Toxicologic Pathology http://tpx.sagepub.com/ Renal Papillary Necrosis−−40 Years On Peter H. Bach and Nguyen Thi Kim Thanh Toxicol Pathol 1998 26: 73 DOI: 10.1177/019262339802600110 The online version of this article can be found at: http://tpx.sagepub.com/content/26/1/73 Published by: http://www.sagepublications.com On behalf of: Society of Toxicologic Pathology Additional services and information for Toxicologic Pathology can be found at: Email Alerts: http://tpx.sagepub.com/cgi/alerts Subscriptions: http://tpx.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://tpx.sagepub.com/content/26/1/73.refs.html >> Version of Record - Jan 1, 1998 What is This? Downloaded from tpx.sagepub.com by guest on December 5, 2011 TOXICOLOGICPATHOLOGY, vol. 26, no. 1, pp. 73-91, 1998 Copyright 0 1998 by the Society of Toxicologic Pathologists Renal Papillary Necrosis40 Years On* F'EER H. BACHAND NGUYENTHI KIM THANH BioMedical Research Centre, Division of Biomedical Sciences, Slieffield Hallam University, Shefield SI I WB, England, United Kitigdoiii ' ABSTRACT 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. Kepr*ords. Analgesic ncphropathy; renal papillary necrosis; nonsteroidal anti-inflammatory drugs INTRODUCHON condition tends to be low and does not adequately reflect Renal papillary necrosis (RF") was first described as a the regional levels of renal disease that may occur. RPN common condition in human diabetic patients, but there in humans develops as a result of chronic consumption or was a progressive realization that RPN has other causes long-term abuse of single and mixed analgesics. The lesion (13), especially as a consequence of analgesic abuse, as also occurs in adults and children who have been pre- many thousands of patients took excessive quantities of scribed NSAIDs, and single analgesics, and it has also mixed analgesics in the 1960-1980s. Initially phenacetin been implicated with a whole spectrum (Table I) of ther- was assumed to be the nephrotoxic common denominator apeutically used NSAIDs and some other drugs. (50, 51, 150, 151), and this compound was progressively banned from over-the-counter (OTC) products, but it is ANALGESICNEPHROPATHY now appreciated that many analgesics and nonsteroidal The progression of renal failure in analgesic-associated anti-inflammatory drugs (NSAIDs) have papillotoxic po- nephropathy has been well documented (13, 32, 47, 78, tential if used in excessive quantities. It is also apparent 96, 142, 170, 171, 203, 204). Analgesic nephropathy is that the problem of excessive use of analgesics continues a degenerative condition leading to renal failure follow- today (13, 46, 56, 87, 96, 171, 185, 200, 201) and this ing long-term analgesic abuse. Pyelonephritis is a hall- healthcare cost is probably preventable (46, 47, 59). An- mark, as a result of an RPN. There are few clinical symp- algesic abuse is a frequent cause of analgesic nephropathy toms associated with the early development of analgesic- that leads to end-stage renal disease and upper urothelial associated RF" (13, 32, 78, 171, 203, 204). The pro- carcinoma throughout Europe (46, 47, 58-64, 179, 180, gression of renal damage is insidious and renal function 203, 204), Australia (149-150, 171, 216), and other parts may be severely compromised before the condition be- of the world (206-210). Interestingly, there are apparently comes obvious (13, 32, 78, 171, 203, 204). only few cases in the USA (21, 29, 56, 96, 184, 200, 201, 226). The condition occurs in national or local clusters, Early symptoms include headaches, upper gastrointes- for reasons that are not clear, but may relate to social cus- tinal disease such as peptic ulceration of stomach and toms, availability of specific medications, or other as yet duodenum, dyspepsia and anemia as a result of gastro- poorly identified factors. Thus, national incidence for the intestinal tract bleeding, hemolysis, and iron deficiency. These are often seen in patients who have emotional * Address all correspondence to: Dr. Peter H. Bach, BioMedical Re- dependence, anxiety, introversion, and neurosis. search Centre, Division of Biomedical Sciences, Sheffield Hallam Uni- Intermediate symptoms include urinary tract disease versity, Pond Street, Sheffield S1 IWB, England, United Kingdom. such as nocturia, dysuria, bacteriuria, sterile pyuria, 73 0192-6233/98$3.00+$0.00 Downloaded from tpx.sagepub.com by guest on December 5, 2011 74 BACHANDTHANH TOXICOLOGICPATHOLOGY TABLEI.-Chemicals and therapeutic agents reprted to cause papillary 3) The late symptoms such as hypertension, cardiovas- necrosis in animals or linked to case reports of papillary necrosis in man. cular disease, peripheral vascular disease, renal calculi and bladder stones and decreased glomerular filtration Chemical or rherapeutic agent References rate, increased blood urea nitrogen, renal tubular aci- Acetaminophen 210 Antipyrine 111 dosis, and carcinoma of upper renal tract are common, Aspirin 30,31,39,4-2, 113 but all these conditions could also have other causes. Benoxaprofen 2 Even radiological examination may not identify pap- 2,2-Bis(bromomethyl)- .3-propanediol I 65 iti 2-Bromoethanamine 13 illary necrosis (if the necrosed papillae remains 3-Bromopropanamine I83 situ), and even when loss of the papillae is obvious Butylated hydroxyanisole 93 (in the presence or absence of other degenerative renal Cacodylic acid 165 2-Chloro-N,N-dimethylethanamine 183 changes) the underlying cause still has to be estab- 2-Chloroethanamine 183 lished. Recently, the combined use of computerized 1 -(2-Chloroethyl)-3-(trans-4- 127 methylcyclohexy1)- 1-nitrosourea tomography and ultrasound ensured a very high de- Cyclophosphamide 175 gree of positive diagnosis (28, 58, 63). The use of Dapsone 37 these diagnostic criteria has resulted in the increased Dibromoneopentyl glycol 65 Diclofenac sodium 205 incidence of previously undiagnosed RPN and anal- Dimethanesulfonate 176 gesic nephropathy (64) in populations where pyelo- Dimethylarsinic acid 165 nephritis had previously been recognized but the un- Diphenylaminc 135-137 Ethoxyquin 91, 146, 147 derlying cause not identified. Ethyleneirnine 13 Fenoprofen 109 Analgesic nephropathy is also reported in patients who Flurbiprofen 167 have taken no phenacetin but who have abused acetyl- Formaldehyde 222 Ibuprofen 212 salicylic acid, acetaminophen, and codeine (60, 174), and Indometacin 2 sales figures of analgesics are presented that suggest sim- Indomethacin 33. 153 Ipsapirone 188 ilarities between the occurrence of the disease and the Ketoprofen 2 sale of the most often consumed coformulated products hlefenamic acid 33.36.98.209 (60, 174). These are thought to warrant legislative mea- hiesalazine 22, 169,221 surements to control analgesic consumption (62). These hiixed analgesics 47.50-52.61, 149-151, data are supported by the changing incidence of analgesic 170-172, 179, 180, 184 nephropathy in Australia where phenacetin was with- I-Naphthol 181 Naproxen 2.35 drawn and the potential to abuse coformulated mixed an- Nefiracetam 117,218 algesics was limited (216). The data are controversial o-Ormaplatin 126 Pentazocine and aspirin I62 from