Boring Question: What is the risk of Contrast-Induced Nephropathy?

I once encountered a patient who was empirically started on warfarin therapy after a presumed diagnosis of pulmonary embolus. The treating team did not want to risk an AKI by performing a CT-PE as the patient’s creatinine was 120 and a V/Q scan was not an option due to underlying lung disease. This made me uncomfortable. There’s a known risk of hemorrhagic stroke (~0.5% per year) and other major bleeding events with warfarin, which should be weighed against the risk of AKI and the need for dialysis from contrast-induced nephropathy from CT-PE.

But what is that risk? Surprisingly, the literature is equivocal on this very important question. This spurred me to do my own study to better approximate this risk. The following discussion will reference this study as well as a few other well designed, recently published studies that have challenged the common assumption that contrast in CKD = high risk of permanent renal injury.

Boring Question:

Why do we think IV contrast is so bad? What is the risk of Contrast-Induced Nephropathy?

Discussion:

Contrast can cause acute kidney injury, which is usually defined as a rise in creatinine by 25% or 44 µmol/L within 24 to 72 hours in the CI-AKI literature, though other definitions (AKIN) are now becoming more common. This has been shown pretty convincingly in animal models (1). But the risk in humans is harder to approximate, because, unlike in animals, we can’t ethically randomize someone to receive a non-contrast or contrast CT scan. Many authors observed patients after they received contrast CTs and presumed the incidence of AKI after the scan as the risk of contrast-induced nephropathy. These studies reported frighteningly high risks of AKI, with one in outpatients finding an incidence of over 10% (2). Most of these AKIs were found to resolve after a few days but some lead to progressive renal failure and dialysis (3).

Why might this be incorrect?

However, there’s an obvious flaw in this approach. Patients getting CTs with contrast are usually pretty sick, and being sick or in hospital is a big risk factor for AKI. In fact, Newhouse et al. assessed a population of inpatients that did not receive any contrast in a preceding 10 day period and found a 10% incidence of substantial AKI (increase of 50% or more in creatinine) in a following 5 day period (4).

How to get a better answer to this question?

The best way to discover the true risk of contrast AKI would be to perform a RCT. As that is not possible, the next best thing would be an observational study with a suitable control group.

Two very large studies were recently published that compared patients having contrast CTs with a control group of patients undergoing non-contrast CTs (5,6). They used propensity matching to control for differences in the control and intervention group unrelated to the intervention. For example, it’s quite likely that patients with more renal risk factors, such as diabetes, are more likely to receive non-contrast scans, as diabetes is thought to increase the risk of contrast-induced nephropathy. Propensity matching controlled for such differences between the groups which allowed for a more accurate assessment of the risk of AKI that was due to the contrast. After propensity matching, these two giant studies found some surprising results: one found no increase in the risk of AKI at any GFR, while the other found risk, but only at GFRs below 30 mL/min/1.73m².

This is pretty solid data, but it is still not an RCT. The problem with propensity matching is that it can only control for factors that the statistician plugs into the model and some confounders may be missed. For example, these propensity-matching trials may not have wholly adjusted for the fact that physicians would be more likely to assign patients undergoing current acute kidney injury to an unenhanced rather than a contrast-enhanced scan. This could potentially mask any increased risk of AKI in the contrast-enhanced group.

A new approach

This is where our study came in (7). It attempted to address the question from a different angle: we compared the incidence of AKI in patients in the 24H-48H after they received a contrast scan (utilizing immediately pre-scan creatinine values as their baseline) with themselves a few days later (72H-96H, with creatinine values at 24H-48H as their baseline). Assuming a relatively constant baseline risk of AKI (ie. the patients had the same risk factors for renal injury 2 days and 4 days after their contrast scan, other than contrast of course), the difference in these incidences should give the risk of AKI attributable to contrast.

We found no increase incidence of AKI (of any severity) immediately after the scan, suggesting that IV contrast administration did not increase the risk of AKI above baseline. We also found no increased risk of dialysis. These results are summarized on the table below. One large limitation of our study was that we had small numbers and poor precision in our GFR < 30 groups, leaving open the possibility for considerable harm in these subgroups. For example, using the maximum value at the 95% confidence interval we found, at worst, a 10% and 25% risk of AKI for GFRs 15-29 and < 15 respectively.

	Immediate post-scan AKI, n (%)	Delayed post-scan AKI, n (%)	Dialysis after scan, immediate post-scan AKI, n (%)	Dialysis after scan, delayed post-scan AKI, n (%)	AKI incidence due to contrast* (95% CI)	Dialysis incidence due to contrast* (95% CI)
All scans (n = 2583)	95 (3.7)	74 (2.9)	4 (0.2)	2 (0.1)	0.8% (-0.2% - 1.8%)	0.1% (-0.2% - 0.4%)
GFR > 60 (n = 1980)	45 (2.3)	35 (1.8)	1 (0.1)	1 (0.1)	0.5% (-0.4% - 1.4%)	0% (-0.3% - 0.3%)
GFR 30-59 (n = 534)	42 (7.9)	29 (5.4)	1 (0.2)	1 (0.2)	2.4% (-0.7% - 5.6%)	0% (-1% - 1%)
GFR 15-29 (n = 47)	5 (10.6)	7 (14.9)	1 (2.1)	0 (0)	-4.3% (-19.8% - 11.3%)	2.1% (-7.5% - 12.7%)
GFR < 15 (n = 22)	3 (13.6)	3 (13.6)	1 (4.5)	0 (0)	0% (-24.5% - 24.5%)	4.5% (-14.4% - 24.9%)

Conclusion

The incidence of IV contrast associated nephropathy is probably much lower than was previously thought. The risk is probably close to 0% in patients with GFRs greater than 30. Unfortunately, the risk below 30 is less well defined. Emphasis should be placed that these statements can only be made for IV contrast administration. The risk of nephropathy from arterial administration (as with cardiac catheterization) is less well studied and could pose a higher risk as the kidneys are exposed to a more concentrated contrast bolus. Hopefully this article has given you real numbers so that you can better weigh the risks and benefits the next time you want to order a contrast CT in a patient with AKI or CKD.

References

Seeliger E, Flemming B, Wronski T, et al. Viscosity of contrast media perturbs renal hemodynamics. J Am Soc Nephrol. 2007; 18:2912–2920.

Mitchell AM, Jones AE, Tumlin JA, Kline JA: Incidence of contrast-induced nephropathy after contrast-enhanced computed tomography in the outpatient setting. Clin J Am Soc Nephrol. 2010; 5: 4–9.

Kooiman, Judith, et al. Meta-analysis: serum creatinine changes following contrast enhanced CT imaging. Eur J Radiol. 2012; 81: 2554-2561.

Newhouse JH, Kho D, Rao QA, Starren J. Frequency of serum creatinine changes in the absence of iodinated contrast material: implications for studies of contrast nephrotoxicity. AJR. 2008; 191:376–382.

Davenport MS, Khalatbari S, Cohan RH, Dillman JR, Myles JD, Ellis JH. Contrast material-induced nephrotoxicity and intravenous low-osmolality contrast material: risk stratification by using estimated glomerular filtration rate. Radiology. 2013; 268:719–728.

McDonald JS, McDonald RJ, Carter RE, Katz- berg RW, Kallmes DF, Williamson EE. Risk of intravenous contrast material-mediated acute kidney injury: a propensity score-matched study stratified by baseline-estimated glomerular filtration rate. Radiology. 2014; 271:65–73.

Garfinkle, MA, Stewart S, Basi R. Incidence of CT Contrast Agent–Induced Nephropathy: Toward a More Accurate Estimation. AJR. 2015; 204: 1146-1151.

Reviewing with the Staff

by Dr. Swapnil Hiremath, MD, FRCPC.
Dr. Hiremath (@hswapnil) is an Assistant Professor at the University of Ottawa, an Attending Nephrologist at the Ottawa Hospital, a Senior Clinical Investigator at the Ottawa Hospital Research institute, and the co-creator of the twitter-based nephrology journal club, #NephJC.

Contrast-induced acute kidney injury (CI-AKI) is often cited as one of the most common causes of hospital-acquired and iatrogenic AKI. This was indeed true a decade or two ago, but is less likely to be true anymore, as Michael Garfinkle nicely reviews above.

There are several reasons for this. Firstly, the advent of safer iodinated contrast agents – the current crop of low-osmolar and iso-osmolar contrast agents are not as nephrotoxic as the high-osmolar agents used before [1]. Secondly, there is increased awareness of the risk of iodinated contrast, and also of chronic kidney disease (the most important risk factor for CI-AKI). Finally, advances in imaging have decreased the need for contrast-enhanced CT scans –plain CTs have improved and other imaging modalities (eg MRI) have become widely available.

Despite this, there are several instances in which we still need to be careful. As MG points out, there is likely still risk with arterial contrast (eg in a coronary angiogram) in patients with moderate CKD and there is equipoise about the risk of contrast-CTs in advanced CKD (GFR <30), and we are relying on observational literature to make these inferences. Additionally, not everyone agrees with the lower risk of venous contrast [2]. As a final point, in patients with advanced CKD (GFR <30), the choice of imaging is still a bit tricky. The decision to proceed should be done after discussion with the radiologist, since MRI with gadolinium also exposes these patient to a very tiny risk of an untreatable and potentially fatal disease, nephrogenic systemic fibrosis [3].

For further reading, the Canadian Association of Radiologists published an updated set of consensus guidelines on preventing contrast-induced nephropathy in 2012 (Disclosure – I was one of the authors of these guidelines) [4].

Barrett BJ & Carlisle EJ. (1993). Metaanalysis of the relative nephrotoxicity of high-and low-osmolality iodinated contrast media. Radiology, 188(1), 171-178.
Nyman U, Almén T, Jacobsson B, & Aspelin P. (2012). Are intravenous injections of contrast media really less nephrotoxic than intra-arterial injections? European radiology, 22(6), 1366-1371.
Grobner T. (2006). Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation, 21(4), 1104-1108.
Owen RJ, Hiremath S, Myers A, Fraser-Hill M, & Barrett BJ. (2014). Canadian Association of Radiologists consensus guidelines for the prevention of contrast-induced nephropathy: update 2012. Canadian Association of Radiologists Journal, 65(2), 96-105.

This post has been edited by Dr Brent Thoma (@Brent_Thoma).