Chronic Renal Disease and Papillary Necrosis Associated With the Long-Term Use of Nonsteroidal Anti-inflammatory Drugs as the Sole or Predominant Analgesic

Segasothy, M; Samad, Sakijan Abdul; Zulfigar, Annuar; Bennett, William M.

doi:10.1016/s0272-6386(12)80155-7

Cited by 89 publications

(26 citation statements)

References 27 publications

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“…In addition, phenylbutazone, an NSAID, has been shown to induce adenomas and RCC in treated rats (Kari et al, 1995). In humans, acute tubular necrosis, papillary necrosis and interstitial nephritis have been histologically or radiographically confirmed in patients consuming therapeutic doses of non-aspirin NSAID (Adams et al, 1986;Segasothy et al, 1994). Due to the novelty of this class of compounds, no prior studies have investigated their carcinogenic potential in humans.…”

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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“…However, suppression of cyclo-oxygenase is associated with significant toxicity in the gastrointestinal tract (20) and, less frequently, in the kidney (21 ). This toxicity limits the utility of aspirin for long-term use as an anti-thrombotic agent.…”

Section: Discussionmentioning

confidence: 99%

Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative.

Wallace

McKnight²,

Soldato³

et al. 1995

J. Clin. Invest.

145

127

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Effects of a nitroxybutylester derivative of aspirin (NCX 4215) on platelet aggregation and prostanoid synthesis were compared to the effects of aspirin. NCX 4215 was approximately seven times more potent than aspirin as an inhibitor of thrombin-induced human platelet aggregation in vitro, but did not inhibit platelet thromboxane synthesis or gastric prostaglandin synthesis. NCX 4215 released nitric oxide when incubated in the presence of platelets and increased platelet levels of cGMP within 10 min of exposure, while aspirin did not. The anti-aggregatory effects of NCX 4215 in vitro were significantly attenuated by 10 juM hemoglobin.In ex vivo studies of ADP-or collagen-or thrombin-induced rat platelet aggregation, aspirin and NCX 4215 had comparable inhibitory effects 3 h after administration. Aspirin (10-120 mg/kg) caused extensive hemorrhagic erosion formation in the stomach of the rat within 3 h of oral administration, while NCX 4215 did not produce significant damage at doses of up to 300 mg/kg, nor when given daily for two weeks at 166 mg/kg. NCX 4215 did not alter systemic arterial blood pressure when administered intravenously to the rat. These studies demonstrate that NCX 4215 has comparable or enhanced anti-thrombotic activity to that of aspirin, but does not cause gastric damage or alter systemic blood pressure. The anti-thrombotic actions of NCX 4215 are, at least in part, due to generation of nitric oxide. (J. Clin. Invest. 1995. 96:2711-2718

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“…Long-term use of COX-inhibiting NSAIDs has been associated with papillary necrosis and progressive renal structural and functional deterioration (10,50). NSAID-induced renal damage is more likely to occur in the setting of dehydration, suggesting a critical dependence of renal function upon COX metabolism in this setting (51).…”

Section: Figure 10mentioning

confidence: 99%

Dehydration activates an NF-κB–driven, COX2-dependent survival mechanism in renal medullary interstitial cells

Hao¹,

Yull²,

Blackwell³

et al. 2000

J. Clin. Invest.

137

157

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Renal prostaglandin (PG) synthesis is mediated by cyclooxygenase-1 and -2 (COX1 and COX2). After dehydration, the maintenance of normal renal function becomes particularly dependent upon PG synthesis. The present studies were designed to examine the potential link between medullary COX1 and COX2 expression in hypertonic stress. In response to water deprivation, COX2, but not COX1, mRNA levels increase significantly in the renal medulla, specifically in renal medullary interstitial cells (RMICs). Water deprivation also increases renal NF-κB-driven reporter expression in transgenic mice. NF-κB activity and COX2 expression could be induced in cultured RMICs with hypertonic sodium chloride and mannitol, but not urea. RMIC COX2 expression was also induced by driving NF-κB activation with a constitutively active IκB kinase α (IKKα). Conversely, introduction of a dominant-negative IκB mutant reduced COX2 expression after hypertonicity or IKKα induction. RMICs failed to survive hypertonicity when COX2 was downregulated using a COX2-selective antisense or blocked with the selective nonsteroidal anti-inflammatory drug (NSAID) SC58236, reagents that did not affect cell survival in isotonic media. In rabbits treated with SC58236, water deprivation induced apoptosis of medullary interstitial cells in the renal papilla. These results demonstrate that water deprivation and hypertonicity activate NF-κB. The consequent increase in COX2 expression favors RMIC survival in hypertonic conditions. Inhibition of RMIC COX2 could contribute to NSAID-induced papillary injury.

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Chronic Renal Disease and Papillary Necrosis Associated With the Long-Term Use of Nonsteroidal Anti-inflammatory Drugs as the Sole or Predominant Analgesic

Cited by 89 publications

References 27 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

Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative.

Dehydration activates an NF-κB–driven, COX2-dependent survival mechanism in renal medullary interstitial cells

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