) with significant bone deformations. C57BL/6 Ctns-/- mice are an animal model for studying INC. Hyperleptinaemia results from the kidney's inability to eliminate the hormone leptin in CKD. Ctns-/- mice have elevated serum leptin concentrations. Leptin regulates bone metabolism through its receptor that signals further via the hypothalamic melanocortin 4 receptor (MC4R). Leptin signalling may affect bone health in Ctns-/- mice. METHODS: We first defined the time course of bone abnormalities in Ctns-/- mice between 1 and 12 months of age. We used both genetic and pharmacological approaches to investigate leptin signalling in Ctns-/- mice. We generated Ctns-/-Mc4r-/- double knockout mice. Bone phenotype of Ctns-/-Mc4r-/- mice, Ctns-/- mice and wild type (WT) mice at 1, 4, and 9 months of age were compared. We then treated 12-month-old Ctns-/- mice and WT mice with a pegylated leptin receptor antagonist (PLA) (7 mg/kg/day, IP), a MC4R antagonist agouti-related peptide (AgRP) (2 nmol, intracranial infusion on days 0, 3, 6, 9, 12, 15, 18, 21, 24, and 27), or vehicle (normal saline), respectively, for 28 days. Whole-body (BMC/BMD, bone area) and femoral bone phenotype (BMC/BMD, bone area, length and failure load) of mice were measured by DXA and femoral shaft biochemical test. We also measured lean mass content by EchoMRI and muscle function (grip strength and rotarod activity) in mice. Femur protein content of JAK2 and STAT3 was measured by ELISA kits, respectively. RESULTS: Bone defects are present in Ctns-/- mice throughout its first year of life. The deletion of the Mc4r gene attenuated bone disorder in Ctns-/- mice. Femoral BMD, bone area, length, and strength (failure load) were significantly increased in 9-month-old Ctns-/-Mc4r-/- mice than in age-matched Ctns-/- mice. PLA and AgRP treatment significantly increased femoral bone density (BMC/BMD) and mechanical strength in 12-month-old Ctns-/- mice. We adopted the pair-feeding approach for this study to show that the protective effects of PLA or AgRP on bone phenotype are independent of their potent orexigenic effect. Furthermore, an increase in lean mass and in vivo muscle function (grip strength and rotarod activity) are associated with improvements in bone phenotype (femoral BMC/BMD and mechanical strength) in Ctns-/- mice, suggesting a muscle-bone interplay. Decreased femur protein content of JAK2 and STAT3 was evident in Ctns-/- mice. PLA or AgRP treatment attenuated femur STAT3 content in Ctns-/- mice. CONCLUSIONS: Our findings suggest a significant role for dysregulated leptin signalling in INC-related bone disorder, either directly or potentially involving a muscle-bone interplay. Leptin signalling blockade may represent a novel approach to treating bone disease as well as muscle wasting in INC.

Outcomes of SARS-CoV-2 and Seasonal Viruses Among 2 Million Adults Hospitalized for Severe Acute Respiratory Infection During the COVID-19 Pandemic in Brazil.

BACKGROUND: The outbreak of the COVID-19 pandemic has had a profound impact on the circulation of seasonal respiratory viruses. This study aimed to compare the outcomes of SARS-CoV-2 and seasonal viruses in adults hospitalized with severe acute respiratory infection during the COVID-19 pandemic. METHODS: This population-based cohort study included patients aged >18 years hospitalized for severe acute respiratory infection in Brazil between February 2020 and February 2023. The primary outcome was in-hospital mortality. A competing risk analysis was used to account for competing events. RESULTS: In total, 2 159 171 patients were included in the study. SARS-CoV-2 was the predominant virus (98.7%). Among patients testing positive, the cumulative incidence of in-hospital mortality was 33.1% for SARS-CoV-2, 31.5% for adenovirus, 21.0% for respiratory syncytial virus, 18.7% for influenza, and 18.6% for other viruses. SARS-CoV-2 accounted for 99.3% of the deaths. Older age, male sex, comorbidities, hospitalization in the northern region, and oxygen saturation <95% were the common risk factors for death among all viruses. CONCLUSIONS: In this large cohort study, individuals infected with SARS-CoV-2 or adenovirus had the highest risk of mortality. Irrespective of the virus type, older age, male sex, comorbidities, hospitalization in vulnerable regions, and low oxygen saturation were associated with an increased risk of fatality.

Outcomes of SARS-CoV-2 and Seasonal Viruses Among Children Hospitalized in Brazil.

BACKGROUND AND OBJECTIVES: Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with other respiratory viruses is crucial for developing effective public health strategies in the postpandemic era. This study aimed to compare the outcomes of SARS-CoV-2 and seasonal viruses in children and adolescents hospitalized with severe acute respiratory infection (SARI). METHODS: This population-based, retrospective cohort study included children and adolescents hospitalized with SARI from February 2020 to February 2023 in Brazil. The main exposure of interest was viral etiology. The primary outcome was in-hospital mortality. Competing risk analysis was used to account for time dependency and competing events. RESULTS: A total of 235 829 patients had available results of the viral tests, with SARS-CoV-2 predominance. According to the competing-risk survival analysis, the estimated probability of a fatal outcome at 30 days of hospitalization according to the viral strain was 6.5%, 3.4%, 2.9%, 2.3%, 2.1%, and 1.8%, for SARS-CoV-2, coinfection, adenovirus, influenza, other viruses, and respiratory syncytial virus, respectively. Individuals with a positive test for SARS-CoV-2 had hazard of death 3 times higher than subjects with a negative test (hazard ratio, 3.3; 95% confidence interval, 3.1-3.5). After adjustment by the competing-risk multivariable analysis, admission in Northeast and North regions, oxygen saturation <95%, and the presence of comorbidities were risk factors for death in all viral strains. CONCLUSIONS: SARS-CoV-2 infection had the highest hazard of in-hospital mortality in this pediatric cohort hospitalized with SARI. Regardless of viral etiology, the presence of underlying medical conditions was a risk factor for death.

Nutrition Management for Chronic Kidney Disease: Differences and Special Needs for Children and Adults.

Common goals of nutritional therapy across the spectrum of pediatric and adult chronic kidney disease (CKD) include maintaining normal body mass and composition and reducing associated morbidity and mortality. Adult nephrologists caring for children and adolescents may be challenged by the existing complexities in identifying and interpreting the nutritional status and growth in children. Pediatric nephrologists may face situations that call for a sound knowledge of assessing nutritional status and providing nutrition therapy for adolescents and young adults. One important additional nutrition goal in children is to achieve normal growth and development. Children are growing and therefore need more calories and nutrients than just maintaining their body weight and composition. Lack of weight and height gain actually is considered failure to thrive in children. Some fundamental differences in approaches to nutritional therapy in CKD are necessitated based on the etiology of CKD. A large proportion of adults with CKD are diabetics, so the approach would be a low-carbohydrate diet. Children with CKD, especially young ones, often are anorexic, so calorie supplements that could include quite a lot of carbohydrates often are prescribed. More adults with CKD have hypertension and atherosclerotic comorbidities, which result in recommendations for low-salt and low-fat diets. Children with CKD often have salt and electrolyte wasting disease states and would require normal- or even high-salt diets, and fats often are included in supplements to bolster calorie intake. Low-protein diets often are recommended in adults with predialysis CKD to slow disease progression. Children are growing and have a higher protein daily requirement. Low-protein diets have not been found to be efficacious in children with CKD, in achieving normal growth, or in slowing disease progression. Adult nephrologists caring for children and adolescents may be challenged by the existing complexities in identifying and interpreting nutritional status and growth in children. Pediatric nephrologists may face situations that call for a sound knowledge of assessing nutritional status and providing nutrition therapy for adolescents and young adults. This article discusses the differences in the assessment of nutritional status between children and adults, as well as provides a comprehensive approach to nutritional management for CKD across the age spectrum. Semin Nephrol 43:x-xx © 2023 Elsevier Inc. All rights reserved.

Is There a Need to "Modernize" and "Simplify" the Diagnostic Criteria of Protein-Energy Wasting?

Protein energy wasting(PEW) is a term that most nephrologists used to define nutritional disorders in patients with acute kidney injury and chronic kidney disease. Although this nomenclature is well implemented in the field of nephrology, the use of other terms such as cachexia or malnutritionin the majority of chronic diseases can induce confusion regarding the definition and interpretation of these terms. There is ample evidence in the literature that the pathways involved in cachexia/malnutrition and PEW are common. However, in kidney diseases, there are pathophysiological conditions such as accumulation of uremic toxins, and the use of dialysis, which may induce a phenotypic specificity justifying the original term PEW. In light of the latest epidemiologic studies, the criteria for PEW used in 2008 probably need to be updated. The objective of this review is to summarize the main mechanisms involved in cachexia/malnutrition and PEW. We discuss the need to modernize and simplify the current definition and diagnostic criteria of PEW. We consider the interest of proposing a specific nomenclature of PEW for children and elderly patients with kidney diseases.

Nutrition in Children With Chronic Kidney Disease: How to Thrive?

The nutritional status and management of children with chronic kidney disease (CKD) are complex and require a combined pediatric nephrology team work approach with physicians, nutritionists, nurses, and physical/occupational therapists. Prospective observational studies such as Children with CKD in the US, the 4C study in Europe and the International Pediatric Peritoneal Dialysis Network have advanced the field. However, most recommendations and guidelines from international task forces such as Kidney Diseases Improving Global Outcomes and Pediatric Renal Nutrition Taskforce are opinion-based rather than evidence-based. There is exciting ongoing research to improve nutrition in children with CKD to help them thrive.

Association of Prior COVID-19 Vaccination With SARS-CoV-2 Infection and Death in Children and Young Persons During the Omicron Variant Period in Brazil.

This case-control study evaluates nationwide information surveillance systems in Brazil to estimate vaccine effectiveness against outcomes of COVID-19 in children and young persons.

Redox Signaling in Chronic Kidney Disease-Associated Cachexia.

Redox signaling alterations contribute to chronic kidney disease (CKD)-associated cachexia. This review aims to summarize studies about redox pathophysiology in CKD-associated cachexia and muscle wasting and to discuss potential therapeutic approaches based on antioxidant and anti-inflammatory molecules to restore redox homeostasis. Enzymatic and non-enzymatic systems of antioxidant molecules have been studied in experimental models of kidney diseases and patients with CKD. Oxidative stress is increased by several factors present in CKD, including uremic toxins, inflammation, and metabolic and hormone alterations, leading to muscle wasting. Rehabilitative nutritional and physical exercises have shown beneficial effects for CKD-associated cachexia. Anti-inflammatory molecules have also been tested in experimental models of CKD. The importance of oxidative stress has been shown by experimental studies in which antioxidant therapies ameliorated CKD and its associated complications in the 5/6 nephrectomy model. Treatment of CKD-associated cachexia is a challenge and further studies are necessary to investigate potential therapies involving antioxidant therapy.

Effectiveness of BNT162b2 and CoronaVac vaccines against omicron in children aged 5 to 11 years.

BACKGROUND: This study aimed to estimate vaccine effectiveness (VE) against omicron variant infection and severe corona virus disease 2019 (COVID-19) in children aged 5-11 years hospitalized with acute respiratory syndrome. METHODS: A test-negative, case-control analysis was conducted from February 2022 to June 2022. We enrolled 6950 eligible children, including 1102 cases and 5848 controls. VE was calculated after immunization with one and two doses of BNT162b2 or CoronaVac. The outcomes were hospitalization with acute respiratory symptoms and detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19. The adjusted odds ratio for the association of prior vaccination and outcomes was used to estimate VE. RESULTS: For fully vaccinated children, the overall estimated VE against hospitalization with SARS-CoV-2 infection was 42% [95% confidence interval (CI) 26 to 54]. VE peaked at 29-42 days (67%, 95% CI 40% to 82%) and then declined to 19% (95% CI, - 20% to 45%) at 57-120 days after the second dose. The BNT162b2 vaccine had a similar VE against hospitalization with SARS-CoV-2 infection (45%, 95% CI, 20 to 61) compared to the CoronaVac vaccine (40%, 95% CI, 17% to 56%). Among cases, 56 (5%) children died; 53 (94.6%) were not fully vaccinated. For cases, the two-dose schedule effectiveness against ICU admission, need for invasive ventilation, severe illness, and death were 10% (95% CI, - 54%-45%), 22% (95% CI - 70%-68%), 12% (95% CI, - 62%-52%), and 16% (95% CI, - 77%-75%), respectively. CONCLUSIONS: For hospitalized children aged 5-11 years during the omicron-predominant period in Brazil, two doses of both vaccines had moderate effectiveness against hospitalization with acute respiratory symptoms and SARS-CoV-2 infection and offered limited protection against endpoints of COVID-19 severity.

Maternal risk factors for congenital anomalies of the kidney and urinary tract: A case-control study.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are significant causes of pediatric morbidity and mortality. The spectrum of CAKUT can be part of a syndrome, but most of these abnormalities occur as isolated and sporadic forms. The etiology of human CAKUT is unknown in the majority of cases. This case-control study aimed to investigate the association between maternal characteristics and the occurrence of CAKUT and specific CAKUT phenotypes. METHODS: In this case-control study, 29,653 newborns were evaluated consecutively in a tertiary neonatal unit using the Latin American Collaborative Study of Congenital Malformations (ECLAMC) registry. Newborns without congenital anomalies were matched to CAKUT cases by sex, date, and place of birth at a ratio of 3:1. For analysis purposes, the cases were stratified into four subgroups: upper tract abnormalities (UTA), including ureteropelvic junction obstruction, vesicoureteral reflux, primary megaureter and others (n = 239), lower urinary tract obstruction (LUTO) (n = 79), cystic diseases (n = 59) and agenesis/hypodysplasia (n = 28). Multivariable logistic regression analyses were used to calculate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for associations between the maternal risk factors and the presence of CAKUT. RESULTS: The prevalence of non-syndromic CAKUT in our sample was 13 per 1000 live births. Data records allowed the analysis of 405 cases and 1208 controls. After adjustment by the binary regression logistic, three covariates remained associated as risk factors for the entire spectrum of CAKUT: consanguinity (Odds ratio [OR], 7.1, 95%CI, 2.4-20.4), family history of CAKUT (OR, 6.4, 95%CI, 1.9-21.3), and maternal chronic hypertension (OR, 14.69, 95%CI, 3.2-67.5) (Figure). These risk factors persisted consistently across the various CAKUT phenotypes with minor variations. Consanguinity was the only factor consistently associated with almost all CAKUT phenotypes. Maternal hypertension was associated with all phenotypes except for the agenesis/hypodysplasia group. The prevalence of CAKUT cases was 15 times higher in hypertensive mothers (3%) compared to normotensive mothers (0.2%). CONCLUSION: Our study suggests that an increased risk of CAKUT is associated with consanguinity, a positive family history of CAKUT, and maternal hypertension. However, the prevalence of these risk factors in our cohort was rare and most cases presented as sporadic forms.

The association between pre-existing asthma and reduced risk of death among children and adolescents hospitalized with COVID-19 in Brazil.

OBJECTIVE: There have been conflicting reports on the relationship between asthma and COVID-19 severity. This study aimed to compare the risk of death among children with asthma and healthy peers hospitalized due to COVID-19. METHODS: We carried out an analysis of all pediatric patients 2-19 years of age with asthma and COVID-19 registered in Influenza Epidemiological Surveillance Information System-Gripe, a Brazilian nationwide surveillance database, between February 2020 and March 2022. The primary outcome was time to death, which was evaluated considering discharge as a competitive risk using the cumulative incidence function. RESULTS: Among 30,405 hospitalized children with COVID-19, 21,340 (70.2%) had no comorbidities, 6444 (21.2%) had comorbidities other than asthma, 2165 (7.1%) had asthma, and 465 (1.5%) had asthma with other comorbidities. The estimated probability of a fatal outcome for each group was 4.1%, 14.9%, 2.1%, and 10.7%, respectively. After adjustment, children with asthma had a 60% reduction in the hazard of death than healthy peers (hazard ratio [HR] = 0.39, 95% confidence interval [CI], 0.29-0.53, p < 0.0001). Among children with asthma and no other comorbidities, two covariates were independently associated with in-hospital mortality, age ≥12 years, HR = 4.0, 95% CI, 2.5-6.4), and low oxygen saturation at admission (HR = 2.3, 95% CI, 1.4-3.2). CONCLUSION: Children with asthma and no comorbidities had a lower risk of death compared with healthy peers after controlling for clinical and demographic confounding factors.

Vaccine Effectiveness against SARS-CoV-2 Variants in Adolescents from 15 to 90 Days after Second Dose: A Population-Based Test-Negative Case-Control Study.

OBJECTIVE: The objective of this study was to estimate the vaccine effectiveness (VE) against hospitalization and severe illness in adolescents due to infection with SARS-CoV-2 variants (gamma, delta, and omicron). STUDY DESIGN: A test-negative, case-control analysis was conducted in Brazil from July 2021 to March 2022. We enrolled 8458 eligible individuals (12-19 years of age) hospitalized with an acute respiratory syndrome, including 3075 cases with laboratory-proven COVID-19 and 4753 controls with negative tests for COVID-19. The primary exposure of interest was vaccination status. The primary outcome was SARS-CoV-2 infection during gamma/delta vs omicron-predominant periods. The aOR for the association of prior vaccination and outcomes was used to estimate VE. RESULTS: In the pre-omicron period, VE against COVID-19 hospitalization was 88% (95% CI, 83%-92%) and has dropped to 59% (95% CI, 49%-66%) during the omicron period. For hospitalized cases of COVID-19, considering the entire period of the analysis, 2-dose schedule was moderately effective against intensive care unit admission (46%, [95% CI, 27-60]), need of mechanical ventilation (49%, [95% CI, 32-70]), severe COVID-19 (42%, [95% CI, 17-60]), and death (46%, [95% CI, 8-67]). There was a substantial reduction of about 40% in the VE against all end points, except for death, during the omicron-predominant period. Among cases, 240 (6.6%) adolescents died; of fatal cases, 224 (93.3%) were not fully vaccinated. CONCLUSION: Among adolescents, the VE against all end points was substantially reduced during the omicron-predominant period. Our findings suggest that the 2-dose regimen may be insufficient for SARS-CoV-2 variants and support the need for updated vaccines to provide better protection against severe COVID-19.

Outcomes and risk factors for death among hospitalized children and adolescents with kidney diseases and COVID-19: an analysis of a nationwide database.

BACKGROUND: Patients with kidney diseases (KD) appear to be at particularly high risk for severe COVID-19. This study aimed to characterize the clinical outcomes and risk factors for COVID-19-related death in a large cohort of hospitalized pediatric patients with KD. METHODS: We performed an analysis of all pediatric patients with KD and COVID-19 registered in SIVEP-Gripe, a Brazilian nationwide surveillance database, between February 16, 2020, and May 29, 2021. The primary outcome was time to death, which was evaluated considering discharge as a competitive risk by using cumulative incidence function. RESULTS: Among 21,591 hospitalized patients with COVID-19, 290 cases (1.3%) had KD. Of these, 59 (20.8%) had a fatal outcome compared with 7.5% of the non-KD cohort (P < 0.001). Pediatric patients with KD had an increased hazard of death compared with the non-KD cohort (Hazard ratio [HR] = 2.85, 95% CI 2.21-3.68, P < 0.0001). After adjustment, the factors associated with the death among KD patients were living in Northeast (HR 2.16, 95% CI 1.13-4.31) or North regions (HR 3.50, 95% CI 1.57-7.80), oxygen saturation < 95% at presentation (HR 2.31, 95% CI 1.30-4.10), and presence of two or more associated comorbidities (HR 2.10, 95% CI 1.08-4.04). CONCLUSIONS: Children and adolescents with KD had a higher risk of death compared with the non-KD cohort. The higher risk was associated with low oxygen saturation at admission, living in socioeconomically disadvantaged regions, and presence of other pre-existing comorbidities. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical Impact and Risk Factors of Mortality in Hospitalized Children and Adolescents With Hematologic Diseases and COVID-19: An Observational Retrospective Cohort Study.

This study aimed to evaluate the risk factors for COVID-19-related death in a large cohort of hospitalized children with hematological disorders. We performed an analysis of all pediatric patients with COVID-19 registered in a Brazilian nationwide surveillance database between February 2020 and May 2021. The primary outcome was time to death, which was evaluated considering discharge as a competitive risk by using the cumulative incidence function. Among 21,591 hospitalized pediatric patients with COVID-19, 596 cases (2.8%) had hematological diseases. Sixty-one children (27.4%) with malignant hematological diseases had a fatal outcome as compared with 4.2% and 7.4% of nonmalignant hematological and nonhematological cohorts, respectively ( P <0.0001). Children with hematological diseases had a significant increased hazard of death compared with those without these conditions (hazard ratio [HR],=2.40, 95% confidence interval, 1.98 - 2.91). In multivariable analysis, the factors associated with death were the presence of malignant hematological disease (HR, 2.22, 95% CI 1.47 - 3.36), age >10 years (HR 2.19, 95% CI 1.46 - 3.19), male (HR 1.52, 95% CI 1.02 - 2.27), oxygen saturation <95% (HR 2.02, 95% CI 1.38 - 2.96), and abdominal pain at admission (HR 2.75, 95% CI 1.76 - 4.27). Children with malignant hematological diseases had a higher risk of death compared with those without these disorders.

Growth Hormone Improves Adipose Tissue Browning and Muscle Wasting in Mice with Chronic Kidney Disease-Associated Cachexia.

Cachexia associated with chronic kidney disease (CKD) has been linked to GH resistance. In CKD, GH treatment enhances muscular performance. We investigated the impact of GH on cachexia brought on by CKD. CKD was induced by 5/6 nephrectomy in c57BL/6J mice. After receiving GH (10 mg/kg/day) or saline treatment for six weeks, CKD mice were compared to sham-operated controls. GH normalized metabolic rate, increased food intake and weight growth, and improved in vivo muscular function (rotarod and grip strength) in CKD mice. GH decreased uncoupling proteins (UCP)s and increased muscle and adipose tissue ATP content in CKD mice. GH decreased lipolysis of adipose tissue by attenuating expression and protein content of adipose triglyceride lipase and protein content of phosphorylated hormone-sensitive lipase in CKD mice. GH reversed the increased expression of beige adipocyte markers (UCP-1, CD137, Tmem26, Tbx1, Prdm16, Pgc1α, and Cidea) and molecules implicated in adipose tissue browning (Cox2/Pgf2α, Tlr2, Myd88, and Traf6) in CKD mice. Additionally, GH normalized the molecular markers of processes connected to muscle wasting in CKD, such as myogenesis and muscle regeneration. By using RNAseq, we previously determined the top 12 skeletal muscle genes differentially expressed between mice with CKD and control animals. These 12 genes' aberrant expression has been linked to increased muscle thermogenesis, fibrosis, and poor muscle and neuron regeneration. In this study, we demonstrated that GH restored 7 of the top 12 differentially elevated muscle genes in CKD mice. In conclusion, GH might be an effective treatment for muscular atrophy and browning of adipose tissue in CKD-related cachexia.

Metabolic Advantage of 25(OH)D3 versus 1,25(OH)2D3 Supplementation in Infantile Nephropathic Cystinosis-Associated Adipose Tissue Browning and Muscle Wasting.

Manifestations of infantile nephropathic cystinosis (INC) often include cachexia and deficiency of circulating vitamin D metabolites. We examined the impact of 25(OH)D3 versus 1,25(OH)2D3 repletion in Ctns null mice, a mouse model of INC. Six weeks of intraperitoneal administration of 25(OH)D3 (75 µg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) resulted in Ctns-/- mice corrected low circulating 25(OH)D3 or 1,25(OH)2D3 concentrations. While 25(OH)D3 administration in Ctns-/- mice normalized several metabolic parameters characteristic of cachexia as well as muscle function in vivo, 1,25(OH)2D3 did not. Administration of 25(OH)D3 in Ctns-/- mice increased muscle fiber size and decreased fat infiltration of skeletal muscle, which was accompanied by a reduction of abnormal muscle signaling pathways. 1,25(OH)2D3 administration was not as effective. In conclusion, 25(OH)D3 supplementation exerts metabolic advantages over 1,25(OH)2D3 supplementation by amelioration of muscle atrophy and fat browning in Ctns-/- mice.

n-3 PUFA dietary lipid replacement normalizes muscle mitochondrial function and oxidative stress through enhanced tissue mitophagy and protects from muscle wasting in experimental kidney disease.

INTRODUCTION AND METHODS: Skeletal muscle mitochondrial dysfunction may cause tissue oxidative stress and consequent catabolism in chronic kidney disease (CKD), contributing to patient mortality. We investigated in 5/6-nephrectomized (Nx) rats the impact of n3-polyunsaturated fatty-acids (n3-PUFA) isocaloric partial dietary replacement on gastrocnemius muscle (Gm) mitochondrial master-regulators, ATP production, ROS generation and related muscle-catabolic derangements. RESULTS: Nx had low Gm mitochondrial nuclear respiratory factor-2 and peroxisome proliferator-activated receptor gamma coactivator-1alpha, low ATP production and higher mitochondrial fission-fusion protein ratio with ROS overproduction. n3-PUFA normalized all mitochondrial derangements and pro-oxidative tissue redox state (oxydized to total glutathione ratio). n3-PUFA also normalized Nx-induced muscle-catabolic proinflammatory cytokines, insulin resistance and low muscle weight. Human uremic serum reproduced mitochondrial derangements in C2C12 myotubes, while n3-PUFA coincubation prevented all effects. n3-PUFA also enhanced muscle mitophagy in-vivo and siRNA-mediated autophagy inhibition selectively blocked n3-PUFA-induced normalization of C2C12 mitochondrial ROS production. CONCLUSIONS: In conclusion, dietary n3-PUFA normalize mitochondrial master-regulators, ATP production and dynamics in experimental CKD. These effects occur directly in muscle cells and they normalize ROS production through enhanced mitophagy. Dietary n3-PUFA mitochondrial effects result in normalized catabolic derangements and protection from muscle wasting, with potential positive impact on patient survival.