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|Title:||Cyclosporin a and renal function in renal transplant recipients.|
|Authors:||Mobb, Gillian Eugenie.|
|Abstract:||Chronic nephrotoxicity is the major limitation to the clinical potential of CyA in both transplantation and autoimmune disease. Retrospective investigation and a prospective study of Leicester renal allograft recipients demonstrated the excellent early graft survival, progressive deterioration of renal function and eventual graft failure characterised by this condition. Thromboxane A2 (TXA2), is a powerful vasoconstrictor prostanoid which has been implicated in the mechanism of CyA-induced nephrotoxicity. Intra-renal production of TXA2 is significantly elevated in animals and humans receiving CyA, whilst endothelial production of the vasodilator prostanoid, prostacyclin, may also be reduced. These substances were detected by radioimmunoassay of their stable hydrolysis products TXB2 and 6-keto PGF1a respectively, in urine and plasma. Renal allograft function was investigated in patients receiving CyA. Isotope clearance techniques using 51Cr ethylene diamine tetra-acetic acid to measure GFR and 125I iodohippuran to measure ERPF, were demonstrated to be superior in assessing changes in function, when compared with more commonly used parameters of serum and urinary biochemistry. The acute effects of a single oral dose of CyA on renal haemodynamics were studied both in transplant recipients and in subjects with normal kidneys. The response of renal function to treatment with a specific TXA2 receptor antagonist, (GR32191B), prescribed on a double-blind placebo- controlled basis was investigated in established allograft recipients. Renal functional reserve (RFR), believed to be prostaglandin-mediated and stimulated by protein ingestion was also investigated in these patients. A CyA-related imbalance in prostaglandin production was clearly demonstrated. This was associated with loss of RFR capacity. TXA2 receptor antagonism failed to ameliorate nephrotoxicity and contrary to anticipation, induced deterioration in renal function in association with a decrease in circulating concentrations of 6kPGF1a. Possible explanations for these findings have been discussed.|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, College of Medicine, Biological Sciences and Psychology|
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