Today, in industrialised countries, we are treating more and more patients with coronary artery disease or structural heart disease, due, in part, to an increase in life expectancy over the last 50 years, as well as an increasing incidence of risk factors such as diabetes and obesity. Accordingly, there has been a rise in the use of contrast-enhanced diagnostic imaging and interventional procedures. This has also increased the risk of contrast-induced nephropathy (CIN) in certain patient populations. It is now well established that the occurrence of CIN has a powerful negative impact on the prognosis of these patients after coronary angiography, percutaneous coronary intervention (PCI) or transcatheter aortic valve implantation (TAVI).
Incidence and Mechanism of Contrast-induced Nephropathy
CIN is usually defined as a sudden, rapid deterioration in renal status after administration of iodinated contrast medium.1,2 It is defined as an increase in serum creatinine value (>0.5 mg/dl) or 25 % increase from baseline renal function between 24 and 120 hours after exposure to contrast media.3 Incidence of CIN in patients with normal renal function is <3 % but can be substantially greater in individuals with at least one risk factor for CIN (12–15 %), including pre-existing renal dysfunction and diabetes.4–6
Intrinsic causes in the mechanism of developing CIN include: direct cytotoxic effects on renal cells leading to increased toxic oxygen free radicals, increased medullary vasoconstriction, increased oxygen consumption, increased intratubular pressure secondary to contrast-induced diuresis, increased urinary viscosity and tubular obstruction, all culminating in renal medulla ischaemia (see Figure 1). There are few therapeutic options to prevent this complication. Many drugs have been tested, but today only N-acetylcysteine is used.
Despite many randomised studies and meta-analyses, the benefit of N-acetylcysteine remains a subject of controversy; some studies being negative and some positive.7 The advantage of this drug in the prevention of CIN is that it has no drug-related adverse events. Moreover, it forces the radiological/interventional team to think about prevention.
Prevention is the most important viewpoint and there are several modifiable factors that the medical team can control:1 the amount of contrast media used, the optimisation of hydration (saline or sodium bicarbonate) before the procedure, and the nephrotoxic drugs that should be stopped before the procedure, such as angiotensin-converting enzyme (ACE) inhibitors and diuretics.
Risk Factors for Developing Contrast-induced Nephropathy and the Effects on Patients
Several risk factors have been described for CIN. As mentioned previously, baseline renal function and diabetes are important predisposing factors. Heart failure, dehydration, hyponatraemia, previous diuretic usage, hypoalbuminaemia, increased age, renal stenosis and contrast dose are also risk factors for elevated serum creatinine and progression to CIN.
A number of PCI studies have identified chronic kidney failure and pre-existing renal dysfunction as significant variables in the risk of developing CIN.8,9 The risk of CIN has been shown to increase in patients with diabetes.4,9–11 A high proportion of older patients (>75 years of age) are treated for cardiovascular disease and aortic valve problems. These patients are typically fragile and have other comorbidities and are considered a high-risk patient population for the development of CIN.9
In addition to the non-modifiable risk factors discussed above, a number of modifiable risk factors have been identified. The volume of contrast agent used has previously been shown to result in a greater risk of CIN.12 More recently it has been shown that following a simple rule may help to prevent the risk of CIN in patients undergoing PCI.13 The recommendation is to use the baseline creatinine clearance to limit the amount of contrast media used. The risk of CIN is low when the volume of contrast media used is less than four times the creatinine clearance, intermediate at between four and eight times and high when more than eight times.
The type of contrast media used (ionic or non-ionic) is still a matter of debate. In all cases low-osmolar or iso-osmolar contrast media are strongly recommended. A recent study of patients receiving intravenous administration of iso-osmolar dimer iodixanol 320 and the low-osmolar non-ionic monomer iopamidol 370 observed a similar rate of CIN.10 Other studies, comparing intra-arterial administration of low-osmolar non-ionic monomer iopamidol 370 and the iso-osmolar dimer iodixanol 320 also observed similar rates of CIN for the two contrast media.14,15
To explore whether a causal link exists between CIN and long-term adverse events, a follow-up study was conducted in 294 patients of the original Cardiac angiography in renally impaired patients (CARE) trial, comparing the differences in the incidence of CIN and adverse events between iopamidol and iodixanol at least one year after contrast exposure in patients with chronic kidney disease who underwent cardiac angiography or PCI. Besides showing that CIN has a negative impact on the long-term prognosis of the patient population in this study, the follow-up data indicated that use of iopamidol reduced both the incidence of CIN and adverse events compared with iodixanol.16
CIN is accompanied by short-term effects, including increased levels of creatinine following the procedure, that require close monitoring to ensure these levels decline. Higher mortality rates have been observed in patients undergoing PCI if CIN develops even if they do not need dialysis. 17
Awareness of Contrast-induced Nephropathy Risks and Current Guidelines
Within the interventional cardiology community there is a good understanding of the complications, comorbidities and risks associated with CIN.1,18 However, there remains scope for improvement, especially with respect to prevention, preparation of the patient, and dose and volume of contrast agent that can be used during cardiac procedures.
Non-ionic contrast media have been shown to result in fewer incidences of CIN.19 However, this is under debate and certainly the choice of contrast media has yet to impact on guidelines. Larger randomised comparison studies comparing non-ionic and ionic contrast media in patients with higher risks of CIN may be warranted.20 At the Institut Cardiovasculaire Paris Sud, non-ionic, low-osmolar contrast media (LOCOM) are being used.
A new device has been developed to prevent CIN in high-risk patients: RenalGuard Therapy®. It is designed to reduce the nephrotoxic effects that contrast media can have on the kidneys. This therapy is based on the theory that creating and maintaining a high urine output is beneficial to patients undergoing imaging procedures where contrast agents are used. The realtime measurement and matched fluid replacement design of the RenalGuard System is intended to ensure that a high urine flow is maintained before, during and after the procedure.
Very promising results from two European prospective randomised studies, Renal insufficiency following contrast media administration trial II (Remedial II) and MYTHOS, have been presented in abstract form.21–23 Remedial II was published in August 2011.24 A pivotal study will start soon in the US and it is hoped that this device will be available soon in France.
Lowering Incidence of Contrast-induced Nephropathy–The Institut Cardiovasculaire Paris Sud Experience
The Institut Cardiovasculaire Paris Sud currently has five catheterisation labs and performs approximately 2,300 PCIs per year including 250 chronic total occlusion (CTO) procedures and 150 TAVI procedures.
Patient preparation is a crucial step before the delivery of any contrast agents. At the Institut, patients are seen by the anaesthesiologist and the clinical cardiologist before the procedure, in order to stop administration of nephrotoxic drugs and ensure that they will be fully hydrated before the procedure. Monitoring the levels of creatinine and the dose of contrast media is required for each patient. In patients with previous renal dysfunction, saline is administered before and throughout the procedure, as well as N-acetylcysteine.
After the procedure, the patient is followed up and the levels of creatinine are monitored at 24 hours and four days in the high-risk patients. Implementation of these measures has led to minimal incidences of CIN at the Institut Cardiovasculaire Paris Sud. CIN has become a rare event at the Institut and few patients require dialysis after a cardiac procedure except those who have concomitant renal failure.
Case Study Example
A borderline patient with creatinine levels of 250 mM/l (creatinine clearance 20 ml/min), undergoing a coronary angiography or angioplasty with 70 ml contrast media (less than four times the creatinine clearance), will be prepared according to the previous rules and followed only by checking creatinine levels at days 1 and 4. If in the same patient 140 ml contrast media is used (seven times the creatinine clearance), following the procedure short-term dialysis will be performed to prevent the risk of long-term renal failure.
Implementation of the ACIST Contrast Delivery System at the Institut Cardiovasculaire Paris Sud
The ACIST contrast delivery system is an automated power injection device that allows for greater control of injectable contrast media (see Figure 2).25,26 In a study in patients undergoing diagnostic catheterisation or PCI, mean contrast volume (± standard deviation) per case was reduced from 204 ± 147 ml to 146 ± 108 ml (p<0.05) by use of the ACIST contrast delivery system.27 Furthermore, administration of contrast agents with the ACIST contrast delivery system, in combination with contemporary hydration procedures and the use of ad hoc N-acetylcysteine and bicarbonate infusion was associated with a lower incidence of CIN (13.3 % versus 19.3 % using manifold injection system; p<0.05).
The Institut Cardiovasculaire Paris Sud began using the ACIST system in 2001 to achieve greater control of the volume of contrast media administered during procedures and to improve the quality of angiograms. Initially the ACIST system was introduced into one catheterisation lab and then subsequently added to the other rooms within two years.
In the first year of use of the ACIST system there was no observable decrease in total amounts of contrast media. Following the second year a decrease by 20 % was attained, and amounts continued to decrease by 30–35 % in four years. The reason for this response is, in part, due to the learning curve required by the medical staff to understand and accept the ACIST system. Over time, experience of the system is achieved and several benefits for the practitioner and patient arise.
The most significant aspect is the ability to control and know exactly the volume of contrast agent being delivered to the patient. In patients with high comorbidities (including diabetes and old age) the ability to reduce the contrast agent to less than 100 ml is essential in lessening the risks and reducing incidences of CIN. Today, the majority of angiograms are performed with less than 70 ml of contrast media. In a recent prospective series of more than 500 high-risk cases (mean age 68 years), 28 % of whom were diabetics, only 1.2 % led to CIN. In comparison, published registry data suggest that the incidence of CIN in low-risk patients is approximately 3 %.5 In the high-risk population the incidence of CIN can be >30 %.28
ACIST has also been observed to produce high-quality coronary angiograms, even in challenging interventional procedures where small catheters are used (4 or 5 French), while using less contrast media.29
The Institut Cardiovasculaire Paris Sud has established a prospective database of >1,300 patients with CTOs. Following the introduction of the ACIST delivery system only 0.2 % required dialysis.
As the literature and experience with ACIST increase, the ability to perform more than one procedure will increase. For example, currently a high-risk patient may undergo a computerised tomography scan with 80 ml contrast media and then a subsequent procedure with 150 ml. The risk of nephropathy will increase as there is an accumulation from the two procedures. With ACIST lowering the volume of contrast media, multiple procedures may be undertaken without enhancing the risk to the patient.
Conclusion
The occurrence of CIN after coronary angiography, percutaneous coronary angioplasty or TAVI has a very negative impact on the short- and mid-term outcome. The risk factors, such as age, diabetes and the amount of contrast media, are now well established. Prevention by optimal patient preparation is crucial, as well as an effort to reduce the amount of contrast media used for the procedure.