Leicester General Hospital

About: Leicester General Hospital is a healthcare organization based out in Leicester, United Kingdom. It is known for research contribution in the topics: Population & Transplantation. The organization has 2481 authors who have published 3034 publications receiving 107437 citations.

Prevalence and correlates of physical activity across kidney disease stages: an observational multicentre study

Abstract: Background People with chronic kidney disease (CKD) report high levels of physical inactivity, a major modifiable risk factor for morbidity and mortality. Understanding the biological, psychosocial and demographic causes of physical activity behaviour is essential for the development and improvement of potential health interventions and promotional initiatives. This study investigated the prevalence of physical inactivity and determined individual correlates of this behaviour in a large sample of patients across the spectrum of kidney disease. Methods A total of 5656 people across all stages of CKD (1–2, 3, 4–5, haemodialysis, peritoneal dialysis and renal transplant recipients) were recruited from 17 sites in England from July 2012 to October 2018. Physical activity was evaluated using the General Practice Physical Activity Questionnaire. Self-reported cardiorespiratory fitness, self-efficacy and stage of change were also assessed. Binominal generalized linear mutually adjusted models were conducted to explore the associations between physical activity and correlate variables. This cross-sectional observational multi-centre study was registered retrospectively as ISRCTN87066351 (October 2015). Results The prevalence of physical activity (6–34%) was low and worsened with disease progression. Being older, female and having a greater number of comorbidities were associated with greater odds of being physically inactive. Higher haemoglobin, cardiorespiratory fitness and self-efficacy levels were associated with increased odds of being active. Neither ethnicity nor smoking history had any effect on physical activity. Conclusions Levels of physical inactivity are high across all stages of CKD. The identification of stage-specific correlates of physical activity may help to prioritize factors in target groups of kidney patients and improve the development and improvement of public health interventions.

Inhibition of SNAT2 by Metabolic Acidosis Enhances Proteolysis in Skeletal Muscle

Abstract: Insulin resistance is a major cause of muscle wasting in patients with ESRD. Uremic metabolic acidosis impairs insulin signaling, which normally suppresses proteolysis. The low pH may inhibit the SNAT2 l-Glutamine (L-Gln) transporter, which controls protein synthesis via amino acid–dependent insulin signaling through mammalian target of rapamycin (mTOR). Whether SNAT2 also regulates signaling to pathways that control proteolysis is unknown. In this study, inhibition of SNAT2 with the selective competitive substrate methylaminoisobutyrate or metabolic acidosis (pH 7.1) depleted intracellular L-Gln and stimulated proteolysis in cultured L6 myotubes. At pH 7.1, inhibition of the proteasome led to greater depletion of L-Gln, indicating that amino acids liberated by proteolysis sustain L-Gln levels when SNAT2 is inhibited by acidosis. Acidosis shifted the dose-response curve for suppression of proteolysis by insulin to the right, confirming that acid increases proteolysis by inducing insulin resistance. Blocking mTOR or phosphatidylinositol-3-kinase (PI3K) increased proteolysis, indicating that both signaling pathways are involved in its regulation. When both mTOR and PI3K were inhibited, methylaminoisobutyrate or acidosis did not stimulate proteolysis further. Moreover, partial silencing of SNAT2 expression in myotubes and myoblasts with small interfering RNA stimulated proteolysis and impaired insulin signaling through PI3K. In conclusion, SNAT2 not only regulates mTOR but also regulates proteolysis through PI3K and provides a link among acidosis, insulin resistance, and protein wasting in skeletal muscle cells. There is now strong evidence that, even in patients without diabetes, insulin resistance in ESRD is a major cause of muscle wasting1,2 with its attendant morbidity and increased risk for mortality. An important contributor to this clinically serious problem is uremic metabolic acidosis,3 suggesting that low pH has a significant impact on insulin signaling in uremic muscle. The SNAT2 amino acid transporter in the plasma membrane of mammalian cells is strongly inhibited by low extracellular pH.4 We previously showed, using cultured skeletal muscle cells (L6 myotubes), that inhibition of SNAT2 rapidly depletes intracellular amino acids and thereby strongly impairs insulin signaling to protein synthesis through mammalian target of rapamycin (mTOR), which is a key sensor of amino acid availability.5 Although this provides a plausible explanation for the inhibition of muscle protein synthesis that occurs during acute metabolic acidosis in humans,6 the response of muscle to chronic uremic metabolic acidosis in renal patients usually involves increased proteolysis.7,8 A possible rationale for this chronic proteolysis is that it is an adaptation to the initial amino acid depletion, whereby amino acids are harvested from muscle protein to restore intracellular amino acid levels,9 thereby minimizing impairment of protein synthesis but at the expense of chronically elevated proteolysis. The stimulation of proteolysis by low pH in L6 myotubes has been attributed to a defect in insulin signaling through insulin receptor substrate 1 (IRS-1)-associated phosphatidylinositol-3-kinase (PI3K), leading to impaired activation of protein kinase B (PKB),10 and a similar defect has been demonstrated in acidotic and uremic rat skeletal muscle in vivo.11 Unlike mTOR signaling, type I PI3K signaling to PKB is not traditionally regarded as an amino acid–sensitive pathway, suggesting that inhibition of SNAT2 by acidosis is not responsible for this effect; however, a type III PI3K has been implicated in amino acid sensing by mTOR.12 There is also evidence from amino acid–starved L6 myotubes that extracellular amino acid concentration is sensed through SNAT2, which acts as a signaling protein in its own right—a so-called “transceptor”13 that signals to SNAT2 gene expression.13 This signal is blunted by inhibitors of PI3K,13 suggesting that coupling exists between SNAT2 and this enzyme. It is not known, however, whether such coupling influences PI3K signaling to PKB and proteolysis. The aims of this study were, first, to determine whether the effect of metabolic acidosis or SNAT2 inhibition on amino acid levels in L6 myotubes shows an adaptive response consistent with compensatory harvesting of amino acids by proteolysis; second, to determine whether metabolic acidosis or SNAT2 inhibition in the presence of insulin activates proteolysis by signaling through mTOR or PI3K; and, third, to determine whether coupling between SNAT2 and PI3K/PKB signaling is detectable when the activity or expression of SNAT2 is impaired

The pathogenic role of IgA1 O-linked glycosylation in the pathogenesis of IgA nephropathy.

Abstract: Numerous abnormalities of the IgA immune system have been reported in IgAN but the most consistent finding remains aberrant IgA1 O-linked glycosylation of the IgA1 hinge region. The defect comprises reduced galactosylation of O-linked N-acetylgalactosamine residues with or without changes in the terminal sialylation of the O-linked sugars. Aberrant O-galactosylation has been found in serum IgA1, in IgA1 isolated from tonsillar lymphocytes, and in IgA1 eluted from mesangial deposits. There is evidence that changes in IgA1 O-galactosylation lead to IgA immune complex formation and mesangial IgA deposition. Mesangial cells exposed to these IgA immune complexes proliferate and adopt a pro-inflammatory phenotype; they secrete cytokines, chemokines, growth factors and extracellular matrix components promoting glomerular inflammation and glomerulosclerosis. Recent evidence suggests that the control of IgA1 O-glycosylation is linked to class switching from IgD to IgA1 synthesis and that the pattern of IgA1 O-glycosylation may be programmed at the time of initial antigen encounter. IgA1 glycosylation varies between systemic and mucosal sites and the association of aberrant IgA1 galactosylation with low affinity, polymeric IgA1 antibodies against mucosal antigens suggests undergalactosylated IgA1 may in fact be a mucosal glycoform of IgA1. Although suited to the mucosal compartment, when these IgA1 glycoforms enter the systemic circulation in appreciable quantities they deposit in the mesangium and trigger glomerular inflammation. This review will discuss the evidence for the role of IgA1 O-glycosylation in the pathogenesis of IgAN and propose an explanation for the presence of aberrantly O-glycosylated IgA1 in the circulation of patients with IgAN.

Increased dimeric IgA-producing B cells in tonsils in IgA nephropathy determined by in situ hybridization for J chain mRNA.

Abstract: The origin of mesangial IgA deposits in IgA nephropathy (IgAN) remains obscure. A significant proportion of deposited immunoglobulin is dimeric (J chain-positive). Previous studies of J chain expression within lymphoid tissue in IgAN have utilized antibodies which other investigators have found to be non-specific. To address this problem, we have developed and in situ hybridization (ISH) method for the detection of J chain mRNA within IgA plasma cells. Tonsils from 12 patients with IgAN and 12 controls were studied using (i) non-isotopic ISH for J chain mRNA, and (ii) combined immunofluorescence (IF) and fluorescent ISH. J chain mRNA-positive cells were identified in germinal centres, and within the subepithelial and interfollicular zones. A greater number of J chain mRNA-positive cells were found in the germinal centres of patients (mean 57.7 +/- 4.6 cells/10(5) micron2) compared with controls (mean 36.9 +/- 3.5 cells/10(5) micron2) (P < 0.001). Combined IF and fluorescent ISH showed a greater proportion of J chain mRNA-positive interfollicular IgA cells in patient tonsils (32 +/- 3.4%) compared with controls (21 +/- 2.3%; P < 0.02). These results indicate a shift towards dimeric IgA production in the tonsils in IgAN. In addition, the finding of excess numbers of J chain-positive Iga-negative cells within germinal centres suggests that an abnormality may be present at the B cell differentiation stage before IgA switching. These results further highlight immune abnormalities within the tonsil as a central feature of abnormal polymeric IgA biology in this common form of glomerulonephritis.