Functional role of thromboxane production by acutely rejecting renal allografts in rats

We investigated the role of thromboxane in mediating the reduction in renal function and renal blood flow characteristic of acute renal allograft rejection. We transplanted kidneys from Lewis rats to Brown-Norway recipients. By the third day after transplantation, histologic changes that were consistent with cellular rejection occurred in the kidney. These changes were associated with a moderate reduction in renal function. By day 6, histologic changes of rejection were advanced and included interstitial and perivascular infiltration by mononuclear cells. The clearances of inulin and para-aminohippuric acid were also markedly reduced. As renal function deteriorated, thromboxane B2 (TXB2) production by ex vivo perfused renal allografts increased progressively from 2 to 6 d after transplantation. However, prostaglandin (PG) E2 and 6-keto PGF1 alpha production remained essentially unchanged. There was a significant inverse correlation between the in vivo clearance of inulin and the log of ex vivo TXB2 production. Infusion of the thromboxane synthetase inhibitor UK-37248-01 into the renal artery of 3-d allografts significantly decreased urinary TXB2 excretion and significantly increased renal blood flow (RBF) and glomerular filtration rate (GFR). Although renal function improved significantly after the acute administration of UK-37248-01, GFR and RBF did not exceed 33 and 58% of native control values, respectively. In other animals, daily treatment with cyclophosphamide improved the clearances of inulin and para-aminohippuric acid and reduced thromboxane production by 6-d renal allografts. These studies demonstrate that histologic evidence of rejection is associated with increased renal thromboxane production. Inhibition of thromboxane synthetase improves renal function in 3-d allografts. Cytotoxic therapy improves renal function, reduces mononuclear cell infiltration, and decreases allograft thromboxane production. Thus, the potent vasoconstrictor thromboxane A2 may play a role in the impairment of renal function and renal blood flow during acute allograft rejection.