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Contrast-induced acute kidney injury

Where contrast media must be given despite dehydration, or if the hydration state of the patient is unknown, it appears advantageous to use low osmolar contrast media to limit acute kidney injury
Pontus B Persson PhD MD
Institute of Physiology, 
Charité – Universitätsmedizin Berlin, 
Renal failure has long been recognised as a severe and devastating disorder. During both World Wars, large numbers of wounded soldiers developed so-called war nephritis, as a consequence of shock, rhabdomyolysis and sepsis. Today, ischaemia/reperfusion, sepsis/ inflammation and rhabdomyolysis are still the leading factors of acute kidney injury (AKI). However, contrast medium-induced AKI (CIAKI) has become more frequent.
Only recently has it been acknowledged that even small changes in kidney function have important effects on outcomes. One of the first studies to demonstrate the importance of these minute changes in renal function was published in 1996 by Levy et al.(1) They found that patients who developed CIAKI had an adjusted odds ratio for mortality of 5.5. Since then, several others have demonstrated that a seemingly slight impairment of kidney function has an important effect on outcome in different cohorts.(2) More than half of the patients undergoing cardiac surgery with renal risk as defined by the RIFLE criteria (renal Risk, renal Injury, renal Failure, Loss of renal function, and End stage renal disease) progress to the next severe categories: RIFLE-injury or RIFLE-failure. Over a third of all patients with AKI classified as RIFLE-injury progress to RIFLE-failure.(3)
As the insight has grown that even minor impairment of kidney function affects outcome, the term AKI has been introduced and widely adopted. In line with this new terminology, the term contrast-induced nephropathy was replaced by CIAKI.
The relevance of AKI is further underscored by studies on hospitalisation time. Prolonged hospitalisation may give an indication of the severity of illness and may also serve as a marker for economic outcome and costs associated with a certain disease. As shown in a multicentre Austrian study, time of intensive care unit (ICU) stay of AKI patients treated with renal replacement therapy is, on average, ten days longer than for other ICU patients.(4)
Similarly, in Pittsburgh, patients without AKI had a median length of hospital stay of six days, compared with eight days for RIFLE-risk, 10 days for RIFLE-injury and 16 days for RIFLE- failure.(5) A harder end point than hospital stay is mortality. It is well established that various forms of AKI are associated with increased mortality, even after correction for comorbidities.(6,7) Increasing RIFLE class is linked to increasing mortality in almost all studies.(8)
Contrast media
It is the iodinated contrast media that can cause CIAKI. By free filtration, these compounds are completely eliminated by the kidney. However, these contrast media cannot be reabsorbed from, or secreted into, the tubules of the kidney. Thus they are trapped in the tubular network.
Iodinated contrast media are split into three groups according to their osmolarity. The pioneer compounds have very high osmolarities, due to their ionic monomeric structure. These pioneer contrast media are referred to as high osmolar contrast media. In the Western world, contrast media of lower osmolarity have almost completely replaced the pioneer substances. These more modern contrast media are divided into two groups: the so-called low osmolar contrast media, which have a lower osmolarity than the pioneer substances, and iso-osmolar contrast media, which have an osmolarity similar to plasma.
Osmolarity is not the only key physicochemical property of contrast media, which is important in the context of CIAKI. The viscosity of the compounds is of great importance, as well as the ionicity. Most of the current contrast media are non-ionic. Low osmolar contrast media have lower viscosity than iso-osmolar contrast media.
Pathophysiology and prevention
Understanding and preventing CIAKI are two sides of the same coin. There are only two generally accepted measures to prevent CIAKI:
  • Make sure that the patient is well hydrated, and
  • Minimise the dose of contrast media.
What does prevention tell us about the underlying pathophysiology? It is obvious that, by giving less contrast media, the risk for CIAKI decreases. Understanding why hydration is so effective in preventing CIAKI is more complex. It is not by simple dilution of contrast media en route to the kidney, which can explain the beneficial effect of hydration. By hydrating the patient, we increase blood volume significantly. However, this takes place in the capacity vessels, that is to say, the large veins, particularly in the splanchnic region.
We will not have a significant increase in blood volume circulating in the arteries. Therefore, we do not have a significant dilution of contrast media on its way to the kidney. So there must be another effect.
By hydrating the patient, vasopressin, the major hormone involved in volume homeostasis, is inhibited. Vasopressin controls the production and insertion of aquaporins in the collecting duct of the kidney.
The concentration of renal tubular fluid varies to a large degree, dependent on the levels of vasopressin. Humans are able to form urine with an osmolality between less than 100 mOsm/kg H2O to up to 1200 mOsm/kg H2O. With regard to contrast media, we can see highly concentrated contrast media in the kidney when vasopressin is high; with low levels of vasopressin, the concentration of contrast media in the collecting duct is very much lower. Contrast media are trapped in the renal tubular network.(3) They are not reabsorbed as most substances and therefore the concentration of contrast media increases proportionally to the concentration of urine. Taken together, the thirsty patient with high vasopressin levels will significantly concentrate contrast media in the urine, which has deleterious effects to kidney function. Highly concentrated contrast media in the renal tubular network can elicit apoptosis, can severely damage the kidney by the high viscosity and can even affect the perfusion of the area at risk for CIAKI.(4,5) The viscosity increases exponentially with concentration. It has been measured that the concentration of contrast media can be as high as Canadian maple syrup in the concentrating kidney.6 In consequence of these high concentrations of contrast media, the filtration rate will dramatically decrease.
Creatinine levels in plasma increased as the filtration rate goes down. This explains why patients with CIAKI exhibit increases in creatinine levels. Typically, the peak increase in creatinine is two to three days after giving contrast media. This again speaks in favour of acute reduction of filtration rate, as the lag of creatinine increase is about 48 hours when the filtration rate abruptly decreases, then slowly recovers.
There has been a lively debate on whether one contrast media is safer than the other with regard to CIAKI. Indeed, this may be so. If the patient is dehydrated, or if the hydration status of a patient is unknown, the incidence of CIAKI may be significantly lower if contrast media with a slightly higher osmolality than plasma are used, that is to say, the so-called low osmolar contrast media.(3) The reason why low osmolar contrast media may be superior to iso-osmolar contrast media in patients that are dehydrated is due to the fact that higher osmolar substances bind water in the collecting duct.
Therefore, they are significantly diluted even in the face of high vasopressin levels. When patients are well hydrated, as in all clinical trials, there may be little or no difference in the safety of contrast media. By contrast, if iso-osmolar contrast media are given to a dehydrated patient, particular attention must be paid to the hydration scheme. When using iso-osmolar contrast media in patients with an unclear hydration status, rigorous hydration with osmotic diuretics is recommended.(7)
How to hydrate the patient
Several guidelines exist regarding the optimum hydration scheme. In general, iso-osmolar saline is recommended at high infusion rates for several hours before and after the intervention. Such a hydration scheme is highly protective, but not always feasible in everyday practice. When considering the pathophysiology of CIAKI, it is clear that we can achieve rapid inhibition of vasopressin by supplying the correct fluid to the patient.
Vasopressin is rapidly inhibited by oral water intake. Inhibition of vasopressin is much more rapid for oral water ingestion than it is for intravenous saline infusion. The reason for the rapid effectiveness of oral water ingestion is the osmolar receptors in the central nervous system, which control vasopressin release. These receptors can inhibit vasopressin and dilution of urine takes place within 30 minutes.
Thus, for everyday practice, it may be advisable to encourage drinking before the intervention. The patient should maintain drinking for several hours after the intervention to make sure that urine is not concentrated during this time. For patients at risk, iso-osmolar saline should be given intravenously. Saline infusion will effectively expand plasma volume and thereby inhibit vasopressin. Saline infusion is more easily controlled than oral water ingestion and is independent of thirst sensation.
Thus, saline infusions are more reliable and probably more effective than oral water ingestion.
Predictive factors for CIAKI
There are many predictive factors for CIAKI. Patients at risk typically have impaired renal function. This is reflected in elevated plasma creatinine levels. Nevertheless, it may not be required to always determine plasma creatinine in every patient undergoing investigation with contrast media. It has been shown that, by simply asking for common risk factors, you will identify 99% of the patients at risk. The main risk factors for developing CIAKI are:
  • patients with history of AKI, or with an estimated glomerular filtration rate 
  • <60ml/min/1.73m²
  • dehydration
  • diabetes mellitus
  • nephrotoxic drugs (for example, metformin)
  • congestive heart failure
  • hypertension
  • gout
  • age >70 years.
Unfortunately, there is no specific therapy for CIAKI. It is basically the same procedure as for AKI of other origins. Attention must be paid to maintaining the patient’s hydration. Moreover,  dialysis may be required. However, it is clear that dialysis is not an effective preventative measure.
In view of the lack of specific therapy for CIAKI, it is clear that careful attention must be paid to all required preventive measures. The contrast media dose must be maintained at the minimum required and the patient must be kept well hydrated.
CIAKI is gaining importance because of the increase of interventions requiring contrast media.
One of the major pathomechanisms leading to CIAKI is renal tubular  obstruction. In consequence, filtration rate decreases and apoptosis takes place. For patients who are not at risk, prevention of CIAKI is quite straightforward: limit the contrast medium dose and hydrate the patient. In emergency situations, where contrast media must be given despite dehydration, or if the hydration state of the patient is unknown, it appears advantageous to use low osmolar contrast media.
  1. Levy EM, Viscoli CM, Horwitz RI The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275(19):1489–94.
  2. Lassnigg A et al. Impact of minimal increases in serum creatinine on outcome in patients after cardiothoracic surgery: do we have to revise current definitions of acute renal failure? Crit Care Med 2008;36(4):1129–37.
  3. Seeliger E et al. Contrast-induced kidney injury: mechanisms, risk factors, and prevention. Eur Heart J 2012; doi 10.1093/euroheart/ehr494.
  4. Sendeski M et al. Iodixanol, constriction of medullary descending vasa recta, and risk for contrast medium-induced nephropathy. Radiology 2009;251(3):697–704.
  5. Sendeski M, Patzak A, Persson PB. Constriction of the vasa recta, the vessels supplying the area at risk for acute kidney injury, by four different iodinated contrast media, evaluating ionic, nonionic, monomeric and dimeric agents. Invest Radiol 2010;45(8):453–7.
  6. Seeliger E et al. Up to 50-fold increase in urine viscosity with iso-osmolar contrast media in the rat. Radiology 2010;256(2):406–14.
  7. Seeliger E et al. Proof of principle: hydration by low-osmolar mannitol-glucose solution alleviates undesirable renal effects of an iso-osmolar contrast medium in rats. Invest Radiol 2012;47(4):240–6.
  8. Hoste EA, Schurgers M. Epidemiology of acute kidney injury: how big is the problem? Crit Care Med 2008;36:S146–151.