Update on contrast induced nephropathy

Background

For the lack of alternatives, despite its renal toxicity, iodinated contrast media remain the agent of choice in cardiac interventional procedures. Patients at high risk for developing CIN should be identified early and low or iso-osmolar, non-ionic contrast media at minimum possible volume should be used. Periprocedural hydration is imperative. A growing number of patients receive cardiac interventions and therefore, contrast induced media. Here are some basic facts regarding contrast induced nephropathy (CIN):

• Common complication: A common cause of hospital-acquired acute renal failure, the reported incidence of CIN varies from 3.1% to 31%, based on the risk factor profile of the patients (1).
• Associated effects: Increased morbidity, prolonged hospital stay, increased need for renal replacement therapy and more major cardiac events are associated. Patients who develop CIN have a 5.5 fold increased risk of death when compared to the patients without CIN (2).
• Dialysis: Risk of dialysis is lower than 1% in general but may be as high as 3 to 12% in patients with significant underlying renal impairment (2). A ≥25% increase in serum creatinine from the baseline value, or an absolute increase of at least 0.5 mg/dL (44.2 µmol/ L), 48-72 hours after the administration of radiographic contrast media that is not attributable to other causes defines CIN. 
• Pathophysiology: At least two significant processes are involved in its pathophysiology: 1) vasoconstriction resulting in medullary hypoxia and 2) direct toxicity caused by the contrast media to renal tubular cells (3). Mechanisms include decreased prostaglandin and nitric oxide induced vasodilatation, impaired endothelial function, increase in renal adenosine concentration, increase in oxygen free radicals in response to hyperosmotic load, increased intratubular pressure owing to contrast induced diuresis, increased urinary viscosity and obstruction of the tubules.

1 - Iodine

The ability of contrast media (CM) to cause renal toxicity is influenced by its ionic content, osmolality and viscosity. While ionic CM are currently seldom used, non-ionic, low osmolar or iso-osmolar CM have emerged as the alternatives to choose from for cardiovascular imaging. Here is what has been determined so far:

• Superiority of iso-osmolar solutions (Iodixanol): When high risk patients with diabetes and renal impairment who underwent cardiac catheterisation were randomised to iso-osmolar Iodixanol versus low osmolar Iohexol in the NEPHRIC study, the risk of CIN was found to be 9 times greater for the low osmolar Iohexol group (4). RECOVER trial has also reinforced that Iodixanol was associated with lower rates of CIN when compared to low osmolar Ioxalgate in patients with renal impairment (5) Although this benefit of Iodixanol has not been uniformly demonstrated in all trials, currently this iso-osmolar agent is preferred over other CM, especially in patients with renal impairment and diabetes. 
• Avoidance of high osmolar agents: Use of high osmolar agents should be avoided in patients with renal impairment. 
• Lowest volumes of CM: The volume of CM is an independent risk factor for CIN and even small volumes (~30 ml) can have adverse effects in patients at particularly high risk while in the general population, more than 100 mL of hyperosmolar CM increases the risk of CIN. Hence, the volume of CM should be kept to the minimum necessary amount, for patients with significant renal impairment 30ml of contrast for diagnostic catheterisation, and 100 ml if followed by PCI should be a reasonable goal (2). The maximal acceptable contrast dose (MACD) which is defined as “5 mL×body weight [kg])/baseline serum creatinine [mg/dL]” (6) should not be exceeded.
• Carbon dioxide, as an alternative to iodine based CM cannot be used via intra arterial route in sites above the diaphragm. Recently updated, portable CO2 administration canisters (CO2mmander) have been used successfully with good safety profile in infra diaphragmatic catheterisation procedures.

Gadolinium based CM have shown no benefit over iodine based CM in patients with moderate renal impairment and their use in this subset of patients is associated with nephrogenic systemic fibrosis, a chronic debilitating condition with no known cure. 

2 - Risk markers

Several risk markers have been implicated in the pathogenesis of CIN:

• Pre-existing renal impairment is the strongest predictor of CIN as consistently shown in virtually all related studies. Patients with substantial decrease in renal function before the procedure have a tenfold risk of CIN when compared to patients with normal renal function (7).
• Diabetes has been shown to increase the risk of CIN, however, it is the patients with diabetic nephropathy that have the highest risk, whereas diabetes without any renal impairment may not have significant risk for CIN (7). In a recent study, we have shown that diabetes if associated with evidence of microangiopathy, becomes a significant risk marker for CIN (8). 
• Other important risk markers are mentioned in the table below. 

3 - Biomarkers

Two novel biomarkers have been proposed to identify early subclinical acute kidney injury (AKI) following contrast admission:

• Serum or urine neutrophil gelatinase-associated lipocalin (NGAL) levels, as a marker of kidney damage, were found to be potentially useful for both early diagnosis (within 4 hours) and prognosis of AKI. 
• Serum Cystatin C levels represent changes in renal function and serum Cystatin C increase of <10% at 24 hours may be a dependable marker for ruling out AKI after contrast exposure. 

However, it is still unclear whether these markers can be used to define and risk stratify patients for CIN.

Table 1. Risk markers for development of CIN.

4 - Risk Estimation

eGFR: eGFR should be calculated for all the patients meant to undergo procedures involving contrast media, and patients with chronic kidney disease (eGFR< 60 ml/min/1,73 m2) are especially at high risk for developing CIN. But since CIN is a result of complex interplay of several risk markers, e GFR alone may not accurately predict the risk, hence, various risk scoring systems have been developed to predict the cumulative effect of these factors on the outcome of CIN (8,9,10).  

• A scoring system with eight variables was developed and validated by Mehran et al (9) consisting of hypotension (5 points), IABP (5 points), congestive heart failure (5points), chronic kidney disease (4 points), diabetes (3 points), age ≥75 years (4 points), anemia (3 points), and volume of contrast (1 point for each 100cc). Based on the attained score, patients were further divided into low, moderate, high, very high risk groups, and the incidence of CIN, risk of dialysis and mortality are calculated for each group. 

5 - Prevention

Prevention of CIN should start with identifying the patients at high risk - figure 1 depicts an integrated algorithm for employing evidence based strategies.

• Intravenous fluid volume loading with isotonic saline (normal saline) is the single most important measure comprehensively proven to prevent the occurrence of CIN.

However, the role of sodium bicarbonate for intravenous hydration, which was advocated earlier, is now questionable, after recent randomised trials have shown no benefit of sodium bicarbonate over isotonic saline in reducing the incidence of CIN (11, 12).  Although a single study showed benefit of administration of higher concentration (833 mEq/L) of sodium bicarbonate to prevent CIN in patients with renal dysfunction (13), currently there are no recommendations yet. 

• N-Acetylcysteine (NAC) has been widely used for the prevention of CIN in high risk patients following initial reports of benefit at 600mg given orally twice daily, two days prior to the procedure (14). Subsequent trials using both higher dose as well as intravenous use have reported conflicting results in nearly 40 clinical trials and 13 meta-analyses. Its use is not associated with any adverse effects (except for anaphylactoid reactions with high-dose intravenous dosages) and its use is not generally contraindicated.

• Prostaglandin E1 and statins have shown some benefit but comprehensive data is lacking. Targeted renal therapy using Benephit™ infusion system to deliver intra renal fenoldopam has shown decreased incidence of CIN (15) and the Renal Guard system, an automated hydration-matching system which maintains high urine output but avoids the negative fluid balance is used to facilitate contrast elimination with successful results (16), further studies are required, before these methods can be implemented in routine clinical practice.  
• Hemofiltration: The benefit of hemofiltration in the high risk groups, needs to be studied further. 
• Hemodialysis: Patients on hemodialysis need not be volume loaded before contrast administration and dialysis after the procedure is useful only if patient has evidence of volume overload. 
• Preventive measures can be used in patients with residual renal function. 
• Repeat contrast exposure: No studies have been conducted for the ideal timing for a repeat contrast exposure, but since in majority of CIN patients renal function is restored in 3 weeks, this time period is usually advised.

6 - ESC guidelines

The 2014 ESC guidelines, based on the currently available evidence, recommend:

Figure 1. An integrated algorithm for employing evidence based strategies in identifying patients at high risk for CIN.

7 - Management 

• Decline in renal function: The most common manifestation of CIN is asymptomatic transient decline in renal function, which usually normalizes within 10-14 days (17). 
• Serial creatinine: Patients at high risk should especially be followed up with serial creatinine measurements daily for 5 days. 
• Electrolyte and fluid balance: If oliguric renal failure occurs, the management should be similar to as that for acute renal failure due to other causes, including judicious acid-base, electrolyte and fluid balance.
• Dialysis: Temporary dialysis may be required in severe cases, with a minority of patients requiring permanent dialysis (18).

Conclusion

In summary, contrast-induced nephropathy (CIN) is a frequent complication following cardiac catheterisation, and is associated with significant morbidity and mortality. Patients at high risk of developing CIN should be identified early and prophylactic measures are to be implemented before the procedure. Low or iso-osmolar, non-ionic contrast media at minimum possible volume should be used in all at high risk for CIN. Periprocedural hydration is imperative in prevention of CIN and current evidence for employing pharmaceutical intervention is inconsistent and warrants further prospective studies.