Contrast-Induced Nephropathy

Contrast-induced nephropathy (CIN) is a form of kidney damage in which there has been recent exposure to medical imaging contrast material without another clear cause for the acute kidney injury. CIN is classically defined as a serum creatinine increase of at least 25% and/or an absolute increase in serum creatinine of 0.5 mg/dL after using iodine contrast agent without another clear cause for acute kidney injury, but other definitions have also been used.

Despite extensive speculation, the actual occurrence of contrast-induced nephropathy has not been demonstrated in the literature. The mechanism of contrast-induced nephropathy is not entirely understood, but is thought to include direct damage from reactive oxygen species, contrast-induced increase in urine output, increased oxygen consumption, changes in dilation and narrowing of the blood vessels to the kidneys, and changes in urine viscosity.

Analysis of observational studies has shown that radiocontrast use in CT scanning is not causally related to changes in kidney function. Given the increasing doubts about the contribution of radiocontrast to acute kidney injury, the American College of Radiology has proposed the name postcontrast acute kidney injury which does not imply a causal role, with CIN reserved for the rare cases where radiocontrast is likely to be causally related.

Risk factors

There are multiple risk factors of contrast-induced nephropathy, whereof a review in 2016 emphasized chronic kidney disease, diabetes mellitus, high blood pressure, reduced intravascular volume, and old age.

Decreased kidney function

European guidelines classify a pre-existing decreased kidney function to be a risk factor of contrast-induced nephropathy in the following cases:

• Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m² of body surface area before intra-arterial administration with first-pass renal exposure (not passing lungs or peripheral circulation before kidneys), or in the intensive care unit
• eGFR < 30 ml/min/1.73 m2 before intravenous administration or intra-arterial administration with second-pass renal exposure
• Known or suspected acute kidney injury

To calculate estimated GFR from creatinine, European guidelines use the CKD-EPI formula in adults ≥ 18 years, and the revised Schwartz formula in children. Swedish guidelines recommends no specific formula in children because of lack of evidence, but on the other hand recommends GFR based on cystatin C rather than creatinine in those with abnormal muscle mass or liver failure or cirrhosis.

Roxana Mehran score

The Roxana Mehran score is a clinical prediction rule to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h):

Risk Factors:

• Systolic blood pressure <80 mm Hg - 5 points (if systolic BP less than 80 mmHg for at least one hour requiring inotropic support)
• Intra-arterial balloon pump - 5 points
• Congestive heart failure, counting as NYHA class III (marked limitation in activity due to symptoms, even during less-than-ordinary activity) or worse, or history of pulmonary edema - 5 points
• Age >75 y - 4 points
• Hematocrit level <39% for men and <35% for women - 3 points
• Diabetes mellitus- 3 points
• Contrast media volume - 1 point for each 100 mL
• Decreased kidney function:
  • Serum creatinine level >1.5 g/dL - 4 points

or

• • Estimated Glomerular filtration rate (online calculator)

• • 2 for 40–60 mL/min/1.73 m2
  • 4 for 20–40 mL/min/1.73 m2
  • 6 for < 20 mL/min/1.73 m2

Scoring:
5 or less points

• Risk of CIN - 7.5
• Risk of Dialysis - 0.04%

6–10 points

• Risk of CIN - 14.0
• Risk of Dialysis - 0.12%

11–16 points

• Risk of CIN - 26.1*
• Risk of Dialysis - 1.09%

>16 points

• Risk of CIN - 57.3
• Risk of Dialysis - 12.8%

Other factors

European guidelines include the following procedure-related risk factors:

• Large doses of contrast given intra-arterially with first-pass renal exposure
• Use of contrast agents with high osmolality (limited use today)
• Multiple contrast injections within 48-72 h. At least Swedish guidelines also include gadolinium MRI contrast agents in this aspect.

Swedish guidelines list the following additional risk factors:

• Hypoxia
• Cirrhosis
• NSAID or nephrotoxic medication
• Individuals on dialysis with residual renal function of at least 400 ml urine/24h
• Individuals having undergone kidney transplantation

Prevention

In case of low glomerular filtration rate (GFR), the procedure depends on whether the dose that can be given is larger or less than the needed dose.

The main alternatives in people with a risk of contrast-induced nephropathy are:

• Adjustment of the radiocontrast dose
• Treating or mitigating risk factors
• Using no intravenous contrast for the investigation.
• Switching to another modality such as ultrasonography or MRI.

Dose adjustment

According to European guidelines, the ratio of the contrast dose (in grams of iodine) divided by the absolute estimated glomerular filtration rate (GFR) should be less than 1.1 g/(ml/min) for intra-arterial contrast medium administration with first-pass renal exposure (not passing lungs or peripheral tissue before reaching the kidneys). Swedish guidelines are more restrictive, recommending a ratio of less than 0.5 g/(ml/min) in patients with risk factors and irrespective of route of administration, and even more caution in first-pass renal exposure.

Treating or mitigating risk factors

Hydration by drinking or intravenous volume expander, either before or after contrast administration, decreases the risk of contrast-induced nephropathy. Evidence also supports the use of N-acetylcysteine with intravenous saline among those getting low molecular weight contrast. The use of statins with N-acetylcysteine and intravenous saline is also supported.

• Oral hydration may be as effective as the intravenous route for volume expansion to prevent contrast-induced nephropathy, according to a review in 2013.
• Adenosine antagonists such as the methylxanthines theophylline and aminophylline, may help although studies have conflicting results.
• N-acetylcysteine (NAC) by mouth twice a day, on the day before and of the procedure if creatinine clearance is estimated to be less than 60 mL/min [1.00 mL/s]) may reduce risk. Some authors believe the benefit is not overwhelming. A systematic review concluded that NAC is "likely to be beneficial" but did not recommend a specific dose.
• Ascorbic acid may be protective against CIN, according to a systematic review of randomized controlled trials.

Research directions

While there are currently no FDA-approved therapies for contrast-induced nephropathy, two therapies are currently being investigated. CorMedix is currently in the latter part of phase II clinical trials with approved phase III Special Protocol Assessment for CRMD001 (unique formulation Deferiprone) to prevent contrast-induced acute kidney injury and to slow progression of chronic kidney disease. Dosing trials began in June 2010 in the sixty patient trial.

There is also a phase III clinical trial of RenalGuard Therapy to prevent contrast-induced nephropathy. The therapy utilizes the RenalGuard System, which measures a person's urine output and infuses an equal volume of normal saline in real-time. The therapy involves connecting the person to the RenalGuard System, then injecting a low dose of the loop diuretic furosemide to induce high urine output rates.

A number of studies have reported the ability of RenalGuard to protect patients from CIN following catheterization procedures when compared to the standard of care, including: MYTHOS, which found RenalGuard to be superior to overnight hydration; REMEDIAL II, which found RenalGuard to be superior to sodium bicarbonate hydration; Protect-TAVI, which reported a significant reduction in post-procedural acute kidney injury (AKI) following transcatheter aortic valve replacement (TAVR) when using RenalGuard during the procedure, compared to standard therapy; and AKIGUARD, which showed significant improvement in long-term outcomes when using RenalGuard vs. standard therapy. Two meta-analysis of these results (Putzu and Mattathil) found RenalGuard consistently reduced kidney injury, dialysis, adverse events and mortality compared to standard therapy.

Clinical relevance

Recently, doubts regarding the significance of the phenomenon appeared in the scientific literature. Several studies have shown that Intravenous contrast material administration was not associated with excess risk of acute kidney injury (AKI), dialysis, or death, even among patients with comorbidities reported to predispose them to nephrotoxicity. Moreover, hydration, the most established prevention measure to prevent contrast induced nephropathy was shown to be ineffective in the POSEIDON trial, raising further doubts regarding the significance of this disease state. A meta-analysis of 28 studies of AKI after CT with radiocontrast showed no causal relationship between the use of radiocontrast and AKI.