Renal Iodine Dye Risk,Age,and the Acute Coronary Syndrome

Mechanism of Contrast Damage to the Kidneys

Contrast-induced AKI can be defined as a sudden decrease in renal function occurring 24 to 48 hours following administration of iodine dye and explains 10% of cases of hospital-acquired kidney failure. ⁴ The Canadian Association of Radiologists (CAR) published consensus guidelines in 2012 regarding the prevention of CI-AKI ⁵ and noted that patients with estimated glomerular filtration rate (eGFR) of ≥60 mL/min have a very low risk of CI-AKI. These authors commented that intra-arterial contrast appears to carry twice the risk of CI-AKI as does intravenous contrast. ⁵ Also, an increase in the contrast volume–eGFR ratio has been shown to be associated with increased CI-AKI following primary percutaneous coronary intervention (PCI), ⁶ also demonstrable by the ratio of contrast volume to creatinine clearance. ⁷ There is ample evidence to support the increased intra-arterial contrast risk. ⁸ It would appear that iodine dye contrast, under the right conditions, is toxic to renal tissue with the risk of CI-AKI markedly increased by preexisting poor renal function and dehydration.

General Prevention of Contrast Damage to the Kidneys

A hydration regimen or fluid volume loading, whether sodium bicarbonate or normal saline, is the single most important preventive measure as emphasized by the CAR and risk is highest with eGFR <30 mL/min. ⁵ The CAR ⁵ also emphasized the following preventive measures: avoidance of dehydration, minimization of contrast volume, avoidance of high osmolar contrast, and discontinuing any nephrotoxic medication for 48 hours. ⁵ Examples of medications with potential nephrotoxicity include any nonsteroidal inflammatory drug, some antibiotics, and some chemotherapeutic agents. ⁹ In a meta-analysis, angiotensin-converting enzyme inhibitors carried no increased risk of CI-AKI whereas angiotensin receptor blockers did. ¹⁰ Diuretics are ineffective for the prevention of CI-AKI and do not improve outcomes when CI-AKI occurs. ¹¹ In fact, volume contraction by a diuretic could possibly contribute to CI-AKI. The approach emphasizing hydration with an isotonic solution was echoed by Au et al based on a MEDLINE search. ¹² However, CI-AKI is confounded by the lack of a standardized definition, appropriate timing of risk assessment measurements such as for plasma creatinine, individual profiles of risk, protocols for fluid administration, and any possible use of preventive medication. ¹³ For extensive standardized clinical trials that consider all aspects of CI-AKI with definitive clinical outcomes, assessment is needed; ¹³ however, this may be difficult to achieve. An example of the problem is shown by a meta-analysis, which included 34 studies and found that CI-AKI is associated with a higher risk of mortality as well as cardiovascular events and a longer time interval of hospitalization; ¹⁴ however, the problem these authors found was that basic patient clinical parameters carried an increased risk of both CI-AKI and mortality. On the other hand, meta-analyses such as the one by McDonald et al involving controlled intravenous contrast (the risk appears less than with the intra-arterial route) and including 25 950 patients in 13 nonrandomized studies demonstrated essentially the same incidence of CI-AKI, need for dialysis, and mortality. ¹⁵ Although of interest and possibly reflecting less risk in the elderly individuals than might be suspected, the study by Toso et al has to be qualified as nondefinitive; ¹ nevertheless, it is of value and offers reassurance that, at least, the usual contrast study in an elderly patient appears to have a favorable benefit–risk ratio. Also, meta-analyses are available, such as the one by McDonald et al, ¹⁵ which suggest minimal contrast risk of CI-AKI, at worst.

Plasma creatinine and urine output lack in sensitivity and specificity but are still very much used measurements in clinical practice to assess the risk of CI-AKI. ¹⁶ Point-of-care testing is a very fashionable issue in emergency departments and in a study to assess already existing renal dysfunction as the most important factor for prediction of CI-AKI risk. You et al performed a retrospective analysis of patients with suspected stroke over a 1-year interval from November 2009 to November 2010 and found that the blood urea nitrogen and creatinine determined in their emergency department correlated well with determination by the hospital central laboratory of the same blood chemistries. ¹⁷ These authors emphasized the possible importance of the rapid point-of-care determination for predicting the risk of CI-AKI.

For the sake of completeness, it has to be mentioned that the use of “extracorporeal blood purification (EBP),” involving modalities such as hemodialysis, continuous venovenous hemofiltration, and continuous venovenous hemodiafiltration, has even been looked at for prevention of CI-AKI. In this regard, Cruz et al evaluated 6 randomized controlled trials and 2 nonrandomized trials involving 412 patients and found no evidence in favor of EBP versus usual medical measures. ¹⁸

In trying to simplify and summarize the issue and prevention of CI-AKI, a repeating refrain, regardless of where the problem has been assessed, and applicable to just before and after contrast administration is hydration, stoppage of nephrotoxic medications, and the usage of the lowest possible contrast dose. ¹⁹ Regarding hydration, a meta-analysis suggested that oral fluid administration may be just as effective as intravenous fluids. ²⁰ This observation has to be placed in the context of reality and dependability. With an early contrast procedure in a weak, lethargic, or undependable patient, it would still be appropriate to push for intravenous fluids.

The article of Katsiki et al discusses an additional caveat for CI-AKI. ²¹ This is that kidney function may deteriorate over a longer term after contrast administration and not just be manifest as CI-AKI. These authors therefore emphasize that renal functional deterioration may not be “all or none”. ²¹ Similarly, it was shown by Abaci et al that even when contrast administration did not cause CI-AKI in patients with decreased kidney function, a composite outcome measure of death or kidney failure needing dialysis was increased in patients at elevated risk of renal disease. ²² Perhaps of value in assessing such risk of renal dysfunction after contrast injection that appears later is the use of some novel biomarkers that offer the potential for earlier detection of such dysfunction and lead to potentially beneficial early intervention. Neutrophil gelatinase-associated lipocalin (NGAL) is one of these biomarkers, and further study is needed to confirm the sensitivity, specificity, and predictive value of NGAL. ²³ Another such novel biomarker is cystatin C, which has been shown either alone or combined with plasma creatinine to improve the association of eGFR and mortality risk and end-stage kidney disease in different populations. ²⁴

Ascorbic Acid

In a meta-analysis of 9 randomized controlled trials involving 1536 people, Sadat et al found that in the group given ascorbic acid a couple of hours before contrast injection and in a usual dose of 1 to 3 g by mouth or intravenously, there was a 33% decreased risk of CI-AKI with ascorbic acid compared with an alternate medical treatment. ²⁵ These authors appeared to consider ascorbic acid a significant possible preventive measure for CI-AKI. Obviously, more extensive evaluation is necessary to make this a major preventive recommendation.

Fluid Intake Increase

Increased fluids prior to contrast exposure appear to have good support as a general measure and in a meta-analysis of 6 prospective randomized controlled trials, Cheungpasitporn et al found no significant difference in risk of CI-AKI with an oral versus an intravenous fluid regimen. ²⁶ Therefore, there appears to be good support for increased fluids by mouth as an outpatient prior to contrast injection to help reduce the risk of CI-AKI.

Mannitol

Interest has been expressed in the administration of intravenous mannitol as a possible protection against CI-AKI. However, the use of intravenous mannitol does not appear to offer any advantage over and above good hydration to prevent CI-AKI in patients at risk. ²⁷ In addition, when used as a forced euvolemic diuresis with furosemide, the outcome with mannitol was a significantly increased risk of CI-AKI. ²⁸

N-Acetylcysteine

There has been an interest in using N-acetylcysteine to decrease the risk of CI-AKI. Considering the available clinical evidence, Sadat concluded that there was insufficient support for the use of N-acetylcysteine over and above good hydration and avoidance of nephrotoxic medications. ²⁹ A similar result from a randomized trial of 2308 patients at risk of CI-AKI was reported by the investigators of Acetylcysteine for Contrast-induced nephropathy Trial study. ³⁰ Their patients were considered at risk of CI-AKI, underwent an intravascular angiographic procedure, and were randomly assigned to placebo or N-acetylcysteine 1200 mg in 2 doses prior to and 2 doses after the procedure. N-Acetylcysteine conferred no advantage for at-risk patients to avoid CI-AKI. ³⁰ On the other hand, there are reports favoring N-acetylcysteine. Wu et al carried out a meta-analysis of 6 randomized controlled trials involving 496 patients and N-acetylcysteine given to patients with plasma creatinine above 1.2 mg/dL showed efficacy in decreasing the incidence of CI-AKI. ³¹ In combination with sodium bicarbonate, Brown et al found that N-acetylcysteine decreased CI-AKI. ³² Obviously, controversy remains regarding the specific need to administer N-acetylcysteine to prevent CI-AKI, especially the question of any specific advantage over improved or increased hydration prior to contrast administration.

Pentoxifylline

There has been some interest in the use of pentoxifylline for offering possible benefit in decreasing CI-AKI, due to an association of the drug with increased erythrocyte deformability, stimulation of prostaglandins with concomitant vasodilatation, prevention of vascular congestion, suppression of tumor necrosis factor α, and a decrease in apoptosis. ³³ It was noted by these authors that there are some animal studies that suggest protection from kidney toxicity but that there is insufficient clinical data to support such renal protection in humans.

Sodium Bicarbonate

Much has been written on the use of sodium bicarbonate to protect against CI-AKI. However, in an assessment of available information, Schiffl concluded that intravenous sodium bicarbonate did not offer any benefit over normal saline. ³⁴ Studies showing superiority of sodium bicarbonate hydration have been published as in the case of the meta-analyses of Meier et al and Jang et al, which reported superiority of hydration with sodium bicarbonate versus normal saline in the prevention of CI-AKI. ^35,36 However, the assessment of Hogan et al from a meta-analysis was that any reported superiority of sodium bicarbonate over normal saline in the prevention of CI-AKI is possibly due to study heterogeneity and publication bias. ³⁷ This issue has also been emphasized in the assessments of other meta-analyses. ^38,39 In another meta-analysis, Brar et al concluded that any large randomized trial showed no benefit for sodium bicarbonate hydration compared with normal saline in preventing CI-AKI and those trials showing benefit were all small and of lesser quality. ⁴⁰ A specific answer regarding any advantage of sodium bicarbonate has to be based on a very large and precisely performed randomized controlled trial not yet performed. ^37,41 Considering the economics, this would not appear likely to be accomplished.

Theophylline

Any value of theophylline in the prevention of CI-AKI appears to be associated with a plasma creatinine level of ≤1.5 mg/dL. In a meta-analysis by Dai et al, it was found that theophylline significantly decreased the occurrence of CI-AKI but this was not observed in patients at higher risk with plasma creatinine level of ≥1.5 mg/dL. ⁴² Theophylline is mentioned for completeness, but there does not appear to be sufficient evidence to consider it for CI-AKI prevention.

Statins

The Atorvastatin for Reduction of Myocardial Damage During Angioplasty (ARMYDA) trial in 2004 showed benefit for pretreatment with a high-dose statin prior to an elective PCI. ⁴³ The ARMYDA investigators found that administration of atorvastatin 40 mg/d for 7 days prior to the PCI resulted in a significant decrease in myocardial injury related to the procedure. ⁴³ In 2009, the Novel Approaches for Preventing or Limiting Events trial showed that a single upper range atorvastatin dose of 80 mg given within 24 hours prior to elective PCI decreased the occurrence of MI associated with the intervention. ⁴⁴ In addition, the use of a statin also had to be considered and evaluated for the prevention of post procedural CI-AKI. However, any patient with suspected vascular disease undergoing assessment with contrast should be on a statin regardless unless there were a specific contraindication. Evidence for statin benefit is extensive but for the sake of completeness, outliers have been reported such as the meta-analysis of Zhang et al who concluded that statin pretreatment did not prevent CI-AKI or decrease the need for renal replacement therapy; ⁴⁵ the meta-analysis of Li et al considered that from their meta-analysis, only a limited recommendation of statin benefit could be made to decrease CI-AKI. ⁴⁶ Nevertheless, support for statins is extensive, and in an analysis of 15 randomized controlled trials, Gandhi et al found that higher statin doses decreased CI-AKI significantly in patients with ACS as compared with placebo or statins in a low dose (relative risk [RR], P < .0001), a benefit not noted with elective procedures. ⁴⁷ It was also found by these authors that there was benefit in decreasing CI-AKI in patients with diabetes mellitus, chronic renal disease, congestive heart failure, and in patients given >140 mL of iodine dye. In a meta-analysis of short-term high-dose atorvastatin versus a low dose of the same statin, an advantage for high-dose atorvastatin was found in preventing CI-AKI in patients undergoing coronary angiography and PCI. ⁴⁸ A repeating theme appears to be the benefit of a high-dose statin for prevention of CI-AKI in coronary angiography and patients. ^{49 –52} The meta-analysis of Zhou et al found that high-dose statins over a short period showed benefit in decreasing CI-AKI in the early stages of chronic renal disease but not in patients with more advanced disease. ⁵³ In assessment by meta-analysis of different preprocedural statins, Giacoppo et al reported that statin type did not appear to make a difference. ⁵⁴

It appears that statins are of value in preventing CI-AKI, and in addition, there is a strong argument that any patient considered to be at sufficient risk of a vascular disease to have a contrast study recommended should be on a statin regardless. Also, if not on a statin, the statin begun in the preprocedural stage should be administered at a high dose around the procedure. There does not appear to be an evidence-based answer as to whether or not a patient already on a moderate statin dose should be administered extra statin before and just after a contrast procedure.