Serum uric acid, disease severity and outcomes in COVID-19.

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) is highly variable between individuals, ranging from asymptomatic infection to critical disease with acute respiratory distress syndrome requiring mechanical ventilation. Such variability stresses the need for novel biomarkers associated with disease outcome. As SARS-CoV-2 infection causes a kidney proximal tubule dysfunction with urinary loss of uric acid, we hypothesized that low serum levels of uric acid (hypouricemia) may be associated with severity and outcome of COVID-19. METHODS: In a retrospective study using two independent cohorts, we investigated and validated the prevalence, kinetics and clinical correlates of hypouricemia among patients hospitalized with COVID-19 to a large academic hospital in Brussels, Belgium. Survival analyses using Cox regression and a competing risk approach assessed the time to mechanical ventilation and/or death. Confocal microscopy assessed the expression of urate transporter URAT1 in kidney proximal tubule cells from patients who died from COVID-19. RESULTS: The discovery and validation cohorts included 192 and 325 patients hospitalized with COVID-19, respectively. Out of the 517 patients, 274 (53%) had severe and 92 (18%) critical COVID-19. In both cohorts, the prevalence of hypouricemia increased from 6% upon admission to 20% within the first days of hospitalization for COVID-19, contrasting with a very rare occurrence (< 1%) before hospitalization for COVID-19. During a median (interquartile range) follow-up of 148 days (50-168), 61 (12%) patients required mechanical ventilation and 93 (18%) died. In both cohorts considered separately and in pooled analyses, low serum levels of uric acid were strongly associated with disease severity (linear trend, P < 0.001) and with progression to death and respiratory failure requiring mechanical ventilation in Cox (adjusted hazard ratio 5.3, 95% confidence interval 3.6-7.8, P < 0.001) or competing risks (adjusted hazard ratio 20.8, 95% confidence interval 10.4-41.4, P < 0.001) models. At the structural level, kidneys from patients with COVID-19 showed a major reduction in urate transporter URAT1 expression in the brush border of proximal tubules. CONCLUSIONS: Among patients with COVID-19 requiring hospitalization, low serum levels of uric acid are common and associate with disease severity and with progression to respiratory failure requiring invasive mechanical ventilation.

SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule.

Coronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). None of the patients had normoglycemic glucosuria. Proximal tubule dysfunction was independent of pre-existing comorbidities, glomerular proteinuria, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Transmission electron microscopy identified particles resembling coronaviruses in vacuoles or cisternae of the endoplasmic reticulum in proximal tubule cells. Among features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation using Cox (adjusted hazard ratio 6.2, 95% CI 1.9-20.1) or competing risks (adjusted sub-distribution hazard ratio 12.1, 95% CI 2.7-55.4) survival models. Thus, our data establish that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction and provide novel insights into COVID-19 severity and outcome.

Oral Tolerance Induction to Newly Introduced Allergen is Favored by a Transforming Growth Factor-ß-Enriched Formula.

Food allergies have become a major healthcare concern, hence preventive efforts to ensure oral tolerance induction to newly introduced antigens are particularly relevant. Given that transforming growth factor-ß (TGF-ß) plays a key role in immune tolerance, we tested whether an infant formula enriched with TGF-ß would improve oral tolerance induction. A partially hydrolyzed whey protein-based formula was enriched with cow's-milk-derived TGF-ß (TGF-ß-enriched formula) by adding a specific whey protein isolate (WPI). The manufacturing process was optimized to achieve a concentration of TGF-ß within the range of human breast milk concentrations. Protection from allergic sensitization and immune response was assessed in a mouse model. Adult mice received the TGF-ß-enriched formula, a control non-enriched formula, or water ad libitum for 13 days before sensitization and suboptimal tolerization to ovalbumin (OVA). When compared to non-tolerized mice, suboptimally-tolerized mice supplemented with the TGF-ß-enriched formula showed significantly lower levels of total immunoglobulin-E (IgE) and OVA-specific (IgG1). Mouse mast-cell protease-1 (mMCP-1) and cytokine levels were also significantly decreased in suboptimally-tolerized mice fed the TGF-ß-enriched formula. In conclusion, oral supplementation with cow's-milk-derived TGF-ß decreased allergic responses to newly introduced allergens and thus reduced the risk of developing food allergy.

Long-term dietary supplementation with cystathionine improves tissue glutathione in ageing rats.

BACKGROUND: Ageing is associated with decrease in tissue glutathione that can be reduced by food fortification with the amino acid cysteine. However, cysteine is not stable in solution and generates bad taste. Cystathionine, the direct precursor of cysteine, could be a valuable alternative. AIMS: This study aimed to determine whether long-term dietary supplementation with cystathionine induces an increase in glutathione pools. METHODS: Aged rats (20.5-month-old) were fed ad libitum during 29 weeks with either a cystathionine-supplemented diet (7.3 g/kg, n = 90 rats) or a control iso-nitrogenous alanine-supplemented diet (2.9 g/kg, n = 90 rats). RESULTS: Cystathionine was detected in the plasma of the cystathionine-supplemented rats but not in the control alanine-supplemented rats. Cystathionine increased glutathione concentrations in liver, small intestine and gastrocnemius muscle (P < 0.03). No adverse effect was observed. CONCLUSION: Cystathionine supplementation being able to increase moderately glutathione in healthy old rats could be considered as a candidate for nutritional supports aiming to revert the stronger glutathione depletions occurring in unhealthy elderly.

Low-allergenic hydrolyzed egg induces oral tolerance in mice.

BACKGROUND: Egg allergy is one of the most common food allergies in children. The standard therapy for egg allergy is strict avoidance. Yet, there is considerable clinical and scientific interest in primary or secondary prevention. A major drawback of oral tolerance (OT) induction protocols, however, is the possibility of severe side effects; thus, we have formulated a hypoallergenic egg product and demonstrate its in vivo capacity to modulate the immune system in the current study. METHODS: Hydrolyzed egg (HE) was produced using a combination of moderate heat treatment and enzymatic hydrolysis. The capacity of HE to induce OT was tested in experimental models and compared to whole egg (WE). Delayed-type hypersensitivity (DTH) responses, immune markers and potential early markers of OT were analyzed. RESULTS: Allergic responses, assessed by both DTH responses upon OVA challenge and serum OVA-specific IgE and IgG1, were decreased after treatment with HE and WE compared to the control group. Additionally, feeding WE and HE significantly decreased Th2 cytokine induction and cell proliferation, induced the activation of effector CD4+ T cells and increased numbers and percentages of ICOS+CD4+CD25+Foxp3+ cells. Furthermore, DO11.10 mouse experiments showed that HE contains other peptides than the OVA323-339 peptide that are able to induce tolerance to OVA. CONCLUSIONS: Altogether, results showed that HE induces OT in mice in a dose-dependent manner. Due to its low allergenicity compared to WE, it may represent a safer alternative for OT induction in at-risk subjects or oral immunotherapy in allergic patients.

A dietary supplementation with leucine and antioxidants is capable to accelerate muscle mass recovery after immobilization in adult rats.

Prolonged inactivity induces muscle loss due to an activation of proteolysis and decreased protein synthesis; the latter is also involved in the recovery of muscle mass. The aim of the present work was to explore the evolution of muscle mass and protein metabolism during immobilization and recovery and assess the effect of a nutritional strategy for counteracting muscle loss and facilitating recovery. Adult rats (6-8 months) were subjected to unilateral hindlimb casting for 8 days (I0-I8) and then permitted to recover for 10 to 40 days (R10-R40). They were fed a Control or Experimental diet supplemented with antioxidants/polyphenols (AOX) (I0 to I8), AOX and leucine (AOX + LEU) (I8 to R15) and LEU alone (R15 to R40). Muscle mass, absolute protein synthesis rate and proteasome activities were measured in gastrocnemius muscle in casted and non-casted legs in post prandial (PP) and post absorptive (PA) states at each time point. Immobilized gastrocnemius protein content was similarly reduced (-37%) in both diets compared to the non-casted leg. Muscle mass recovery was accelerated by the AOX and LEU supplementation (+6% AOX+LEU vs. Control, P<0.05 at R40) due to a higher protein synthesis both in PA and PP states (+23% and 31% respectively, Experimental vs. Control diets, P<0.05, R40) without difference in trypsin- and chymotrypsin-like activities between diets. Thus, this nutritional supplementation accelerated the recovery of muscle mass via a stimulation of protein synthesis throughout the entire day (in the PP and PA states) and could be a promising strategy to be tested during recovery from bed rest in humans.

Characterization of candidate anti-allergic probiotic strains in a model of th2-skewed human peripheral blood mononuclear cells.

BACKGROUND: Pre-clinical and clinical studies have evaluated the efficacy of probiotics in allergy. However, predictive in vitro systems for rational strain selection are still missing. METHODS: We developed a novel in vitro screening system for the characterization of probiotics with anti-allergic potential. In this model, human peripheral blood mononuclear cells (PBMC) from healthy donors (n = 68) were skewed towards a Th2 cytokine phenotype by culture with IL-4 and anti-CD40, to resemble cells from allergic donors. Th2-skewed cells were then co-cultured with probiotics; a total of 35 strains were tested. Levels of IFN-γ, IL-10, IL-5 and 7 additional cytokines in culture supernatants were determined by ELISA or multiplex assay. Gene expression was assessed by real-time PCR. For validation, splenocytes from ovalbumin-primed mice and PBMC from grass-allergic donors were restimulated with respective antigen and co-cultured with probiotics, and cytokine profiles were correlated. RESULTS: Culture with IL-4 and anti-CD40 antibody induced secretion of IL-5 from PBMC, indicative of induction of a Th2 phenotype. Cytokine profiles induced by probiotics were strain specific even though species- and genus-specific clustering was observed for many strains by principal component analysis. This was paralleled by mRNA levels of the corresponding genes such as increased Tbet and reduced GATA-3 gene expression. Cytokine profiles induced by probiotics in PBMC stimulated with IL-4 and anti-CD40 correlated with those obtained from allergen-stimulated murine splenocytes or human PBMC from grass-allergic donors. CONCLUSIONS: Cytokine profiling of probiotic strains with IL-4-/anti-CD40-stimulated PBMC allowed to determine the effect of probiotics on Th2-skewed cells and thus to classify probiotic strains with anti-allergic potential.

New measurements of energy expenditure and physical activity in chronic kidney disease.

The accurate estimation of total daily energy expenditure (TEE) in chronic kidney patients is essential to allow the provision of nutritional requirements; however, it remains a challenge to collect actual physical activity and resting energy expenditure in maintenance dialysis patients. The direct measurement of TEE by direct calorimetry or doubly labeled water cannot be used easily so that, in clinical practice, TEE is usually estimated from resting energy expenditure and physical activity. Prediction equations may also be used to estimate resting energy expenditure; however, their use has been poorly documented in dialysis patients. Recently, a new system called SenseWear Armband (BodyMedia, Pittsburgh, PA) was developed to assess TEE, but so far no data have been published in chronic kidney disease patients. The aim of this review is to describe new measurements of energy expenditure and physical activity in chronic kidney disease patients.