An Ultrastructural Histochemistry and Light Microscopy Study of the Early Development of Renal Proximal Tubular Vacuolation after a Single Administration of the Contrast Enhancement Medium "Iotrolan"

Abstract

The time course of contrast media (CM)-induced renal proximal tubular vacuolation was investigated in rats by light microscopy, transmission electron microscopy (TEM), and ultrastructural histochemistry for acid phosphate activity. Young adult male rats were treated with a single dose of 3.0 g I/kg Iotrolan (Isovist 300 mg I/ml) and sacrificed at 0 min, 5-min, 15-min, 15-min, 2-hr, and 24-hr intervals. Light microscopy of vibratome sections of freshly excised tissue of cryostat and paraffin sections was also performed to allow comparison of the appearance of the vacuoles in the fresh state with light and electron microscopy. The sequence of events seen to occur can be summarized as follows. CM-induced vacuolation occurred at a low level a soon as 5 min after compound administration. The vacuolation was observed by TEM but could not be detected by light microscopy. This was followed by an increase in size and numbers of vacuoles up to the 24-hr timepoint with a sequential increase in the staining for acid phosphatase activity of the vacuoles, most marked at the 24-hr timepoint. At timepoints less than 24 hr there appeared to be no marked increased in the normal complement by lysosomes or in the components of the Golgi-endoplasmic reticulum-lysosome pathway. At 24 hr, the vast majority, but not all, of the CM-induced vacuoles were positive for acid phosphatase activity. The intensity of staining varied, and there was evidence of infusion of small lysosomes with CM-induced vacuoles. These results suggest that formation of CM-induced vacuoles is a 2-stage process, following a normal pathway for the handling of endogenous and exogenous substances.

Histopathological Evaluation of Contrast-Induced Acute Kidney Injury Rodent Models

“…Therefore, rabbits offer more reliable model; however, rabbit facilities are not as common as mouse or rat facilities as rabbits are much more expensive to keep. Although tubular epithelial cell vacuolization was described in rats following a single injection of RCM without additional kidney pathology [72, 90, 91], vacuolization alone is not specific enough as a sole end-point to demonstrate CI-AKI. Although functional and histological damage was absent, molecular changes (increased adenosine receptor expressions) were induced by a single iodixanol injection even in mice [92].…”

“…Tubular vacuolization is commonly interpreted as a sign of drug toxicity [107]. A single injection of RCM to intact rats induced tubular vacuolization in the absence of other kidney pathologies [72, 90, 91]. Ultrastructural studies of these kidneys suggested that the vacuoles were membrane-bound lysosomes [42, 65, 90].…”

“…A single injection of RCM to intact rats induced tubular vacuolization in the absence of other kidney pathologies [72, 90, 91]. Ultrastructural studies of these kidneys suggested that the vacuoles were membrane-bound lysosomes [42, 65, 90]. Although in one study vacuoles were absent if the CT contrast gadolinium DTPA was used, a more recent study did not confirm the absence of vacuoles by CT contrast materials [106].…”

Urinary Tract

“…74,240À242 Ultrastructural study has shown that after administration of sucrose solutions renal tubular vacuoles are large, pale, surrounded by a simple membrane and show acid phosphatase activity indicating their lysosomal nature. 246 Although nephropathy induced by iodinated contrast medium remains a clinically important complication of their use in patients with compromised renal function, dosing normal healthy animals with clinically relevant doses produces only minor changes to renal blood flow, not sufficient to cause persistent derangement of renal function. While these vacuoles induced by sugar solutions and dextrans may be considered mild reversible lesions, renal failure may result from infusions of certain dextrans of particular molecular weight.…”

Contrast Material‐Induced Renal Failure: An Overview

“…All water‐soluble, nephrotropic, iodinated CM exert direct toxic effects on renal epithelial cells and might produce contrast‐induced renal medullary ischemia 17,18 . Direct cytotoxic effects in the form of cytoplasmic vacuolization and lysosomal alteration in the proximal convoluted tubular cells and in the inner cortex of the kidneys have been demonstrated following exposure to a variety of iodinated CM 19–21 . Studies in animals have suggested that oxidant‐mediated injury might arise due to an enhanced production of oxygen‐free radicals concomitant with a reduction in the activity of the antioxidant enzymes catalase and superoxide dismutase in the renal cortex 22 .…”