Experimentally Induced Renal Papillary Necrosis and Upper Urothelial Carcinoma

Bach, Peter H.; Gregg, Neill J.

doi:10.1016/b978-0-12-364930-0.50005-1

Cited by 18 publications

(13 citation statements)

References 143 publications

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“…The renal functional changes following BEA closely parallel those reported for human analgesic abusers (13,16,17) and include loss of urinary concentrating ability (15,(192)(193)(194)(195)(196)(197)(198)(199)225), electrolyte wasting (192)(193)(194)(195)(196)(197)(198)(199)225), and severe cortical degeneration, which is a late but consistent secondary consequence of the medullary lesion (13,(192)(193)(194)(195)(196)(197)(198)(199)225). …”

Section: Firnctional Changes Carrsed By Beamentioning

confidence: 51%

“…The earliest change in the papilla was marked pyknosis of the renal medullary interstitial cells at a time when other cells were normal or near normal. Other investigations using lower doses of BEA and shorter time intervals (15,16,19,82,85) were unable to show any role for microvasculature injury in the pathogenesis of RPN. The only microvascular effects seen were platelet adhesion well after interstitial necrosis had occurred.…”

Section: Target-selective Injirry To the Renal Mediillary Interstitiamentioning

confidence: 99%

“…Papillary necrosis is associated with the progressive deposition of neutral lipid material in the capillaries, collecting duct, and covering epithelial cells. Lipid staining extends into the outer medulla that would appear as normal by routine staining (15,16,19). The lipid staining of epithelial and microvascular cells for neutral lipid appears to be pathognomonic for RPN, as it also occurs in the pig (83), baboon, and marmoset following BEA (Bach and Gregg, unpublished observations) and aspirin-induced (160) RPN.…”

Section: The Pathologic Corrrse Of Bea-induced Rpnmentioning

confidence: 99%

“…The morphological and histochemical changes (8,15,19,82,85) support distinct pathological changes following a papillotoxic insult. The primary morphological changes occur in the interstitial cells in acute (13,16,82,85), subchronic (92), and chronic (13) papillary necrosis. This is followed by damage to the endothelial cells and loops of Henle, and then collecting duct changes (Fig.…”

Section: Clironic Degenerative Cliaitgesmentioning

confidence: 99%

“…MECHANIShl OF RPN CAUSED BY ANALGESICS AND NSAIDs Data derived from the BEA and other models of RPN together with what is known about the chronically induced lesion in animals and man have been synthesized into what is now regarded as the "textbook explanation" for RPN (9,10,13,16,18). The morphological and histochemical changes (8,15,19,82,85) support distinct pathological changes following a papillotoxic insult.…”

Section: Clironic Degenerative Cliaitgesmentioning

confidence: 99%

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Renal Papillary Necrosis—40 Years On

Bach

Thanh

1998

Toxicol Pathol

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Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are well recognized as a major class of therapeutic agent that causes renal papillary necrosis (RPN). Over the last decade a broad spectrum of other therapeutic agents and many chemicals have also been rcportcd that have the potential to cause this lesion in animals and man. There is consensus that RPN is the primary lesion that can progress to cortical degeneration; and it is only at this stage that the lesion is easily diagnoscd. In the absence of sensitive and selective noninvasive biomarkers of RPN there is still no clear indication of which compound, under what circumstances, has the greatest potential to cause this lesion in man. Attempts to mimic RPN in rodents using analgesics and NSAIDs have not provided robust models of the lesion. Thus, much of the research has concentrated on those compounds that cause an acute or subacute RPN as the basis by which to study the pathogenesis of the lesion. Based on the mechanistic understanding gleaned from these model compounds it has been possible to transpose an understanding of the underlying processes to the analgesics and NSAIDs. The mechanism of RPN is still controversial. There are data that support microvascular changes and local ischemic injury as the underlying cause. Alternatively, several model papillotoxins, some analgesics, and NSAIDs target selectively for the medullary interstitial cells, which is the earliest reported aberration, after which there are a series of degenerative processes affecting other renal cell types. Many papillotoxins have the potential to undergo prostaglandin hydroperoxidase-mediated metabolic activation, specifically in the renal medullary interstitial cells. These reactive intermediates, in the presence of large quantities of polyunsaturated lipid droplets, result in localized and selective injury of the medullary interstitial cells. These highly differentiated cells do not repair, and it is generally accepted that continuing insult to these cells will result in their progressive erosion. The loss of these cells is thought to be central to the degenerative cascade that affects the cortex. There is still a need to understand better the primary mechanism and the secondary consequences of RPN so that the risk of chemical agents in use and novel molecules can be fully assessed.

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Section: Firnctional Changes Carrsed By Beamentioning

confidence: 51%

Section: Target-selective Injirry To the Renal Mediillary Interstitiamentioning

confidence: 99%

Section: The Pathologic Corrrse Of Bea-induced Rpnmentioning

confidence: 99%

Section: Clironic Degenerative Cliaitgesmentioning

confidence: 99%

Section: Clironic Degenerative Cliaitgesmentioning

confidence: 99%

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Renal Papillary Necrosis—40 Years On

Bach

Thanh

1998

Toxicol Pathol

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Determination of urinary glutathione S-transferase and lactate dehydrogenase for differentiation between proximal and distal nephron damage

et al. 1990

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Cytosolic glutathione S-transferase (GST) activity is confined to the proximal convoluted and straight tubules. Damage to these parts of the nephron should result in leakage of GST into the urinary space. Lactate dehydrogenase (LDH), in contrast, is more generally distributed along the nephron. Measurement of both enzyme activities could therefore be expected to discriminate between different localizations of nephrotoxicity. To test this hypothesis, we determined both enzyme activities in 24 h urine samples from 10-12 female Sprague-Dawley rats, each treated with single i.p. injections of puromycin aminonucleoside (PAN, 130 mg/kg), Na2 CrO4 10, 20, 30 mg/kg), mercuric chloride (HgCl2, 0.5, 0.75, 1.0 mg/kg), folic acid (125, 350, 375 mg/kg), ethyleneimine (0.5, 2.0, 5.0 microliters/kg). Bovine serum albumin (BSA) was injected by the same method, twice daily on 3 consecutive days (2.5, 7.14 g/kg). The results obtained indicate a characteristic dose- and time-dependent pattern of excreted enzyme activities for each of the tested compounds. In both models with primarily glomerular damage, proximal tubular parts were also affected, as could be demonstrated by increased urinary GST and histopathological changes. Damage, mainly to the S1/S2 segment by 20 or 30 mg Na2 CrO4/kg, resulted in moderate to marked increases in LDH excretion, while GST was only moderately elevated at 30 mg/kg. Extreme increases in GST and LDH output were measured after predominant S3 segment damage after 0.75 and 1.0 mg HgCl2/kg. The distally active compounds, folic acid and ethyleneimine, did not increase GST excretion at lower doses. At the high doses, a small rise in GST excretion indicated some, probably secondary, proximal tubular involvement, which correlated with the histopathological findings in these groups.

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Urinary antigens as markers of papillary toxicity.

Hildebrand

Rinke

Schlüter

et al. 1999

Archives of Toxicology

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We have previously reported the preparation of monoclonal antibodies specific for antigens localized in the rat renal papilla. Three of the monoclonal antibodies reacting with antigens localized in papillary and cortical collecting duct epithelia were selected for the development of enzyme-linked immunosorbent assay (ELISA)-type assays. The papillary antigens ('PapA') determined in these tests were designated PapAl (applying the monoclonal antibody PapX 5C10), PapA2 (applying the monoclonal antibody PapX 12F6), and PapA3 (applying the monoclonal antibody PapXI 3C7). Using these assays antigen excretion was determined in the urine of rats. Depending on the test compound used. the application route, and the dose, the observed antigen release patterns differed. Whereas after a single intraperitoneal application of 2-bromoethanamine or of propyleneimine an increased release of PapA1 but not of the two other antigens was observed oral application of bromoethanamine had minor effects. In contrast, both a single intraperitoneal application or repeated oral applications of indomethacin resulted in an increased release of all the three antigens. Daily application of ipsapirone in the diet or in drinking water resulted in significantly elevated urinary release of PapAl which increased incrementally for the duration of the application. Release of PapA2 and PapA3 was not affected and remained in the normal range. These results show that with the tests developed changes in the rat renal papilla caused by xenobiotics can be detected early by urinary analysis and monitored during follow-up studies. Moreover. the different antigen release patterns obtained after application of the different compounds suggest a possible differing mode of action.

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Experimentally Induced Renal Papillary Necrosis and Upper Urothelial Carcinoma

Cited by 18 publications

References 143 publications

Renal Papillary Necrosis—40 Years On

Renal Papillary Necrosis—40 Years On

Determination of urinary glutathione S-transferase and lactate dehydrogenase for differentiation between proximal and distal nephron damage

Urinary antigens as markers of papillary toxicity.

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