Contrastinduced Nephrotoxicity

Contrast-induced nephrotoxicity (CIN), a nonidiosyncratic reaction, is often defined on laboratory, rather than clinical, grounds. Although there are a variety of definitions employed in various studies, CIN usually refers to an acute elevation in the level of serum creatinine by >0.5mg/dL or >50% of baseline. The incidence of this complication is estimated to be 2% to 7% (17), though the incidence varies with the criteria used to define CIN and with the population under study. Direct measurements of creatinine clearance or mathematical estimations of creatinine clearance based on various clinical parameters (18) would likely be more accurate determinants of CIN; however, serum creatinine is the most common value measured in clinical studies. Most clinical studies of CIN suffer from two problems: the clinical significance of the arbitrary choice of the degree of creatinine elevation defining CIN is unknown, and may be too sensitive a marker; and long-term follow-up of patients is not done to quantify the consequence of RICM administration.

In patients who suffer from CIN, serum creatinine elevation is first detectable between one and three days after contrast material injection and peaks by three to seven days (19). The creatinine level usually eventually returns to baseline, most often within 10 to 14 days (17,20); however, in some series, as many as one in four patients who developed CIN suffered a sustained reduction in renal function (17).

Patients at Risk

A number of risk factors for the development of CIN have been described, particularly pre-existing renal insufficiency (21-26). Patients whose renal failure is the result of diabetic nephropathy are at even greater risk, and when renal failure occurs, it is more likely to be irreversible (27). However, the presence of diabetes mellitus alone (in the absence of renal failure) is probably not a risk factor for contrast-induced renal failure (28-30). Other risk factors that have been implicated include American Heart Association class IV congestive heart failure, hyperuricemia, dehydration, concurrent use of such nephrotoxic drugs as aminoglycoside antibiotics and nonsteroidal anti-inflammatory agents, advanced age, and administration of large doses of contrast media for one or multiple contrast-enhanced studies performed within a short period of time (14,19,31,32). Multiple myeloma has long been considered a risk factor but may not be important if the patient is hydrated (14,33). The incidence of contrast-induced renal failure is greatest when multiple risk factors are present (17).

Reducing Risk

Because the only treatment for CIN is at best supportive, prevention is the key. Avoiding large or closely repeated doses of contrast media and discontinuing other nephrotoxic drugs (when possible) reduces the risk.

Premedication

Hydration of the patient (commonly beginning 12 hours before and continuing two hours after contrast media administration) has long been used to reduce the risk of CIN. For intravenous hydration, normal saline has been shown to be more efficacious as a hydrating agent than half-normal saline (34). A preliminary study (35) of 119 patients suggests that hydration with sodium bicarbonate solutions may be even more effective than hydration with normal saline in reducing CIN risk.

Over the years, many drug therapies have been proposed to reduce the incidence of CIN. Attempts to improve upon saline administration alone by adding other drugs such as mannitol, furosemide, theophylline, calcium antagonists, dopa-mine, endothelin receptor blockers, prostaglandin E1, and atrial natriuretic peptide have not proven uniformly successful (36-38). Many of these drugs have side effects the significance of which are not yet fully understood. The search for pharmaco-therapeutic agents that might mitigate the nephrotoxic effects of contrast media continues, however.

Tepel et al. (37), relying on evidence (39) that reactive oxygen species may play a causative role in CIN, administered the antioxidant acetylcysteine in a prospective, placebo-controlled, randomized trial in high-risk patients and demonstrated a protective effect of the drug. In patients with chronic renal insufficiency, oral acetyl-cysteine combined with intravenous hydration was better than placebo and hydration in reducing the incidence of CIN. (Acetylcysteine is better known by its various trade names, including Mucomyst, Mucosil, Fluimucil, Genac, and many others).

Some questions about this study can be raised. The amount of contrast agent administered to the patients for computed tomography (CT) scans was relatively small (75 mL of a 300mgI/mL nonionic agent). For reasons not fully explained, patients with serum creatinine as low as 1.2mg/dL (which would be within the range of normal at many institutions) were included as ''chronic renal failure'' patients. The number of patients in the study was small (83 in total), especially given the low incidence of clinically significant renal failure caused by RICM. None of the patients in this series required dialysis, and no long-term outcome information about any of the patients was reported. Thus, the cost-effectiveness and clinical significance of this intervention remained undetermined. Because patients with acute renal failure were excluded, the study provided no evidence as to whether acetylcys-teine may protect patients in acute renal failure from CIN.

Since the publication of the Tepel study, a number of other studies have been performed in an attempt to replicate the results and perhaps overcome some of the deficiencies of the initial work. Results from these studies have been mixed. Some (40-44) have supported the use of acetylcysteine to reduce CIN risk and others

(45-50) have not. In an attempt to resolve these differences, meta-analyses of the data from multiple studies have been performed. Two such meta-analyses (51,52) have indicated that acetylcysteine is effective in reducing CIN risk in patients with chronic insufficiency. Both meta-analyses were performed on the same seven studies (37,40-42,45-47), of which four showed that acetylcysteine reduced risk in patients with chronic renal insufficiency and three did not show a reduction in risk. When the results of those studies were combined as a meta-analysis of 805 patients, the combination of hydration and acetylcysteine reduced relative risk by 56% (P = 0.02) compared to hydration alone (51). One meta-analysis (51) noted that the results might have been limited by publication bias, whereas the other (52) found no evidence of publication bias. Both meta-analyses noted that the studies they reviewed did not give much insight into the clinical significance of the reduction of CIN (as CIN was defined in the studies, an issue discussed previously in this chapter). The incidence of dialysis was the same (0.75%) in the drug and placebo groups (52), and the studies did not investigate such clinical endpoints as in-hospital morbidity and mortality (51). The optimum dose of acetylcysteine is not known; for example, preliminary evidence (53) suggests that doubling the dose used in many earlier studies might be more effective.

Another drug that was proposed to have protective action against contrast nephropathy is fenoldopam (trade name: Corlopam®). Fenoldopam is a selective dopamine-1-receptor agonist for intravenous use as an antihypertensive. It is a vasodilator that increases renal perfusion but does not have the unwanted systemic effects of dopamine (54). In dogs, fenoldopam blunted the decrease in renal blood flow and glomerular filtration rate caused by contrast media, but the study did not prove whether it would reduce clinical nephrotoxicity (55). In a small study of 46 angiography patients with minimum serum creatinine values of 1.5mg/dL who were treated with fenoldopam, contrast nephropathy occurred in 13%; the authors employed published data to suggest that 38% should have been expected to demonstrate nephrotoxi-city (56). This study, weakened by the lack of a true control group, demonstrates why confirmatory controlled studies are important before the wholesale adoption of new approaches. In a subsequent randomized, controlled, sufficiently powered study of 315 patients, Stone et al. (57) showed no positive effect of fenoldopam in the prevention of CIN. Thus, at present, the use of fenoldopam cannot be recommended.

Choice of Contrast Medium

While it is now well accepted that LOCM are less nephrotoxic than HOCM in patients with pre-existing renal impairment (30,58), two studies have suggested that the use of iso-osmolality agents may further reduce the risk of CIN from RICM administration. In a randomized comparison (59) of iodixanol (iso-osmolality contrast medium) and iohexol (LOCM) in 102 patients with serum creatinine of more than 1.7mg/dL, only 15% of the patients in the iodixanol group showed a rise of greater than 10% in serum creatinine, compared to 31% of patients in the iohexol group (P < 0.05). Similarly, in a study (60) of 129 patients with serum creatinine in the range of 1.5 to 3.5 mg/dL, an increase in serum creatinine of at least 0.5 mg/dL occurred in only 3% of the iodixanol group, compared to 26% in the iohexol group (P = 0.002). The peak increase in serum creatinine within three days of RICM administration averaged 0.13 mg/dL in the iodixanol group compared to 0.55 mg/dL in the iohexol group (P = 0.001). Comparable studies comparing iodix-anol with other LOCM are not yet available.

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