The effect of N-phenylanthranilic acid-induced renal papillary necrosis on urinary acidification and renal electrolyte handling

Hardy, T. L.; Bach, Peter H.

doi:10.1016/0041-008x(84)90209-6

Cited by 25 publications

(8 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

Renal Papillary Necrosis—40 Years On

Bach

Thanh

1998

Toxicol Pathol

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Clironic Degenerative Cliaitgesmentioning

confidence: 99%

Renal Papillary Necrosis—40 Years On

Bach

Thanh

1998

Toxicol Pathol

Self Cite

View full text Add to dashboard Cite

show abstract

“…which induces RPN. Previous stud ies have shown that N-PAA caused a doserelated selective apex-limited RPN that af fected no more than 30% of the papilla and secondary cortical changes in Sprague-Dawley rats [4,5]. In this investigation Wistar rats showed a less severe and more diffuse lesion that increased from 7 to 15 days, but without secondary cortical changes.…”

Section: Discussionmentioning

confidence: 55%

“…The same sex rats and basic dosing protocol were used in this investigation, thus the absence of an apex-lim ited lesion supports the concept [2] that there are strain differences in the responses to papillotoxins. In common with previous investiga tions [5], we have shown that the earliest de generative change was located in the inter stitial cells, followed by changes in the endothelium, distal tubules, collecting ducts Results are expressed as mean value (n = 3) 1 SEM.…”

Section: Discussionmentioning

confidence: 65%

“…has very low ulcerogenic properties in the rat, and causes a dose-related selective apex-limited RPN when 0.1-5 mmol/kg p.o. is given to rodents over 14 days [4,5], There are some metabolic data on fenamate analogues [6][7][8][9][10][11], but none on the pharmacokinetics and tissue distribution of N-PAA. In this study we have documented plasma, urinary, biliary and faecal excretion rates and tissue distributions following single and multiple doses of 'H-N-PAA and provided preliminary data on metab olites as the basis for more-detailed mecha nistic investigations.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Kinetics of Papillotoxic Doses of <sup>3</sup>H-N-Phenylanthranilic Acid in Rats

Whittingham

Delacruz²,

Gregg³

et al. 1989

Kidney Blood Press Res

Self Cite

View full text Add to dashboard Cite

N-phenylanthranilic acid (N-PAA; 4mmol/kg/day p.o.) causes a diffuse renal papillary necrosis and a polyuria in 7 days. A single dose of ³H-N-PAA was widely distributed with second-order elimination kinetics, t_½ ± 50 h for stomach, heart, kidney, and bladder and t_½ ≧90 h for liver, spleen, muscle and lung. The estimated plasma t_½ = 10.2 h, and over 75% was excreted via urine in 36h and 13% via faeces in 72 h. In chronically cannulated animals 29% of N-PAA-derived material was in bile and 24% in urine at 36 h, which suggests enterohepatic circulation. Bile and urine contained several metabolites but no parent compound. Multiple doses for 8 and 16 days increased urinary N-PAA excretion to 90% in 36 h, but faecal contents decreased to 6-8% in 72 h and plasma t_1/2 to ≤ 7.5h.

show abstract

“…NSAID administration led to papillary necrosis in cats, including tigers (28), dogs, and horses (1 1). Experimentally, RPN has been induced in hamsters ( 5 ) and in rats of several strains using chemicals (e.g., BEA, ethyleneimine, propyleneimine), analgesics such as phenacetin and aspirin, or NSAIDs such as mefanamic acid, phenylbutazone, and indomethacin (13,19,23). However, it has also to be noted that there exist strain differences in the potency of development of the finding.…”

Section: Rerial Papillary Necrosismentioning

confidence: 99%

Serotonin (5-HT1_A-Receptor) Agonist-Induced Collecting Duct Vacuolation and Renal Papillary Necrosis in the Rat

et al. 1998

View full text Add to dashboard Cite

General anxiety in humans is treated with azaspirodecanedions, which act through a reduction of serotonin transmission. Ipsapirone also represents a serotonin (5-HT,,) receptor agonist and was under development as an anxiolytic drug. Histopathologic evaluation of animal experiments revealed cellular swelling andor vacuolation of renal papillary and medullary collecting duct (MCD) epithelium in rats but not in dogs or mice. The changes ensued already after 1 wk of dosing and were first localized in the inner MCDs. Longer treatment periods showed that these changes proceeded from proximal to distal, approaching the papillary collecting ducts. The changes were most likely the result of altered hemodynamics in the papillary tip. Swelling resulted in partial or total papillary necrosis in some cases. Furthermore, rats treated with ipsapirone showed a sharp and transient rise in urinary endothelin excretion. Concomitantly, urinary PGE, levels were elevated. In contrast, no elevated levels of endothelin were detected in urine samples of patients from a volunteer study, leading to the conclusion that the human kidney is not susceptible to the ipsapirone-induced alterations seen in the collecting ducts of rats.

show abstract

The effect of N-phenylanthranilic acid-induced renal papillary necrosis on urinary acidification and renal electrolyte handling

Cited by 25 publications

References 25 publications

Renal Papillary Necrosis—40 Years On

Renal Papillary Necrosis—40 Years On

The Kinetics of Papillotoxic Doses of <sup>3</sup>H-N-Phenylanthranilic Acid in Rats

Serotonin (5-HT1_A-Receptor) Agonist-Induced Collecting Duct Vacuolation and Renal Papillary Necrosis in the Rat

Contact Info

Product

Resources

About

The effect of N-phenylanthranilic acid-induced renal papillary necrosis on urinary acidification and renal electrolyte handling

Cited by 25 publications

References 25 publications

Renal Papillary Necrosis—40 Years On

Renal Papillary Necrosis—40 Years On

The Kinetics of Papillotoxic Doses of <sup>3</sup>H-N-Phenylanthranilic Acid in Rats

Serotonin (5-HT1A-Receptor) Agonist-Induced Collecting Duct Vacuolation and Renal Papillary Necrosis in the Rat

Contact Info

Product

Resources

About

Serotonin (5-HT1_A-Receptor) Agonist-Induced Collecting Duct Vacuolation and Renal Papillary Necrosis in the Rat