Contrast and acute kidney injury: what is left to enhance?

INTRODUCTION

Contrast-enhanced imaging provides important diagnostic information and contrast-based therapeuticinterventions have become a mainstay of cardiovascular care. The annual estimated iodinated contrast use of 80 million doses administeredworldwide comes from a decade ago, and is likely to be vastly higher now [1]. One of the possible complications of using iodinated contrast is contrast-induced acute kidney injury (CI-AKI), previously known as contrast-induced nephropathy. Despite its potential harms to the kidneys, avoiding the use of iodinated contrast for diagnostic imaging can hinder the overall care of patients. In this review, we will critically examine recent literature on this topic, including data which suggest that the risk of CI-AKI is very low and that most interventions to prevent it are ineffective.

CAUSES AND CONSEQUENCES OF CI-AKI

The mechanism of injury for CI-AKI was elucidated for high-osmolar contrast agents and relied on the physicochemical properties of the viscous contrast media. Recent literature on low-osmolar contrast suggests a role for Nod-like receptor pyrin 3-deficient-induced inflammation [2]. The most commonly used definition of CI-AKI relies on a change in creatinine after contrast administration within 48–72 h in the absence of other causes of AKI. Excluding other causes of AKI (such as cholesterol emboli, acute tubular necrosis or interstitial nephritis) should be done carefully, but these are rarely considered when the smoking gun of contrast makes for an obvious, albeit innocent, suspect. The absence of markers of tubular injury following contrast administration suggests that most CI-AKI reported in the literature reflects changes in kidney hemodynamics and noise rather than direct kidney damage [3]. Recent epidemiological literature suggests that the risk of AKI after contrast is not higher compared with propensity-matched cohorts, but these study designs miss underlying selection bias, since higher risk patients are less likely to receive contrast, biasing such studies toward the null [4]. A high contrast dose, arterial administration and impaired kidney function, especially in combination, remain robust risk factors for CI-AKI. For dialysis patients with residual function, contrast use does not change the natural trajectory of decline [5]. Although observational literature suggests patients developing AKI have worse longer-term outcomes, this probably reflects the role of underlying risk factors, since prevention of AKI, using data from randomized clinical trials, does not change this longer term risk.

PREVENT IATROGENIC AKI

Since contrast is mostly an elective administration, interventional studies to prevent AKI are easy to plan and perform, but in this case have led to more missteps than enlightenment.

VOLUME EXPANSION IN CONTRAST NEPHROPATHY

Volume expansion interventions to prevent CI-AKI, over the years, have spanned from the use of 0.45% saline (better than saline + mannitol) to 0.9% saline, and on to bicarbonate-based near-isotonic fluids. The largest trial in the field so far conclusively proves that intravenous 0.9% saline should be the fluid of choice for patients at risk [i.e. patients with impaired kidney function, glomerular filtration rate (GFR) <45 mL/min/1.73 m², receiving intra-arterial contrast] [6]. What of lower risk patients, or patients with severe chronic kidney disease, perhaps with GFR <30 mL/min/1.73 m², receiving intravenous contrast, as with contrast-enhanced computed tomography (CECT)? Two large, Dutch non-inferiority trials suggest that no prophylaxis is just as good as intravenous volume expansion. The A MAstricht Contrast-Induced Nephropathy Guideline (AMACING) trial reported no benefit with intravenous 0.9% saline in 660 patients with GFR 30–59 mL/min/1.73 m² undergoing a mix of contrast-enhanced procedures, 48% of which was intra-arterial. The Kompas trial reported similar results in 523 patients with GFR 30–59 mL/min/1.73 m² undergoing CECT. Thus, among most patients with GFR >30 mL/min/1.73 m², unless deemed necessary (e.g. intra-arterial administration and large contrast dose in a patient with diabetes), no prophylaxis is necessary. Among patients with GFR <30 mL/min/1.73 m² or higher with additional risk factors as mentioned above, intravenous 0.9% saline seems currently reasonable.

However, intravenous 0.9% saline requires a longer hospital stay and additional healthcare resources. For CECT and contrast administration that takes place outside the hospital setting where nursing staff and healthcare resources may be scarce or unavailable, limited trials suggest that oral salt and water may provide similar benefit to intravenous volume expansion, and could be utilized when the intravenous route is not feasible [7].

CONTRAST AS THE CULPRIT

High-osmolar contrast agents (∼1200 mOsm/kg) did cause CI-AKI at a higher rate, and current practice worldwide is to use low- or iso-osmolar contrast agents (osmolality approximately ≤600 mOsm/kg), which carries lower risk. The difference between iso-osmolar and low-osmolar contrast agents however is smaller, with the literature providing heterogeneous data, with probable reason to believe there is little real difference in outcomes. The dose of the contrast does matter, however, with a higher dose being a risk factor for AKI across all the literature. Thus, minimizing the dose of contrast, at the cost of having fewer pretty pictures, is a smart option in high-risk patients, with some recent techniques also developed using very low dose, or zero contrast interventional procedures [8].

PHARMACOTHERAPY: THE MEANDERING COURSE OF EVIDENCE GENERATION

The antioxidant n-acetylcysteine (NAC) has created confusion in the care of patients receiving contrast since the first positive randomized clinical trial (RCT) two decades ago. Despite not having a clear mechanism of effect, with small trials showing a fantastic reduction in AKI risk, there was a huge uptick in its use. It has taken the recent completion and publication of large and well-conducted RCTs to cool the fervor of NAC use [6, 9]. There is no role for using NAC anymore for preventing CI-AKI. Similar sentiments apply to fenoldopam, mannitol and statins in this setting (the last of which should be used for appropriate cardiovascular indications).

FUTURE RESEARCH

Do we need any more trials, or is all the science settled? From the discussion on volume expansion, we would suggest there is now equipoise for examining whether no prophylaxis is noninferior to intravenous 0.9% saline in the population so far deemed high risk for CI-AKI. Studies with an adaptive enriched design using biomarkers could allow for faster resolution of this issue since poor enrolment and inadequate power have been a problem with past trials [10]. Lastly, a clinical rather than biochemical definition of CI-AKI would eliminate noise in future epidemiological research in this area [1]. See Figure 1 for a summary of the evidence and future research needs.

FUNDING

S.H. and E.G.C. receive research salary support from the Department of Medicine, University of Ottawa. S.H. has received grant funding from the Canadian Institutes of Health Research for a study on CI-AKI.

CONFLICT OF INTEREST STATEMENT

None declared.

REFERENCES