DISEASE of the MONTH J Am Soc Nephrol 11: 177–182, 2000
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DISEASE OF THE MONTH J Am Soc Nephrol 11: 177–182, 2000 Contrast Nephropathy SEAN W. MURPHY, BRENDAN J. BARRETT, and PATRICK S. PARFREY Division of Nephrology and Clinical Epidemiology Unit, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada. With the increasing use of radiographic contrast media in changes of cell injury and enzymuria after contrast administration diagnostic and interventional procedures, contrast-induced ne- (9). The nature of the contrast, associated ions, concentration, and phropathy (CN) has become an important cause of iatrogenic concomitant hypoxia are all important to the degree of cellular acute renal impairment. In fact, CN is the third leading cause damage, while the osmolality of the solution seems to be of of new acute renal failure in hospitalized patients (1). The secondary importance (8). The injection of contrast induces a pathophysiology and risk factors for this complication are biphasic hemodynamic change in the kidney, with an initial, becoming better understood, but there is still controversy sur- transient increase and then a more prolonged decrease in renal rounding many aspects. The purpose of this article is to review blood flow (2). The mediators of these changes are still unknown. recent developments in the area of CN. Particular emphasis Alterations in the metabolism of prostaglandin, nitric oxide, en- will be placed on means of minimizing the risk or preventing dothelin, or adenosine may play a role. this important problem. Risk Factors and Epidemiology Definition and Clinical Features Mild, transient decreases in GFR occur after contrast admin- Many different definitions of CN appear in the literature, but istration in almost all patient (10). Whether a patient develops it is commonly defined as an acute decline in renal function clinically significant acute renal failure, however, depends very following the administration of intravenous contrast in the much on the presence or absence of certain risk factors (Table absence of other causes. For research purposes, a definition 1). A multivariate analysis of prospective trials has shown that such as a rise in serum creatinine Ն25 or 50% above the baseline renal impairment, diabetes mellitus, congestive heart baseline value is often used. Patients with CN typically present failure, and higher doses of contrast media increase the risk of with an acute rise in serum creatinine anywhere from 24 to 48 h CN (8). Other risk factors include reduced effective arterial after the contrast study. Serum creatinine generally peaks at 3 volume (e.g., due to dehydration, nephrosis, cirrhosis) or con- to 5 d and returns to baseline value by 7 to 10 d (2–4). The current use of potentially nephrotoxic drugs such as nonsteroi- acute renal failure is nonoliguric in most cases (5,6). Urinalysis dal anti-inflammatory agents and angiotensin-converting en- often reveals granular casts, tubular epithelial cells, and mini- zyme inhibitors. Multiple myeloma has been suggested as a mal proteinuria, but in many cases may be entirely bland. potential risk factor for CN, but a large retrospective study Most, but not all, patients exhibit low fractional excretion of failed to demonstrate an increased risk in these patients (11). sodium (5,7). The diagnosis of CN is frequently obvious if the Of all these risk factors, preexisting renal impairment appears typical course of events follows the administration of contrast. to be the single most important; patients with diabetes mellitus However, other causes of acute renal failure, including ather- and renal impairment, however, have a substantially higher risk omatous embolic disease, ischemia, and other nephrotoxins of CN than patients with renal impairment alone (12,13). should always be considered. This is particularly true if sig- Prospective studies have produced extremely varied esti- nificant renal impairment should occur in patients without risk mates of the incidence of CN. These discrepancies are due to factors for CN. differences in the definition of renal failure as well as differ- ences in patient comorbidity and the presence of other potential Pathogenesis causes of acute renal failure. A recent epidemiologic study CN appears to be the result of a synergistic combination of reported a rate of 14.5% in a series of approximately 1800 direct renal tubular epithelial cell toxicity and renal medullary consecutive patients undergoing invasive cardiac procedures ischemia (8). Direct cytotoxicity in CN is suggested by histologic (14). Patients without any significant risk factors have a much lower risk, averaging about 3% in prospective studies (9). On the other hand, the risk of renal failure after contrast rises with Received October 25, 1999. Accepted October 27, 1999. the number of risk factors present. In one study, the frequency Correspondence to Dr. Brendan J. Barrett and Dr. Patrick S. Parfrey, Division of renal failure rose progressively from 1.2 to 100% as the of Nephrology, Health Sciences Center, St. John’s, Newfoundland, Canada, number of risk factors went from zero to four (15). A1B 3V6. Phone: 709-737-5157; Fax: 709-737-6995; E-mail: [email protected] 1046-6673/1101-0177 Clinical Outcomes Journal of the American Society of Nephrology The clinical importance of CN may not be immediately Copyright © 2000 by the American Society of Nephrology obvious given the high frequency of recovery of renal function, 178 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 177–182, 2000 Table 1. Risk factors for contrast nephropathy clear indication. Methods not requiring iodinated contrast such as magnetic resonance imaging, ultrasound, nuclear medicine Preexisting renal impairment techniques, or carbon dioxide angiography are becoming more Diabetes mellitus widely available and should be used preferentially if they will Decrease in effective arterial volume provide the required information. The decision to give contrast congestive heart failure should reflect a risk-to-benefit ratio established for an individ- dehydration ual patient. In most patients, the risk factors for CN can be nephrosis identified with a routine history and physical examination. cirrhosis Renal impairment may be asymptomatic until advanced, but it High doses of contrast is impractical to measure renal function before contrast admin- Concurrent use of nephrotoxic drugs istration in all cases. If no other risk factors for renal impair- nonsteroidal anti-inflammatory drugs ment are present, it is probably not necessary to determine angiotensin-converting enzyme inhibitors renal function. When contrast administration is deemed appro- priate, the lowest dose of contrast possible should be used. Optimally, any risk factors for CN should be corrected before but it is by no means a benign complication. Dialysis is contrast administration. If contrast must be administered in the infrequently required (16,17). Some degree of residual renal presence of an uncorrectable or uncorrected risk factor, it is impairment has been reported in as many as 30% of those advisable to monitor renal function by serum creatinine before affected by CN (18). Other comorbid events such as hypoten- and at 48 to 72 h after the procedure. sion, sepsis, and atheroembolic disease certainly contribute. A variety of specific measures have been used in an attempt The occurrence of acute renal failure can prolong the hospital to decrease the risk of CN, particularly in high-risk patients. stay (19). Finally, there is some evidence that mortality may be The following is a discussion of the evidence supporting the increased in patients with CN. In a retrospective study, Levy et use of some of the more common practices. al. compared the outcomes of hospitalized patients with CN to a control group of patients matched for age, baseline serum Nonionic and Low-Osmolality Media creatinine, and type of diagnostic procedure that received con- These alternative forms of contrast media, which have ap- trast but did not develop CN. The mortality in the CN group proximately one-half to one-third the osmolality of standard was 34% compared with 7% in the control group (P Ͻ 0.001, agents, were developed at great expense in an attempt to reduce odds ratio 5.5), even when severity of comorbid illness was the incidence of complications associated with radiocontrast controlled by matching patients by APACHE II scores (20). agents. Unfortunately, they are also capable of inducing CN, CN is no different from acute renal failure of any other although perhaps less frequently than high-osmolality contrast etiology in terms of the complications that may ensue. The agents. Because of their high cost relative to the standard possibility that patients who are receiving the oral antidiabetic agents, however, considerable debate has taken place regarding agent metformin may develop lactic acidosis as a result of CN the role of low-osmolality media in clinical practice. There has received particular attention. This rare complication can have been numerous studies addressing this question, but few occur only if the contrast causes significant renal failure and individual studies had the power to determine the relative the patient continues to take metformin. In a recent review of clinical nephrotoxicity of high- and low-osmolality agents. For this subject, no conclusive evidence was found to indicate that this reason, Barrett and Carlisle performed a meta-analysis of the use of contrast precipitated metformin-induced lactic aci- all the randomized trials available before the end of 1991 dosis in patients with a normal serum creatinine (Ͻ1.5 mg/dl or comparing the nephrotoxicity of high- and low-osmolality con- 130 mol/L). The complication was almost always observed in trast in humans by serial measurement of GFR or serum non-insulin-dependent diabetic patients with decreased renal creatinine. Pooling the P values from the trials suggested a function before injection of contrast media (21). There is really reduction in nephrotoxicity with low-osmolality media, which no justification to discontinue metformin before the day of the was of borderline statistical significance (P ϭ 0.02).