Contrast Nephropathy

Contrast Induced Nephropathy (CIN)
CIN is defined as a deterioration of renal function (defined as an increase in serum creatinine by more than 25%) within 3 days of intravascular administration of contrast in the absence of an alternative etiology.
CIN usually manifests as transient asymptomatic elevation of serum creatinine, which begins within 24 hours of contrast injection, peaks within 4 days, and returns to baseline within 7–10 days.
The American College of Radiology suggests that we use the term “post contrast acute kidney injury” (PC-AKI), because “contrast induced nephropathy” (CIN) implies a degree of causality not supported in this literature. (ACR manual 2017).
All contrast is rapidly distributed into intravascular and extracellular fluids following intravascular administration. They are solely eliminated by glomerular filtration.  100% of contrast is excreted within the first 24 hours after administration in patients with normal renal function.  On the contrary, in patients with reduced renal function, the half-life of elimination can increase by up to 40 hours or more.
The exact pathophysiology of CIN is not well understood. The accepted etiologic factors comprise three different but potentially interacting pathways:
  1. Afferent arteriolar vasoconstriction leading to medullary hypoxia
  2. Reactive oxygen species generation due to medullary hypoxia. These cause oxidative stress and lead to ischemia reperfusion injury at the cellular level.
  3. Direct tubular cellular toxicity by contrast. High osmolality contrast has been shown to produce a more pronounced toxic effect than low- or iso-osmolar contrast
  4. Contrast induced diuresis
How common is contrast induced nephropathy:
Among established intensive care unit patients declines in glomerular filtration following contrast-enhanced scanning are common, but these changes are far more likely to be attributable to factors other than the contrast exposure itself. The upper bound for the incidence of contrast induced renal injury lasting more than three days was 2% in the population studied. Crit Care. 2012 Dec 12;16(2):R67.
Normal saline:
Intravenous 0.9% sodium chloride at a rate of 1 mL/kg/hour for 12 hours pre- and post- procedure has been the accepted therapy for a long time and was widely believed to prevent CIN. 
Isotonic hydration is superior to half-isotonic hydration in the prevention of contrast media-associated nephropathy. Arch Intern Med. 2002 Feb 11;162(3):329-36 , Clin J Am Soc Nephrol. 2008 Jan;3(1):273-80 
Newer studies showed that no hydration strategy is not inferior to normal saline infusions for prevention of CIN. Eur Radiol. 2015 Jul;25(7):1926-34
Bicarb drip:
Isotonic bicarb at 3cc/kg for 1 hour pre and 6 hours post-procedure has been the accepted therapy and was widely believed to prevent CIN.
Newer studies showed that no hydration strategy is not inferior to bicarb infusions for prevention of CIN. J Thromb Haemost. 2014 Oct;12(10):1658-66 , Circ Cardiovasc Interv. 2014 Apr;7(2):216-24
N-Acetyl cysteine:
N-acetylcysteine (NAC) was once widely advocated in patients at risk of CIN following an initial publication by Tepel et al in the year 2000. N Engl J Med. 2000 Jul 20;343(3):180-4 , N Engl J Med. 2006 Jun 29;354(26):2773-82. The typical regime consists of 600 mg of NAC oral BID orally for two days prior to the procedure.
However, current literature suggests that NAC is not efficacious in CIN prevention. ACT Trial ,  J Am Coll Cardiol. 2010 May 18;55(20):2201-9 , BMC Med. 2007 Nov 14;5:32
Normal saline vs NaHCO3
In earlier studies, sodium bicarb was considered to be superior to normal saline to prevent CIN. JAMA. 2004 May 19;291(19):2328-34 , JAMA. 2008 Sep 3;300(9):1038-46 , Am Heart J. 2007 Sep;154(3):539-44.  
However, subsequent studies proved that bicarb is not superior to normal saline. Ann Intern Med. 2009 Nov 3;151(9):631-8
Prophylactic dialysis in preventing CIN:
Dialysis does not play a prophylactic role in reducing the risk of CIN. Administered contrast reaches the kidneys within 1–2 cardiac cycles, making it biologically implausible for removal by dialysis. Am J Kidney Dis. 2006 Sep;48(3):361-71 , Am J Med. 2012 Jan;125(1):66-78.e3
Does contrast induced nephropathy exist at all?
CIN incidence has ranged from 1% to more than 30%. Risk factors include sepsis, antibiotics and antifungals, CKD, diabetes, older age, CHF, anemia, chloride rich fluid resuscitation and hypotension, all common among ICU patients. Critically ill patients have therefore been presumed to be at relatively high risk for CIN. The presumption that critically ill patients are at high risk for CIN has clinical consequences. Perhaps most importantly, it may influence how often physicians avoid exposing their critically ill patients to iv contrast during CT scanning even when it would provide better imaging.
Identification of CIN among ICU patients using serum creatinine is problematic for several reasons: rapidly varying GFR with dynamic clinical states; rapidly changing volumes of distribution, from both disease and therapy; and varying creatinine production.
The assumption of causality between intravenous contrast media administration and acute kidney injury has been challenged in multiple recent publications. Diminished eGFR is associated with an increased risk of SCr-defined AKI following CT examinations. However, the risk of AKI is independent of contrast material exposure, even in patients with eGFR of less than 30. AJR Am J Roentgenol. 2008 Aug;191(2):376-82 , Radiology. 2014 Apr;271(1):65-73 , Radiology. 2013 Apr;267(1):119-28 , Radiology. 2014 Dec;273(3):714-25 , Eur J Radiol. 2014 Jun;83(6):886-892 , AJR Am J Roentgenol. 2010 Aug;195(2):414-22 .  In one of the studies, the incidence of contrast induced AKI was actually lower in contrast exposed group compared to unexposed (5.69% vs 8.96%).  Acad Emerg Med. 2012 Nov;19(11):1261-7.
Drawbacks of studies which showed CIN: all of them have no control group. When they noticed AKI in patients who are exposed to IV contrast, they invariably blamed it on IV contrast, with the notion that those patients wouldn’t have had AKI, if they didn’t get IV contrast. There was never a causal relationship between AKI and contrast exposure.
Also, most of the studies showing CIN were done during the time period where the IV contrast medium used was urograffin, gastrograffin (All with a osmolarity > 1500 mOsm). They definitely have higher risk of CIN. However, now-a-days, we only use isoosmolar ( Iodixanol) or low osmolar ( iohexol, ioxaglate, iomeprol, iopromide , iopamidol) contrast, which doesn’t have much higher risk than a chloride rich normal saline.
Iopamidol , Iodixanol, iomeprol and ioversol are iodine-based contrast media with a similar renal safety profile. My hospital uses Iopamidol-370.  Iohexol and ioxaglate have a poorer renal safety profile. Int J Cardiol. 2014 Mar 15;172(2):375-80
An excellent article for people who are worried about medicolegal aspects of causing CIN can be found here.
In one of the largest studies using a cohort of 21000 patients, Intravenous contrast material administration was not associated with excess risk of AKI acute kidney injury, dialysis, or death, even among patients with comorbidities reported to predispose them to nephrotoxicity. Radiology. 2014 Dec;273(3):714-25
In another large retrospective study with 18000 patients, the probability of developing acute kidney injury was 6.8%, 8.9%, and 8.1% in the contrast-enhanced CT, unenhanced CT, and non-CT groups, respectively. Even in patients with creatinine more than 4, the incidence of CIN did not differ between the groups. So, Contrast-enhanced CT patients were no more likely to develop AKI than patients who had non-contrast CT.  Ann Emerg Med. 2017 May;69(5):577-586.e4
In a very large meta-analysis involving 28 studies, no significant differences in the outcomes between patients receiving contrast-enhanced CT vs non-contrast CT. Ann Emerg Med. 2018 Jan;71(1):44-53.e4
Similarly, incidence of AKI after Cardiac Cath had a similar risk of AKI as compared with that of CT scanning involving IV administration.  Invest Radiol. 2016 Dec;51(12):804-809.
In patients with impaired kidney function undergoing angiography, there was no benefit from Peri-procedural IV isotonic sodium bicarbonate or oral acetylcysteine with respect to the risk of dialysis, death, or acute kidney injury. The incidence of AKI was 9% in bicarb group, 8% in normal saline group, 9% in acetyl cysteine group and 8% in placebo group. Composite outcome of death, dialysis or a > 50% creatinine increase at 90 days were not different in any of the groups. N Engl J Med. 2017 Nov 12
AMACING Trial: In another prospective study at Netherlands, they found no prophylaxis to be non-inferior and cost-saving in preventing contrast-induced nephropathy compared with intravenous hydration. Lancet. 2017 Apr 1;389(10076):1312-1322.
Questions to ask ourselves: Does elevation in creatinine following contrast mean a reduction in GFR or simply an elevation in number due to random daily variance? Does an increase in serum creatinine transiently mean anything for clinically meaningful outcomes like long term dialysis, morbidity or death?
Take home message:
A significant percentage of hospitalized patients experience AKI, and an even larger percentage receive IV contrast during their hospital stay. There will thus always be an argument for anecdotal observed instances of contrast induced nephropathy, whether or not contrast-induced acute kidney injury still exists.
Among established ICU patients, the risk for CIN, if it exists at all, lasting more than 3 days is less than 2%. Individual cases of nephropathy occurring in critically ill patients after use of intravenous contrast cannot be reliably attributed to the contrast exposure. Crit Care. 2012; 16(2): R67
Currently, there is no strong evidence to suggest that isoosmolar IV contrast causes kidney injury, especially if it involves less than 100cc of contrast. However, absence of evidence doesn’t mean lack of evidence.  In cases in which contrast-enhanced CT is indicated to avoid delayed or missed diagnosis, the potential morbidity and mortality resulting from a failure to diagnose possibly life-threatening conditions outweigh any potential risk of contrast-induced nephropathy in patients with serum creatinine levels up to 4.0 mg/dL. It should not be delayed for baseless fear of causing AKI.
PS: We all agree that today’s cars are much safer than how they were 20 years ago. But, we are very reluctant to agree that current generation contrast media are much safer than previous contrast media. NOT ALL CONTRAST MEDIA ARE CREATED EQUAL.
  • MRI with IV contrast uses gadolinium, which is not the same as regular IV contrast. It is associated with the risk of developing Nephrogenic Systemic Fibrosis (NSF). Nephrogenic Systemic Fibrosis is a severe fibrosis of the skin resulting in extensive limitation in mobility. So, in patients with AKI, it’s advisable not to give gadolinium contrast.
  • Metformin is not nephrotoxic but is exclusively excreted via the kidneys. Therefore patients on metformin who develop AKI following contrast are at risk of developing lactic acidosis due to the accumulation of the drug.

1 thought on “Contrast Nephropathy

Leave a Comment