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Low Molecular Weight Heparin Reduces Ischemia/Referfusion-Induced Acute Renal Injury in Rats by Increasing Renal Tissue Level of Prostacyclin
Akio Mizutani, M.D.; Kenji Okajima, Ph.D.; Mitsuhiro Uchiba, Ph.D.; Shigenori Yoshitake, Ph.D.; Takayuki Noguchi, Ph.D.
Intensive Care Unit, Oita Medical University, Oita, Japan
Introduction: Low molecular weight heparin (LMWH) is an anticoagulant with less incidence of bleeding than heparin. LMWH also promotes endothelial release of prostacyclin (PGI2) in vitro (1). PGI2 has been shown to inhibit leukocyte activation by inhibiting the monocytic production of tumor necrosis factor-α (TNF-α) (2). Renal ischemia followed by reperfusion (I/R) is a pathologic mechanism in acute renal injury associated with renal transplantation and shock (3). Since TNF-α plays a pivotal role in I/R-induced organ damage by activating neutrophils leading to injuring vascular endothelial cells and thereby decreasing renal tissue blood flow (3,4). LMWH may reduce the renal injury by inhibiting leukocyte activation. We examined this hypothesis in this study.

Methods: After approval of the institutional Animal Care and Use Committee, male Wistar rats were subjected to renal I/R by clamping the right pedicle for 40 min after left nephrectomy, and divided into four groups as follows: 1) sham (without I/R) operation; 2) vehicle (saline) treatment; 3) LMWH (300 U/kg) treatment; 4) indomethacin (IM) pretreatment-LMWH treatment. LMWH was intravenously administered 30 min before reperfusion. IM, a potent inhibitor of PGI2 synthesis, was subcutaneously administered 30 min before ischemia. We assessed renal dysfunction measuring serum levels of blood urea nitrogen (BUN) and creatinine. Renal PGI2 production was evaluated by renal tissue levels of 6-keto PGF1α. Cytokine production was assessed by renal tissue levels of TNF-α and cytokine-induced neutrophil chemoattractant (CINC; equivalent to human interleukin-8). Renal accumulation of neutrophils was assessed by renal tissue levels of myeloperoxidase (MPO) activity. Renal vascular permeability was evaluated by assessing leakage of Evans blue dye. Renal cortical blood flow was measured by using a laser-Doppler flow meter. Data were analyzed using ANOVA and Scheffes post hoc test. A p<0.05 was considered statistically significant.

Results: LMWH significantly improved I/R-induced increase in BUN and creatinine (24 hrs after reperfusion), increase in TNF-α and CINC, and decrease in renal cortical blood flow (3 hrs after reperfusion), and increase in MPO activity and renal vascular permeability (6 hrs after reperfusion). IM pretreatment-LMWH had no effects on these variables. LMWH significantly increased 6-keto PGF1α 1 h after reperfusion compared with vehicle, whereas IM pretreatment-LMWH significantly reduced.

Conclusions: LMWH could reduce I/R-induced acute renal injury by inhibiting leukocyte activation through its promotion of endothelial production of PGI2.


(1) Chem Pharm Bull 1991; 39:3368

(2) Blood 1999; 93:157

(3) N Engl J Med 1996; 334:1448

(4) Blood 2000; 95:3781

Anesthesiology 2001; 95:A409