Contrast-induced Acute Kidney Injury
Keywords:
contrast-induced acute kidney injury,
chronic kidney disease,
risk factor,
cholesterol embolism,
biomarkers
Article ID: 2015-0013-IR
Details
Article ID: 2015-0013-IR
The procedural use of contrast media has increased, but with it the potential risk of developing contrast-induced acute kidney injury (CIAKI). The most important risk for CIAKI is chronic kidney disease (CKD), an affliction with continually increasing incidence in modern society. The current prevalence of CIAKI is difficult to estimate because most victims are asymptomatic. The first Japanese guidelines regarding contrast agent examinations were recently announced, but their only recommendation is to provide classic fluid replacement, with saline 6–12 h before and after the contrast procedure. According to a review summarizing the recent literature, little evidence supports this suggestion. In order to diagnose early and treat emergent patients, it is appropriate to perform procedures using contrast media, even without knowledge of patients' renal function. Prevention is the most important consideration for CIAKI, and the usefulness of risk scores predicting the development of CIAKI has been reported. However, no prospective studies have been performed to date, and therefore, they will be necessary in the future. Furthermore, the development of novel preventative interventions for CIAKI is also required.
In recent years, an ageing population has led to an increase in the frequency of tests that use contrast medium. Normally, contrast-induced acute kidney injury (CIAKI) remits without accompanying oliguria, but some patients require blood purification therapy or develop irreversible renal failure. Particularly in emergency care facilities, tests and treatments utilizing contrast media must be performed on patients with a high risk of developing CIAKI, so it is essential that medical professionals understand the disease's characteristics and preventative measures.
The currently widely used definition of CIAKI, according to the European Society of Urogenital Radiology (ESUR) is "a renal disorder occurring within three days after intravascular administration of a contrast agent, in the absence of any other etiology, and in which serum creatinine levels are elevated by 25% or more, or show elevated levels of 0.5 mg/dl or higher."1,2 The ESUR has continuously consolidated and examined new knowledge and has continued to revise the guidelines.
The term CIAKI is widely used in the literature and usually defined as a rise in serum creatinine of ≥0.5 mg/dl or a 25% increase from baseline value, assessed at 48 hours after a radiological procedure. In 2012 a joint effort by the Japanese Society of Nephrology, the Japan Radiological Society, and the Japanese Circulation Society resulted in the country's first guidelines for CIAKI. Similarly to those from ESUR, these guidelines defined CIAKI as follows: "within 72 hours after the administration of iodine contrast agent an increase in serum creatinine level of at least 0.5 mg/dl or 25% over the pre-administration level." Although CIAKI is a type of acute kidney injury (AKI), since it is not generally accompanied by oliguria, urinary output is not included among the criteria. Since there had been no established definition of CIAKI prior to the creation of these guidelines, clinical study of the issue can be expected to increase in the future.
After administration of contrast agent, the secretion of endothelin and other peptides derived from vascular endothelial cells and having a vasoconstrictive action is promoted in the renal parenchyma, and vasospasms cause a decline in renal blood flow and the oxygen supply.3 In addition, the amount of NaCl that reaches the ascending limb of the loop of Henle increases due to the osmotic activity caused by the contrast medium, and as the amount that is reabsorbed increases, oxygen demand and consumption increase. This causes the kidney medulla to suffer from hypoxia, which in turn causes damage to the parenchyma due to the increased production of free radicals by tubular epithelial cells.4 Moreover, the concentration of the contrast medium flowing through the renal tubule lumen gradually increases to such a high degree that the toxicity of the contrast medium itself is thought to cause direct damage to the tubular epithelial cells.5,6,7
Representative risk factors for CIAKI are shown in Table 1.8,9 The most important risk factor is pre-existing chronic kidney disease (CKD). In fact, many recent studies no longer consider diseases such as diabetes and multiple myeloma to be risk factors if they are not accompanied by CKD.1,8 McCullough reported that decreased renal function leads to increased incidence of CIAKI.10 The European Society of Urogenital Radiology (ESUR) Contrast Media Safety Committee's guidelines, released in 2011, indicate that the CIAKI onset risk threshold for intravenous contrast administration is a glomerular filtration rate (GFR) of 45 mL/min/1.73 m2. Thus, it is advisable to implement the preventative measures mentioned below when administering contrast medium to patients with risk factors. Cigarroa et al. previously calculated the maximal doses of contrast agents on the basis of the body weight and serum creatinine levels and reported that the incidence of CIAKI resulting from the administration of contrast agents at doses exceeding the maximum limit was 21%, which was significantly higher than the 2% incidence found with the administration of contrast agents within the limits of maximum authorized doses.11 Meanwhile, no definitive conclusion has yet been reached regarding whether the risk of developing CIAKI differed between iso-osmolar contrast media and low-osmolar contrast media. In addition, thus far, there has been no evidence that intra-arterial injection of contrast medium was an independent risk factor for developing CIAKI; however, the incidence of CIAKI associated with intravenous administration of contrast media tends to be lower than that associated with intra-arterial administration.12 Thus, if the benefit of using contrast medium on patients who have the risk factors listed in the Table 2 outweighs the risk of CIAKI, contrast medium should be used.
| CKD (GFR<60 mL/min/1.73m2) |
| Advanced age (especially 75 and above) |
| Dehydration |
| Heart failure |
| Drugs (diuretics, NSAIDs, aminoglycoside, vancomycin, etc.) |
| Diabetes (it is not known if diabetes is a risk factor when it is not accompanied by CKD) |
| Multiple myeloma (it is not known if multiple myeloma is a risk factor when it is not accompanied by CKD) |
| Contrast medium dose |
| Cardiogenic shock |
| Left ventricular ejection fraction |
| Risk factor | Score | |
|---|---|---|
| Hypotension | 5 | |
| Intra-aortic balloon pump | 5 | |
| Congestive heart failure | 5 | |
| Age >75 | 4 | |
| Anemia | 3 | |
| Diabetes | 3 | |
| Contrast medium dose | 1 per 100 mL | |
| Serum creatinine level of >1.5 mg/dl | 4 | |
| Or | ||
| eGFR | 2: eGFR 40–60 | |
| 4: eGFR 20-<40 | ||
| 6: eGFR <20 | ||
| Total risk score | CIAKI risk | Dialysis risk |
| 0–5 | 7.5% | 0.04% |
| 6–10 | 14.0% | 0.12% |
| 11–16 | 26.1% | 1.09% |
| >16 | 57.3% | 12.6% |
Care is also required when carrying out contrast medium procedures on patients currently taking insulin sensitizers such as biguanide, due to the risk of lactic acidosis associated with CIAKI onset. Although lactic acidosis is rare, once it develops, prognosis is poor and the mortality rate is high. It is recommended that such patients cease taking insulin-sensitizing medication two days prior to and following tests involving contrast medium.
The effectiveness of risk scores for CIAKI onset in patients undergoing percutaneous coronary intervention (PCI) has been reported; these data are described in Table 2.13 However, since prospective studies of this issue have not yet been conducted, it is not yet possible to make recommendations based on these data.
Reports on prevalence vary, but Kim et al.14 reported CIAKI prevalence after contrast-enhanced CT as 0% at eGFR 45–59 mL/min/1.73 m2, 2.9% at eGFR 30–44 mL/min/1.73 m2, and 12.1% at eGFR <30 mL/min/1.73 m2.
Most patients who undergo contrast-enhanced CT do so as outpatients, which makes it difficult to assess post-procedure renal function. However, reports indicate that approximately 12% of patients who undergo contrast-enhanced CT later develop CIAKI after returning home.15 An investigation of patients hospitalized in our medical department indicated that 9% of hospitalized patients who underwent procedures involving contrast medium developed CIAKI.16 This issue requires further study. The overestimation of the prevalence of CIAKI is also subject to debate.17
Research has shown that although the 5-year survival rate in cases of reversible CIAKI that occurs as a result of coronary arteriography on CKD patients is 90%, in irreversible cases the 5-year survival rate is 32%.18 In addition, in a study of patients who underwent PCI, the total mortality rate after one year for patients who did not develop CIAKI was 19.4%, which was significantly lower than the 37.7% rate for those who did develop CIAKI.19 Another report indicated that among patients who underwent PCI, the in-hospital mortality rate for those who did not develop CIAKI was 3.3%, which was significantly lower than the 9.4% in who did develop CIAKI.20 Although reports link CIAKI onset and vital prognosis, currently it is not known if the complication of CIAKI is a predictor for poor vital prognosis or if having a poor general prognosis is a predictor for CIAKI onset.
The most important disease from which CIAKI must be differentiated is cholesterol embolism. Cholesterol embolism is a disorder that mainly causes renal disorder and generally has a poor prognosis. It is caused by intravascular catheter and anticoagulant therapy, which cause cholesterol crystal formation when atheromatous plaques in the aorta break free and occlude a artery to the extent of 100–300 μm. It is characterized by progressively decreasing renal function that may be delayed several days or weeks after a catheter procedure.21,22 The following are the main points of differentiation between this disorder and CIAKI. Cholesterol embolism is characterized by the following:
Serum creatinine is used in the CIAKI guidelines, but sensitivity is low in cases of early decreases in GRF, which has been pointed out as a problem in the past. Since serum creatinine does not increase until the GFR decreases to approximately 40 mL/min/1.73 m2, there is a danger that renal function will be overestimated. Serum creatinine may also be underestimated in cases of anemia23 and hypervolemia.24 Currently, there is no alternative to the use of serum creatinine, which is easy to measure, but new biomarkers for renal function monitoring are required to avoid its limitations. Although a variety of biomarkers have been investigated and reported, there has been no major advance in this area.
Since serum cystatin C shows increases even when renal dysfunction causes GFR of only approximately 70 mL/min/1.73 m2, it is an effective marker for early diagnosis. Its further merits include the fact that it is not affected by muscle mass, diet, or exercise.25,26 However, much about serum cystatin C is still unknown, and some reports indicate that serum cystatin C is affected by such things as pregnancy, HIV infection, thyroid dysfunction, and drugs; therefore, further study is still required.27
In addition, a recent report on the TRIBE-AKI multi-facility prospective study investigating the efficacy of NGAL and IL-18 in serum and urine indicated that NGAL and IL-18 are useful as biomarkers.28 In addition, recent reports on the usefulness of urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) have gained attention.29,30 Even more of these types of studies of biomarkers are required so that they can be used as clinical points of care.
When performing procedures utilizing contrast medium on patients with risk factors, it is necessary to implement appropriate prevention (Table 3). Currently, the most commonly recommended preventative measure is transfusion before and after the contrast medium procedure. The specific protocol calls for replacement of physiological saline solution at the rate of 1 mL/kg/h for 12 hours before and after the procedure. This protects the blood flow to the renal parenchyma by increasing extracellular fluid and is thought to suppress the onset of CIAKI by reducing the concentration of contrast medium within the renal tubule lumen.31 Careful interpretation is necessary, however, as this protocol is not the established optimum protocol but rather is the standard transfusion method used as the control in many clinical studies.32
| ● | Ascertain renal function and assess risk prior to the use of contrast medium |
| ● | Cease the use of drugs known to be risk factors (diuretics, NSAIDs, etc.) |
| ● | Use of the minimum possible dose of contrast medium |
| ● | Transfusions before and after administration of contrast medium |
| Administration example 1: Physiological saline solution for 12 hours prior to contrast medium administration at 1 ml/kg/hr + for 12 hours after at 1 ml/kg/hr. | |
| Administration example 2: Sodium bicarbonate solution (152 mEq/L) for 1 hour prior to contrast medium administration at 3 ml/kg/hr + 6 hours after at 1 ml/kg/hr. | |
| ● | Avoid repeated use of contrast medium |
When there is little time before the start of a contrast medium procedure, a protocol calling for isotonicity-adjusted sodium bicarbonate solution (152 mEq/l) to be administered at 3 mL/kg/h for one hour prior to the contrast medium procedure and at 1 mL/kg/h for 6 h following the procedure can be expected to prevent CIAKI.33,34 The mechanism for this is thought to involve increased blood flow to the renal parenchyma, which then suppresses the production of tubular epithelial cell free radicals by bicarbonate.35 However, short-term transfusions are not recommended, as they may increase the risk of CIAKI as compared to long-term transfusions.36
Additionally, there is insufficient evidence to support the idea that simply drinking water can suppress the onset of CIAKI in the same way as a transfusion. Currently, it is recommended that patients receive transfusions rather than simply drink water as a form of fluid replacement. In addition, most studies report that blood purification therapy is not effective as a preventative of CIAKI.37,38,39,40
Pharmacotherapies previously thought to have the potential to prevent CIAKI include N-acetylcysteine, hANP, ascorbic acid, and statin, but the effectiveness of these drugs has since been ruled out. In a meta-analysis of 26 randomized controlled trials on the effects of N-acetylcysteine, the conclusions supported that it had a prophylactic effect at a relative risk of 0.62.41 However, questions have also been raised regarding the validity of these conclusions.42
The most effective ways to prevent CIAKI, as with AKI due to other causes, are the above-mentioned preventative measures. Additionally, although it is not effective as a preventative measure, early emergency blood purification therapy on CIAKI patients in poor general condition and with accompanying oliguria may improve either mortality rate or renal function and is recommended for this reason.43,44
However, while the effects of diuretics,45,46 hANP,47,48 low-dose dopamine,49,50 etc. are currently being investigated, there is no clearly effective drug. Additionally, the effectiveness of transfusion therapy after CIAKI onset has not yet been elucidated, and since the risk of mortality may be increased by increasing the volume of body fluid, transfusion therapy that increases body fluid volume over the appropriate stasis level is not recommended.51,52
As mentioned above, nothing but long-term transfusion prior to contrast medium administration is recommended for the prevention of CIAKI, though this is not practical in emergency care facilities. Thus, we recently created contrast medium model rats and reported on our investigation of the effectiveness of hydrogen gas inhalation as a preventative for CIAKI.53 Specifically, we investigated the effect on renal function and renal tissue of hydrogen gas inhaled by rats when they were administered contrast medium, as compared to a control group. The results indicated that the inhalation of hydrogen gas suppressed the decrease in renal function caused by the administration of contrast medium. Immunostaining using a marker for oxidative stress on renal tissue known as 8-OHdG indicated that there were significantly fewer 8-OHdG-positive cells in the hydrogen gas group. We therefore believe that the suppression of oxidative stress due to hydrogen gas inhalation is one cause of the suppression of renal dysfunction. Since the administration of hydrogen gas takes place only when the contrast medium is administered, there is no gap in time between the gas inhalation and contrast medium administration, which may make it effective for use on emergency patients who cannot be provided with sufficient fluid replacement. Preparations are underway for clinical study of this issue.
In patients at risk of developing CIAKI, the advisability of the use of a contrast agent needs to be carefully taken into consideration. If alternative tests such as MRI are available, the latter should be carried out instead. However, in clinical settings, the potential benefits of the use of contrast agents often exceed the risk of developing CIAKI; hence, the advisability of the use of contrast agents should primarily be decided by consideration of the patient's ultimate benefit, and tests using contrast agents should still be performed if necessary. In such cases, preventive measures are of utmost importance and must be implemented; establishment of a therapeutic framework for use in cases of CIAKI is also crucial. In addition, the development of new preventive measures is desired in order to deal with emergent cases in which it is impossible to provide sufficient fluid replacement, such as hydrogen gas inhalation, which we discussed elsewhere.
