| Abstract |
Recent advances in medicine have led to increased use of iodinated contrast media (CM) in diagnostic and interventional procedures. Despite advances in molecular structures, all CM can cause mild to severe side effects such as contrast-induced nephropathy (CIN). CIN is associated with significant morbidity/mortality, increased hospital admissions, and increased medical care costs.
The pathophysiology of CIN is not fully understood but appears to be multifactorial. Oxidative stress plays a central role. Hemodynamic changes leading to renal medulla hypoxia and direct toxic effects of contrast agents on renal tubular epithelial cells appear to be major pathophysiological factors. Contrast agents cause vasoconstriction through induction of adenosine and endothelin, reduction of blood flow from the medulla to the renal cortex, and ischemia of the medulla leading to the release of reactive oxygen species (ROS) through oxidative stress. Direct toxic effects on renal tubular epithelial cells lead to their osmotic necrosis/vacuolar degeneration leading to tubular necrosis. Free radicals directly constrict renal microcirculation and indirectly affect renal vascular tone by mediating the effects of other vasoconstrictor factors, stimulating the production of vasoconstrictors and modulating the action of vasodilators, such as nitric oxide (NO).
It is generally accepted that the higher the dose of CM administered, the greater the risk of CIN, and multiple administrations within a few days are not recommended. Age is also a factor to consider as it is associated with reduced renal mass, function and perfusion. A lower glomerular filtration rate increases the risk, and pre-existing renal dysfunction is the most important risk factor. Antioxidant mechanisms in chronic kidney disease are impaired and individuals have an increased level of oxidative stress due to pre-existing inflammation/ endothelial dysfunction. Also, diabetes is a very important predisposing factor for CIN, and diabetic patients with CIN have a reduced survival compared to non-diabetics. Patients with diabetes and renal failure are at high risk due to decreased levels of endogenous vasodilators (NO and prostaglandins) leading to decreased renal blood flow and glomerular filtration. Other factors leading to renal failure, such as cardiovascular disease, hypotension, and liver cirrhosis also predispose to CIN. All individuals who are to receive CM should be assessed for risk of CIN, and high-risk individuals should be considered for preventive methods supported by clinical data since CIN is a potentially preventable clinical condition. In low-risk individuals, the incidence appears to be low (< 5%) in contrast to high-risk individuals, in whom the incidence is high (up to 20%). Management remains supportive based primarily on intravenous hydration in high-risk individuals using saline or bicarbonate. New biomarkers and agents with antioxidant and vasodilator properties are attracting attention due to their ability to reduce oxidative stress and regulate vascular tone. The potential reno-protective effects of several antioxidants have been evaluated, but none have been shown to be effective in human studies. Resveratrol (Res) and lycopene (Lyc) are powerful natural antioxidants with antimicrobial and anti-inflammatory effects found in red grapes and tomatoes, respectively. Their reno-protective effects have been evaluated in a limited number of animal studies and have been attributed to neutralization of free radicals, inhibition of cell apoptosis, and alteration of hemodynamics through promotion of NO synthesis. The aim of the present study was to evaluate the potential reno-protective actions of Res and Lyc in an animal model of CIN.
Twenty-four adult male New Zealand white rabbits were equally assigned into four groups: control (normal saline), CIN (intravenous iopromide; 7.5g iodine/kg), Res+CIN (per os Res; 5mg/kg), and Lyc+CIN (per os Lyc; 4mg/kg). Serum Cr (sCr); symmetric and asymmetric dimethylarginine (SDMA and ADMA); oxidative stress biomarkers: malondialdehyde; total antioxidant capacity; catalase; reduced glutathione) were evaluated in blood samples at three time points: right after 0h; 24h; 48h after iopromide/saline administration. CD20+ and CD3+ lymphocytes were determined at 48h post CM exposure. All animals were sacrificed at 48h and both kidneys collected. Oxidative stress biomarkers were measured in renal tissue, as well. sCr, SDMA and ADMA levels increased significantly in CIN compared to all groups. Oxidative stress secondary to CIN in blood and kidneys was suppressed by Resveratrol and Lycopene. B and T lymphocytes decreased significantly in CIN compared to all groups. The present study provides emerging evidence that Resveratrol and Lycopene ameliorate CIN by modulating oxidant and antioxidant balance in blood and renal tissue and by inhibiting vasoconstriction and blood cytotoxicity.
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