PA PSRS Patient Saf Advis 2007 Mar 30;(Suppl. 1):1-24.
Contrast-Induced Nephropathy: Can This Iatrogenic Complication of Iodinated Contrast be Prevented?

Introduction

Iodinated contrast material used in diagnostic imaging is associated with many types of adverse reactions, including the following: idiosyncratic/anaphylactoid, delayed, dose-dependent, extravasations, and renal failure.1-3 This article focuses on one of these complications—contrast-induced nephropathy (CIN). CIN is a potentially serious complication associated with the administration of iodinated contrast media in patients who are at risk for acute renal injury.4 In fact, in the United States and Europe, CIN is the third most common cause of hospital-acquired renal failure, accounting for approximately 10% to 12% of all such cases,1,5-10 after hypotension/decreased renal perfusion11 and major surgery.7 Moreover, hospital-acquired renal failure occurs in approximately 5% of hospital admissions.10 Since June 2004, at least 70 reports have been submitted to PA-PSRS that reflect the challenges of contrast media administration to renal function. (For more information, see the sidebar “What Do PA-PSRS Reports Tell Us?”). As a reference, refer to Figures 1 and 2, which depict the structure and function of the various components of the kidney.

Figure 1. Internal Structure of the Kidney   Figure 2. The Nephrons

Why the Recent Interest?

CIN has generated increasing interest over many years,5 not only because it is an important cause of hospital-acquired renal failure,12 but also because it is a significant clinical concern with long-term sequelae.10 In recent years, a large number of articles have suggested that CIN may be prevented or its severity reduced.5 Advances in medical imaging have produced a range of non-invasive diagnostic procedures that are used in severely ill patients13 The expanding scope of interventional radiology has increased the use of image-guided interventions as alternatives to open procedures for serious conditions.13 Concurrently, the growing older adult population (with its attendant comorbidities) is undergoing an increasing number of procedures utilizing contrast.5,12-14 The wider use of contrast media in seriously ill patients increases the number of clinical situations where patients may be at increased risk for CIN.13

Definition

Over the past 50 years, this complication has gone by many names: contrast nephropathy, contrast nephrotoxicity, contrast agent nephropathy, radiocontrast-induced nephropathy, and contrast media nephropathy.5 All these terms refer to the same entity, which will be referred to as contrast-induced nephropathy (CIN) in this article.

Clinical and experimental studies have used various laboratory parameters to define CIN.1,5 Today, CIN is most commonly defined when either of the following occur within 48 hours after contrast administration and persisting for two to five days:2,4,6,9,10,15,16

  • a 25% increase in serum creatinine (SCr) concentration from baseline value, OR 
  • an absolute increase in SCr of at least 0.5 mg/dL (44.2 µmol/L)

Diagnosis

CIN is usually nonoliguric, which means that it may not reduce urine production.8 Therefore, diagnosis most often depends on changes in SCr levels.11 CIN is usually characterized by a decrease in creatinine clearance immediately after iodinated contrast administration.5 A significant increase in SCr, as defined above, indicates impairment in renal function.12 In patients with pre-existing normal renal function, CIN is diagnosed when SCr levels peak within one to two days after contrast media administration with an increase over the baseline level lasting one to five days. However, in patients with pre-existing impaired renal function, the SCr peaks later, and the increase may last for 7 to 21 days.1,5,11,17

SCr is not necessarily an accurate reflection of true renal function because it is affected by a number of factors, such as the patient’s age, sex, and muscle mass.4,5,9 Moreover, a more than 50% reduction in the glomerular filtration rate (GFR) may occur before any elevation in SCr level because there is a nonlinear relationship between SCr and the GFR.12,18

Incidence

In the United States, the incidence of CIN is approximately 150,000 cases annually.19 The reported incidence of CIN varies markedly depending on the following:1,8,10,12,20

  • The definition used
  • The dose, type, and route of contrast media administered
  • Different patient risk factors
  • The extent and duration of patient follow up

Overall, incidence estimates of renal failure reported in the literature following contrast administration have ranged from 0.1% to 50%.1,6-8,10,15,20 Over the past decade, the general incidence of CIN has declined from about 15% to about 7%15 because of growing awareness of the problem, improved contrast media with less renal toxicity, and better risk prevention methods. However, many cases of CIN continue to occur because of increasing numbers of procedures performed that require contrast media.15

CIN occurs rarely in patients with pre-existing normal renal function.8,9 The incidence of CIN is 1% to 3% in non-diabetic patients with a baseline SCr of ≤1.1mg/dL.1,8,9,12 However, in patients with multiple risk factors, the incidence can rise dramatically.15 For example, 50% of patients with diabetic nephropathy and a mean SCr of 5.9mg/dL who receive iodinated contrast develop CIN.8,9 Incidence of renal failure may approach 100% in patients with multiple risk factors.20

Because SCr is not measured routinely and SCr may not accurately reflect renal function, cases of CIN may be overlooked. Therefore, the true magnitude of CIN may be underreported.15

In 2003, more than 80 million doses of iodinated intravascular contrast media were administered worldwide.14 This is one of the highest volumes of medical drugs used.17

Sequelae

Patients who develop CIN have more complications,15 a worse prognosis,5,15 more serious long-term outcomes,8,16 and prolonged hospital stays,8,9,11,15 which result in increased medical costs.9,11 In 2000, for those CIN patients not requiring dialysis, the estimated average hospital stay was prolonged by two days, resulting in additional costs of $148 million annually.19 For those patients requiring dialysis, hospital stays were prolonged an average of 27 days, costing approximately $32 million annually.19 Costs may be even higher in critically ill patients with multiple comorbidities.19

Less than 0.5% to 2% of patients who develop CIN require dialysis.1,8,9,15 However, those needing dialysis are more likely to experience serious long-term outcomes. For example, up to 30% of such patients may experience chronic renal impairment.1,15

CIN may also be associated with an increased risk of death that is independent of other risk factors.10,15 Hospital mortality rates in such patients have been reported as 36% and the two-year survival rate as only 19%.8,9,21  Levy et al. compared 181 inpatients who developed CIN with matched control patients who did not develop it; both groups underwent contrast-related procedures. 22 The mortality rate in the control group was 7%, compared to 34% in the CIN group. Another study reported an overall in-hospital mortality rate of 4.9% in patients with renal insufficiency from all causes. 23 Yet, if there was an increase in SCr greater than 3mg/dL, the mortality rate was 64%.

In addition, non-renal complications (e.g., sepsis, respiratory failure, bleeding, coma) may also follow CIN.10,12 In a study of 7,230 patients who underwent percutaneous coronary interventions, patients who developed CIN had more frequent myocardial infarctions, longer hospital stays, and higher one-year mortality rates than those without CIN.15,24 CIN patients are more likely to have target vessel revascularization after one year, bypass surgery, bleeding that requires transfusion, and other vascular complications.15 Patients who undergo a primary percutaneous cardiac intervention for acute myocardial infarction and develop CIN were reported to be significantly more likely to have major in-hospital complications such as acute pulmonary edema, the need for pacemakers, cardiogenic shock, and respiratory failure.15  Patients with renal insufficiency also are at greater risk of developing atherosclerosis.25 In fact, following a contrast procedure, an increase in SCr is a more powerful indicator of late mortality than an elevated creatine kinase-MB isoenzyme (i.e., an enzyme indicative of cardiac damage).15

Clinician Practice

Various studies indicate wide variations in knowledge and practice patterns related to screening and prevention of CIN.18,26 For example, more than half of non-radiology referring physicians from three university hospitals were not completely aware of all the risks associated with contrast media injection.27 In another study21 that involved 157 physicians, including radiologists, pediatricians, internists, surgeons, and primary care physicians, most were unfamiliar with risk reduction measures.

Pathophysiology

The pathophysiology of CIN is complex and not fully understood.16,20,28  A variety of factors may act together to promote acute renal failure.19

Little is also known about the cellular mechanisms involved in the development of CIN.6 Initially, the injection of iodinated contrast media increases osmotic load which produces vasodilation.1,17 A prolonged period of renal arterial vasoconstriction follows, leading to renal medullary ischemia.1,17 Intrinsic mechanisms appear to be two-fold: contrast media produces changes in renal hemodynamics as well as direct renal tubular toxicity.1,2,6,8,9,11,20,19,28

Risk Factors

In healthy patients with normal kidney function, the structural and functional changes produced by contrast media are usually of no consequence.12 However, patients with the following risk factors may develop CIN in response to intravascular administration of contrast media.12

Pre-Existing Impairment of Renal Function1-3,6,8-11,14,15,17,18,20,29

Pre-existing renal impairment is the most important risk factor and the most powerful predictor of CIN.8,9,17 The risk of CIN is directly proportional to the severity of the pre-existing renal insufficiency.3,12,17 This was evident in a study conducted by Rihal et al. of 7,586 patients who underwent translumenal coronary interventions at the Mayo Clinic, which yielded the following results:30

Baseline SCr

CIN Incidence

0-1.1mg/dL

2.4%

1.2-1.9mg/dL

2.5%

2.0-2.9mg/dL

22.4%

>3.0mg/dL

30.6%

Diabetes Mellitus (Type 1 and 2) Associated with Renal Insufficiency2,5,6,10-12,17,19,20,31

As many as 56% of diabetic patients who develop CIN also develop irreversible renal failure.2,10 Diabetes mellitus has a significant impact on the development of CIN in patients with mild to moderate renal insufficiency (<2.0mg/dL). While patients with diabetic nephropathy are at highest risk for CIN, diabetics with normal renal function and without vascular complications are at moderate risk.5 The risk of diabetics developing CIN increases with rising creatinine levels.19 Moreover, patients with both renal impairment and diabetes mellitus are at higher risk for CIN than patients who have pre-existing renal impairment alone.8

While diabetes mellitus may not be an independent risk factor,5,19,29 many authorities consider it a risk factor because combined with other comorbid conditions, it may be predictive of an abnormal SCr, and therefore CIN.1,8,10,12,15,18,19,29,31,32

Nephrotoxic Drugs

The risk of CIN may increase when patients take any of the following nephrotoxic drugs during the periprocedural period when iodinated contrast has been administered:

  • Antibiotics, including the following:
    • Aminoglycosides1-3,5,8-12,31
    • Vancomycin1,33
    • Amphotericin B1,34 
  • NSAIDs1,5,9,11,12,34
  • Chemotherapy agents/antineoplastics,
    including the following:1,35
    • Methotrexate1,34
    • Cisplatin3,5,9,10,34
    • Carboplatin34
    • Ifosfamide34
    • Azactidine34
    • Chloroethylnitrosourea compounds (carmustine, semustine,
      streptozocin)34
  • Acyclovir1,17
  • Immunosuppressants, including the following:
    • Cyclosporin1,35
    • Tacrolimus1
  • Dipyridamol20
  • ACE inhibitors1,10
  • Furosemide1,18 and other loop diuretics
  • Lithium18
  • Oral sodium phosphate bowel cleansing products36 (see the sidebar “Oral Phosphate Nephropathy and CIN”)

Moreover, when used concurrently with other drugs, contrast media is associated with adverse drug reactions and incompatibilities.1

Contrast Media

Osmolality. Renal toxicity has long been known to be associated with administration of high osmolar contrast media (HOCM).2 The incidence of CIN is lower when low osmolar contrast media (LOCM) are administered intra-arterially in patients with renal insufficiency and diabetics with impaired renal function.4,5,10,16,37 Recent studies document a lower incidence of CIN when iso-osmolar contrast media (IOCM), rather than LOCM, is used in high-risk patients with chronic kidney disease.1,3,10,12 Further study, however, is indicated to confirm the efficacy of IOCM in reducing CIN. (See the sidebar “Contrast Media Chemistry.”)

Volume/dose. The nephrotic effect of contrast media is dose-dependent. Ordinarily, the higher the dose, the higher the risk for CIN.1,3,5,6,8,9,11,12,29 While there is no definitive threshold limit of contrast volume established,1,8 contrast volumes greater than 100 to 200 mL are associated with a higher incidence of CIN in high-risk patients.4,6,9,11,37 Doses greater than 200mL or 300mgI/mL contrast are a potential risk factor in patients with a normal SCr.11

It is important to realize, however, that CIN requiring dialysis can occur in very high-risk patients who are given even a small amount of iodinated contrast (approximately 30mL).4,10,37 In high-risk patients, the risk of nephropathy increases 65% for each 5mL increment of contrast administered.10

Timing.The risk of CIN increases when high-risk patients receive multiple injections of contrast within a short period of time, such as within 72 hours.3,6,9,10-12

Route. Intra-arterial administration of contrast media poses a higher risk of CIN than intravenous administration.4,5,10,11,37

Intravascular Volume Depletion

Several conditions reduce effective intravascular volume, reduce renal perfusion, enhance the ischemic insult to the kidneys, and enhance the risk for CIN after contrast administration.8,10-12,20,29,31These conditions include periprocedural hypotension;5,8,31 acute pulmonary edema;31 nephrosis/nephrotic syndrome;3,8,10,15 congestive heart failure AHA Class IV, particularly with a reduced ejection fraction;1,3,5,6,10-12,18 liver cirrhosis;1,3,5,12 dehydration;1,3,5,12 coronary artery disease;18  and other abnormal fluid losses.10 Prolonged hypotension increases the risk of CIN, especially when caused by intensive antihypertensive treatment combined with angiotension-converting enzyme (ACE) inhibitors and diuretics (most notably furosemide).10

Multiple Myeloma

In patients with nephritic-range proteinuria secondary to multiple myeloma, high amounts of protein in tubular lumens combined with contrast material load may cause obstructive nephropathy.1,10,12,20 This mechanism is thought to promote the development of renal insufficiency. However, in the clinical setting, acute renal failure occurs rarely after contrast administration, unless dehydration exists.2,11,29 Without other risk factors, multiple myeloma is not likely to be associated with increased risk of CIN.10,17

Nonetheless, these patients are at increased risk of renal failure for reasons other than contrast administration, including hypercalcemia, volume depletion, hyperuricemia, amyloidosis, or light chain nephropathy.10 As a result, this condition is usually included as part of a risk assessment for CIN.10

Advanced Age1,5,6,9-11,15,18,20,29

Advanced age (i.e., older than 70 years of age) is associated with a reduction in renal mass, function, and perfusion, predisposing these older patients to renal sodium and water wasting.9 The risk for CIN increases with advanced age, especially when other risk factors are present.9

Conditions that May Damage the Kidneys

Sepsis causes direct damage to renal tubules by bacterial toxins and circulatory impairment.10 As a result of anemia, the number of red blood cells may be inadequate to carry enough oxygen to the kidneys, thus promoting hypoxia and renal cell damage.29,31 These conditions may enhance the risk of CIN.

Conditions that May be Indicators of Kidney Damage

All of the following have been reported as risks associated with CIN: a solitary kidney,35 debilitating conditions (e.g., HIV),35 hypoalbuninemia,31 albuminuria with creatinine ratio greater than 30,8 history of structural kidney disease or damage (e.g., polycystic kidneys),8 hypercholesteremia10 and cholesterol emboli syndrome,8 low serum sodium (<135mM),32 hyperuricemia/gout,1,3,10,12 and proteinuria.12

Procedures

Any association between CIN and specific procedures is most likely a reflection of the underlying medical conditions for which such procedures are required. For instance, severe atherosclerosis, intravascular volume depletion, or advanced, longstanding coronary artery disease may be underlying CIN risk factors in patients who require coronary angiography followed by bypass graft intervention,9,13 percutaneous coronary intervention,13 or intra-aortic balloon pump/intra-aortic counter pulsation.8 Similarly, cirrhosis may be the underlying risk factor of increased CIN risk associated with transarterial chemoembolization of the liver.13

Multiple Risk Factors

The incidence of CIN is greater when multiple risk factors are present in the same patient.3 Moreover, the effect of risk factors is additive, with the likelihood of CIN, as well as the need for dialysis, rising sharply as the number of risk factors in the same patient increases, 31, 38 as evidence by the following study:32

Number of Risk Factors

Percentage of Patients
Developing CIN

None

1.2%

1

11.2%

2 or more

>20%

A Word about Metformin

While this drug is not a risk factor for CIN,39 severe, and even fatal, lactic acidosis can develop as a complication of metformin treatment in the presence of acute renal failure.2,3 Therefore, metabolic acidosis can result if renal function declines after contrast administration.39 There is no conclusive evidence of contrast-precipitated, metformin-induced lactic acidosis in patients with a baseline SCr of less than 1.5 mg/dL or 130µmol/L.8 However, this complication has almost always been observed in non-insulin dependent diabetics who had impaired renal function prior to contrast injection.8

Risk Reduction Strategies

In 2006 alone, more than 130 articles were published concerning CIN, its risk factors, and prevention. The CIN Consensus Working Panel—an international multidisciplinary group of radiologists, cardiologists, and nephrologists practicing in Europe and the United States—completed a review of 865 references relevant to CIN.1 There is currently no treatment to reverse or ameliorate CIN once it occurs.17,19,39 To date, there also is no single therapeutic intervention that has been conclusively proven effective to prevent CIN. However, some strategies, such as the following, may reduce the incidence of CIN.12,29

Risk Identification

The first step is to identify those people who are at risk for developing CIN.1,16,18 This can be accomplished with laboratory testing and history-taking/questionnaires before contrast exposure.10,40 Interventions will vary according to the extent of the patient’s risk for developing CIN.

Laboratory tests. The National Kidney Foundation’s Kidney Disease Outcome Quality Initiative and the CIN Consensus Working Panel support the use of an estimated glomerular filtration rate (eGFR)—a calculation that incorporates the SCr into a more accurate indication of renal function, rather than using the SCr alone.12,18 (See the sidebar “Calculating Estimated Glomular Filtration Rate.”) 

Persons at increased risk for CIN have the following baseline renal function results prior to contrast administration:31

An eGFR <60mL/min/1.73m2

            OR

Males with a SCr of 1.3mg/dL (114 µmol/L)

Females with a SCr of 1.0mg/dL (88.4µmol/L)

If eGFR is used, the risk can be stratified further, as indicated in the following:

Risk

eGFR (mL/min/1.73m2)

Low

≥60

Moderate

30-59

High

<30

See Appendix A for a visual representation of this stratification.

It has also been suggested that one can roughly estimate the percentage of risk for CIN by multiplying the patient’s SCr in mg/dL by 10.17

Screening Questionnaires

History-taking, using standardized questionnaires, can promote consistency in obtaining information prior to a contrast-related procedure and differentiate patients with CIN risk factors from the general population who are not at risk.4,18 The European Society of Urogenital Radiology (ESUR) and the CIN Consensus Working Panel both support the use of such questionnaires.4

Choyke et al. used a questionnaire and performed SCrs before computed tomography (CT) scans in 673 patients.41 The questionnaire identified patients at CIN risk, as verified by elevated creatinine levels, as well as those without risk, as verified by normal creatinine levels. The authors determined that identifying low-risk patients using a preprocedure questionnaire reduced the need for preprocedure SCr testing by 67%. However, laboratory testing was preferable when feasible.

Another study successfully identified patients at risk by using a questionnaire that included the following CIN risk factors identified in a multivariate analysis:31 

  • Chronic kidney disease (state III or greater; eGFR of <60mL/min/1.73m2)
  • Diabetes mellitus (type 1 or 2)
  • Volume depletion
  • Nephrotoxic drug use
  • Preprocedural hemodynamic instability
  • Anemia
  • Congestive heart failure
  • Hypoalbuminemia

Cochran et al. also utilized a logistic regression analysis to determine the following five factors that could predict a high probability of CIN: 42

  1. Age (i.e., older than 55 years) 
  2. Proteinuria
  3. Abnormal baseline SCr 
  4. Planned use of HOCM 
  5. Pre-existing renal disease 

In this study, the probability of developing CIN increased markedly with the number of risk factors present. For example, two risk factors were associated with <5% probability of developing CIN, while the presence of three risk factors increased the likelihood of CIN to over 30%.

ESUR43 states that obtaining information about the following five factors will identify those at risk for CIN:

  1. Elevated SCr levels (particularly secondary to diabetes mellitus)
  2. Dehydration
  3. Congestive heart failure
  4. Age (i.e., older than 70 years)
  5. Concurrent nephrotoxic drugs

The American College of Radiology44 advises obtaining a SCr measurement prior to intravascular administration of contrast in persons with the following risk factors:

  • Drugs/medications
    • Regular use of nephrotoxic antibiotics
    • NSAIDs
    • Metformin or metformin-containing drug combinations
  • Diseases
    • Collagen vascular disease
    • Paraproteinemia syndromes or diseases (such as multiple myeloma)
    • Diabetes mellitus—insulin-dependent and non-insulin-dependent treated with hypoglycemic agent
  •  History
    • Kidney disease (including transplant or tumor)
    • Family history of kidney failure

Risk Scoring

Risk scoring schemes have been developed in an effort to predict CIN risk. While they may potentially be useful in clinical practice, further study is needed to prospectively validate such scoring mechanisms in different populations.31

One risk scoring mechanism has been used to predict the risk of CIN after percutaneous coronary intervention.29 The score is based on eight available patient-related and procedure-related characteristics:29

Characteristics

Score

Patient-related

 

>75 years

4

Diabetes mellitus

3

Chronic congestive heart failure or admission with acute pulmonary edema

5

Hypotension

5

Anemia

3

Chronic kidney disease

 

SCr >1.5mg/dL
OR
eGFR <60mL/min/1.73m2

5

Procedure-related

 

Use of intra-aortic
balloon pump

5

Contrast media volume

1 for each 100c3

The scores are added together. The higher the score, the greater the risk for CIN.

Risk Score

CIN Risk

Dialysis Risk

≤5

7.5%

0.04%

6-10

14.0%

0.12%

11-16

26.1%

1.09%

≥16

57.3%

12.6%

  

A standard protocol to assess CIN risk can be developed, similar to the safety checklists/questionnaires used in magnetic resonance imaging (MRI) departments.10 This standard assessment can be completed and communicated by the ordering clinician, prior to the patient’s arrival to the MRI department, so that if risk factors are present, the patient can receive appropriate preventive measures to reduce the risk of CIN.

Risk-Benefit Analysis

After a full risk assessment, a risk-benefit analysis will determine whether a contrast-related study is essential, especially in high-risk patients.10 For example, in emergency situations, a contrast-related procedure may be appropriate if the benefit of early imaging outweighs the risk of waiting, even if risk factors, the SCr, or the eGFR are unknown or unavailable.4

Alternatives

For high-risk patients, clinicians can consider alternative diagnostic procedures that do not require the use of iodinated contrast media, such as sonography, MRI, or CT without contrast.10,11,17,45 For cardiac patients, there is the alternative of CO2 angiography.20 Gadolinium-based contrast media have previously been considered a safe alternative for high-risk patients, but recent clinical reports raise concern about renal tolerance of these agents12 (see the sidebar “Renal Disease and Gadolinium-Based Agents.”)

Optimize Renal Function

If feasible, when an iodinated contrast media procedure is necessary in a high-risk patient, delaying the procedure to medically optimize the patient’s renal function prior to the procedure may reduce the risk of CIN.11,40 Such optimization would be reflected in a decline in SCr and/or increase in eGFR.

To retain as much renal function as possible, diabetic patients who are candidates for renal transplants can have their pre-transplant angiography postponed until the patient is accepted for transplantation and on dialysis.11

Hydration

Both observational and clinical trials have documented the value of hydration supplementation to reduce the risk of CIN.46 It is the most widely accepted preventive strategy1,3-8,10-12,16,17,19,45 and is inexpensive and safe. Such supplementation can be considered in all patients receiving intravenous or intra-arterial contrast media, but it is particularly important for patients with pre-existing CIN risk factors.46

Intravenous infusion of isotonic crystalloid is effective. Normal saline (0.9% sodium chloride) is generally administered at 1 to 1.5mL/kg/hour for 3 to 12 hours before and for 6 to 24 hours after the contrast-related procedure.2,4,10,39,46 Normal saline (0.9%) appears to be more effective than half-normal
saline (0.45%).5,6,12,16,20,47

Some studies have shown that infusion of isotonic sodium bicarbonate solution at 3ml/kg/hour for one hour before the procedure and three to six hours after contrast administration has been more effective than saline in reducing the incidence of CIN.48  Alkalyzing renal tubular fluid with bicarbonate is postulated to reduce free radical formation, thereby reducing renal injury.46  Larger, multicenter studies need to be performed to determine its true efficacy.17

Insufficient data exist concerning the effectiveness of oral fluids as a prevention strategy.5,39 It is suggested that before a contrast-related procedure, replacing the routine order for NPO status after midnight with an order allowing clear liquids up to two hours before the procedure and forcing fluids after the procedure, might enhance hydrated status.10

If the patient has uncompensated congestive heart failure, the clinician can consider right heart catheterization for hemodynamic monitoring so that the infusion rate can be adjusted appropriately to reduce the risk of volume overload.39

Avoid Nephrotoxic Drugs

Another effective prevention strategy involves discontinuing nephrotoxic drugs during the periprocedural period when iodinated contrast media must be used.2,3,8,11,12,16,17,39 Such drugs are usually withdrawn 24 hours or more before contrast administration in high-risk patients, when medically feasible.8,10,20,39,45

If concomitant nephrotoxic drugs are used, monitoring kidney function with glomerular filtration rate measurements (e.g., the level of a cysteine proteinase inhibitor, cystatin C, produced by nucleated cells) may be more effective in detecting acute renal failure than monitoring creatinine levels, especially in the elderly.46

Contrast

Osmolality. If the iodinated contrast-related procedure is medically essential, the use of LOCM or IOCM may reduce the likelihood of CIN in high-risk patients.1,4,8,10-12,16,17,19 The American College of Radiology advises that patients with renal insufficiency (particularly diabetics) are likely to benefit from use of LOCM.49 IOCM may be less nephrotoxic than LOCM, but it is more expensive.6,16,20 Further study is necessary concerning whether IOCM is beneficial compared to LOCM. It is likely that IOCM are less nephrotoxic compared to some LOCM, but with other LOCM, IOCM do not offer any advantage. While lower osmolality agents are less nephrotoxic, they can still cause CIN, especially in high-risk patients.12,29

Volume/dose. Using the lowest volume/dose of iodinated contrast will reduce the risk of CIN.1-3,8,10-12,19,20,45 While there is disagreement about the threshold for a safe contrast volume limit, limiting the volume to less than 100mL in high-risk patients has been suggested.8

Cigarroa et al. developed this formula to limit the volume of iodinated contrast in high-risk patients undergoing coronary angiography: 5mL of contrast media per kg of body weight up to a maximum of 300mL divided by SCr in mg/dL. 50 In this study, 21% of the patients who received a contrast volume that exceeded the formula developed CIN, while only 2% of the patients who received contrast within the formula’s volume limit developed CIN (p<0.001).12,50 If LOCM is administered, the volume limit of this formula can be increased by a factor of 1.5.12

Timing/staging. If multiple contrast-related studies are necessary, allotting time (5 to 14 days) between studies allows the kidneys to recover from the insult of contrast media injection.3,10,11,17,37 If CIN occurs with the first contrast exposure, it may be necessary to wait even longer before the next contrast administration, until laboratory testing confirms adequate renal function.3,37

Route. Intra-arterial injection of contrast media is associated with higher risk of CIN than intravenous administration.11 Intravenous administration is preferred, except in patients with congestive heart failure.11

Premedication Regimens

Over time, many drug interventions have been studied in an effort to prevent CIN, based on one or more of the pathogenic mechanisms believed to be involved in CIN.10 The focus has primarily been on attempts to improve renal blood flow or to block mediators implicated in the development of CIN.11 For the most part, however, these drugs have either had no effect or were detrimental to renal function. The few drugs that have evidenced positive results have also yielded conflicting findings in subsequent studies.1 (See the sidebar “Efficacy of Premedication Regimens.”) To date, no pharmacologic agent has had consistently positive results in preventing CIN.8,10 The following drugs are discussed in detail because studies—in some cases systematic reviews or meta-analyses—have yielded positive findings, and some may judge their effectiveness adequately demonstrated.

N-acetylcysteine (NAC). NAC is an antioxidant and a scavenger of free radicals. It also enhances the biologic effect of the endogenous vasodilator, nitric oxide, which maintains kidney perfusion.  Several meta-analyses of study results from randomized controlled trials indicate that NAC is effective in preventing CIN,1,6,8,11 but studies continue to provide conflicting results.5,10,12,16,17,39

NAC is widely used as a prophylactic intervention against CIN in several countries as a result of the work of Tepel et al. in which the incidence of CIN was reduced considerably with oral use of NAC in patients with chronic renal insufficiency following CT.51 NAC is used prophylactically in high-risk patients, but is not as a routine in contrast-related examinations.11

It is inexpensive, has a low incidence of adverse effects, and is generally available and easy to administer.19,52 It is not, however, a substitute for close monitoring of renal function and adequate hydration.32 NAC, combined with hydration and LOCM or IOCM, may be of value in high-risk patients.9,52

NAC doses range from 600mg to 1200mg orally twice daily on the day before and day of contrast administration for high-risk patients.8,9,20,52  (Use of intravenous NAC poses a risk of anaphylactoid reactions.53)

In a recent randomized placebo controlled trial of 180 patients undergoing percutaneous coronary interventions, those receiving oral NAC had a significant reduction in the incidence of CIN.6 However, there was no influence on the long term clinical events associated with CIN, such as myocardial infarction and mortality. Because NAC did not affect long term clinical outcomes, the prophylactic use of NAC for CIN prophylaxis remains in doubt.

Ascorbic acid. Ascorbic acid, an antioxidant, is widely available and well tolerated.6   A randomized, double-blind, placebo-controlled trial of 231 patients undergoing cardiac catheterization studied the prophylactic effectiveness of oral ascorbic acid (3g before and 2g after the procedure).54 The incidence of CIN was 20% in the placebo group and 9% in the ascorbic acid group. Further study is necessary, however, to clarify and confirm ascorbic acid’s effectiveness in reducing CIN related to this and other procedures.

Prostaglandin E1 (PGE1). Prostaglandins are vasodilators. Preliminary studies have been conducted using PGE1. One pilot study using intravenous PGE1 evaluated the effect of three doses on high-risk patients undergoing coronary and peripheral angiography. The increase in SCr was less in each PGE1 group compared to the placebo group, but no clinically relevant changes occurred in the calculated creatinine clearance.6,55 In another study, infusion of PGE1 started 30 to 60 minutes before contrast injection significantly diminished the SCr increase at 48 hours post radiographic examination.

Theophylline.Theophylline, an adenosine antagonist, has been evaluated in the prevention of CIN to determine its effectiveness in counteracting the action of adenosine.  Adenosine is an intrarenal vasoconstrictor, which mediates the tubuloglomerular feedback mechanism. A meta-analysis of several trials indicated that theophylline or aminophylline significantly reduced the risk of CIN after contrast administration.52,56 In several other placebo-controlled studies, theophylline prevented contrast-induced declines in creatinine clearance, but the subjects were low risk and the data were mixed.17 Therefore, further studies are needed to validate this drug’s effectiveness.

If prophylactic use of theophylline is considered for patients at high risk for CIN, any potential benefits must be balanced in light of the potential for serious adverse effects (e.g., gastrointestinal, cardiovascular, neurological) and its narrow therapeutic index.5,39 When iodinated contrast is required, it may be appropriate for critically ill patients with reactive lung disease to continue receiving previously prescribed theophylline.6 It has also been given prior to contrast administration in emergency situations or when adequate prehydration has not been possible.20

Statins. Statins maintain nitric oxide production, reduce oxidative stress, and beneficially affect endothelial function.57 In one retrospective study of more than 1,000 patients with renal impairment undergoing coronary angiography, the risk of CIN was significantly decreased in patients receiving a statin before the procedure.58 Another study of more than 29,000 patient records in a percutaneous cardiac intervention registry revealed that patients who received statins before the procedure had both a lower CIN incidence (p<0.0001) and nephropathy requiring dialysis (p<0.03).59  While these studies are promising, further study is necessary to determine whether statin use is appropriate for other procedures and for imaging patients in which statins are not otherwise medically indicated.39,40 Moreover, there have been rare reports of rhabdomyolysis leading to renal failure, as well as exacerbated myotoxicity in patients with chronic renal failure who were taking statins.33

Combination of antioxidant compounds. To determine whether a combination of different antioxidant compounds might provide an additive benefit in preventing CIN, Briguori et al.60 conducted a randomized, prospective, double-blind study. The trial involved 326 patients with chronic kidney disease who were at moderate to high risk for CIN. These patients received iso-osmolar contrast media during coronary or peripheral procedures, and they were randomly assigned to one of three treatment regimens:

  • 0.9% saline infusion plus NAC,
  • Sodium bicarbonate infusion plus NAC, or
  • 0.9% saline plus ascorbic acid plus NAC

The rate of CIN was significantly lower in the bicarbonate plus NAC group. Further study is needed to determine whether the results of this study can be reproduced in high risk and very high-risk patients.

Hemodialysis/hemofiltration. Patients with severe renal impairment prior to contrast-related procedures may develop non-oliguric or oliguric acute renal failure requiring dialysis.11 While two to three hours of hemodialysis removes from 60% to 90% of the contrast medium,61 many studies indicate that hemodialysis provides no prophylactic value in reducing either the incidence of CIN6,11,12,16,39,45 or its long-term outcomes.5,61 Hemodialysis may even worsen renal injury by promoting hypovolemia or activating inflammatory reactions, thus releasing vasoactive substances that may promote acute hypotension.8,12,45

Most end-stage renal disease patients on chronic hemodialysis who undergo a contrast-related procedure can safely wait 24 to 36 hours after contrast exposure for their next hemodialysis treatment.17,44 However, hemodialysis patients with some residual renal function may develop permanent loss of this function and increased dialysis requirements following radiocontrast exposure. Therefore, alternative imaging studies not requiring iodinated contrast media would more likely protect such patients’ remaining renal function.44

On the other hand, hemofiltration for several hours before and after contrast injection has been proposed to  significantly reduce the risk of CIN.12,16,17,62 Hemofiltration provides a continuous form of renal replacement therapy, in which large volumes of intravenous isotonic replacement fluid exactly match the rate of ultra-infiltrate production. Therefore, there is no net fluid loss in the patient, and no overload occurs.6,8,45

However, routine use of hemofiltration to prevent CIN is not indicated at this time, primarily because of methodologic flaws in study design calling into question the value of hemofiltration.19 In addition, it is costly and can only be provided in intensive care settings.6,17,39 To improve long-term survival, though,  some believe that prophylactic hemofiltration may be beneficial and cost-effective for patients with severe cardiac and renal dysfunction who are undergoing cardiac catheterization if the baseline SCr is >4mg/dL.6,19,20

Metformin

If the patient’s baseline renal function is normal, metformin-containing medications can be discontinued the day of the study and restarted no less than 48 hours after contrast administration, once the patient’s renal function has returned to baseline.2,8,20,29,39

If the patient’s baseline renal function is abnormal, the drug is stopped either the day of or up to 48 hours before the study and restarted no earlier than 48 hours after the contrast is administered, if renal function is unchanged.39

Following the Procedure

Many physicians check high-risk patients (eGFR <60mL/min/1.73m2) for diuresis and obtain follow-up SCr 24 to 48 hours after contrast exposure.11,63  Usually, people who develop severe CIN experience an increase in SCr within the first 24 to 48 hours after contrast administration.8 This measurement is compared with the baseline level obtained before volume expansion began prior to contrast administration. A relative increase in SCr of ≥25% or a rise in the serum creatinine of >0.5 mg% identifies patients with CIN.63 Using an absolute change in SCr does not accurately reflect patient outcomes.63

If CIN occurs, monitoring renal function (usually daily SCr levels) occurs until it returns to baseline levels.63 While the SCr is elevated, avoid further insults to the kidneys, such as further contrast studies, nephrotoxic drugs, and elective surgery with general anesthesia.63 During this time, drugs that alter GFR can be avoided, such as ACE inhibitors, and angiotensin receptor blockers, and diuretics.63 Moreover, drugs excreted by glomular filtration can be held, if possible.

Because patients who develop CIN should be considered at high-risk for cardiovascular events, efforts can be intensified to control blood pressure, dyslipidemia, and glycemia.63 Aggressive treatment of other conditions that placed patients at risk for CIN may also be beneficial.63

Algorithm

Institutions can benefit from developing pathways or algorithms to identify patients with risk factors for CIN and standardize guidelines for prophylactic approaches to contrast-related procedures for high-risk patients.4,8,9,64-67

The algorithm that follows this article (see Appendix B) is a modification of the one developed by the CIN Consensus Working Panel.4

Conclusion

CIN cannot be viewed as a treatable or acceptable complication of iodinated contrast-related procedures, because it is associated with serious short-term and long-term consequences.5,68 Yet, fear of renal failure should not dictate avoidance of diagnostic studies using iodinated contrast.10,44 As in all clinical situations, the decision to administer iodinated contrast is based upon clinical judgment about the clinical status of the patient, knowledge of the risks and effective prophylactic measures, and the expected benefits of the procedure.13

Notes

  1. Costa N. Understanding contrast media. J Infus Nurs 2004 Sep/Oct;27(5):302-12.
  2. Maddox TG. Adverse reactions to contrast material: recognition, prevention, and treatment. Am Fam Phys 2002 Oct 1;66(7):1229-34.
  3. Cohan RH, Ellis JH. Iodinated contrast material in uroradiology. Urol Clin North Am 1997 Aug;24(3):241-91.
  4. McCullough PA, Stacul F, Davidson C, et al. Overview. Contrast-induced nephropathy: clinical insights and practical guidance. A report from the CIN consensus working panel. Am J Cardiol 2006 Sep 18;98(6A):2K-4K.
  5. Bettmann MA. Contrast medium-induced nephropathy: critical review of the existing clinical evidence. Nephrol Dial Transplant 2005 Feb;20[Suppl1]:i2-i17.
  6. Itoh Y, Yano T, Sendo T, et al. Clinical and experimental evidence for prevention of acute renal failure induced by radiographic contrast media. J Pharmacol Sci 2005 Apr;97(4):473-88.
  7. Hou SH, Bushinsky DA, Wish JB, et al. Hospital-acquired renal insufficiency: a prospective study.  Am J Med 1983 Feb;74(2):
    243-48.
  8. McCullough PA, Soman SS. Contrast-induced nephropathy. Crit Care Clin 2005 Apr;21(2):261-80.
  9. Maeder M, Klein M, Fehr T, et al. Contrast nephropathy: review focusing on prevention. J Am Coll Cardiol 2004 Nov 9;44(9):
    1763-71.
  10. Gleeson TG, Bulugahapitiya S. Contrast-induced nephropathy. Am J Roentgenol 2004 Dec;183(6):1673-1689.
  11. Andrew E, Berg KJ. Nephrotoxic effects of x-ray contrast media. J Toxicol Clin Toxicol 2004;42(3):325-32.
  12. Morcos SK. Prevention of contrast media-induced nephrotoxicity after angiographic procedures. J Vasc Interv Radiol 2005 Jan;16(1):13-23.
  13. Becker CR, Davidson C, Lameire N, et al. High-risk situations and procedures. Am J Cardiol 2006 Sep 18;98(6A):37K-41K.
  14. Katzberg RW, Haller C. Contrast-induced nephrotoxicity: clinical landscape. Kidney Int Suppl 2006 Apr;69:S3-S7.
  15. McCullough PA, Adam A, Becker CR, et al. Epidemiology and pragmatic implications of contrast-induced nephropathy. Am J Cardiol 2006 Sep 18;98(6A):5K-13K.
  16. Aspelin P. Nephrotoxicity and the role of contrast media. Radiat Med 2004 Nov-Dec;22(6):377-8.
  17. Rudnick MR, Kesselheim A, Goldfarb S. Contrast-induced nephropathy: how it develops, how to prevent it. Cleve Clin J Med 2006 Jan;73(1):75-87.
  18. Lamiere N, Adam A, Becker C, et al. Baseline renal function screening. Am J Cardiol 2006 Sep 18;98(6A):21K-26K.
  19. Asif A, Epstein M. Prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 2004 Jul;44(1):12-24.
  20. Oudemans-Van Straaten HM. Contrast nephropathy, pathophysiology and prevention. Int J Artif Organs 2004 Dec;27(12):1054-65.
  21. Confino-Cohen R, Goldberg A. Safe administration of contrast media: what do physicians know? Ann Allergy Asthma Immunol 2004 Aug;93(2):166-70.
  22. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality: a cohort analysis. JAMA 1996 May 15;257(19):1489-94.
  23. Taliercio CP, Vlietstra RE, Fisher LD, et al. Risks of renal dysfunction with cardiac angiography. Ann Intern Med 1986 Apr;104(4):501-4.
  24. Dangas G, Iakovou I, Nikolsky E, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005 Jan 1;95(1):13-9.
  25. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal failure. Am J Kidney Dis 1998 Nov;32(5 Suppl 3):S112-9.
  26. Elicker BM, Cypel YS, Weinreb JC. IV contrast administration for CT: a survey of practices for the screening and prevention of contrast nephropathy. Am J Roentgenol 2006 Jun;186(6):1651-8.
  27. Konen E, Konen O, Katz M, et al. Are referring clinicians aware of patients at risk from intravenous injection of iodinated contrast media? Clin Radiol 2002 Feb;57(2):132-5.
  28. Tumlin J, Stacul F, Adam A, et al. Pathophysiology of contrast-induced nephropathy. Am J Cardiol 2006 Sep 18;98(6A):14K-20K.
  29. Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy. J Am Coll Cardiol 2004 Oct 6;44(7):1393-9.
  30. Rihal CS, Textor SC, Grill DE. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002 May 14;105(19):2259-64.
  31. McCullough PA, Adam A, Becker C. Risk prediction of contrast-induced nephropathy. Am J Cardiol 2006 Sep 18;98(6A):27K-41K.
  32. Rich MW, Crecelius CA. Incidence, risk factors, and clinical course of acute renal insufficiency after cardiac catheterization in patients 70 years of age or older. A prospective study. Arch Intern Med 1990 Jun;150 (6):1237-1242.
  33. Deray G. Dialysis and iodinated contrast media. Kidney Int Suppl 2006 Apr;69:S25-S29.
  34. University of California San Francisco. Guidelines on the administration of intravenous iodinated contrast media prior to CT [online]. 2003 [cited 2007 Jan 22]. Available from Internet: http://www.radiology.ucsf.edu/instruction/abdominal/ab_handbook/03-Contrast_guidelines.html.
  35. Tippins RB, Torres WE, Baumgartner BR, et al. Are screening serum creatinine levels necessary prior to outpatient CT examinations? Radiology 2000 Aug;216(2):481-4.
  36. U.S. Food and Drug Administration Center for Drug Evaluation and Research. Food and drug administration science background paper: acute phosphate nephropathy and renal failure associated with the use of oral sodium phosphate bowel cleansing products [online]. 2006 May 5 [cited 2006 Dec 15]. Available from Internet: http://www.fda.gov/cder/drug/infopage/OSP_|solution/backgrounder.htm.
  37. Davidson C, Stacul F, McCullough PA, et al. Contrast medium use. Am J Cardiol 2006 Sep 18;98(6A):42K-58K.
  38. Mueller C. Prevention of contrast-induced nephropathy with volume supplementation. Kidney Int Suppl 2006 Apr;69:S16-S19.
  39. Stocul F, Adam A, Becker CR, et al. Strategies to reduce the risk of contrast-induced nephropathy. The American Journal of Cardiology 2006 Sep 18;98(6a)59K-77K.
  40. Bagshaw SM, Culleton BF. Contrast-induced nephropathy: epidemiology and prevention. Minerva Cardioangiol. 2006 Feb;
    54(1):109-129.
  41. Choyke PL, Cady J, DePollar SL, et al. Determination of serum creatinine prior to iodinated contrast media: is it necessary in all patients? Tech Urol 1998 Jun;4(2):65-9.
  42. Cochran ST, Wong WS, Roe DJ. Predicting angiography-induced acute renal function impairment. A clinical risk model. Am J Roentgenol 1983 Nov;141(5):1027-33.
  43. Morcos SK, Thomsen HS, Webb JA. Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Contrast media-induced nephrotoxicity: a consensus report. Eur Radiol 1999;9(8):1602-13.
  44. American College of Radiology. Manual on contrast media version 5.0 [online]. 2006 Oct 26 [cited 2007 Jan 22]. Available from Internet: http://www.acr.org.
  45. Thomsen HS. How to avoid CIN: guidelines from the European Society of Urogenital Radiology. Nephrol Dial Transplant 2005 Feb;20[Suppl 1]:i18-i22.
  46. Erley C. Concomitant drugs with exposure to contrast media. Kidney Int Suppl 2006 Apr;69:S20-S24.
  47. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy. Randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 2002 Feb 11;162(3):329-36.
  48. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004 May 19;291(19):2328-34.
  49. American College of Radiology. ACR practice guideline for the use of intravascular contrast media [online]. 2006 Oct 1 [cited 2007 Jan 22]. Available from Internet: http://www.acr.org.
  50. Cigarroa RG, Lange RA, Williams RH, et al. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. Am J Med 1989 Jun;86(6 pt 1):649-52.
  51. Tepel M, van der Giet M, Schwartzfeld C, et al. Prevention of radiographic contrast agent-induced reductions in renal function by acetylcystein. N Engl J Med 2000 Jul 20;343 (3):180-4.
  52. Briguori C, Marenzi G. Contrast-induced nephropathy: pharmacologic prophylaxis. Kidney Int Suppl 2006;69:S30-S38.
  53. PDRhealth. Acetylcysteine. [Web site].[cited 2007 Feb 28]. Thomson Healthcare. Available from Internet: http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/ace_0178.shtml.
  54. Spargias K, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation 2004 Nov 2;110(18):2837-42.
  55. Koch JA, Plum J, Grabensee B, et al. Prostaglandid E1: a new agent for the prevention of renal dysfunction in high risk patients caused by rediocontrast media? Nephrol Dial Transplant 2000 Jan;15(1):43-9.
  56. Ix JH, McCulloch CE. Chertow GM. Theophylline for the prevention of radiocontrast nephropathy: a meta-analysis. Nephrol Dial Transplant 2004 Nov;19(11):2747-53.
  57. Wolfrum S, Jensen KS, Liao JK. Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol 2003 May 1;23(5):729-36.
  58. Attallah N, Yassine L, Musial J, et al. The potential role of statins in contrast nephropathy. Clin Nephrol 2004 Oct;62(4):
    273-278.
  59. Khanal S, Attallah N, Smith DE, et al. Statin therapy reduces contrast-induced nephropathy: an analysis of contemporary percutaneous interventions. Am J Med 2005 Aug;118(8):843-9.
  60. Briguori C, Airoldi F, D’Andrea D, et al. Renal insufficiency following contrast media administration trial (REMEDIAL). A Randomized comparison of 3 preventive strategies. Circulation 2007 Feb 19 [cited 2007 Feb 27]. Available from Internet: http://www.circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.106.687152v1.
  61. Sterner G, Frennby B, Kurkus J, et al. Does post-angiographic dialysis reduce the risk of contrast medium nephropathy? Scand J Urol Nephrol 2000 Oct;34(5):323-6.
  62. Marenzi G, Marana I, Lauri G, et al. The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N Eng J Med 2003 Oct;349(14):1333-40.
  63. Solomon R, Barrett B. Follow-up of patients with contrast-induced nephropathy. Kidney Int Suppl 2006;69:S46-S50.
  64. Di Francesco L, Williams MV. Prevention of Contrast-induced nephropathy. Chapter 32. In: Markowitz AJ (ed). Making Health Care Safer: a Critical Analysis of Patient Safety Practices. Agency for healthcare Research and Quality (AHRQ). Evidence Report/Technology Assessment Number 43. AHRQ Publication 01-E058. Plymouth Meeting (PA): AHRQ; 2001 Jul 20:349-357. 25[22]. 25[23].
  65. Thomsen HS, Morcos SK; Members of the Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). In which patients should serum creatinine be measured before iodinated contrast medium administration? Eur Radiol 2005 Apr;15 (4):749-54.
  66. Lameire N. Contrast-induced nephropathy-prevention and risk reduction. Nephrol Dial Transplant 2006 Jun;21(6):i11-i23.
  67. Pannu N, Wiebe N, Tonelli M. Prophylaxis strategies for contrast-induced nephropathy. JAMA 2006 Jun 21;295(23):2765-75.
  68. Finn WF. The clinical and renal consequences of contrast-induced nephropathy. Nephrol Dial Transplant 2006 Jan;21(6):i2-i10. 

 Supplemental Material

What Do PA-PSRS Reports Tell Us?

Since the inception of PA-PSRS in June 2004, at least 70 reports have been submitted concerning occurrences that reflect system/process issues related to renal function and contrast media. About 10% of the reports are categorized as Serious Events, compared to 4% of submitted PA-PSRS reports overall. Five percent of the reports indicated that the patient required dialysis after a contrast-related procedure. Some of the patterns and examples include: 

Good News 
Imaging Study was Cancelled because of Elevated Creatinine

A physician ordered a contrast-related study. No creatinine level was charted. A creatinine was drawn, and the result was 6.0. The procedure was cancelled. 

Contrast Study was Delayed Until Creatinine Results were Available

A CT of the chest was ordered with contrast pending normal BUN [blood urea nitrogen] and Creatinine results. The study was delayed one hour until the laboratory results were received and reviewed. 

Opportunities for Improvement 
Creatinine Level was Not Checked Prior to Study

A patient’s creatinine ranged from 3.1 to 5.0 after undergoing repair of an abdominal aortic aneurysm. The attending physician ordered an abdominal/pelvic CT, without contrast, to rule out colitis. The radiologist ordered to follow the radiology protocol to rule out colitis using contrast if the creatinine was normal. IV contrast was administered without checking the creatinine. The patient became anuric, and the creatinine was increased to 5.5. The patient was placed on continuous venovenous hemodialysis filtration. 

Wrong Laboratory Results were Checked Prior to Study

A CT scan of the abdomen and pelvis with contrast was ordered on a patient with a history of compromised renal function. The technician referred to the previous day’s creatinine results (1.5), rather than the most current creatinine (2.5). IV contrast was administered. 

A Contrast-Related Study was Performed in a Patient with CIN Risk Factors

The patient underwent a CT scan of the abdomen following a femoral popliteal bypass surgery, to rule out peritoneal bleed. The patient had a history of chronic renal insufficiency, and the creatinine was 3.4 prior to the imaging pro-cedure. After the procedure, the patient’s creatinine level increased, and dialysis was required.

Order Entry Error

The physician ordered a CT scan without contrast, but the nursing unit entered the study with contrast. The radiology technician injected the IV contrast without checking the creatinine. The creatinine was 1.9. Post procedure, the patient received hydration and Mucomyst. A patient on metformin had a CT scan with contrast. Medical imaging department placed an order sheet on the patient’s chart indicating to discontinue metformin and to repeat the creatinine level in 48 hours. The orders were not placed in the computer system. The patient received metformin the day of the procedure and the following two days. 

Contrast Administered Despite Order for Study without Contrast

A CT of the abdomen was ordered without contrast. The technician gave IV contrast and completed the CT without checking creatinine results with ER or in the computer. The creatinine was 1.7. 

Multiple Contrast-Related Studies

A patient underwent an abdominal CT scan with contrast for complaints of abdominal pain, nausea, and vomiting at one facility. The creatinine was 1.5. The next day, the patient was seen at another ED with similar complaints, and a CT scan with contrast was repeated. Thereafter, his creatinine was 3.1 and continued to rise, resulting in transfer to another facility for further treatment. 

Lessons Learned from PA-PSRS Reports
  • Reporting facilities use creatinine levels, rather than eGFR to evaluate renal function. 
  • Having the most recent renal function study available and reviewed immediately before contrast administration may prevent untoward patient outcomes.
  • Physicians ordering contrast-related studies may not always consider CIN risk factors. 
  • Delaying studies until renal function studies are reviewed may prevent untoward outcomes. 
  • Implementing standard CIN prevention strategies prior to contrast-related study in high-risk patients reduces reliance on memory. 
  • Written guidelines and standing orders help standardize care given, but are effective only if the healthcare team is aware of such tools and fully implements them. 
  • Double checking order entries may prevent high-risk patients from receiving contrast. 
  • If medically feasible, spacing multiple contrast-related studies will allow the patient’s creatinine level to return to baseline before the next study is  performed. 
  • Conducting a full risk assessment and history may identify patients at CIN risk. 
  • Heightening awareness of the long-term sequelae of CIN may help the healthcare team understand that CIN is not an acceptable complication, and that its prevention must be taken seriously.

Oral Phosphate Nephropathy and CIN

The following report was submitted to PA-PSRS: 

A patient received IV contrast for a CT scan, and two days later received Fleets Phospho-Soda for a bowel prep. The patient went into acute renal failure and subsequently died.

What happened here? A FDA notice1 may shed some light on this issue. The FDA Center for Drug Evaluation and Research reported that acute phosphate nephropathy—a type of acute renal failure—is a rare but serious patient outcome associated with oral sodium phosphate (OSP) bowel clean-sing products (e.g., Fleet Phospho-Soda, Fleet ACCU-PREP, Visical). Permanent renal impairment requiring chronic dialy-sis may result when acute phosphate nephropathy occurs. OSP products are commonly used for bowel cleansing before colonoscopy, certain radiographic procedures, and surgery. 

Data

The FDA Adverse Event Reporting System has received 10 such cases associated with OSP solution, and 10 cases as-sociated with OSP tablets. The FDA notice also reported a case series study by Markowitz et al. in which 21 patients had acute phosphate nephropathy proven by biopsy and had previously taken an OSP product; 20 used an OSP solution and 1 used OSP tablets. The FDA notice also refers to two published articles suggesting that electrolyte solution rehydra-tion may reduce intravascular depletion and electrolyte abnor-malities associated with OSP bowel cleansing products.1

FDA Risk Reduction Strategies
  • If another bowel cleansing alternative is available [such as the PEG solution Go-Lytely], avoid the use of OSP bowel cleansing products in at-risk patients. 
  • Follow the OSP product package directions for fluid intake. However, currently, the volume of hydration that minimizes electrolyte abnormalities and re-duces the risk of this complication is not known. Moreover, it is unknown whether individualizing the hydration volume according to patient variables such as weight, age, gender, or concomitant medi-cations or comorbidities affect the likelihood of developing acute phosphate nephropathy.

While the PA-PSRS report does not indicate any other po-tential factors in this Serious Event, it is not certain that the use of an OSP product contributed to acute renal failure in this patient. 

Note
  1. U.S. Food and Drug Administration Center for Drug Evalua-tion and Research. Food and drug administration science background paper: acute phosphate nephropathy and renal failure associated with the use of oral sodium phosphate bowel cleansing products [online]. 2006 May 5 [cited 2006 Dec 15]. Available from Internet: http://www.fda.gov/cder/drug/infopage/OSP_solution/backgrounder.htm.

Contrast Media Chemistry

The osmolality of a specific contrast agent is determined by the number of osmotically active particles when it is dissolved in an aqueous solution.1

High osmolar contrast media (HOCM).These earliest agents (predominantly used until the 1980s) contain a sodium ion that dissociates from the molecule when dis-solved in a solution. Each molecule of the agent has iodine atoms associated in a benzene ring. Thus, these agents have two types of osmotically active particles. They have extremely high osmolality—higher than blood and are called high osmolar or ionic contrast media. 1,2

Low osmolar contrast media (LOCM). This next generation of contrast agents (introduced in the 1980s) are pre-dominantly used today. When dissolved in aqueous solu-tion, they do not dissociate into separate particles. Therefore, only one type of osmotically active particle delivers iodine atoms, and they are called low osmolar or nonionic. They are about half the osmolality of HOCMs.1,2  

Iso-osmolar contrast media (IOCM). The newest contrast media is a nonionic dimer which has six iodine at-oms attached to two benzene rings that are linked together in one type of osmotically active particle. It is iso-osmolar with normal plasma (about half the osmolality of LOCMs).1,2   Both LOCMs and IOCMs are more costly, which may prevent them from being used exclusively.1 

Notes
  1. Katzberg RW, Haller C. Contrast-induced nephrotoxicity: clinical landscape. Kidney Int Suppl 2006 Apr;69:S3-S7.
  2. Asif A, Epstein M. Prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 2004 Jul;44(1):12-24.

Calculating Estimated Glomular Filtration Rate (eGFR)

Two formulas can be used to calculate the eGFR. 

eGFR Formulas
Modification of Diet in Renal Disease (MDRD) Equation 

This formula for estimating creatinine clearance does not rely on patient weight.1,2 

eGFR (mL/min/1.73.m2)=186.3 x [SCr-1.154] x [age in years-0.203]

Multiply the calculated value by 0.742 for women and by 1.21 for blacks/African Americans.

This formula is available on the Internet: http://www.kidney.org/professionals/kdoqi/cap.cfm#palm or http://www.nephron.com—this latter site allows easy entry of the patients age, gender, race, and Scr and will provide a calculated eGFR online. It can be downloaded for use by laboratories or healthcare professionals onto a personal digital assistant.2  See this Web site for information on the patient populations in which this formula has been validated. 

(Also see Appendix A in this supplementary Advisory for a visual display of this CIN risk calculation, according to all of its variables.) 

Cockroft & Gault Formula

This formula is based on the SCr, age, and body weight. 3,2

One version of the formula:4 

Males: Creatinine clearance=(140-age in years) x (weight in kg/0.81) x SCr in µmol/L

Females: multiply result by 0.85 

Another version of the formula:2 

(140-age in years) x weight in kg x1.23 / SCr (µmol/L)  

Patients deemed to be at increased risk for CIN5 are: 

  • Males with SCr >1.3 mg/dL (114 µmol/L) 
  • Females with SCr >1.0 mg/dL (88.4 µmol/L) 

Both are equivalent to a creatinine clearance of <60mL/min/1.73m2

Notes
  1. Itoh Y, Yano T, Sendo T, et al. Clinical and experimental evidence for prevention of acute renal failure induced by radiographic contrast media. J Pharmacol Sci 2005 Apr;97(4):473-88.
  2. Aspelin P. Nephrotoxicity and the role of contrast media. Radiat Med 2004 Nov-Dec;22(6):377-8.
  3. Gleeson TG, Bulugahapitiya S. Contrast-induced nephropathy. Am J Roentgenol 2004 Dec;183(6):1673-1689.
  4. Bettmann MA. Contrast medium-induced nephropathy: critical review of the existing clinical evidence. Nephrol Dial Transplant 2005 Feb;20[Suppl1]:i2-i17.
  5. McCullough PA, Adam A, Becker C. Risk prediction of contrast-induced nephropathy. Am J Cardiol 2006 Sep 18;98(6A):27K-41K.

 Renal Disease and Gadolinium-Based Agents

Gadolinium-based contrast agents were once believed to be safe and not nephrotoxic when administered in the usual doses for MRI procedures (up to 0.3mmol/kg body weight). But the dosage required to conduct a satisfactory radio-graphic study is different because different properties of gadolinium are used in the two techniques.1 Use of gadolin-ium as an alternative contrast media to avoid the risk of CIN has not been substantiated in clinical trials.2 In a study of 195 patients with abnormal pre-examination creatinine clear-ance levels, 3.5% developed acute renal failure (anuria) after gadolinium contrast administration.1 Therefore, it can no longer be assumed that gadolinium-based contrast media are not nephrotoxic. 

Recently, the U.S. Food and Drug Administration (FDA) issued an alert3 reporting a serious new kidney disease as-sociated with gadolinium-based contrast agents used for MRI and magnetic resonance angiography (MRA). FDA has received reports of 90 patients in the United States (and 215 patients worldwide) with moderate to end-stage renal disease who developed nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy (NSF/NFD) following an MRI or MRA with gadolinium-based contrast agent. 

Onset

This complication ordinarily begins 2 days to 18 months after exposure to gadolinium-based contrast. Many patients, but not all, received a high dose of the contrast, but some received only one dose. 

Symptoms
  • Burning, itching, swelling, hardening, darkening skin 
  • Yellow spots on sclera 
  • Red or dark patches on the skin 
  • Joint stiffness with difficulty moving and straightening extremities
  • Deep bone pain in hips or ribs 
  • Muscle weakness 
  • Scarring of internal organs may occur 
FDA Notification
  • NSF/NFD is a debilitating condition and it may be fatal. 
  • If a gadolinium-based contrast agent must be used, consider prompt dialysis in high-risk patients following MRI or MRA. 
  • It is unclear why NSF/NFD occurs in patients with moderate to end-stage kidney disease who re-ceive gadolinium-based contrast agents. 
  • Patients who believe they may have NSF/NFD should contact their physicians for evaluation. 
FDA Recommendations

Whenever possible, perform imaging with methods other than MRI or MRA involving gadolinium-based contrast in patients with moderate to severe chronic kidney disease and end-stage renal disease. Consideration should be given to performing hemodialysis immediately after gadolinium administration in patients with moderate to end-stage renal disease. 

Notes
  1. Thomsen HS. How to avoid CIN: guidelines from the European Society  of Urogenital Radiology. Nephrol Dial Transplant 2005 Feb;20[Suppl 1]: i18-i22.
  2. Davidson C, Stacul F, McCullough PA, et al. Contrast medium use. Am J Cardiol 2006 Sep 18;98(6A):42K-58K.
  3. Bloom M. FDA issues alert on gadolinium-based contrast agent for kidney patients. MedPage Today [online]. 2006 Dec 22 [cited 2007 Jan 2]. Available from Internet: http://www.medpagetoday.com/Nephrology/GeneralNephrology/dh/4760.

Efficacy of Premedication Regimens

May be Effective
  • N-Acetylcysteine 
  • Ascorbic Acid 
  • Prostaglandin E1
  • Theophylline 
  • Statins 
Insufficient/Conflicting Data
  • ACE inhibitors 
  • Calcium antagonists 
  • Calcium channel blockers 
Not Effective
  • Atrial natriuretic factor 
  • Dopamine 
  • Endothelin receptor antagonists 
  • Fenoldapam 
Detrimental
  • Furosemide 
  • Mannitol

Key Points

  • CIN is a clinically important, iatrogenic complication that is the third most common cause of hospital-acquired renal failure.  
  • Pathogenesis is unclear. 
  • It may be associated with a poor prognosis independent of other risk factors. 
  • It primarily occurs in patients with some degree of renal compromise, and it is directly proportional to the severity of pre-existing renal insufficiency. 
  • Patients at greatest risk are those with combined pre-existing renal insufficiency and diabetes. 
  • The most widely accepted preventive intervention is intravenous hydration with normal saline solution. The use of bicarbonate solutions may be superior for hydration. 
  • Preferably, use eGFR rather than SCr to determine whether the patient is at risk for CIN 
  • Use nonpharmacologic interventions, including the following, to reduce CIN risk:
    • Minimizing contrast volume
    • Avoiding repeated contrast exposure within short period of time
    • Using alternative imaging studies
    • Avoiding nephrotoxic drugs, gadolinium contrast, oral sodium phosphate cleansing products 
  • No single premedication regimen has been conclusively shown to be effective in preventing CIN or its long-term sequelae. 
  • Different types of contrast media are associated with different degrees of nephrotoxicity. LOCM and IOCM are less nephrotoxic than HOMC, but can still cause nephropathy.

Self-Assessment Questions

The following questions about this article may be useful for internal education and assessment. You may use the following examples or come up with your own.

  1. A common symptom of CIN is oliguria.
    1. True
    2. False 
  2. Gadolinium-based contrast agents are safe alternatives to iodinated contrast media in patients with moderate to end stage renal disease.
    1. True
    2. False
  3. Risk factors for CIN include
    1. immune deficiency, seizure disorder, and erosive acid reflux disease.
    2. clinical depression, cardiac arrhythmia, and inflamma-tory bowel disease.
    3. pre-existing renal function impairment, concurrent nephrotoxic drug use, and intravascular volume depletion.
    4. none of the above. 
  4. Premedication regimens found to be detrimental to renal function in patients at high risk for CIN include
    1. furosemide and mannitol.
    2. n-acetylcysteine and ascorbic acid.
    3. theophylline and statins.
    4. none of the above. 
  5. Which of the following drugs may increase the risk of  CIN when given around the time of iodinated contrast  administration?
    1. Heparin, insulin, potassium chloride
    2. Narcotic analgesics, selective serotonin reuptake  inhibitors
    3. Anticonvulsants, proton pump inhibitors, hormone  replacement therapy
    4. Vancomycin, ibuprofen, Cisplatin

 Appendix A

 Stratification of CIN Risk in White Males, According to MDRD Equation
 Stratification of CIN Risk in White Males, According to MDRD Equation

 




 

  Stratification of CIN Risk in Black/ African-American  Males, According to MDRD Equation

 Stratification of CIN Risk in Black/ African-American Males, According to MDRD Equation*

 

 

 

  
  Stratification of CIN Risk in White Females, According to MDRD Equation

 Stratification of CIN Risk in White Females, According to MDRD Equation

; 

 

 

Stratification of CIN Risk in Black/ African-American Females, According to MDRD Equation

 Stratification of CIN Risk in Black/ African-American Females, According to MDRD Equation

 

 

 

 


Appendix B

Management of Patients Undergoing Iodinated Contrast-related Procedures 
  Management of Patients Undergoing Iodinated Contrast-related Procedures

 

 

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