|Year : 2009 | Volume
| Issue : 5 | Page : 753-765
|Prevention of iodinated contrast induced acute kidney injury (ICI-AKI) - what have we learnt so far?
Department of Medicine, Nephrology Section, Hamad General Hospital, Doha, Qatar
Click here for correspondence address and email
|Date of Web Publication||2-Sep-2009|
| Abstract|| |
The use of imaging modalities and endovascular procedures has escalated phenolmenally in the last two decades. In view of increasing number of elderly patients, rising incidence of chronic kidney disease and diabetes along with the complication of nephrogenic systemic fibrosis with gadolinium, a large patient population will be at risk of developing iodinated contrast induced acute kidney injury (ICI-AKI) which is associated with significant morbidity and mortality and increased health care costs. Hence a search for more effective ways to prevent ICIAKI continues to be a focus within the medical community.
|How to cite this article:|
Asim M. Prevention of iodinated contrast induced acute kidney injury (ICI-AKI) - what have we learnt so far?. Saudi J Kidney Dis Transpl 2009;20:753-65
|How to cite this URL:|
Asim M. Prevention of iodinated contrast induced acute kidney injury (ICI-AKI) - what have we learnt so far?. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Jan 22];20:753-65. Available from: http://www.sjkdt.org/text.asp?2009/20/5/753/55357
| Introduction|| |
Iodinated contrast media (ICM), by virtue of their ability to enhance the visibility of vascular structures and organs during radiographic procedures, have greatly facilitated the diagnosis and treatment of many diseases. Conversely, their use has been associated with serious complications like acute kidney injury (AKI). This resulted in a trend towards the use of gadolinium-based contrast media in patients with pre-existing renal impairment. However, over the past few years, gadolinium-based contrast media is linked with the development of a severe, life-threatening condition, i.e. nephrogenic systemic fibrosis, especially in patients with advanced kidney disease. Thus far, over 400 patients with nephrogenic systemic fibrosis have been reported. , More than 95% of the evaluated patients had been exposed to gadolinium within three months prior to the onset of disease. Consequently, ICM continue to be utilized as the main radiocontrast agents for imaging procedures in patients with renal impairment. The purpose of this article is to provide an up to date of strategies for preventing AKI secondary to the use of ICM. This will help in translating the available evidence into daily clinical practice.
| Nomenclature|| |
"What's in a name? That which we call a rose, by any other name would smell as sweet" (William Shakespeare)
Uniformity of medical terminology and the abbreviations is important to clarify and enhance international medical scientific communication and to avoid misunderstanding. Keeping in line with this concept, the terminology in the field of Nephrology has evolved with time and new terms have been coined e.g. "Acute Kidney Injury" and "Chronic Kidney Disease".
"Contrast induced Nephropathy" has been the most frequently used term to describe kidney injury seen after exposure to ICM. The word "nephropathy" has recently been replaced by "Acute kidney injury" (emphasizing that it is an acute renal insult resulting in abrupt change in serum creatinine/urine output), leading to the new term "Contrast induced Acute Kidney Injury" (CI-AKI). Various materials are used as contrast agents for radiological imaging e.g. Barium Sulphate, Iodine based contrast media, Gadolinium and Carbon dioxide. Though there are reports of AKI induced by Gadoliniumbased CM, , for all practical purposes, whenever we talk of "CI-AKI", we refer to AKI induced by iodinated contrast media. Similarly, the pathogenesis, risk factors and preventive strategies that have been studied and recommended in literature apply only to ICM. Hence, to avoid confusion, "Iodinated Contrast Induced Acute Kidney Injury" (ICI-AKI) is preferable to describe this clinical entity.
"The beginning of wisdom is to call things by their right names." (Chinese proverb)
| How Do ICM Damage the Kidneys?|| |
"You can discover what your enemy fears most by observing the means he uses to frighten you"
Various pathophysiologic mechanisms form the basis of rationale for using various strategies to reduce the risk of ICI-AKI , [Figure 1].
The predominant mechanism appears to be ischemia in outer medulla which is supplied by vasa recta- small diameter blood vessels with high vascular resistance. Because of the counter current mechanism, metabolic activity and therefore oxygen consumption is very high in this area. This might result in a thin balance of supply and demand of oxygen and possibility of hypoxia with any metabolic stress. ICM administration potentiates hypoxia by increasing the demand and reducing the supply of oxygen to this area. ICM activate adenosine, reninangiotensin system and endothelin on one hand; and inhibit nitric oxide and vasodilatory prostaglandins on the other, resulting in vasoconstriction of vasa recta. They also increase the osmolality/viscosity of blood making the blood flow sluggish and increasing tubular activity to excrete the administered osmotic load. Osmotic natriuresis and diuresis activates tubuloglomerular feedback mechanism leading to vasoconstriction of glomerular afferent arterioles thus decreasing glomerular filtration rate (GFR).
Another proposed mechanism is direct tubular cytotoxicity as evidenced by intense vaculization of the proximal tubular cells, loss of brush border and sometimes frank tubular necrosis after the injection of ICM.  However, these findings may represent ICM exposure rather than a true nephrotoxicity, since kidney ische-mia molecule (KIM-1), an indicator of tubular necrosis has not been detected in urine in clinical ICI-AKI. 
Hypo perfusion of tissues and direct tubulotoxicity can lead to production of reactive oxygen species, oxidative stress and inflammation that contributes to additional injury causing death of tubular cells.
Finally, tubular plugging can take place secondary to cast formation from aggregation of Tamm-horsfall proteins, increased tubular fluid viscosity and increased urate excretion with tubular precipitation.
| Reducing the Risk of ICI-AKI|| |
"Intellectuals solve problems; geniuses prevent them." (Einstein)
Since ICI-AKI is an iatrogenic complication with predictable timing, it is amenable to preventative strategies. These can be broadly divided into five categories:
- Peri-procedural intravascular volume expansion
- Withdrawal of potentially nephrotoxic medication
- Adjunctive pharmacotherapy
- Selection of type and dose of ICM and
- Prophylactic extra-corporeal therapy
| Peri-Procedural Intravascular Volume Expansion|| |
"We never know the worth of water 'til the well is dry" (English Proverb)
Volume supplementation increases renal blood flow by expanding plasma volume, down-regulating the renin-angiotensin-alsodterone axis and reducing the levels of vasoconstrictive hormones. Increased urinary flow by fluid administration shortens the intratubular transit time of ICM reducing the duration of nephron exposure to the ICM. It also helps dilute the ICM and prevent tubular obstruction. 
There have been no randomized controlled trials (RCTs) directly comparing intravascular volume expansion with no volume expansion but most patients with ICI-AKI reported in the early literature were volume depleted; many of them intentionally to increase the concentration of ICM in the urinary tract for best visualization. , Effectiveness of hydration therapy was recognized in 1980s. ,
Search for the best type of intravenous (IV) fluid has been ongoing for the last two decades. Recommendations for the use of half normal saline  changed in favor of normal saline after randomized data in patients undergoing coronary angioplasty demonstrated added advantage by isotonic hydration.  Later, Merten et al in a RCT showed that sodium bicarbonate was more effective than normal saline in reducing ICI-AKI.  Both types of fluids were infused at a rate of 3 mL/kg per hour for 1 hour immediately before ICM injection followed by 1 mL/kg per hour during the contrast exposure and for 6 hours after the procedure. Following this a number of randomized, prospective trials in patients undergoing coronary angiography/ percutaneous coronary intervention (PCI) using intra-arterial ICM found that bicarbonate had a protective effect that was equal to or greater than that of normal saline. ,,,, However, in a retrospective cohort study of about 8000 patients at Mayo clinic comparing the effect of sodium bicarbonate and N-acetylcysteine used together and alone, From et al demonstrated that bicarbonate was associated with an increased incidence of ICI-AKI despite the favorable baseline risk profile in the bicarbonate group.  The authors speculated that contrary to the earlier belief, bicarbonate may actually possess pro -oxidant properties. The most recent and largest prospective RCT showed no advantage of bicarbonate over normal saline in patients with chronic kidney disease (GFR < 60 mL/min/1.73m 2 ) and additional risk markers for ICI-AKI who were undergoing coronary angiography.  Procedure duration, contrast volume and hydration protocol was similar in both groups (3 mL/kg for 1 hr pre and 1.5 mL/ kg/hr during and up to 4 hrs post-procedure) though the sodium content and osmolality of the two intravenous fluids differed. The results of these studies have blunted the enthusiasm about the use of sodium bicarbonate. Another disadvantage of sodium bicarbonate solution is that it is not readily available in hospitals and has to be prepared.
In conclusion, isotonic hydration remains the gold standard prophylactic hydration therapy. Rate and duration of IV fluid administration must be tailored to the patient's cardiac status. Forced diuresis is however not recommended , as both mannitol and frusemide have been shown to increase the risk of ICI-AKI. ,
| Withdrawing Potentially Nephrotoxic Medication|| |
In patients with GFR < 60mL/ min/1.73m 2 , every effort should be made to withhold drugs that have nephrotoxic potential at least 24 hours prior to a planned ICM study. These recommendations are mostly "opinion-based" since there are no RCTs addressing this issue.
Nonsteroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors should be withdrawn as they adversely affect renal hemodynamics by inhibiting the vasodilatory prostaglandins. Dipyridamol should also be avoided as it enhances the effect of ICM by increasing renal adenosine.  Diuretics, unless required for pulmonary odema, should be discontinued as they aggravate ICM tubulo-toxicity. ,,], Concomitant use of Aminoglycosides, Vancomycin and Amphotericin is best avoided but if not possible, then drug levels should be monitored closely.
It is controversial if angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) should be withheld or not. Some reports have shown decreased , and others increased , risk of ICI-AKI with ACEIs. A recent prospective RCT of 220 patients by Rosenstock et al showed that withholding ACEIs and ARBs 24 hours before coronary angiography did not influence the incidence of ICI-AKI in stable patients with chronic kidney disease (CKD) stages 3-4.  Based on this study and considering their beneficial effects, these agents can be continued as long as hypotension is avoided.
Metformin should also be discontinued on the day of procedure and resumed after 2-3 days if no increase in creatinine is seen since toxicity can be enhanced if ICI-AKI sets in.
| Adjunctive Pharmacotherapy|| |
Many pharmacological agents have been evaluated for reduction in the risk of ICI-AKI, but none has shown a consistent trial evidence to receive approval from regulatory authorities for clinical use.
Pharmacological manipulation aiming at preventing ICM induced vasoconstriction failed to yield beneficial effects in RCTs using dopamine,  atrial natriuretic peptide,  calcium channel blockers,  non-selective endothelin receptor antagonists  and Fenoldopam.  Interestingly, use of vasodilators such as dopamine and atrial natriuretic peptide may actually exacerbate medullary ischemia by causing redistribution of blood flow from the medulla to the cortex.
N-Acetyl Cysteine (NAC), by virtue of its antioxidant and vasodilator properties was widely accepted as a prophylactic measure after the first prospective placebo controlled study showed benefit in patients with renal insufficiency undergoing computed tomography with a nonionic, low-osmolality contrast agent.  Numerous studies have been published since then in support and against the efficacy of NAC.  The divergent results were partly due to significant heterogeneity among studies reflecting difference in patient population, definition of ICIAKI, route of administration, types and volumes of ICM, types of imaging procedures and dosing regimens of NAC. Even a series of meta-analysis failed to clarify the efficacy of NAC. ,,,,,,,,, A most comprehensive meta-analysis of 41 RCTs by Kelly et al involving 6379 patients showed more effective reduction in ICIAKI risk by periprocedural NAC than by any other pharmacological agent.  Results of all these meta-analyses must be interpreted with caution since it is difficult to derive a summary effect given the heterogeneous results of individual trials. Furthermore, recent demonstration by Hoffmann et al of lowered serum creatinine without change in serum cystatin C levels following the use of NAC suggested possible changes in muscle metabolism or renal tubular secretion rather than a true change in GFR.  IV and combined IV and oral routes have been utilized for patients undergoing emergency coronary interventions but once again showing mixed results. ,,, Safety remains an additional concern with IV use of NAC. There is also evidence that higher dose of NAC (1200 mg orally twice daily) might be more effective than the standard dose , but this still needs to be explored further. In summary, consensus on the benefit of NAC has not been reached, however, since it is safe, economical and readily available, it has found a place in the preventive strategies adopted by several societies including the American College of Radiology  and the Canadian Association of Radiologists. 
Theophylline and aminophylline cause intrarenal vasodilatation by non-selective adenosine antagonism but their use has been limited because of the narrow therapeutic index with potential adverse effects and inconsistent results across studies. Pooled results of 7 trials by Ix et al revealed renoprotective effect  but a meta-analysis by Bagshaw et al including 9 RCTs  and a recent meta-analysis by Kelly et al did not find a statistically significant beneficial effect. 
Recognizing the antioxidant potential of Ascorbic acid, Spargias et al conducted a randomized, double-blind, placebo-controlled trial of 231 patients with a serum creatinine concentration > 1.2 mg/dL who underwent coronary angiography and/ or intervention.  3 g of Ascorbic acid, at least 2 hours before the procedure and 2 g in the night and the morning after the procedure, or placebo was administered orally. ICI-AKI occurred in 9% of patients in the ascorbic acid group and in 20% patients in the placebo group. Additive protective effect was however not seen when Ascorbic acid was used in combination with NAC in the REMEDIAL trial.  Boscheri et al evaluated the efficacy of ascorbic acid as an adjunct to hydration in a randomized, doubleblind, prospective, single center-study.  143 consecutive patients with CKD who were undergoing coronary angiography/intervention were randomly assigned to receive 1 g ascorbic acid or placebo as adjunct to saline hydration prior to and after angiography. No significant difference was detected in the incidence of ICI-AKI in the two groups (Vitamin C 6.8% patients; placebo 4.3% patients).
Statins increase nitric oxide production, reduce oxidative stress and have anti-inflammatory properties. Attallah et al in a retrospective study of 1002 patients with CKD undergoing cardiac catheterization showed that prophylactic administration of statins along with hydration was associated with less (17% VS 22%) ICI-AKI (defined as 50% increase in creatinine).  This beneficial effect was confirmed in retrospective and prospective studies in patients undergoing PCI. , More recently, Bouzas-Mosquera et al did not observe a protective effect of statins in 589 consecutive patients with acute myocardial infarction who underwent primary angioplasty.  Hence there is not enough evidence to support routine initiation of statin therapy in patients at risk of ICI-AKI, in whom these agents are not otherwise indicated.
In summary, conflicting results, rather than convincing conclusions have been observed in the studies of pharmacological agents and additional large prospective RCTs are needed before any of these agents become the standard of care for ICI-AKI prevention. These trials should use clinically relevant outcomes like doubling of serum ceatinine/ requirement for dialysis and all cause mortality rather than using surrogate end-points. Head to head studies of different agents will identify the most effective prophylactic pharmacologic preventive regimen.
"He who would search for pearls, must dive deep below" (John Dryden)
| Selection of Type of ICM|| |
"Know your enemy. The supreme art of war is to subdue the enemy without fighting." (Sun Tzu)
Strategies to attenuate toxicity of ICM have focused on reducing protein binding (to minimize anaphylactoid reactions), manipulating hydroxyl groups and adding calcium ions (to improve neural and cardiac tolerance) as well as on reducing the osmolality and ionicity (for reno-protection).
The chemical structure of ICM consists of benzoic acid molecule where each benzene ring has 3 Iodine atoms. From the radiological point of view, the higher the number of Iodine atoms in a contrast molecule, the better the opacification with fewer number of contrast molecules and therefore lesser osmotic load. If there is only one benzene ring in each molecule, we call it a monomer; and dimmer if there are 2 benzene rings (joined by a side chain) in each molecule. In addition, ICM can be ionic if there is a carboxyl group coupled with a cation (usually Na or meglumine) - or non-ionic if there is no carboxyl group attached [Figure 2].
Based on osmolality, ICM are classified as hyper-osmolar (HO-ICM) with osmolality of up to 2000 mOsm/L, low-osmolar (LO-ICM) with osmolality of 600-900 mOsm/L or isoosmolar (IO-ICM) with osmolality approaching that of blood. It should be noted that though LO-ICM are "low-osmolar" compared to the first generation HO-ICM, their osmolality is still 2-3 times higher than that of blood.
There is evidence that nephrotoxic potential of ICM is related to their osmolality.
Large trial by Rudnick et al (comparing Iohexol, a LO-ICM with Diatrizoate, a HOICM) and a meta-analysis of comparative randomized trials by Barrett et al convincingly showed that in patients with CKD, incidence of ICI-AKI was much less with the use of LO ICM as compared to HO-ICM. , But whether IO-ICM are safer than LO-ICM with regards to their nephrotoxicity is debatable as a clear benefit has not been shown in many studies. The reason might be that despite having the same osmolality as that of blood, IO-ICM have higher viscosity compared to LO-ICM which leads to increased resistance to flow in micro vessels.
When administered intravenously, no advantage of IO-ICM over LO-ICM was seen in ACTIVE,  (comparing Iodixanol and Iomeprol), IMPACT  and PREDICT  studies (comparing Iodixanol and Iopamidol). This reduced the interest in the use of the Iodixanol which in NEPHRIC  study was shown to be less nephrotoxic than Iohexol in high risk patients having angiographic studies. On the other hand, after intra-arterial administration, the LO-ICM Iohexol was documented to be of greater toxic potential than IO-ICM Iodixanol in diabetic patients with CKD.  Similarly, Ioxaglate, an ionic dimeric LO-ICM was found to be more nephrotoxic than its competitor Iodixanol in RECOVER study  that recruited patients with creatinine clearance < 60 mL/min undergoing coronary angiography with or without percutaneous coronary intervention. However there is a wide range of LO-ICM in the non-ionic monomers group that is approved for intravascular use. Out of these, Iopamidol was demonstrated to have lower incidence of ICI AKI than Iohexol. ,,]
The American College of Cardiology/American Heart Association guidelines  recommend the use of IO-ICM in CKD patients undergoing angiography, whereas the American College of Radiology,  Canadian Association of Radiologists  and European Society of Urogenital Radiology guidelines  recommend the use of either LO-ICM or IO-ICM in patients at increased risk of ICI-AKI. NKF KDOQI guidelines recommend use of IO-ICM in dialysis patients with residual renal function. 
| Minimizing the Dose of ICM|| |
Both retrospective and prospective studies have shown that the risk of ICI-AKI directly correlates with the dose of ICM administered, which is an independent predictor of ICI-AKI. ,, There are no cut-off doses below which ICM are absolutely safe; the toxic "volume-threshold" of ICM decreases as the CKD progresses, since the filtered load of the ICM per surviving nephron is increased. In other words, it's the dose of ICM relative to the level of renal function that best reflects ICI-AKI risk and it is the load of ICM per functioning nephron that is the best measure of contrast dosage (approximated by mg of Iodine/ eGFR ratio).  Laskey et al showed that the volume of ICM to the creatinine clearance (V/Creatinine clearance) ratio > 3.7 was a significant and independent predictor of ICI-AKI after PCI.  Earlier, in a study of 115 patients with CKD who underwent cardiac catheterization and angiography, Sigarroa et al suggested that safe limit could be calculated by the formula: 5 mL of ICM per kg body weight (max 300 mL) divided by creatinine in mg/dL.  Using Renografin, a HO-ICM, they found out that ICI-AKI (defined as an increase in serum creatinine greater than or equal to 1.0 mg/dL) occurred in 21% patients if this limit was exceeded and in 2% if the limit was not exceeded. A correction multiplying factor of 1.5 was later established for low osmolar monomeric ICM. 
| Avoiding Repeated, Closely Spaced Exposures to ICM|| |
Repeated ICM studies in a short period of time increase the cumulative dose of ICM administered and at the same time expose the functional nephrons that might be recovering from the previous insult. Ranucci et al showed that cardiac surgery performed on the day of cardiac catheterization was independently associated with increased risk of postoperative AKI and suggested that delaying cardiac surgery after exposure to ICM can potentially decrease the incidence of ICI-AKI in patients undergoing elective cardiac surgery. [89\ In the absence of randomized controlled trial data, it is reasonable to allow a renal "recess" of atleast three days between ICM studies. , If serum creatinine rises during this time, the next study should be delayed until creatinine decreases and stabilizes or ideally, decreases to pre-study level.
| Prophylactic Extracorporeal Therapy|| |
Since most cases of ICI-AKI have been reported in patients having coronary angiograms and interventions, a novel strategy would be to remove the blood rich in ICM from the coronary sinus, into which major cardiac veins drain, thus preventing/ reducing renal exposure to these agents. , While this has not become possible in humans, attempts have been made to remove ICM soon after the systemic exposure using extracorporeal therapy.
Except for a very small, uncontrolled study  all studies have shown that prophylactic hemodialysis (HD) is either ineffective in reducing the risk or even harmful though it eliminates the administered ICM effectively from the intravascular and interstitial compartments. ,,,, This raises the possibility that by the time HD is initiated, renal damage has already incurred. One interesting development with regards to renoprotection by prophylactic HD is a recent RCT by Lee et al of 82 patients with advanced CKD (creatinine > 3.5 mg/dL and Cr Cl < 25 mL/min) undergoing coronary angiograms using low volumes (100 mL) of LOICM, Iohexol.  Patients were assigned randomly to receive either normal saline and high flux HD or fluids only. Prophylactic dialysis group in this study maintained creatinine clearance and had reduced risk for renal injury requiring temporary or permanent dialysis. Larger multicenter studies are warranted before routine prophylactic HD therapy can be recommended in this subgroup of patients.
Effect of continuous veno-venous hemofiltration (CVVH) as a prophylactic procedure in high risk patients undergoing PCI was studied twice by Marenzi et al. In the first study, CVVH was initiated before exposure to ICM and continued for 18-24 hrs after.  Authors' conclusion was that CVVH treatment prevented ICI-AKI. The second study compared the effect of pre-and-post to only-post-ICM exposure-CVVH to find that pre-ICM exposure CVVH was essential component for obtaining maximum clinical benefit.  Both the studies have been heavily criticized since the apparent beneficial effect seen from CVVH could have been due to confounding factors such as hydration, alkalinizing effect of bicarbonate based replacement fluid and heparin therapy during CVVH. A more recent but small study of multimorbid CKD patients (eGFR < 40 mL/min) undergoing interventional radiological cardiovascular procedures involving an IO-ICM (Visipaque) has suggested effectiveness of post ICM exposure CVVH.  Nevertheless, before such an expensive and invasive prophylaxis is recommended, it is important that further studies are done to establish its efficacy, and to define the subgroup of CKD population that would benefit most from such treatment.
| Conclusion|| |
ICM are used for majority of intravascular contrast enhanced imaging procedures. Although a causal relationship has not been established, observational studies have shown that shortterm and long-term mortality is increased in patients who develop ICI-AKI  . Hence these agents should be utilized in a way that optimizes the imaging study but at the same time minimizes risk to the patient. Expert consensus has been reached on the benefit of isotonic hydration, discontinuation of nephrotoxic medication and administration of the smallest dose of ICM consistent with a diagnostic result. Use of IO-ICM and adjunct pharmacotherapy is recommended/ practiced by some but not all due to inconsistent trial evidence.
"In necessary things, unity; in doubtful things, liberty" (Ann Baxter)
| Caution|| |
CKD is recognized as an independent risk factor for the development of coronary artery disease. It adversely affects the prognosis from cardiovascular disease including increased mortality after an acute coronary syndrome and after PCI. , The risk of death due to cardiovascular disease in patients with CKD is in fact much higher than the risk of eventually requiring renal replacement therapy. , Considering this, patients with CKD should not be denied the benefits of diagnostic/ therapeutic coronary interventions just because of the concern of possible ICI-AKI, when cardiac benefits clearly outweigh the potential risks.
"And the day came when the risk to remain tight in a bud was more painful than the risk it took to bloom"(Anais Nin)
| Acknowledgement|| |
I thank Hania Asim for her assistance with graphics.
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Department of Medicine, Nephrology Section, Hamad General Hospital P.O. Box 3050, Doha
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