A deterioration of renal function is one preoccupying complication of iodinated radiocontrast agents in clinical practice. These compounds have direct toxic effects on renal cells, which are only in part related to their physicochemical properties. The hyperosmolal monomeric ionic radiocontrast agents, like diatrizoate, have the highest toxicity, whereas renal cells are less affected by (nonionic) compounds with reduced osmolality. The toxic effects include cellular energy failure, a disruption of calcium homeostasis, a disturbance of tubular cell polarity and programmed cell death (apoptosis). The molecular mechanisms of the direct cytotoxicity are still unclear, although oxidative stress has been implicated. Radiocontrast cytotoxicity has been demonstrated in glomerular mesangial cells and in renal epithelial cells in vitro. In vivo, the direct cellular toxicity of radiocontrast agents is compounded with alterations in blood flow and/or viscosity, ultimately resulting in renal medullary hypoxia, which is a hallmark feature of the complex clinical syndrome of radiocontrast nephropathy.
Over 80 million doses of iodinated intravascular contrast media (CM) were administered in the most recent tabulations of 2003, corresponding to approximately 8 million liters, making it one of the highest volume medical drugs used compared to any other pharmaceutical. The evolution of CM has focused on minimizing adverse events by eliminating ionicity, increasing hydrophilicity, lowering osmolality and increasing the number of iodine atoms per molecule. Contrast media are classified into three general categories based on their osmolality relative to blood: high osmolar (5 times or greater than blood), low osmolar (2-3 times blood) and iso-osmolar (the same as blood). All imaging modalities that employ CM, especially computerized tomography (CT), have shown rapid growth. In the last two decades, the use of CT scanning has increased by 800%. From 1979 to 2002, the number of cardiac catheterization procedures in the USA increased by 390% and in Europe from 1992 to 1999 by 112%. There is a general consensus that renal insufficiency and diabetes are major risk factors for contrast-induced nephropathy (CIN), particularly when co-existing. The US Renal Data System documents a 'relentless' increase in kidney failure, projecting a 90% increase by 2010. Diabetes affects 194 million people worldwide and the number is anticipated to increase by 75% by 2025. The unavoidable conclusion is that patient exposure and prevalence of risk factors for CIN will continue to increase.
The radiocontrast/hypertonicity-induced DNA fragmentation of MDCK cells is attenuated by taurine but not by NAC. Because both agents are antioxidants, the antioxidant property is not sufficient for the observed cytoprotective effect. Hence, the antiapoptotic effect of taurine has to be attributed to other, yet to be defined mechanisms. Our results suggest that pharmacological doses of taurine may be particularly protective against RCIN.
The DNA fragmentation of MDCK cells induced by diatrizoate is related to its hypertonicity in this in vitro model of radiocontrast cytotoxicity. Nuclear disintegration with subsequent cell death may contribute to the pathophysiology of radiocontrast-induced nephropathy, particularly in the hypertonic/hypoxic environment of the renal medulla. The present results underscore the importance of avoiding hyperosmolal urine states in patients at high risk of radiocontrast-induced nephropathy.
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