Body composition indices as predictors of humoral response to mRNA vaccination against COVID-19 in patients on maintenance hemodialysis.

INTRODUCTION: Patients on maintenance hemodialysis show lower serological response to mRNA vaccines. Main causes that contribute to this phenomenon are uremic milieu and older age. However, there are no data on the impact of body composition parameters to humoral response. MATERIALS AND METHODS: In this retrospective study, we used data from adult patients on maintenance hemodialysis who received vaccination with 2 doses of BNT162b2. Quantitative determination of antibodies to SARS-CoV-2 spike (S) protein receptor binding domain was performed using the Elecsys immunoassay. Antibody levels higher than 0.8 and 264 U/mL were considered positive and protective, respectively. Body composition parameters were assessed using multifrequency bioelectrical impedance spectroscopy. RESULTS: Overall, 49 patients were included in the study. Three weeks after the 1st vaccination, 34% of patients, and 3 weeks and 3 months after the 2nd vaccination, 100% of patients had detectable titers. Protective titer was developed in 43% of patients 3 weeks after the 2nd vaccination and then decreased to 24% 3 months after the 2nd vaccination. More years on dialysis were correlated to the absence of protective titers. Higher prediction marker values correlated to poor antibody response, and phase angle was negatively associated with the development of protective titers. Patients with protective titers at 3 months after the 2nd vaccination had significantly lower prediction marker and higher phase angle values. CONCLUSION: Parameters of body composition correlate and affect antibody response in patients on hemodialysis. The main observation is that immunogenicity of mRNA vaccines is influenced by phase angle and prediction marker.

Maternal Calorie Restriction Induces a Transcriptional Cytoprotective Response in Embryonic Liver Partially Dependent on Nrf2.

BACKGROUND: Calorie restriction is known to enhance Nrf2 signaling and longevity in adult mice, partially by reducing reactive oxygen species, but calorie restriction during pregnancy leads to intrauterine growth retardation. The latter is associated with fetal reprogramming leading to increased incidence of obesity, metabolic syndrome and diabetes in adult life. Transcription factor Nrf2 is a central regulator of the antioxidant response and its crosstalk with metabolic pathways is emerging. We hypothesized that the Nrf2 pathway is induced in embryos during calorie restriction in pregnant mothers. METHODS: From gestational day 10 up to day 16, 50% of the necessary mouse diet was provided to Nrf2 heterozygous pregnant females with fathers being of the same genotype. Embryos were harvested at the end of gestational day 16 and fetal liver was used for qRT-PCR and assessment of oxidative stress (OS). RESULTS: Intrauterine calorie restriction led to upregulation of mRNA expression of antioxidant genes (Nqo1, Gsta1, Gsta4) and of genes related to integrated stress response (Chac1, Ddit3) in WT embryos. The expression of a key gluconeogenic (G6pase) and two lipogenic genes (Acacb, Fasn) was repressed in calorie-restricted embryos. In Nrf2 knockout embryos, the induction of Nqo1 and Gsta1 genes was abrogated while that of Gsta4 was preserved, indicating an at least partially Nrf2-dependent induction of antioxidant genes after in utero calorie restriction. Measures of OS showed no difference (superoxide radical and malondialdehyde) or a small decrease (thiobarbituric reactive substances) in calorie-restricted WT embryos. CONCLUSIONS: Calorie restriction during pregnancy elicits the transcriptional induction of cytoprotective/antioxidant genes in the fetal liver, which is at least partially Nrf2-dependent, with a physiological significance that warrants further investigation.

Factors associated with anti-SARS-CoV-2 antibody titres 3 months post-vaccination with the second dose of BNT162b2 vaccine: a longitudinal observational cohort study in western Greece.

OBJECTIVES: Vaccination against SARS-CoV-2 has been extensively deployed during COVID-19 pandemic. One efficient method to evaluate response to vaccination is the assessment of humoral immunity by measuring SARS-CoV-2 antibody titres. We investigated the association between anthropometric parameters (age, body mass index), smoking, diabetes, statin use, hypertension, levels of 25(OH)D and dehydroepiandrosterone sulfate (DHEAS), and SARS-CoV-2 antibody titres after vaccination. DESIGN: In this longitudinal observational cohort study, 712 subjects were tested for SARS-CoV-2 antibodies 3 months after the second dose of BNT162b2 vaccine. Multiple linear regression analysis was performed to identify which factors are associated with the antibody titres. SETTING: Healthcare units of western Greece (University Hospital of Patras and "St Andrews" State General Hospital of Patras). PARTICIPANTS: All adults receiving their second dose of BNT162b2 vaccine at the participating healthcare units were eligible to participate in the study. Exclusion criteria were SARS-CoV-2 infection or positive SARS-CoV-2 antibody titre at baseline. Patients who did not provide all necessary information were excluded from our analyses. RESULTS: We found age to be negatively associated with antibody titre (-0.005; 95% CI -0.009 to -0.001, p=0.0073), as was male gender (-0.11; 95% CI -0.1738 to -0.04617, p=0.0008). The interaction of age and gender was significant (-0.01090; 95% CI -0.01631 to -0.005490, p<0.0001), highlighting that the rate of decline in antibody titre with increasing age tends to be higher in men rather than in women. No linear trend was found between DHEAS levels and antibody titres when the lower quartile of DHEAS levels was used as reference. Tobacco use was associated with low antibody titre (-0.1097; 95% CI -0.174 to -0.046, p=0.0008) but overweight, obese or underweight subjects had similar antibody responses to normal-weight individuals. Although subjects with diabetes and hypertension had numerically lower antibody titres, this association was not statistically significant. Vitamin D levels showed no clear relationships with antibody titres. CONCLUSIONS: Age, male gender and tobacco use are negatively associated with antibody titres after COVID-19 vaccination, but our data showed no clear correlation with vitamin D levels. TRIAL REGISTRATION NUMBER: NCT04954651; Results.

Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2.

Glucocorticoids are used widely on a long-term basis in autoimmune and inflammatory diseases. Their adverse effects include the development of hyperglycemia and osteoporosis, whose molecular mechanisms have been only partially studied in preclinical models. Both these glucocorticoid-induced pathologies have been shown to be mediated at least in part by oxidative stress. The transcription factor nuclear erythroid factor 2-like 2 (NRF2) is a central regulator of antioxidant and cytoprotective responses. Thus, we hypothesized that NRF2 may play a role in glucocorticoid-induced metabolic disease and osteoporosis. To this end, WT and Nrf2 knockout (Nrf2KO) mice of both genders were treated with 2 mg/kg dexamethasone or vehicle 3 times per week for 13 weeks. Dexamethasone treatment led to less weight gain during the treatment period without affecting food consumption, as well as to lower glucose levels and high insulin levels compared to vehicle-treated mice. Dexamethasone also reduced cortical bone volume and density. All these effects of dexamethasone were similar between male and female mice, as well as between WT and Nrf2KO mice. Hepatic NRF2 signaling and gluconeogenic gene expression were not affected by dexamethasone. A 2-day dexamethasone treatment was also sufficient to increase insulin levels without affecting body weight and glucose levels. Hence, dexamethasone induces hyperinsulinemia, which potentially leads to decreased glucose levels, as well as osteoporosis, both independently of NRF2.