title: High fat feeding promotes obesity and renal inflammation and protects against post cardiopulmonary bypass acute kidney injury in swine.
abstract: BACKGROUND
  Obesity confers a survival advantage in the critically ill and in patients undergoing cardiac surgery. We explored whether an obesogenic high fat diet could confer protection against post cardiopulmonary bypass (CPB) acute kidney injury (AKI) in a swine model.
  
  
  METHODS
  In this study, 28 anaesthetised adult female Landrace White swine (55 to 70 kg) were allocated into a 4 group design to either 2.5 hours of CPB or Sham operation with or without pre-procedural high fat (HF) feeding containing 15% lard, 1.5% cholesterol and 1% cholic acid for 12-weeks (Groups: Sham, CPB, CPB + HF and Sham + HF). Our primary endpoint was creatinine clearance measured at 1.5 and 24 hours post intervention. This is a validated index of the glomerular filtration rate (GFR) in swine and an endpoint used in our clinical studies. Secondary endpoints included measures of systemic and renal inflammation, endothelial homeostasis, tubular injury and dysfunction, and inflammatory cell signalling. Differences between groups were calculated using analysis of variance with adjustment for baseline differences for repeated measures.
  
  
  RESULTS
  CPB in pigs fed a normal chow diet resulted in AKI. This was characterised by reductions in GFR sustained for up to 24 hours post injury relative to Sham operated pigs fed a normal diet; mean difference 50.2 ml/min (95% CI 5.9 to 94.4). Post CPB AKI was also characterised by renal inflammation, parallel activation of both pro-inflammatory (NF-kB, iNOS) and pro-survival pathways (pAkt, p70s6k, HIF-1α) and apoptosis. Pigs fed a 12-week high fat diet developed obesity and hyperlipidaemia. This was associated with increased redox sensitive pro-inflammatory and anti-apoptotic signalling, and tubular epithelial cell proliferation. High fat feeding also protected swine against post CPB AKI; mean difference in creatinine clearance CPB - CPB + HF -65.3 ml/min (95% CI -106.9 to -23.7), by preserving endothelial homeostasis and function, and preventing the reductions in GFR, loss of ATP and tubular apoptosis that characterise the extension phase of AKI in swine at 24 hours post injury. Reno-protection was not attributed to pAkt signaling.
  
  
  CONCLUSIONS
  A high fat diet promoted obesity and renal inflammation and prevented post CPB AKI in swine. This study provides insights into the obesity paradox and the failure of anti-inflammatory interventions to improve clinical outcomes in patients at risk of post cardiac surgery AKI.
authors.forename: Philippa
authors.initials: P
authors.lastname: Sleeman
authors.forename: Nishith N
authors.initials: NN
authors.lastname: Patel
authors.forename: Hua
authors.initials: H
authors.lastname: Lin
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Walkden
authors.forename: Paramita
authors.initials: P
authors.lastname: Ray
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Welsh
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Murphy
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D005919:Glomerular Filtration Rate; D007249:Inflammation / Q000209:etiology; D007677:Kidney Function Tests; D009765:Obesity / Q000209:etiology*; D013552:Swine
chemical_list: D015415:Biomarkers