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The effect of caffeine given in combination with mefenamic acid on the renal medulla was examined. Sprague-Dawley rats were divided into four groups and gavage fed either vehicle suspension (control), mefenamic acid, mefenamic acid+caffeine or caffeine only for 4 months. Renal tissue taken from the corticomedullary junction was processed for electron microscopy. Ultrathin sections were cut after identification of vasa rectae on survey sections. On subsequent morphometric analysis, percentage interstitial tissue was calculated from the total area of vasa recta less the non-interstitial tissue. The median percentage of interstitial tissue in the mefenamic acid and caffeine group was 41 (range 33-50; n = 15) compared with 34 (20-48; n = 20) in mefenamic acid (P less than 0.01), 29 (15-42; n = 15) in caffeine only (P less than 0.001) and 32 (20-46; n = 18) in vehicle-treated animals (P less than 0.001). There were no significant differences between mefenamic acid alone and vehicle or caffeine-only groups or between caffeine-only and vehicle-treated controls. This suggests that caffeine potentiates the effect of the non-steroidal anti-inflammatory drug, mefenamic acid, on the rat renal medulla, resulting in a quantitative increase in the interstitial tissue between adjacent afferent and efferent vasa recta.

The effect of caffeine given in combination with mefenamic acid on the renal papilla was studied. Sprague-Dawley rats were divided into four groups and gavage fed either control suspension, mefenamic acid, mefenamic acid and caffeine or caffeine alone for 4 months. Semiquantitative urinalysis was performed at 3 months and showed increased haematuria in the mefenamic acid and caffeine group. There were no significant differences in serum creatinine at sacrifice. Renal histology revealed more advanced papillary necrosis in rats gavage fed mefenamic acid and caffeine compared with all other groups (p less than 0.0001). Rats fed mefenamic acid alone showed more damage than control and caffeine-fed groups (p less than 0.0001, p less than 0.0002, respectively). This suggests that caffeine potentiates the nephrotoxicity of the non-steroidal anti-inflammatory drug, mefenamic acid, on the rat renal papilla. The mechanism of this potentiation by caffeine is yet to be defined.