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Investigation of urinary neutrophil gelatinase-associated lipocalin concentration for the diagnosis of ischaemia-reperfusion induced acute kidney injury in dogs

Davis, JenniferORCID: 0000-0002-7078-1645 (2015) Investigation of urinary neutrophil gelatinase-associated lipocalin concentration for the diagnosis of ischaemia-reperfusion induced acute kidney injury in dogs. Masters by Research thesis, Murdoch University.

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Acute kidney injury (AKI) is a devastating potential consequence of renal ischaemia and reperfusion (I-R) subsequent to severe intra-operative hypotension and fluid resuscitation. Acute tubular epithelial damage is a common early histological abnormality in this syndrome. The high mortality rate associated with AKI in dogs is attributed in part to the limitations of current diagnostic techniques that can only detect AKI in the late stages when damage is irreversible. Early detection of renal tubular injury could improve outcome and might be possible by measuring urinary neutrophil gelatinase-associated lipocalin concentration (uNGAL) in at-risk dogs.

The objectives of this study were to establish a clinically relevant canine model of renal I-R injury, and use this model to determine changes in uNGAL within three hours of initiation of injury.

A pilot study was performed to establish the severity and duration of hypotension caused by haemorrhage, and duration of reperfusion, that produced histological evidence of acute tubular damage. Urine samples obtained during this pilot were used to determine optimal sample dilutions for use with a commercial dog NGAL immunoassay. Investigation into potential interference of synthetic colloid fluid solutions with the immunoassay was also performed. This experimental model was then used to determine changes in uNGAL in seven anaesthetised greyhound dogs. Urinary NGAL concentrations were measured before (T0) and immediately following (T1) haemorrhage, and hourly following fluid resuscitation (T2 - T4). After T4, dogs were euthanised, and renal tissue collected for histopathology. Statistical analysis for the main study was performed using repeated measures one-way ANOVA and data presented are mean (95% confidence interval).

The pilot study showed that maintenance of mean arterial pressure (MAP) below 40 mmHg for one hour (ischaemic phase); followed by fluid resuscitation to maintain MAP > 60 mmHg for three hours (reperfusion phase) was required to ensure tubular damage was produced. Optimal dilution of urine samples for accurate NGAL measurement using the immunoassay was 1 in 1000. A 4% gelatin-based colloid solution did not interfere with the immunoassay. In the main study, histopathology confirmed renal tubular epithelial damage in all dogs. Urine NGAL increased from a mean of 12.1 (confidence interval 0 – 30.6) ng mL-1 at T0 to 122.0 (64.1 – 180.0) ng mL-1 by T3. Compared to T0, uNGAL was significantly higher at T3 (p = 0.016). Fold change in uNGAL at T3 was 24.2 (7.3 – 41.0).

Pressure-guided acute haemorrhage followed by colloid resuscitation produced a clinically relevant model of I-R AKI in dogs. Despite wide individual variation in baseline uNGAL, increases in uNGAL were observed in all dogs suggesting this biomarker has potential for detecting early tubular injury caused by renal I-R in this species.

Item Type: Thesis (Masters by Research)
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Notes: Research Masters with Training
Supervisor(s): Raisis, Anthea, Shiel, Robert and Miller, David
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