Contrast Induced Nephropathy: Is it Real?

You are managing a trauma and request a CT abdomen to exclude an intra-abdominal injury. The radiology registrar asks about the patients’ renal function. Sound familiar?

The good news is that the scan go ahead without knowing the renal function. This is supported by the current guidelines of the Royal Australasian and New Zealand College of Radiologists that suggest that Emergency imaging procedures requiring contrast media administration e.g. acute stroke, acute bleeding, trauma etc. should not be delayed in order to obtain renal function testing results prior to the procedure (1).

It states that intravascular iodinated contrast media should be given to any patient regardless of renal function status if the perceived diagnostic benefit to the patient and in your opinion justifies this administration (1).

However, Emergency medicine is rarely so black and white. For example, consider the following 2 cases

1. 80 yo male with sharp chest pain with a background of diabetes and hypertension. ECG shows non-specific changes and there is no acute rise in serial troponins. The eGFR is 40. Your intern asks you could it be an aortic dissection? You don’t think it is but it is hard to exclude clinically.
2. 80 yo male with ill defined abdominal pain with a background of diabetes and hypertension. Lactate 2. The eGFR is 40. Your intern wants to admit to your short stay unit with a presumptive diagnosis of constipation. But you are worried about mesenteric ischaemia and want to order to a CT abdomen with contrast

Your gut feeling is that both the CT aortogram and CT abdomen with IV contrast will be normal. You need the IV contrast to answer your clinical questions. You don’t want to cause harm. But you don’t want miss potentially lethal conditions.
You aim to balance the risks of imaging such radiation, anaphylaxis and contrast induced nephropathy (CIN). There has been some recent evidence questioning the risk and incidence of CIN and even whether is actually exists.

A definition

Contrast Induced Nephropathy (CIN) reflects the temporal relationship between contrast administration and a raised serum creatinine (Cr) Absolute (44 mmol/L) or relative (25%) increase in baseline serum Cr concentration at 48-72 hours

The pathophysiology of CIN remains unclear.  Proposed mechanisms include vasoconstriction, oxidative stress, medullary ischemia, and the direct toxic effects of contrast media. It is more common in patients with chronic renal failure -less nephrons, more contrast dye per nephron and subsequent worsening toxicity.

It is also recognised that the risk of contrast-induced nephropathy is higher with intra-arterial contrast associated with coronary angiography.

Possible explanations include:

• Higher volume of contrast
• Higher osmolar solutions
• Arterial catheterization may dislodge athero-emboli leading to renal failure
• Cardiac patients often have tenuous renal perfusion

But as an ED doctor, you are more interested in the risk associated with intravenous contrast dye for CT scanning.

When you start to look at the evidence, historical studies of contrast-induced nephropathy have inferred causality from a temporal relationship between iodinated contrast media administration and the occurrence of acute kidney injury. In fact, the majority of papers about contrast nephropathy have focused on whether serum creatinine increases after administration of contrast dye.  Many studies were performed without a control group, based on the assumption that any increase in creatinine must be due to contrast nephropathy.  However, recent papers have shown that creatinine elevation is common even in the absence of contrast dye (2,3.4).

Defining contrast nephropathy on the basis of elevated creatinine 2-3 days after receiving contrast is convenient for researchers, but it is unclear what these creatinine elevations really mean. If we look for patient based outcomes, we would expect that IV contrast will lead to renal impairment with a subset of patients requiring a renal transplant, dialysis or they die.

A challenge for researchers is to ensure that there are not other confounding factors that will make it more likely that some people would get the IV contrast (or not get IV) that are associated with mortality. For example, we are more likely to avoid IV contrast in sicker people and those with diabetes.

What does the evidence tell us?

The two following observational studies on IV contrast media looked for an association of IV contrast and CIN.

Contrast Material–induced Nephrotoxicity and Intravenous Low-Osmolality Iodinated Contrast Material: Risk Stratification by Using Glomerular Filtration Rate. Davenport et al Radiology: Volume 268: Number 3—September 2013

In the Davenport study there was an association with IV contrast and CIN in patients with a stable eGFR less than 30, with a trend toward significance at eGFR 30–44. The numbers were small in the subgroup  (<1%) with a eGFR < 30.

IV contrast did not appear to be a nephrotoxic risk factor in patients with a pre-CT eGFR of 45 or greater.

They did not analyse the nephrotoxic effect of IV contrast media in patients with unstable renal function. Therefore, the results are only applicable to patients with chronic stable renal insufficiency.

Risk of Intravenous Contrast Material–mediated Acute Kidney Injury: A Propensity Score–matched Study Stratified by Baseline-estimated Glomerular Filtration Rate McDonald et al Radiology: Volume 271: Number 1—April 2014

The second study had similar methods and showed that contrast material–induced nephropathy could not be differentiated from contrast material– independent causes of AKI, even in patients with severely compromised renal function. This study had larger numbers in the low eGFR group

Both studies were in a predominantly inpatient cohort. ED patients are different. We see patients who are more likely to have sepsis and haemodynamic instability as risk factors that could increase the risk of non-contrast media related AKI on blood testing within the days following

Risk of Acute Kidney Injury After Intravenous Contrast Media Administration Hinson et al Ann Emerg Med 2017 Jan

This study was of patients presenting to an Emergency department. It compared patients who underwent 1) contrast-enhanced CT, 2) unenhanced CT or 3) no CT. The primary outcome was incidence of acute kidney injury; secondary outcomes were new chronic kidney disease, dialysis or renal transplant.

• The rates of acute kidney injury were similar among all groups.
• Contrast administration was not associated with increased incidence of acute kidney injury
• Contrast administration was not associated with increased incidence of chronic kidney disease, dialysis, or renal transplant at 6 months.

This has led some investigators to suggest that we no longer use CIN but rather the term post-contrast Acute Kidney Injury (AKI)

Do fluids prevent post contrast AKI?

There have been a number of studies that have demonstrated that higher volumes of fluid administered in patients peri-procedurally is independently associated with a reduction of the rate of contrast-induced nephropathy. Fluids often form the control arm in previous studies investigating the prevention of CIN

Patients who received less fluid may have been sicker (eg, suffered from congestive heart failure) and this may explain why they received less fluid and had a higher rate of contrast-induced nephropathy. There is also considerable heterogeneity in the type, route and timing of fluid given in the studies (NS vs 1/2 NS, oral vs IV, pre and post procedure).

Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING):  a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. The Lancet February 20, 2017

This study examined if withholding prophylaxis would be non-inferior to the standard-of-care administration of intravenous normal saline

It was a single centre study in 660 consecutive elective patients (IV and IA) thought to be at “high risk” (eGFR 30-59) of post contrast AKI. They were randomised to pre and post IV NS or no hydration

The results showed that IV hydration was not associated with a reduction in the risk of post contrast acute kidney injury. There were also a number of complications (fluid overload, hyponatraemia)

• 2·6% 8/307) no hydration
• 2·7% (8/296) hydration
• 5·5% (18/328) had complications associated with IV hydration

The number of elective patients and those admitted for coronary angiography may explain the low risk of AKI and the higher rate of pulmonary oedema. However, it does raise questions over the use of IV hydration in the prevention of post contrast AKI

Conclusions

The risk of intravenous contrast media related acute kidney injury (CI-AKI) is likely to be non-existent for patients with eGFR > 30

In patients with severe renal function impairment (eGFR < 30) or actively deteriorating renal function consider the risk versus the benefit of iodinated contrast media administration. Severe renal function impairment should not be regarded as an absolute contraindication to medically indicated iodinated contrast media administration and the risk is likely much lower than we have previously thought

The role of peri-procedural renal protection using intravenous hydration with 0.9% saline is uncertain

If they need a scan with IV contrast, get the scan. Don’t withhold IV contrast based on the renal function.

References

1. The Royal Australian and New Zealand College of Radiologists. Iodinated Contrast Media Guideline. Sydney: RANZCR; 2016
2. Contrast Material–induced Nephrotoxicity and Intravenous Low-Osmolality Iodinated Contrast Material: Risk Stratification by Using Glomerular Filtration Rate. Davenport et al Radiology: Volume 268: Number 3—September 2013
3. Risk of Intravenous Contrast Material–mediated Acute Kidney Injury: A Propensity Score–matched Study Stratified by Baseline-estimated Glomerular Filtration Rate McDonald et al Radiology: Volume 271: Number 1—April 2014
4. Risk of Acute Kidney Injury After Intravenous Contrast Media Administration Hinson et al Ann Emerg Med 2017 Jan
5. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. The Lancet February 20, 2017

Dr James Edwards
Deputy Director, Royal Prince Alfred Hospital Sydney
CEO ‘On The Wards’  www.onthewards.org