Changes in renal medulla gene expression in a pre-clinical model of post cardiopulmonary bypass acute kidney injury

Abstract

BackgroundAcute kidney injury (AKI) is a common and serious complication of cardiac surgery using cardiopulmonary bypass (CPB). The pathogenesis is poorly understood and the study of AKI in rodent models has not led to improvements in clinical outcomes. We sought to determine the changes in renal medullary gene expression in a novel and clinically relevant porcine model of CPB-induced AKI.ResultsAdult pigs (n = 12 per group) were randomised to undergo sham procedure, or 2.5 hours CPB. AKI was determined using biochemical (Cr51 EDTA clearance, CrCl, urinary IL-18 release) and histological measures. Transcriptomic analyses were performed on renal medulla biopsies obtained 24 hours post intervention or from sham group. Microarray results were validated with real-time polymerase chain reaction and Western Blotting.Of the transcripts examined, 66 were identified as differentially expressed in CPB versus Sham pig’s kidney samples, with 19 (29%) upregulated and 47 (71%) down-regulated. Out of the upregulated and downregulated transcripts 4 and 16 respectively were expression sequence tags (EST). The regulated genes clustered into three classes; Immune response, Cell adhesion/extracellular matrix and metabolic process. Upregulated genes included Factor V, SLC16A3 and CKMT2 whereas downregulated genes included GST, CPE, MMP7 and SELL.ConclusionPost CPB AKI, as defined by clinical criteria, is characterised by molecular changes in renal medulla that are associated with both injury and survival programmes. Our observations highlight the value of large animal models in AKI research and provide insights into the failure of findings in rodent models to translate into clinical progress.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-916) contains supplementary material, which is available to authorized users.

Impact of Custodiol‐N cardioplegia on acute kidney injury after cardiopulmonary bypass

“…Porcine models of CPB‐induced AKI are preferred for translational research because of their significant homology to AKI in cardiosurgical patients . Several studies have demonstrated via biochemical and histological measures that porcine models have a higher degree of functional, urinary and histological similarities to humans than do rodent models …”

“…Moreover, Hb levels were higher in the HTK‐N group than in the HTK group. We hypothesized that the addition of the iron chelators deferoxamine and LK‐614 to the HTK‐N solution could be responsible for the reduction of CPB‐induced hemolysis that is associated with the production of free Hb and free iron …”

“…This is the first large animal study to assess the renal effects of HTK compared to those of HTK-N and to allow for the translational research of clinical benefits.Porcine models of CPB-induced AKI are preferred for translational research because of their significant homology to AKI in cardiosurgical patients 8. Several studies have demonstrated via biochemical and histological measures that porcine models have a higher degree of functional, urinary and histological similarities to humans than do rodent models 8,9. Within the scope of this work, HTK-N cardioplegia prevented tubular cell swelling in the proximal tubules, and induced less cytochrome c release into the cytosol of kidney cells, which indicated a lower risk for apoptosis induction.…”

Tissue alkaline phosphatase activity and expression in an experimental infant swine model of cardiopulmonary bypass with deep hypothermic circulatory arrest

“…We chose to use a porcine model due to the similarities in both the physiologic response to CPB and drug metabolism. [87][88][89][90][91][92] However, staged clinical trials in children and adults undergoing cardiac surgery are needed to de nitively prove both the safety and e cacy of this therapy. While it is possible to differentiate among human AP isoenzymes/isoforms, [46] the previously published lack of available antibodies to exogenous BiAP and native non-human AP makes this differentiation challenging in animal models.…”

Modulating microRNAs in cardiac surgery patients: Novel therapeutic opportunities?

“…The latter can provide a more suitable setting to simulate surgical practices and/or replicate scenarios, e.g. large animal models in AKI research (Ghorbel et al, 2014), instead of murine models that are unlikely to mimic sufficiently the pathology of the surgical scenarios of interest ).…”