Contrast induced nephropathy primary prevention

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Overview

Many strategies have aimed at preventing CIN. Non-therapeutic measures include smaller doses of contrast and use of low-osmolar or iso-osmolar agents. Several therapeutic measures have also been investigated notably volume expansion, N-acetylcysteine (NAC) , theophylline, statins, and fenoldopam. Evidence regarding the efficacy and benefit of each of these medical therapies has been contradictory although some have shown more promise than others. Currently only 2 therapies are indicated as preventative measures for CIN. Volume expansion via isotonic crystalloid administration (normal saline or isotonic bicarbonate) is recommended with most studies suggesting initiation 1-2 hours before and maintenance for 3–6 hours after contrast exposure. NAC is also recommended at 600-1200 mg orally twice daily, one day before the procedure and on the day of the procedure.[1]

Prevention

Strategies proposed to prevent the occurrence of CIN have been extensively studied but compelling evidence regarding the implementation of most of these approaches is still lacking. Prophylactic measures were recently defined in the 2012 KDIGO Guidelines and divided broadly into pharmacologic and non-pharmacologic approaches.

Non-Pharmacologic Approaches

Dose of contrast media

It has been shown that larger doses of contrast media are associated with higher risks of CIN. Still, no specific dose recommendations have been made due to lack of robust evidence. The 2012 KDIGO guidelines recommended using the smallest possible dose in every procedure requiring IV contrast especially in patients at high risk for developing CIN.[1] Nyman et al suggested an alternative approach, using the ratio of dose of iodine (in grams) to estimated glomerular filtration rate (eGFR). The team found the ratio to be predictive of the risk of CIN. A ratio I(g)/eGFR < 1 was shown to be relatively safe even in patients with many possible risk factors. The estimated risk decreased eightfold when the ratio dropped below 1.[2]

Route of Administration

Most studies illustrating the pathophysiology, treatment and prophylaxis of CIN focus on intra-arterial (IA) injection of contrast media considering it has been associated with the highest cases of CIN. A number of trials have also shown that intra-venous (IV) contrast has a significantly lower risk of CIN than IA contrast.[3][4] In fact, a review by Rao and Newhouse showed that in studies with proper controls, the risk of CIN after IV contrast administration did not differ between the study groups and the control groups.[5] This further emphasizes the importance of the route of contrast administration, and points to the fact that IV contrast has not been explicitly shown to be nephrotoxic.

Osmolarity of Contrast Agent

The osmolarity of the contrast medium has been clinically linked to differences in outcome. Initially, small scale studies showed no difference between high-osmolar and low-osmolar contrast media.[6] However, in 1995, a prospective randomized trial by Rudnick et al revealed that patients with renal insufficiency and diabetes mellitus had a significantly lower risk of CIN with low-osmolar media.[7] With the introduction of iso-osmolar media, several comparative studies most importantly the NEPHRIC trial by Aspelin et al showed that iso-osmolar media is highly superior in high risk patients with pre-existing renal disease and diabetes. The trial demonstrated that the incidence of CIN in the iso-osmolar contrast group was 3.1% compared with 26.2% in the low-osmolar contrast group.[8] Results of the NEPHRIC trial have sometimes been questioned to the lack of reproducibility in other trials. However, it is generally agreed that iso-osmolar contrast media pose the lowest risk of CIN among other contrast agents. The 2012 KDIGO Guidelines advocated the use of either iso-osmolar or low-osmolar iodinated contrast media, rather than high-osmolar media particularly in patients at increased risk of CIN.[1]

Preventative Strategies in CT scan - Click to Enlarge
Preventative Strategies in Angiography - Click to Enlarge

Pharmacologic Approaches

Volume Expansion

Volume expansion has been shown to significantly decrease the risk of CIN; however, no randomized control trials comparing fluids to placebo have been conducted. Results are extrapolated from comparison with historically untreated patients.[1] The mechanisms by which volume expansion decrease the risk of CIN may include dilution of the contrast media, increase in renal prostaglandins, counteraction of altered renal hemodynamics, and inhibition of the renin-angiotensin system. Many fluids have been investigated for expansion prior to contrast administration including normal saline (0.9%), hypotonic saline (0.45%), and isotonic sodium bicarbonate. Results of the studies comparing these fluids are variable and interpretation is not always easy given the significant limitations of these studies and the many confounding factors not accounted for.

Still, most studies suggest that fluid administration should be initiated 1-2 h before and maintained for 3–6 hours after contrast exposure.[1] Normal saline has been shown to be more effective than hypotonic saline in patients undergoing coronary angiography.[9] Bicarbonate has been suggested to be more efficacious than normal saline via additional benefits through free radical scavenging.[10] However, no robust evidence on the use of bicarbonate has been presented. A thorough meta-analysis of all randomized trials between 1950 and 2008 showed no clear benefit from bicarbonate expansion on the risk of mortality and dialysis.[11] In contrast, acetazolamide in combination with normal saline was found to be more beneficial than bicarbonate alone.[12] Nonetheless, the 2012 KDIGO guidelines did not recommend against the use of bicarbonate stating possible benefit but inconsistent data. They also recommended against the use of oral volume expansion.[1]

N-acetylcysteine

N-acetylcyteine (NAC) is a mycolytic agent and an antioxidant used in the treatment of acetaminophen overdose. Although studies on the use of NAC have variable results, a trend towards benefit from using NAC in addition to isotonic crystalloids prevails. Seven out of 11 meta-analyses on the effectiveness of NAC in preventing CIN have shown significant benefit.[1] However, no data is present showing the contribution of NAC on the reduction of mortality and need for renal replacement therapy. Even large trials have shown little to no benefit of adding NAC. Still, given the modest evidence, the low cost, and the relative safety of NAC, most centers use it as part of the CIN prophylaxis regimen. The 2012 KDIGO guidelines recommend the use of NAC along with isotonic crystalloids.[1]

Two commonly used regimens are N-acetylcysteine (NAC) 600 mg orally twice daily, one day before the procedure and on the day of the procedure,[13] or a higher dose of 1200 mg orally twice daily administered in the similarly.[14].

Prophylactic Hemodialysis

Considering studies have shown association with estimated GFR and risk of CIN, and given the fact that contrast media can be effectively removed with as little as one session of hemodialysis, many studies have aimed at evaluating the benefit of pre-emptive hemodialysis in patients with underlying renal disease. Studies until recently have had very variable results with some showing lower risk of CIN,[15][16] some showing no added benefit over saline infusion or NAC,[17][18] and some even showing a worse outcome following hemodialysis.[19] Given the very conflicting evidence, the eleveated costs, and the difficult logistics, no recommendations can be made about the use of prophylactic hemodialysis for CIN prevention. The 2012 KDIGO guidelines recommend against the use of prophylactic hemodialysis stating that use can only be advocated if future studies convincingly show added benefit.[1]

Theophylline

Interest in theophylline for CIN prophylaxis stems from the association of adenosine with the pathophysiology of CIN in certain studies.[20] Theophylline is a methylxanthine previously used for the treatment of asthma that also acts as an adenosine antagonist. Data about the use of theophylline is conflicting and several meta-analysis have shown little to not benefit from the use of theophylline prophylaxis.[21][22] However, more recent studies have shown some significant decrease in the risk of CIN when theophylline was compared to other prophylactic measures notably N-acetylcysteine and bicarbonate.[23][24] Still, the use of theophylline is not advocated given the limited data and the skewed risk to benefit ratio. Theophylline has many side effects including cardiac and CNS toxicity, and a very narrow therapeutic index entailing cautious use. The 2012 KDIGO guidelines recommend against the use of theophylline for CIN prophylaxis.

Statins

Recently, statins have been investigated as pre-treatment before contrast administration. Small scale studies have shown promise but no large scale randomized trials have been conducted.[1] One study by Yoshida et al showed that patients already with renal insufficiency on pravastatin treatment prior to contrast media exposure had a lower risk of CIN.[25] Very recently, results of the PRATO-ACS Study (Protective effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome) reported that high-dose rosuvastatin (40 mg on-admission following by 20 mg/day) in patients presenting for ACS and scheduled for early PCI can prevent CIN and decrease the 30-day incidence of adverse cardiovascular and renal events.[26] Still, no recommendations about statin use prior to contrast administration have been made.

Fenoldopam

Fenoldopam is a selective dopamine A1 receptor agonist used as an anti-hypertensive with the added effect of increased renal medullary blood flow. Although small retrospective reviews showed benefit from using fenoldopam with isotonic saline, two randomized control trials showed no added benefit from using fenoldopam with saline compared to saline alone.[27][28] The 2012 KDIGO AKI guidelines recommend against using fenoldopam as a CIN prophylactic agent.[1]

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.[29][30]

2012 KDIGO Clinical Practice Guideline for Acute Kidney Injury (DO NOT EDIT)[31]

Nonpharmacological prevention strategies of CI-AKI

Level 1
"1. We recommend using either iso-osmolar or low-osmolar iodinated contrast media, rather than high-osmolar iodinated contrast media in patients at increased risk of CI-AKI. (Level of Evidence: 1B)"
Not Graded
"1. Use the lowest possible dose of contrast medium in patients at risk for CI-AKI. (Level of Evidence: Not Graded)"
Level 2
"1. We suggest not using prophylactic intermittent hemodialysis (IHD) or hemofiltration (HF) for contrast-media removal in patients at increased risk for CI-AKI. (Level of Evidence: 2C)"

Pharmacological prevention strategies of CI-AKI

Level 1
"1. We recommend i.v. volume expansion with either isotonic sodium chloride or sodium bicarbonate solutions, rather than no i.v. volume expansion, in patients at increased risk for CI-AKI. (Level of Evidence: 1A)"
"2. We recommend not using oral fluids alone in patients at increased risk of CI-AKI. (Level of Evidence: 1C)"
"3. We recommend not using fenoldopam to prevent CI-AKI. (Level of Evidence: 1B)"
Level 2
"1. We suggest using oral NAC, together with i.v. iso-tonic crystalloids, in patients at increased risk of CI-AKI. (Level of Evidence: 2D)"
"2. We suggest not using theophylline to prevent CI-AKI. (Level of Evidence: 2C)"

2011 ACCF/AHA/SCAI Guideline Recommendations: Pre-procedural Considerations (DO NOT EDIT)[32]

Contrast-Induced Acute Kidney Injury

Class I
"1. Patients should be assessed for risk of contrast-induced acute kidney injury before PCI.[33][34] (Level of Evidence: C)"
"2. Patients undergoing cardiac catheterization with contrast media should receive adequate preparatory hydration.[35][36][29][37] (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.[38][39][40] (Level of Evidence: B)"
Class III: Harm
"'1. Administration of N-acetyl-L-cysteine is not useful for the prevention of contrast-induced acute kidney injury.[41][42][43][44][45] (Level of Evidence: B)"

References

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