Tubular Nephrotoxicity of Water-soluble Iodinated Contrast Media

Abstract

Usual hyperosmolar water-soluble triiodinated contrast media (WTCM) are known to induce intense vacuolization of the cytoplasm of the renal proximal tubular cells, termed “osmotic nephrosis” (ON). The first cases were described in patients who developed oligoanuric acute renal failure after IVP. It was expected that the WTCM nephrotoxicity might result from a mechanical obstruction of the tubular lumens induced by the swelling of the cytoplasms. From a previous retrospective study of 47 cases in humans, it appeared that diffuse ON was often found in patients with severe chronic renal failure, submitted to high doses of iodine, who developed acute episodes of renal functional impairment, anuric or not, after injection; focal ON usually occurred in patients with previously normal or slightly impaired renal function, submitted to low doses of iodine, who did not develop acute renal failure after injection. However, data inconsistent with that scheme (anuria occuring without ON development, diffuse ON observed without renal functional impairment) led the authors to think that ON was not the prominent factor of WTCM nephrotoxicity. The pathogenesis of ON is unclear. The adjective “osmotic” is not appropriate, because it has been proven that the hyperosmolality of WTCM is not responsible for the cytoplasmic vacuolization. Prospective studies of the nephrotoxicity of two new iso-osmolar WTCM (metrizamide, ioxaglate) showed that these new molecules and usual hyperosmolar WTCM induce ON in the same conditions. Iopamidol is also able to induce ON. Osmotic nephrosis probably results from changes of WTCM tubular metabolism, inducing pinocytosis. Acute or chronic underlying nephropathies are needed to induce ON by WTCM in humans. ON develops neither in kidneys without underlying nephropathies, even when very high doses of iodine are injected, or in tubular cells destroyed by necrosis or atrophy. In a given patient with a transplanted kidney, WTCM may induce ON when it is injected during an acute rejection crisis, but does not induce ON when it is injected during a period with normal renal function. ON can be localized to only a few cells in one tubular section. Data provided by animal experiment cannot be easily extrapolated to humans, because the tubular metabolism of WTCM differs within the different species and with the different molecules. No lesions of ON were induced in Wistar rats, despite the injection of very high doses of iodine (> 3.5 g/kg bw), even in rats with severe renal insufficiency induced by nephron reduction and submitted to 24-hour dehydration. No ON was found in Lewis rats with permanent nephrotic syndrome induced by Heymann's method, submitted to high doses of diatrizoate, ioxitalamate, metrizamide, or ioxaglate (2 g I/kg bw).