Increasing Awareness of and Concern About Contrast-induced Nephropathy

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The use of iodinated contrast media (CM) for both diagnostic imaging and interventional studies continues to increase. The introduction of multi-detector computed tomography (MDCT) scanners allows for quicker imaging of internal organs, and image acquisition is now fast enough for study of the coronary arteries. This technology requires the delivery of a high concentration of iodine to the vascular system and precise timing of the image acquisition.

With this expansion of the use of iodinated CM, the nature of the patients is also changing. More patients with chronic conditions, such as atherosclerotic cardiovascular disease, renal insufficiency, and congestive heart failure, are becoming candidates for contrast studies. Patients in emergency rooms with trauma, respiratory symptoms, and acute sepsis syndrome are also being sent for contrast-enhanced imaging. The consequence of the technological improvements and increased burden of disease in patients is that more patients are at risk for the development of contrast-induced nephropathy (CIN).

CIN remains defined by changes in serum creatinine. An increase of 25%, or more than 0.5mg/dL over baseline levels, is recognized as a significant change in renal function and is predictive of both in-hospital and out-of-hospital adverse events. However, creatinine is a relatively inaccurate marker of glomerular filtration rate (GFR) and, thus, renal function, because it is excreted in the urine as a result of both filtration and secretion. Furthermore, when GFR changes acutely—following a toxic insult, for example—creatinine rises slowly, usually over days.Thus, there is a delay in the recognition of renal injury when using the serum creatinine. Other markers of GFR, such as cystatin C, appear to be more sensitive and accurate but have not found widespread application in clinical medicine.

Pathogenesis of CIN and Risk Factors

The pathogenesis of CIN remains complex and involves both toxic and ischemic injury to the kidney. The toxic effect, evident in vitro, is mediated at least in part by the generation of free oxygen radicals. These reactive oxygen species produce injury to the renal tubular cells and lead the cells towards apoptosis. The situation is exacerbated, particularly in the medulla of the kidney, by a reduction in medullary blood flow and oxygen delivery caused by CM. The nephron segments within the medulla include the loop of Henle; this part of the nephron has the highest oxygen consumption because of the active transport of sodium out of the urine. A reduction in medullary blood flow therefore creates critical hypoxia, causing cell necrosis.

In patients with normal renal function (i.e. normal GFR), the incidence of CIN is less than 5%. As renal function diminishes, the incidence of CIN rises, with approximately 15% to 50% of patients with GFRs of 50ml/min to 20ml/min, respectively, developing this complication. In addition to baseline level of renal function, any condition that reduces renal blood flow—such as congestive heart failure, intravascular volume depletion, or drugs - can increase the risk of CIN (see Table 1).

Apart from patient characteristics, procedural characteristics also influence the risk of developing CIN. Most important is the volume of iodinated CM administered. While there is no 'safe' amount of CM, the greater the volume of administered contrast, the greater the risk of CIN. In patients undergoing percutaneous coronary interventions (PCI), the requirement for an intra-aortic balloon pump (IABP), severe hypotension, and age are also significant predictors of CIN. Most of the data on the incidence of CIN have been generated in the setting of intra-arterial administration, such as coronary or peripheral angiography. Whether the incidence is similar with intravenous (IV) administration is unclear at this time. Certainly, with moderate to severe renal insufficiency (creatinine >1.8), the incidence of CIN in CT angiography (CTA) is comparable with that in digital subtraction angiography (DSA).

Outcomes in Patients with CIN

Levy et al. highlighted the increased in-hospital mortality seen in those who developed CIN compared with a matched contemporaneous group who underwent contrast studies without developing acute renal insufficiency. After adjusting for co-morbidities, the risk of mortality was 5.5-fold higher in those who developed CIN. These patients received both IV and intra-arterial contrast for diagnostic and intervention studies. The increased mortality was related to sepsis, hemorrhage, and pulmonary complications, not to renal failure per se. Subsequent studies have confirmed the increase in in-hospital as well as one-year and five-year mortality in patients undergoing percutaneous coronary interventions who developed CIN. It is challenging to relate the mortality at one year directly to the development of CIN. Again, mortality in these patients was related to increased incidence of cardiovascular events, primarily acute myocardial infarction (MI). It is possible that the development of CIN is simply a marker for generalized cardiovascular disease. Alternatively, CIN is associated with an upregulation of inflammatory cytokines, which persist long after renal function has returned to baseline. Additional studies in this area are clearly needed to further the understanding of the association between CIN and adverse cardiovascular outcomes. Noteworthy is that increased mortality has been observed primarily in those patients who had at least a 25% increase in creatinine following contrast exposure, supporting the clinical use of this definition of CIN.

In addition to short- and long-term implications for survival, CIN is associated with increased length of stay and hospital costs, and delay in subsequent procedures. Since the timing of CIN is predictable, many efforts have been made to prevent its occurrence.

Strategies for Prevention of CIN

The most important strategy for prevention of CIN is careful consideration of whether exposure to contrast is necessary for the diagnosis and/or management of the patient. For many diagnostic studies, other imaging modalities, such as ultrasound or magnetic resonance imaging (MRI), may suffice. The next step is minimizing the vulnerability of the kidney by enhancing renal perfusion and reducing any vasoconstrictive influences. This usually means volume expansion with sodium-containing fluids.

The first clear example of the importance of saline infusion before and after contrast exposure was a prospective randomized trial in patients with renal insufficiency who were undergoing cardiac catheterization. In this trial, CIN occurred in 11% of those who received 0.45% saline, in 26% of those who received saline and mannitol, and in 46% of those who received saline and furosemide. While this trial demonstrated the importance of pre-contrast volume administration, the protocol called for the infusion to begin 12 hours before the administration of contrast. This is not practical, except in already hospitalized patients. Mueller compared 0.9% saline with 0.45% saline, starting the morning of the coronary angiogram, and found some benefit to the isotonic saline. However, no benefit was noted in the 288 patients with mild renal insufficiency. Nor was the use of oral hydration starting the night before or 300ml of 0.9% saline given at the time of contrast exposure associated with a decrease in the incidence of CIN. The most recent use of sodium-containing fluids involves infusion of isotonic sodium bicarbonate one hour before contrast exposure at a rate of 3ml/kg/h. This was associated with a 2% incidence of CIN in high-risk patients compared with 17% in a group randomized to normal saline. All the infusion protocols continue the infusion at 1ml/kg/h for six to 12 hours following contrast exposure.

It seems intuitive that renal vasodilation would protect the kidney from an insult that involves renal vasoconstriction and decreased renal perfusion. However, attempts to induce renal vasodilation with a variety of substances have been generally unsuccessful. Part of the problem may be the systemic effects of the agents used. Hypotension was frequently noted in trials of atrial natriuretic peptide and fenoldopam.

In addition, renal blood flow to the medulla may be mitigated by excessive vasodilation in the cortex, which receives ten times the blood flow of the medulla. Cortical vasodilation may actually 'steal' blood from the medulla, exacerbating the contrast injury. Current strategies involving vasodilator agents target selective delivery to the renal vascular bed through special catheters placed in the proximal renal arteries.

The most widely used preventive strategy after IV fluid administration is the use of N-acetylcysteine (Mucomyst™), a renal vasodilator and antioxidant. The efficacy of N-acetylcysteine in preventing CIN in patients with renal insufficiency (creatinine 2.4mg/dL) was first demonstrated in 42 patients undergoing abdominal CT. While further studies in CTA have not been reported, the use of N-acetylcysteine in angiography, particularly coronary, has been widespread. While initial trials supported a reduction in the incidence of CIN, subsequent trials failed to find a benefit. The inconsistent results probably reflect differences in study population, the amount of contrast administered, and the amount and route of N-acetylcysteine administration. The strongest evidence in the cardiac literature indicates that a dose of 1,200mg given twice-daily, starting the day before the contrast exposure, is protective.

As noted above, the amount of CM administered is one risk factor for CIN. It is not known how the physicochemical properties of CM cause CIN. One prevalent hypothesis is that the osmolality of the CM is a major determinant of nephrotoxicity. Support for this can be found in animal studies employing hyperosmolal solutions of mannitol or saline. In humans, a meta-analysis of multiple studies found that patients with renal insufficiency had a reduced incidence of CIN when low-osmolality contrast agents (600-800 milliosmoles (mOsm) per kg) were used compared with high-osmolality contrast agents (1,500-2,000mOsm/kg). No difference in the incidence of CIN was noted in those with normal renal function. Among the many low-osmolality CM available, there is little evidence of significant differences in the incidence of nephropathy, although iohexol may be an exception (see Figure 1). There are no head-to-head comparisons of iohexol with any other low-osmolality contrast agent in high-risk patients undergoing intra-arterial administration of contrast. Nevertheless, a systematic review of all the prospective trials in this cohort of patients suggests a higher rate of CIN. However, this difference relates only to patients who do not receive any prophylaxis (e.g. N-acetylcysteine) except volume expansion.

Iso-osmolality CM is also available and appears to be associated with a low incidence of CIN (see Figure 2).The incidence of CIN, at least as revealed in these studies, does not appear to be different to most low-osmolality CM. Unfortunately, the only head-to-head comparison trials in high-risk patients used iohexol as the comparator. One trial showed a benefit for the iso-osmolality agent, and one did not. A third trial,VALOR, comparing iodixanol and ioversol in high-risk patients, has yet to be published.

Intuitively, if one could remove the CM before it reaches the kidney, CIN would be prevented. Attempts to do this with hemodialysis performed immediately after contrast exposure have uniformly failed, presumably because the nephrotoxicity occurred prior to effective removal of contrast. A trial of hemofiltration before and after contrast exposure was, however, effective in reducing the incidence of CIN. It is not clear whether this benefit derived from removal of contrast or improved volume expansion or alkalinization of the urine. The procedure is costly, requires intensive-care unit (ICU) staff, and is generally considered impractical for most patients.

Finally, all high-risk patients should have a serum creatinine repeated at 48 to 72 hours post contrast exposure—only thus can CIN be detected. While there is no specific treatment to reverse CIN, patients with this condition should avoid other procedures that might impair renal function, such as general anesthesia, cardiopulmonary bypass, nephrotoxins, additional contrast studies, and ACE inhibitors, or angiotensin receptor blockers—at least until the serum creatinine has returned to the baseline level. Drugs eliminated from the body by the kidney, such as metformin, should also be held, or have their doses reduced.

In summary, CIN is increasingly of concern to cardiologists and radiologists. High-risk patients must be recognized and steps to minimize the risk must be implemented. Follow-up of high-risk patients with repeat serum creatinine levels after contrast exposure will identify those who still develop this complication.