Contrast Induced Nephropathy (CIN)

What is CIN and why does it occur?
How common is CIN?
What are the risk factors?
What is the natural course and prognosis after CIN?
What is the management of CIN?
How can CIN be prevented?
Available contrast agents and their use:
Fluid managment:
N. Acetylcystiene (NAC):
Statins:
Other interventions:
Summary:
References:

What is CIN and why does it occur?

Contrast induced nephropathy (CIN) refers to a form of acute kidney injury (AKI) that occurs after parenteral administration of radio-contrast agent in the absence of other identifiable causes. CIN is generally defined as an increase in serum creatinine concentration of 44 mol/L (0.5 mg/dl) or 25% above baseline within 48 hours after contrast administration.(1, 2) Animal data suggest that CIN is due to an acute tubular dysfunction, however mechanisms underlying such acute tubular dysfunction in the context of CIN are rather poorly understood.(2, 3) Acute tubular dysfunction seen in settings of CIN is generally less severe and tends to recover more quickly when compared with other forms of acute tubular necrosis (ATN). Postulated mechanisms of this form of acute tubular dysfunction seen in context of CIN include renal vasoconstriction, oxygen-free radical induced tubular injury and a direct toxic effect of the contrast agent. All iodinated contrast agents are highly water soluble, freely filtered by the glomerulus and retained in patients with chronic kidney disease within the tubular cells and the peritubular space. Once filtered by the glomerulus they cause direct oxidative cellular damage, sloughing of renal tubular cells and brush border material and thus result in acute tubular dysfunction. (3)

How common is CIN?

It is not straightforward to estimate the frequency of CIN for a number of reasons. Firstly, the definition of CIN in the published studies is variable. Secondly, the reported frequency depends upon the presence or absence of risk factors in any given population. Thirdly, it is challenging to reliably exclude other causes of AKI unrelated to CIN. Finally, a reduction in renal function is not uncommon in hospitalized patients who do not receive a contrast agent. With the above in mind it is not surprising to note that the reported risk of CIN ranges from 2-30%.(2, 4-8)

What are the risk factors?

Following risk factors have been described in the literature(1, 7, 8) :

• Chronic kidney disease
• Diabetic Mellitus
• Congestive Cardiac Failure
• High total volume and hyperosmolar ionic contrast agent
• Age >75
• Persistent Hypotension
• Use of an intra-aortic balloon pump

A risk score for the prediction of CIN following PCI has been devised by Mehran et al. This scoring system incorporates many of the above mentioned risk factors. A score of <6, 6-10, 11-16 and >16 indicates a 7.5%, 14%, 26% and 57% risk of developing CIN after PCI respectively.(8)

What is the natural course and prognosis after CIN?

CIN usually manifests itself within the first 24 to 48 hours after the contrast study. Most patients are non-oliguric and the only apparent abnormality is a mild increase in the serum creatinine. The decline in the estimated GFR after parenteral use of a contrast agent is usually mild. In most cases the serum creatinine starts to improve within 3-7 days and baseline renal function is restored. Renal replacement therapy is rarely required for AKI after contrast administration. For example in one study of 1800 consecutive patients who underwent PCI the incidence of severe AKI requiring dialysis was <1%.(6) Data to support more long term effects of CIN are hard to capture. However, it is increasingly appreciated that residual renal dysfunction may persist even among patients in whom the creatinine returns to baseline. Rudnick et al suggested that CIN is a marker for increased mortality.(9)

What is the management of CIN?

The diagnosis is based upon the clinical presentation and the exclusion of other causes of AKI. The differential diagnosis includes ischemic ATN, acute interstitial nephritis, and renal atheroembolism. Ultrasound has no specific role and renal biopsy is not helpful in CIN.
The mantra that “prevention is better than cure” holds true in the case of CIN. There is no specific treatment once contrast-induced AKI develops, and management is largely supportive with the focus on maintaining fluid and electrolyte balance. The indications for renal replacement therapy are the same as in other forms of AKI.

How can CIN be prevented?

Available contrast agents and their use:

Contrast agents can be ionic or non-ionic and have variable osmolality.(2) First generation contrast agents were ionic monomers and had a higher osmolality (1500 to 1800 mosmol/kg). Newer contrast agents are non-ionic and have lower osmolality. The potential to cause CIN varies with different agents. In general non-ionic agents are better than ionic and low and iso-osmolal agents are superior to hyperosmolal agents.
In the UK two types of nonioinic contrast agents are in widespread use. Iohexol (Omnipaque) is a “low osmolal” agent with osmolality of 600 to 850 mosmol/kg and hence still has a higher viscosity than that of plasma. Iodixanol (Visipaque) is an iso-osmolal agent with approximate osmolality of 290 mosmol/kg which is similar to that of plasma. In a cohort of 129 patients at high risk of developing CIN undergoing coronary angiography, Iodixanol (Visipaque) was shown to be superior to Iohexol (Omnipaque) with less patients developing CIN.(4) A subsequent meta-analysis of 16 randomised trials concluded that the iso-osmolal nonionic contrast agent, iodixanol (Visipaque), appears to reduce the risk of contrast nephropathy in high-risk patients, such as diabetic patients with patients with renal insufficiency, compared with the low-osmolal nonionic agent iohexol (Omnipaque), but not when compared with other low-osmolal nonionic agents.(10) Based on this data the AHA/ACC recommend the use of either an iso-osmolal contrast agent [e.g, iodixanol (Visipaque)] or a low-molecular weight contrast agent other than iohexol (Omnipaque) in patients with CKD(11)

Fluid management:

Where there is no contraindication to volume expansion pre-hydration remains critical. It has been shown that oral rehydration, particularly without salt loading, may not be as effective as intravenous fluid administration in reducing the risk of CIN.(12) On the other hand the optimal intravenous hydration regimen for prevention of CIN remains unclear.
Published data suggest that volume expansion with isotonic saline is superior to hypotonic saline.(13) Many studies have explored the role of alkalinisation and some have shown that volume expansion with isotonic sodium bicarbonate may be superior to that achieved with isotonic saline while other studies have found no significant difference. A meta-analysis published in 2010 found that the use of sodium bicarbonate reduced the risk for CIN.(5, 14, 15) Examples of intravenous volume expansion regimens include:

• Normal Saline: 1ml/kg/hr for 12 hours pre and post procedure.
• Sodium bicarbonate (150-166 mEq/L): 3ml/kg/hr for 1 hour before and 1 ml/kg/hr post procedure.

RenalGuard is a device which creates high urine output and fluid balancing. Two trials have studied the potential role of forced diuresis and matching hydration compared to standard hydration. This strategy is aimed at reducing contrast exposure and uptake by renal tubular cells by accelerating urinary excretion of contrast agents. In both the trials a forced diuresis and matched volume repletion decreased the incidence of contrast nephropathy.(16, 17)

N. Acetylcystiene (NAC):

More than 40 trials using NAC have been completed in the last decade and have reported inconsistent results. Over a dozen meta-analyses have attempted to assimilate the available data. These show great heterogeneity and conflicting results from the available clinical trials. The Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT) in many ways may have closed the debate on the use of NAC as it failed to show any benefit with the additional short term use of NAC (1200mg bd before and after procedure).(18-20)

Statins:

Since statins improve endothelial dysfunction and reduce oxidative stress it is plausible that they may reduce the risk of CIN. In fact this notion is supported by several observational studies and small RCTs.(21, 22) In the NAPLES II trial patients undergoing elective coronary angiography or percutaneous coronary intervention in a native coronary artery were randomly assigned to receive atorvastatin treatment at a dose of 80 mg before the intervention or placebo.(23) CIN, defined as an increase >10% of serum cystatin C concentration (an established marker of AKI) within 24 hours after contrast exposure, occurred in 4.5% patients in the atorvastatin group and in 17.8% patients in the control group (P=0.005; odds ratio=0.22; 95% confidence interval, 0.07–0.69). Another RCT, the Statin Contrast Induced Nephropathy Prevention [PRATO-ACS], published in 2014 showed that high-dose rosuvastatin given on admission to statin-naive patients with acute coronary syndrome who are scheduled for an early invasive procedure prevented CIN.(24) Han et al randomized 2998 patients with DM and CKD who were scheduled to have angiography to receive Rosuvavtatin (2 days prior to procedure and 3 days after) or no statin. The primary endpoint of the study was the development of CIN, defined as an increase in serum creatinine concentration by 44.2 mmol/l or 0.25% above baseline at 72 h after exposure to contrast medium. Patients randomized to the rosuvastatin group had a significantly lower incidence of CIN than controls (2.3% vs. 3.9%, respectively; p< 0.01).(25, 26)

Other interventions:

Many other interventions have been attempted with unproven benefit. These include Ascorbic acid, atrial Natriuretic peptide, mannitol, theophylline and sodium citrate. There is also general lack of data to support interventions like prophylactic haemodialysis, ischemic preconditioning and withholding ACE inhibitors or Metformin. There is some emerging evidence that transradial coronary procedures may have lower risk of CIN compared to transfemoral.(27)

Summary:

CIN is a reversible form of acute kidney injury with poorly understood underlying pathophysiology. No specific treatment exists and prevention is the key. Despite the huge amount of published data the optimal strategy to prevent CIN remains elusive. Notwithstanding initial enthusiasm there is lack of conclusive evidence to support the routine use of NAC. However, where there is no contraindication to volume expansion, hydration preferably with isotonic fluids remains an appropriate preventative strategy. Novel fluid management systems like RenalGuard and the prophylactic use of high dose statins are a new area of interest.

References:

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