TY - CONF
T1 - OP2 Prophylactic, N-Acetylcysteine unsuccessful in influencing plasma antioxidant capacity in a parallel-group randomized controlled trial of patients with chronic kidney disease stage III; implications for contrast induced nephropathy
AU - Raja, KI
AU - Hickson, K
AU - Treweeke, AT
AU - Rushworth, G
AU - Morrison, E
AU - Sandilands, E
AU - Cobley, JN
AU - McEneaney, D
AU - Eddleston, M
AU - Megson, IL
N1 - © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2020/4/5
Y1 - 2020/4/5
N2 - Introduction N‐acetyl‐L‐cysteine (NAC) has been proposed as a prophylactic for the prevention of contrast induced nephropathy (CIN), a common, undesirable complication following the administration of contrast media in patients with diabetes and chronic kidney disease (CKD).1 However, clinical trial results have failed to consistently demonstrate beneficial qualities of NAC in this setting. The proposed mechanism by which NAC has been proposed to be effective is via antioxidant activity, but NAC itself is not a powerful antioxidant. Intracellular conversion of NAC to glutathione (GSH) is essential for antioxidant effects (Tre‐weeke, Winterburn et al. 2012). We tested the hypotheses that whilst oral or intravenous NAC fails to increase antiox‐idant activity in the plasma of CKD stage III patients undergoing elective coronary angiography, intracellular conversion of NAC to GSH can occur in buffy coat cells deficient in GSH. Methods 66 patients with CKD stage III undergoing elective coronary angiography were recruited to a parallel‐group randomized controlled trial. Each patient was randomised to receive NAC (i.v.; 50 mg/kg/hr infusion for 2 h, followed by 20 mg/kg/hr infusion for a further 5 h), or NAC (oral; 1200 mg twice daily, commencing the day before contrast exposure) or placebo upon visiting the Clinical Research Facility. On the day of the study, patients were infused with PAH and inulin to regulate several renal function parameters and infused with contrast media prior to the coronary angiogra‐phy (Sandilands, Cameron et al. 2012). Plasma and paired buffy coat samples were collected at several time points during the trial in order to measure various clinical parameters, along with intracellular and plasma thiol concentrations and the plasma antioxidant capacity (oxygen radical antioxidant capacity; ORAC). Results Plasma NAC concentrations peaked at 348 mM following infusion of NAC of the 11 data sets included; the corresponding peak concentrations were 2.8 mM following oral NAC treatment from 7 data sets. No comparable increase in the plasma compartment ORAC antioxidant capacity was measured in any of the treatment groups. Equally, contrast infusion itself did not significantly reduce antioxidant capacity in plasma, even in the placebo group. Buffy coat measures showed that there was a significant increase of intracellular GSH some patients, although the effect was variable. Also, no clear additional benefit was witnessed by increasing plasma NAC >10‐fold through infusion of NAC over oral administration. Conclusion NAC fails to influence ORAC antioxidant capacity in the plasma compartment of CKD stage III patients receiving contrast media. Our results question the importance of oxidative stress in contrast‐induced nephropathy. Furthermore, the findings fail to demonstrate a direct antioxidant impact of NAC in the plasma compartment. Instead, we found that NAC can increase intracellular GSH in some deficient individuals, which might carry some benefits in terms of detoxification and question the antioxidant hypothesis related to contrast‐induced nephropathy and NAC.
AB - Introduction N‐acetyl‐L‐cysteine (NAC) has been proposed as a prophylactic for the prevention of contrast induced nephropathy (CIN), a common, undesirable complication following the administration of contrast media in patients with diabetes and chronic kidney disease (CKD).1 However, clinical trial results have failed to consistently demonstrate beneficial qualities of NAC in this setting. The proposed mechanism by which NAC has been proposed to be effective is via antioxidant activity, but NAC itself is not a powerful antioxidant. Intracellular conversion of NAC to glutathione (GSH) is essential for antioxidant effects (Tre‐weeke, Winterburn et al. 2012). We tested the hypotheses that whilst oral or intravenous NAC fails to increase antiox‐idant activity in the plasma of CKD stage III patients undergoing elective coronary angiography, intracellular conversion of NAC to GSH can occur in buffy coat cells deficient in GSH. Methods 66 patients with CKD stage III undergoing elective coronary angiography were recruited to a parallel‐group randomized controlled trial. Each patient was randomised to receive NAC (i.v.; 50 mg/kg/hr infusion for 2 h, followed by 20 mg/kg/hr infusion for a further 5 h), or NAC (oral; 1200 mg twice daily, commencing the day before contrast exposure) or placebo upon visiting the Clinical Research Facility. On the day of the study, patients were infused with PAH and inulin to regulate several renal function parameters and infused with contrast media prior to the coronary angiogra‐phy (Sandilands, Cameron et al. 2012). Plasma and paired buffy coat samples were collected at several time points during the trial in order to measure various clinical parameters, along with intracellular and plasma thiol concentrations and the plasma antioxidant capacity (oxygen radical antioxidant capacity; ORAC). Results Plasma NAC concentrations peaked at 348 mM following infusion of NAC of the 11 data sets included; the corresponding peak concentrations were 2.8 mM following oral NAC treatment from 7 data sets. No comparable increase in the plasma compartment ORAC antioxidant capacity was measured in any of the treatment groups. Equally, contrast infusion itself did not significantly reduce antioxidant capacity in plasma, even in the placebo group. Buffy coat measures showed that there was a significant increase of intracellular GSH some patients, although the effect was variable. Also, no clear additional benefit was witnessed by increasing plasma NAC >10‐fold through infusion of NAC over oral administration. Conclusion NAC fails to influence ORAC antioxidant capacity in the plasma compartment of CKD stage III patients receiving contrast media. Our results question the importance of oxidative stress in contrast‐induced nephropathy. Furthermore, the findings fail to demonstrate a direct antioxidant impact of NAC in the plasma compartment. Instead, we found that NAC can increase intracellular GSH in some deficient individuals, which might carry some benefits in terms of detoxification and question the antioxidant hypothesis related to contrast‐induced nephropathy and NAC.
KW - chronic kidney failure
KW - contrast induced nephropathy
KW - parallel design
KW - Adult
KW - Adverse drug reaction
KW - Clinical research
KW - Clinical trial
KW - Conference abstract
KW - Controlled study
KW - Coronary angiography
KW - Detoxification
KW - Drug therapy
KW - Female
KW - Human
KW - Human tissue
KW - Major clinical study
KW - Male
KW - Oral drug administration
KW - Oxidative stress
KW - Randomized controlled trial
KW - Treatment failure
UR - https://www.mendeley.com/catalogue/36f08b63-3933-3962-bda5-4e9b2dbb787e/
U2 - 10.1136/heartjnl-2020-SCF.2
DO - 10.1136/heartjnl-2020-SCF.2
M3 - Paper
SP - A1
ER -