P9 N-actylcysteine fails to impact on plasma antioxidant status in a placebo controlled crossover study in healthy volunteers and patients with chronic kidney disease: implications for its value in preventing contrast-induced nephropathy

Introduction N-acetyl-l-cysteine (NAC) has been proposed as a prophylactic for the prevention of contrast induced nephropathy (CIN), a severe, undesirable consequence following angiography that accounts for ∼12% of all hospital-acquired acute renal injury. However, results from clinical trials of NAC in this setting to date have been inconclusive. The potential benefits of NAC in CIN have been attributed to its antioxidant potential, but NAC itself is a very weak antioxidant; intracellular conversion to the detoxifying agent, glutathione (GSH) is a pre-requisite for antioxidant benefits. 1 We tested the hypothesis that neither oral nor intravenous NAC conveys antioxidant activity in the plasma of healthy volunteers or patients with chronic renal disease (CKD), but that intracellular conversion to GSH was achieved in those patients depleted of intracellular GSH. Materials and methods 8 healthy volunteers and 8 patients with chronic renal failure were recruited to separate studies conducted in parallel. Each volunteer or patient was randomised to receive NAC (i.v.; 50 mg/kg/hr infusion for 2 hour, followed by 20 mg/kg/hr infusion for a further 5 hour), or NAC (oral; 1200 mg twice daily, commencing the day before the study visit) or placebo on each of three visits to the Clinical Research Facility. On study days, volunteers were infused with inulin and PAH to facilitate a number of renal function measures. 2 Plasma samples and matched buffy coat samples were obtained at intervals throughout the study for measurement of clinical parameters, together with plasma antioxidant capacity, plasma and intracellular thiol concentrations. Results Plasma NAC concentrations peaked at 187 µM (healthy volunteers) and 280 µM (CKD patients) when infused with NAC; the equivalent peak concentrations were 2 µM in both groups after oral administration of NAC. There was no equivalent increase in plasma antioxidant capacity in any of the treatment groups. Intracellular measures from buffy coat cells indicated that there was a significant increase in GSH in some healthy volunteers and some patients, but the effect was variable. In addition, there was no added benefit of increasing plasma NAC ∼10 fold through the i.v. delivery route over oral administration. Conclusion NAC is ineffective in altering antioxidant capacity in the plasma compartment, but can be converted to GSH in the intracellular environment in subjects with low intracellular GSH at baseline. Subsequent studies will determine the impact of contrast medium on both plasma and intracellular thiol concentrations and antioxidant capacity, as well as the extent of the capability of NAC to protect against the effects. Our results, however, call into question whether NAC could be effective in this setting and highlight the complexity of the concept of antioxidant capacity in vivo . This project has been funded by the EU’s INTERREG VA programme, managed by the Special EU Programmes Body (SEUPB). References Sandilands, E. A., S. Cameron, F. Paterson, S. Donaldson, L. Briody, J. Crowe, J. Donnelly, A. Thompson, N. R. Johnston, I. Mackenzie, N. Uren, J. Goddard, D. J. Webb, I. L. Megson, N. Bateman and M. Eddleston (2012). ‘Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol.’ BMC Clin Pharmacol 12 :3. Treweeke, A. T., T. J. Winterburn, I. Mackenzie, F. Barrett, C. Barr, G. F. Rushworth, I. Dransfield, S. M. MacRury and I. L. Megson (2012). ‘N-Acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial.’Diabetologia55(11):2920–2928.