10/29/2019 Contrast Nephropathy, myth thereof - EMCrit Project

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Contrast Nephropathy, myth thereof

May 1, 2019 by Josh Farkas

CONTENTS
Venous injection of contrast (e.g. for CT scan)
The birth of the contrast nephropathy myth (#contrast_nephropathy:_a_myth_is_born)
Current lack of evidence regarding contrast nephropathy (#current_lack_of_evidence_regarding_contrast_nephropathy)
Weighing the risks vs. bene ts of using contrast (Renalism) (#weighing_the_risks_vs._bene ts_of_using_contrast_(Renalism))

The attention given to contrast nephropathy is insane (#the_attention_given_to_contrast_nephropathy_is_disproportionately_insane)

Intra-arterial contrast (e.g. cardiac catheterization) (#intra-arterial contrast_(e.g._cardiac_catheterization))
Algorithm (#checklist)
Podcast (#podcast)
Questions & discussion (#questions_&_discussion)
Pitfalls (#pitfalls)

contrast nephropathy: a myth is born

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The concept of contrast nephropathy was born in the 1950's, when it was observed that some patients developed renal failure following injection
of IV contrast dye for intravenous pyelography.1  This might have represented a true nephrotoxic reaction.  The contrast dye used at that time

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probably was poisonous (50% diodone, a high-osmolar contrast dye which nobody would imagine using today).  However, none of these early
studies had adequate control groups, so it's impossible to know for sure.  This was before the establishment of evidence-based medicine.

Regardless, a myth was born.  Over time, fear of contrast nephropathy blossomed and took root.  Any renal failure which occurred following the
administration of contrast was likely to be labeled as “contrast nephropathy.”  Over the ensuing decades, well over a thousand publications were
written about contrast nephropathy.

current lack of evidence regarding contrast nephropathy

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Older contrast dyes probably were nephrotoxic.  However, modern contrast dyes (with lower osmolarity) don't seem to cause renal failure.

True kidney
Patient-centered
Increased injury with
Contrast Dye outcome
Creatinine elevated renal
(e.g. Dialysis)
biomarkers

(https://emcrit.org/wp-content/uploads/2019/04/conneph.svg)

“Contrast nephropathy” is usually de ned as a small increase in creatinine within the days following contrast administration (e.g. 0.3 mg/dL).  The
assumption driving this is that even small bumps in creatinine re ect genuine renal damage, which in turn is clinically relevant.  However, upon
closer examination, this chain of reasoning doesn't hold up…

(1) does contrast dye cause an increase in creatinine?  

? True kidney
Patient-centered
Increased injury with
Contrast Dye outcome
Creatinine elevated renal
(e.g. Dialysis)
biomarkers

(https://emcrit.org/wp-content/uploads/2019/04/conneph2.svg)

Unfortunately, it would be unethical to perform a prospective RCT to evaluate this.  Consequently, we are limited to retrospective, propensity-
matched studies (which attempt to eliminate confounding variables).  Recently, numerous studies and meta-analyses have emerged which don't
detect any relationship between contrast dye administration and elevation of creatinine.2–12

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One clever study examined creatinine changes in patients who had received both a contrasted CT scan and also a non-contrasted CT scan at
different points in time.4  Changes in creatinine following both scans were the same, regardless of whether the patient had received a contrasted
or non-contrasted CT scan.  This demonstrates that creatinine levels normally bounce a certain amount.  If we examine only creatinine elevations
and assume that these represent “contrast nephropathy,” then we may manufacture a disease – when in fact we are looking at random statistical
noise.

Indeed, several studies have found that the average creatinine of a group of patients exposed to IV contrast doesn't change at all.9,13–15 Some
patients experience an increase in creatinine, while an equal number experience a decrease.  By focusing on the former patients and ignoring the
latter, we convert statistical noise into a clinical “disease.”

(2) do creatinine bumps re ect genuine renal injury?  

? True kidney
Patient-centered
Contrast Dye Increased injury with
outcome
Creatinine elevated renal
(e.g. Dialysis)
biomarkers

(https://emcrit.org/wp-content/uploads/2019/04/conneph3.svg)

Let's imagine for a moment that contrast dye does cause a transient elevation in creatinine.  Creatinine is an inert molecule, with no physiological
effect.  The next question is whether small elevations in creatinine actually re ect genuine kidney injury (or whether they might simply re ect
transient reductions in creatinine secretion).  It's crucial to realize that some drugs cause transient reductions in creatinine secretion without
actually damaging the kidneys – such drugs are termed pseudo-nephrotoxins.

There is no evidence in the literature that small increases in creatinine sometimes seen following contrast dye administration re ect actual kidney
injury.  Studies using renal biomarkers have found no signal of renal injury following contrast dye exposure – even in patients with elevated
creatinine levels meeting the de nition of “contrast nephropathy.”16 Thus, the de nition of “contrast nephropathy” in terms of small creatinine
bumps is awed, as these elevations don't seem to re ect any genuine renal injury.

(3) what is the impact on patient-oriented clinical endpoints?

True kidney ? Patient-centered

Increased injury with
Contrast Dye outcome
Creatinine elevated renal
(e.g. Dialysis)
biomarkers

(https://emcrit.org/wp-content/uploads/2019/04/conneph4.svg)

Let's be honest though – what everyone worries about most is dialysis.  We're not really worried about causing a small bump in the patient's
creatinine, or even causing transient renal injury.  We're worried about a severe renal insult which would require dialysis.  And, of course, we worry
about mortality.

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Virtually every study has found no evidence that contrast increases the risk of dialysis or death.2,5,8,11,17,18 One study focusing on ICU patients did
nd that contrast correlated with an increased likelihood of requiring dialysis among patients with a GFR<45 ml/min.  Bizarrely, this same study
found no signal that contrast correlated with increased creatinine levels.  How could contrast dye increase the risk of dialysis, without affecting
renal function?  The answer might be an increased rate of dialysis due to the volume overload associated with contrast dye (which may largely
re ect uid given to prevent “contrast nephropathy”).19

bottom line:  no coherent evidence of harm

? ? True kidney
?
Patient-centered
Increased injury with
Contrast dye outcome
Creatinine elevated renal
(e.g. Dialysis)
biomarkers

(https://emcrit.org/wp-content/uploads/2019/04/conneph5.svg)

Despite decades of searching and literally thousands of publications, there is no coherent evidence that modern contrast dyes cause clinically
meaningful harm.  The vast majority of recent publications suggest that modern contrast dyes are safe.  A few publications raise the possibility of
harm, but these studies are overall inconsistent (e.g. increased risk of dialysis without increased risk of kidney injury).

Unfortunately, we will never be able to exclude the possibility that contrast dye is nephrotoxic with 100% certainty (this is methodologically
impossible, because it would require a massive prospective RCT).  However, the best available evidence indicates that contrast dye is safe.  If
contrast dye were nephrotoxic, then it would have to be an extremely weak nephrotoxin of no real clinical signi cance.

Overall, given the massive amount of study which has been spent on this issue, it's highly reassuring that no de nitive evidence of harm has been
found.  The renal effects of contrast dye have probably been more intensely investigated than the renal effect of any other drug or substance in
medical history.

Lauren Westafer
@LWestafer

Replying to @LadyWhoLifts
Basically 5-8% of people who have Cr measured for 24-72 h will
have an AKI (bc they’re sick and/or getting nephrotox meds) and
if you control for confounders, no assoc w/contrast. Whole myth
came from this crazy case report
onlinelibrary.wiley.com/doi/abs/10.111…

Acute Annria Following Intravenous Pyelogr…

Click on the article title to read more.
onlinelibrary.wiley.com

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32 8:40 AM - Mar 17, 2019

See Lauren Westafer's other Tweets

weighing the risks vs. bene ts of using contrast (Renalism)

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Clinicians are often tasked with balancing the risk-vs-bene t of the administration of IV contrast for CT scanning.  Currently, this calculation would
seem to be as follows:

Risk of using contrast dye:  There is no high-quality evidence that this risk exists.
Bene t of using contrast dye:  This is often quite real (although it will certainly vary, depending on the clinical scenario).

From an evidentiary standpoint, avoidance of contrast dye is di cult to justify.  Physicians are often risk-averse, as we certainly want to avoid
causing harm.  However, the best available evidence suggests that our patients will bene t the most if we don't shy away from using contrast dye
in scenarios where it is indicated.

ATS Crit Care

@ATSCritCare

Still avoiding iodinated contrast in sick patients going for CT

scan? Radiology literature no longer suggests that contrast-
induced nephropathy is a significant threat ow.ly/63xp30jG5aP
126 2:30 PM - Apr 27, 2018

83 people are talking about this

“Renalism” refers to the avoidance of contrast dye in patients with renal dysfunction, causing a failure to perform important studies and leading to
harm.20 In the current era of improved contrast dyes, renalism poses a greater risk to our patients than does “contrast nephropathy.”

Hinson et al. sums this up well in their conclusions following a trial involving septic patients at John Hopkins (CM=contrast medium):6

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the attention given to contrast nephropathy is disproportionately insane

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Given how much we worry about contrast nephropathy, you might think that contrast dye is the only potentially nephrotoxic substance in the
hospital.  In fact, contrast dye is probably among the least nephrotoxic things that we prescribe.   The following list includes commonly used
drugs which are de nitely nephrotoxic:

known nephrotoxins commonly encountered in critical care:

Antibiotics
Vancomycin
Aminoglycosides
Amphotericin
Antivirals:  Acyclovir, ganciclovir
ACE-inhibitors, Angiotensin receptor blockers (ARBs)
NSAIDs
Mannitol
Normal saline (in large volumes)

We worry a lot about contrast nephropathy because it has its own special name.  Meanwhile, we often don't think much about other drugs, which
are proven nephrotoxins.  This is entirely illogical.

Vancomycin nephrotoxicity Contrast nephropathy

Does it exist? Definitely, yes. Probably not.

(No debate about this) (Debatable)
Do alternatives exist? Yes (linezolid, ceftaroline, Not really.
daptomycin)
How much do we worry about it? Not much. A lot.

Do concerns about nephrotoxicity Not really. Yes (delay in imaging due to

delay care? clearance for CT scans and/or labs
to return)
The Internet Book of Critical Care, by @PulmCrit

(https://emcrit.org/wp-content/uploads/2019/04/vancocontr.svg)

Avoiding nephrotoxins among critically ill patients is obviously important.  Our efforts along this vein should be aimed at drugs which are known
nephrotoxins.  We need to stop worrying about IV contrast dye and focus more on drugs which are actually causing harm.  We're wasting our time
chasing a ghost, while true card-carrying nephrotoxins often pass by without much attention.

intra-arterial contrast (e.g. cardiac catheterization)

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Renal injury can occur following intra-arterial procedures (e.g. cardiac catheterization).  It's unclear why this occurs, with possible causes
including the following:

1. Patients are in heart failure or cardiogenic shock with high risk of renal failure (regardless of any intervention).  The occurrence of renal
failure following catheterization may merely represent association, not causation.
2. Dislodgment of cholesterol plaques with embolization to the kidneys.
3. Other peri-procedural complications (e.g. arrhythmia, hemorrhage).
4. Use of intra-aortic balloon pumps (which may occlude renal blood ow when positioned incorrectly).21
5. Direct effect of contrast dye.

This is hard to sort out because it's impossible to perform a non-contrast cardiac catheterization.  Therefore, it's even harder to investigate this
topic than it is to investigate IV contrast for CT scans.

No clear statement can be made on this topic currently.  Unlike CT scans, this issue is less ubiquitous among critically ill patients.  It may be best
to defer management of this issue to interventional cardiologists (who will invariably be involved in the management of any patient going to the
cardiac catheterization lab).

algorithm
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Algorithm for avoiding contrast nephropathy from CT scans

Critically ill patient who needs a CT scan

What is the glomerular filtration rate (GFR)?

Actually, forget it. I don’t really care.

Could IV contrast help improve diagnostic imaging & provide better therapy?

No Yes

Don’t use contrast Use contrast

The Internet Book of Critical Care, by @PulmCrit

(https://emcrit.org/wp-content/uploads/2019/04/contrastalgo2.svg)

podcast
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questions & discussion

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(back to contents) (#top)

To keep this page small and fast, questions & discussion about this post can be found on another page here (https://emcrit.org/pulmcrit/contrast/) .

(https://i1.wp.com/emcrit.org/wp-content/uploads/2016/11/pitfalls2.gif)

Failing to use contrast for CT scans due to fear of nephropathy, leading to suboptimal imaging studies which impair subsequent
management (a.k.a. Renalism).
Delaying scans in critically ill patients while awaiting “clearance” to use IV contrast.
Administration of additional uid to prevent “contrast nephropathy” for CT scans in critically ill patients who have already been volume
resuscitated (if the patient is already euvolemic, additional uid may provoke volume overload, which itself is nephrotoxic!).

Key articles to cite supporting the use of IV contrast dye 

If you need some solid peer-reviewed articles to drop into the chart & protect your posterior:
Aycock RD, Westafer LM, Boxen JL et al.  Acute Kidney Injury after CT:  A meta-analysis.  Annals of Emergency Medicine 2018 PMID
28811122.8  Exhaustive, modern literature review in the Annals showing no difference in acute kidney injury, mortality, or dialysis.  PDF here
(https://emcrit.org/wp-content/uploads/2019/04/aycock2017.pdf) .  
Hinson JS, Jalbout NA, Ehmann MR et al.  Acute kidney injury following contrast media administration in the septic patient:  A retrospective
propensity-matched analysis.  Journal of Critical Care 2019 PMID 28131489.5   Large study evaluating patients presenting to John Hopkins
with suspected sepsis.  No effect was detected from contrast dye, even among patients with GFR<30 ml/min.  
Ehrmann S, Aronson D, Hinson JS.  Contrast-associated acute kidney injury is a myth: Yes.  Intensive Care Medicine 2017 PMID 29242967.22

Going further:

Post Contrast AKI (https://emergencymedicinecases.com/journal-jam-post-contrast-acute-kidney-injury-pcaki/) :  EM Cases with Lauren Westafer, Justin

Morgenstern, Rory Spiegel and Anton Helman.
Contrast Induced Nephropathy:  A unicorn? (https://thesgem.com/2018/10/sgem234-contrast-induced-nephropathy-a-unicorn/)   Lauren Westafer on the
Skeptics Guide to EM.
Does contrast cause kidney injury? (https:// rst10em.com/cin/) Justin Morgenstern First10EM.
Contrast nephropathy: Confounding causation (http://www.emdocs.net/contrast-induced-nephropathy-confounding-causation/)   Robert Sinert, EMDocs
Is contrast induced nephropathy really not a thing? (https://rebelem.com/contrast-induced-nephropathy-cin-really-not-thing/)   Salim Rezai, RebelEM
Do CT scans cause contrast nephropathy? (https://emcrit.org/pulmcrit/do-ct-scans-cause-contrast-nephropathy/) PulmCrit archives from 2015.

References

1. BARTELS E, BRUN G, GAMMELTOFT A, GJØRUP P. Acute anuria following intravenous pyelography in a patient with myelomatosis. Acta
Med Scand. 1954;150(4):297-302. https://www.ncbi.nlm.nih.gov/pubmed/13217726 (https://www.ncbi.nlm.nih.gov/pubmed/13217726) .
2. McDonald J, McDonald R, Comin J, et al. Frequency of acute kidney injury following intravenous contrast medium administration: a
systematic review and meta-analysis. Radiology. 2013;267(1):119-128. https://www.ncbi.nlm.nih.gov/pubmed/23319662 (https://www.ncbi.nl
m.nih.gov/pubmed/23319662) .

3. McDonald J, McDonald R, Carter R, Katzberg R, Kallmes D, Williamson E. Risk of intravenous contrast material-mediated acute kidney injury:
a propensity score-matched study strati ed by baseline-estimated glomerular ltration rate. Radiology. 2014;271(1):65-73. https://www.ncb
i.nlm.nih.gov/pubmed/24475854 (https://www.ncbi.nlm.nih.gov/pubmed/24475854) .
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2013;267(1):106-118. https://www.ncbi.nlm.nih.gov/pubmed/23360742 (https://www.ncbi.nlm.nih.gov/pubmed/23360742) .
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2017;69(5):577-586.e4. https://www.ncbi.nlm.nih.gov/pubmed/28131489 (https://www.ncbi.nlm.nih.gov/pubmed/28131489) .
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propensity-matched analysis. J Crit Care. 2019;51:111-116. https://www.ncbi.nlm.nih.gov/pubmed/30798098 (https://www.ncbi.nlm.nih.gov/pub

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med/30798098) .

7. Ehrmann S, Quartin A, Hobbs B, et al. Contrast-associated acute kidney injury in the critically ill: systematic review and Bayesian meta-
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679) .

8. Aycock R, Westafer L, Boxen J, Majlesi N, Schoenfeld E, Bannuru R. Acute Kidney Injury After Computed Tomography: A Meta-analysis. Ann
Emerg Med. 2018;71(1):44-53.e4. https://www.ncbi.nlm.nih.gov/pubmed/28811122 (https://www.ncbi.nlm.nih.gov/pubmed/28811122) .
9. Azzouz M, Rømsing J, Thomsen H. Fluctuations in eGFR in relation to unenhanced and enhanced MRI and CT outpatients. Eur J Radiol.
2014;83(6):886-892. https://www.ncbi.nlm.nih.gov/pubmed/24656402 (https://www.ncbi.nlm.nih.gov/pubmed/24656402) .
10. Ng C, Shaw A, Bell C, Samuels J. Effect of IV contrast medium on renal function in oncologic patients undergoing CT in ICU. AJR Am J
Roentgenol. 2010;195(2):414-422. https://www.ncbi.nlm.nih.gov/pubmed/20651198 (https://www.ncbi.nlm.nih.gov/pubmed/20651198) .
11. McDonald R, McDonald J, Carter R, et al. Intravenous contrast material exposure is not an independent risk factor for dialysis or mortality.
Radiology. 2014;273(3):714-725. https://www.ncbi.nlm.nih.gov/pubmed/25203000 (https://www.ncbi.nlm.nih.gov/pubmed/25203000) .
12. Gorelik Y, Yaseen H, Heyman S, Khamaisi M. Negligible Risk of Acute Renal Failure Among Hospitalized Patients After Contrast-Enhanced
Imaging With Iodinated Versus Gadolinium-Based Agents. Invest Radiol. 2019;54(5):312-318. https://www.ncbi.nlm.nih.gov/pubmed/3048
0553 (https://www.ncbi.nlm.nih.gov/pubmed/30480553) .
13. Lencioni R, Fattori R, Morana G, Stacul F. Contrast-induced nephropathy in patients undergoing computed tomography (CONNECT) – a
clinical problem in daily practice? A multicenter observational study. Acta Radiol. 2010;51(7):741-750. https://www.ncbi.nlm.nih.gov/pubm
ed/20707658 (https://www.ncbi.nlm.nih.gov/pubmed/20707658) .
14. Sandstede J, Roth A, Machann W, Kaupert C, Hahn D. Evaluation of the nephrotoxicity of iodixanol in patients with predisposing factors to
contrast medium induced nephropathy referred for contrast enhanced computed tomography. Eur J Radiol. 2007;63(1):120-123. https://w
ww.ncbi.nlm.nih.gov/pubmed/17317065 (https://www.ncbi.nlm.nih.gov/pubmed/17317065) .
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tomographic angiography. Int J Cardiol. 2014;177(3):1129-1130. https://www.ncbi.nlm.nih.gov/pubmed/25183538 (https://www.ncbi.nlm.nih.g
ov/pubmed/25183538) .

16. Kooiman J, van de, Sijpkens Y, et al. No increase in Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin excretion
following intravenous contrast enhanced-CT. Eur Radiol. 2015;25(7):1926-1934. https://www.ncbi.nlm.nih.gov/pubmed/25773936 (https://w
ww.ncbi.nlm.nih.gov/pubmed/25773936) .

17. McDonald J, McDonald R, Lieske J, et al. Risk of Acute Kidney Injury, Dialysis, and Mortality in Patients With Chronic Kidney Disease After
Intravenous Contrast Material Exposure. Mayo Clin Proc. 2015;90(8):1046-1053. https://www.ncbi.nlm.nih.gov/pubmed/26250726 (https://
www.ncbi.nlm.nih.gov/pubmed/26250726) .

18. Gar nkle M, Stewart S, Basi R. Incidence of CT Contrast Agent-Induced Nephropathy: Toward a More Accurate Estimation. AJR Am J
Roentgenol. 2015;204(6):1146-1151. https://www.ncbi.nlm.nih.gov/pubmed/26001222 (https://www.ncbi.nlm.nih.gov/pubmed/26001222) .
19. McDonald J, McDonald R, Williamson E, Kallmes D, Kashani K. Post-contrast acute kidney injury in intensive care unit patients: a propensity
score-adjusted study. Intensive Care Med. 2017;43(6):774-784. https://www.ncbi.nlm.nih.gov/pubmed/28213620 (https://www.ncbi.nlm.nih.go
v/pubmed/28213620) .

20. Weisbord S. AKI and medical care after coronary angiography: renalism revisited. Clin J Am Soc Nephrol. 2014;9(11):1823-1825. https://w
ww.ncbi.nlm.nih.gov/pubmed/25318756 (https://www.ncbi.nlm.nih.gov/pubmed/25318756) .
21. Rastan A, Tillmann E, Subramanian S, et al. Visceral arterial compromise during intra-aortic balloon counterpulsation therapy. Circulation.
2010;122(11 Suppl):S92-9. https://www.ncbi.nlm.nih.gov/pubmed/20837932 (https://www.ncbi.nlm.nih.gov/pubmed/20837932) .
22. Ehrmann S, Aronson D, Hinson J. Contrast-associated acute kidney injury is a myth: Yes. Intensive Care Med. 2018;44(1):104-106. https://
www.ncbi.nlm.nih.gov/pubmed/29242967 (https://www.ncbi.nlm.nih.gov/pubmed/29242967) .

The Internet Book of Critical Care is an online textbook written by Josh Farkas (@PulmCrit), an associate professor of
Pulmonary and Critical Care Medicine at the University of Vermont.

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