(Screen 4 - 5:45 PM Friday) Kidney tissue kynurenine pathway alterations in an infant piglet model of cardiopulmonary bypass with deep hypothermic circulatory arrest

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Abstract:

Background: Tryptophan is catabolized primarily through the kynurenine pathway (KP). The KP produces multiple toxic and immune modulating metabolites and is also the sole source of de novo nicotinamide adenine dinucleotide (NAD) production. Circulating KP metabolites increase following infant cardiac surgery and increased kynurenic acid is strongly associated with postoperative acute kidney injury (AKI), ICU length of stay, and mortality. We have previously shown via metabolomic profiling that several KP intermediates are higher in kidney tissue from piglets with post-bypass AKI. However, comprehensive kidney KP changes, expression of the rate limiting pathway enzyme (indolamine 2,3 dioxygenase [IDO]), and the effects of modulating KP flux after cardiac surgery with cardiopulmonary bypass (CPB) are unknown.

Objective: In a piglet model of CPB with deep hypothermic circulatory arrest (DHCA), perform quantitative mapping of KP metabolites in kidney, measure tissue IDO expression, and determine the feasibility of KP modulation using the selective IDO inhibitor Linrodostat (BMS 986205).

Methods: Infant male and female pigs (5-10kg) underwent peripheral CPB followed by 75 minutes of DHCA at 180C. The piglets were then rewarmed, separated from CPB, and provided ICU care for 6h (n=4). An additional group of piglets (n=3) received 25mg of i.v. Linrodostat (LIN) divided between pre- and post-CPB. Control animals (n=4) were mechanically ventilated (MV) for 12h without CPB (n=4). Snap frozen kidney tissue was processed, metabolites analyzed by liquid chromatography–tandem mass spectrometry and gene expression of IDO determined using real time-PCR. One-way ANOVA and Kruskal-Wallis test were utilized to assess differences across groups.

Results: An increasing trend in kynurenine (KYN)/ tryptophan (TRP) ratio was observed in kidney tissue of CPB/DHCA animals compared to MV controls indicating increased IDO activity (Fig1). Gene expression of IDO was also increased (p=0.05) in kidney of CPB/DHCA animals (2.78±1.55) compared to MV controls (0.98±0.35). Consistent with increased IDO activity, CPB/DHCA exposure increased the levels of all downstream pathway metabolites (Fig1). IDO inhibition with Linrodostat resulted in decreased KYN/ TRP ratio (Fig1) and decreased levels of most downstream metabolites to near control levels without affecting IDO gene expression (2.32±0.77), indicating effective IDO blockade.

Conclusions: In our piglet model we show for the first time that exposure to CPB/DHCA causes increased IDO expression and increased KP flux in the kidney. Linrodostat decreases kidney IDO activity, leading to normalization of KP metabolites. Further research is essential to understanding the effect of KP modulation on the incidence and severity of post-CPB AKI.