Question 19

Question 19
a) With respect to contrast-induced nephropathy (CIN), list six risk factors for its development.
(30% marks) 

b) Outline the strategies that have been used for prevention of CIN (70% marks)

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College answer

    a) Risk factors for CIN: (any 6)                                         
1.    Age > 75 years 
2.    Pre-existing kidney disease (creatinine > 120 umol/L) 
3.    Diabetes Mellitus  
4.    Congestive Heart Failure 
5.    Liver Cirrhosis 
6.    Nephrotic Syndrome 
7.    Peripheral Vascular Disease 
8.    Dehydration or prior diuretic use, especially frusemide 
9.    Multiple Myeloma 
10.    Use of 1st generation hyperosmolal ionic contrast agents 
11.    High dose of IV contrast 
12.    Treatment with nephrotoxic agents, such as NSAIDs, aminoglycosides, amphotericin & cyclosporine A 
•    Use nonionic low-osmolal agents/avoid high osmolal agents 
•    Use lower doses of contrast and avoid repetitive, closely spaced studies (e.g. <48 hours apart).  
•    Avoid volume depletion and NSAIDs  
•    For patients at high risk, in the absence of contraindications to volume expansion, intravenous fluids prior to and continued for several hours after contrast administration. While no placebocontrolled studies have proven a benefit of prophylactic intravenous fluid in these risk groups, indirect data support its use. 
•    Either isotonic bicarbonate or isotonic saline may be used, preference for isotonic saline since less expensive and no risk of compounding errors. There are no commercially available isotonic sodium bicarbonate solutions available. Rate e.g.1 mL/kg/hour for 6 to 12 hours preprocedure, intraprocedure, and for 6 to 12 hours post procedure.  
•    For at-risk patients, acetylcysteine may be administered the day before and the day of the procedure, based upon its potential for benefit, low toxicity and cost. Although data are conflicting, acetylcysteine may be warranted based on some studies showing a benefit. If acetylcysteine is administered, a preferred dose is 1200 mg orally twice daily rather than 600 mg twice daily the day before and the day of the procedure.  
•    (No role for mannitol or other diuretics prophylactically. However, diuretics may be used to treat volume overload if present 
•    Prophylactic hemofiltration or hemodialysis after contrast exposure to prevent contrast nephropathy is not recommended 
•    Avoidance of contrast, alternative imaging modalities. 


Risk factors for contrast-induced nephropathy can be divided into modifiable and non-modifiable:

Risk Factors for Contrast-Induced Nephropathy
Non-modifiable risk factors Modifiable risk factors
  • Old age (over 75)
  • Existing renal dysfunction
    • Nephrotic syndrome
  • Poor cardiac systolic function
  • Peripheral vascular disease
  • Acute coronary syndrome
  • Renal transplant recipient
  • Multiple myeloma
  • Liver cirrhosis
  • Volume of contrast
  • Vintage of contrast (1st generation agents)
  • Hypotension
  • Anaemia
  • Dehydration
  • ACE-inhibitors
  • Diuretics
  • NSAIDs
  • Nephrotoxic antibiotics
  • IABP counterpulsation

Preventative strategies "that have been used" can be presented in a massive table:

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

Some reviewers disagree- their data suggests that there does not seem to be very much difference in nephrotoxicity between modern contrast media of different osmolarities and ionicities. A 2014 meta-analysis found some differences in renal safety between different low-osmolar and iso-osmolar contrast media. High-osmolar contrast media are no longer used; their nephrotoxicity was indeed significant.

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.


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 have found 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.


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.


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.


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)



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.


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.

Biondi-Zoccai, Giuseppe, et al. "Nephropathy after administration of iso-osmolar and low-osmolar contrast media: evidence from a network meta-analysis." International journal of cardiology 172.2 (2014): 375-380.