Development of Renal Dysfunction in an Infant Model of Polymicrobial Sepsis

Abstract

Sepsis‐induced acute kidney injury increases mortality from 25% to nearly 45% in infants. We used a clinically relevant cecal ligation and puncture (CLP) sepsis model in rat pups 17–19 days old (developmentally comparable to a 5 to 6‐month‐old human infant) to characterize the development of renal dysfunction. Renal injury was assessed using intravital video microscopy (IVVM), blood urea nitrogen (BUN), and glomerular filtration rate (GFR) at 4, 6, and 18h following CLP. Temperature was measured as an indicator of Systemic Inflammatory Response Syndrome. Temperature was decreased as early as 6h following CLP and remained decreased through 18h. Lactate, an indicator of general organ hypoperfusion and hypoxia, was nearly doubled as early as 4h following CLP and remained elevated through 18h. IVVM analysis of the renal microcirculation showed a significant decrease in the percentage of continuously flowing capillaries (72% to 36%) and an increase in the percentage of capillaries with no flow (2% to 26%) at 6h following CLP that persisted through 18h. Clinically, measurement of BUN is used to assess renal function when GFR is difficult to measure. In this model, BUN was significantly increased by 4h following CLP and was increased even further by 18h. GFR is the gold standard measurement of renal function and it was measured using non‐invasive transcutaneous measurements of sinistrin clearance in conscious rat pups. GFR was decreased 50% as early as 4h following CLP and remained decreased through 18h. These findings show that this model of polymicrobial sepsis produces early and sustained renal dysfunction suggesting it could be used in preclinical studies to evaluate new targeted therapies for sepsis‐induced renal injury in infants.Support or Funding InformationCRS supported by T32 GM106999, F31DK104533, AHA PRE20450050; PRM supported by AHA 15GRNT2508025 and UAMS Medical Research Foundation; PCG supported by ASPET Institutional SURF Award 2015.