Arulkumaran, N; (2016) P2X7 receptor and Sepsis-Induced Acute Kidney Injury. Doctoral thesis , UCL (University College London).

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Abstract

Acute kidney injury (AKI) is a common clinical problem within the intensive care unit. Sepsis is implicated in half the cases of AKI; in those patients requiring acute renal replacement therapy there is an associated mortality of 50%. However, other than maintenance of an adequate circulation, no specific therapy exists for septic AKI. This is in large part related to a poor understanding of the underlying pathophysiology.. I used a 72 hr clinically relevant, fluid-resuscitated rat model of sepsis and recovery to undertake a detailed temporal characterization of the pathophysiology of septic AKI and relevant biomarkers of kidney injury and dysfunction, and to assess the impact of targeted treatments. As with human studies, renal histology demonstrated minimal tissue injury or early inflammatory cell infiltration, however renal recovery was associated with a marked increase in renal macrophage infiltration. A panel of 8 renal biomarkers revealed that urine NGAL was the most sensitive marker, having risen by 3 hours’ post-insult and elevated for 24hrs. Renal blood flow was maintained over the first 24 hrs, however a fall in renal cortical oxygenation occurred despite similar renal oxygen delivery and utilization at 24 hrs. Though electron microscopy showed normal mitochondrial structure, I found an increased expression of mitochondrial uncoupling protein-2 (UCP-2); this may further uncouple mitochondrial respiration. Multiphoton imaging of live healthy kidney slices incubated in either sham or septic serum showed a rise in tubular reactive oxygen species (ROS) and falls in NADH and mitochondrial membrane potential in the septic serum group, findings that are consistent with uncoupling. Pre-incubation with the ROS scavenger, 4-OHTEMPO, prevented these effects. The NLRP3 inflammasome plays an important role in pro-inflammatory cytokine production. A NLRP3 inflammasome inhibitor, P2X7 antagonist, prevented LPS-induced IL-1β production by peripheral blood monocytes in vitro, however this was related in part to its diluent vehicle, dimethyl sulfoxide (DMSO). In the kidney, proximal tubular P2X7 and caspase-1 expression was seen both in vivo and ex vivo during sepsis. DMSO/P2X7 antagonist treatment after the onset of sepsis was associated with reduced renal IL-1β expression and improvements in tachycardia, stroke volume, albumin and lactate however effects on renal function were inconclusive. Further studies targeting the NLRP3 inflammasome in sepsis are warranted.

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