Contrast induced nephropathy

Synonyms and keywords: CIN

Overview
Contrast-induced nephropathy is defined as either a greater than 25% increase of serum creatinine or an absolute increase in serum creatinine of 0.5 mg/dL.

Pathophysiology
Several mechanisims have been put forth to explain the development of nephropathy following contrast administration:

Renal medullary hypoxia secondary to renal vasoconstriction
It has been hypothesized that vasoconstriction occurs due to contrast induced release of adenosine and possibly endothelin as well as the high osmolality of the contrast medium. Volume depletion and heart failure may also be associated with renal vasoconstriction as a result of stimulation of the renin-angiotensin cascade and impaired nitric oxide generation. Taken together, these factors potentiate renal medullary ischemia. Normally the metabolic rate and thereby oxygen consumption in the renal medulla is high as a result of active salt reabsorption by the thick ascending limbs of Henle's loop. Hence renal vasoconstriction, increased blood-contrast viscosity, and a leftward shift of the oxygen-hemoglobin dissociation curve may all contribute to intrarenal hypoxia, with an imbalance between oxygen demand and supply thereby playing a major role in radiocontrast-induced outer medullary hypoxic damage

Cytotoxic effects of contrast
Contrast agents themselves can directly cause renal tubular injury. Contast agents can also cause the generation of free oxygen radicals such as superoxide anions, hydrogen peroxide, hydroxyl radicals and hypochlorous acid. The endothelial dysfunction discussed above is also partly due to oxygen free-radical generation during post ischemic reperfusion as they decrease bioavailibility of nitric oxide leading to vasoconstriction. These reactive species also exerts their oxidative and nitrosative effects on the sulf hydrylic groups and aromatic rings of proteins, cellular membrane lipids and nucleic acids and contribute to vasoconstriction. This occurs through the nitrosation of tyrosine residues of enzymes, such as prostacycline synthase and nitric oxide synthase, which are involved in the synthesis of medulla vasodilators. Mitochondrial injury/cytochrome-c release and plasma membrane damage may be other causes of renal injury as shown in animal experiments. Reduction in creatinine clearence was also seen with increase in adenosine excreation on administration of low osmolality, non-ionic contrast and with use of theophylline the fall in creatinine clearance declined.

Predictors of Contrast-Induced Nephropathy

 * Three factors have been associated with an increased risk of contrast-induced nephropathy: pre-existing renal insufficiency (such as Creatinine clearance < 60 mL/min [1.00 mL/s] - online calculator), pre-existing diabetes, and reduced intravascular volume.


 * A clinical prediction rule is available 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
 * Intraarterial balloon pump - 5 points
 * Congestive heart failure (Class III-IV or history of pulmonary edema) - 5 points
 * Age >75 y - 4 points
 * Hematocrit level <39% for men and <35% for women - 3 points
 * Diabetes - 3 points
 * Contrast media volume - 1 point for each 100 mL


 * Renal insufficiency:
 * 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%

Choice of contrast agent
The osmolality of the contrast agent has traditionally been believed to be of great importance in contrast-induced nephropathy. Ideally, the contrast agent should be iso-osmolar to blood. Modern iodinated contrast agents are non-ionic.


 * Iso-osmolar, nonionic contrast media may be the best according to a randomized controlled trial.


 * Hypo-osmolar, non-ionic contrast agents are beneficial if iso-osmolar, nonionic contrast media is not available due to costs.

Hydration with or without bicarbonate
Administration of sodium bicarbonate 3 mL/kg per hour for 1 hour before, followed by 1 mL/kg per hour for 6 hours after contrast was found superior to plain saline on one randomized controlled trial of patients with a creatinne of at least 1.1 mg/dL (97.2 µmol/L). To make the solution, the study used 154 mL of 1000 mEq/L sodium bicarbonate to 846 mL of 5% dextrose. This is approximately three 50 ml ampules of bicarbonate in 850 ml of water with 5% dextrose. This was subsequently corroborated by a multi-center randomized controlled trial, which also demonstrated that IV hydration with sodium bicarbonate was superior to 0.9% normal saline. The renoprotective effects of bicarbonate are thought to be due to urinary alkalinization, which creates an environment less amenable to the formation of harmful free radicals. .

Alternatively, one randomized controlled trial of patients with a creatinine over 1.6 mg per deciliter (140 µmol per liter) or creatinine clearance below 60 ml per minute used 1 ml/kg of 0.45 percent saline per per hour for 6-12 hours before and after the contrast.

Methylxanthines
Adenosine antagonists such as the methylxanthines theophylline and aminophylline, may help although studies have conflicting results. The best studied dose is 200 mg of theophylline given IV 30 minutes before contrast administration.

N-acetylcysteine
N-acetylcysteine (NAC) 600 mg orally 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 nephropathy. . A randomized controlled trial found higher doses of NAC (1200-mg IV bolus and 1200 mg orally twice daily for 2 days) benefited (relative risk reduction of 74%) patients receiving coronary angioplasty with higher volumes of contrast.

Since publication of the meta-analyses, two small and underpowered negative studies, one of IV NAC and one of 600 mg give four times around coronary angiography, found statistically insignificant trends towards benefit.

Some authors believe the benefit is not overwhelming. The strongest results were from an unblinded randomized controlled trial that used NAC intravenously. A systematic review by Clinical Evidence concluded that NAC is "likely to beneficial" but did not recommend a specific dose. One study found that the apparent benefits of NAC may be due to its interference with the creatinine laboratory test itself. This is supported by a lack of correlation between creatinine levels and cystatin C levels.

ACT Trial which is a randomized, placebo controlled trial randomized 2308 patients undergoing angiography with at least one risk factor for contrast induced nephropathy. Patients were randomized to receive either high dose of NAC or placebo on the day before and after the procedure. No difference was noted in rates of developing nephropathy between the two groups. Therefore short-term use of NAC for the prevention of contrast induced nephropathy should be avoided.

In a series, 15% of patients receiving NAC intravenously had allergic reactions.

Prophylactic hemodialysis
Patients with chronic renal insufficiency and a creatinine over 309.4 µmol/L (3.5 mg.dl) who have elective coronary catheterization, a randomized controlled trial found benefit from prophylactic hemodialysis

Other interventions
Other pharmacological agents, such as furosemide, mannitol, dopamine, and atrial natriuretic peptide have been tried, but have either not had beneficial effects, or had detrimental effects.

REMEDIAL II Trial which is a randomized, multicenter, investigator-driven trial involving patients who are at high risk (GFR ≤30 mL · min−1 · 1.73 m−2 and/or a risk score ≥11) for contrast induced nephropathy tested the strategy of forced diuresis. These patients were randomized to receive either NAC + saline or NAC + saline + furosemide. Rates of developing nephropathy was lower among the group receiving diuretic as furosemide reduces the contrast exposure and renal reuptake while promoting accelerated elimination of contrast.

Contrast-Induced Acute Kidney Injury
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Class I
1. 1. Patients should be assessed for risk of contrast-induced acute kidney injury before PCI. (Level of Evidence: C)

2. Patients undergoing cardiac catheterization with contrast media should receive adequate preparatory hydration. (Level of Evidence: B)

3. In patients with chronic kidney disease (CKD) (creatinine clearance ≤60 mL/min), the volume of contrast media should be minimized. (Level of Evidence: B)

Class III
1. Administration of N-acetyl-L-cysteine is not useful for the prevention of contrast-induced acute kidney injury. (Level of Evidence: A)}}

Guideline Resource
2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions