Summary
Despite the potential tolerability advantage of enteric‐coated mycophenolate sodium (EC‐MPS), no prospective, randomized trial has evaluated whether conversion from mycophenolate mofetil (MMF) to EC‐MPS permits mycophenolic acid dose to be increased or gastrointestinal side‐effects to be ameliorated. In a randomized, multicenter, open‐label trial, kidney transplant recipients experiencing gastrointestinal side‐effects either remained on MMF or switched to an equimolar dose of EC‐MPS, adjusted 2 weeks subsequently to target the highest tolerated dose up to 1440 mg/day (EC‐MPS) or 2000 mg/day (MMF). Patients were followed up to 12 weeks postrandomization. One hundred and thirty‐four patients were randomized. The primary efficacy endpoint, the proportion of patients receiving a higher mycophenolic acid (MPA) dose at week 12 than at randomization, was significantly greater in the EC‐MPS arm (32/68, 47.1%) than the MMF arm (10/61, 16.4%; P < 0.001). At the final visit, 50.0% (34/68) of EC‐MPS patients were receiving the maximum recommended dose versus 26.2% (16/61) of MMF patients (P = 0.007). Kidney transplant patients receiving reduced‐dose MMF because of gastrointestinal side‐effects can tolerate a significant increase in MPA dose after conversion to EC‐MPS. Patient‐reported gastrointestinal outcomes with higher doses of EC‐MPS remained at least as good as in MMF‐treated controls.
The mediators of cyclosporine (CsA) nephrotoxicity remain ill defined. In this study, we describe evidence of increased amounts of transforming growth factor-beta (TGF-beta) in the kidneys of adult male Wistar rats treated with CsA (5 to 25 mg/kg/day) for four weeks. Localization of TGF-beta was undertaken immunocytochemically at both light and electron microscope levels and Northern blot analysis was applied to detect changes in transcription of TGF-beta. In control rats, weak to moderate immunostaining for TGF-beta was observed, in the juxtaglomerular arterioles. CsA treatment resulted in a dose-dependent increase in the number of stained afferent and interlobular arterioles and in the intensity of staining. The number of stained afferent arterioles increased from a control value of 0.21 +/- 0.08/mm2 cortex to 0.84 +/- 0.15/mm2 cortex, P < 0.01, and to 1.12 +/- 0.10/mm2 cortex, P < 0.01, in rats treated with CsA 12.5 mg/kg/day and 25 mg/kg/day, respectively. The number of interlobular arterioles stained for TGF-beta increased from a control value of 0.07 +/- 0.05/mm2 to 0.31 +/- 0.02/mm2, P < 0.05, and 0.39 +/- 0.07/mm2, P < 0.01, in rats treated with CsA, 12.5 mg/kg/day and 25 mg/kg/day, respectively. At the electron microscope level, TGF-beta was localized exclusively within the granular cells of the juxtaglomerular arterioles. Northern blot analysis suggested that this enhanced staining is due to increased transcription of TGF-beta 1. We have therefore observed an association between TGF-beta and CsA-induced nephrotoxicity. While this does not establish a causal link, it leads us to postulate that TGF-beta, alone or in combination with other growth factors, may play a role in the pathogenesis of CsA induced nephrotoxicity.
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