Abstract
Objectives: Gadolinium-based contrast media (Gd-CM) are reported to induce acute kidney injury (AKI) in a high-risk population group at the usual dose for magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) examinations. We assessed gadolinium-induced nephropathy in patients with renal impairment who underwent MRI or MRA examinations, and evaluated the risk factors. Materials and methods: In this retrospective study, 238 patients with baseline renal impairment, who received MRI or MRA examinations with Gd-CM, were recruited. After all other AKI causes—liver decompensation, severe heart failure, all kinds of shock, and severe sepsis—and patients on dialysis were excluded, 158 patients were enrolled. AKI was defined as a decrease in glomerular filtration rate (GFR) >10% of baseline data within 3 days after administration of Gd-CM. Regression analysis was used to find independent risk factors for gadolinium-induced AKI (Gd-AKI). Results: Twenty-six of the 158 patients (16.5%) developed Gd-AKI. There were no significant differences in gender, age, or baseline GFR between those who did and who did not develop AKI. Comorbid coronary artery disease, liver cirrhosis, diabetes mellitus, and hypertension were not significantly associated with the development of Gd-AKI. However, sepsis was an independent risk factor for Gd-AKI after multivariate regression analysis (adjusted odds ratio: 4.417; 95% confidence interval: 1.671–11.676, p = 0.03). Conclusions: It is potential AKI after administration of Gd-CM under sepsis condition at the dose for MRI and MRA examinations in patients with renal impairment. It is important to identify high-risk patients and closely monitor renal function after administration of Gd-CM.
INTRODUCTION
Contrast medium-induced nephropathy (CIN) is a serious complication of radiological examinations that require iodinated contrast media (I-CM) enhancement in high-risk patients.Citation1 With increased diagnostic and therapeutic procedures requiring contrast medium, it has been reported that CIN is the third most common cause of acute kidney injury (AKI) in hospitalized patients.Citation2 Because of the well-documented risk of AKI with I-CM in patients with underlying chronic renal impairment, intravenous gadolinium-based contrast media (Gd-CM) have been widely used for magnetic resonance imaging (MRI) as an alternative for diagnostic and interventional angiographic procedures before the era of nephrogenic systemic fibrosis (NSF).Citation3
Although it was thought to be safe and non-nephrotoxic at the approved doses for MRI and magnetic resonance angiography (MRA) examinations (≤0.3 mmol/kg),Citation4 Gd-CM has recently been reported to induce a reversible decrease of the glomerular filtration rate (GFR) in a high-risk group, especially in patients with renal impairment.Citation5–9 Additionally, patients usually have varied preexisting comorbidities [such as coronary artery disease (CAD), hypertension (HTN), diabetes, sepsis] when undergoing MRI or MRA examinations. However, additional studies have not confirmed whether these comorbid conditions are risk factors for Gd-induced nephropathy at low doses of Gd-CM.
We hypothesized that Gd-CM is associated with AKI in patients with baseline renal impairment and comorbidities. Therefore, the purpose of our study was to evaluate AKI after administration of Gd-CM in patients with renal impairment who underwent MRI or MRA examinations. Results were compared between patients with and without AKI. Comorbid conditions and risk factors were also analyzed.
MATERIALS AND METHODS
Patients
We systematically reviewed the charts of 238 patients who underwent MRI or MRA examinations with Gd-CM from January 2005 to December 2005. To be included, patients were required to have at least two serum creatinine (sCre) values for a span of 7 or more days before the MRI/MRA examinations and one sCre value within 3 days after the examination. We selected patients whose renal function had been stable for 1 week (definition: GFR change <10% during the week) before they were given Gd-CM. Impaired baseline renal function was defined as a pre-MRI/MRA examination of GFR below 90 mL/min/1.73 m2. The GFR value was calculated using the Modification of Diet in Renal Disease (MDRD) study equation.Citation10
Data Collection
Patients who had been given any nephrotoxic agents or other forms of contrast media (CM) within 4 weeks before the MRI/MRA examinations were excluded. We also excluded patients with AKI with all other causes, including liver decompensation, severe heart failure (New York Heart Association Class III and IV), all kinds of shock, and sepsis-related AKI, septic shock, severe sepsis,Citation11 and patients on dialysis.
In this study, three kinds of intravenous contrast agents were used during MRI/MRA: Gd-DTPA (Magnevist, Schering AG, Berlin, Germany), Gd-DTPA-BMA (Omniscan, Amersham Health PLC, Carrigtwohill, Ireland), and Gd-DO3A (Gadovist, Schering AG, Berlin, Germany). The dose of Gd-CM for MRI or MRA examinations was 0.2 mmol/kg body weight in nearly all the patients. All patients received Gd-CM via intravenous injection.
The protocol of this study was approved by the Research and Ethics Review Board of Chi-Mei Medical Center.
Statistical Analysis
The data were analyzed using the Statistical Package for Social Sciences for Windows Version 17.0 (SPSS Inc., Chicago, IL, USA). A χ2 test was used for non-numerical data. Regression analyses were done to find independent variables for AKI. Significance was set at p < 0.05.
RESULTS
After excluding 80 patients by our exclusion criteria, 158 patients with impaired baseline renal function were analyzed finally. Seventy-two (46%) were women and 86 (54%) were men (). More than half of the patients were older than 65 years. Baseline GFR was between 90 and 60 mL/min/1.73 m2 for 74 patients (46.8%), between 60 and 30 mL/min/1.73 m2 for 41 patients (25.9%), and below 30 mL/min/1.73 m2 for 43 patients (27.2%). Of the 158 patients, 58 patients (36.7%) had diabetes mellitus (DM), 66 patients (41.8%) had HTN, and 65 patients (39.2%) had sepsis.
Table 1. Demographic characteristics of study patients at baseline.
A decrease in GFR >25% below baseline data within 3 days after administration of Gd-CM was noted in only four patients (2.5%). However, there was no significant difference between the number of patients with and without GFR decline >25% based on gender, age, baseline GFR, and comorbidities ( and ).
Table 2. Associated factors and rapid decline in eGFR after administration of gadolinium-based contrast media (Gd-CM).
Table 3. Regression table showing significant independent variables for rapid decline in eGFR after administration of gadolinium-based contrast media (Gd-CM).
Table 4. Gadolinium-based contrast-induced acute kidney injury (AKI) at dose ≤0.3 mmol/kg.
We further analyzed the patient with a less stringent criterion who had a decrease in GFR >10% below baseline data within 3 days after administration of Gd-CM. Twenty-six of the 158 patients (16.5%) developed GFR decline >10% after administration of Gd-CM. Comorbid conditions with CAD, liver cirrhosis (LC), DM, and HTN were not significantly associated with a decline in GFR after administration of Gd-CM (). However, 16 patients with sepsis (25.8%) had a rapid decline in estimated glomerular filtration rate (eGFR). Patients with sepsis had a higher risk for GFR decline after administration of Gd-CM (p = 0.011).
Logistic regression analysis showed that sepsis was an independent risk factor for GFR decline after administration of Gd-CM (). GFR decline after administration of Gd-CM was 3.417 times higher for patients with sepsis than those without sepsis (95% confidence interval: 1.67–11.68, p = 0.03).
DISCUSSION
In this study, we found that intravenous Gd-CM at the dose for MRI and MRA examinations caused rapid GFR decline (defined as a decrease >10% in GFR) in 16.5% of patients with preexisting renal impairment. Age, gender, baseline GFR, DM, HTN, CAD, and LC were not associated with AKI after administration of Gd-CM. However, it is potential AKI after administration of Gd-CM under sepsis condition.
DM, old age (>75 years old), heart failure, LC, HTN, and lower baseline GFR are risk factors for I-CM nephropathy,Citation1 but these risk factors for Gd-CM nephropathy at the dose for MRI and MRA examinations are controversial. This is because there are wide variations in definitions of AKI from one study to another (). AKI has been defined as an increase in sCre >0.3 mg/dL,Citation12 >0.5 mg/dL,Citation5,8,13 and >1 mg/dL.Citation14 Additionally, outcome data based on comorbidities before MRI examinations were not reported in many studies.Citation4 Tombach et al.Citation14 reported that the use of Gd-CM at a dose of 0.3 mmol/kg in patients with impaired renal function appeared not to be nephrotoxic. Ergün et al.,Citation8 however, found that AKI occurred after Gd-CM in patients with preexisting stage 3 or 4 chronic kidney disease. Risk factors for gadolinium-induced AKI include diabetic nephropathy and low GFR.
Cases of CIN usually use the definition by a fixed (0.5 mg/dL) or proportionate (25%) decline in GFR levels after exposure to contrast media.Citation1,5,8 However, sCre is not significantly changeable in early AKI, because in the non-steady-state conditions of AKI, as GFR falls, sCre secretion increases.Citation15 In fact, histological data from a few animal studies suggest that Gd-CM induces acute tubular necrosis and cytoplasmic vacuolization in renal tubular cells in several hours.Citation16–18 For the above reasons, we further used a less stringent criterion (a decrease >10% in GFR) for AKI. This may explain why we found a higher incidence of AKI after administration of Gd-CM at the doses for MRI and MRA examinations.
The risk of gadolinium-induced nephrotoxicity is strongly demonstrated by some experimental studies. For example, when cultured renal tubular cells were incubated with Gd-CM and I-CM, the degree of cytotoxicity was similar.Citation17 Nyman et al.Citation19 report a significantly more pronounced decrease in GFR in animals given Gd-CM than in those given I-CM.
Although the risk factors for I-CM nephropathy are well characterized, including renal impairment, diabetic nephropathy, congestive heart failure, volume depletion, old age, high doses of CM simultaneously using nephrotoxic agents, and using a high osmolar contrast agent, Citation1 however, the risk factors for Gd-induced nephrotoxicity are not yet clear. Sam et al.Citation6 showed that underlying chronic renal impairment might be associated with Gd-induced nephrotoxicity, and Ergün et al.Citation8 reported that lower GFR and diabetic nephropathy were independent risk factors for AKI after exposure to Gd-GM. However, we found it is potential AKI in GFR after administration of Gd-CM under sepsis condition.
An increase in oxygen radical scavengers and a decrease in renal blood flow, which causes renal ischemia, have been proposed as the primary pathogenetic sources of sepsis.Citation11 The mechanism of Gd-induced nephrotoxicity is not currently clearly understood. Gd-CM is hypertonic, has an osmolarity 2–7 times greater than that of plasma, and is not absorbed by renal tubular epithelial cells. These characteristics of Gd chelates are similar to those of I-CM. The injection of Gd-CM results in a substantial osmotic load to the kidneys. High osmolar contrast media may induce intense and prolonged vasoconstriction at the corticomedullary junction of the kidneys and directly impair the autoregulatory ability of the kidney through a loss of nitric oxide production.Citation20–23 A sepsis-related decrease in renal blood flow and an increase in reactive oxygen species expression may increase renal injury in patients given Gd-CM. Therefore, Gd-CM and sepsis appear to synergistically interact in rapid GFR decline. If Gd-CM is used in patients with sepsis, it will increase the incidence of GFR decline. We found that patients with sepsis but without evidence of AKI had a 3.417 times higher incidence of rapid GFR decline after exposure to Gd-CM than did patients without sepsis.
A new and mysterious clinical–pathological entity condition, NSF, has been described in patients with severe renal failure within the past few years.Citation24 Recent observations have linked NSF to using Gd-CM in these renal-impaired patients.Citation25 The Food and Drug Administration has warnedCitation26 that physicians should carefully assess the need for Gd-CM when doing an MRI or MRA on patients with moderate to severe renal failure.
Our study has some limitations. First, it was retrospective. A retrospective study has a disadvantage to interpret this group of patients because numerous variables can influence renal function. Second, it lacked a control group. To show that Gd-CM is the cause of AKI, it is better to have a control group, although we have excluded the patients with septic shock, sepsis-related AKI, severe sepsis and selected patients whose renal function had been stable for 1 week before they were given Gd-CM. From our study, we cannot conclude that Gd-CM itself is the cause of AKI, however, it appeared Gd-CM may be associated with rapid GFR decline under the clinical condition with sepsis. Prospective studies with a control population of similar sepsis patients who did not undergo Gd-CM are needed to establish the conclusion that Gd-CM is the cause of AKI in sepsis condition in the future. Third, a significant association between exposure to Gd-CM and AKI was only found with criterion of 10% decrease in GFR, but not with criterion of 25% decrease in GFR in our study. This is possibly an overstatement due to technical and biological reasons, which may expect a measurement variation from 5% to 20% in the assessment of GFR. Fourth, these patients were with varying levels of kidney function exposed to three different contrast agents. In addition, it is better to evaluate the dose–effect relationship regarding the development of AKI. However, the dose of Gd-CM for MRI or MRA examinations was 0.2 mmol/kg body weight in nearly all the patients. The number of patients was insufficient to explore the dose–effect relationship. Finally, we used the MDRD formula to calculate the GFR. However, the MDRD formula may be less accurate for assessing GFR above 60 mL/min/1.73 m2.Citation27,28
In conclusion, it is potential AKI after administration of Gd-CM under sepsis condition at the dose for MRI and MRA examinations in patients with renal impairment. Further prospective study with a control population is needed to evaluate the association between Gd-CM, sepsis, and AKI. The combination of sepsis and AKI is associated with high hospital mortality. It is important to identify high-risk patients before administration of Gd-CM. Using prophylactic measures before giving renal-impaired patients Gd-CM and closely following up renal function afterward should be considered.
ACKNOWLEDGMENT
This study was supported by grant CMFHR9951 from the Chi-Mei Medical Center, Taiwan.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Related Research Data
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