Contrast-Induced Nephropathy

One of the leading causes of renal failure for both in-patients and outpatients is contrast-induced nephropathy (CIN) following diagnostic and interventional procedures. As imaging modalities continue to evolve, more patients will be treated and diagnosed with contrast enhanced imagery. CIN varies from 5% to 38% depending on the patients risk factors. So in perspective, a lab performing 1000 plus cases a year puts almost 400 patients at risk for CIN. As cardiovascular professionals working in the lab we rarely see the latent effects of our patients once they leave, and their intervention is complete. So we are unlikely to ever see the renal damage that can occur 48 – 72 hours following these cases. The only effects we may ever encounter would be a case with anaphylactic response, cardiac arrhythmia or arrest. What can we do to help decrease the incidence of CIN and preserve the renal function of our patients?

CIN is defined as a 25% or greater increase in serum creatinine, or a decrease in calculated creatinine clearance in the appropriate clinical setting: exposure to intravenous or intra-arterial contrast, a rise in creatinine within 24-48 hours within contrast exposure, and the absence of other explanations for acute renal failure such as nephrotoxins, hypotension, and urinary obstruction. CIN occurs with much greater frequency and is more insidious, with effects that may not be visible. At this point it is believed that contrast agents stimulates vasoconstriction in the kidneys and decreases the kidneys ability to vasodilate. Some agents appear to cause ischemia by causing an increase of calcium ions into the renal vascular smooth-muscle cells. This in turn lowers the glomerular filtration rate (GFR). Contrast Medias are also known to irritate erythrocytes which increase blood viscosity reducing oxygen delivery. Because CIN takes several days to develop, patients might be discharged before any symptoms are evident. It should be taught on discharge that the patient be aware of any sings and symptoms and to contact their physician if they appear. Oral hydration is imperative and should be emphasized (provided that their overall health condition does not contraindicate increased fluid intake as in congestive heart failure). Patients should be instructed to watch for weight gain (>1kg or 2lbs per day), edema or if other signs appear the first days following their procedure. By the time symptoms of renal failure appear their renal function is decreased by as much as 75%.

Some patients function will recover and could return to normal over time (unless additional contrast studies are needed). So it is clear that we not only need to be aware of the potential of CIN, but we must be prepared to reduce the likely hood of occurrence.

Recognizing which of our patients are high risk and have the potential for contrast-induced acute renal failure is the key to improving our patient’s outcomes. There are many factors that may predispose a patient’s incidence of CIN. Pre-existing decreased renal function puts them in the high risk factor. The lower their function the higher their risk. We should as well be aware of any other comorbities, particularly diabetes and impaired cardiac function. Patients with diabetes and pre-existing renal insufficiency have the greatest risk of CIN. When patients in this group develop CIN they more than often develop oliguria as well. Screening for any contrast related problems would be the simplest approach. Check the blood urea nitrogen and creatinine levels prior to procedure to assure that they are within normal limits. Calculating the patients glomerular filtration rate (GFR) or creatinine clearance is another way to recognize any potential issues.

The normal ranges of GFR, adjusted for body surface area, are:

• Males: 70 ± 14 mL/min/m2

• Females: 60 ± 10 mL/min/m2

Estimation using creatinine clearance

In clinical practice, however, creatinine clearance is used to measure GFR. Creatinine is an endogenous molecule, synthesized in the body, which is freely filtered by the glomerulus (but also secreted by the renal tubules in very small amounts).

Creatinine clearance is therefore a close approximation of the GFR. However, the approximation of the GFR calculation is best measured by the evaluation and visualization of the frequency and duration of urination. The GFR is typically recorded in units of volume per time, e.g. milliliters per minute (ml/min).

Example: A person has a plasma creatinine concentration of 0.01 mg/ml and in 1 hour he excretes 75 mg of creatinine in the urine. The GFR is calculated as M/P (where M is the mass of creatinine excreted per unit time and P is the plasma concentration of creatinine).

Modification of Diet in Renal Disease (MDRD) formula

The most commonly used formula is the “4-variable MDRD” which estimates GFR using four variables: serum creatinine, age, race, and gender. The original MDRD used six variables with the additional variables being the blood urea nitrogen and albumin levels. The equations have been validated in patients with chronic kidney disease; however both versions underestimate the GFR in healthy patients with GFRs over 60 mL/min. The equations have not been validated in acute renal failure (see figure 1).

There was a presentation given at the CTO Summit this past year by Dr. Roxana Mehran in reference to CIN prevention, causes and treatments. A “scheme to define CIN risk” was introduced along with a scoring system that incorporated a series of risk factors predicting the potentional for CIN (see Figure 2).

• Figure 1 Figure 1
• Figure 2 Figure 2
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Prevention is key and should focus on limiting risk factors. Hydration is imperative to preventing CIN. The Cardiovascular Research Foundation Columbia University Medical Center conducted a trial comparing the efficacy of 0.9% Saline and 0.45% Sodium Chloride in 1383 patients to help determine an optimal hydration regimen. The study showed that 0.45% Sodium Chloride had an increased incidence by 2% where 0.9% Saline only had an increased incidence of less than 1%. In addition to hydration NAC (N-acetylcysteine) also proves to be very effective in the prevention of CIN. A prospective randomized study at Columbia University Medical Center took 83 high risk patients with a CrCl < 50 ml/min gave them NAC 600 Bid X 2 days prior to 75ml of low osmolar contrast followed by hydration with 0.45% @ 1 ml/kg/h X 24 h. The end resulted in the control group (42) having a 21% increase incidence of CIN compared to a 2% increase in patients (41) that received NAC. A meta-analysis of 13 randomized placebo controlled trials showed that 4 of the 13 trials reported statistically significant reduction in CIN after NAC. Sodium Bicarbonate is also being used in conjunction with NAC helping to decrease the incidence of CIN. The REMEDIAL trial compared saline + NAC with Bicarbonate + NAC as well as Saline + AA + NAC. Out of 326 patients about a hundred in each group Bicarbonate + NAC showed only a 1.9% incidence in CrCl increase where saline + NAC resulted in 9.9% and saline + AA + NAC at 10.3%.

Limiting the amount of contrast given to patients with reduced renal function has been the historical standard of care for angiography. The damage associated with contrast agents can be minimized also by using lower doses of contrast medium and by using low-osmolal or iso-osmolal nonionic contrast agents. Iso-osmolal nonionic agents have shown the lowest incidence of contrast-induced nephropathy. The type and amount of contrast agent is important. High osmolar, ionic agents were suggested to be highly nephrotoxic, whereas low-osmolar, non-ionic contrast agents where not. A meta-analysis of 39 studies found that patients with renal insufficiency had a reduced incidence of CIN when low-osmolar agents were used. No difference in CIN was noted in those with normal renal function. One recent study compared iodixanol (non-ionic dimmer, iso-osmolar) with iohexol (non-ionic monomer, low osmolar) in patients with renal impairment and diabetes. This high risk group, iodixanol was associated with a significantly lower rate of CIN as compared with iohexol. Studies have found that a single agent in high risk patients undergoing cardiac catheterization or peripheral angiography suggest that both iodixanol and iopamidol may have a lower rate of CIN compared with iohexol. Additionally, the volume of contrast is important. There is a thought that the risk of CIN is proportional to the volume infused. There is a retrospective study (the tadros study) that investigated the association between the volume of iso-osmolar agents and CIN. In this study the mean dose of contrast (84.3 +/- 67 ml in 117 patients) was not associated with higher incidence of CIN. So the real question is, is the type of contrast agent important? Current evidence says that iso-osmolar contrast, in high risk patients reduces the incidences of CIN. An ongoing, prospective study (VALOR trial) may provide additional evidence in favor of iodixanol.

Eventually we may find that iodixanol will provide better outcomes for all patients with decreased renal function. Compared to low-osmolar, iodixanol needs to be studied for cost effectiveness. But the optimism that the Tadros study promises could defiantly improve the safety and improve the outcomes of our patients in the future.

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