Effects of intravenous injection of diatrizoate ...

Acta Radiologica

ISSN: 0284-1851 (Print) 1600-0455 (Online) Journal homepage: http://www.tandfonline.com/loi/iard20

Effects of intravenous injection of diatrizoate, iohexol or ioxilan on renal size, urine profiles and blood profiles in the rabbit H. Rygaard, S. Dorph, H. S. Thomsen, T. Mygind, H. Nielsen, S. Larsen, P. Skaarup, L. Hemmingsen & J. Holm To cite this article: H. Rygaard, S. Dorph, H. S. Thomsen, T. Mygind, H. Nielsen, S. Larsen, P. Skaarup, L. Hemmingsen & J. Holm (1988) Effects of intravenous injection of diatrizoate, iohexol or ioxilan on renal size, urine profiles and blood profiles in the rabbit, Acta Radiologica, 29:4, 491-494 To link to this article: http://dx.doi.org/10.3109/02841858809175026

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Date: 25 September 2017, At: 03:35

Acta Radiologica 29 (1988) F a x . 4

FROM THE DEPARTMENT OF DIAGNOSTIC RADIOLOGY AND THE INSTITUTE OF PATHOLOGY, KgBENHAVNS AMTS SYGEHUS I HERLEV, FACULTY OF MEDICINE, UNIVERSITY OF COPENHAGEN, DK-2730 HERLEV, AND

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THE DEPARTMENT OF CLINICAL CHEMISTRY, CENTRALSYGEHUSET, DK-4800 NYKgBING FALSTER, DENMARK.

EFFECTS O F INTRAVENOUS INJECTION OF DIATRIZOATE, IOHEXOL OR IOXILAN ON RENAL SIZE, URINE PROFILES AND BLOOD PROFILES IN THE RABBIT H.RYGAARD, S. DORPH,H. S. THOMSEN, T. MYGIND, H. NIELSEN, S. LARSEN, P. SKAARUP, L. HEMMINGSEN and J. HOLM

Abstract Diatrizoate, iohexol or ioxilan were injected intravenously in 18 rabbits. The contrast medium passage through the kidneys was recorded on digital subtraction images for the first 50 s followed by 100 mm exposures up to 15 min after injection. The renal area was measured planimetrically. Urine profiles (glucose, phosphate, LDH, GGT, NAG), blood profiles (potassium, urea) and the relative clearance of albumin and sodium were followed for 5 days and compared with a control group injected with saline. All kidneys were examined by light and immunofluorescence microscopy. All three contrast media produced excellent arteriograms and urograms. The three different contrast media caused a rapid increase of the kidney area within the first minute, reaching an average maximum of 10 to 12 per cent after 5 min, followed by a gradual decline. Contrary to expectations the increase in renal area was similar for all three contrast media, so hyperosmolality is no likely explanation of this phenomenon. None of the contrast agents caused significant changes in any of the profile components with one exception: the GGT excretion was significantly elevated during the first 24 h after diatrizoate administration as compared with the effect of saline. Light and immunofluorescence microscopy revealed no differences.

Key words: Urography, experimental; contrast media, comparative studies; diatrizoate, iohexol, ioxilan; renal area.

In the investigation of renal tolerance of new contrast media it is important to study markers which enable the detection of glomerular and tubular changes before a reduction in the glomerular filtration rate occurs. The effect on glomerular function has generally been studied by measurement of the urinary output of albumin or other high molecular weight proteins. Increased urinary excretion of low molecular weight proteins, enzymes, sodium or glucose is indicative of a possible tubular influence of CM. Recently a new CM, ioxilan, a non-ionic monomer, has been synthesized (9). Therefore we undertook a comparative study of renal effects following high dose urography with ioxilan and iohexol, both non-ionic monomers, the ionic monomer diatrizoate and saline in normal rabbits. The chemical structure of ioxilan, iohexol and diatrizoate is shown in Fig. 1. The osmolality of the three CM, all 350 mg Uml at 37°C is: ioxilan 690 mmotlkg, iohexol 880 mmolkg and diatrizoate 1850 mmoYkg. Change in kidney area was also compared.

Material and Methods

Contrast medium (CM) induced renal damage has attracted increasing interest. While clinically detectable renal damage is extremely rare in healthy persons, certain high risk patients have been identified, in whom even intravenous administration of CM represents a significant threat to their residual kidney function (6, 7). Administration of the new low osmolar CM causes less marked unphysiologic alterations than are seen following administration of the conventional ionic CM, supporting the prospect that the new media would also cause less affection of the kidney function.

Twenty-four New Zealand white female rabbits (Thomae, Biberach, West Germany) weighing 2.6 to 3.2 kg were randomly divided into 4 groups (n=6). They were deprived of food and water for 6 h before the CM injection and anesthetized with intramuscular ketamin hypochloride (40 m a g ) and xylazin (2 mdanimal) during the radiographic part of the study (15 min). Diatrizoate (Schering AG, Berlin), iohexol (Nycomed, Norway), ioxilan (BioAccepted for publication 7 February 1988.

49 1


492

H. RYGAARD ET COLL.

physica Foundation, California, USA) (all 350 mg I/ml; 5 mYkg BW), or the same volume of saline were injected into an ear vein as a bolus (20-30 s). The CM passage through the kidneys was recorded on a Philips digital subtraction unit (Model DVI-V with a 15 cm image intensifier) with a.p. exposures taken every second from 8 to 50 s after start of injection, and thereafter by 100 mm a.p. exposures 1, 2, 3, 4, 5, 7, 10 and 15 min after injection. Subsequently the rabbits were placed in metabolic cages with free access to food and tapwater. Blood samples were taken from an ear vein 24, 72 and 120 h after injection. All urine voided during the 24 h period prior to each blood sample was collected and two samples were obtained. The blood samples were centrifuged after coagulation, and all serum and urine samples were frozen for later analysis. Chemical analysis. The concentration of U- and Salbumin was determined by a modified two sided enzymelinked immunosorbent assay (ELISA) (5) employing commercially available agents. For determination of the cytoplasmic enzyme lactate dehydrogenase (LDH), the lysoma1 tubular enzyme N-Acetyl-8-D-glucosaminidase (NAG), the brush border enzyme L-y-Glutamyltransferase (GGT) and glucose in urine, commercially available kits were used. Concentration of phosphate, sodium and creatinine in urine, and of potassium, sodium, urea, and creatinine in serum were determined by routine methods of the department. A total of 936 analyses were performed. The excretion of LDH, NAG, GGT, phosphate, and glucose was expressed as (UpxV/UCrxV)/(g)and of albumin and sodium (relative clearance) as (UPxV/ S,)/((UcrxV/S~r)x(g)),where Up denotes the urinary concentration and Sp the serum concentration of the component, Ucr the urinary concentration and Scr the serum concentration of creatinine, V the volume of urine per unit of time and g the body weight of the rabbit. Changes in kidney area. The renal area was carefully outlined with a pencil directly on the radiographs and the circumscribed area was measured with a planimeter. Changes in kidney size were expressed as per cent change in total area of both kidneys compared with the area on the first digital subtraction-image in which the renal contour could be easily percepted (zero-image). Measurements were performed on the digital images obtained 15, 30 and 45 s after the zero-image and on 100 mm films taken 1, 2, 3, 4, 5, 7, 10 and 15 min after the start of the injection. A coin placed on the lower part of the abdomen within the field of view, but outside the kidney regions, made it possible to compensate for the difference in magnification between the magnified digital images and the 100 mm films. Pathonnutomy. All rabbits were killed by an overdose of pentobarbital 120 h after the intravenous injection of CM or saline. Both kidneys were immediately removed, and specimens obtained. For light microscopy 2 pm thick

OH

I

OH

Dlatrlzoate

lohexol

loxllan

Fig, 1 . The chemical structure of ioxilan, iohexol and diatrizoate.

Fig. 2. Subtracted digital image (a) showing the arteriogram 10 s after start of intravenous injection of ioxilan and non-subtracted digital image (b) showing the nephrogram 40 s later (350 mg V d ; 5 mlkg BW).

sections were stained with H&E, silver methenamine + H&E, PAS, and Picro-Sirius. For immunofluorescence examination sections of similar size were applicated with

493

CONTRAST MEDIUM, RENAL DAMAGE AND RENAL SIZE

Table Changes (per cent) in renal area of both kidneys following intravenous injection of diatrizoate, iohexol or ioxilan. Mean and range (n-5, since one animal had to be omitted from each group due t o technical reasons)


Radiograph obtained

I5 s* 30 s* 45 s* 1 min** 2 min** 3 min** 4 min** 5 min** 7 min** 10 min** 15 min**

Diatrizoate

Iohexol

Ioxilan

Mean

Range

Mean

Range

Mean

Range

1.3 6.4 7.5 6.2 8.3 10.5 11.7 12.2 11.6 11.0 10.1

1.0-4.5

2.9-8.4 4.3-9.2 1.9-10.8 1.7-I2.3 4.1-12.7 4.1-16.3 4.1-16.3 4.1-15.8 4.1-15.0 4.1-14.3

3.0 6.4 7.7 6.3 10.1 11.2 12.0 12.7 10.5 7.4 5.1

0.0-6.3 3.8-8.6 5.3-10.5 4.7-9.8 8.5-12.4 9.8-12.6 9.8-15.1 9.9-15.1 9.8-12.6 6.3-8.5 5.0-5.1

1.5 6.8 8.3 5.1 6.9 9.4 10.4 10.1 9.4 8.6 7.9

0.0-3.6 4.5-1 1.5 4.5-17.0 2.5-7.1 7.4-9.6 4.2-13.6 4.2-1 3.6 2.5-15.O 1.1-13.6 1.1-1 1.3 1.1-1 1.3

* Digital image. ** 100 mm radiograph. Change in renal area %

k-

5 4

3

2

1

0

015304560

2 3

4

5

7

10

15

A*

from first CM appearance in the kidney

Fig. 3. Average changes (per cent) in renal area (both kidneys) following intravenous injection of diatrizoate (O),iohexol ( A ) or ioxilan (m).Five animals in each group (one animal in each group had to be omitted due to technical reasons). The range is given in the Table.

fluorescence isothiocyanate conjugated Goat-anti-Rabbit serum, Swine-anti-Rabbit serum, Goat-anti-Rabbit polyglobulin, and Goat-anti-Rabbit C’3 (Nordic Immunological Laboratories, The Netherlands). Statistics. For the statistical analysis a Student’s t-test was employed, and a significance level of 0.05 was adopted. Results

AU 3 contrast media produced excellent subtraction arteriograms and urograms. Examples with ioxilan are shown in Fig. 2.

Urinelblood profiles. None of the CM caused significant changes of any profile component with one exception: the excretion of the enzyme GGT was significantly elevated during the first 24 h period in rabbits injected with diatrizoate as compared with the effect of saline. No differences were found in later samples. Changes in kidney area following intravenous injection of the three CM appear in Fig. 3 and the Table. For all 3 groups a prompt distension during the first minute was followed by a slower increase up to an average maximum of 10 to 12 per cent during the next 3 to 4 min. After 5 min a gradual decrease was observed. The slope after 5 min seemed to be more pronounced with iohexol than with diatrizoate, but the difference was statistically insignificant. After 50 s-at the time where the technique was changed from digital images to 100 mm exposures-a short insignificant interruption of the ascent of the curve was observed in all 3 groups. Pathoanatomy. No differences were found between the four groups by either light microscopy or immunofluorescence . Discussion

The sensitivity to CM varies considerably from species to species and may be less in some animals than in man (8). In rabbits, chosen for the present study, both high and low sensitivity to CM have been reported (3, 8). The present study revealed no signs of renal injury except for a temporary significant increase in the excretion of the brush border enzyme GGT in rabbits receiving diatrizoate. An increase of GGT excretion in the urine is considered as a sign of nephrotoxicity (4), so the actual increase in GGT excretion indicates a temporary dysfunc-


494

H. RYGAARD ET COLL.

tion of the tubular cells. Previously we have studied the same three CM in normal rats using equivalent doses (1 750 mg I/kg BW) (9). We found significantly increased excretion of albumin, LDH, NAG, GGT, sodium and glucose after diatrizoate, but not of all 6 components after iohexol or ioxilan. There were also marked quantitative differences between the conventional ionic diatrizoate and the two non-ionic media and minor differences between the latter two media in favour of ioxilan (9). In spite of a difference in the first sample collection period between the two studies (i.e. rat 2 h after injection; rabbit 24 h after injection) the magnitude of the increase of the components, if similar in rabbits as in rats, should have been detected in the 24-h sample. An explanation may be the difference in the sensitivity to CM between the rat and the rabbit kidney. The changes in the renal area shown in the present rabbit study follow the pattern known from several previous studies of ionic CM in dogs and man (1, 2, 10). The short intemption of the ascent of the curve in Fig. 3 after 50 s was insignificant and probably due to the fact that at this time the imaging technique was changed. The outer contour of the kidney was slightly less well-defined on the 100 mm radiographs as compared with the digital images. Since the renal distension has been believed to be due to the osmolality of the CM (the diuretic effect) (2) a smaller distension was expected following administration of low osmolar CM. However, this did not occur, probably due to the fact that all three CM have almost the same effect on diuresis (9). Neither could WHITEHOUSE (10) find any differences in the increase of kidney length in man following intravenous injection of ionic or non-ionic CM. Thus, the phenomenon of renal distension following

CM administration seems unrelated to the osmolality of the CM. Request f o r reprints: Dr Henrik Rygaard, Department of Diagnostic Radiology 54 E2, University of Copenhagen, KAS Herlev, Herlev Ringvej, DK-2730 Herlev, Denmark.

REFERENCES 1. DORPHS. and @IGAARD A.: Variations in size of the normal

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kidney following intravenous administration of water-soluble contrast media and urea. Brit. J. Radiol. 46 (1973). 183. - SOVAKM., TALNERL. B. and ROSENL.: Why does kidney size change during i.v. urography? Invest. Radiol. 12 (1977), 246. GOLMAN K. and ALMBNT.: Urographic contrast media and methods of investigative uroradiology. In: Radiocontrast agents/Handbook of experimental pharmacology. Vol. 73, p. 159. Edited by M. Sovak. Springer-Verlag, Berlin 1985. HARTMANN H. G.: Enzymuria after administration of watersoluble X-ray contrast media. I n : Contrast media in urography, angiography and computerized tomography, p. 30. Edited by V. Taenzer and E. Zeitler. Georg Thieme Verlag, Stuttgart 1983. HEMMINGSEN L. and SKAARUP P.: ,9’-microglobulin in urine and serum determined by ELISA-technique. Scand. J. Clin. Lab. Invest 45 (1985). 367. HENEGHAN M.: Contrast induced renal failure. (Editorial.) Amer. J. Roentgenol. 131 (1978), 1113. M A W M. and BEITMANNM. A,: Contrast-induced renal failure. Postgrad. Radiol. 5 (1985), 343. SPECKU., MUETZELW. and PRESSW. R.: Kidney toxicity testing in animals. Invest. Radiol. 19 (1984). S123. T. et coll.: Intravenous THOMSEN H. S., DORPHS., MYGIND injection of ioxilan, iohexol and diatrizoate. Effects on urine profiles in the rat. Acta Radiol. 29 (1988), 131. WHITEHOUSE R. W.: High- and low-osmolar contrast agents in urography. A comparison of the appearances with respect to pyelotubular opacification and renal length. Clin. Radiol. 37 (1986), 395.