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1
Department of Radiology, University of Virginia Health System, Lee St., Box
170, Charlottesville, VA 22908.
2
Department of Health Evaluation Sciences, University of Virginia Health
System, Charlottesville, VA 22908.
3
Department of Medicine, University of Virginia Health System, Charlottesville,
VA 22908.
4
Department of Medicine, Martha Jefferson Hospital, Locust Ave.,
Charlottesville, VA 22901.
Received June 28, 2000;
accepted after revision October 27, 2000.
Presented at the annual meeting of the American Roentgen Ray Society,
Washington, DC, May 2000.
Abstract
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SUBJECTS AND METHODS. One hundred forty-six consecutive patients with chronic renal insufficiency (serum creatinine > 1.5 mg/dL) were examined for renal artery stenosis using CO2 and gadodiamide as the angiographic contrast agents. If renal artery stenosis was detected, percutaneous balloon angioplasty with or without stenting was performed. In patients for whom 48-hr creatinine levels were available, we performed an analysis to determine the incidence of contrast-involved nephropathy (increase in serum creatinine of 0.5 mg/dL at 48 hr without identifiable cause). Major complications were reported up to 1 week, and mortality was reported up to 30 days after the procedure.
RESULTS. Ninety-five patients had serum creatinine levels available at 48 hr. An increase in creatinine of greater than 0.5 mg/dL at 48 hr occurred in three patients (3.2%), presumably caused by CO2, by gadodiamide, or by both. Neither diabetes nor the degree of preexisting chronic renal insufficiency was a predictor of worsening renal function 48 hr after the procedure. The volumes of CO2 and gadodiamide used for diagnostic studies alone versus the volume used for interventional studies was not significantly different (for CO2, p = 0.09; for gadodiamide, p = 0.30). Eleven major complications occurred in eight patients (5.5%). Two deaths (1.4%) occurred within 30 days. One death was due to cholesterol embolization and the other was not believed to be related to the procedure.
CONCLUSION. Angiography and percutaneous treatment of renal artery stenosis in patients with chronic renal insufficiency and suspected ischemic nephropathy can be performed relatively safely using CO2 and gadodiamide as angiographic contrast agents without an increased risk of complications. Contrast-induced nephropathy potentially occurred in 3.2% of patients. Neither the degree of underlying renal insufficiency nor diabetes was a risk factor for predicting a greater likelihood of renal function worsening at 48 hr of follow-up. The volumes of CO2 and gadodiamide used in this study did not result in an increased risk of contrast-involved nephropathy.
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Patients were referred for angiography and potential percutaneous revascularization on the basis of the clinical history and physical examination findings, with or without positive findings on a noninvasive test. Before the procedure, patients were hydrated with a minimum of 300 mL of normal saline solution for 1-3 hr. In patients with no history of congestive heart failure, as much as 1 L of normal saline was administered before the procedure. Antihypertensive medications, with the exception of diuretics, were not withheld before the procedure. Patients received a minimum of 1000 mL of normal saline over a period of 12-18 hr after the procedure.
The diagnostic CO2 and gadodiamide angiography was performed as previously described [6]. Arterial access was obtained via either the common femoral artery or the brachial artery. CO2 angiography was then performed, and 20-30 mL of CO2 was administered with the aid of a bag delivery system into a pigtail catheter (Ultra High-Flow; Mallinckrodt, St. Louis, MO) positioned at the level of the renal arteries. The findings of the CO2 angiography can be confirmed by administering 10-12 mL of gadodiamide at 20-25 mL/sec through the pigtail catheter using a power injector. When stenosis exceeded 50% of the luminal diameter or when a pressure gradient of 20 mm Hg across the lesion was detected, renal percutaneous transluminal angioplasty with or without stent insertion was performed as previously described [7]. Selective angiography of the treated artery before and after intervention was performed with hand injections of 10-20 mL of CO2 or 4-8 mL of gadodiamide, or both, as needed (Fig. 1A,1B,1C,1D,1E). Injections of CO2 and gadodiamide through a 6-French vascular sheath (Balkin; Cook, Bloomington, IN) positioned at or near the renal artery origin provided diagnostic images to monitor progress of the interventional procedure. The total dose of gadodiamide was limited to 0.4 mL/kg of body weight (approximately 40 mL of 0.5 mmol/mL of gadodiamide per 100 lb [45 kg] of body weight).
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Serum creatinine levels were obtained on the day of the procedure before the examination, and at approximately 48 hr (2 days) after the procedure. A change in the serum creatinine level of more than 0.5 mg/dL at 48 hr was considered clinically important [8]. Major complications were defined as events that negatively affected the duration of the patient's hospitalization or necessitated an action (i.e., transfusion) to treat the complication, and were reported at the time of discharge or on readmission within 7 days. Telephone follow-up with the referring physician, the patient, or the patient's family was obtained after 30 days to assess survival and complications.
All data are summarized as median (minimum to maximum) values for continuous variables (i.e., serum creatinine levels) and percentage for categoric variables (e.g., yes or no answers, sex). Difference from baseline was calculated as creatinine measurement at 48 hr minus the baseline creatinine value. Continuous variables compared across categoric variables were tested using Wilcoxon's rank sum tests. Relationships between continuous variables and the difference from baseline were tested using Spearman's rank correlation tests. Categoric variables were compared with other categoric variables using chi-square tests of independence. Age, baseline creatinine value, CO2 volume, and gadodiamide volume were treated as continuous variables for statistical testing but were tabulated in categories that achieve groups of approximately equal size.
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Three (3.2%) patients had no other recognizable cause for the rise in serum creatinine at 48 hr except the use of the contrast agents, CO2 and gadodiamide. All three patients underwent an interventional study. One patient had an increase in serum creatinine level related to dehydration (diarrhea) resulting from transient mesenteric ischemia induced by the CO2. In this patient, bloody diarrhea developed 24 hr after the CO2 angiography. The patient rapidly became dehydrated, with a significant rise in the blood urea nitrogen. Both the serum blood urea nitrogen and the creatinine levels returned to baseline with rehydration. Two patients (2.1%) had no other recognizable cause for the rise in serum creatinine at 48 hr. Therefore, it was presumed that contrast-induced nephropathy resulting from either the CO2 or the gadodiamide was seen in only three patients (3.2%).
The volumes of CO2 and gadodiamide were not significantly different for diagnostic imaging only and for interventional studies (Table 1). The presence or absence of diabetes and the degree of preexisting renal insufficiency were not associated with an increased risk for worsening renal function after the procedure for either the diagnostic imaging only or the interventional group. In addition, the amount of CO2 or gadodiamide was not associated with worsening renal function in the diagnostic group (Table 2). In the interventional group, CO2 and gadodiamide volumes were not associated with an increased incidence of contrast-induced nephropathy; however, larger CO2 volumes (p = 0.0014) and larger gadodiamide volumes (p = 0.035) were associated with a statistically significant increase (but less than the threshold of 0.5 mg/dL used for this study) in creatinine after the procedure (Table 2).
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Eleven major complications occurred in eight patients (5.5%) (Table 3). In this group of patients, the median serum creatinine level before the procedure was 3.3 mg/dL (range, 1.7-5.1 mg/dL), and the median serum creatinine level 48 hr after the procedure was 3.6 mg/dL (range, 1.5-6.4 mg/dL). No complications occurred in the patients undergoing only diagnostic angiography. All major complications occurred in the interventional group. Two patients developed transient mesenteric ischemia, presumably caused by the CO2. One of these patients (who also had a history of atrial fibrillation) suffered a cerebral vascular accident 30 hr after the procedure. Another patient developed unexplained hemolysis that resolved over a 3-week period. This patient was also on antihypertensive medications and received one dose of a cephalosporin. The cause of the hemolysis was unclear. One patient awaiting a heart for emergency transplantation who underwent bilateral renal stenting in a desperate attempt to reduce the afterload on his heart, died 4 days after the procedure of refractory heart failure. One patient who developed severe systemic cholesterol embolization after a technically difficult bilateral percutaneous transluminal angioplasty and stenting procedure, died 10 days after the procedure from multisystem organ failure. One puncture site complication occurred: a brachial artery pseudoaneurysm treated with sonographically guided compression repair. One patient developed chest pain and mild elevation of cardiac enzymes 1 day after the procedure but recovered uneventfully. Finally, one patient required percutaneous coil embolization of an upper pole renal artery branch because of a guidewire-induced pseudoaneurysm and bleeding during the initial percutaneous stenting of the main renal artery.
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The incidence of major complications in the interventional group was associated with higher gadodiamide volumes (p = 0.0093) and higher CO2 volumes (p = 0.057).
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The true incidence of worsening renal function in the patients with suspected ischemic nephropathy who undergo diagnostic renal angiography or a percutaneous renal intervention is unknown. Determining the incidence of contrast-induced nephropathy after angiography in patients with renal insufficiency is difficult because of the large number of variables involved: volume of contrast material used, type of contrast material used, hydration state of the patient, associated comorbid conditions (diabetes, cardiac, or liver disease), medications, type of study performed, degree of underlying renal insufficiency, and inconsistency in follow-up.
In addition, the incidence of worsening renal function in patients undergoing renal angiography for the diagnosis and treatment of ischemic nephropathy is frequently not reported. In eight major studies reporting the success of percutaneous revascularization in patients with renal artery stenosis and suspected ischemic nephropathy, the incidence of worsening renal function in the early period after the procedure was reported in only three of the studies and was found to occur in 0-13% of patients [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. The definition of "worsening renal function" in these studies is not clear and often includes only the worst outcomes (i.e., need for temporary or permanent dialysis). Other investigators have reported an incidence of worsening renal function caused by iodinated contrast material after renal angiography in patients with renal insufficiency to be approximately 25% [6, 26]. Furthermore, it is difficult to determine if the volume or type of iodinated contrast material plays a role in the worsening of renal function in patients with renal insufficiency because these variables are often not monitored. Although it is controversial, the use of low-osmolality iodinated contrast material has been touted as reducing the incidence of contrast-induced nephropathy in patients with risk factors for contrast-induced nephropathy (namely, preexisting renal insufficiency with or without diabetes mellitus and congestive heart failure) by approximately 50% when compared with the use of high-osmolality iodinated contrast agents [27]. The benefit of limiting the volume of iodinated contrast material during an angiographic study in patients with chronic renal insufficiency is less clear [28].
Most patients who develop contrast-induced nephropathy because of the use of iodinated contrast media for diagnostic renal angiography or percutaneous revascularization recover. However, some patients experience permanent deterioration in renal function. In patients who develop contrast material-induced nephropathy, the need for temporary dialysis has been reported in 10-25% of patients, and permanent deterioration of renal function from the baseline is seen in up to 30% of patients. Increases in length of hospital stay and in inpatient mortality have also been reported in these patients [28]. However, these results include a mixed group of patients who have not only chronic renal insufficiency but also other associated medical problems that may contribute to their poor outcomes.
In an attempt to reduce the incidence of contrast-induced nephropathy in patients with renal insufficiency, CO2 has been advocated as an angiographic contrast agent. Its benefits have been described previously [29]. Because CO2 is a gas, it floats in the bloodstream and better fills the anterior vessels. The kidney of interest is elevated to better visualize the renal arteries and their branches by placing a wedge cushion under the appropriate side of the patient. The low viscosity of CO2 makes it an excellent contrast agent to deliver through the vascular sheath or catheter around wires, balloons, or stents. Although CO2 angiography has been successful in reducing the incidence of worsening renal function resulting from the use of contrast material, when used as an angiographic contrast agent it does not always provide adequate diagnostic images of the renal arteries and its branches [6, 30]. Rarely, CO2 angiography has been reported to result in transient mesenteric ischemia caused by the buoyancy of the gas and its ability to at least temporarily occlude or diminish flow in the mesenteric vessels [31, 32].
Because of the shortcomings of CO2 angiography, gadolinium-based contrast agents have been used to supplement CO2 angiography [33,34,35,36]. Gadolinium-based contrast agents have been shown to have minimal nephrotoxicity when administered IV in patients with chronic renal insufficiency [37,38,39]. The risk of worsening renal function may also be less than with traditional iodinated contrast material when gadodiamide is used in small volumes intraarterially as an angiographic contrast agent [6, 33,34,35]. The total incidence of worsening renal function in our study group related to either CO2 or gadodiamide was only 3.2%, which compares favorably with results of studies using iodinated contrast that reported an incidence of contrast-induced nephropathy between 10% and 25% [6, 23, 26].
In addition, neither the degree of preexisting renal insufficiency nor diabetes influenced the total complication rate or the incidence of worsening renal function related to the procedure. One group of researchers described worsening renal function attributed to the intraarterial use of gadolinium-based contrast agents [40]. Two patients in our study developed transient worsening of renal function after intraarterial CO2 and gadodiamide administration without any other recognizable cause. This finding raises the possibility that although gadolinium-based contrast agents appear to be less nephrotoxic than iodinated agents, gadolinium-based agents, when given intraarterially, may still be potentially nephrotoxic in some patients. However, the similar volumes of CO2 and gadodiamide used in the patients undergoing diagnostic angiographic studies only compared with those undergoing intervention suggest that the percutaneous revascularization procedure itself could be responsible for the increase in serum creatinine levels in these two groups of patients. This possibility is further supported by the increase in serum creatinine levels that were less than the threshold value of 0.5 mL/dL in patients in the intervention group but not in patients in the diagnostic group, who received similar volumes of CO2 and gadodiamide. Lately, increased attention has been given to the likelihood that cholesterol embolization may be partially responsible for contributing to this increase in creatinine level [41].
Several authors tout the success of percutaneous renal revascularization with or without vascular stenting to test renal artery stenosis to improve or stabilize renal function in patients with chronic renal insufficiency [42]. These authors also report major complication rates in the range of 0-34%. The use of CO2 and gadodiamide as angiographic agents during diagnostic renal angiography and percutaneous renal revascularization does not appear to increase the potential for complications when compared with the use of iodinated agents. The major complication rate of 5.5% in our study is similar to that reported in other major studies in which iodinated contrast media were used [18,19,20,21,22,23,24,25]. However, when larger volumes of CO2 and gadodiamide are used, complications and deterioration in renal function appear more likely to occur. The use of greater volumes of contrast agents may be a marker for more complicated renal anatomy and percutaneous repair, thereby increasing the potential for a major complication.
In the one patient who developed unexplained hemolysis, an extensive hematologic workup had negative results, and the hemolysis resolved during the next 3 weeks. Although hemolysis has been associated with stent placement in the portal vein for transjugular intrahepatic portosystemic shunts [43, 44], in our patient only 1 or 2 mm of the stent was protruding into the aortic lumen, making trauma to RBC from the stents unlikely. We are not aware of any reports of gadolinium-based agents causing hemolytic anemia, although the potential for increased hemolysis in patients with underlying hemolytic anemia (which was not detected in this patient) from gadolinium-based contrast agents is unknown. Our patient was also taking a variety of antihypertensive medications and an H2 blocker, none of which was clearly implicated as a cause for hemolysis. The patient also received one dose of cephalosporin antibiotic immediately before stent placement.
Cholesterol embolization, myocardial infarction, renal branch vessel injury, and puncture site complications are well-known risks of renal artery revascularization. The occurrence of these complications in our study is similar to the experience of others [9,10,11,12,13,14,15,16, 26, 45].
A significant learning curve exists when incorporating the use of CO2 and gadodiamide into an angiography regimen. The visibility provided by these agents is inferior to that provided by iodinated contrast material, so an understanding of the pitfalls of interpreting angiographic images is required. Neither of these agents is readily visible with fluoroscopy alone; therefore, digital subtraction angiography is needed to visualize these agents. Because of dose and volume limitations of gadodiamide (0.4 mmol/kg based on IV gadolinium use), each gadodiamide injection has to be carefully planned to ensure that the total dose limit of gadodiamide is not exceeded. Another major consideration is the cost of the gadodiamide, which is approximately 10 times the cost of nonionic iodinated contrast material on a permilliliter basis. Finally, the use of CO2 as an angiographic contrast agent is required in many cases. That two patients experienced CO2 complications emphasizes the importance of closely watching for signs of impending transient mesenteric ischemia—namely, crampy abdominal pain, nausea, and the urge to defecate. When these symptoms occur after a second injection of CO2, the use of CO2 as a contrast agent should be discontinued. The increased incidence of complications associated with larger volumes of CO2 and gadodiamide is a reminder that even in experienced hands, more technically demanding procedures can potentially lead to more complications.
Limitations of this study include the lack of a control group treated with
CO2 and limited amounts of iodinated contrast material. Such a
control group would help to determine whether limiting amounts of iodinated
contrast material would reduce the incidence of contrast-induced nephropathy.
We are currently undertaking a study to compare the effects on renal function
of using CO2 and gadodiamide or CO2 and equal amounts of
nonionic contrast agents in patients with renal insufficiency who undergo
diagnostic renal angiography with or without percutaneous revascularization.
Ideally, it would also be best to administer iodinated contrast material to
those patients studied with CO2 and gadodiamide to compare the
accuracy of these agents in detecting the various degrees of renal artery
stenosis. However, concern regarding adverse effects on renal function if all
three agents were used in all patients has prevented us from performing this
comparison. Finally, 48-hr serum creatinine follow-up was available in most
(
80%) of the first 90 patients studied. However, as we and the referring
clinicians became more confident that CO2 and gadodiamide were not
likely to cause worsening renal function after the procedure, patients were
increasingly discharged at 24 hr, making it more difficult for us to obtain
48-hr serum creatinine levels.
In conclusion, the use of CO2 and gadodiamide as angiographic contrast agents in patients with suspected renal artery stenosis and ischemic nephropathy is a safe alternative to the use of iodinated contrast material. CO2 and gadodiamide do not result in an increase in the incidence of complications compared with iodinated contrast material. Indeed, CO2 and gadodiamide appear to reduce the incidence of contrast-induced nephropathy as compared with iodinated contrast material. CO2 and gadodiamide potentially allow the examination and percutaneous treatment of patients with various degrees of preexisting renal insufficiency and clinically significant renal artery stenosis, even when diabetes mellitus is present. Additional studies are needed to determine the safety of higher doses of intraarterial gadolinium-based contrast agents and the long-term benefit on renal function and patient survival when these contrast agents are used for aggressive angiographic screening and percutaneous treatment of renal artery stenosis.
Acknowledgments
Special thanks to Sherry Deane, Geneve Shifflett, and Shirley Yowell for
their expert assistance in the preparation of this manuscript.
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