FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia reperfusion injury

ObjectiveAcute tubular necrosis (ATN) secondary to induced warm ischemia (WI) results in inflammatory and delayed fibrotic processes and remains a common clinical problem with serious consequences. Because tumor necrosis factor-α (TNF-α) is a prominent proinflammatory factor implicated in the pathophysiology of acute renal ischemia reperfusion injury (IRI), we hypothesized that FR167653 (FR), a potent inhibitor of TNF-α and interleukin-1β production, may reduce IRI.MethodsIRI was induced in male pigs by bilateral clamping of the renal pedicle for 90 minutes (WI90), or unilateral renal clamping (90 minutes) after contralateral nephrectomy (1/2N×90), or unilateral renal clamping without contralateral nephrectomy (WIuni90). FR was administered intravenously 60 minutes before WI (1 mg/kg/h), during WI, and continuously for 3 hours (1 mg/kg/h) during reperfusion in treated groups (FRWI90, FR1/2N×90, or FRWIuni90). Blood and urine samples were collected between day 1 and 3 months after reperfusion for assessment of renal function. Kidneys were excised and renal tissues were collected at 3 months for morphologic and inflammation evaluation and protein analysis. Experimental groups were compared with sham operated (control) and heminephrectomized (Unif) groups without renal ischemia.ResultsThree WI90 animals (43%) and five 1/2N×90 (70%) were euthanized and necropsied at day 7 because of no urine production or poor conditions. Mortality was significantly improved after FR treatment. Survival was 100% in the control, Unif, WIuni90, and FR groups. In Unif groups, FR significantly reduced renal failure and bilateral renal ischemia (P < .05). At 3 months, proteinuria was significantly reduced in FR-treated groups (P < .01). Inflammatory cells count was also dramatically diminished in FR-treated pigs (P < .01 for CD3-positive cells). The second aspect of transient ischemia is the fibrotic process determined at 3 months. FR treatment was characterized by a reduction of renal fibrosis, particularly in Unif groups. TNF-α protein expression was diminished in FR-treated groups.ConclusionThis is the first evidence that FR reduced the early and long-term effect of WI in the severe ischemia model. This effect was particularly marked against fibrosis and inflammation, which would contribute to deterioration of a patient's renal function.Clinical RelevanceAcute ischemia of the kidney is common in the setting of renal artery or aortic surgery. Deterioration in renal function is a common cause of morbidity in patients treated surgically for juxtarenal and suprarenal abdominal aortic aneurysms. FR167653 represents a useful therapeutic approach to prevent renal damage in a planned period of warm ischemia and during suprarenal aortic surgery