Contrast-induced nephropathy (CIN) is interesting for several reasons. First, it is a significant clinical concern in this era of increasing use of contrast agents for CT and image-guided interventional procedures. Second, it is not clear how much concern radiologists really should have. Is CIN a creatinopathy with little consequence, or is it an important entity that, as at least one study 1 suggests, heralds increased morbidity and mortality, with a poor prognosis? Third, despite the hundreds of articles on CIN published in peer-reviewed journals over the past few years, the natural history and the pathophysiology of CIN remain poorly defined. In light of the concerns and unknowns associated with CIN, it is important to consider the relationship of image quality and the risk of CIN.

There are numerous determinants of image quality for any specific examination, including both patient-based and modality-based factors. The many considerations that relate to the contrast agent include the specific molecule, whether the agent is ionic or nonionic, its osmolality, its iodine concentration, its viscosity, the total volume used, the injection rate and site, and possible side effects (both CIN and others). The major contrast-related determinants of image quality are iodine concentration, viscosity (as it affects the injection rate and, possibly, the stability of the bolus), the site of injection, the injection rate, and the total volume administered. In performing any examination, the radiologist, in essence, tries to solve a complex equation that includes all of these factors. For example, an abdominal CT study of a small patient with severe congestive heart failure, performed using a 64-slice scanner, requires a relatively small volume of a contrast agent having a relatively high iodine content, with relatively delayed scanning. A CT pulmonary angiogram of a large patient in a hyperdynamic state, performed using a 4-slice scanner, requires a larger volume of contrast, perhaps a higher iodine content, and a shorter delay, with a longer scan time. A selective renal arteriogram, performed using a flat-panel imaging system, requires more rapid injection of a lower volume of contrast with a lower iodine content. There is obviously much overlap in these three scenarios; a contrast agent with 300 to 380 mg of iodine per mL would be satisfactory for all three. In the first two situations, an increase in the iodine concentration might allow a decrease in the total volume administered, but in the third, it would be unnecessary and might, in fact, obscure fine arterial-wall detail. The equation cannot be solved, however, without considering the possible adverse events associated with the contrast agent and the risk factors for each specific patient.

Normal Renal Function

Numerous studies 2 suggest that, in the presence of normal renal function, the total volume of contrast administered is not a predictor of complications. This is, perhaps, counterintuitive, and it certainly runs counter to what many physicians believe. It means that in stable patients with normal renal function, optimizing the quality of the study to gain the necessary information is the real consideration, and there is no reason to limit the volume of contrast used. This is not to say that complications will not occur. Obviously, severe and even fatal reactions do occur, but they are not specifically dependent on the volume injected.

This changes in patients with abnormal renal function, and the decision making becomes more complex. If serum creatinine is elevated, renal function is compromised. If the serum creatinine is normal, however, renal function is not necessarily normal. Serum creatinine is a balance of creatinine production by muscle and filtration through the glomeruli, both of which decrease with age. Both are also decreased in women. Serum creatinine may, then, be normal when the glomerular filtration rate is substantially decreased. This is particularly common in the elderly. A good way to avoid missing renal dysfunction is to use one of the two well-validated formulas for calculating creatinine clearance (Cockcroft-Gault and Modification of Diet in Renal Disease). 3 Many laboratories now simplify this by reporting a calculated creatinine clearance as well as serum creatinine.

When renal dysfunction is present, other risk factors become relevant. These include intrinsic, uncontrollable factors, such as age and diabetes, and factors that can be controlled at least partially, such as hydration status, concurrent nephrotoxic medications, recent surgery, prophylactic measures used, volume of contrast administered, and the specific contrast agent. Hydration is worth particular consideration. It is common practice for patients to be advised to take nothing by mouth for a variable period prior to administration of a contrast agent. This may come from radiologists, from referring physicians, or from other personnel. There are two reasons for this, both with historical origins and both of no real current relevance. Starting in the 1930s, contrast was administered for intravenous urography and given in small doses because of relatively high toxicity. Dehydration was necessary, then, to achieve diagnostic-quality images. Today, toxicity has decreased and image quality has improved dramatically, so dehydration is no longer either necessary or helpful. There was also concern that injection of a contrast agent would cause nausea, vomiting, and perhaps aspiration, so avoiding intake was sensible. With current contrast agents, however, nausea and vomiting are uncommon and aspiration is rare. Perhaps most important, volume expansion through hydration is widely accepted as the most effective way of preventing, or at least limiting, CIN. 2

Since the pathophysiology of CIN remains incompletely understood, it is hard to define either risk factors or effective prophylactic measures with certainty. For example, some work suggested that fenoldopam, a dopamine ß2-agonist that leads to postglomerular vasodilation, lowered the incidence of CIN, consistent with the idea that CIN is related in some way to a decrease in renal blood flow. A large prospective randomized trial, 4 however, showed that fenoldopam had no protective effect. It has been suggested that N-acetylcysteine (NAC) is an effective prophylactic agent. Its mode of action is twofold: it acts as a free-radical scavenger and, through the stimulation of production of endothelial nitric oxide, it may cause intrarenal small-vessel vasodilation. Other studies, 5 though, have shown no benefit for NAC. It is unclear whether this apparent contradiction is related to differences in the dose and timing of administration, to differences in patient characteristics (such as level of renal dysfunction or of patient hydration), or to other factors. Similar questions exist about other agents that have been used or considered for the prevention of CIN, such as endothelin antagonists.

Data Inconclusive

Possible differences between different classes of iodinated contrast agents, and even between specific agents, are also a problem. Studies 6 have shown that, in patients with underlying renal dysfunction, the risk of developing CIN is lower with low-osmolality contrast media than with high-osmolality agents. One influential study 7 suggested that the risk was lower with an isotonic contrast medium than with a specific low-osmolality agent. It is important to note, however, that this study was a small one with a somewhat heterogeneous patient population, and the results (published nearly 3 years ago) have not been confirmed by subsequent studies. In fact, analysis of available data raises the possibility that, instead of the isotonic agent being better than low-osmolality agents in general, the specific low-osmolality agent used in this study may actually be more toxic than other, similar low-osmolality contrast media. 8 Additional concerns have been raised because of the increase in viscosity of the iso-osmolal contrast agent since, in theory, this may lead to renal tubular damage.

There is little that is certain in considering the balance of image quality and risk. Optimizing image quality is a complex, difficult task. Staggering technological improvements, particularly in flat-panel imaging and multidetector CT, have made image quality easier to achieve. Iodinated contrast agents continue to play a central role; despite improvements over the past few decades in both the molecules and in the understanding of complications, there are still risks associated with the use of these drugs. Some of these risks can be eliminated and some can be controlled. The most important complications, CIN and anaphylactoid reactions, still can and do occur. The latter is fortunately very rare and generally can be successfully treated with cardiopulmonary resuscitation. At this point, many questions remain concerning CIN. It cannot be eliminated with certainty, but because of improved agents, improved understanding, and the use of hydration, fear of it rarely needs to affect image quality.

Michael Bettmann, MD, is professor and vice chair for interventional services, department of radiology, Wake Forest University School of Medicine, Winston-Salem, NC.


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