Contrast-associated acute kidney injury: does it really exist, and if so, what to do about it?

Hydration

Adequate hydration before and after contrast agent administration is regarded as the most important preventive strategy. Its rationale is that hydration leads to a lower concentration of contrast agent at the site of the renal tubules, which will reduce interaction of the contrast with the kidneys. Despite the wide adoption of hydration as a preventive measure for CA-AKI, this gets only level B evidence in the 2011 and 2018 guidelines for contrast medium–induced nephropathy by the contrast media safety committee of the European Society of Urogenital Radiology^2,16,17. Recently, the AMACING trial, one of the few studies that actually compared hydration with no hydration, could not show a benefit for hydration as a preventive measure for CA-AKI¹³. In this study, patients who had an elective contrast-enhanced procedure and who had an eGFR lower than 60 mL/min per 1.75 m² but greater than 30 mL/min per 1.75 m², were prospectively included and allocated to a group with or without hydration¹³. The AMACING trial included patients with reduced kidney function for whom hydration as a preventive strategy is recommended. Interestingly, the incidence of CA-AKI in this study cohort was less than 3% in both the intervention and control groups. Severely ill ICU patients who undeniably have a higher risk for the development of CA-AKI were excluded and therefore the results cannot be extrapolated to this population.

Hydration is also not without side effects and especially patients with reduced cardiac and kidney function are at risk of pulmonary edema. In this population, the volume of hydration is often reduced to prevent fluid overload, which of course may increase the risk of inadequate renal protection.

Hydration with bicarbonate or isotonic saline? Hydration with isotonic saline has been the standard for over a decade in coronary angiography¹⁸. Merten used bicarbonate as a scavenger for free reactive oxygen species in a solution with a concentration similar to that of NaCl 0.9% in order to protect kidneys against contrast¹⁹. Follow-up studies in which a bicarbonate regimen was compared with isotonic saline showed conflicting results; some studies and meta-analyses confirmed the benefits shown by the original study by Merten and others showed equal risk for CA-AKI. Unfortunately, most of these studies had important limitations in study design/conduct and most importantly were underpowered, limiting their interpretation^2,20–23.

Recently, the adequately powered PRESERVE study, a prospective randomized study that had a 2 × 2 factorial design and that included 4993 patients with a high risk for renal complications after contrast administration, showed no benefit of intravenous sodium bicarbonate over intravenous sodium chloride for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of CA-AKI²⁴. The absence of benefit for sodium bicarbonate compared with isotonic saline was confirmed in a prospective multicenter randomized study in an ICU setting in patients with stable renal function²⁵. Therefore, we should conclude that sodium bicarbonate solutions and isotonic saline are equally effective for prevention of CA-AKI in this type of patient.

Diuretics

Some preventive strategies such as the use of the osmotic diuretic mannitol or the loop diuretic furosemide are aimed at a reduction of exposure of the tubular cells to contrast by increasing tubular flow²⁶. When increased urine production and negative fluid balance were not corrected, these strategies resulted in net fluid loss and so provided a nice model to show that volume depletion comes with increased risk for CA-AKI²⁶. The RenalGuard System uses forced diuresis by means of furosemide in combination with a device that provides continuous intravenous fluid compensation of the urine produced²⁷. This system prevented CA-AKI and fluid overload in three studies in patients who underwent coronary angiography or PCI with reduced cardiac function^28,29.

N-acetylcysteine

Similar to sodium bicarbonate pre-hydration, N-acetylcysteine has been explored for prevention of CA-AKI for the supposed anti-oxidant effects on reactive oxygen species³⁰. Since the original study by Tepel et al.³⁰ in 2000, numerous studies and meta-analyses, most underpowered and with methodological flaws, have reported conflicting results on the use of N-acetylcysteine for the prevention of CA-AKI. Recently, however, two large and adequately powered studies could show no benefit of N-acetylcysteine over placebo in different study cohorts. First, the ACT (Acetylcysteine for Contrast-Induced Nephropathy Trial), including 2308 patients in coronary angiography and peripheral vascular angiography, showed that at-risk patients exposed to high-dose N-acetylcysteine and placebo had similar rates of CA-AKI³¹. Also, the PRESERVE study (n = 4998) showed that the two groups had similar incidences of CA-AKI (N-acetylcysteine 9.1% versus placebo 8.7%, P = 0.58)²⁴. In summary, the supposed preventive effect of N-acetylcysteine for CA-AKI could not be confirmed in several well-designed and adequately powered studies.

Statins

Statins have anti-oxidant, anti-inflammatory, and anti-thrombotic properties and restore renal nitric oxide (NO) production³². These mechanisms play a role in CA-AKI and therefore several trials have investigated various types and doses of statins as a preventive measure³³. A meta-analysis containing 150 trials with several preventive strategies for CA-AKI found only a beneficial effect of statins on the general population³⁴. In 2017, Liang et al. performed a meta-analysis of 15 randomized controlled trials (RCTs) about moderate- to high-dose rosuvastatin for the prevention of CA-AKI after angiography or PCI³⁵. A moderate to high dose of rosuvastatin, compared with low-dose or no statin, reduced CA-AKI in that specific cohort³⁵. In the same year, an RCT with atorvastatin confirmed the benefit for reducing CI-AKI³⁶. Therefore, in patients undergoing coronary angiography, an expert panel of the European Society of Intensive Care Medicine suggests the short-term use of atorvastatin or rosuvastatin to prevent CA-AKI³⁷.

Renal replacement therapy

Hemodialysis is able to remove between 70 and 80% of the injected low-osmolar contrast media (LOCM) dose during a 4-hour session^38–40. Although it is technically possible to remove a certain amount of contrast dose, a 2012 meta-analysis by Cruz et al. showed insufficient evidence to support renal replacement therapy (RRT) to prevent CA-AKI⁴¹.

A potential explanation for the discrepancy between the ability to remove contrast by RRT and the lack of effect in preventing CA-AKI is that RRT induces inflammation, coagulation, and hypotension that in themselves may negatively affect kidney function⁴¹. Second, for practical reasons, there will inevitably already be a considerable time of contrast exposure between time of administration and start of RRT. Probably, the nephrotoxic effects of contrast are most important immediately after administration when contrast concentration in the renal arteries and kidneys is highest⁴¹. Marenzi et al. randomized patients with severely impaired kidney function beforehand to initiation of hemofiltration before coronarography and continued afterwards and showed a less frequent rise in serum creatinine (which is not unexpected when RRT is used) and fewer complications in the intervention group compared to standard of care⁴². Limitations of this study, including unblinding and a higher level of care in the intervention arm compared with control patients, mean that this intervention cannot be recommended at present.

Vitamins C and E

Vitamins C and E have been evaluated as a preventive measure for CA-AKI for their anti-oxidant and scavenging effects. For vitamin C, encouraging results from cohort studies could not be confirmed in prospective studies^43–45. Vitamin E was evaluated in four small prospective studies, and the individual studies and a meta-analysis (n = 623) showed that adding vitamin E to hydration regimens lowered the risk for CA-AKI⁴⁶. These encouraging results should be confirmed in adequately powered studies before wide adoption of this preventive strategy can be recommended.

Route of administration

The risk for CA-AKI seems lower when contrast media is administered intravenously rather than intra-arterially¹⁶. There are several explanations for this. During an intra-arterial contrast procedure, a higher dose is usually used and the transit time to the kidneys is shorter. The combination of these two factors will result in potentially higher concentrations of contrast medium in the kidneys. In addition, there are more procedure-related reasons for AKI. Advancing the catheter via the femoral artery to the aorta increases the risk for thrombo-emboly entering the renal arteries. The risk for CA-AKI is lower in coronary angiography via the radial artery compared with the femoral approach⁴⁷. This line of reasoning is merely theoretical since in clinical practice the route of administration—intravenous or intra-arterial—is procedure-related. Importantly, a higher risk for CA-AKI in patients with intra-arterial contrast may be explained by differences in baseline characteristics when compared with patients who undergo intravenous contrast examination. Both Kooiman et al.^48,49 and McDonald et al.^48,49 addressed this potential bias by investigating paired cohorts of patients receiving both intra-arterial and intravenous contrast. The authors were not able to show a difference in occurrence rate of CA-AKI between intra-arterial versus intravenous contrast administration^48,49.

Type of contrast medium

Contrast agents are categorized according to their osmolality as high-, iso-, or low-osmolar contrast media (HOCM, IOCM, and LOCM, respectively). Especially HOCM is a risk factor for CA-AKI and is not used anymore. Whether IOCM and LOCM agents have an advantage over each other is unclear. The Visipaque Angiography/Interventions with Laboratory Outcomes in Renal Insufficiency (VALOR) and Cardiac Angiography in Renally Impaired Patients (CARE) trials were not able to show a different in occurrence of CA-AKI when IOCM and LOCM were used in patients with chronic kidney disease undergoing angiography^50,51. This was supported by a meta-analysis by Heinrich et al.⁵². Similar results were found recently in a meta-analysis including prospectively randomized trials in diabetes patients, a high-risk group for CA-AKI⁵³.

Volume of contrast agent

For every drug, too much is not good and will cause toxicity. Similarly, increased volumes of administered contrast will lead to a higher occurrence rate of AKI. Laskey et al. related volume of contrast to kidney function and found that a contrast volume equal to 3.7 times creatinine clearance was associated with an early abnormal increase in serum creatinine in patients undergoing PCI⁵⁴. This finding also nicely illustrates that patients may have different risk profiles. Patients with normal kidney function have a very low risk for CA-AKI whereas patients with decreased kidney function are at greater risk. A safe dose does not exist, and it is prudent to always use the smallest amount of contrast agent necessary to perform the investigation¹⁶.

Use of other imaging techniques: magnetic resonance imaging and gadolinium and carbon dioxide

Magnetic resonance imaging (MRI) could be an alternative for imaging in certain situations. Of course, a major disadvantage of MRI is the limited availability of this procedure. Also, early experience showed that gadolinium-based contrast agents (GBCAs) are associated with a decline in kidney function and evolution to nephrogenic systemic fibrosis (NSF). In 2017, Scharnweber et al. investigated the use of GBCA in patients with AKI, severe chronic kidney insufficiency, or even kidney failure with or without dialysis⁵⁵. Currently, according to their findings, macrocyclic agents and the newer linear agents (“cyclic” and “linear” are both chemical structures of GBCA) have a low risk of causing NSF when administered in a routine dose and when repeated injections are avoided⁵⁵.

In clinical practice, it is probably very seldom that a physician chooses MRI above CT solely for kidney-protective reasons and this is because of limited availability and the potential negative effects of MRI GBCAs on kidney function, especially in patients with chronic kidney disease. Carbon dioxide (CO₂) is inexpensive and can be used in certain procedures as an alternative to iodinated contrast agents when MRI and gadolinium are used⁵⁶.