How to prevent contrast-induced nephropathy in patients undergoing invasive cardiac procedures

KEY FEATURES

• Iodinated contrast media injection is an inherent part of invasive cardiac procedures but it carries the risk of contrast-induced nephropathy (CIN). This important complication prolongs hospitalisation and increases morbimortality and health care costs.
• A key preventive measure is to 1) assess renal function and 2) identify high-risk patients, in order to 3) adopt preventive strategies. These are to 1) prescribe intensive hydration prior to the procedure, 2) reduce the contrast volume injected to a minimum, and 3) use iso- or low-osmolarity contrast agents.
• Patients at increased risk of CIN include those having previous chronic kidney disease (CKD), especially if diabetes is also present. Thus, the estimation of GFR is mandatory prior to the procedure.
• Saline or bicarbonate infusion before and after the procedure can prevent the onset of CIN; only in very high-risk patients is hemofiltration or dialysis before the procedure suitable to prevent renal function impairment. Many other preventive strategies are being tested and need further investigation.

1 - Definition, epidemiology and prognosis of CIN

Contrast-induced acute kidney injury is an important complication of iodinated contrast media. The most commonly used definition in clinical trials is an increase in serum creatinine (Cr) by > 0,5 mg/dl or > 25% assessed at 48h after the intravascular administration of contrast medium, without any other plausible aetiology(1).

The reported incidence varies from 1,1 to 34% depending on the patient population and baseline risk factors. Recent data show an important decrease in its incidence from ~15% to ~7% in hospitalised patients. However, many cases of CIN continue to occur because of the increasing number of procedures requiring contrast and the characteristics of patients undergoing those procedures. CIN is the third cause of iatrogenic renal failure(2).

2 - Impact of CIN on outcomes

Patients with CIN are at increased mortality risk even after adjusting for comorbidities. Rihal et al reported an in-hospital death rate of 22% in patients who developed CIN, compared with 1,4% in patients who did not. Moreover, mortality rates at 1 year (12,1%) and at 5 years (44,6%) after development of CIN were higher compared with rates of 3,7% and 14,5% respectively, in patients who did not develop CIN (p<0,001)(3).

In patients undergoing primary percutaneous coronary interventions (PCI) for myocardial infarction (MI), short- and long-term mortality rates were also significantly higher in those who developed CIN and it has been shown that CIN is an independent predictor of mortality. In a recent study conducted by Marenzi et al, contrast volume was closely related to the development and severity of CIN (defined as an increase in serum creatinine > 25% within 72 hours after the procedure)(4).

Apart from increasing the risk of death, CIN is also associated with other adverse outcomes including late cardiovascular events after PCI (MI and target vessel revascularization) and more in-hospital events (bypass surgery, bleeding requiring transfusion, and vascular complications)(2,5).

The development of CIN has also been associated with an increased hospital stay and an average additional economic cost of ~ 8000 euros (data from a recent economic analysis)(6).

3 - Risk assessment of CIN

The risk of CIN is increased in patients with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1,73 m2 (stage 3 to 5 of Chronic Kidney Disease), as is described in reports describing risk factors for CIN. In critically ill patients, renal function may be temporarily impaired (cardiogenic shock, heart failure, drug-induced injury), making the risk even greater. Table 1 summarises the main risk factors for developing CIN.

Several risk markers (non-modifiable and not necessarily causative) have been described: diabetes, volume depletion, anemia, nephrotoxic drugs, hemodynamic disturbances and other comorbidities. The effect of risk factors is additive, and the likelihood of CIN rises sharply as the number of risk factors increases.

4 - Preventive strategies

It is important to assess renal function before injection of contrast medium to ensure that appropriate measures to reduce the risk are taken. Since serum creatinine alone does not provide a reliable measure of renal function, calculation of estimated glomerular filtration rate is advisable (see Figure 1 for calculations)(7).

In emergency situations, where the benefit of very early imaging outweighs the risk of waiting for the results of a blood test, general preventive measures should be taken.

5 - Contrast media type and dosing

Contrast media are classified according to their osmolality, which reflects the total particle concentration of the solution, and can be categorised as follows: high osmolality (~ 2000 mOsm/kg), low osmolality (600 to 800 mOsm/kg) and isosmolal (290 mOsm/kg). Low osmolality and isosmolal agents, compared to high osmolality, have shown a significant reduction in the risk of CIN. Iodixanol, a isosmolal contrast agent, has been shown to have the lowest risk for CIN in patients with chronic kidney disease and diabetes. Only in this subset of patients and in renal dialysis patients is superior to low osmolality agents, as it is recommended by The National Kidney Foundation Kidney Disease Outcome Quality Initiative guidelines.

As contrast volume increases, the risk of developing CIN sharply increases. As a general rule for patients with chronic kidney disease, a diagnostic catheterization should plan to use < 30 ml of contrast, and < 100 ml if percutaneous coronary intervention should be a reasonable goal. Figure 1 summarises strategies to assess maximum contrast volume as a reasonable goal individualised for each patient.

6 - Withholding nephrotoxic drugs

While there are no studies in this area, it seems reasonable to withhold nonsteroidal anti-inflammatory drugs, calcineurin inhibitors, high-dose loop diuretics, aminoglycosides and other nephrotoxic agents if possible for several days before contrast exposure.

It is a routine practice to stop metformin before all contrast procedures, due to the risk of lactic acidosis in the setting of CIN. If CIN is developed and accidental administration of metformin has occurred, it can be cleared from the body with dialysis.

7 - Volume expansion

It has a well-established role in the prevention on CIN. The evidence indicates that isotonic crystalloid (saline or bicarbonate solution) can prevent CIN. The infusion starts 3 to 12 hours before and 6 to 12 hours after contrast exposure administered at = 1 to 1,5 ml/kg/min, in order to achieve a good urine flow (at least 150 ml/h). The largest trial to date has shown no benefit of sodium bicarbonate over normal saline.

8 - Dialysis and hemofiltration

Contrast medium is removed by dialysis, but there is no clinical evidence that prophylactic dialysis reduces the risk of CIN. However, hemofiltration performed 6 hours before and 12-18 hours after contrast exposure deserves consideration, given reports of reduced mortality and need for hemodialysis in the post-procedure period in very high-risk patients (Cr 3 to 4 mg/dl, eGFR 15 to 20 ml/min/1,73m2).

9 - Pharmacologic strategies

There are currently no approved pharmacologic agents for the prevention of CIN. Of these agents, only ascorbic acid (vitamin C) has been shown to reduce rates of CIN (3 g orally the night before and 2 g orally twice a day after the procedure).

Although popular, n-acetylcysteine has not consistently shown to be effective, because it appears to falsely lower creatinine levels and not really protect against CIN. In a recent trial, nevertheless, it has shown a beneficial effect together with sodium bicarbonate.

Several studies have demonstrated lower rates of CIN in patients on statin therapy during cardiovascular procedures, probably due to the preservation of endothelial function at the glomerular level.

Fenoldopam, dopamine, calcium-channel blockers, atrial natriuretic peptide and L-arginine have not been effective. Furosemide, mannitol and endothelin receptor antagonist are potentially detrimental.

CONSENSUS STATEMENTS

• Contrast-induced nephropathy is a common and potentially serious complication after the administration of contrast media in patients at risk for acute renal injury (chronic kidney disease with eGFR< 60 ml/min/1,73 m2, particularly when diabetes is present).
• The presence of multiple CIN risk factors in the same patient can create a very high risk (~ 50%) for CIN and (~ 15%) for acute renal failure requiring dialysis after contrast exposure.
• For intra-arterial administration of contrast in high-risk patients with chronic kidney disease, non-ionic, iso-osmolar agents are associated with lower risk of contrast-induced nephropathy.
• Higher contrast volumes (> 100 ml) are associated with higher rates of CIN. However, even small (~ 30 ml) volumes of iodinated contrast in very high-risk patients can cause CIN and acute renal failure requiring dialysis, suggesting the absence of a threshold effect.
• Adequate intravenous volume expansion with isotonic crystalloid (1-1,5 ml/kg/h) for 3-12 h before the procedure and continued for 6-24 h afterwards can lessen the probability of CIN. The data on oral as opposed to intravenous volume expansion as a CIN-prevention measure are insufficient.
• No adjunctive medical o mechanical treatment has been proven to effectively reduce the risk of CIN after exposure to iodinated contrast. Prophylactic hemodialysis or hemofiltration have shown good results that need further validation.

Practical guidelines for the clinician:
Before the procedure:
1. Assess renal function and calculate GFR.
2. Withdraw NSAIDs, metformin and nephrotoxic drugs.
3. Ensure hydration (iv preferably 3-12 h before the procedure).

After the procedure
1. Clinical follow-up (access site hematoma, urine flow rate, oedema).
2. Assess renal function to rule out CIN 2 to 5 days after the procedure.

Table 1 : Risk factors for developing CIN

Chronic kidney disease (eGFR< 60 ml/min/1,73 m2)Diabetes mellitus
Increased age
Volume depletion and high-dose diuretic regimen
Nephrotoxic drugs (NSAIDs, calcineurin inhibitors, aminoglycosides)
Anemia
Hemodynamic instability or cardiogenic shock
Periprocedural hypotension
Intra-aortic balloon pump
High osmolality contrast media

eGFR: estimated glomerular filtration rate; NSAIDs: non esteroidal anti-inflammatory drugs

Figure 1: Three simple ways of calculating maximum contrast volume to reduce CIN.

1 -  5 x weight (kg) / serum creatinine
2 -  4 x eGFR*
3 -  < 100 ml if significant chronic kidney disease and PCI is planned
 * Two formulas can be used to calculate eGFR:
                                                      140 - age x weight (kg)
a) Cockcroft-Gault:                        ___________________________________                 
                                  72 x serum creatinine (mg/dl) x 0,85 (women)

b) MDRD (Modification in Diet in Renal Disease):

186,3 x creatinine (mg/dl)-1,154 x age-0,203 x 0,742 (women) x 1,21 (afroamericans

Figure 2 summarises the general management in patients undergoing cardiac catheterisation using iodinated contrast agents.