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/Design

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.

Discussion

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.

Trial registration

Clinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18.     

A gas chromatography-mass spectrometry method for the quantitative analysis of melatonin in plasma and cerebrospinal fluid

A method has been developed for the quantitative analysis of melatonin in human plasma and cerebrospinal fluid. The technique involves a simple one-step extraction with chloroform and conversion of the melatonin in the extract to its N-trimethylsilyl derivative, which is then measured by means of high-sensitivity gas chromatography—mass spectrometry. Intra-assay precision for triplicate samples at the 20-pg/ml level was better than 20%, while the interassay precision for separate determinations made over the course of a week was better than 18%. In a series of human plasma samples taken over several times during a 24-hr period, a significant increase in melatonin level was noted during the hours of darkness.     

The influence of changes to river hydrology on freshwater fish in regulated rivers of the Murray–Darling basin

Freshwater fish are often used as an indicator of the response of the ecosystem to the restoration of river flows or the provision of environmental flows. The ability to model the biological response of fish depends on the capacity to establish clear relationships between changes in river hydrology and the fish assemblages in a river. The fish assemblage structure and the abundances of individual fish species were examined in relation to a hydrological index that described hydrological change in six regulated rivers in the Murray–Darling Basin. The hydrological index explained only a small amount of variation in fish assemblage structure. In addition, the abundances of individual fish species were only weakly correlated with the index of flow deviation. It is suggested that these results make the modelling of responses of fish assemblages to environmental water allocations unfeasible at a large scale and that future studies should concentrate on potentially more simple responses, such as the relationships of fish spawning and recruitment to specific aspects of river hydrology.     

Role of IGF system of mitogens in the induction of fibroblast proliferation by keloid-derived keratinocytes in vitro

Keloids areproliferative dermal growths representing a pathological wound-healingresponse. We report high proliferation rates in normal (NF) andkeloid-derived fibroblasts (KF) cocultured with keloid-derivedkeratinocytes (KK). IGF binding protein (IGFBP)-3 mRNA and secretedIGFBP-3 in conditioned media were increased in NF cocultured with KKcompared with NF but markedly reduced in KF cocultured with KK ornormal keratinocytes (NK). IGFBP-2 and IGFBP-4 mRNA levels wereelevated, whereas IGFBP-5 mRNA was decreased in KF cocultured with KKor NK. Significant increases in IGFBP-2 and -4 mRNA in KF coculturedwith KK did not correlate with protein secretion. Downstream IGFsignaling cascade components, phospho-Raf, phospho-MEK1/2,phospho-MAPK, PI-3 kinase, phospho-Akt, and phospho-Elk-1, wereelevated in KF cocultured with KK. Addition of recombinant humanIGFBP-3 or antibodies against IGF-I or IGF-IR significantly inhibitedproliferation of KF. The bioavailability of IGF-I may be related to thelevels of IGFBP-3 produced, which in turn influences KF proliferation,suggesting that modulation of IGF-I, IGF-IR, and IGFBP-3, individuallyor in combination, may represent novel approaches to the treatment of keloids.