- Email: [email protected]
Effects of angiography on renal function and histology in infants and piglets
January, 1970 T h e J o u r n a l of P E D I A T R I C S
41
Effects of angiograpby on renal function and bistology in infants and piglets Histologic examination of the kidneys of 34 infants who died following cardiac catheterization revealed medullary necrosis in 3 and proximal tubular epithelial vacuolization in another 4. In piglets, intra-aortie administration of either sodium iothalamate or meglumine dlatrizoate caused a prompt and sustained decrease in renal blood flow. Histologlc examination of the kidneys revealed changes in tubular epithelium similar to those observed in the infants. In a prospective study of children undergoing cardiac catheterization, 8 infants developed hematuria after administration of contrast material, 3 to 5 ml. per kilogram of body weight. Hematurla did not occur when the dose did n,ot exceed 3 ml. per kilogram. These studies indicate that contrast material utilized in cardiac catheterization can influence renal function and may produce irreversible renal damage.
Alan B. Gruskin, M.D., Oskar H. Oetliker, M.D., Norman M. Wolfish, M.D., Norman L. Gootman, M.D., Jay Bernstein, M.D., and Chester M. Edelmann, Jr., M.D. ~' BRONX
AND
NEW
HYDE
PARK=
N.
Y.
DIAGNOSTIC INVESTIGATION of many disease states in infants includes arteriographi c visualization of the involved structures, achieved usually by selective injections of large boluses of contrast material From the Departments of Pediatrics and Pathology, Albert Einstein College of Medicine, and the Department of Pediatric Cardiology, Long Island Jewish Hospital. Supported in part by the Rosenburg Toner Heart Fund and United States Public Health Service Research Grants Nos. A M 07840, 5 T I H E 5267, and H E 05561. Address for reprints: Dr. Edelmann, Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris'Park Ave., Bronx, N. Y. 10461. ~Reelpient of Research Career Development Award No. I-K3-HD 19369 ]rom the National Institute of Child Health and Human Development.
under high pressure. Numerous renal complications have been attributed to injections of contrast media into the aorta. 1-12 Since 1964, we have observed 3 cases of medullary necrosis following diagnostic cardiac angiography in infants. Although the mechanism by which radiographic media affect renal function is unclear, hypotheses have included direct renal toxicity, 2, 3 changes in systemic hemodynamics with secondary renal involvement, 13 and primary effects on glomerular filtration rate and renal blood flow. s The purpose of these studies was to examine the effects of injections of contrast media on renal function and histology in children and newborn animals. Vol. 76, No. 1, pp. 41-48
42
Gruskin et al.
MATERIAL
AND METHODS
Piglets. Investigations were performed on 8 unanesthetized female piglets, ranging in age from 6 to 48 hours. The piglets were restrained on their side, and body temperature was maintained by both surgical draping and a heat lamp. The bladder was catheterized with a No. 5 or 8 premature feeding tube. At the end of each period of urine collection, the bladder was emptied by suprapubic compression following instillation of 3 ml. of distilled water and then 10 ml. of room air. Under local lidocaine anesthesia, either the femoral artery and vein or the carotid artery and jugular vein were isolated. Polyethylene catheters were placed through them into the thoracic aorta and vena cava. Arterial blood samples and urine collections were obtained at 15 to 20 minute intervals throughout the study. After collections of control samples of blood and urine, priming solutions of inulin (50 mg. per kilogram of body weight) and para-aminohippurate (PAH) (8 rag. per kilogram) were given intravenously. A continuous infusion, containing sufficient inulin and PAH to maintain blood levels of 25 and 2 mg. per 100 ml., respectively, was given at a rate of 0.4 ml. per minute. Following initial clearance periods, a rapid injection s by hand of 2.5 ml. per kilogram of body weight of either sodium iothalamate (sodium concentration 960 /,Eq per milliliter; osmolality > 3,000 mOsm. per kilogram) or meglumine diatrizoate (sodium concentration 4 /~Eq per milliliter; osmolality > 3,000 mOsm. per kilogram) was made into the aorta. Each piglet received either a single dose of dye or 2 doses 15 minutes apart. Clearance periods of 15 minutes duration were continued for at least one hour following the injection of dye. Upon completion of the study the piglets were killed by intravenous injection of pentobarbital. The correct position of the *Trade and generic terms of contrast material employed: Renovlst--sodlum ~iatrlzoate and meglumlne diatrizoate; Renografin--meglumine dlatrlzoate ; Conray-4OO-sodium iothalamate.
The ]ournal of Pediatrics 1anuary 1970
aortic catheter was verified. T h e kidneys were removed immediately and placed in 10 per cent formalin. Sections of paraffinembedded tissues were stained with hematoxylin and eosin. The chemical methodology employed has been described. 14 Clearances of inulin and PAH were calculated in the usual manner. Fractional excretion of sodium (FNaE) was calculated as follows: Fm~ E
UNa V --
x
100.
CIa X ~Na
UN,V represents the rate of excretion of sodium in the urine and PNa is the concentration of sodium in plasma. Corrections were not made for Donnan equilibria. Children undergoing cardiac catheterization. Urinalyses. Urine was obtained before and after cardiac catheterization in 100 children ranging in age from birth to 16 years. Either sodium iothalamate or sodium and meglumine diatrizoate was employed, and the total amount administered varied from 2 to 5 ml. per kilogram. Single injections did not exceed 1 ml. per kilogram. The majority of these injections were performed from the left atrium or left ventricle. In all patients, urine was collected for 24 hours following the procedure. In those individuals in whom urinary abnormalities were found, collections were continued for 72 hours. All urine was examined for the presence of protein, using 10 per cent sulfosalicylic acid, and the sediment was examined microscopically for red and white blood cells and casts. Histologic changes in the kidneys. Histologic sections of the kidneys were examined in 34 infants who had had cardiac catheterization with or without anglography between 4 days and 4 months of age. The total amount of sodium iothalamate or sodium and meglumine diatrizoate administered during angiography ranged from 0.5 to 5.2 ml. per kilogram. The time of death ranged from 3 hours to 2 years after cardiac catheterization. Routine light microscopy was performed after the sections had been
Volume 76 Number 1
Effects o[ angiography on renal [unction
stained with hematoxylin and eosin and with periodic acid-Schiff stain for glycogen. Fat stains of frozen sections were also done in 3 of the 4 cases in which proximal tubular vacuolization occurred.
RESULTS Piglets. Renal hemodynamics. Data concerning inulin and P A H clearances and filtration fractions are shown in Fig. 1. Each study is represented as a mean control value, a value for the period immediately following injection of contrast material, and a final value representing the mean of the ensuing 45 minutes. In order to compare animals of varying size, the results have. been corrected to one square meter of body surface area. The average control values for inulin clearance (24 mL per minute per square meter), PAH clearance (70 ml. per minute
per square meter), and filtration fraction (0.35) are similar to results obtained in other newborn animals, including man. 15 No consistent changes in these variables were observed in the period immediately following administration of either dye. During the final 45 minutes of each study a consistent drop in P A H clearance and elevation in filtration fraction occurred, without consistent changes in the glomerular filtration rate. Both dyes had the same effects. Sodium excretion. Following injection of contrast material, a persistent increase in the absolute rate and in fractional excretion of sodium occurred in all piglets, despite the large difference in sodium concentrations in the two dyes (Fig. 2). In those animals given a second dose of contrast material, a further increase in the rate of sodium excretion occurred, whereas, in those animals given only a single dose, the rate of sodium excre-
60
~40
110
{ 9o
30
~s
4
2
I
Control
Pre Injection
43
I
O-15rnin.
I
15-60min.
I ~ Post InjectionI
Fig. 1. Renal hemodynamic effects of intra-aortic injection of angiographlc material in piglets. Open circles, meglumine diatrizoate; closed circles, sodium iothalamate.
44
Gruskin et al.
The ]ournal o/ Pediatrics January 1970
SODIUM IOTHALAMATE I
I 15 m
z
N PRE INJECTION
13--
~ ] POST INJECTION
o
11-U
9-o
7--
z 0
5--
co
MEGLUMINE DIATRIZOATE I
I-U
.r
1i I
I
DOUBLE D O S E
I
I
~
I
I
~
I
I
SINGLE DOUBLE DOSE DOSE
I
I
SINGLE DOSE
Fig. 2. Effect of angiographic material on renal excretion of sodium in piglets.
tion fell progressively toward control values. The rate of urine flow followed a similar pattern. In the piglets given sodium iothalamate, 65 to 100 per cent of the administered sodium was excreted; whereas in those piglets given meglumine diatrizoate, the amount of sodium excreted during the study was greater than that given, resulting in a negative sodium balance. Renal histology. Histologic examination of the kidneys showed similar changes in both groups of piglets. Focal tubular dilatation and focal vacuolization within proximal tubular cells were observed in 3 animals. These changes were felt to be similar to those described following administration of various osmotic agents, such as mannitol,lG sucrose,17, is and glucose? 9 Children. Urinalyses. Of the 100 infants and children undergoing cardiac catheterization, 8 of 30 infants aged one day to 3 months developed marked microscopic hematuria (Table I ) . Hematuria did not persist beyond 28 hours. Infants who developed hematuria had received 3 to 5 ml. per kilogram of contrast media, whereas less than
Table I. Urinalyses in infants and children after cardiac angiography
Data Number Abnormalities i n WBC, casts, or protein excretion Injected dose 3 ml./Kg. 3 ml./Kg. Developed hematuria ~> 3 ml./Kg, 3 ml./Kg.
I <~3 months I > 3 months 30
70
0
0
8 22
0 70
8 0
0 0
3 ml. per kilogram was administered to all the others. No changes in rates of excretion of white blood cells, casts, or protein occurred in any subject following angiography. No differences were noted which could be attributed to the various radiographic media utilized.
Histologic changes in kidneys [ollowing angiography. Histologic changes were o b served in the kidneys of 7 of the 34 infants who died after having undergone cardiac study before the age of 4 months. All 7 died
Volume 76 Number 1
Effects o[ angiography on renal [unction
45
Fig. 3. Ischemic necrosis of the renal papilla, demarcated from the rest of the medulla by a hemorrhagic zone, in 4~-day-old infant. (Hematoxylin and eosin stain. Original magnificantion x18.)
24 to 72 hours following study. Three of the 7 had medullary necrosis (Fig. 3). One of the 3 also had sepsis, and bacteria were demonstrated in the renal medulla. The kidneys of the other 4 infants showed severe vacuolization of the proximal tubular epithelium (Fig. 4). In 2 of 3 that were examined, the vacuoles were shown by histologic stains to be negative for fat and glycogen. The quantity of angiogrgphic media administered to these patients was 3 ml. per kilogram or more with the exception of one patient who developed medullary necrosis after receiving only 1.1 ml. per kilogram. This patient had an arterial oxygen
saturation at the time of catheterization of 47 per cent. The other 6 patients had saturations greater than 90 per cent. In total, 16 of the 34 patients received more than 3 ml. per kilogram of contrast media. Of the 16 patients, 7 developed histologic lesions. Since the end of 1965, when the amount of contrast material administered has been less than 3 ml. per kilogram, no histologic lesions have been found in those children who died. DISCUSSION
Intra-arterial injections of contrast media into adult dogs and man have had variable effects on the glomerular filtration rate and
4 6
Gruskin et al.
Fig. 4. Marked vacuolization of epithelium lining the proximal convoluted tubules, compatible with an osmotic effect, in 17-day-old infant. (PAS stain. Original magnification x600.) CpA~x. s, 10, 20 This wide range of response appears to be related to the structure of the dye, the concentration used, and the rate of administration2, ~, 20 The marked drop in PAH clearance in the present studies, combined with a concomitant rise in filtration fraction following dye injection, may be the result of one or more mechanisms. Increased renal efferent arteriofar resistance, redistribution of intrarenal blood flow (with blood being shunted away from the cortex), diminished cardiac output, decreased renal perfusion pressure with appropriate changes in afferent and efferent resistances to allow for continuation of glomerular filtration, or any combination of these factors may be evoked. In adult man, measurements of intrarenal blood flow distribution, utilizing the xenon laa washout technique, before and after selective renal angiography, have shown no change31 This finding of course may not be relevant to infants and young children. Although acute changes in myocardial function 22 and arterial pressure 2a have been observed subsequent to injection of contrast material, the duration of these changes is not sufficiently long Lo explain the changes in renal function. It is likely, therefore, that
The Journal of Pediatrics January 1970
the major effect observed upon renal hemodynamics in the piglets was an increase in renal efferent arteriolar resistance, reflecting a direct effect of the contrast material, although reflexly induced vasocostriction cannot be excluded. Both sodium iothalamate 24 and meglumine diatrizoate ~ are excreted principally by glomerular filtration. As nonreabsorbable substances, they act as osmotic diuretics. The magnitude and duration of diuresis they produce depends upon the concentration of dye reaching the kidney and the length of time taken to clear the dye. Assuming the absence of left-to-right shunts, the total amount of dye reaching the kidney on the primary circulation is related to the fraction of cardiac output that perfuses the kidney. In newborn piglets, the kidney receives an average of 4.8 per cent of the cardiac output. 26 The fractional cardiac output to the kidney increases with age, suggesting that old6r animals might be expected to excrete greater amounts of dye during the primary circulation. Furthermore, administered dye would be diluted rapidly and persist in the newborn infant's relatively large extracellular space 27 for a longer period of time. Thus, the newborn piglet might be expected to have a more prolonged diuresis than an older animal. In addition to the osmotic effects of these agents, other mechanisms involved in the control of sodium excretion may be involved. 2s-a~ Intra-arterial injections of hypertonic material increase the effective arterial volume, causing a secondary sodium and water diuresis by inhibiting sodium reabsorption. Although sufficient sodium was contained in the sodium-rich material to balance the sodium loss, the sodium-poor material resulted in a negative sodium balance. A study of renal histology following administration of osmotic diuretics, such as mannitol, glucose, and sucrose, reveals that within minutes after starting a continuous infusion, cells located in the proximal tubule become edematous and develop vacuolization? 6-19" Kidneys from 3 animals in the
Volume 76 Number 1
present study exhibited a similar type of vacuolization. The failure to Observe changes in all animals may be related to the degree a n d duration of osmotic diuresis as well as to the type of osmotic agents employed, T h e presence of dilated tubules and collecting ducts in most of the kidneys was felt to be a reflection of the increased intratubular volume that occurs in osmotic diuresis. Two types of changes in the proximal tubule were noted in the infants. The presence of nonlipid, nonglycogen vacuoles in the kidneys of one and possibly 2 o f the infants may reflect the effect of an osmotic diuresis. The vacuolar changes regress with time and apparently do not have a permanent effect on renal function. Lipld-containing vacuoles, seen in 2 cases, have been described previously i n newborn infants 31 and may be attributed in part to anoxia. Previous studies have n o t revealed histologic changes following administration of meglumine diatrizoate, 2~ although severe changes, including cortical necrosis, have been described following administration of other agents.2, ~, 20 Medullary necrosis has not been described previously following administration of angiographic media. That it occurred in 3 infants suggests some relationship to the injection of dye. The precise etiology of medullary necrosis is unclear, although vascular stasis may play a significant role? 2 In newborn infants, who may have a very small medullary flow, general hypoxia or localized ischemia can have severe effects on medullary tissue. It is suggested that the medullary necrosis observed in these infants may have resulted from diminution in oxygen delivery to the renal medulla. During angiography, injection was made into the left side of the heart, permitting a relatively undiluted bolus to reach the kidney. Toxicity of the contrast media appears to be dose related; no infant receiving less than 3 ml. per kilogram developed hematuria arid only one receiving less than that dose developed histologic abnormalities. It is of interest that the infant who developed medullary necrosis after re-
Effects of angiography on renal [unction
47
ceiving only 1.1 m l : per kilogram had an arterial oxygen saturation of only 47 per cent. SUMMARY
Of 34 children who died following cardiac angiography, renal medullary necrosis was found in 3 and severe proximal tubular vacuolization was found in 4. Of 100 children studied before and after angiography, none over 3 months of age, but 8 of 30 infants less than 3 months of age, developed hematuria, which persisted as long as: 28 hours. Hematuric infants had received a total dose of contrast material of more than 3 ml. p e r kilogram, whereas the other infants were given less than 3 ml. per kilogram. To extend these investigations, either sodium-rich or sodium-poor contrast material was injected into the ascending aortas Of 8 newborn piglets. An average decrease of 40 per cent in the clearance of ~PAH was observed; there were no consistent changes in rates of glomerular filtration, suggesting an increase in renal vascular resistance. Examination of the kidneys revealed tubular epithelial vacuolization regarded as an osmotic effect in 3 of the 8 animals. On the basis of these clinical, functional, and histologic findings, it is concluded that angiographic materials must be considered to be nephrotoxic. The toxicity appears to be related to the production of an osmotic diuresis and renal ischemia. The authors gratefully acknowledge the assistance of Richard Greisberg, Armida B. Martinez, and Lilliane B. Velez. REFERENCES
1. Hall, J. W., and Childs, D. S., Jr.: The effect of diagnostic and therapeutic roentgenologic procedures on renal function, Med. Clin. N. Amer. 50: 969, 1966. 2. McCallister, B. D., Hunt, J. C., and Kincaid, O. W.: Unilateral renal atrophy subsequent to renal arteriography, Proc. Mayo Clin. 37: 323, 1962. 3. Killen, D. A., and Foster, J. H.: Severity of renal injury incident to abdominal aortography: Effect of concentration of contrast solution, Arch. Surg. 87: 650, 1963.
48
Gruskin et al.
4. Kirkland, J. A., and Haslock, M. R.: Transient proteinuria following intravascular injection of contrast media, Lancet 1: 693, 1961. 5. Lasser, E. C., Lee, S. H., Fisher, E., and Fisher, B.: Some further pertinent considerations regarding the comparative toxicity of contrast materials for the dog kidney, Radiology 78: 240, 1962. 6. McAfee, J. G.: A survey of complications of abdominal aortography, Radiology 68: 825, 1957. 7. Bunnell, I. L., and Greene, D. G.: Rewards and hazards of selective renal arteriography, J. A. M. A. 194: 1177, 1965. 8. Mullady, T. F., Wakim, K, G., Hunt, J. C., and Kincaid, O. W.: Effects of diatrizoate sodium on kidney function in dogs, J, A. M. A. 184: 716, 1963. 9. Rhea, W. G., Jr., Killen, D. A., and Foster, J. H.: Renal recovery following contrast medium injury, Surgery 57: 53, 1965. I0. Stokes, J. M., and Bernard, H. R.: Nephrotoxicity of iodinated contrast media: Quantitative effects of high condg~trations upon glomerular and tubular functions, Ann. Surg. 153: 299, 1961. 11. Leadbetter, G. W., Jr., and Markland, C.: Evaluation of techniques and complications of renal angiography, New Eng. J. Med. 266: 10, 1962. 12. Sidd, J. J., and Decter, A.: Unilateral renal damage due to massive contrast dye injection with recovery, J. Urol. 97: 30, 1967. 13. Sako, Y.: Circulatory changes provoked by contrast media, Surg. Forum 13: 121, 1962. 14. Edelmann, C. M., Jr., Rodriguez Soriano, J., Boichis, H., Gruskln, A. B., and Acosta, M. I.: Renal bicarbonate reabsorption and hydrogen ion excretion in normal infants, J. Clin. Invest. 46- 1309, 1967. 15. Rubin, M. I., Bruck, E., and Rapaport, M.: Maturation of renal function in childhood, J. Clin. Invest. 28" 1144, 1949. 16. DiScala, V. A., Mautner, W., Cohen, J. A., Levitt, M. F., Churg, J., and Yunis, S. L.: Tubular alterations produced by osmotic diuresis with mannitol, Ann. Intern. Med. 63: 767, 1965. 17. Wang, K. M.: Morphological and histochemical changes in the kidney of the sucrose-fed rats, Acta Histochem. 18: 95, 1964. 18. Trump, B. F., and Janigan, D. T.: The pathogenesis of cytologic vacuolization in
The Journal of Pediatrics January 1970
19.
20.
21.
22. 23.
24.
25. 26. 27.
28. 29.
30.
31. 32.
sucrose nephrosis. An electron microscopic and histochemical study, Lab. Invest. 11: 395, 1962. Latta, i . , Benscome, S. A., Knigge, K. M., and Madden, S. C.: Extracellular comuartments in renal tubules assoclated with polyuria from glucose imbibition, Lab. Invest. I1: 569, 1962. Morris, S. E., Lasser, E. C., Fisher, B., Lee, S. H., and Granke, R. C.: A comparative experimental approach to contrast materials in renal angiography, Radiology 77: 764, 1961. Hollenberg, N. K., Epstein, M., Basch, I., and Merrill, J. P.: Intrarenal blood flow distribution in hypertensive man, J. Clin. Invest. 46: 1072, 1967. Gootman, N.: Unpublished observations. Brown, R., Rahimtoda, S. H., Davis, G. D., and Suan, H. J'. C.: The effect of anglographic contrast medium on circulatory dynamics in man, Circulation 31: 234, 1965. Sigman, E. M., Elwood, C., Reagan, M. E., Morris, A. M., and Catanzaro, A.: The renal clearance of I T M labelled sodium iothalamate in man, Invest. Urol. 2: 432, 1965. Woodruff, M. W., and Malvin, R. L.: Localization of renal contrast media excretion by stop flow analysis, J. Urol. 84: 677, 1960. Gruskm, A. B., Edelmann, C. M., Jr., and Yuan, S.: Maturational changes in renal blood flow, Fed. Proc. 27: 630, 1968. Friis-Hansen, B.: Hydrometry of growth and aging, In Brovek, J., editor: Human body composition, Oxford, 1965, Pergamon Press, p. 197. Bricker, N. S.: The control of sodium excretion with normal and reduced nephron populations, Amer. J. Med. 43: 313, 1967. Levinsky, N. G., and Lalone, R. C.: The mechanism of sodium diuresis after saline infusion in the dog, J. Clin. Invest. 42: 1261, 1963. Dirks, J. H., Cirksena, W. J., and Berliner, R. W.: The effect of saline infusion on sodium reabsorption by the proximal tubule of the dog, J. Clin. Invest. 44: 1t60, 1965. Kwitten, J., and Reiner, L.: Acute tubular nephrosis in the newborn infant, a manifestgtion of anoxia, Pediatrics 33: 380, 1964. Bernstein, J., and Meyer, R.: Congenital abnormalities of the urinary system. II. Renal cortical and medullary necrosis, J. PEDIAT. 59: 657, 1961.
41
Effects of angiograpby on renal function and bistology in infants and piglets Histologic examination of the kidneys of 34 infants who died following cardiac catheterization revealed medullary necrosis in 3 and proximal tubular epithelial vacuolization in another 4. In piglets, intra-aortie administration of either sodium iothalamate or meglumine dlatrizoate caused a prompt and sustained decrease in renal blood flow. Histologlc examination of the kidneys revealed changes in tubular epithelium similar to those observed in the infants. In a prospective study of children undergoing cardiac catheterization, 8 infants developed hematuria after administration of contrast material, 3 to 5 ml. per kilogram of body weight. Hematurla did not occur when the dose did n,ot exceed 3 ml. per kilogram. These studies indicate that contrast material utilized in cardiac catheterization can influence renal function and may produce irreversible renal damage.
Alan B. Gruskin, M.D., Oskar H. Oetliker, M.D., Norman M. Wolfish, M.D., Norman L. Gootman, M.D., Jay Bernstein, M.D., and Chester M. Edelmann, Jr., M.D. ~' BRONX
AND
NEW
HYDE
PARK=
N.
Y.
DIAGNOSTIC INVESTIGATION of many disease states in infants includes arteriographi c visualization of the involved structures, achieved usually by selective injections of large boluses of contrast material From the Departments of Pediatrics and Pathology, Albert Einstein College of Medicine, and the Department of Pediatric Cardiology, Long Island Jewish Hospital. Supported in part by the Rosenburg Toner Heart Fund and United States Public Health Service Research Grants Nos. A M 07840, 5 T I H E 5267, and H E 05561. Address for reprints: Dr. Edelmann, Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris'Park Ave., Bronx, N. Y. 10461. ~Reelpient of Research Career Development Award No. I-K3-HD 19369 ]rom the National Institute of Child Health and Human Development.
under high pressure. Numerous renal complications have been attributed to injections of contrast media into the aorta. 1-12 Since 1964, we have observed 3 cases of medullary necrosis following diagnostic cardiac angiography in infants. Although the mechanism by which radiographic media affect renal function is unclear, hypotheses have included direct renal toxicity, 2, 3 changes in systemic hemodynamics with secondary renal involvement, 13 and primary effects on glomerular filtration rate and renal blood flow. s The purpose of these studies was to examine the effects of injections of contrast media on renal function and histology in children and newborn animals. Vol. 76, No. 1, pp. 41-48
42
Gruskin et al.
MATERIAL
AND METHODS
Piglets. Investigations were performed on 8 unanesthetized female piglets, ranging in age from 6 to 48 hours. The piglets were restrained on their side, and body temperature was maintained by both surgical draping and a heat lamp. The bladder was catheterized with a No. 5 or 8 premature feeding tube. At the end of each period of urine collection, the bladder was emptied by suprapubic compression following instillation of 3 ml. of distilled water and then 10 ml. of room air. Under local lidocaine anesthesia, either the femoral artery and vein or the carotid artery and jugular vein were isolated. Polyethylene catheters were placed through them into the thoracic aorta and vena cava. Arterial blood samples and urine collections were obtained at 15 to 20 minute intervals throughout the study. After collections of control samples of blood and urine, priming solutions of inulin (50 mg. per kilogram of body weight) and para-aminohippurate (PAH) (8 rag. per kilogram) were given intravenously. A continuous infusion, containing sufficient inulin and PAH to maintain blood levels of 25 and 2 mg. per 100 ml., respectively, was given at a rate of 0.4 ml. per minute. Following initial clearance periods, a rapid injection s by hand of 2.5 ml. per kilogram of body weight of either sodium iothalamate (sodium concentration 960 /,Eq per milliliter; osmolality > 3,000 mOsm. per kilogram) or meglumine diatrizoate (sodium concentration 4 /~Eq per milliliter; osmolality > 3,000 mOsm. per kilogram) was made into the aorta. Each piglet received either a single dose of dye or 2 doses 15 minutes apart. Clearance periods of 15 minutes duration were continued for at least one hour following the injection of dye. Upon completion of the study the piglets were killed by intravenous injection of pentobarbital. The correct position of the *Trade and generic terms of contrast material employed: Renovlst--sodlum ~iatrlzoate and meglumlne diatrizoate; Renografin--meglumine dlatrlzoate ; Conray-4OO-sodium iothalamate.
The ]ournal of Pediatrics 1anuary 1970
aortic catheter was verified. T h e kidneys were removed immediately and placed in 10 per cent formalin. Sections of paraffinembedded tissues were stained with hematoxylin and eosin. The chemical methodology employed has been described. 14 Clearances of inulin and PAH were calculated in the usual manner. Fractional excretion of sodium (FNaE) was calculated as follows: Fm~ E
UNa V --
x
100.
CIa X ~Na
UN,V represents the rate of excretion of sodium in the urine and PNa is the concentration of sodium in plasma. Corrections were not made for Donnan equilibria. Children undergoing cardiac catheterization. Urinalyses. Urine was obtained before and after cardiac catheterization in 100 children ranging in age from birth to 16 years. Either sodium iothalamate or sodium and meglumine diatrizoate was employed, and the total amount administered varied from 2 to 5 ml. per kilogram. Single injections did not exceed 1 ml. per kilogram. The majority of these injections were performed from the left atrium or left ventricle. In all patients, urine was collected for 24 hours following the procedure. In those individuals in whom urinary abnormalities were found, collections were continued for 72 hours. All urine was examined for the presence of protein, using 10 per cent sulfosalicylic acid, and the sediment was examined microscopically for red and white blood cells and casts. Histologic changes in the kidneys. Histologic sections of the kidneys were examined in 34 infants who had had cardiac catheterization with or without anglography between 4 days and 4 months of age. The total amount of sodium iothalamate or sodium and meglumine diatrizoate administered during angiography ranged from 0.5 to 5.2 ml. per kilogram. The time of death ranged from 3 hours to 2 years after cardiac catheterization. Routine light microscopy was performed after the sections had been
Volume 76 Number 1
Effects o[ angiography on renal [unction
stained with hematoxylin and eosin and with periodic acid-Schiff stain for glycogen. Fat stains of frozen sections were also done in 3 of the 4 cases in which proximal tubular vacuolization occurred.
RESULTS Piglets. Renal hemodynamics. Data concerning inulin and P A H clearances and filtration fractions are shown in Fig. 1. Each study is represented as a mean control value, a value for the period immediately following injection of contrast material, and a final value representing the mean of the ensuing 45 minutes. In order to compare animals of varying size, the results have. been corrected to one square meter of body surface area. The average control values for inulin clearance (24 mL per minute per square meter), PAH clearance (70 ml. per minute
per square meter), and filtration fraction (0.35) are similar to results obtained in other newborn animals, including man. 15 No consistent changes in these variables were observed in the period immediately following administration of either dye. During the final 45 minutes of each study a consistent drop in P A H clearance and elevation in filtration fraction occurred, without consistent changes in the glomerular filtration rate. Both dyes had the same effects. Sodium excretion. Following injection of contrast material, a persistent increase in the absolute rate and in fractional excretion of sodium occurred in all piglets, despite the large difference in sodium concentrations in the two dyes (Fig. 2). In those animals given a second dose of contrast material, a further increase in the rate of sodium excretion occurred, whereas, in those animals given only a single dose, the rate of sodium excre-
60
~40
110
{ 9o
30
~s
4
2
I
Control
Pre Injection
43
I
O-15rnin.
I
15-60min.
I ~ Post InjectionI
Fig. 1. Renal hemodynamic effects of intra-aortic injection of angiographlc material in piglets. Open circles, meglumine diatrizoate; closed circles, sodium iothalamate.
44
Gruskin et al.
The ]ournal o/ Pediatrics January 1970
SODIUM IOTHALAMATE I
I 15 m
z
N PRE INJECTION
13--
~ ] POST INJECTION
o
11-U
9-o
7--
z 0
5--
co
MEGLUMINE DIATRIZOATE I
I-U
.r
1i I
I
DOUBLE D O S E
I
I
~
I
I
~
I
I
SINGLE DOUBLE DOSE DOSE
I
I
SINGLE DOSE
Fig. 2. Effect of angiographic material on renal excretion of sodium in piglets.
tion fell progressively toward control values. The rate of urine flow followed a similar pattern. In the piglets given sodium iothalamate, 65 to 100 per cent of the administered sodium was excreted; whereas in those piglets given meglumine diatrizoate, the amount of sodium excreted during the study was greater than that given, resulting in a negative sodium balance. Renal histology. Histologic examination of the kidneys showed similar changes in both groups of piglets. Focal tubular dilatation and focal vacuolization within proximal tubular cells were observed in 3 animals. These changes were felt to be similar to those described following administration of various osmotic agents, such as mannitol,lG sucrose,17, is and glucose? 9 Children. Urinalyses. Of the 100 infants and children undergoing cardiac catheterization, 8 of 30 infants aged one day to 3 months developed marked microscopic hematuria (Table I ) . Hematuria did not persist beyond 28 hours. Infants who developed hematuria had received 3 to 5 ml. per kilogram of contrast media, whereas less than
Table I. Urinalyses in infants and children after cardiac angiography
Data Number Abnormalities i n WBC, casts, or protein excretion Injected dose 3 ml./Kg. 3 ml./Kg. Developed hematuria ~> 3 ml./Kg, 3 ml./Kg.
I <~3 months I > 3 months 30
70
0
0
8 22
0 70
8 0
0 0
3 ml. per kilogram was administered to all the others. No changes in rates of excretion of white blood cells, casts, or protein occurred in any subject following angiography. No differences were noted which could be attributed to the various radiographic media utilized.
Histologic changes in kidneys [ollowing angiography. Histologic changes were o b served in the kidneys of 7 of the 34 infants who died after having undergone cardiac study before the age of 4 months. All 7 died
Volume 76 Number 1
Effects o[ angiography on renal [unction
45
Fig. 3. Ischemic necrosis of the renal papilla, demarcated from the rest of the medulla by a hemorrhagic zone, in 4~-day-old infant. (Hematoxylin and eosin stain. Original magnificantion x18.)
24 to 72 hours following study. Three of the 7 had medullary necrosis (Fig. 3). One of the 3 also had sepsis, and bacteria were demonstrated in the renal medulla. The kidneys of the other 4 infants showed severe vacuolization of the proximal tubular epithelium (Fig. 4). In 2 of 3 that were examined, the vacuoles were shown by histologic stains to be negative for fat and glycogen. The quantity of angiogrgphic media administered to these patients was 3 ml. per kilogram or more with the exception of one patient who developed medullary necrosis after receiving only 1.1 ml. per kilogram. This patient had an arterial oxygen
saturation at the time of catheterization of 47 per cent. The other 6 patients had saturations greater than 90 per cent. In total, 16 of the 34 patients received more than 3 ml. per kilogram of contrast media. Of the 16 patients, 7 developed histologic lesions. Since the end of 1965, when the amount of contrast material administered has been less than 3 ml. per kilogram, no histologic lesions have been found in those children who died. DISCUSSION
Intra-arterial injections of contrast media into adult dogs and man have had variable effects on the glomerular filtration rate and
4 6
Gruskin et al.
Fig. 4. Marked vacuolization of epithelium lining the proximal convoluted tubules, compatible with an osmotic effect, in 17-day-old infant. (PAS stain. Original magnification x600.) CpA~x. s, 10, 20 This wide range of response appears to be related to the structure of the dye, the concentration used, and the rate of administration2, ~, 20 The marked drop in PAH clearance in the present studies, combined with a concomitant rise in filtration fraction following dye injection, may be the result of one or more mechanisms. Increased renal efferent arteriofar resistance, redistribution of intrarenal blood flow (with blood being shunted away from the cortex), diminished cardiac output, decreased renal perfusion pressure with appropriate changes in afferent and efferent resistances to allow for continuation of glomerular filtration, or any combination of these factors may be evoked. In adult man, measurements of intrarenal blood flow distribution, utilizing the xenon laa washout technique, before and after selective renal angiography, have shown no change31 This finding of course may not be relevant to infants and young children. Although acute changes in myocardial function 22 and arterial pressure 2a have been observed subsequent to injection of contrast material, the duration of these changes is not sufficiently long Lo explain the changes in renal function. It is likely, therefore, that
The Journal of Pediatrics January 1970
the major effect observed upon renal hemodynamics in the piglets was an increase in renal efferent arteriolar resistance, reflecting a direct effect of the contrast material, although reflexly induced vasocostriction cannot be excluded. Both sodium iothalamate 24 and meglumine diatrizoate ~ are excreted principally by glomerular filtration. As nonreabsorbable substances, they act as osmotic diuretics. The magnitude and duration of diuresis they produce depends upon the concentration of dye reaching the kidney and the length of time taken to clear the dye. Assuming the absence of left-to-right shunts, the total amount of dye reaching the kidney on the primary circulation is related to the fraction of cardiac output that perfuses the kidney. In newborn piglets, the kidney receives an average of 4.8 per cent of the cardiac output. 26 The fractional cardiac output to the kidney increases with age, suggesting that old6r animals might be expected to excrete greater amounts of dye during the primary circulation. Furthermore, administered dye would be diluted rapidly and persist in the newborn infant's relatively large extracellular space 27 for a longer period of time. Thus, the newborn piglet might be expected to have a more prolonged diuresis than an older animal. In addition to the osmotic effects of these agents, other mechanisms involved in the control of sodium excretion may be involved. 2s-a~ Intra-arterial injections of hypertonic material increase the effective arterial volume, causing a secondary sodium and water diuresis by inhibiting sodium reabsorption. Although sufficient sodium was contained in the sodium-rich material to balance the sodium loss, the sodium-poor material resulted in a negative sodium balance. A study of renal histology following administration of osmotic diuretics, such as mannitol, glucose, and sucrose, reveals that within minutes after starting a continuous infusion, cells located in the proximal tubule become edematous and develop vacuolization? 6-19" Kidneys from 3 animals in the
Volume 76 Number 1
present study exhibited a similar type of vacuolization. The failure to Observe changes in all animals may be related to the degree a n d duration of osmotic diuresis as well as to the type of osmotic agents employed, T h e presence of dilated tubules and collecting ducts in most of the kidneys was felt to be a reflection of the increased intratubular volume that occurs in osmotic diuresis. Two types of changes in the proximal tubule were noted in the infants. The presence of nonlipid, nonglycogen vacuoles in the kidneys of one and possibly 2 o f the infants may reflect the effect of an osmotic diuresis. The vacuolar changes regress with time and apparently do not have a permanent effect on renal function. Lipld-containing vacuoles, seen in 2 cases, have been described previously i n newborn infants 31 and may be attributed in part to anoxia. Previous studies have n o t revealed histologic changes following administration of meglumine diatrizoate, 2~ although severe changes, including cortical necrosis, have been described following administration of other agents.2, ~, 20 Medullary necrosis has not been described previously following administration of angiographic media. That it occurred in 3 infants suggests some relationship to the injection of dye. The precise etiology of medullary necrosis is unclear, although vascular stasis may play a significant role? 2 In newborn infants, who may have a very small medullary flow, general hypoxia or localized ischemia can have severe effects on medullary tissue. It is suggested that the medullary necrosis observed in these infants may have resulted from diminution in oxygen delivery to the renal medulla. During angiography, injection was made into the left side of the heart, permitting a relatively undiluted bolus to reach the kidney. Toxicity of the contrast media appears to be dose related; no infant receiving less than 3 ml. per kilogram developed hematuria arid only one receiving less than that dose developed histologic abnormalities. It is of interest that the infant who developed medullary necrosis after re-
Effects of angiography on renal [unction
47
ceiving only 1.1 m l : per kilogram had an arterial oxygen saturation of only 47 per cent. SUMMARY
Of 34 children who died following cardiac angiography, renal medullary necrosis was found in 3 and severe proximal tubular vacuolization was found in 4. Of 100 children studied before and after angiography, none over 3 months of age, but 8 of 30 infants less than 3 months of age, developed hematuria, which persisted as long as: 28 hours. Hematuric infants had received a total dose of contrast material of more than 3 ml. p e r kilogram, whereas the other infants were given less than 3 ml. per kilogram. To extend these investigations, either sodium-rich or sodium-poor contrast material was injected into the ascending aortas Of 8 newborn piglets. An average decrease of 40 per cent in the clearance of ~PAH was observed; there were no consistent changes in rates of glomerular filtration, suggesting an increase in renal vascular resistance. Examination of the kidneys revealed tubular epithelial vacuolization regarded as an osmotic effect in 3 of the 8 animals. On the basis of these clinical, functional, and histologic findings, it is concluded that angiographic materials must be considered to be nephrotoxic. The toxicity appears to be related to the production of an osmotic diuresis and renal ischemia. The authors gratefully acknowledge the assistance of Richard Greisberg, Armida B. Martinez, and Lilliane B. Velez. REFERENCES
1. Hall, J. W., and Childs, D. S., Jr.: The effect of diagnostic and therapeutic roentgenologic procedures on renal function, Med. Clin. N. Amer. 50: 969, 1966. 2. McCallister, B. D., Hunt, J. C., and Kincaid, O. W.: Unilateral renal atrophy subsequent to renal arteriography, Proc. Mayo Clin. 37: 323, 1962. 3. Killen, D. A., and Foster, J. H.: Severity of renal injury incident to abdominal aortography: Effect of concentration of contrast solution, Arch. Surg. 87: 650, 1963.
48
Gruskin et al.
4. Kirkland, J. A., and Haslock, M. R.: Transient proteinuria following intravascular injection of contrast media, Lancet 1: 693, 1961. 5. Lasser, E. C., Lee, S. H., Fisher, E., and Fisher, B.: Some further pertinent considerations regarding the comparative toxicity of contrast materials for the dog kidney, Radiology 78: 240, 1962. 6. McAfee, J. G.: A survey of complications of abdominal aortography, Radiology 68: 825, 1957. 7. Bunnell, I. L., and Greene, D. G.: Rewards and hazards of selective renal arteriography, J. A. M. A. 194: 1177, 1965. 8. Mullady, T. F., Wakim, K, G., Hunt, J. C., and Kincaid, O. W.: Effects of diatrizoate sodium on kidney function in dogs, J, A. M. A. 184: 716, 1963. 9. Rhea, W. G., Jr., Killen, D. A., and Foster, J. H.: Renal recovery following contrast medium injury, Surgery 57: 53, 1965. I0. Stokes, J. M., and Bernard, H. R.: Nephrotoxicity of iodinated contrast media: Quantitative effects of high condg~trations upon glomerular and tubular functions, Ann. Surg. 153: 299, 1961. 11. Leadbetter, G. W., Jr., and Markland, C.: Evaluation of techniques and complications of renal angiography, New Eng. J. Med. 266: 10, 1962. 12. Sidd, J. J., and Decter, A.: Unilateral renal damage due to massive contrast dye injection with recovery, J. Urol. 97: 30, 1967. 13. Sako, Y.: Circulatory changes provoked by contrast media, Surg. Forum 13: 121, 1962. 14. Edelmann, C. M., Jr., Rodriguez Soriano, J., Boichis, H., Gruskln, A. B., and Acosta, M. I.: Renal bicarbonate reabsorption and hydrogen ion excretion in normal infants, J. Clin. Invest. 46- 1309, 1967. 15. Rubin, M. I., Bruck, E., and Rapaport, M.: Maturation of renal function in childhood, J. Clin. Invest. 28" 1144, 1949. 16. DiScala, V. A., Mautner, W., Cohen, J. A., Levitt, M. F., Churg, J., and Yunis, S. L.: Tubular alterations produced by osmotic diuresis with mannitol, Ann. Intern. Med. 63: 767, 1965. 17. Wang, K. M.: Morphological and histochemical changes in the kidney of the sucrose-fed rats, Acta Histochem. 18: 95, 1964. 18. Trump, B. F., and Janigan, D. T.: The pathogenesis of cytologic vacuolization in
The Journal of Pediatrics January 1970
19.
20.
21.
22. 23.
24.
25. 26. 27.
28. 29.
30.
31. 32.
sucrose nephrosis. An electron microscopic and histochemical study, Lab. Invest. 11: 395, 1962. Latta, i . , Benscome, S. A., Knigge, K. M., and Madden, S. C.: Extracellular comuartments in renal tubules assoclated with polyuria from glucose imbibition, Lab. Invest. I1: 569, 1962. Morris, S. E., Lasser, E. C., Fisher, B., Lee, S. H., and Granke, R. C.: A comparative experimental approach to contrast materials in renal angiography, Radiology 77: 764, 1961. Hollenberg, N. K., Epstein, M., Basch, I., and Merrill, J. P.: Intrarenal blood flow distribution in hypertensive man, J. Clin. Invest. 46: 1072, 1967. Gootman, N.: Unpublished observations. Brown, R., Rahimtoda, S. H., Davis, G. D., and Suan, H. J'. C.: The effect of anglographic contrast medium on circulatory dynamics in man, Circulation 31: 234, 1965. Sigman, E. M., Elwood, C., Reagan, M. E., Morris, A. M., and Catanzaro, A.: The renal clearance of I T M labelled sodium iothalamate in man, Invest. Urol. 2: 432, 1965. Woodruff, M. W., and Malvin, R. L.: Localization of renal contrast media excretion by stop flow analysis, J. Urol. 84: 677, 1960. Gruskm, A. B., Edelmann, C. M., Jr., and Yuan, S.: Maturational changes in renal blood flow, Fed. Proc. 27: 630, 1968. Friis-Hansen, B.: Hydrometry of growth and aging, In Brovek, J., editor: Human body composition, Oxford, 1965, Pergamon Press, p. 197. Bricker, N. S.: The control of sodium excretion with normal and reduced nephron populations, Amer. J. Med. 43: 313, 1967. Levinsky, N. G., and Lalone, R. C.: The mechanism of sodium diuresis after saline infusion in the dog, J. Clin. Invest. 42: 1261, 1963. Dirks, J. H., Cirksena, W. J., and Berliner, R. W.: The effect of saline infusion on sodium reabsorption by the proximal tubule of the dog, J. Clin. Invest. 44: 1t60, 1965. Kwitten, J., and Reiner, L.: Acute tubular nephrosis in the newborn infant, a manifestgtion of anoxia, Pediatrics 33: 380, 1964. Bernstein, J., and Meyer, R.: Congenital abnormalities of the urinary system. II. Renal cortical and medullary necrosis, J. PEDIAT. 59: 657, 1961.