Ischemia and tubule obstruction during acute renal failure in dogs: Mannitol in protection

The pathogenetic factors involved in norepinephrine- (NE) induced reversible acute renal failure (ARF) were examined in untreated (U) and mannitol-treated (M) animals. At 3 and 24 h after NE infusion renal blood flow (RBF) was significantly higher in M compared to U animals (174 vs. 138 and 191 vs. 148 ml/min, respectively, both P < 0.05). At 3 h, glomerular filtration rate (GFR) was higher in M animals (8 vs. 4 ml/min, P < 0.01), while at 24 h protection was even greater (18 vs. 3 ml/min, P < 0.01). In U animals proximal tubule pressure (Pt) was lower at 1 h than before NE (13 vs. 23 mmHg, P < 0.01); from 1 to 3 h Pt increased to elevated levels in parallel with restoration of RBF (r = 0.62, P < 0.01). At 3 h in U animals stop-flow pressure (SFP), as an index of glomerular capillary pressure, was below normal (35 vs. 44 mmHg, P < 0.05) yet Pt was increased (35 vs. 23 mmHg, P < 0.05). Thus, little transglomerular pressure gradient was present for ultrafiltration. Further evidence of tubular obstruction was obtained by microperfusion at 6 nl/min, which increased Pt from 30 to 45 mmHg (P < 0.001), a finding not present in unobstructed tubules. Delayed excretion (~20 min) of microinjected [³H]inulin was also compatible with renal ischemia and tubule obstruction. Microinjection studies provided no evidence for backleak of tubular fluid. At 1 h, Pt was higher in M vs. U animals (31 vs. 13 mmHg, P < 0.05). In M animals at 3 h SFP was normal (50 vs. 44 mmHg) and Pt was below SFP (32 vs. 50 mmHg, P < 0.01), thus preserving a substantial transglomerular pressure gradient for ultrafiltration. In summary, reduced GFR in U animals is characterized by a combination of reduced glomerular capillary pressure and tubule obstruction. In contrast, animals receiving mannitol were protected against ARF through maintenance of glomerular capillary pressure and prevention of tubular obstruction, perhaps by increasing Pt within the first hour of the NE insult.