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Contrast-Induced Nephropathy (CIN): Current State of the Evidence on Contrast Media and Prevention of CIN

Clinician Summary
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Focus of This Summary

This is a summary of two systematic reviews. One review evaluated the evidence regarding the comparative effects of different contrast media in patients requiring diagnostic imaging studies or image-guided procedures. The other review assessed the evidence regarding the comparative efficacy of measures to prevent CIN. The former systematic review included 29 randomized controlled trials (RCTs) and 10 observational studies published from 1988 through 2015. The latter systematic review included 163 RCTs and 23 observational studies published from 1998 through 2015. This summary is provided to assist in informed clinical decisionmaking. However, reviews of evidence should not be construed to represent clinical recommendations or guidelines.

Background

CIN is a possible complication of iodinated contrast media used for radiologic imaging. It has been traditionally defined, in the absence of an alternative etiology, as an increase in serum creatinine of more than 25 percent or 0.5 mg/dL within 2 to 3 days after a contrast medium is administered. In 2013, the National Kidney Foundation– Kidney Disease Outcomes Quality Initiative recommended the use of these criteria for all types of acute kidney injury, including CIN: an increase in serum creatinine of at least 0.3 mg/dL over a 48-hour period or to at least 1.5 times baseline.

The precise mechanism of CIN is not entirely understood. Leading theories state that CIN results from hypoxic injury of the renal tubules induced by renal vasoconstriction or from the direct cytotoxic effects of contrast media. Oxidative stress, leading to an excess of oxygen free radicals over antioxidants, has been implicated in playing an important role in mediating the cytotoxic effects.

The osmolality of a contrast medium is a key factor in determining its nephrotoxicity. Over a decade ago, low- osmolar contrast media (LOCM) replaced high-osmolar media as the standard of care for intravenous (IV) or intra- arterial (IA) injection. The osmolality of LOCM is generally about two to three times plasma osmolality, although it varies from 322 to 915 mOsm/kg, depending on the concentration of the commercially available solution. Iso-osmolar contrast medium (IOCM) is the newest class of iodinated contrast agents; the only IOCM currently available is iodixanol. The osmolality of the IOCM is the same as plasma osmolality: 290 mOsmol/kg. Characteristics of the IOCM and individual LOCM are shown in Appendix Table A.

Numerous strategies have been used to try to prevent CIN, including oral hydration; intravascular volume expansion with sodium chloride or bicarbonate; administration of N-acetylcysteine (NAC) or statins; withdrawal of nonsteroidal anti-inflammatory drugs; withdrawal of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers; hemofiltration or hemodialysis; and avoiding repeat contrast administration within a short period of time.

For more background information, go to the Comparative Effectiveness of Preventive Measures report and the Comparative Effects of Different Contrast Media report.

Conclusions

The reviewed studies provided the following evidence:

  • The risk of CIN does not differ between the various types of LOCM (low strength of evidence [SOE]).
  • The IOCM has a slightly lower risk of CIN than an LOCM (moderate SOE). The lower risk was statistically significant but unlikely to be clinically important.
  • The risk of CIN was similar for both an LOCM and the IOCM when studies involving IV (low SOE) or IA (moderate SOE) administration were considered separately.

In preventing CIN, evidence to support a statistically significant and potentially clinically important benefit is available for only three interventions, and that evidence is limited to these specific contexts:

  • NAC plus IV saline is superior to IV saline (alone or with placebo) when an LOCM is used (moderate SOE).
  • Low-dose NAC plus IV saline is superior to IV saline (alone or with placebo) (low SOE). Low-dose NAC was defined as 1200 mg/day or less.
  • Statins plus NAC plus IV saline (or bicarbonate) is superior to NAC plus IV saline (or bicarbonate) in patients receiving IA-administered contrast media (low SOE).

The evidence is insufficient to determine if outcomes other than CIN differ between LOCM; whether differences in CIN risk are modified by various patient factors (e.g., comorbidities, baseline kidney function) or contrast dose; and how the efficacy of preventive strategies varies according to patient characteristics. For preventive strategies with sufficient evidence to determine whether they prevent CIN, the SOE is often insufficient for other outcomes (e.g., cardiovascular events, mortality).

Go to the Comparative Effects of Different Contrast Media and Comparative Effectiveness of Preventive Measures reports for a complete review of the conclusions.

Overview of Clinical Research Evidence

Table 1: Comparative Effects of Low-Osmolar and Iso-Osmolar Contrast Media*
Contrast Media Comparison Outcome No. of RCTs No. of Subjects Effect on Outcomea Clinically Important Effectb Risk Ratio (95% CI) SOE
*Note: Outcomes with insufficient SOE are not included in this table.
CI = confidence interval; CIN = contrast-induced nephropathy; IA = intra-arterial; IOCM = iso-osmolar contrast medium; IV = intravenous; LOCM = low-osmolar contrast medium; NR = not reported; No. = number; RCT = randomized controlled trial; SOE = strength of evidence
a Based on statistical significance for meta-analysis or qualitative synthesis of studies when meta-analysis was not performed: = decreased; = no difference.
b Clinically important effect was defined by a risk ratio less than 0.75 or greater than 1.25.
c Twenty-three studies were included in the meta-analysis.
d Seventeen studies were included in the meta-analysis.
e Renal replacement therapy consisted of hemodialysis or hemofiltration. f All adverse events are included except CIN (e.g., hypersensitivity reactions, need for renal replacement therapy, cardiovascular events, death).
LOCM vs. another LOCM Development of CIN 5 429 NR [evidence low]
IOCM vs. LOCM Development of CIN 25c 5097 0.80 (0.65 to 0.99) [evidence medium]
Development of CIN (with IV administration) 6 790 0.84 (0.42 to 1.71) [evidence low]
Development of CIN (with IA administration) 18d 4194 0.80 (0.64 to 1.01) [evidence medium]
Need for renal replacement therapye 5 1740 NR [evidence low]
Cardiovascular outcomes 7 2258 NR [evidence low]
Mortality 8 2028 NR [evidence low]
Adverse eventsf 12 3363 NR [evidence low]

Go to table 4 of the Comparative Effects of Different Contrast Media report for a complete summary of the strength of evidence: iso-osmolar contrast media versus low-osmolar contrast media

Strength of Evidence Scale*

High: [evidence high]
High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.

Moderate: [evidence medium]
Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.

Low: [evidence low]
Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.

Insufficient:[evidence insufficient]
Evidence is either unavailable or does not permit a conclusion.

* The overall evidence grade was assessed based on the ratings for the following domains: study limitations, directness, consistency, precision, and reporting bias. Other domains that were considered, as appropriate, included dose-response association, plausible confounding, and strength of association (i.e., magnitude of effect). For additional details on the methodology used to assess strength of evidence, please refer to: Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions--Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol. 2010 May;63(5):513-23. PMID: 19595577.

Table 2: Strategies To Prevent Contrast-Induced Nephropathy*
Preventive Strategy Comparison Outcome No. of RCTs No. of Subjects Effect on Outcomea Clinically Important Effectb Risk Ratio (95% CI) SOE
*Note: Outcomes with insufficient SOE are not included in this table.
CI = confidence interval; CIN = contrast-induced nephropathy; IA = intra-arterial; IOCM = iso-osmolar contrast medium;
IV = intravenous; LOCM = low-osmolar contrast medium; NR = not reported; NAC = n-acetylcysteine; No. = number;
RCT = randomized controlled trial; SOE = strength of evidence
a Based on statistical significance for meta-analysis or qualitative synthesis of studies when meta-analysis was not performed:
= decreased; = increased; = no difference.
b Clinically important effect was defined by a risk ratio less than
0.75 or greater than 1.25. = clinically important decrease;
= clinically important increase.
c In the analyzed studies, NAC was usually administered orally.
d High-dose = more than 1200 mg/day; low-dose = 1200 mg/day or less. e One study included in this meta-analysis compared a statin + sodium bicarbonate + IV saline versus NAC + sodium bicarbonate + IV saline.
f Three studies were included in the meta-analysis.
g Renal replacement therapy consisted of hemodialysis or hemofiltration.
NACc plus IV saline vs. IV saline (alone or with placebo) Development of CIN (with high-dose NACd) 18 4336 0.78 (0.59 to 1.03) [evidence low]
Development of CIN (with low-dose NACd) 36 5217 (borderline) 0.75 (0.63 to 0.89) [evidence low]
Development of CIN (in patients receiving an LOCM) 40 6665 0.69 (0.58 to 0.84) [evidence medium]
Development of CIN (in patients receiving the IOCM) 7 1339 1.12 (0.74 to 1.69) [evidence low]
Need for renal replacement therapy 20 4881 NR [evidence low]
Cardiac events 7 1207 NR [evidence low]
Hospitalization, length of stay 9 1461 NR [evidence low]
IV sodium bicarbonate vs. IV saline Development of CIN 19 3303 0.93 (0.68 to 1.27) [evidence low]
Development of CIN (in studies using an LOCM) 11 1555 0.65 (0.33 to 1.25) [evidence low]
Development of CIN (in studies using the IOCM) 7 1748 1.02 (0.70 to 1.48) [evidence low]
Need for renal replacement therapy 11 1558 NR [evidence low]
Mortality 6 1237 NR [evidence low]
Statins plus IV saline vs. IV saline (alone or with placebo) Development of CIN (with IA administration) 8 5024 0.68 (0.39 to 1.20) [evidence low]
Statins plus NAC plus IV saline (or bicarbonate) vs. NAC plus IV saline (or bicarbonate) Development of CIN (with IA administration) 5e 1477 0.52 (0.29 to 0.93) [evidence low]
Hemodialysis vs. IV saline Development of CIN 4f 584 or possibly 1.50 (0.56 to 4.04) [evidence low]
Ascorbic acid plus IV saline vs. IV saline (alone or with placebo) Development of CIN 6 1387 0.72 (0.48 to 1.01) [evidence low]
Need for renal replacement therapyg 2 397 NR [evidence low]
Cardiac events 2 237 NR [evidence low]
Ascorbic acid plus IV saline vs. NAC plus IV saline Development of CIN 3 583 0.89 (0.34 to 2.30) [evidence low]

Go to the results section of Comparative Effectiveness of Preventive Measures report for a complete review of the findings.

Other Findings of the Reviews

  • Evidence is too limited to determine how the dose of the different contrast media, patient demographics, comorbid conditions, or baseline renal function modifies CIN risk.
  • Although the small beneficial effect of NAC did not appear to differ between IA and IV routes, the SOE was insufficient to rule out a possible difference in benefit.
  • The SOE was insufficient to determine the effect of other interventions on the risk of CIN, including adenosine antagonists, diuretics, vasoactive agents, various fluid regimes, probucol, and pentoxifylline. Limited evidence suggests that fenoldopam and dopamine may increase CIN risk.
  • Because of methodological heterogeneity between studies, the SOE was insufficient to assess how the effectiveness of strategies to prevent CIN varies according to baseline kidney function and other patient characteristics.

Limitations of the Evidence Base

  • Variable definitions of CIN have been used in studies regarding the effects of different contrast media and strategies to prevent CIN. The majority used the traditional definition; few used recent guideline definitions.
  • Most studies examining preventive strategies focused on patients receiving IA contrast media. The applicability of those studies to modern-day protocols of LOCM and the IOCM administered via the IV route is uncertain.

Go to the Comparative Effectiveness of Preventive Measures report for a complete review of the study’s overall limitations.

Additional Resources for Clinicians

  1. Eng J, Wilson RF, Subramaniam RM, et al. Comparative effect of contrast media type on the incidence of contrast-induced nephropathy: a systematic review and meta-analysis. Ann Intern Med. 2016 Mar;164(6):417-24. PMID: 26830055.
  2. Subramaniam RM, Suarez-Cuervo C, Wilson RF, et al. Effectiveness of prevention strategies for contrast-induced nephropathy: a systematic review and meta-analysis. Ann Intern Med. 2016 Mar;164(6):406-16. PMID: 26830221.

Appendix

Table A: Low-Osmolar and Iso-Osmolar Contrast Media
Name Trade Name Classification Osmolalitya (mOsm/kg)
IOCM = iso-osmolar contrast medium; LOCM = low-osmolar contrast medium
a Ranges represent the lowest and highest values for the range of commercially available concentrations.
Iodixanol Visipaque® IOCM 290
Iohexol Omnipaque® LOCM 322–844
Iopromide Ultravist® LOCM 328–774
Ioversol Optiray® LOCM 355–792
Iopamidol Isovue® LOCM 413–796
Ioxaglate Hexabrix® LOCM 580
Ioxilan Oxilan® LOCM 585–695
Iobitridol Xenetix® LOCM 585–915

Source

The information in this summary comes from two comparative effectiveness reviews:

Eng J, Subramaniam RM, Wilson RF, Turban S, Choi MJ, Zhang A, Suarez-Cuervo C, Sherrod C, Hutfless S, Iyoha EE, Bass EB. Contrast-Induced Nephropathy: Comparative Effects of Different Contrast Media. Comparative Effectiveness Review No. 155. (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No. 290-2012-00007-I.) AHRQ Publication No. 15(16)-EHC022-EF. Rockville, MD: Agency for Healthcare Research and Quality; December 2015.

Subramaniam RM, Wilson RF, Turban S, Suarez-Cuervo C, Zhang A, Sherrod C, Aboagye J, Eng J, Choi MJ, Hutfless S, Bass EB. Contrast-Induced Nephropathy: Comparative Effectiveness of Preventive Measures. Comparative Effectiveness Review No. 156. (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No. 290-2012-00007-I.) AHRQ Publication No. 15(16)-EHC023-EF. Rockville, MD: Agency for Healthcare Research and Quality; January 2016.

This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX. It was written by M. Denise Daley, M.D., Geetha Achanta, Ph.D., Sreedhar Mandayam, M.D., and Michael Fordis, M.D.