Abstract
IntroductionObesity 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.MethodsIn 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.ResultsCPB 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.ConclusionsA 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.
Highlights
Obesity confers a survival advantage in the critically ill and in patients undergoing cardiac surgery
We have described a novel large animal recovery model of post-cardiopulmonary bypass acute kidney injury (AKI) in swine [15] that shows quantitative and qualitative homology to the renal injury and dysfunction observed in cardiac surgery patients [16]
For graphs pooled estimates for pairwise comparisons derived from Analysis of Covariance with adjustment for baseline Creatinine Clearance estimated at 114 ml/min, serum creatinine 135 μmol/L, serum IL-6 estimated at 18.6 pg/ml, urinary neutrophil gelatinase-associated lipocalcin (NGAL) creatinine ratio estimated at 3.69 ng/μmol, were as follows: Creatinine Clearance; Post cardiopulmonary bypass (CPB) Intervention: Sham- Sham + high fat (HF), 25.9 ml/min, p = 0.249, Sham-CPB 50.2 ml/min, p = 0.028, Sham-CPB + HF 52.9, p = 0.026
Summary
Obesity confers a survival advantage in the critically ill and in patients undergoing cardiac surgery. A number of epidemiological studies have reported improved outcomes in critically ill patients who are obese when compared with normal weight individuals [5]. This phenomenon, termed the obesity paradox, includes improved outcomes in intensive care patients with acute kidney injury [6], as well as following cardiac surgery [7,8]. A beneficial effect of obesity on inflammatory organ injury is not universally accepted, ; other authors have shown that very obese patients are at increased risk of AKI following cardiac surgery [9]. There is no clear mechanistic explanation, and the findings of these studies have been variously attributed to statistical bias [10], confounding and reverse epidemiology [11], the anti-inflammatory effects of adipose tissue [12,13], and the thrifty genotype [14]
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