Regular Analgesic Intake and the Risk of End-Stage Renal Failure

Pommer, Wolfgang; Bronder, Elisabeth; Greiser, Eberhard; Helmert, Uwe; Jesdinsky, H. J.; Klimpel, Andreas; Börner, K.; Molzahn, M

doi:10.1159/000168002

Cited by 105 publications

(71 citation statements)

References 11 publications

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“…One such possible pathway is the shared ability of these drugs to induce renal damage leading to increased cell proliferation at the target site, a recognized mechanism of increased cancer risk in humans (Henderson et al, 1991). Aspirin, non-aspirin NSAID, phenacetin and acetaminophen used alone or in combination have been reported to be associated with chronic nephropathy, chronic renal failure or endstage renal disease in several case-control studies (Pommer et al, 1989;Sandler et al, 1989;Perneger et al, 1994). In vivo and in vitro rodent models have shown that aspirin, non-aspirin NSAID and acetaminophen undergo in situ metabolic activation in the kidney with subsequent covalent binding of the highly reactive metabolites to tissue/microsomal proteins, leading to tubular necrosis (Mitchell et al, 1977;McMurtry et al, 1978;Kyle and Kocsis, 1985;Emeigh Hart et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Regular use of analgesics is a risk factor for renal cell carcinoma

et al. 1999

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Summary Phenacetin-based analgesics have been linked to the development of renal pelvis cancer and renal cell carcinoma (RCC). The relationship between non-phenacetin types of analgesics and kidney cancer is less clear, although laboratory evidence suggests that these drugs possess carcinogenic potential. A population-based case-control study involving 1204 non-Asian RCC patients aged 25-74 and an equal number of sex-, age-and race-matched neighbourhood controls was conducted in Los Angeles, California, to investigate the relationship between sustained use of analgesics and risk of RCC according to major formulation categories. Detailed information on medical and medication histories, and other lifestyle factors was collected through in-person interviews. Regular use of analgesics was a significant risk factor for RCC in both men and women (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4-1.9 for both sexes combined). Risks were elevated across all four major classes of analgesics (aspirin, non-steroidal anti-inflammatory agents other than aspirin, acetaminophen and phenacetin). Within each class of analgesics, there was statistically significant increasing risk with increasing level of exposure. Although there was some minor variability by major class of formulation, in general individuals in the highest exposure categories exhibited approximately 2.5-fold increase in risk relative to non-or irregular users of analgesics. Subjects who took one regular-strength (i.e. 325 mg) aspirin a day or less for cardiovascular disease prevention were not at an increased risk of RCC (OR = 0.9, 95% CI = 0.6-1.4).

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Section: Discussionmentioning

confidence: 99%

Regular use of analgesics is a risk factor for renal cell carcinoma

et al. 1999

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“…Epidemiological studies easily identify the adverse effects of long-term analgesic use or abuse (50,51,61,179,180,200,201). The diffuse symptoms, the protracted period of time over which the lesion develops, and the fact that it is difficult to gauge how much of which analgesic or NSAIDs was consumed over what period of time has precluded more detailed analysis of the epidemiolo$ical databases.…”

Section: Analgesic Nephropathymentioning

confidence: 99%

“…There are no indications as to whether there are risk factors that could predispose individuals to the lesion. While the role of coformulation of caffeine has been presented as a risk factor (36,95,98,179,180), there is no clear experimental (67,68,133,140) or epidemiological (48,152,153) evidence that this is so.…”

Section: Conclusion and Future Research Directionsmentioning

confidence: 99%

“…It is also apparent that the problem of excessive use of analgesics continues today (13,46,56,87,96,171,185,200,201) and this healthcare cost is probably preventable (46,47,59). Analgesic abuse is a frequent cause of analgesic nephropathy that leads to end-stage renal disease and upper urothelial carcinoma throughout Europe (46, 47, 58-64, 179,180,203,204), Australia (149-150, 171, 216), and other parts of the world (206)(207)(208)(209)(210). Interestingly, there are apparently only few cases in the USA (21,29,56,96,184,200,201,226).…”

Section: Introduchonmentioning

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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“…The mixtures often also contained caffeine. Interestingly, in some epidemiological studies caffeine content was the best predictor for subsequent renal failure (5,6). The renal medullary toxicity of these particular analgesic drugs was apparently supported by animal studies, but interpretation of both the epidemiological and animal studies has been questioned (7)(8)(9).…”

mentioning

confidence: 99%

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

Rocha

Michea

Peters

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Antipyretic analgesics, taken in large doses over a prolonged period, cause a specific form of kidney disease, characterized by papillary necrosis and interstitial scarring. Epidemiological evidence incriminated mixtures of drugs including aspirin (ASA), phenacetin, and caffeine. The mechanism of toxicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the active metabolite of phenacetin), caffeine, and other related drugs individually and in combination on mouse inner medullary collecting duct cells (mIMCD3). The number of rapidly proliferating cells was reduced by Ϸ50% by 0.5 mM ASA, salicylic acid, or APAF. The drugs had less effect on confluent cells, which proliferate slowly. Thus, the slow in vivo turnover of IMCD cells could explain why clinical toxicity requires very high doses of these drugs over a very long period. Caffeine greatly potentiated the effect of acetaminophen, pointing to a potential danger of the mixture. Cyclooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell number except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic. APAF arrests most cells in late G1 and S and produces a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthesis of DNA and cause chromosomal aberrations due to inhibition of ribonucleotide reductase. Such effects of APAF might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations.acetaminophen ͉ aspirin ͉ salicylic acid ͉ indomethacin ͉ caffeine

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Regular Analgesic Intake and the Risk of End-Stage Renal Failure

Cited by 105 publications

References 11 publications

Regular use of analgesics is a risk factor for renal cell carcinoma

Regular use of analgesics is a risk factor for renal cell carcinoma

Renal Papillary Necrosis—40 Years On

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

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