Caffeine potentiation of mefenamic acid‐induced lesions in the rat renal medulla

Hewitson, Tim D.; Crespigny, Paul J. Champion de; Kincaid‐Smith, Priscilla

doi:10.1002/path.1711650411

Cited by 8 publications

(5 citation statements)

References 14 publications

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“…Mefenamic acid is a most potent papillotoxin in rats (36,98) and the Syrian hamster (34) where indomethacin also caused RPN (34). Mesalazine causes RPN in several species (22, 169).…”

Section: Other Tlierapeiitic Agentsmentioning

confidence: 99%

“…There are reports (36,98) that the coformulation of mefenamic acid and caffeine exacerbate RPN, but mefenamic acid is the most papillotoxic of the NSAIDs (34) and the observation has apparently not been repeated.…”

Section: Nsaids Arid Caffeinementioning

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%

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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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“…Mefenamic acid is a most potent papillotoxin in rats (36,98) and the Syrian hamster (34) where indomethacin also caused RPN (34). Mesalazine causes RPN in several species (22, 169).…”

Section: Other Tlierapeiitic Agentsmentioning

confidence: 99%

Section: Nsaids Arid Caffeinementioning

confidence: 99%

Section: Conclusion and Future Research Directionsmentioning

confidence: 99%

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Renal Papillary Necrosis—40 Years On

Bach

Thanh

1998

Toxicol Pathol

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“…London. UK) [17]. Serial sec tions mounted on uncoated nickel grids were oxidized with 3% hydrogen peroxide for 10 min prior to immunolabeling.…”

Section: Electron Microscopymentioning

confidence: 99%

Interstitial Myofibroblasts in IgA Glomerulonephritis

Hewitson

Becker

1995

Am J Nephrol

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We examined renal biopsy specimens from patients with mesangial IgA glomerulonephritis (n = 25; plasma creatinine 0.05-0.30 mmol/l) to ascertain whether the myofibroblast has a role in progressive renal interstitial fibrosis. Myofibroblasts were identified by morphology and alpha smooth muscle actin (α-SMA) immunostaining at the light and electron microscope level. Results were related to staining for interstitial leukocytes and collagen III. A control group consisted of 6 normal renal transplant donors from whom biopsy specimens were taken at the time of vascular anastomosis. The fractional volume of interstitial α-SMA staining was greater in patients with mesangial IgA glomerulonephritis than in the control group (17.2 vs. 1.3%; p < 0.001). α-SMA staining was increased in areas of interstitial fibrosis with prominent periglomerular and peritubular distribution. Ultrastructural studies established that α-SMA staining in the renal interstitium was intracellular, cytoplasmic, and confined to myofibroblast-like cells and processes. The α-SMA expression correlated with fractional volume of tubular atrophy/dilation (r = 0.79, p < 0.001), interstitial connective tissue (r = 0.66, p < 0.001), leucocytes (r = 0.72, p < 0.005), and collagen III (r = 0.71, p < 0.001). Staining correlated with renal function at the time of biopsy (r = 0.64, p < 0.005) and after 2 years of follow-up (r = 0.77, p < 0.01). In conclusion, cells with a myofibroblast-like phenotype have a significant role in the progression of tubulointerstitial injury.

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“…Side effects of NSAIDs include nephrotoxicity caused by inhibition of renal PG biosynthesis, which interferes with the function of PGs as important physiological modulators of renal hemodynamics and salt and water homeostasis [24]. In fact, there are results indicating that caffeine can, especially in the renal medulla, enhance nephrotoxic effects when co-administered with NSAID [25][26][27][28][29][30]. This is of particular interest, since in the clinical setting of reduced renal perfusion (given in various forms of dehydration, cardiorenal disease and the aging kidney) increased renal PG production plays a significant cytoprotective role in the activation of compensatory renal hemodynamics [31].…”

Section: Introductionmentioning

confidence: 99%

Ketoprofen-Induced Cyclooxygenase Inhibition in Renal Medulla and Platelets of Rats Treated with Caffeine

Sommerauer

Ateş²,

Gühring³

et al. 2001

Pharmacology

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It has been suggested that caffeine can augment analgesic activity and aggravate side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of the present study was to investigate a possible interaction between ketoprofen and caffeine on prostaglandin (PG) biosynthesis and cyclooxygenase (COX) mRNA expression in the rat renal medulla ex vivo. Treatment of rats with ketoprofen (60 min before) resulted in a dose-dependent (estimated ID₅₀ 0.3 mg/kg p.o.) reduction of PGE₂ biosynthesis in renal medulla ex vivo. Ketoprofen (0.3 mg/kg)-induced inhibition of PGE₂ biosynthesis was stable between 30 and 180 min and still detectable 300 min after drug administration. Caffeine (10 mg/kg) did not cause a detectable effect on its own, nor did it significantly affect ketoprofen-induced inhibition of renal medullary PGE₂ biosynthesis. Similar results were obtained with repeated daily drug administration for 1 week: there was no significant effect of caffeine on ketoprofen-induced inhibition of renal medullary PGE₂ biosynthesis. The absence of significant caffeine effects on ketoprofen-induced inhibition of renal medullary PGE₂ biosynthesis was paralleled by experiments showing no significant effect of caffeine on ketoprofen-induced inhibition of platelet thromboxane (TX)B₂ biosynthesis. Additional experiments showed increased COX-2 mRNA expression in the renal medulla 60 min after ketoprofen administration, that was not significantly influenced by concomitant caffeine treatment. Treatment of rats with ketoprofen for 1 week had no significant effects on COX-2 mRNA expression. The present results show that ketoprofen caused inhibition of PGE₂ biosynthesis in the rat renal medulla ex vivo with a potency similar to that reported for in vivo models suggesting that the ex vivo approach is a valid model to test a possible interference of caffeine with ketoprofen-induced COX inhibition. The absence of detectable effects of caffeine on time course or magnitude of ketoprofen-induced suppression of PGE₂ biosynthesis in this model indicates, therefore, that possible adverse actions of co-administered caffeine on renal function are not related to interference with renal COX inhibition.

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Caffeine potentiation of mefenamic acid‐induced lesions in the rat renal medulla

Cited by 8 publications

References 14 publications

Renal Papillary Necrosis—40 Years On

Renal Papillary Necrosis—40 Years On

Interstitial Myofibroblasts in IgA Glomerulonephritis

Ketoprofen-Induced Cyclooxygenase Inhibition in Renal Medulla and Platelets of Rats Treated with Caffeine

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