Renal ischemic injury in the dog: characterization and effect of various pharmacologic agents.

Renal ischemia has been implicated as a major factor in the pathogenesis of acute renal failure. Despite several differences between the intrarenal norepinephrine infusion and renal artery occlusion models, they have been assumed to be prototypic models of ischemic renal injury. In our previous studies, an intrarenal infusion of norepinephrine caused a marked reduction in inulin clearance 3 hours after infusion. This reduction could be significantly attenuated by the concurrent infusion of mannitol, furosemide, or bradykinin. The effects of these three protective agents were evaluated before and after variable durations of renal artery occlusion to establish the similarities between the models and the magnitude of versatility of these protective agents. In the renal artery occlusion model, capsular fascia was stripped to eliminate collateral flow and ensure maximal renal ischemia. Three hours after 120 minutes of renal artery occlusion (n = 7), inulin clearance returned to 5.7% +/- 2.2% (SEM) of the control values and was not statistically different from that observed in the norepinephrine model. Intrarenal infusion of mannitol, furosemide, or bradykinin prior to and during the occlusion period, however, had no protective effect. Shorter durations of renal artery occlusion were evaluated to ensure an equivalent or decreased severity of acute renal failure compared with the norepinephrine model. After 90 or 60 minutes of renal artery occlusion, the clearance of inulin returned to 10.9% +/- 3.3% (n = 8) and 31.1% +/- 8.2% (n = 4) of control values, respectively. An intrarenal infusion of mannitol, furosemide, or bradykinin still had no significant protective effect, despite the decreased insult in the 60-minute renal artery occlusion studies. In summary, these findings demonstrate fundamental differences between renal artery occlusion and the norepinephrine model of renal functional impairment, and they suggest that the insult associated with norepinephrine infusion may involve factors other than cessation of blood flow.

Alterations in vascular function and morphology in acute ischemic renal failure.

Left renal arteries of rats were clamped for 40 min, and the kidneys were studied 48 hr and 7 days following restoration of blood flow. At 48 hr, there was severe oliguria or anuria. Renal blood flow (RBF) was in the normal range, but there was a loss of RBF autoregulation between 95 to 120 mm of mercury in seven out of nine rats. Morphologically, arcuate and interlobular arteries and afferent arterioles showed focal, segmental necrosis of smooth muscle cells and diapedesis of red blood cells across their walls. At 7 days, renal function was still severely depressed. RBF showed a slight decrease that did not reach statistical significance, and RBF autoregulatory capacity was lost in 8 out of 11 rats. Morphologically, vascular lesions were characterized at this stage by marked thickening and fibrosis of the tunica adventitia of the interlobular arteries and afferent arterioles. Structural vascular alterations may impair smooth muscle contractile function and thus interfere with RBF autoregulatory function in this model of acute renal failure.