• Nishkantha Arulkumaran, Marije L Sixma, Elisa Jentho, Elias Ceravola, Paul S Bass, John A Kellum, Robert J Unwin, Fred W K Tam, and Mervyn Singer.
• 1Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom.2Department of Nephrology, Division of Medicine, University College London, London, United Kingdom.3Hammersmith Hospital, Imperial College Renal and Transplant Centre, London, United Kingdom.4Department of cellular pathology, Royal Free Hospital, London, United Kingdom.5Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.
• Crit. Care Med. 2017 Aug 1; 45 (8): e821-e830.

ObjectivesTo characterize the temporal pattern of a panel of blood and urinary biomarkers in an animal model of fecal peritonitis and recovery.DesignProspective observational animal study.SettingUniversity research laboratory.SubjectsMale Wistar rats.InterventionsA fluid-resuscitated, long-term (3 d) rat model of sepsis (fecal peritonitis) and recovery was used to understand the temporal association of sepsis biomarkers in relation to systemic hemodynamics, inflammation, and renal function. At predefined time points (3, 6, 12, 24, 48, 72 hr), animals (≥ 6 per group) underwent echocardiography, blood and urine sampling, and had kidneys taken for histological analysis. Comparison was made against sham-operated controls and naïve animals.Measurements And Main ResultsThe systemic proinflammatory response was maximal at 6 hours, corresponding with the nadir of stroke volume. Serum creatinine peaked late (24 hr), when clinical recovery was imminent. Histological evidence of tubular injury and cell death was minimal. After a recovery period, all biomarkers returned to levels approaching those observed in sham animals. Apart from urine clusterin and interleukin-18, all other urinary biomarkers were elevated at earlier time points compared with serum creatinine. Urine neutrophil gelatinase-associated lipocalin was the most sensitive marker among those studied, rising from 3 hours. While serum creatinine fell at 12 hours, serum cystatin C increased, suggestive of decreased creatinine production.ConclusionsNovel information is reported on the temporal profile of a panel of renal biomarkers in sepsis in the context of systemic and renal inflammation and recovery. Insight into the pathophysiology of acute kidney injury is gleaned from the temporal change markers of renal injury (urine neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, calbindin), followed by a marker of cell cycle arrest (urine insulin-like growth factor-binding protein 7) and, finally, by functional markers of filtration (serum creatinine and cystatin C). These clinically relevant findings should have significant influence on future clinical testing.

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