ABSTRACT. Thrombosis of hemodialysis vascular access grafts represents a major medical and economic burden. Experimental and clinical models suggest a role for antiplatelet agents in the prevention of thrombosis. The study was designed to determine the efficacy of the combination of aspirin and clopidogrel in the prevention of graft thrombosis. The study was a randomized, double-blind trial conducted at 30 hemodialysis units at Veterans Affairs medical centers. Participants undergoing hemodialysis with a polytetrafluoroethylene graft in the arm were randomized to receive either double placebos or aspirin (325 mg) and clopidogrel (75 mg) daily. Participants were to be monitored while receiving study medications for a minimum of 2 yr. The study was stopped after randomization of 200 participants, as recommended by the Data Safety and Monitoring Board because of a significantly increased risk of bleeding among the participants receiving aspirin and clopidogrel therapy. The cumulative incidence of bleeding events was significantly greater for those participants, compared with participants receiving placebos [hazard ratio, 1.98; 95% confidence interval (CI), 1.19 to 3.28; P = 0.007]. Twenty-three participants in the placebo group and 44 participants in the active treatment group experienced a bleeding event (P = 0.006). There was no significant benefit of active treatment in the prevention of thrombosis (hazard ratio, 0.81; 95% CI, 0.47 to 1.40; P = 0.45), although there was a trend toward a benefit among participants who had not experienced previous graft thrombosis (hazard ratio, 0.52; 95% CI, 0.22 to 1.26; P = 0.14). In the hemodialysis population, therapy with aspirin and clopidogrel was associated with a significantly increased risk of bleeding and probably would not result in a reduced frequency of graft thrombosis. E-mail: james.kaufman@med.va.gov

Unfractionated heparin (UFH) is the anticoagulant of choice for most maintenance hemodialysis units in the United States. Low molecular weight heparin (LMWH) is the norm in Western Europe, but is not approved for this indication in the United States. UFH is likely to remain the agent of choice in the United States because of its relative ease of use, safety, and low cost. Coating tubing and dialyzers with heparin is now possible, but systemic anticoagulation with heparin is usually still required. The additional cost of this innovation does not yet justify its use. Side effects of both UFH and LMWH include heparin-induced thrombocytopenia, hypertriglyceridemia, and hyperkalemia. It is uncertain whether osteoporosis is an important side effect, as vitamin D deficiency, secondary hyperparathyroidism, age, and debility are confounding factors. When UFH poses a risk or its use is contraindicated, e.g., after development of heparin-induced thrombocytopenia, the use of direct thrombin inhibitors, regional citrate anticoagulation, citrate dialysate, and heparin-free dialysis may be appropriate.

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 less than 0.05). At 3 h, glomerular filtration rate (GFR) was higher in M animals (8 vs. 4 ml/min, P less than 0.01), while at 24 h protection was even greater (18 vs. 3 ml/min, P less than 0.01). In U animals proximal tubule pressure (Pt) was lower at 1 h than before NE (13 vs. 23 mmHg, P less than 0.01); from 1 to 3 h Pt increased to elevated levels in parallel with restoration of RBF (r = 0.62, P less than 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 less than 0.05) yet Pt was increased (35 vs. 23 mmHg, P less than 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 less than 0.001), a finding not present in unobstructed tubules. Delayed excretion (approximately 20 min) of microinjected [3H]inulin also was 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 less than 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 less than 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.

To clarify the mechanisms involved in the stability of blood pressure during ultrafiltration (UF) alone versus regular dialysis, this study systematically examined the importance of changes in serum potassium, osmolality, and plasma norepinephrine during several dialysis maneuvers. Six stable, normotensive chronic dialysis patients were subjected to a uniform 2 to 3% decrease in body weight during the 2 hours of each dialysis maneuver. Supine to upright mean blood pressure (MBP) decreased (90 to 75 mm Hg, P less than 0.05), and three patients became symptomatic after weight loss during regular dialysis, but orthostatic blood pressure was stable (89 to 86 mm Hg, NS) and the patients were asymptomatic after UF and weight loss. Isokalemic regular dialysis did not afford hemodynamic stability, as orthostatic MBP declined (85 to 56 mm Hg, P less than 0.02), and four of the patients were again asymptomatic after standing. A continuous hypertonic mannitol (25%) infusion during the 2-hour dialysis, however, kept osmolality from decreasing and was associated with a stable orthostatic MBP (89 to 83 mm Hg, NS). A continuous infusion of isotonic mannitol (5%) given in a volume of five times that of the hypertonic mannitol failed to prevent orthostatic hypotension (80 to 60 mm Hg, P less than 0.005). Plasma norepinephrine concentrations were high in these patients and increased only modestly after weight loss. These results implicate constant plasma osmolality as a critical protective factor of blood pressure during UF and further demonstrate that changes in blood pressure may be associated from changes in both serum potassium and plasma norepinephrine concentration.