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Renal failure following major angiography
Renal Failure Following Major Angiography
RICHARD D. SWARTZ,
M.D.
JAMES E. RUBIN, M.D. BRIAN W. LEEMING, M.D. PATRICIO SILVA,
M.D.
l
Boston, Massachusetts
From the Thorndike Laboratory, the Department of Medicine, and the Department of Diagnostic Radiology, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts. This study was supported by Grant 5TOl-AM05555 from the U.S. Public Health Service (R.D.S. and J.E.R.). Requests far reprints shoufd be addressed to Dr. Patricia Sllva, Renal Unit, Beth Israel Hospital, 370 Brookline Avenue, Boston, Massachusetts 02215. Manuscript accepted January 5, 1978. Established Investigator, American Heart Association. l
Acute renal failure following angiography with contrast agents ts known to occur, but the circumstances and frequency of its occurrence are not well described. A retrospective review of consecutive angiographic procedures performed over a six month interval revealed a 12 per cent lnctdence of renal faifure tottowIng angiography. The degree of failure was severe In approximately 30 per cent of these cases and was associated with a stgniflcant mortality even though renal function usually recovered. The occurrence of renal failure was associated with the presence of renal insufficiency, impaired liver function, diabetes mellttus, hypoalbuminemla and proteinuria at the time of anglography to a statlstically significant level. Furthermore, combinations of these factors, particularly preextstlng comblned renal insuffkiency and impaked liver function, were associated with an increased incidence of acute renal failure. It is concluded that angiography poses a significant hazard to patients with underlytng medical problems, particularly those involving the excretory routes of the contrast agent. Although the nephrotoxicity of roentgenographic contrast agents is recognized in several clinical settings, it has been difficult to identify precisely those patients who are particularly predisposed to this complication. Recent reports have stressed the potential danger of irreversible loss of renal function in diabetic patients undergoing such diagnostic studies [l-5]. Earlier reports suggested that patients with multiple myeloma were also at risk following the administration of contrast agents although the advent of water-soluble contrast agents has decreased this risk considerably [6-81. Beyond these few welldescribed situations, there is only speculation concerning additional clinical conditions in which contrast agent nephrotoxicity is likely to develop. There are reports suggesting that volume depletion or dehydration [3,4,8-l I], preexisting renal disease [ 6,9, lo], impaired liver function [6,9,10] and increased dose of agent [2,6,10,12,13] predispose to loss of renal function, but the etiologic association of these factors remains to be proved. A recent increase in the number of consultations for renal failure following the administration of contrast agents for major abdominal angiography has prompted us to review the problem at our institution. Since such diagnostic studies are often undertaken in patients with complicated medical illnesses in which one or more of the previously mentioned risk factors are present, it woutd be advantageous to identify those factors which definitely predispose to renal toxicity. With this information, we can better evaluate the potential risk and benefit of these invasive procedures. Using the cases coming to our attention
July 1979
The American Journal of Medlclne
Volume 65
31
RENAL FAILURE AFTER MAJOR ANGIOGRAPHY-SWARTZ
ET AL.
as an index group, we undertook to review the larger group of all patients undergoing similar roentgenologic studies in the same time period. By comparing the group of patients in whom renal failure developed after they received contrast agents with the group of unaffected patients, we were able to identify circumstances in which an adverse outcome from the roentgenologic procedures was more likely to occur. Furthermore, the spectrum of identified factors allowed us to speculate more definitively on the possible mechanism(s) of toxicity. METHODS An index group of eight patients required nephrologic consultation at the Beth Israel Hospital because of the development of acute renal failure after the administration of contrast agents in the inclusive period from January to June 1976. In seven of the eight cases the patients had undergone angiographic study, and one had undergone combined oral and intravenous cholangiography. The population chosen for review consisted of all inpatients who underwent an angiographic study other than cardiac or cerebral angiography at Beth Israel Hospital over the same six month interval. It was reasoned that this larger group represented a population closely approximating the index group because (1) the large doses and mode of administration of contrast agent were similar, (2) all such patients were hospitalized for angiography and had complicated medical conditions and (3) ample procedure notes, follow-up laboratory data and clinical records were more readily available. Since the contrast agent used in cholangiography differs from that used in vascular angiography, the patient in whom renal failure developed after cholangiography will be described, but will not be included in the tabulation of data and statistics in this report. The agents employed in the angiographic studies were meglumine and sodium diatrizoate,” or sodium iotha1amate.t Doses reported here are only those specifically recorded in angiography or clinical records, as reviewed by an experienced angiographer, and represent conservative estimates. Routes of administration, volume of injection and specific injection sites were determined by the requirements of the diagnostic or therapeutic study at the discretion of the angiographer; these data are not reported here. In all the studies reported here, it was routine for patients to receive 5 per cent dextrose in water at a rate of 60 ml/hour for the duration of the roentgenologic procedure. For the purposes of this review, acute renal failure following angiography was defined as an increase in the blood urea nitrogen of 50 per cent or 20 mg/dl, and/or an increase in the serum creatinine of 50 per cent or 1 mg/dl, within 46 hours of the angiography procedure. Patients were not considered to have contrast agent toxicity if another etiology of the renal failure was likely from the clinical record. Those cases in which gastrointestinal bleeding was present were excluded if any rapid change in blood pressure or clinical evidence of bleeding was temporally related to the develRenografin-60, Renografin-76; E. R. Squibb & Sons; Princeton, N.J. t Conray-60; Mallinckrodt Chemical Works; St. Louis, MO. l
32
July 1978
The American Journal of Medicine
Volume 85
opment of acute renal failure. The presence of the following clinical factors before angiography was extracted from case records, when available: (1) preexisting renal insufficiency, defined as a blood urea nitrogen of 30 mg/dl or more, or a serum creatinine of 1.8 mg/dl or more; (2) hepatic cirrhosis or impaired liver function, the latter being defined as an abnormality in any two of the serum glutamic-oxaloacetic transaminase, alkaline phosphatase and serum total bilirubin; (3) low serum albumin, defined as a concentration of 3 g/d1 or less; (4) increased urinary concentration as an index of dehydration, defined as a specific gravity of 1.020 or more in the absence of glucosuria or heavy proteinuria; (5) pathologic proteinuria, defined as a “spot” urine protein of 300 mg/liter or more; (6) gout or hyperuricemia, the latter being defined as a serum uric acid of 7 mg/dl or more; (7) diabetes mellitus, or an abnormality in a glucose tolerance test, or a random blood sugar of 250 mg/dl or more; (8) acute reactions to the contrast agent or to the angiographic procedure, including allergic symptoms, abrupt changes in blood pressure or pulse rate, and blood loss; and (9) the administration of any sedative or vasoactive medications during the procedure. For the purposes of this review, it was assumed that when renal function was not measured after the administration of the contrast agent, the renal function remained unchanged. Although this assumption may exclude some cases of unrecognized mild renal insufficiency, it allows determination of the minimum incidence of nephrotoxicity as well as the attendant clinical features in the well defined cases. Statistical treatment of data includes the Student’s “t” test for comparing the mean of different groups, and the “chi square” test for comparing the frequency of specific factors between groups. All numerical data are expressed as the mean f the standard error of the mean (SEM) when applicable.
RESULTS The records of 109 patients who underwent angiography over a six month period were reviewed. This number represents over 90 per cent of cases for that time period and excludes only those cases in which recorded data were unavailable. In addition to the eight cases that prompted this review, another six cases of unrecognized renal failure following administration of contrast media were discovered. Table I lists the clinical features of the 13 cases of renal failure following angiography and the single case following cholangiography. As already noted, available data precluded other explanations for changes in renal function in these 14 cases. For example, three patients (Cases 2.7 and 10) had upper gastrointestinal bleeding at the time of angiography, but renal function parameters had been stable or improved until immediately after the administration of the contrast agent. Data seldom indicated volume depletion or dehydration before or after administration of the contrast agent in the total group of patients. Finally, we would emphasize that all data regarding acute reactions and dose of contrast media are taken from specific recorded
RENAL FAILURE AFTER MAJOR ANGIOGRAPHY--SWARTZ
notes, and these data are minimum estimates of the incidence of complications and doses of agent. Table I demonstrates that patients in whom acute renal failure developed had complicated medical or surgical diseases requiring intensive diagnostic investigation, and that abdominal or renal angiography was generally the study performed. The low frequency of particular diagnoses among these patients, however, precluded any specific conclusions based on diagnosis. The estimated total dose of contrast agent ranged from 30 g iodine to 146 g iodine, and the estimated timed dose from 12 g iodine/hour to 42 g iodine/hour. Preexisting renal insufficiency was present in nine of 13 patients in whom acute renal failure developed after angiography, and was mild in all patients except one (Case 9, Table I). Proteinuria was present in four patients, three of whom had preexisting renal insufficiency as well. Liver function was abnormal in six of 13 patients at the time of angiography, and serum albumin was decreased in six of 12 patients in whom it was measured. Diabetes mellitus was present in eight patients. Dehydration, as evidenced by an increase in urine specific gravity, was present in three patients. Only two patients had noteworthy acute reactions to angiography, one having a 20 to 30 mm Hg decrease in blood pressure, and the other having a slow, 300 cc blood loss from the angiography site. The over-all incidence of acute blood pressure changes or recorded weight loss following angiography was low in these patients, as well as in the control group. Two patients received tolazoline, a vasodilator, one patient received vasopressin for gastrointestinal bleeding, and four patients received sedation with morphine or diazepam. (The single patient with acute renal failure following cholangiography had preexisting renal insufficiency with abnormal liver function and hypoalbuminemia.) The development of acute renal failure after angiography was characterized by oliguria in Cases 1,3,4 and 9 (as well as 14) in which loss of function was severe. When measured, urine sodium was greater than 20 meq/liter, but measurements were often taken after administration of furosemide or parenteral sodium, and diagnostic interpretation was not warranted. Dialysis was required for uremic complications in two cases that occurred after angiography (and the case that followed cholangiography). Recovery of renal function, to levels equal to or better than those before angiography, was observed in 90 per cent of patients. The ultimate prognosis, however, was poor in this group, with death during the hospitalization under review in five of 13 patients who underwent angiography. The role of acute renal failure in this outcome is speculative, but acute renal failure obviously worsened the outlook for some patients. Table II compares the frequency of several underlying pathologic factors in both the group of patients in whom
ET AL.
acute renal failure developed and the group of patients with an uneventful outcome. Several results are immediately apparent in the group manifesting renal failure following administration of the contrast agent. This group tended to be older and to have received a higher dose of contrast agent, although these differences were not statistically significant. They had a significantly higher prevalence of preexisting renal insufficiency, impaired liver function and hypoalbuminemia. This group also had a higher prevalence of diabetes mellitus, often with severe peripheral vascular disease, and proteinuria was significantly more common, although high urine concentration was not. Finally, there was no significant increase in the prevalence of hyperuricemia, in the incidence of acute reactions or in the administration of additional drugs among the group of patients in whom nephrotoxicity developed. Table Ill illustrates the higher prevalence of multiple factors among the patients who manifested nephrotoxicity. Risk factors tabulated here were those which were found to be significantly associated with the development of acute renal failure, as previously described in Table II. Eighty-five per cent (11 of 13) of the patients in whom acute renal failure developed had two or more risk factors present at the time of angiography, whereas only 22 per cent (21 of 95) of unaffected patients had two or more risk factors present at the time of angiography. The mean number of risk factors prevalent in the former group was 2.5 and was significantly higher (p
July 1978
The American Journal of Mediclne
Volume 85
33
66.M
2
65.M
56.F
29.M
5 1,M Hypercalcemia
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55,M
52.M
6
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Hepatic
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outcoms DlRenal alysts Recovery Death
l
This case is described for purposes of illustrating the same spectrum of underlying factors in a case of renal failure following a procedure other than angiography; this case is not included in statistical analysis or tabulation of data in angiography cases.
Cirrhosis, vascular disease Polyarteritis
? Vasculitis
Parathyroid
Mallory-Weiss Abdominal syndrome Malnutrition, Abdominal gastrointestinal
90.M
Cirrhosis hepatoma Cirrhosis, gastrointestinal bleeding Hypernephroma Renovascular hypertension Cirrhosis, colon bleeding Peripheral vascular disease Gastrointestinal bleeding ? Pancreatic carcinoma
MajorDfaffsosss
ConcenAbnormal Low High Mine Serum Diabetes Uric Urine trated Acute BUNlCreatlnine Llvsr Dose g g/hr Before After Funcffsn AlbumIn Mslllfus ACM Prolefn Urine Reactions Dfher Drqs OlQurla
Patients in Whom Renal Failure Developed Following Angiography
7
72.M
75.F
73,M 69,F
75.M
1
Case (yr) and No. Sex
Age
TABLE I
RENAL FAILURE AFTER MAJOR ANGIOGRAPHY---SWARTZ
may run from 10 to 15 per cent, with severe renal failure occurring in about one-third of the cases. Although many diabetic patients undergo angiography without incident, the well-documented predisposition of diabetic patients to this complication is supported by the present data. There is a striking prevalence of underlying renal insufficiency and impaired liver function in the cases of acute renal failure reviewed here, as well as the presence of hypoalbuminemia and proteinuria. Several reports have suggested that renal and liver disease may be factors in the predisposition to contrast agent toxicity, [6,9, lo] whereas other investigators have been unable to demonstrate deterioration of renal function in patients with renal impairment, hepatic impairment or both [ 181. The discrepancy between these latter reports and our own data may well reflect the type of roentgenologic procedure under review, the dose and route of administration of contrast agent, and/or the selection of patients inherent to each report. In the present review, patients underwent angiography rather than urography, administration was generally intraarterial in the abdomen rather than intravenous, and our patient group may well have had more severe medical problems, which our data clearly show are important determinants of complications. Other clinical parameters are conspicuous in the present review for their lack of association with contrast agent nephrotoxicity. Increased urinary concentration and other evidence of fluid depletion at the time of angiography were uncommon in either group of patients listed in Table II. This finding probably reflects the recent increased attention to fluid status during roentgenographic procedures, prompted by reports suggesting enhanced toxicity in the presence of depletion [3,4,8-l 11. Likewise, acute allergic and hemodynamic reactions to contrast agent, well-described in large scale case reviews [ 15,161, were unusual in our patients and were not particularly associated with the development of renal failure. Finally, use of sedative or vasoactive drugs was not more frequent among affected patients. Although previous case reports suggest that contrast agent toxicity is dose related [6,10,13,17], we were unable to document dose as a significant independent factor. It is well known that the major route of excretion of the agents studied here is via the kidney, and that liver excretion becomes significant in the presence of renal insufficiency [6,19]. It has been demonstrated that the half-life of these agents is prolonged in the presence of impairment of the excretory routes [ 14,181, thus it would not be surprising to find enhanced toxicity of any dose of contrast agent in the presence of impaired renal and/or liver function. Our data, in fact, confirm that the presence of impairment of the excretory mechanisms is a more important factor than the actual dose of
ET AL..
Prevalence of Clinically Determined Risk Factors at the Time of Angiography in Cases in Which Renal Failure Developed
TABLE ii
Without With RenalFailure RenalFailure
Data
P Value
Age W
66f4’
56 f 2‘
N.S.+
Dose of contrast agent g iodine g iodine/hour Renal insufficiency Abnormal liver function Hypoalbuminemia Diabetes mellitus Proteinuria Concentrated urine High uric acid Acute reactions Sedative drugs Vasoactive drugs
75 f 9’ 22 f 3’ 9113 6113 6112 8113 4112 2112 4/a 219 4113 3113
53 f 4’ 18f 1’ 28195 13181 9163 32190 5180 21179 16144 14181 44195 10192
N.S.+ N.S.’ p
Mean f standard error of the mean. + Student’s “t” test; N.S. = not significant. $ “Chi square” test: N.S. = not significant. l
contrast agent used. Hypoalbuminemia may influence contrast agent toxicity in a similar way, enhancing the initial blood concentration of the agent by decreasing the effective vascular volume into which the agent is injected. Although protein binding of the agent may also be affected in hypoalbuminemia, this is probably of little importance with the agents under consideration in this review, since they are largely unbound in plasma
c121.
Since the dose of contrast agent does not correlate well with the development of acute renal failure, it would be useful to know if direct injection of the agent into the renal artery is associated with a higher incidence of acute renal failure. Table IV shows the outcome among patients who underwent selective unilateral or bilateral renal angiography. These patients are also divided according to the presence or absence of preexisting renal insufficiency. It is important to note that acute renal
Prevalence of Multiple Risk Factors at the Tlme of Anglography in Cases In Which Renal Failure Developed
TABLE ill
0
Data With renal failure Without renal failure
Frequencyof Risk Factors’ 1 2 3 4
2.5 f 0.3+ (p
11524
41
33
Mean Risk Factors per Case
12
7
2
0.9 f 0.01+
Risk factors are those found to be significant statistically as listed in Table II. + Mean f standard error of the mean. l
July 1978
The
American Journal of Medicine Volume 65
35
RENAL FAILURE AFTER MAJOR ANGIOGRAPHY-SWARTZ ET AL.
TABLE IV
Typeof Anglography Unilateral renal angiography
Bilateral renal angiography
incidence of Renal Failure Following Angiography in Patients Undergoing Selective Renal Angiography
RenalStatus Preexisting renal insufficiency Normal renal function Preexisting renal insufficiency Normal renal function
Casesin Which RenalFailure Developed Total
214 o/7
2/11
O/l Of4
Of5
failure occurred in two patients, both of whom had preexisting renal insufficiency (Cases 3 and 4, Table I). Furthermore, the 13 per cent (two of 16) incidence of acute renal failure in this group of patients undergoing renal angiography is identical to the 12 per cent incidence in the over-all group reviewed in this report. Although the number of procedures shpwn in Table IV is small, these data imply that the process of contrast agent injection directly into the kidney is not more toxic than other modes of administration, unless other complicating risk factors, such as preexisting renal insufficiency, are present. The present review does not approach the problem of contrast agent nephrotoxicity experimentally, but the results may offer some insight into the possible mechanism(s) of the renal injury. For example, the prevalence of proteinuria in affected patients may imply that tubular obstruction by precipitated protein casts in the presence of contrast media is a causative factor in the observed renal failure. This mechanism has been postulated in the past [7,20,21] and could be operative here; but proteinuria is not necessarily an independent risk factor in the development of renal failure, and the postulated mechanism remains speculative. As another example, the failure to demonstrate that rapid hemodynamic changes or vasoactive drug administration were associated with the development of acute renal failure, supports the view that vascular changes play
little role in contrast agent toxicity. The literature is replete with studies which describe alterations in renal blood flow [ 13,22-241, blood viscosity [25], cardiovascular dynamics [ 11,261 and kidney size [27], as well as changes in endogenous vasoactive substances [28]. Such findings are not uniform, however, and other reports tend to minimize their significance [ 29,301, as do our own data. As a final example, uric acid precipitation has been suggested as a mechanism for the renal injury by some contrast agents [31]. The present data would suggest that hyperuricemia is not a significant risk factor, and none of the patients in this review who were examined by our renal group for the development of acute renal failure had uric acid crystalluria characteristic of acute uric acid nephropathy. It would appear from the data presented here that the major identifiable risk factors enhance contrast agent toxicity by one or both of two mechanisms. First, certain conditions, such as diabetes mellitus and perhaps proteinuria, may make the kidney more sensitive to injury by a substance which is directly toxic to the nephron. Second, other conditions, such as renal insufficiency, liver insufficiency and hypoalbuminemia enhance the blood concentration or prolong the elimination of the toxic substance. It would be expected, therefore, that combinations of these risk factors would increase the risk of nephrotoxicity of roentgenographic contrast agents, and our data strongly suggest that this is the case. This hypothesis, of course, does not imply any specific toxic mechanism, since accurate description of that mechanism remains elusive and requires better insight into the nature of toxic acute renal failure itself. Angiography has contributed greatly to our understanding and diagnosis of many disease processes. We recognize that such studies are often necessary, but we would hope that the present data will promote a more objective assessment of the clinical setting in which such procedures are required and in which complications can be anticipated. In this way it will be possible to defer a potentially dangerous study when the benefits are questionable, and to plan ahead for diagnosis and treatment of complications when they are expected.
REFERENCES 1.
2.
3.
4.
36
Barshay ME, Kaye JH, Goldman R, et al.: Acute renal failure in diabetic patients after intravenous infusion pyelography. Clin Nephrol 1: 36, 1973. Bergman LA, Ellison MR. Dunea G: Acute renal failure after drip infusion pyelography. N Engl J Med 279: 1277, 1968. Diaz-Buxo JA, Wagoner RD, Hattery RR, et al.: Acute renal failure after excretory urography in diabetic patients. Ann Intern Med 83: 155, 1975. Pillay VKG, Robbins PC, Schwartz FD, et al.: Acute renal failure following intravenous urography in patients with
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5.
6. 7. 8.
long-standing diabetes mellitus and azotemia. Radiology 95: 633, 1970. Weinrauch LA, Healy RW, Leland OS, et al.: Coronary angiography and acute renal failure in diabetic azotemic nephropathy. Ann Intern Med 86: 56, 1977. Grainger RG: Renal toxicity of radiologic contrast media. Br Med Bull 28: 191, 1972. Lasser Bc, Lang JH, Zawadski ZA: Contrast media. JAMA 198: 945, 1966. Morgan C, Hammack WJ: Intravenous urography in multiple myeloma. N Engl J Med 275: 77, 1966.
RENAL FAILURE AFTER MAJOR ANGIOGRAPHY-SWARTZ ET AL.
9.
Ansari 2, Baldwin D: Acute renal failure due to radio-contrast agents. Nephron 17: 28, 1976. 10. Port FK, Wagoner RD. Fulton RE: Acute renal failure after angiography. Am J Radio1 121: 544, 1974. 11. Obeid Al, Johnson L, Potts J, et al.: Fluid therapy in severe systemic reaction to radiopaque dye. Ann Intern Med 83: 317.1975. 12. Bollerup AC, Hesse B, Steinesse E: Renal handling of iodamide and diatrazoate. Eur J Clin Pharmacol 9: 63, 1975. 13. Lindgren P, Saltzman GF, Tornell G: Vascular reaction to water soluble contrast media. Acta Radio1 Diagn 7: 152, 1968. 14. Becker JA, Berdon WE: Blood clearance of contrast material in patients with impaired renal functii. Radiology 93: 1301, 1969. 15. Davies P, Roberts MB, Roylance J: Acute reactions to urographic contrast media. Br Med J 2: 434, 1975. 16. DeNosaquo N: Reactions to contrast media. Radiology 91: 92, 1968. 17. Fulton. RE, Witten DM, Wagoner RD: Intravenous urography in renal insufficiency. Am J Roentgen01 106: 623, 1969. 18. Davidson AJ, Becker J, Rothfield N, et al.: An evaluation of the effect of high dose urography on previously impaired renal and hepatic function in man. Radiology 97: 249, 1970. 19. Becker JA, Gegoire A, Berdon W, et al.: Vicarious excretion of urographic media. Radiology 90: 243, 1968. 20. Berdon WE, Schwartz RH, Becker J, et al.: Tamm-Horsfall
21.
22.
23. 24. 25. 26.
27. 28. 29.
30.
31.
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proteinuria. Radiology 92: 714, 1969. Schwartz RH, Berdon WE, Wagner J, et al.: Tamm-Horsfall urinary mucoprotein precipitation by urographic contrast agents. Am J Roentgen01 108: 698, 1970. Caldicott WJH, Hollenberg NK, Abrams HL: Characteristics of the response of renal vascular bed to contrast media. Invest Radio1 5: 539, 1970. Fischer HW: Hemodynamic reactions to angiographic media. Radiology 91: 66, 1968. Talner LB, Davidson AJ: Renal hemodynamic effects of contrast media. Invest Radio1 2: 340, 1968. Dean RE, Andrew JH, Read RC: The red cell factor in renal damage from angiographic media. JAMA 187: 27. 1964. Fischer HW, Reuter SR, Moscow NP: Further toxicity studies with methylglucamine contrast agents. Invest Radio13: 324, 1968. Arkless R: The normal kidney’s reaction to intravenous pyelography. J Roentgen01 107: 746, 1969. Branch RC, Rockoff SD, Kuhn C, et al.: Contrast media as histamine liberators. Invest Radio1 5: 510, 1970. Hollenberg NK, Rosen SM. O’Connor JF, et al.: Effect of aortography on renal hemodynamics in normal man. Invest Radio1 3: 92, 1968. Krovetz IJ, Grumbar PA, Hardin S, et al.: Complications following use of four angiographic contrast media in infants and children. Invest Radio1 4: 13, 1969. Mudge GH: Uricosuric action of cholecystographic agents. N Engl J Med 284: 929, 197 1,
The American Journal of Medlclne
Volume 85
37
RICHARD D. SWARTZ,
M.D.
JAMES E. RUBIN, M.D. BRIAN W. LEEMING, M.D. PATRICIO SILVA,
M.D.
l
Boston, Massachusetts
From the Thorndike Laboratory, the Department of Medicine, and the Department of Diagnostic Radiology, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts. This study was supported by Grant 5TOl-AM05555 from the U.S. Public Health Service (R.D.S. and J.E.R.). Requests far reprints shoufd be addressed to Dr. Patricia Sllva, Renal Unit, Beth Israel Hospital, 370 Brookline Avenue, Boston, Massachusetts 02215. Manuscript accepted January 5, 1978. Established Investigator, American Heart Association. l
Acute renal failure following angiography with contrast agents ts known to occur, but the circumstances and frequency of its occurrence are not well described. A retrospective review of consecutive angiographic procedures performed over a six month interval revealed a 12 per cent lnctdence of renal faifure tottowIng angiography. The degree of failure was severe In approximately 30 per cent of these cases and was associated with a stgniflcant mortality even though renal function usually recovered. The occurrence of renal failure was associated with the presence of renal insufficiency, impaired liver function, diabetes mellttus, hypoalbuminemla and proteinuria at the time of anglography to a statlstically significant level. Furthermore, combinations of these factors, particularly preextstlng comblned renal insuffkiency and impaked liver function, were associated with an increased incidence of acute renal failure. It is concluded that angiography poses a significant hazard to patients with underlytng medical problems, particularly those involving the excretory routes of the contrast agent. Although the nephrotoxicity of roentgenographic contrast agents is recognized in several clinical settings, it has been difficult to identify precisely those patients who are particularly predisposed to this complication. Recent reports have stressed the potential danger of irreversible loss of renal function in diabetic patients undergoing such diagnostic studies [l-5]. Earlier reports suggested that patients with multiple myeloma were also at risk following the administration of contrast agents although the advent of water-soluble contrast agents has decreased this risk considerably [6-81. Beyond these few welldescribed situations, there is only speculation concerning additional clinical conditions in which contrast agent nephrotoxicity is likely to develop. There are reports suggesting that volume depletion or dehydration [3,4,8-l I], preexisting renal disease [ 6,9, lo], impaired liver function [6,9,10] and increased dose of agent [2,6,10,12,13] predispose to loss of renal function, but the etiologic association of these factors remains to be proved. A recent increase in the number of consultations for renal failure following the administration of contrast agents for major abdominal angiography has prompted us to review the problem at our institution. Since such diagnostic studies are often undertaken in patients with complicated medical illnesses in which one or more of the previously mentioned risk factors are present, it woutd be advantageous to identify those factors which definitely predispose to renal toxicity. With this information, we can better evaluate the potential risk and benefit of these invasive procedures. Using the cases coming to our attention
July 1979
The American Journal of Medlclne
Volume 65
31
RENAL FAILURE AFTER MAJOR ANGIOGRAPHY-SWARTZ
ET AL.
as an index group, we undertook to review the larger group of all patients undergoing similar roentgenologic studies in the same time period. By comparing the group of patients in whom renal failure developed after they received contrast agents with the group of unaffected patients, we were able to identify circumstances in which an adverse outcome from the roentgenologic procedures was more likely to occur. Furthermore, the spectrum of identified factors allowed us to speculate more definitively on the possible mechanism(s) of toxicity. METHODS An index group of eight patients required nephrologic consultation at the Beth Israel Hospital because of the development of acute renal failure after the administration of contrast agents in the inclusive period from January to June 1976. In seven of the eight cases the patients had undergone angiographic study, and one had undergone combined oral and intravenous cholangiography. The population chosen for review consisted of all inpatients who underwent an angiographic study other than cardiac or cerebral angiography at Beth Israel Hospital over the same six month interval. It was reasoned that this larger group represented a population closely approximating the index group because (1) the large doses and mode of administration of contrast agent were similar, (2) all such patients were hospitalized for angiography and had complicated medical conditions and (3) ample procedure notes, follow-up laboratory data and clinical records were more readily available. Since the contrast agent used in cholangiography differs from that used in vascular angiography, the patient in whom renal failure developed after cholangiography will be described, but will not be included in the tabulation of data and statistics in this report. The agents employed in the angiographic studies were meglumine and sodium diatrizoate,” or sodium iotha1amate.t Doses reported here are only those specifically recorded in angiography or clinical records, as reviewed by an experienced angiographer, and represent conservative estimates. Routes of administration, volume of injection and specific injection sites were determined by the requirements of the diagnostic or therapeutic study at the discretion of the angiographer; these data are not reported here. In all the studies reported here, it was routine for patients to receive 5 per cent dextrose in water at a rate of 60 ml/hour for the duration of the roentgenologic procedure. For the purposes of this review, acute renal failure following angiography was defined as an increase in the blood urea nitrogen of 50 per cent or 20 mg/dl, and/or an increase in the serum creatinine of 50 per cent or 1 mg/dl, within 46 hours of the angiography procedure. Patients were not considered to have contrast agent toxicity if another etiology of the renal failure was likely from the clinical record. Those cases in which gastrointestinal bleeding was present were excluded if any rapid change in blood pressure or clinical evidence of bleeding was temporally related to the develRenografin-60, Renografin-76; E. R. Squibb & Sons; Princeton, N.J. t Conray-60; Mallinckrodt Chemical Works; St. Louis, MO. l
32
July 1978
The American Journal of Medicine
Volume 85
opment of acute renal failure. The presence of the following clinical factors before angiography was extracted from case records, when available: (1) preexisting renal insufficiency, defined as a blood urea nitrogen of 30 mg/dl or more, or a serum creatinine of 1.8 mg/dl or more; (2) hepatic cirrhosis or impaired liver function, the latter being defined as an abnormality in any two of the serum glutamic-oxaloacetic transaminase, alkaline phosphatase and serum total bilirubin; (3) low serum albumin, defined as a concentration of 3 g/d1 or less; (4) increased urinary concentration as an index of dehydration, defined as a specific gravity of 1.020 or more in the absence of glucosuria or heavy proteinuria; (5) pathologic proteinuria, defined as a “spot” urine protein of 300 mg/liter or more; (6) gout or hyperuricemia, the latter being defined as a serum uric acid of 7 mg/dl or more; (7) diabetes mellitus, or an abnormality in a glucose tolerance test, or a random blood sugar of 250 mg/dl or more; (8) acute reactions to the contrast agent or to the angiographic procedure, including allergic symptoms, abrupt changes in blood pressure or pulse rate, and blood loss; and (9) the administration of any sedative or vasoactive medications during the procedure. For the purposes of this review, it was assumed that when renal function was not measured after the administration of the contrast agent, the renal function remained unchanged. Although this assumption may exclude some cases of unrecognized mild renal insufficiency, it allows determination of the minimum incidence of nephrotoxicity as well as the attendant clinical features in the well defined cases. Statistical treatment of data includes the Student’s “t” test for comparing the mean of different groups, and the “chi square” test for comparing the frequency of specific factors between groups. All numerical data are expressed as the mean f the standard error of the mean (SEM) when applicable.
RESULTS The records of 109 patients who underwent angiography over a six month period were reviewed. This number represents over 90 per cent of cases for that time period and excludes only those cases in which recorded data were unavailable. In addition to the eight cases that prompted this review, another six cases of unrecognized renal failure following administration of contrast media were discovered. Table I lists the clinical features of the 13 cases of renal failure following angiography and the single case following cholangiography. As already noted, available data precluded other explanations for changes in renal function in these 14 cases. For example, three patients (Cases 2.7 and 10) had upper gastrointestinal bleeding at the time of angiography, but renal function parameters had been stable or improved until immediately after the administration of the contrast agent. Data seldom indicated volume depletion or dehydration before or after administration of the contrast agent in the total group of patients. Finally, we would emphasize that all data regarding acute reactions and dose of contrast media are taken from specific recorded
RENAL FAILURE AFTER MAJOR ANGIOGRAPHY--SWARTZ
notes, and these data are minimum estimates of the incidence of complications and doses of agent. Table I demonstrates that patients in whom acute renal failure developed had complicated medical or surgical diseases requiring intensive diagnostic investigation, and that abdominal or renal angiography was generally the study performed. The low frequency of particular diagnoses among these patients, however, precluded any specific conclusions based on diagnosis. The estimated total dose of contrast agent ranged from 30 g iodine to 146 g iodine, and the estimated timed dose from 12 g iodine/hour to 42 g iodine/hour. Preexisting renal insufficiency was present in nine of 13 patients in whom acute renal failure developed after angiography, and was mild in all patients except one (Case 9, Table I). Proteinuria was present in four patients, three of whom had preexisting renal insufficiency as well. Liver function was abnormal in six of 13 patients at the time of angiography, and serum albumin was decreased in six of 12 patients in whom it was measured. Diabetes mellitus was present in eight patients. Dehydration, as evidenced by an increase in urine specific gravity, was present in three patients. Only two patients had noteworthy acute reactions to angiography, one having a 20 to 30 mm Hg decrease in blood pressure, and the other having a slow, 300 cc blood loss from the angiography site. The over-all incidence of acute blood pressure changes or recorded weight loss following angiography was low in these patients, as well as in the control group. Two patients received tolazoline, a vasodilator, one patient received vasopressin for gastrointestinal bleeding, and four patients received sedation with morphine or diazepam. (The single patient with acute renal failure following cholangiography had preexisting renal insufficiency with abnormal liver function and hypoalbuminemia.) The development of acute renal failure after angiography was characterized by oliguria in Cases 1,3,4 and 9 (as well as 14) in which loss of function was severe. When measured, urine sodium was greater than 20 meq/liter, but measurements were often taken after administration of furosemide or parenteral sodium, and diagnostic interpretation was not warranted. Dialysis was required for uremic complications in two cases that occurred after angiography (and the case that followed cholangiography). Recovery of renal function, to levels equal to or better than those before angiography, was observed in 90 per cent of patients. The ultimate prognosis, however, was poor in this group, with death during the hospitalization under review in five of 13 patients who underwent angiography. The role of acute renal failure in this outcome is speculative, but acute renal failure obviously worsened the outlook for some patients. Table II compares the frequency of several underlying pathologic factors in both the group of patients in whom
ET AL.
acute renal failure developed and the group of patients with an uneventful outcome. Several results are immediately apparent in the group manifesting renal failure following administration of the contrast agent. This group tended to be older and to have received a higher dose of contrast agent, although these differences were not statistically significant. They had a significantly higher prevalence of preexisting renal insufficiency, impaired liver function and hypoalbuminemia. This group also had a higher prevalence of diabetes mellitus, often with severe peripheral vascular disease, and proteinuria was significantly more common, although high urine concentration was not. Finally, there was no significant increase in the prevalence of hyperuricemia, in the incidence of acute reactions or in the administration of additional drugs among the group of patients in whom nephrotoxicity developed. Table Ill illustrates the higher prevalence of multiple factors among the patients who manifested nephrotoxicity. Risk factors tabulated here were those which were found to be significantly associated with the development of acute renal failure, as previously described in Table II. Eighty-five per cent (11 of 13) of the patients in whom acute renal failure developed had two or more risk factors present at the time of angiography, whereas only 22 per cent (21 of 95) of unaffected patients had two or more risk factors present at the time of angiography. The mean number of risk factors prevalent in the former group was 2.5 and was significantly higher (p
July 1978
The American Journal of Mediclne
Volume 85
33
66.M
2
65.M
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29.M
5 1,M Hypercalcemia
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55,M
52.M
6
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Hepatic
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Oral and intravenous cholangiogram
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outcoms DlRenal alysts Recovery Death
l
This case is described for purposes of illustrating the same spectrum of underlying factors in a case of renal failure following a procedure other than angiography; this case is not included in statistical analysis or tabulation of data in angiography cases.
Cirrhosis, vascular disease Polyarteritis
? Vasculitis
Parathyroid
Mallory-Weiss Abdominal syndrome Malnutrition, Abdominal gastrointestinal
90.M
Cirrhosis hepatoma Cirrhosis, gastrointestinal bleeding Hypernephroma Renovascular hypertension Cirrhosis, colon bleeding Peripheral vascular disease Gastrointestinal bleeding ? Pancreatic carcinoma
MajorDfaffsosss
ConcenAbnormal Low High Mine Serum Diabetes Uric Urine trated Acute BUNlCreatlnine Llvsr Dose g g/hr Before After Funcffsn AlbumIn Mslllfus ACM Prolefn Urine Reactions Dfher Drqs OlQurla
Patients in Whom Renal Failure Developed Following Angiography
7
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75.F
73,M 69,F
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1
Case (yr) and No. Sex
Age
TABLE I
RENAL FAILURE AFTER MAJOR ANGIOGRAPHY---SWARTZ
may run from 10 to 15 per cent, with severe renal failure occurring in about one-third of the cases. Although many diabetic patients undergo angiography without incident, the well-documented predisposition of diabetic patients to this complication is supported by the present data. There is a striking prevalence of underlying renal insufficiency and impaired liver function in the cases of acute renal failure reviewed here, as well as the presence of hypoalbuminemia and proteinuria. Several reports have suggested that renal and liver disease may be factors in the predisposition to contrast agent toxicity, [6,9, lo] whereas other investigators have been unable to demonstrate deterioration of renal function in patients with renal impairment, hepatic impairment or both [ 181. The discrepancy between these latter reports and our own data may well reflect the type of roentgenologic procedure under review, the dose and route of administration of contrast agent, and/or the selection of patients inherent to each report. In the present review, patients underwent angiography rather than urography, administration was generally intraarterial in the abdomen rather than intravenous, and our patient group may well have had more severe medical problems, which our data clearly show are important determinants of complications. Other clinical parameters are conspicuous in the present review for their lack of association with contrast agent nephrotoxicity. Increased urinary concentration and other evidence of fluid depletion at the time of angiography were uncommon in either group of patients listed in Table II. This finding probably reflects the recent increased attention to fluid status during roentgenographic procedures, prompted by reports suggesting enhanced toxicity in the presence of depletion [3,4,8-l 11. Likewise, acute allergic and hemodynamic reactions to contrast agent, well-described in large scale case reviews [ 15,161, were unusual in our patients and were not particularly associated with the development of renal failure. Finally, use of sedative or vasoactive drugs was not more frequent among affected patients. Although previous case reports suggest that contrast agent toxicity is dose related [6,10,13,17], we were unable to document dose as a significant independent factor. It is well known that the major route of excretion of the agents studied here is via the kidney, and that liver excretion becomes significant in the presence of renal insufficiency [6,19]. It has been demonstrated that the half-life of these agents is prolonged in the presence of impairment of the excretory routes [ 14,181, thus it would not be surprising to find enhanced toxicity of any dose of contrast agent in the presence of impaired renal and/or liver function. Our data, in fact, confirm that the presence of impairment of the excretory mechanisms is a more important factor than the actual dose of
ET AL..
Prevalence of Clinically Determined Risk Factors at the Time of Angiography in Cases in Which Renal Failure Developed
TABLE ii
Without With RenalFailure RenalFailure
Data
P Value
Age W
66f4’
56 f 2‘
N.S.+
Dose of contrast agent g iodine g iodine/hour Renal insufficiency Abnormal liver function Hypoalbuminemia Diabetes mellitus Proteinuria Concentrated urine High uric acid Acute reactions Sedative drugs Vasoactive drugs
75 f 9’ 22 f 3’ 9113 6113 6112 8113 4112 2112 4/a 219 4113 3113
53 f 4’ 18f 1’ 28195 13181 9163 32190 5180 21179 16144 14181 44195 10192
N.S.+ N.S.’ p
Mean f standard error of the mean. + Student’s “t” test; N.S. = not significant. $ “Chi square” test: N.S. = not significant. l
contrast agent used. Hypoalbuminemia may influence contrast agent toxicity in a similar way, enhancing the initial blood concentration of the agent by decreasing the effective vascular volume into which the agent is injected. Although protein binding of the agent may also be affected in hypoalbuminemia, this is probably of little importance with the agents under consideration in this review, since they are largely unbound in plasma
c121.
Since the dose of contrast agent does not correlate well with the development of acute renal failure, it would be useful to know if direct injection of the agent into the renal artery is associated with a higher incidence of acute renal failure. Table IV shows the outcome among patients who underwent selective unilateral or bilateral renal angiography. These patients are also divided according to the presence or absence of preexisting renal insufficiency. It is important to note that acute renal
Prevalence of Multiple Risk Factors at the Tlme of Anglography in Cases In Which Renal Failure Developed
TABLE ill
0
Data With renal failure Without renal failure
Frequencyof Risk Factors’ 1 2 3 4
2.5 f 0.3+ (p
11524
41
33
Mean Risk Factors per Case
12
7
2
0.9 f 0.01+
Risk factors are those found to be significant statistically as listed in Table II. + Mean f standard error of the mean. l
July 1978
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American Journal of Medicine Volume 65
35
RENAL FAILURE AFTER MAJOR ANGIOGRAPHY-SWARTZ ET AL.
TABLE IV
Typeof Anglography Unilateral renal angiography
Bilateral renal angiography
incidence of Renal Failure Following Angiography in Patients Undergoing Selective Renal Angiography
RenalStatus Preexisting renal insufficiency Normal renal function Preexisting renal insufficiency Normal renal function
Casesin Which RenalFailure Developed Total
214 o/7
2/11
O/l Of4
Of5
failure occurred in two patients, both of whom had preexisting renal insufficiency (Cases 3 and 4, Table I). Furthermore, the 13 per cent (two of 16) incidence of acute renal failure in this group of patients undergoing renal angiography is identical to the 12 per cent incidence in the over-all group reviewed in this report. Although the number of procedures shpwn in Table IV is small, these data imply that the process of contrast agent injection directly into the kidney is not more toxic than other modes of administration, unless other complicating risk factors, such as preexisting renal insufficiency, are present. The present review does not approach the problem of contrast agent nephrotoxicity experimentally, but the results may offer some insight into the possible mechanism(s) of the renal injury. For example, the prevalence of proteinuria in affected patients may imply that tubular obstruction by precipitated protein casts in the presence of contrast media is a causative factor in the observed renal failure. This mechanism has been postulated in the past [7,20,21] and could be operative here; but proteinuria is not necessarily an independent risk factor in the development of renal failure, and the postulated mechanism remains speculative. As another example, the failure to demonstrate that rapid hemodynamic changes or vasoactive drug administration were associated with the development of acute renal failure, supports the view that vascular changes play
little role in contrast agent toxicity. The literature is replete with studies which describe alterations in renal blood flow [ 13,22-241, blood viscosity [25], cardiovascular dynamics [ 11,261 and kidney size [27], as well as changes in endogenous vasoactive substances [28]. Such findings are not uniform, however, and other reports tend to minimize their significance [ 29,301, as do our own data. As a final example, uric acid precipitation has been suggested as a mechanism for the renal injury by some contrast agents [31]. The present data would suggest that hyperuricemia is not a significant risk factor, and none of the patients in this review who were examined by our renal group for the development of acute renal failure had uric acid crystalluria characteristic of acute uric acid nephropathy. It would appear from the data presented here that the major identifiable risk factors enhance contrast agent toxicity by one or both of two mechanisms. First, certain conditions, such as diabetes mellitus and perhaps proteinuria, may make the kidney more sensitive to injury by a substance which is directly toxic to the nephron. Second, other conditions, such as renal insufficiency, liver insufficiency and hypoalbuminemia enhance the blood concentration or prolong the elimination of the toxic substance. It would be expected, therefore, that combinations of these risk factors would increase the risk of nephrotoxicity of roentgenographic contrast agents, and our data strongly suggest that this is the case. This hypothesis, of course, does not imply any specific toxic mechanism, since accurate description of that mechanism remains elusive and requires better insight into the nature of toxic acute renal failure itself. Angiography has contributed greatly to our understanding and diagnosis of many disease processes. We recognize that such studies are often necessary, but we would hope that the present data will promote a more objective assessment of the clinical setting in which such procedures are required and in which complications can be anticipated. In this way it will be possible to defer a potentially dangerous study when the benefits are questionable, and to plan ahead for diagnosis and treatment of complications when they are expected.
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Barshay ME, Kaye JH, Goldman R, et al.: Acute renal failure in diabetic patients after intravenous infusion pyelography. Clin Nephrol 1: 36, 1973. Bergman LA, Ellison MR. Dunea G: Acute renal failure after drip infusion pyelography. N Engl J Med 279: 1277, 1968. Diaz-Buxo JA, Wagoner RD, Hattery RR, et al.: Acute renal failure after excretory urography in diabetic patients. Ann Intern Med 83: 155, 1975. Pillay VKG, Robbins PC, Schwartz FD, et al.: Acute renal failure following intravenous urography in patients with
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long-standing diabetes mellitus and azotemia. Radiology 95: 633, 1970. Weinrauch LA, Healy RW, Leland OS, et al.: Coronary angiography and acute renal failure in diabetic azotemic nephropathy. Ann Intern Med 86: 56, 1977. Grainger RG: Renal toxicity of radiologic contrast media. Br Med Bull 28: 191, 1972. Lasser Bc, Lang JH, Zawadski ZA: Contrast media. JAMA 198: 945, 1966. Morgan C, Hammack WJ: Intravenous urography in multiple myeloma. N Engl J Med 275: 77, 1966.
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proteinuria. Radiology 92: 714, 1969. Schwartz RH, Berdon WE, Wagner J, et al.: Tamm-Horsfall urinary mucoprotein precipitation by urographic contrast agents. Am J Roentgen01 108: 698, 1970. Caldicott WJH, Hollenberg NK, Abrams HL: Characteristics of the response of renal vascular bed to contrast media. Invest Radio1 5: 539, 1970. Fischer HW: Hemodynamic reactions to angiographic media. Radiology 91: 66, 1968. Talner LB, Davidson AJ: Renal hemodynamic effects of contrast media. Invest Radio1 2: 340, 1968. Dean RE, Andrew JH, Read RC: The red cell factor in renal damage from angiographic media. JAMA 187: 27. 1964. Fischer HW, Reuter SR, Moscow NP: Further toxicity studies with methylglucamine contrast agents. Invest Radio13: 324, 1968. Arkless R: The normal kidney’s reaction to intravenous pyelography. J Roentgen01 107: 746, 1969. Branch RC, Rockoff SD, Kuhn C, et al.: Contrast media as histamine liberators. Invest Radio1 5: 510, 1970. Hollenberg NK, Rosen SM. O’Connor JF, et al.: Effect of aortography on renal hemodynamics in normal man. Invest Radio1 3: 92, 1968. Krovetz IJ, Grumbar PA, Hardin S, et al.: Complications following use of four angiographic contrast media in infants and children. Invest Radio1 4: 13, 1969. Mudge GH: Uricosuric action of cholecystographic agents. N Engl J Med 284: 929, 197 1,
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