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A light microscopic study of chemically induced renal papillary necrosis and upper urothelial carcinoma in animal models.

Gregg, Neill J. (1989) A light microscopic study of chemically induced renal papillary necrosis and upper urothelial carcinoma in animal models. Doctoral thesis, University of Surrey (United Kingdom)..

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Renal papillary necrosis (RPN) and upper urothelial carcinoma (UUC) can both be caused by the long-term abusive consumption of analgesics and non-steroidal anti-inflammatory drugs (NSAID). A "cause-and-effect" relationship between RPN and UUC has been proposed. However, despite a considerable amount of clinical data and experimental evidence this relationship has not been proven nor is it widely accepted. Experimental models of RPN and UUC have been difficult to establish using analgesics and NSAID because of the chronic periods of dosing required with these compounds which frequently have extra-renal toxicities and there is a large biological variation in response. These problems have lead to the use of alternative models using chemicals with known papillotoxic potential such as 2-bromoethanamine (BEA) hydrobromide. This compound will induce a dose related RPN in the rat in 24-48 hr. Studies to determine which was the earliest cellular change occurring as a consequence of BEA-induced RPN were performed in a number of different species (rat, mouse, marmoset and pig), and to determine whether this acute RPN lesion was relevant to the chronic clinical situation in man. High resolution light microscopy using semithin glycolmethacrylate sections in conjunction with routine and enzyme histochemical staining was used throughout these studies to assess the histopathological changes. Comparison with renal tissue obtained from human analgesic abusers was also performed. The results from these investigations show for the first time that the earliest cell type affected, in BEA-induced RPN in the rat and mouse is the medullary interstitial cell in the renal papilla. These cells were also affected in the marmoset and pig where only terminal studies were undertaken. A degenerative cascade results affecting the medulla, cortex (in rats and nude mice) and a pronouced hyperplasia of the urothelium of the pelvis and ureter occurs in the rat and pig. Longterm changes in the rat closely resembled the changes observed in tissues from human analgesic abusers. A series of investigations was performed to try and establish the link between RPN and UUC using the classical 2-stage "initiation-promotion" model for experimental carcinogenesis. A specific urothelial carcinogen N-butyl-N-(4-hydroxybutyl)-nitros-amine (BBN) was used to initiate the urothelium of Wistar rats, followed by an acute BEA-induced RPN. The development of preneoplastic papillary and nodular hyperplasias (within 13 weeks of this regimen) and macroscopic transitional cell tumours in the renal pelvis and upper ureter (at 30-40 weeks) suggests that the localised injury associated with an acute RPN can "promote" an already initiated urothelium to induce pre-neoplastic and neoplastic changes. Studies where single analgesics were superimposed on to this BBN/BEA regimen produced results that suggest that analgesics may exacerbate these RPN related changes to induce more severe pre-neoplastic and neoplastic changes earlier than with BBN/BEA alone. A number of possible mechanisms are discussed the light of the data from these investigations to link RPN and UUC. Peroxidative metabolism of potential carcinogenic compounds seems to be the most likely mechanism although the actual mechanistic process is probably a complex one with a multifactorial basis.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors :
Gregg, Neill J.
Date : 1989
Contributors :
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1989.
Depositing User : EPrints Services
Date Deposited : 22 Jun 2018 13:01
Last Modified : 06 Nov 2018 16:52

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