Radiocontrast dye-induced nephropathy
I. What every physician needs to know.
As the number of imaging studies for diagnostic and therapeutic procedures continues to increase, complications of these procedures also become more important. Side effects of contrast media used are one such problem. In addition to other possible risks (such as an anaphylactoid reaction and contrast extravasation), contrast-induced nephropathy (CIN) is a major complication of contrast media use.
CIN has been reported to be the third leading cause of acute kidney injury (AKI) in hospitalized patients in the United States (behind pre-renal kidney injury and nephrotoxic medications). AKI occurs in about 5% of all hospital admissions. CIN is defined as a serum creatinine concentration increase of 0.5mg/dl or 25% above baseline levels 48-72 hours after contrast administration, without another cause of AKI.
Creatinine levels typically begin to rise within 24-48 hours after contrast exposure, peak around day 3-5, and return to baseline by about day 7-14. In more severe cases, however, the peak creatinine and lowest glomerular filtration rate (GFR) can be delayed longer and renal function may not return to previous levels, resulting in chronic kidney disease. Severe CIN and renal failure requiring dialysis support is rare, occurring most often in patients with significant renal insufficiency prior to contrast exposure.
The exact mechanism of disease is unknown at this time. The current theory behind the pathophysiology of CIN involves several mechanisms of action. One proposed mechanism involves direct toxic effects on the kidney mediated by an increase in oxidative stress from free radicals. Damage to cells from free radicals then causes increased resistance to renal blood flow resulting in hypoxic ischemic insult.
The osmotic property of contrast media also decreases water reabsorption. This leads to a larger load of salt and water in the distal tubules causing compression of the vasa recta and further vasoconstriction and hypoxia.
Finally, contrast media leads to an increase in adenosine and endothelin, and decrease in nitric oxide, causing further vasoconstriction. Extrarenal circumstances such as hypovolemia and nephrotoxic medications can compound the risk for renal failure with contrast administration (see risk factors below).
Different contrast agents confer varying toxicities, as well. Older, ionic, and hyperosmolar (about 1500mOsm/kg and thus 5-7 times the osmolarity of blood) contrast media have been shown to be more toxic than newer, low-osmolar (about 500-900mOsm/kg and thus 2-3 times the osmolarity than blood) or iso-osmolar (290mOsm/kg) agents in high-risk patients. A meta-analysis of high-risk patients with baseline serum creatinine of at least 1.5mg/dl given a low-osmolarity versus high-osmolarity contrast agent showed the high-osmolarity group was 3.3 times more likely to develop CIN. The NEPHRIC (Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media) study then showed a nine times greater risk of CIN in the low-osmolar as compared to iso-osmolar group.
For a discussion on the use of gadolinium contrast in the use of magnetic resonance imaging see the Chronic Kidney Disease chapter.
II. Diagnostic Confirmation: Are you sure your patient has radiocontrast dye-induced nephropathy?
CIN is diagnosed in patients with an acute increase (of 25% or above 0.5mg/dL) in creatinine within 48 hours of contrast exposure in the absence of another more likely diagnosis. As stated previously, the decrease in renal function is typically noted within the first 24-48 hours, peaks at 3-5 days, and returns to baseline by about 10-14 days following contrast administration.
This form of AKI is typically non-oliguric (though in severe cases can lead to oliguria). Urine sediment is similar to that seen in acute tubular necrosis (ATN), demonstrating granular casts, renal tubular epithelial cells, and debris. In oliguric CIN, urinary sodium and the fractional excretion of sodium are characteristically low (<1%) despite a normal volume status. Of note, other types of ATN have a fractional excretion of sodium greater than 1%.
A. History Part 1. Pattern Recognition
Radiocontrast dye-induced nephropathy results in a rise in creatinine 48-72 hours after contrast administration. Although this type of AKI is usually non-oliguric, more severe cases can be oliguric. Common exposures to contrast include percutaneous coronary interventions, CT scans with IV contrast, angiographies or venographies, and intravenous pyelograms.
B. History Part 2: Epidemiology
The risk of CIN is highly variable, ranging from less than 1% to over 20%, depending on risk factors present, amount and type of contrast used, and the specifics of the definition of CIN used. Patients with normal kidney function, without risk factors discussed below, have <1% chance of CIN with contrast exposure, while highest rates of CIN are seen in hospitalized patients with underlying renal impairment (and, especially those with diabetes).
Some studies suggest an approximate risk of 10-40% in hospitalized diabetics undergoing contrast exposure with baseline mild to moderate kidney disease, while patients with creatinine greater than 4 can have a 50% or more chance of developing CIN. The reported incidence of CIN requiring hemodialysis is very low (<1%). However, of patients who require dialysis for CIN, in-hospital mortality has been reported to be about 35%.
The best proven predictor, and as such best proven risk factor, for developing CIN is pre-existing renal insufficiency (especially secondary to diabetic nephropathy) with a creatinine equal to 1.3-1.5mg/dL (or GFR <60ml/min/1.73m2).
Using the serum creatinine alone to determine the risk of CIN has limitations, especially when compared to the estimated GFR through the Cockroft-Gault formula or Modification of Diet in Renal Disease (MDRD) formula. The Cockroft-Gault formula takes into account age, sex, and body weight while the MDRD formula also includes albumin and blood urea nitrogen (BUN). For example, a female patient with a low body weight and older age may seem falsely at lower risk when only looking at the serum creatinine. As a result, the estimated GFR has become more common and reliable for reflecting existing kidney function.
A newer method of estimating existing kidney function and the risk of CIN is the use of serum cystatin C. This protein is secreted into the serum by nucleated cells and is filtered by the glomerulus. Cystatin C levels change faster than serum creatinine levels (allowing for detection of CIN before the standard rise 3-5 days later) and are not affected by age, sex, and body weight. Thus, serum creatinine, estimated GFR, and cystatin C levels can all be used to determine risk of CIN.
Many other risk factors are thought to contribute, including: hypovolemia (and states that decrease the effective arterial blood flow to the kidney such as congestive heart failure, cirrhosis and intra-aortic balloon pump), diuretic use, nephrotoxic medications (such as aminoglycosides and NSAIDs), diabetes, hypertension, multiple myeloma, and age (especially age greater than 70 years). Type of contrast (as discussed above), larger amounts, and repeated doses (within 72 hours) are also risk factors for developing CIN. There is some evidence that contrast given intra-arterially (such as with cardiac catheterization) may have more harmful effects than intravenous administration. Ultimately, the greatest risk of CIN is in patients with pre-existing renal dysfunction.
C. History Part 3: Competing diagnoses that can mimic radiocontrast dye-induced nephropathy.
The differential diagnosis is patient specific, but includes other causes of ATN and AKI. In patients who have undergone interventional procedures, an atheroembolic event (such as cholesterol emboli) should be considered in the initial differential diagnosis. Also consider drug-induced interstitial nephritis and decompensated heart failure (especially after cardiac catheterization) as causes of post-contrast exposure nephropathy.
D. Physical Examination Findings
Patients with radiocontrast dye-induced nephropathy are typically non-oliguric and thus there are no classic physical exam findings associated with this condition. However, a physical exam is important for ruling out other causes of acute kidney injury such as drug-induced interstitial nephritis (rash), cholesterol emboli (livedo reticularis, blue or necrotic toe), volume depletion (skin tenting, dry mucous membranes, slow capillary refill), or decompensated heart failure (pulmonary crackles, lower extremity pitting edema, elevated jugular venous pressure).
E. What diagnostic tests should be performed?
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Serum tests should include blood urea nitrogen (BUN), creatinine, electrolytes, and bicarbonate. A rise in blood urea nitrogen and creatinine signals worsening renal function. Potassium may be elevated and bicarbonate may be decreased in renal failure.
Urine studies may include urine sodium (or urine urea if the patient has recently taken diuretics), urine creatinine, and urinalysis. Radiocontrast dye-induced nephropathy is generally non-oliguric. If the patient has oliguric contrast nephropathy, the fractional excretion of sodium is generally <1%. This is in contrast to other forms of acute tubular necrosis where the fractional excretion of sodium is generally > 2%.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
In patients with a clinical presentation consistent with contrast-induced nephropathy, a renal ultrasound can be deferred.
3. Over-utilized or “wasted” tests associated with this diagnosis.
See above for discussion of the utility of a renal ultrasound.
III. Default Management.
As there is no specific treatment fr CIN, many investigations have been conducted to find a preventative solution. To date, no definitive preventative strategy has been discovered. Thus, avoidance of contrast media if possible is preferable though often not clinically feasible.
The most universally accepted and successful prevention is hydration. There is no proven best hydration schedule, but the use of 0.9% sodium chloride has been shown to be superior to hydration with 0.45% sodium chloride in the prevention of CIN, and slow hydration has demonstrated superiority to bolus treatment. Of note, a 2002 study of patients undergoing coronary angiography found that the incidence of CIN was lower in patients receiving periprocedural 0.9% versus 0.45% sodium chloride, though in a subgroup of patients with a baseline creatinine greater 1.5mg/dl, there was no difference of CIN between patients given 0.9% versus 0.45% sodium chloride.
One generally accepted regimen is 0.9% sodium chloride at a rate of 1ml/kg/hr for 24 hours, beginning 12 hours pre-contrast exposure if time allows, intra-procedure, and 12 hours post-contrast exposure. Lower infusion rates should be considered in patients with risk factors for fluid overload, such as congestive heart failure.
Some studies have suggested an even greater benefit to hydration with sodium bicarbonate over 0.9% sodium chloride.
This is based on the notion that alkalinization may reduce free radical injury. A 2010 meta-analysis found a preventive effect of sodium bicarbonate on the risk of CIN but with borderline significance. The PREVENT (Preventive Strategies of Renal Insufficiency in Patients with Diabetes Undergoing Intervention or Arteriography) trial in 2011 showed similar efficacy of normal saline and sodium bicarbonate hydration in prevention of CIN in patients with diabetic nephropathy. In addition, the 2015 BOSS trial was a multi-center randomized study of 391 patients undergoing coronary angiography, and showed no difference in death, dialysis, or six-month sustained reduction in GFR between patients given sodium bicarbonate or normal saline infusions periprocedure.
N-acetylcysteine (NAC) use has also been proposed to help prevent CIN. A landmark paper published by Tepel et al in 2000 demonstrated a marked superiority of hydration with NAC (600mg orally twice a day, pre- and post-contrast, for 4 doses) over hydration alone. The APART (acetylcysteine to prevent angiography-related renal tissue injury) trial in 2002 also showed a protective effect of NAC administration.
However, results have been conflicting with some studies showing no benefit to NAC use. Meta-analyses of the subject have not consistently found benefit. The ACT (acetylcysteine for the prevention of contrast-induced nephropathy) trial showed no benefit in the prevention of CIN in patients undergoing angiography with NAC administration (1200mg orally twice a day, pre- and post-contrast, for 4 doses) versus placebo.
Though no longer the standard of care, given the low cost, low side effect profile, and possible benefit of use, it is reasonable to consider NAC use in the prevention of CIN at a dose of 600-1200 mg orally twice a day for 4 doses, starting 12 hours pre-contrast and continuing post-contrast exposure.
As noted above, low osmolar or iso-osmolar contrast agents are now the standard of care and have shown a lower rate of CIN in those with underlying renal insufficiency over the older high osmolar contrast media. Still, the lowest dose of contrast needed to complete the imaging or procedure should be administered.
Given their effect on prostaglandins, NSAIDS should be avoided in patients undergoing contrast media studies. As well, other nephrotoxic agents (aminoglycosides, etc.) or volume depleted medications (diuretics, etc.) should be avoided if clinically possible.
Contrast media is removed with hemodialysis. Prophylactic dialysis currently has no role in the prevention of CIN in patients with normal, mild, or moderate renal dysfunction. However, dialysis soon after contrast administration may be considered in patients with stage 5 chronic kidney disease in whom contrast exposure cannot be avoided. More studies are needed to further define the role of this therapy. Consultation with a nephrologist is recommended before administering contrast agents to patients with advanced renal impairment.
Theophylline, an adenosine receptor antagonist, has been postulated to help prevent renal vasoconstriction and therefore help prevent CIN. Results of investigations have been inconclusive. Further investigation is necessary before this strategy can be considered for recommendation given the potential toxicity and side effects of theophylline.
The use of mannitol and furosemide have shown possible harm. Dopamine and the dopamine agonist fenoldopam, ascorbic acid, and atrial natriuretic peptide are thought to provide no benefit in protection against CIN, while other novel theories are still being explored (such as the use of statins and prostaglandins).
Another topic of discussion in CIN prevention is whether or not to withhold angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) prior to contrast administration. A 2012 Korean retrospective propensity score-matched study of 5299 patients with varying baseline renal function undergoing coronary angiography showed a higher adjusted odds ratio (OR, 1.43; 95% CI 1.06-1.94, p=0.02) of CIN in patients taking ACE inhibitors or ARBs versus not taking ACE inhibitors or ARBs. However, a 2008 U.S. study of 220 patients with CKD (GFR 15-60 ml/min/1.73m2) undergoing coronary angiography showed no statistically significant difference in the incidence of CIN in patients who continued their ACE inhibitor or ARB, compared with either patients who discontinued their ACE inhibitor or ARB 24 hours prior to coronary angiography or patients who were never on an ACE inhibitor or ARB. Although study findings are mixed regarding whether or not to withhold ACE inhibitors and ARBs before contrast exposure, common practice is to continue these medications.
A. Immediate management.
There is no individualized treatment for CIN. Treatment should follow that for AKI and ATN, with monitoring of fluid balance and electrolyte disorders that may arise.
B. Physical Examination Tips to Guide Management
Patients with radiocontrast dye-induced nephropathy are typically non-oliguric and thus there are no classic physical exam findings associated with this condition. However, a physical exam is important for ruling out other causes of acute kidney injury.
C. Laboratory Tests to Monitor Response to, and Adjustments in, Management
Serum tests include blood urea nitrogen, creatinine, electrolytes, and bicarbonate. Urine studies include urinalysis, urine sodium (or urine urea), and urine creatinine.
D. Long-term management
Long-term management is based on the degree of nephropathy. If a patient’s renal function improves after the creatinine peak, it is important to monitor for electrolyte and fluid replenishment during the post-ATN auto-diuresis phase. Patients with severe cases of contrast nephropathy may require long-term hemodialysis.
E. Common pitfalls and side effects of management
If a post-ATN diuresis phase occurs, the patient may become significantly volume depleted (requiring fluid replenishment) leading to acute kidney injury from volume depletion.
IV. Management with Co-Morbidities
A. Renal Insufficiency.
Patients with underlying renal insufficiency have an increased risk of CIN, as discussed above. Patients who are already on hemodialysis may require same or next day dialysis after contrast administration.
B. Liver Disease
No change in standard management.
C. Systolic and Diastolic Heart Failure
Patients with heart failure are at risk of contrast nephropathy given rapid changes in volume status and perfusion to the kidneys.
D. Coronary Artery Disease or Peripheral Vascular Disease
Patients undergoing percutaneous coronary intervention or vascular angiography may receive a significant amount of contrast dye exposure.
E. Diabetes and other endocrine issues
Patients with diabetes are at risk for having underlying renal insufficiency.
No change in standard management.
Patients on immunosuppressive medication may need dose adjustments given impaired renal clearance.
H. Primary Lung Disease
No change in standard management.
I. Gastrointestinal or Nutritional Issues
Patients with diarrhea, vomiting, or poor calorie intake may be hypovolemic and thus predisposed to contrast nephropathy.
J. Hematologic or Coagulation Issues
No change in standard management.
K. Dementia or Psychiatric Illness/Treatment
Patients with dementia or psychiatric illness may have reduced oral intake leading to hypovolemia and increased risk of contrast nephropathy.
V. Transitions of Care
A. Sign-out considerations while hospitalized
Patients are at risk for significant electrolyte abnormalities (specifically potassium and bicarbonate) during the peak of contrast nephropathy and the post-ATN auto-diuresis phase.
B. Anticipated Length of Stay
The length of stay depends on the degree of contrast nephropathy including fluid repletion during the post-ATN auto-diuresis phase and initiation of hemodialysis.
C. When is the Patient Ready for Discharge?
The patient can be discharged when ready from all other aspects of the inpatient stay, fluid balance and electrolytes are stable, and renal function has trended downward.
D. Arranging for Clinic Follow-up
1. When should clinic follow up be arranged and with whom?
Follow-up with the patient’s primary care physician (or nephrologist) should be arranged within several days of discharge.
2. What tests should be conducted prior to discharge to enable best first clinic visit?
While the patient is still in the hospital, continue to monitor electrolytes and volume status if a post-ATN auto-diuresis phase ensues
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?
Electrolytes and renal function should be checked.
E. Placement Considerations
There are no specific placement considerations for contrast nephropathy.
F. Prognosis and Patient Counseling.
The majority of patients with CIN will experience a mild and transient nonoliguric kidney injury, with full recovery. However, in patients with pre-existing advanced renal impairment, CIN is much more likely to occur, be more severe, and persist leaving the patient with a new worsened baseline renal function. As noted above, of patients who require dialysis for CIN, in-hospital mortality has been reported to be about 35%.
Ultimately, CIN may be a predictor of poor outcomes. It is known that patients undergoing percutaneous coronary angiography who subsequently develop ARF (including CIN) have increased mortality rates over those whose renal function remains stable. CIN carries a burden of increased morbidity and mortality, and novel preventive strategies continue to be investigated.
VI. Patient Safety and Quality Measures
Core Indicator Standards and Documentation
Appropriate prophylaxis and other measures to prevent readmission.
Avoidance of contrast dye is preferred if clinically feasible. If contrast dye is necessary then pre- and post-procedure hydration and use of low- or iso-osmolar contrast dye is preferred. It is also crucial to avoid nephrotoxic medications prior to contrast exposure. The use of N-acetylcysteine or sodium bicarbonate is controversial but may aid in preventing contrast nephropathy with relatively few side effects.
What is the Evidence?
Mueller, C, Buerkle, G, Buettner, H, Petersen, J, Perruchoud, AP, Eriksson, U, Marsch, S, Roskamm, H. “Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty”. Archives of Internal Medicine. vol. 162. 2002. pp. 329-336.
Hoste, E, De Waele, J, Gevaert, S, Uchino, S, Kellum, J. “Sodium bicarbonate for prevention of contrast-induced acute kidney injury: a systematic review and meta-analysis”. Nephrology, Dialysis, Transplantation. vol. 25. 2010. pp. 747-758.
Lee, S, Kim, W, Kim, Y, Park, S, Park, D, Yun, S, Lee, J, Kang, S, Lee, C, Lee, J, Choi, S, Seong, I, Suh, J, Cho, Y, Lee, N, Cheong, S, Yoo, S, Lee, B, Lee, S, Hyon, M, Shin, W, Lee, S, Jang, J, Park, S. “Preventive strategies of renal insufficiency in patients with diabetes undergoing intervention or arteriography (the PREVENT Trial)”. American Journal of Cardiology. vol. 107. 2011. pp. 1447-1452.
Solomon, R, Gordon, P, Manoukian, S, Abbott, J, Kereiakes, D, Jeremias, A, Kim, M, Dauerman, H. “Randomized trial of bicarbonate or saline study for the prevention of contrast-induced nephropathy in patients with CKD”. Clinical Journal of the American Society of Nephrology. vol. 10. 2015. pp. 1519-1524.
Tepel, M, van der Giet, M, Schwarzfeld, C, Liermann, D. “Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine”. New England Journal of Medicine. vol. 343. 2000. pp. 180-184.
Diaz-Sandoval, L, Kosowsky, B, Losordo, D. “Acetylcysteine to prevent angiography-related renal tissue injury (the APART trial”. The American Journal of Cardiology. vol. 89. 2002. pp. 356-358.
“Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT)”. Circulation. vol. 124. 2011. pp. 1250-1259.
Rim, M, Ro, H, Kang, W, Kim, A, Park, H, Chang, J, Lee, H, Chung, W, Jung, J. “The effect of renin-angiotensin-aldosterone system blockade on contrast-induced acute kidney injury: a propensity-matched study”. American Journal of Kidney Disease. vol. 60. 2012. pp. 576
Rosenstock, J, Bruno, R, Kim, J, Lubarsky, L, Schaller, R, Panagopoulous, G, DeVita, M, Michelis, M. “The effect of withdrawal of ACE inhibitors or angiotensin receptor blockers prior to coronary angiography on the incidence of contrast-induced nephropathy”. International Urology and Nephrology. vol. 40. 2008. pp. 749
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- Radiocontrast dye-induced nephropathy
- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has radiocontrast dye-induced nephropathy?
- A. History Part 1. Pattern Recognition
- B. History Part 2: Epidemiology
- C. History Part 3: Competing diagnoses that can mimic radiocontrast dye-induced nephropathy.
- D. Physical Examination Findings
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 3. Over-utilized or “wasted” tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management
- C. Laboratory Tests to Monitor Response to, and Adjustments in, Management
- D. Long-term management
- E. Common pitfalls and side effects of management
- IV. Management with Co-Morbidities
- A. Renal Insufficiency.
- B. Liver Disease
- C. Systolic and Diastolic Heart Failure
- D. Coronary Artery Disease or Peripheral Vascular Disease
- E. Diabetes and other endocrine issues
- F. Malignancy
- G. Immunosuppression
- H. Primary Lung Disease
- I. Gastrointestinal or Nutritional Issues
- J. Hematologic or Coagulation Issues
- K. Dementia or Psychiatric Illness/Treatment
- V. Transitions of Care
- A. Sign-out considerations while hospitalized
- B. Anticipated Length of Stay
- C. When is the Patient Ready for Discharge?
- D. Arranging for Clinic Follow-up
- 1. When should clinic follow up be arranged and with whom?
- 2. What tests should be conducted prior to discharge to enable best first clinic visit?
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?
- E. Placement Considerations
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures