The Cytotoxicity of Iodinated Radiocontrast Agents on Renal Cells In Vitro

Abstract

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.

The Effects of the Iodinated X-Ray Contrast Media Iodixanol, Iohexol, Iopromide, and Ioversol on the Rat Kidney Epithelial Cell Line NRK 52-E

“…Exposure periods of several hours are required to induce toxicity in NRK 52-E cells, and this is consistent with the findings of others. 8 This prolonged exposure is relevant to the clinical setting as renal retention of low doses of ICM in the kidney has been reported for up to 32 h after administration of ICM. 20 The concentration of the ICM used in the current study was selected on the basis of previously reported in vitro …”

“…6 In vitro studies support the hypothesis that the toxicity is related to the osmolality of the ICM, as low-osmolal ICM (LOCM) have considerably less toxic effects than high-osmolal ICM (HOCM) on various cell types, with the observed toxicity being dose dependent. 8,9 The ionic force of the molecule seems to be irrelevant to the toxicity. 8 However, other studies have shown that mannitol, when tested at equal osmolality to the contrast media, induced less toxicity than ICM.…”

“…8,9 The ionic force of the molecule seems to be irrelevant to the toxicity. 8 However, other studies have shown that mannitol, when tested at equal osmolality to the contrast media, induced less toxicity than ICM. 10,11 This indicates that physicochemical properties other than osmolality may be important for the toxicity of ICM.…”

“…The molecular mechanisms of ICM-induced cytotoxicity are still unclear; however, cellular energy failure, disruption of calcium homeostasis, disturbance of tubular cell polarity, apoptosis, altered cellular metabolism, pathological changes, and intracellular enzyme release are among the observations reported. 2,8 The aim of the present study was to evaluate the toxicity of four ICM with different physicochemical properties in the rat kidney cell line NRK 52-E by using the trypan blue exclusion assay and the MTT assay, in addition to scoring of dead cells. The ICM selected were the iso-osmolal iodixanol, and the low-osmolal iohexol, iopromide, and ioversol.…”

Engineering imaging probes and molecular machines for nanomedicine

“…Currently, small iodinated molecules are routinely used for in vivo contrast enhancement in the clinical setting, since iodine has a high X-ray absorption coefficient among nonmetal atoms. However, short circulation half-life, non-specific distribution, and potential renal toxicity have limited their imaging and targeting performance in vivo [129]. Liposomes with entrapped iodinated molecules are effective contrast agents due to their prolonged circulation half-time [130].…”