SEARCH

SEARCH BY CITATION

Keywords:

  • computed tomography;
  • contrast medium;
  • contrast-induced nephropathy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence
  6. Risk factors
  7. Ways to reduce the risk of CIN
  8. Conclusion
  9. Conflict of interest
  10. References

Contrast-induced nephropathy (CIN) is a serious complication resulting from the use of iodinated contrast medium (CM) with potentially high morbidity and mortality. Patients with pre-existing renal insufficiency appear to be at higher risk of CIN. To prevent CIN among patients undergoing contrast-enhanced computed tomography, every effort is required, including routine identification of at-risk patients, the use of appropriate hydration regimens, withdrawal of nephrotoxic drugs, selection of low-osmolality CM or iso-osmolar CM, and using the minimum volume of CM possible.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence
  6. Risk factors
  7. Ways to reduce the risk of CIN
  8. Conclusion
  9. Conflict of interest
  10. References

Contrast-induced nephropathy (CIN) is defined as an acute form of kidney injury resulting from exposure to intravascular administration of iodinated contrast medium (CM). It is the third most important cause of hospital-acquired renal failure, accounting for 12% of all cases1 and associated with high morbidity and mortality.2

The past decade has seen a marked increase in the use of computed tomography (CT) procedures. As increasing numbers of elderly patients with multiple comorbidities now undergo contrast-enhanced CT (CECT), more are consequently at risk of CIN. It is clinically important for physicians to be sufficiently aware of the incidence, impact, and risk factors for CIN, as well as the measures to reduce the risk of CIN among patients undergoing CECT. This article attempts to place the controversies surrounding CIN at CECT into perspective.

Definition

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence
  6. Risk factors
  7. Ways to reduce the risk of CIN
  8. Conclusion
  9. Conflict of interest
  10. References

Although there is no universally accepted definition of CIN that most commonly used is a 0.5 mg/dL increase in the serum creatinine level following CM administration. The European Society of Urogenital Radiology (ESUR) defines CIN as impairment of renal function (an increase in serum creatinine levels by >25% or 0.5 mg/dL) occurring within 3 days after intravascular administration of CM in the absence of an alternative etiology.3,4 The ESUR guidelines advise that serum creatinine should always be measured no earlier than 7 days before CM administration in patients who have renal disease, a history of renal surgery, proteinuria, diabetes, hypertension, gout, or recent intake of nephrotoxic drugs.5 Typically, CIN results in acute renal dysfunction, with the increase in creatinine level occurring within 24–48 h, often peaking at 3–5 days. If renal function returns to normal, it usually does so within 7–10 days after CM administration.

Although serum creatinine has long been used to diagnose CIN, reliance on this parameter can result in CM being administered to some patients with mild to moderate renal failure despite the presence of a normal serum creatinine level. In fact, serum creatinine levels are often not elevated until the glomerular filtration rate (GFR) is reduced by at least 50%, by which time a patient is at increased risk of developing significant CIN.6 Moreover, the serum creatinine level is dependent not only on renal function, but also, at least in part, on muscle mass because creatinine is a breakdown product of skeletal and smooth muscle.7 In a patient with a less than normal muscle mass, less creatinine is produced and serum creatinine levels may be normal despite the presence of kidney dysfunction.

To account for these uncertainties, renal function status has been reclassified by the National Kidney Foundation into five stages of chronic kidney disease on the basis of the GFR8 as follows: Stage 1, chronic kidney disease in patients with kidney damage and a GFR between 120 and 90 mL/min; Stage 2, kidney damage with a mildly decreased GFR of between 60 and 89 mL/min; Stage 3, moderate renal impairment defined as a GFR of between 30 and 59 mL/min; Stage 4, severe chronic kidney disease (CKD), defined as a GFR of between 15 and 29 mL/min; and Stage 5, renal failure with a GFR of <15 mL/min or with a patient on dialysis. In general, CKD is defined as either kidney damage or a GFR of <60 mL/min per 1.73 m2 for more than 3 months.8 The actual GFR would, of course, be an ideal screening tool for renal failure and its measurement is now being advocated as an alternative to serum creatinine levels as an indicator of renal function.3 Estimated (e) GFR can be calculated using a variety of formulas, including the Modification of Diet in Renal Disease (MDRD) equation9 and the Cockcroft-Gault equation.10 The most basic form estimates GFR on the basis of serum creatinine level, age, race, and sex. Moreover, the Cockcroft-Gault equation factors in a patient's weight. However, the eGFR has several shortcomings. This parameter was originally intended for use in patients with CKD; it was not designed to monitor acute changes in renal function and it does not perform well in patients who are ill and those who are hospitalized10 (i.e. the very population most at risk of CIN). Moreover, in healthy patients, it has been reported that eGFR underestimates GFR by up to 30%.7

Incidence

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence
  6. Risk factors
  7. Ways to reduce the risk of CIN
  8. Conclusion
  9. Conflict of interest
  10. References

It is uncommon for patients with normal pre-existing renal function to develop CIN; rather, CIN is more frequent in patients with renal impairment, especially when the renal insufficiency (RI) is attributable to diabetic nephropathy. In the general population, the incidence of CIN is estimated to be 1%–6%.11 Recent studies have demonstrated that the incidence of CIN after CECT ranges from 1.3% to 11.1% among patients with RI.12–18 This wide variation in incidence is attributed to factors that include a lack of consensus regarding definitions, differing patient populations, variations in the CM used, wide variability in the CM dose, and likely variation in the patient's hydration status. A recent review has indicated that the incidence of CIN is 2.2-fold greater for intra-arterial administration than for intravenous administration.19 Sometimes, CIN may increase the risk for renal failure and is associated with dialysis, prolonged hospital stay, increased health care costs, potentially irreversible reduction in renal function, and death. Whereas several authors have reported that associated dialysis rates and death rates were 0% in a CECT study,13–16 two studies20,21 reported that the 7% of CIN resulted in irreversible renal function requiring dialysis.

The pathogenesis of CIN is not clearly understood. Although the CM may be directly toxic to cells of the renal tubules, most authors believe that the tubule injury caused by CM is attributable to renal ischemia.

Risk factors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence
  6. Risk factors
  7. Ways to reduce the risk of CIN
  8. Conclusion
  9. Conflict of interest
  10. References

The presence of renal failure is generally accepted as the most important risk factor for the development of CIN.18,21 The ESUR guidelines identify patients at high risk of CIN as those with pre-existing renal impairment (serum creatinine >1.5 mg/dL), particularly when secondary to diabetic nephropathy.22 The CIN Consensus Working Panel of international experts reported that the risk of CIN is elevated in patients with CKD, particularly when diabetes is also present, and they defined CKD as a serum creatinine level of ≥1.3 mg/dL in men and ≥1.0 mg/dL in women, approximating an eGFR of <60 mL/min per 1.73 m2.23Table 1 summarizes the risk factors for CIN that have been identified in published studies and guidelines.5,22–24 Although diabetes alone is not always considered to be an independent risk factor for CIN,24 diabetes associated with RI has been identified as an independent predictor.22 The CIN Consensus Working Panel concluded that patients with multiple risk factors have a very high (∼50%) risk of CIN and a moderate (∼15%) risk of acute renal failure requiring dialysis.25

Table 1.  Risk factors for contrast-induced nephropathy after contrast-enhanced computed tomography
  1. NSAIDs, non-steroidal anti-inflammatory drugs; ACEI, angiotensin-converting enzyme inhibitor; CsA, cyclosporin A.

Pre-existing renal impairment
Diabetes mellitus associated with renal impairment
Advancing age >70 years
Reduction in effective intravascular volume
 Dehydration
 Congestive heart failure
Multiple myeloma
Concurrent use of nephrotoxic drugs (e.g. NSAIDs, ACEI, aminoglycosides, sulfoamides, amphotericin B, CsA, tacrolimus and platinum-based drugs)
Contrast media-related factors
 Osmolarity
 Large dose or repeated doses within 72 h

Table 2 lists the most common scenarios in which it would be advisable for a radiologist to consult a urologist and nephrologist before performing CECT.24,8,26–27 Consultation and collaboration between radiologists, urologists, and nephrologists is always necessary in every institution to develop clear policies and evidence-based protocols for the prevention of CIN in both routine and emergency CECT.

Table 2.  Patients for whom nephrologists and urologists should be consulted before contrast-enhanced computed tomography investigations
  1. GFR, glomerular filtration rate.

Patients with:
 Estimated GFR <30 mL/min or if the possibility of dialysis exists post-procedure
 Active renal failure
 Diabetic nephropathy with renal insufficiency
 Multiple renal risk factors
 Established, relatively uncommon causes of kidney disease
  Membranous nephropathy
  IgA nephropathy
  Polycystic kidney disease
 Known renal artery stenosis
 Advanced heart failure or other cause of reduced renal perfusion (e.g. hypovolemis)
 Multiple myeloma
Complicated patients on transplant-related medications (e.g. cyclosporin)
High total dose of contrast media

Ways to reduce the risk of CIN

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence
  6. Risk factors
  7. Ways to reduce the risk of CIN
  8. Conclusion
  9. Conflict of interest
  10. References

Hydration

Hydration has long been considered effective for reducing the risk of CIN.28–31 Hydration is inexpensive, low-risk, and likely to be effective on the basis of physiology: hydration reduces the concentration of iodinated CM within the blood stream and kidneys, thereby decreasing the concentration to which the kidney is exposed. Although intravenous hydration appears to reduce the risk of CIN to a greater extent than oral hydration alone,28,30 we recommend that when possible all patients should be encouraged to drink water liberally for 12 h prior to and after exposure to CM.

Intravenous hydration with normal saline is reportedly more effective than that with half-normal saline.28 At present, the evidence suggests that intravenous hydration with sodium bicarbonate reduces the risk of CIN to a greater extent than that with normal saline in high-risk patients.29,30 It is possible that post-procedure hydration may be even more important than preprocedure hydration for preventing CIN, based on evidence of a prolonged reduction in renal blood flow following exposure to CM.32 The optimum timing and duration of intravenous hydration are unknown, but beginning earlier and continuing for longer are probably desirable.28,29,31 The CIN Consensus Working Panel has recommended that inpatients at high risk of CIN should receive isotonic crystalloid at a rate of 1.0–1.5 mL/kg per h for 12 h before the procedure and for 6–24 h afterwards, and that outpatients with a high risk of CIN should receive isotonic crystalloid at a rate of 1.0–1.5 mL/kg per h for 1–3 h before the procedure and for 6–12 h afterwards.23 Mueller et al.28 reported that for elective in-hospital patients, a 24-h protocol using 1 mL/kg per h saline started 12 h before and after the procedure should be implemented, and that if the CM study is performed on an emergency basis a high saline infusion rate of 300 mL/h should be used 60 min before the procedure and continued for at least 6 h after administration of CM. Diuretics offer no additional benefit in reducing the risk of CIN when added to hydration.32,33

Dose reduction

Because the renal toxicity of iodinated CM is dose dependent,30 decreasing the dose will reduce the risk of CIN, although by how much is unknown. The CIN Consensus Working Panel concluded that higher CM volumes (>100 mL) are associated with higher rates of CIN in at-risk patients; even small (∼30 mL) volumes of CM in very high-risk patients can cause CIN, suggesting the absence of a threshold.23 It is generally agreed that the smallest possible volume of CM necessary for imaging should be used.6

Pharmacologic premedication

Although several studies have reported that N-acetylcysteine (NAC) is effective in reducing CIN risk,34 there is little evidence to recommend the use of NAC specifically to reduce the risk of CIN. Based on the currently available data, the ESUR guidelines do not recommend any pharmacologic manipulation for routine use in the prevention of CIN.5 Based on a review of 27 published studies of varying quality and nine meta-analyses, the CIN Consensus Working Panel concluded that NAC is not consistently effective in reducing the risk of CIN.23

Choice of CM

Iodinated CM for intravascular use became available in the 1950s when creation of the tri-iodinated benzene ring led to the development of the agents now known as ionic, high-osmolality CM (HOCM). In the half century that has passed since then, non-ionic, monomer, low-osmolality CM (LOCM) have been developed, followed by non-ionic, dimer, iso-osmolar CM (IOCM). The HOCM have five- to eightfold the osmolality of plasma (>1500 mOsm/kg), LOCM, such as iopamidol, iohexol, and iomeprol, have two- to threefold the osmolarity (600–850 mOsm/kg), and IOCM, which are being used increasingly, such as iodixanol, have the same osmolality (290 mOsm/kg) as blood, plasma, and cerebrospinal fluid. One large study has shown that patients receiving HOCM have a 3.3-fold greater risk of developing CIN than those receiving LOCM.34 Possible explanations for the lower incidence of CIN after LOCM administration include reduced osmolality, as well as differences in iconicity and physiochemical properties.35 It has been suggested that if the lower risk of CIN associated with LOCM compared with HOCM is due to the lower osmolality of the former, then perhaps the even lower osmolality of IOCM may further decrease the risk of CIN. Given the conflicting results of many studies that have compared the CIN risk of IOCM and various LOCM,11–14,16,17,36,37 we believe that, at present, a clear benefit of IOCM has yet to be demonstrated. Currently, HOCM tends to be used rarely.

Withdrawal of nephrotoxic drugs

One study has found that 64% of patients were taking nephrotoxic medications at the time of CM administration: diuretics were discontinued in only 3% of patients, angiotensin-converting enzyme (ACE) inhibitors in 5%, and non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs in 5%.38 One group has suggested that although drugs should be withdrawn at least 24 h before the CM procedure, a gap of 2–3 days is ideal.21

Hemodialysis and hemofiltration

Although CM can be efficiently removed from the blood by hemodialysis,39 the usefulness of hemodialysis in clinically settings is contentious. The ESUR guidelines conclude that because hemodialysis does not offer any protection against CIN, hemodialysis is unnecessary for patients with severely reduced renal function and relating the time of the CM injection to the dialysis schedule is unnecessary for people receiving hemodialysis.40 Marenzi et al.41 demonstrated in a single-center trial of patients with advanced CKD (serum creatinine level >2 mg/dL) that hemofiltration started 4 h before contrast administration for coronary intervention and continued for 24 h after the procedure prevented the deterioration of renal function after CM administration, decreased the need for renal replacement therapy, and improved in-hospital and long-term outcomes compared with administration of isotonic saline.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence
  6. Risk factors
  7. Ways to reduce the risk of CIN
  8. Conclusion
  9. Conflict of interest
  10. References

Pre-existing renal insufficiency, defined as a GFR stably below 60 mL/min per 1.73 m2, is the most important factor involved in the development of CIN. To prevent CIN among patients undergoing CECT, clinicians need to make every effort, including routine identification of at-risk patients, the use of appropriate hydration regimens, withdrawal of nephrotoxic drugs, the selection of LOCM or IOCM, and the use of the lowest possible volume of CM. Although clinically necessary imaging examinations should not be withheld due to concerns about CIN, it is sensible to exercise greater caution in patients with severe RI, for whom alternative imaging techniques that do not require CM should be seriously considered.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence
  6. Risk factors
  7. Ways to reduce the risk of CIN
  8. Conclusion
  9. Conflict of interest
  10. References
  • 1
    Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am. J. Kidney Dis. 2002; 39: 9306.
  • 2
    Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort snalysis. JAMA 1996; 275: 148994.
  • 3
    Thomsen HS. Guidelines for contrast media from the European Society of Urogenital Radiology. AJR Am. J. Roentgenol. 2003; 181: 146371.
  • 4
    Morcos SK, Thomsen HS. European Society of Urogenital Radiology guidelines on administering contrast media. Abdom. Imaging 2003; 28: 18790.
  • 5
    Thomsen HS, Morcos SK. ESUR guidelines on contrast media. Abdom. Imaging 2006; 31: 13140.
  • 6
    Thomsen HS, Morcos SK. In which patients should serum creatinine be measured before iodinated contrast medium adminidtration? Eur. Radiol. 2005; 15: 74954.
  • 7
    Halvorsen RA. Which study when? Iodinated contrast-enhanced CT versus gadolinium-enhanced MR imaging. Radiology 2008; 249: 915.
  • 8
    National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am. J. Kidney Dis. 2003; 39 (Suppl 1): S1266.
  • 9
    Diskin CJ. Creatinine and glomerular filtation rate: evolution of an accommodation. Ann. Clin. Biochem. 2007; 44: 1619.
  • 10
    Poggio ED, Nef PC, Wang X et al. Performance of the Cockroft-Gault and Modification of Diet in Renal Disease equations in estimating GFR in ill hospitalized patients. Am. J. Kidney Dis. 2005; 46: 24252.
  • 11
    Parfrey P. The clinical epidemiology of contrast-induced nephropathy. Cardiovasc. Intervent. Radiol. 2005; 28 (Suppl 2): S311.
  • 12
    Barrett BJ, Katzberg RW, Thomsen HS et al. Contrast-induced nephropathy in patients with chronic kidney disease undergoing computed tomography. A double blind comparison of iodixanol and iopamidol. Invest. Radiol. 2006; 41: 81521.
  • 13
    Thomsen HS, Morcos SK, Earley CM et al. The ACTIVE trial: comparison of the effects on renal function of iomeprol-400 and iodixanol-320 in patients with chronic kidney disease undergoing abdominal computed tomography. Invest. Radiol. 2008; 43: 1708.
  • 14
    Nguyen SA, Suranyi P, Ravenel JG et al. Iso-osmolality versus low-osmolality iodinated contrast medium at intravenous contrast-enhanced CT: effect on kidney function. Radiology 2008; 248: 97113.
  • 15
    Weisbord SD, Mor MK, Resnick AL et al. Incidence and outcomes of contrast-induced AKI following computed tomography. Clin. J. Am. Soc. Nephrol. 2008; 3: 127481.
  • 16
    Kuhn MJ, Chen N, Sahani DV et al. The PRDICT study: a randomized double-blind comparison of contrast-induced nepropathy after low- or iso-osmolar contrast agent exposure. AJR Am. J. Roentgenol. 2008; 181: 1517.
  • 17
    Thomsen HS, Morcos SK. Risk of contrast-medium-induced nephropathy in high-risk patients undergoing MDCT: a pooled analysis of two randomized trials. Eur. Radiol. 2009; 19: 8917.
  • 18
    Lencioni R, Fattori R, Morana G, Stacul F. Contrast-induced nephropathy in patients undergoing computed tomography (CONNET): a clinical problem in daily practice ? A multicenter observational study. Acta Radiol. 2010; 51: 74150.
  • 19
    Katzberg RW, Barrett BJ. Risk of iodinated contrast material-induced nephropathy with intravenous administration. Radiology 2007; 243: 6228.
  • 20
    Gruberg L, Mintz GS, Mehran R et al. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J. Am. Coll. Cardiol. 2000; 36: 15428.
  • 21
    Mitchell AM, Jones AE, Tumlin JA, Kline JA. Incidence of contrast-induced nephropathy after contrast-enhanced computed tomography in the outpatient setting. Clin. J. Am. Soc. Nephrol. 2010; 5: 49.
  • 22
    Gleeson TG, Bulugahapitiya S. Contrast-induced nephropathy. AJR Am. J. Roentgenol. 2004; 183: 167389.
  • 23
    Stacul F, Adam A, Becker C et al. Strategies to reduce the risk of contrast-induced nephropathy. Am. J. Cardiol. 2006; 98 (Suppl 1): 5977.
  • 24
    Reddan D, Fishman EK. Radiologists’ knowledge and perceptions of the impact of contrast-induced nephropathy and its risk factors when performing computed tomography examinations: a survey of European radiologists. Eur. J. Radiol. 2008; 66: 23545.
  • 25
    Parfrey PS, Griffiths SM, Barrett BJ et al. Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N. Engl. J. Med. 1989; 320: 1439.
  • 26
    Snyder S, Pendergraph B. Detection and evaluation of chronic kidney disease. Am. Fam. Physician 2005; 72: 172332.
  • 27
    Stigant C, Stevens L, Levin A. Nephrology: 4. Strategies for the care of adults with chronic kidney disease. CMAJ 2003; 168: 155360.
  • 28
    Mueller C. Prevention of contrast-induced nephropathy with volume supplementation. Kidney Int. Suppl. 2006; 100: S1619.
  • 29
    Thomsen HS. Current evidence on prevention and management of contrast-induced nephropathy. Eur. Radiol. 2007; 17 (Suppl 6): F337.
  • 30
    Hogan SE, L’Allier P, Chetcuti S et al. Current role of sodium bicarbonate-based preprocedural hydration for the prevention of contrast-induced acute kidney injury: a meta-analysis. Am. Heart J. 2008; 156: 41421.
  • 31
    Committee on Drugs and Contrast Media, American College of Radiology (ACR) Website. Mannual on Contrast Media, v. 6. [Cited 4 Jan 2009.] Available from URL: http://Acr.org/SecondaryMain-MenuCategories/quality_safety/contrast_manual.aspx
  • 32
    Solomon R, Werner C, Mann D, D’Elia J, Silva P. Effects of saline, manitol, and furosemide on acute decreases in renal function induced by radiocontrastagents. N. Engl. J. Med. 1994; 331: 141620.
  • 33
    Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann. Intern. Med. 2008; 148: 28494.
  • 34
    Rudnick MR, Goldfarb S, Wexler L et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidney Int. 1995; 47: 25461.
  • 35
    Ellis JH, Cohan RH, Sonnad SS, Cohan NS. Selective use of radiographic low-osmolality contrast media in the 1990s. Radiology 1996; 200: 297311.
  • 36
    Reed M, Meier P, Tamhane UU, Welch KB, Moscussi M, Gurm HS. The relative renal safety of iodixanol compared with low-osmolar contrast media. JACC Cardiovasc. Interv. 2009; 2: 64554.
  • 37
    Heinrich MC, Haberle L, Muller V, Bautz W, Uder M. Nephrotoxicity of iso-osmolar iodixanol compared with nonionic low-osmolar contrast media: meta-analysis of randomized controlled trials. Radiology 2009; 250: 6886.
  • 38
    Alamartine E, Phayphet M, Thibaudin D, Barral FG, Veyret C. Constrast medium-induced acute renal failure and cholesterol embolism after radiological procedures: incidence, risk factors, and compliance with recommendations. Eur. J. Intern. Med. 2003; 14: 42631.
  • 39
    Sterner G, Frennby B, Mansson S, Ohisson A, Prutz KG, Almen T. Assessing residual renal function and efficiency of hemodialysis: an application for urographic contrast media. Nephron 2000; 85: 32433.
  • 40
    Morcos SK, Thomsen HS, Webb JAW, Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR). Dialysis and contrast media. Eur. Radiol. 2002; 12: 302630.
  • 41
    Marenzi G, Marana I, Lauri G et al. The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N. Eng. J. Med. 2003; 349: 133340.