Pathogenic mechanisms in early norepinephrine-induced acute renal failure: Functional and histological correlates of protection

Abstract

The present study investigated the protective effect of acute volume expansion (25%) with isotonic saline, isotonic mannitol, and hypertonic mannitol in a model of unilateral norepinephrine-induced acute renal failure (ARF). Three hours following a 40-min intrarenal infusion of norepinephrine (NE) (0.75 μg/kg/min), inulin clearance had fallen from a control value of 54.1±6.5 to 1.3±1.3 ml/min in untreated dogs and fell similarly (P=NS) to 3.3±1.5 ml/min in animals preexpanded with 0.9% saline (0.75 ml/kg/min). In contrast, as compared to the untreated animals, inulin clearance 3 hr post NE infusion was significantly greater in dogs preexpanded with 5% mannitol (9.2±2.5 ml/min, P<0.01), or 20% mannitol (16.6±3.9 ml/min, P<0.01). The protective effects of 5% and 20% mannitol were not statistically different from each other. Recovery of renal excretory function in all groups, expressed as 3-hr post NE inulin clearance, correlated with the magnitude of pre NE solute excretion rate (r=0.612, P<0.001) and osmolar clearance rate (r=0.593, P<0.001), but not with pre insult inulin clearance (r=0.233, P=NS) or renal blood flow (r=0.249, P=NS). In the presence of a profound fall in inulin clearance, proximal tubular (PT) pressures in untreated dogs 3 hr post NE infusion achieved a value equal to control 26±11 vs. 25±2 mm Hg). In contrast, pretreatment with isotonic mannitol produced a rise in PT pressure both before (45±4 mm Hg, P<0.05) and 3 hr post NE infusion (38±5 mm Hg, P<0.05). In all groups of animals, at both 3 and 24 hr post NE, tubular injury was observed but glomerular architecture remained normal by light and electron microscopy. Conclusion. the protective effect of mannitol in this reversible model of ARF did not correlate with inulin clearance, renal blood flow, extracellular fluid (ECF) volume, ECF hypertonicity, or renal histologic changes but did correlate with the solute excretion rate. The increased PT pressures with mannitol both before and after the NE insult could contribute to the protective effect of attenuating any relative intratubular obstruction.