Question 12

Created on Thu, 05/21/2015 - 17:23
Last updated on Sun, 11/01/2015 - 03:59
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Critically evaluate strategies that have been used in the prevention of acute kidney injury (AKI) associated with the administration of iodinated  radio contrast medium.

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College Answer

 General
°     Identify high risk patients-baseline renal impairment, other organ failure e.g. circulatory, age, diabetes, hypovolemia, myeloma. Multiple risks factors in the one patient are additive for AKI/dialysis dependence following contrast.

°     Review need for imaging in every patient-consider alternative imaging methods USS, MRI ( without gadolinium) and non contrast CT

Contrast Media

Type : - Use of iso-osmolar or lower osmolality contrasts associated with lower risk of nephrotoxicity – supported by double blind trials and meta-analysis

Volume :- contrast volume is an independent predictor of contrast induced AKI- avoid repetitive closely spaced studies.

Route: - The risk is greater if given intra arterially as opposed to IV.

Volume expansion  Volume expansion has a well established role in the prevention of contrast induced AKI. 0.9 % saline probably preferable to 0.45% saline (Mueller; Arch Int Med: 2002). Most pronounced in diabetics and larger volumes

IV Bicarbonate  Alkalisation may protect against free radical injury.
Merten (JAMA, 2004) The REMEDIAL trial also demonstrated a benefit of bicarbonate when combined with N-Acetylcysteine (NAC)
Recent trials dispute the use of bicarbonate. Brar, (JAMA 2008) included 353 patients undergoing coronary angiograms. Patients received either isotonic saline or bicarbonate. There was no difference in the primary outcome which was a 25% decrease in GFR on days 1 to 4 following angiography.

Candidates were not expected to provide specific details of authors and journal names

D- Pharmacologic
Many agents have been examined. NAC most effective, although not clearly proven
because of considerable heterogeneity exists in the studies examined and effect on clinical outcome (other than minor changes in serum creatine levels) remains unknown.

E- Dialysis and hemofiltration
Contrast medium is removed by dialysis. Both hemofiltration and dialysis have been studied. Marenzi (NEJM 2003) examined 114 patients with a mean creatinine of 265 umol/l who required coronary intervention. They were then randomised to either isotonic saline or hemofiltration begun 4-8 hours prior and resumed for 18-24 hours after. Those in the hemofiltration group had significantly lower rates of serum creatinine elevation, requirement for dialysis and one year mortality. The applicability of these findings to clinical practice is unclear. The high cost and need for prolonged ICU care will limit the utility of these techniques.

Candidates were not expected to provide specific details of authors and journal names

Discussion

This question would benefit from a tabulated answer.

Drug therapies for contrast-induced nephropathy are well presented in this review article from 2008.

Prophylaxis strategies are discussed in this 2006 paper from JAMA.

For some nice raw biochemistry of contrast media, one cannot look past this gem from Biomed Research International (2014)

Protective Strategies against Contrast-Induced Nephropathy
Strategy Theoretical rationale Evidence
Identification of patients with non-modifiable risk factors

If these patients are identified early, perhaps for some a contrast-free imaging option could be appropriate

The risk of contrast induced nephropathy in the general population is about 0.6-2.3%; in the at-risk population it is as high as 20%.

Identification of patients with modifiable risk factors

If these patients are identified early, in a non-urgent situation some of the risk factors can be attended to prior to the imaging study.

Use of nonionic contrast media

High-osmolarity ionic contrast media are thought to be responsible for the tubule-damaging increase in tubular fluid viscosity

Contrary to popular belief, there does not seem to be very much difference in nephrotocitiy between contrast media of different osmolarities and ionicities.

Use of a smaller volume of contrast media

The harm is thought to be dose-related

Use of automated injectors seems to deliver less contrast, and thus seems to be associated with less AKI.

N-acetylcysteine

Antioxidant effects of N-Ac (and its vasodilating tendency to regenerate nitric oxide) are thought to decrease the oxidative damage in the tubules and improve renal blood flow.

One meta-analysis had identified 22 trials of N-Ac in this setting, and complained that they are too heterogeneous and there is no way to generate a conclusion from them. Others however, performing similar searches have arrived at fewer trials, and havefound some benefit.

Overall, there is no stong evidence to support the ongoing use of N-acetylcysteine. In fact some go as far as to say that ongoing use is"against principles of evidence-based clinical medicine".

Pre and post-hydration

This is a fairly benign therapy; the theoretical benefit depends on diluting the tubular fluid.and increasing the volume of distribution for the contrast agent, as well as increasing the rate of its clearance by the kidneys, and improving the renal blood flow by volume expansion.

Many trials (such as this recent one) have used saline as the control for comparison to an agent thought to be protective against CIN. The outcomes of such trials have thus far been largely negative, supporting the idea that crystalloid is at least as good as any other agent.

Knowing that dehydration is a risk factor for CIN, one is left to conclude that rehydration must be beneficial.

Interestingly, oral hydration may be at least as effective as IV hydration (though this is not a consistent finding).

The Australian College of Radiologists recommend an IV regimen of 1ml/kg/hr for a minimum of 6 hours.

Dopamine / fenoldopam

There is a theoretical benefit associated with increasing renal blood flow; and these agents theoretically increase renal blood flow. Ergo, they might be protective.

There is no good evidence to support the use of either dopamine or fenoldopam as protective agents for contrast-induced nephropathy.

Mannitol

Forced diuresis with mannitol was at one stage thought to improve the removal of toxic oxidants from the tubule by forcing large volumes of fluid through it.

RCTs have abundantly demonstrated that this strategy is without merit.

Frusemide

Similarly to mannitol, frusemide was though to protect the tubules both by forcing dilute fluid through them, and by decreasing their oxygen consumption (by inhibiting ATP-expensive ion pumps).

RCTs have shown that in this setting frusemide is either useless or actually harmful, and its use cannot be recommended.

Sodium bicarbonate

Apart from stimulating diuresis and natriuresis, sodium bicarbonate is thought to protect tubule cells by buffering the reactive oxygen species in the tubular fluid.

An early (2009) meta-analysis found some benefit, but no change in the risk of needing dialysis. A subsequent (2011) meta-analysis supported this finding. Trials released more recently have refuted it. Confusion remains.

At least one country's Consensus Guidelines support this strategy while admitting that the evidence for it is not very strong. Local guidelines make no mention of it.

Statins

The endothelium-protective antioxidant properties of statins may extend to protecting the tubular lumen.

A recently published meta-analysis of 8 trials found evidence of a significant protective effect. A similar meta-analysis had confirmed these findings. The effect size is considerable (halved RR) but the NNT is high, 26.

Prophylactic CVVHDF

The forcible evacuation of contrast from the body fluids seems an inelegant solution, but it certainly removes the contrast and thus theoretically decreases the kidney's exposure to it..

The use of this strategy has only been assessed in a few small trials, with inconsistent findings.

It seems CVVHDF may be cost-effective as a prophylactic post-exposure measure in patients with a very high baseline creatinine (Cr > 265 mcg/L)

Vitamin C

The mechanism of the theoretical benefit of Vitamin C is based on its antioxidant effect and renal clearance. Plus, its a relatively benign substance.

One small 2004 trial investigated this, and found some benefit. Since then, there has been little interest in ascorbic acid as a nephroprotective agent.

It is not included in any guidelines.

\

As for the risk factors for contrast-induced nephropathy, they are well summarised in an article from Kidney International (2006) which within it contains a table closely resembling the one below:

Risk Factors for Contrast-Induced Nephropathy
Non-modifiable risk factors Modifiable risk factors
  • Old age
  • NIDDM
  • Existing renal dysfunction
  • Poor cardiac systolic function
  • Acute coronary syndrome
  • Renal transplant recipient
  • Volume of contrast
  • Hypotension
  • Anaemia
  • Dehydration
  • ACE-inhibitors
  • Diuretics
  • NSAIDs
  • Nephrotoxic antibiotics
  • IABP counterpulsation

References

​UpToDate has an excellent article on this, for the paying public.

Mehran, R., and E. Nikolsky. "Contrast-induced nephropathy: definition, epidemiology, and patients at risk." Kidney International 69 (2006): S11-S15.

Kelly, Aine M., et al. "Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy." Annals of internal medicine 148.4 (2008): 284-294.

Minsinger, Kristopher D., et al. "Meta-analysis of the effect of automated contrast injection devices versus manual injection and contrast volume on risk of contrast-induced nephropathy." The American journal of cardiology 113.1 (2014): 49-53.

Solomon, Richard. "Contrast Media: Are There Differences in Nephrotoxicity among Contrast Media?." BioMed research international 2014 (2014).

Thayssen, Per, et al. "Prevention of Contrast-Induced Nephropathy With N-Acetylcysteine or Sodium Bicarbonate in Patients With ST-Segment–Myocardial Infarction A Prospective, Randomized, Open-Labeled Trial."Circulation: Cardiovascular Interventions 7.2 (2014): 216-224.

Sadat, Umar. "N-acetylcysteine in contrast-induced acute kidney injury: clinical use against principles of evidence-based clinical medicine!." Expert review of cardiovascular therapy 12.1 (2014): 1-3.

Mahmoodi, Khalil, et al. "The efficacy of hydration with normal saline versus hydration with sodium bicarbonate in the prevention of contrast-induced nephropathy." Heart Views 15.2 (2014): 33.

Wu, Mei-Yi, et al. "The effectiveness of N-acetylcysteine in preventing contrast-induced nephropathy in patients undergoing contrast-enhanced computed tomography: a meta-analysis of randomized controlled trials." International urology and nephrology 45.5 (2013): 1309-1318.

Albabtain, Monirah A., et al. "Efficacy of Ascorbic Acid, N‐Acetylcysteine, or Combination of Both on Top of Saline Hydration versus Saline Hydration Alone on Prevention of Contrast‐Induced Nephropathy: A Prospective Randomized Study." Journal of interventional cardiology 26.1 (2013): 90-96.

Solomon, Richard, et al. "Effects of saline, mannitol, and furosemide on acute decreases in renal function induced by radiocontrast agents." New England Journal of Medicine 331.21 (1994): 1416-1420.

Dussol, Bertrand, et al. "A randomized trial of saline hydration to prevent contrast nephropathy in chronic renal failure patients." Nephrology Dialysis Transplantation 21.8 (2006): 2120-2126.

Weinstein, J-M., S. Heyman, and M. Brezis. "Potential deleterious effect of furosemide in radiocontrast nephropathy." Nephron 62.4 (1992): 413-415.

Navaneethan, Sankar D., et al. "Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: a systematic review and meta-analysis."American Journal of Kidney Diseases 53.4 (2009): 617-627.

Kunadian, Vijayalakshmi, et al. "Sodium bicarbonate for the prevention of contrast induced nephropathy: a meta-analysis of published clinical trials."European journal of radiology 79.1 (2011): 48-55.

Mahmoodi, Khalil, et al. "The efficacy of hydration with normal saline versus hydration with sodium bicarbonate in the prevention of contrast-induced nephropathy." Heart Views 15.2 (2014): 33.

Saint-Laurent, Qc. "Consensus Guidelines for the Prevention of Contrast Induced Nephropathy."Canadian Association of Radiologists, 1740 Côte-Vertu, Saint-Laurent, Qc

Barbieri, Lucia, et al. "The role of statins in the prevention of contrast induced nephropathy: a meta-analysis of 8 randomized trials." Journal of thrombosis and thrombolysis (2014): 1-10.

Kapadia, Carl Behram, et al. "EFFICACY OF SHORT TERM, HIGH DOSE STATINS FOR PREVENTING CONTRAST-INDUCED ACUTE KIDNEY INJURY IN PATIENTS UNDERGOING CORONARY ANGIOGRAPHY AND/OR PERCUTANEOUS CORONARY INTERVENTION: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS." Journal of the American College of Cardiology 63.12_S (2014).

Spargias, Konstantinos, et al. "Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention." Circulation 110.18 (2004): 2837-2842.