Contrast-induced nephropathy (CIN) represents an increasing healthcare burden and challenge as the frequency of diagnostic imaging and interventional studies increase, particularly among populations at risk of developing CIN. As the population ages, decreased renal function and increased atherosclerotic cardiovascular disease become more prevalent. Increasing levels of obesity with resultant metabolic syndrome and/or adult diabetes mellitus also increases the population at risk for CIN.
CIN is the third most common cause of hospital-acquired acute renal failure. Recently, important clinical trials on CIN have been completed. Today, there is more agreement on the definition of CIN and a better understanding of which patients are at increased risk of developing CIN. Also, new insights into the pathogenesis of the renal injury are leading to innovative pharmacologic strategies.
Definition and Clinical Implications of CIN
For clinical and research purposes CIN is defined as an acute decline in renal function (rise in serum creatinine by 25% or greater than 0.5mg/dL from baseline or fall in glomerular filtration rate (GFR) by greater than 25%) after systemic contrast administration in the absence of other causes.1 Typically, CIN onset occurs within 24-48 hours of exposure, serum creatinine levels peak in 3-5 days, and renal function returns to baseline in 7-21 days. If renal function does not return to baseline, other possible causes of renal injury like atheroembolism should be suspected.1 The incidence of CIN is less than 5% in patients with normal renal function and 15-50% in patients with baseline renal dysfunction (creatinine clearance less than 60mL/min).1 The incidence of dialysis-dependent acute tubular necrosis is 1.3 to 19%. CIN is an indicator of marked increase in short-term and late mortality. Acute renal failure after coronary intervention is associated with a 36% in-hospital mortality rate and a 19% two-year survival rate.2-4
Pathogenesis of CIN
The pathogenesis of CIN is complex, with a cascade of contributing factors that are not fully understood.5 After injection of contrast media, renal blood flow increases transiently, followed by a more prolonged decrease, particularly at the corticomedullary junction of the kidney. The outer medulla is particularly susceptible to ischemic injury because of its high metabolic activity and low prevailing oxygen tension.
Associated with the decrease in renal blood flow there is a decrease in glomerular filtration rate due to afferent renal arteriolar vasoconstriction which is calcium dependent with increased intrarenal adenosine and increased endothelium-1 activity as likely mediators of the vasoconstriction. The risk of CIN increases if there are inadequate compensatory vaso-dilatory responses such as prostaglandins (E2 and I2) and nitric oxide.
Renal tubular cellular injury at least in part is mediated by generation of oxygen-free radicals. Intrarenal adenosine accumulates due to the depletion of adenosine triphosphate as a consequence of proximal tubular stress due to osmotic load and the large size of CM molecules.The renal toxicity from the direct effects of CM is reversible, as has been shown in vitro in studies in which renal tubular cells responded to CM exposure by increasing the concentrations of extracellular adenosine and by decreasing the activity of mitrochondrial enzymes without altering viability.6 A late effect of intrarenal adenosine is oxygen free radical production due to the catabolism of intrarenal adenosine to xanthine.7
A role for intrarenal adenosine as a renal vasoconstrictor and substrate for oxygen-free radical formation is supported in human studies. Adenosine increases in urine following CM; the magnitude of adenosine release and depression of creatinine clearance is proportional to the osmolatity of the contrast agent, essentially a dose response relation.8 Further, an inhibitor of adenosine uptake, dipyridamole, exacerbates the fall in GFR after CM.
In addition, blockade of the renal vascular adenosine receptors with theophylline attenuates the fall in GFR following CM.8 Finally, following pre-treatment with allopurinol (a xanthine oxidase inhibitor) urinary xanithine increases and the fall in GFR seen after CM is lessened.7
Endothelin is a potent renal afferent arteriole vasoconstrictor like intrarenal adenosine.5 Infusion of CM induces exaggerated release of urinary endothelin in patients with impaired renal function.9 In patients with normal renal function receiving varying amounts of CM, no significant increase in plasma endothelin levels are detected until the volume of CM administered is greater than 150mL.10 This response is exaggerated in patients with diabetes and/or renal insufficiency.
In patients with normal GFR the risk of CIN is likely less not only because of more rapid clearance of CM from the kidney (less time for generation of oxygen free radicals) but presumably because of the presence of a variety of endogenous vasodilators that protect against renal ischemia, including prostaglandins (E2 and I2), atrial natriuretic peptide, and nitric oxide.5 In patients with GFR less than 60mL/min the risk of CIN increases with prolonged clearance of CM. Patients with diabetes mellitus appear to be at increased risk of CIN not only because chronic renal disease is common in these patients but also because there appears to be greater vasoconstriction of the renal anterioles to intrarenal adenosine and suppressed NO bioavailability in the kidney due to endothelial dysfunction.11,12 Recent reports indicate that severe renal dysfunction need not be present to create a risk of CIN in diabetic patients with measured creatinine clearance of 100mL/min and receiving proper hydration.13
Risk Factors for CIN
With these mechanisms of CIN outlined, many of the procedures-related risk factors for CIN are identifiable and should and can be avoided in higher risk patients except in medical emergencies (see Table 1). Table 2 provides websites for estimating GFR. Patients who are at particular risk of developing CIN include those with a creatinine clearance of less than 60mL/min and/or diabetes mellitus, those with clinical conditions such as hypovolemia, those with decreased cardiac output and those receiving concomitant nephrotoxins.14 Procedure-related risk factors for CIN include the use of a high-osmolality CM, high CM volume, and multiple CM exposures within 72 hours.14 As the mechanisms for CIN are better understood, there is a growing list of medications which may exacerbate the risk of CIN. Many of these medications are taken by patients with cardiovascular disease and should be addressed prior to proceeding with angiography. Medications that increase the risk of a patient developing CIN include nonsteroidal (nonacetylsalicylic acid) anti-inflammatory medications that inhibit compensatory renal prostaglandin synthesis, diuretics that dehydrate the kidney and increase the risk of medullary ischemia, and dipyridamole that blocks the normal cellular uptake of adenosine resulting in a greater intrarenal adenosine effect.8,14 Discontinuing nonsteroidal anti-inflammatory medications and dipyridamole prior to proceeding with elective diagnostic studies using CM should benefit patient management.
Beneficial Medicines and CIN
There are also medications that may attenuate the risk of CIN. Experimental and clinical studies suggest that calcium-channel blocking medications attenuate both the magnitude and duration of renal vasoconstriction after CM.15 As mentioned above, the adenosine receptor antagonist, theophylline, attenuates the decrease in GFR normally seen after CM.8 Recent research suggests that the 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins,may reduce the risk of CIN because they have beneficial effects on endothelial function, maintain NO production, and reduce oxidative stress.Two recent retrospective reviews of patients with renal impairment undergoing angiography suggested that the risk for CIN was lower in patients in whom a statin was initiated before the procedure.16,17 Thus, patients on calcium-channel blocking medications or on theophylline-containing agents may be at a decreased risk of developing CIN. In patients with diabetes mellitus and in nondiabetic patients with coronary artery disease, there are strong clinical recommendations for the use of statins. These recent retrospective reviews reinforce the rationale for the introduction of statin therapy before undergoing diagnostic or interventrial coronary angiography in these patients.17
Hypomagnesemia (serum magnesium level less than 2mg/dL) may also be a correctible risk factor for CIN in patients with renal dysfunction (creatinine clearance of 60mL/min).7 This risk factor warrants further study because many patients become hypomagnesemic from chronic diuretic therapy in combination with low dietary magnesium intake. In addition, patients after renal transplantation who are given cyclosporine usually develop a cyclosporine-mediated renal tubular defect, which causes them to excrete excess magnesium and become hypomagnesemic. Patients with long-standing diabetes mellitus also may acquire a renal tubular defect for magnesium and become hypomagnesemic. Magnesium has been shown to protect the kidney from CM-produced oxygen free radicals.7 The renal protective effect of magnesium is likely multifactorial. Besides its role as an antioxidant and as a coenzyme for compensatory sodium-potassium adenosine triphosphastase, magnesium has calcium-channel blocking properties. Based on these results, magnesium replacement in hypomagnesemic patients may be indicated before diagnostic studies using CM.
Strategies to Reduce the Risk of CIN
In view of the clinical relationship between CIN and patients' morbidity and mortality, many risk-reduction strategies have been evaluated. Identifying patients at risk and considering whether exposure to CM is necessary for the diagnosis and/or intervention is implicit. Limiting the amount of CM administered and choosing a safe contrast agent are important and have received much study. Clinical trials published in the 1990s clearly showed that the use of the high osmolar ionic monomer diatrizoate in high-risk patients was associated with a higher incidence of CIN than that associated with nonionic monomers.18,19 In general, lower osmolar CM have since replaced diatrizoate for routine clinical use. It is less clear whether there are appreciable differences among the various nonionic low osmolar CM regarding the incidence of CIN. As individual CM have specific effects on renal cells, head-to- head studies are needed to compare the safer CM in at-risk patients undergoing angiography. In vitro proximal renal tubular cell studies suggest that the nonionic low osmolar monomers iomeprol (not available in the US) and iopamidol and the isotonic nonionic dimer iodixanol are the least nephrotoxic molecules.6 One comparative study has suggested a clinical benefit of one nonionic contrast agent over another. In the NEPHRIC study, which compared the nonionic dimer iodixanol with the nonionic monomer iohexol in diabetic patients with renal impairment, a much higher rate of CIN (defined as a serum creatinine rise least 0.5mg/dL after angiography) was noted after iohexol (26.2%) than after iodixanol (3.1%).20 On the other hand, a double-blind, randomized comparison of iopamidol and iodixanol in 122 diabetic patients with moderate renal dysfunction (serum creatinine less than 2.0mg/dL) revealed comparable renal responses.13 More recently, two randomized, double-blind comparison of the renal tolerability of iopamidol and iodixanol in patients with moderate-to severe chronic disease (estimated GFR, 20-59mL/min) also found that the renal effects of these two agent were comparable.21,22 In both studies, CIN was defined as post-contrast rise in serum creatinine of at least 0.5mg/dL.
In one trial in 166 high-risk patients undergoing enhanced computed tomography, the rate of CIN was 2.6% after iodixanol, and 0% after iopamidol.21 In the second study, performed in high-risk 414 patient undergoing coronary angiography, the rate of CIN was 6.7% after iodixanol, and 4.4% after iopamidol.22
Based on recent systematic review of angiographic contrast media in high-risk patients, the likely explanation for the unexpected findings in the NEPHRIC study is that the low-osmolar agent iohexol may be more nephrotoxic than other low-osmolar CM like iopamidol and iodixanol, at least in high-risk patients.23 Since it is now clear that the rate of CIN is comparable following the intra-arterial administration of iopamidol or iodixanol in high-risk patients, with and without diabetes, it appears that osmolality may not be a primary determinant of CIN among nonionic contrast media.
The universally accepted prevention strategy for CIN is adequate intravenous volume expansion with isotonic saline (1.0-1.5 mL/kg per hr) for 3-12 hours before the procedure and continued 6-24 hours.17 An additional strategy which is under study is for patients to receive prophylactic volume expansion with isotonic sodium bicarbonate solution, administered at 3mL/kg/hr for one hour prior to angiography, and at lmL/kg/hr for six hours afterward 150mL or less CM used, for nine hours afterward if 151-299mL of CM is administered, and for 12 hours if greater than 300mL of CM is used. It is thought that an alkaline environment decreases oxygen-free radical formation in the renal tubule.24
At this time the CIN Consensus Working Panel concludes that no adjunctive medical pre-treatment has been validated as effective for preventing CIN.17 Use of furosemide, mannitol, or an endothelin receptor antagonist is potentially detrimental.17 Fenoldopam, dopamine, atrial natriuretic peptide and L-arginine have not been shown to be effective.17
Future Directions to Reduce the Risk of CIN
Since the pathophysiology of CIN involves both afferent arteriole vasoconstriction with resultant decreased GFR and cellular injury from oxygen-free radicals, prevention of CIN will likely require a combination pharmalogic approach aimed at the multiple mechanisms. Table 3 lists beneficial and potential strategies for attenuating CIN.17 Systemic administration of renal vasodilators is limited by hypotension. Intrarenal adenosine is a potent renal afferent arteriole vasoconstrictor which can be effectively blocked with oral theophylline 3mg/kg before and 12 hours later.8
Since theophylline blocks renal vasoconstriction, its benefit would be to maintain GFR for more rapid clearance of CM. It would only be expected to attenuate CIN not prevent it. The dose of theophylline recommended effectively blocks both A1 and A2 renal vascular receptors and results in plasma theophylline levels of approximately 7 micograms/mL so few gastrointestinal, neurological or cardiovascular effects are expected to occur.8 Some studies testing the benefits of theophylline pre-treatment in CIN have used too low a dosage.17 To test the benefits of theophylline pre-treatment for CIN will also require patients in the placebo group to avoid consumption of caffeine and theobromine before and after angiography, because these compounds also are A1 and A2 receptor antagonists.
In regard to pre-treatment approaches to limit oxygen free radical injury following CM, three pharmacological approaches warrant further study with adequately powered, appropriately designed randomized trials in high-risk patients perhaps combined with theophylline pre-treament. One is isotonic sodium bicarbonate infusion with the length of post procedure treatment determined by the volume of CM administered.24 Maintaining an alkaline environment should decrease oxygen free radical formation in the renal tubule. As discussed above, one source of oxygen free radical production after CM is the catabolism of intrarenal adenosine to xanthine.
Allopurinol, a xanthine oxidase inhibitor (4mg/kg orally daily starting 24 hours before administration of CM) has shown benefit.7 This dose of allopurinol, if given 24 hours before elective procedures, is metabolized into oxypurinol, which is a more effective xanthine oxidase inhibitor than allopurinol. This 24-hour pretreatment approach has been shown to attenuate the fall in GFR after CM exposure.7 Besides limiting oxygen-free radical formation, allopurinol also may protect the kidney after CM exposure by its ability to inhibit adenine nucleotide degradation (thus, preservation of adenine nucleotides required for recovery from renal injury). Allopurinol also has been found to markedly decrease the vasodilatation response to intrarenal adenosine in the renal vasculature. Less adenosine-mediated efferent renal arteriolar vasodilation would preserve glomerular perfusion pressure. In view of the possible role of oxidative stress and oxygen free radical generation in CIN, ascorbic acid as an antioxidant warrants further study.25 N-acetylcysteine, as an antioxidant and renal vasodilator, has not been shown to be consistently effective when given orally.17 Perhaps a larger oral dose is needed or intravenous administration may be required. Allopurinol, ascorbic acid, and N-acetylcysteine if proven beneficial require pre-treatment and would be less helpful in patients requiring emergency diagnostic and/or interventional CM usage.
In summary, CIN remains an important clinical challenge and its definition and pathogenesis are becoming better understood. Reducing the incidence of CIN requires recognizing high-risk patients and providing them with appropriate premedication and adequate hydration. Appropriately designed randomized trials combining pharmalogic approaches aimed at both the renal vasoconstriction and the apparent oxygen free radical generation are needed to devise the best preventative strategies.