Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol.
BACKGROUND
Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease.


METHODS
We designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance.


CONCLUSIONS
Contrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials.


BACKGROUND
Clinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18.
National Poisons Information Service (Edinburgh), Royal Infirmary of Edinburgh, Edinburgh, UK.
Euan A
EA
Sandilands
Sharon
S
Cameron
Frances
F
Paterson
Sam
S
Donaldson
Lesley
L
Briody
Jane
J
Crowe
Julie
J
Donnelly
Adrian
A
Thompson
Neil R
NR
Johnston
Ivor
I
Mackenzie
Neal
N
Uren
Jane
J
Goddard
David J
DJ
Webb
Ian L
IL
Megson
Nicholas
N
Bateman
Michael
M
Eddleston
D000111:Acetylcysteine / Q000494:pharmacology*; D000209:Acute-Phase Proteins / Q000652:urine; D003287:Contrast Media / Q000009:adverse effects*; D018592:Cross-Over Studies; D055316:Cystatin C / Q000097:blood; D005919:Glomerular Filtration Rate; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008297:Male; D008562:Membrane Glycoproteins / Q000652:urine; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000652:urine; D011991:Receptors, Virus; D012079:Renal Circulation / Q000187:drug effects*; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*
D000209:Acute-Phase Proteins; D003287:Contrast Media; D055316:Cystatin C; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D011991:Receptors, Virus; D000111:Acetylcysteine