Cardiovascular disease is the leading cause of morbidity and mortality in hemodialysis patients and it has proven refractory to therapies, such as lipid-lowering agents, that lessen the severity of the disease in the normal population. Oxidant stress has been identified as a non-traditional risk factor for cardiovascular disease in hemodialysis patients. Oxidant stress in hemodialysis patients arises from an increase in production of reactive oxygen species and a consequent depletion of anti-oxidant defenses. One result of this imbalance is depletion of plasma protein thiols and low molecular weight thiols, such as glutathione. Plasma protein thiols form the major extracellular anti-oxidant and their depletion leads to an increase in oxidized lipids and proteins that play a role in cardiovascular disease. Depletion of glutathione activates redox-regulated signaling pathways in endothelial and vascular smooth muscle cells, which promote atherogenic plaque formation. Our hypothesis is that repletion of thiol stores will correct the redox state, thereby reducing lipid and protein oxidation and turning off the pro-atherogenic signals. N-acetylcysteine (NAC) is an aminothiol, which acts as a source of cysteine for glutathione synthesis. In addition to glutathione formation, NAC directly scavenges reactive oxygen species and hypochlorous acid. NAC has been used as a source of thiols in patients with normal renal function; however, there is little information on the disposition of NAC in hemodialysis patients. This research program addresses this gap in knowledge. The specific objectives are: 1. To determine the pharmacokinetics and pharmacodynamics of NAC in hemodialysis patients; 2. To examine the ability of NAC to provide a sustained reduction in protein and lipid oxidation in hemodialysis patients; and 3. To examine the safety profile and tolerability of NAC in hemodialysis patients. The pharmacokinetic and pharmacodynamic studies to be performed in the first year of the project will establish the optimal dose for thiol repletion in hemodialysis patients of an oral sustained release form of NAC. In the second year of the project, this optimal dose will be used in a pilot study to investigate the ability and practicability of NAC to provide a sustained increase in reduced thiols and a concomitant reduction in protein and lipid oxidation in hemodialysis patients. The information gained from these studies will allow the design of a large clinical trial in hemodialysis patients to examine the effectiveness of N-acetylcysteine in reducing oxidant stress and cardiovascular disease, the leading cause of death in these patients.
| Nolin, Thomas D; Ouseph, Rosemary; Himmelfarb, Jonathan et al. (2010) Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease. Clin J Am Soc Nephrol 5:1588-94 |
