Contrast NephropathyContrast Nephropathy

Dr. Kristine OwenDr. Kristine Owen

Types of radiocontrast agentsTypes of radiocontrast agents Iodinated radiocontrast agents are either ionic or nonionic and, are Iodinated radiocontrast agents are either ionic or nonionic and, are

of variable osmolality of variable osmolality First generation agentsFirst generation agents are ionic monomers (single benzene ring are ionic monomers (single benzene ring

with three iodine atoms) they are highly hyperosmolal with three iodine atoms) they are highly hyperosmolal (approximately 1400 to 1800 mosmol/kg) compared with the (approximately 1400 to 1800 mosmol/kg) compared with the osmolality of plasma.osmolality of plasma.

Second generation agentsSecond generation agents, such as iohexol, are nonionic , such as iohexol, are nonionic monomers with a lower osmolality than the first generation monomers with a lower osmolality than the first generation radiocontrast media; however, they still have an increased radiocontrast media; however, they still have an increased osmolality (500 to 850 mosmol/kg) compared with plasma). osmolality (500 to 850 mosmol/kg) compared with plasma).

The newest nonionic contrast agentsThe newest nonionic contrast agents are dimers (two benzene are dimers (two benzene rings joined together as a single molecule) with an even lower rings joined together as a single molecule) with an even lower osmolality, with iodixanol being iso-osmolal (approximately 290 osmolality, with iodixanol being iso-osmolal (approximately 290 mosmol/kg).  mosmol/kg).  

Clinical significanceClinical significance The osmolality of the agent is the factor most strongly The osmolality of the agent is the factor most strongly

associated with immediate hypersensitivity reactions:associated with immediate hypersensitivity reactions: Mild to moderate IHRs occur with 5 to 12 percent of Mild to moderate IHRs occur with 5 to 12 percent of

procedures using ionic HOCM agents and 1 to 3 percent procedures using ionic HOCM agents and 1 to 3 percent of those using nonionic LOCM agents. of those using nonionic LOCM agents.

Life-threatening immediate reactions, which are usually Life-threatening immediate reactions, which are usually hypersensitivity reactions, occur in 0.22 to 0.04 percent hypersensitivity reactions, occur in 0.22 to 0.04 percent of ionic HOCM infusions and in 0.04 to 0.004 percent of of ionic HOCM infusions and in 0.04 to 0.004 percent of nonionic LOCM administrations. However, there does nonionic LOCM administrations. However, there does not appear to be a difference in overall mortality between not appear to be a difference in overall mortality between lower or higher osmolality RCM. lower or higher osmolality RCM.

The iso-osmolal agent iodixanol may be associated with The iso-osmolal agent iodixanol may be associated with similar or even fewer IHRs than the nonionic LOCM similar or even fewer IHRs than the nonionic LOCM agents. agents.

Shellfish Allergies?!Shellfish Allergies?! It is a misconception that patients allergic to fish or shellfish are at It is a misconception that patients allergic to fish or shellfish are at

additional increased risk for adverse reactions to RCM beyond that additional increased risk for adverse reactions to RCM beyond that of any atopic individual or patients with other food allergies.of any atopic individual or patients with other food allergies.

The epidemiological association between seafood allergy and RCM The epidemiological association between seafood allergy and RCM reactions has been attributed to a common iodine allergy since reactions has been attributed to a common iodine allergy since there is a high iodine content in seafood. there is a high iodine content in seafood.

However, iodine and iodide are small molecules that do NOT cause However, iodine and iodide are small molecules that do NOT cause anaphylactic or anaphylactoid reactions and are structurally anaphylactic or anaphylactoid reactions and are structurally unrelated to shellfish allergens (which are tropomyosin proteins). unrelated to shellfish allergens (which are tropomyosin proteins).

The likely explanation for the association is that seafood is a The likely explanation for the association is that seafood is a common cause of food allergy, and individuals with any atopic common cause of food allergy, and individuals with any atopic condition are at higher risk for RCM reactions. Another source of condition are at higher risk for RCM reactions. Another source of confusion can be previous contact dermatitis in response to the skin confusion can be previous contact dermatitis in response to the skin disinfectant providone-iodine. Patients with this history also do not disinfectant providone-iodine. Patients with this history also do not appear to be at higher risk for RCM reactions.appear to be at higher risk for RCM reactions.

Hypersensitivity reactionsHypersensitivity reactions Hypersensitivity reactions to radiocontrast are Hypersensitivity reactions to radiocontrast are

idiosyncratic and largely independent of rate of idiosyncratic and largely independent of rate of infusion. They can occur in response to minute infusion. They can occur in response to minute amounts of contrast agent. These reactions can amounts of contrast agent. These reactions can be further subdivided into immediate (developing be further subdivided into immediate (developing within one hour of administration) and delayed within one hour of administration) and delayed (developing from one hour to one week after (developing from one hour to one week after administration). Signs and symptoms include administration). Signs and symptoms include pruritus, urticaria, angioedema, laryngospasm, pruritus, urticaria, angioedema, laryngospasm, bronchospasm, hypotension, with loss of bronchospasm, hypotension, with loss of consciousness, and rarely hypovolemic shock consciousness, and rarely hypovolemic shock and death. and death.

Chemotoxic reactionsChemotoxic reactions

  Related to the chemical properties of radiocontrast Related to the chemical properties of radiocontrast agents and are dose and infusion rate dependent. These agents and are dose and infusion rate dependent. These include vasovagal reactions, seizures, arrhythmias, and include vasovagal reactions, seizures, arrhythmias, and organ (especially renal) toxicity.organ (especially renal) toxicity.

Vasovagal reactions are considered to be a form of Vasovagal reactions are considered to be a form of chemotoxic reaction because they may be related to rate chemotoxic reaction because they may be related to rate of infusion and concentration. These relatively common of infusion and concentration. These relatively common reactions present with warmth, flushing, nausea, or reactions present with warmth, flushing, nausea, or emesis and are usually transient and self-limited. Severe emesis and are usually transient and self-limited. Severe reactions can involve hypotension or bradycardia. reactions can involve hypotension or bradycardia.

PATHOGENESIS of CINPATHOGENESIS of CIN

The best data comes from animal models. The best data comes from animal models. Some studies show evidence of acute Some studies show evidence of acute

tubular necrosis, although the mechanism tubular necrosis, although the mechanism is not well understood. The two major is not well understood. The two major theories are renal vasoconstriction theories are renal vasoconstriction resulting in medullary hypoxemia, possibly resulting in medullary hypoxemia, possibly mediated by alterations in nitric oxide, mediated by alterations in nitric oxide, endothelin and/or adenosine, and direct endothelin and/or adenosine, and direct cytotoxic effects of the contrast agents cytotoxic effects of the contrast agents

?ATN??ATN?

If ATN does occur, it is not clear why recovery If ATN does occur, it is not clear why recovery occurs within a few days in contrast occurs within a few days in contrast nephropathy, compared to one to three weeks nephropathy, compared to one to three weeks with ATN due to other causes. with ATN due to other causes.

A similar short duration of "clinical" ATN (low A similar short duration of "clinical" ATN (low glomerular filtration rate (GFR), elevated glomerular filtration rate (GFR), elevated fractional excretion of sodium [FENa]) has been fractional excretion of sodium [FENa]) has been described after suprarenal aortic clamping for described after suprarenal aortic clamping for aortic aneurysm surgery aortic aneurysm surgery

2 ATN Theories2 ATN Theories

The degree of tubular necrosis is much less The degree of tubular necrosis is much less severe than seen in other settings. severe than seen in other settings.

There is postischemic or posttoxic tubular There is postischemic or posttoxic tubular dysfunction in which the tubular cells remain dysfunction in which the tubular cells remain morphologically normal. This phenomenon, morphologically normal. This phenomenon, which is similar to postischemic dysfunction in which is similar to postischemic dysfunction in the "stunned" myocardium, may be at least in the "stunned" myocardium, may be at least in part due to redistribution of membrane transport part due to redistribution of membrane transport proteins from the basolateral to the luminal proteins from the basolateral to the luminal membrane.membrane.

Additional thoughtsAdditional thoughts

However, the FENa may be below 1 percent in However, the FENa may be below 1 percent in patients with contrast nephropathy, suggesting a patients with contrast nephropathy, suggesting a prerenal event or intratubular obstruction.prerenal event or intratubular obstruction.

Another possibility is that tubular injury, due to Another possibility is that tubular injury, due to direct cytotoxic effects or in association with the direct cytotoxic effects or in association with the generation of free radicals, is the primary event.generation of free radicals, is the primary event.

Tubular injury may also be exacerbated by and Tubular injury may also be exacerbated by and act in concert with renal vasoconstriction act in concert with renal vasoconstriction

DefinationDefination

INCIDENCEINCIDENCE    Negligible with normal renal function, even if the patient Negligible with normal renal function, even if the patient

is diabetic. is diabetic. 4 to 11 percent with mild to moderate renal insufficiency 4 to 11 percent with mild to moderate renal insufficiency

alone (plasma creatinine between 1.5 and 4.0 mg/dL) alone (plasma creatinine between 1.5 and 4.0 mg/dL) this risk, however, may be increased to above 40 this risk, however, may be increased to above 40 percent by more advanced renal dysfunction, marked percent by more advanced renal dysfunction, marked volume depletion, severe heart failure, or multiple volume depletion, severe heart failure, or multiple contrast studies within a 72 hour period. contrast studies within a 72 hour period.

9 to 38 percent with mild to moderate renal insufficiency 9 to 38 percent with mild to moderate renal insufficiency and diabetes mellitus. and diabetes mellitus.

50 percent or more if the baseline plasma creatinine is 50 percent or more if the baseline plasma creatinine is greater than 4 to 5 mg/dL, particularly in patients with greater than 4 to 5 mg/dL, particularly in patients with diabetic nephropathy diabetic nephropathy

Incidence con’tIncidence con’t

Acute renal failure, defined as an increase in Acute renal failure, defined as an increase in plasma creatinine of more than 0.5 mg/dL plasma creatinine of more than 0.5 mg/dL above baseline, occurred in 3.3 percent overall above baseline, occurred in 3.3 percent overall and in 25 percent of patients with a baseline and in 25 percent of patients with a baseline serum creatinine above 2.0 mg/dL. serum creatinine above 2.0 mg/dL.

Acute renal failure was associated with Acute renal failure was associated with significant increases in mortality in-hospital (22 significant increases in mortality in-hospital (22 versus 1.4 percent without renal failure) and at versus 1.4 percent without renal failure) and at one and five years (12 versus 4 percent and 45 one and five years (12 versus 4 percent and 45 versus 15 percent). versus 15 percent).

Risk FactorsRisk Factors Underlying renal insufficiency, with the plasma Underlying renal insufficiency, with the plasma

creatinine exceeding 1.5 mg/dL or, although not creatinine exceeding 1.5 mg/dL or, although not measured clinically, the GFR being less than 60 measured clinically, the GFR being less than 60 mL/min mL/min

Diabetic nephropathy with renal insufficiency Diabetic nephropathy with renal insufficiency Advanced heart failure or other cause of Advanced heart failure or other cause of

reduced renal perfusion (such as hypovolemia) reduced renal perfusion (such as hypovolemia) Percutaneous coronary intervention, which also Percutaneous coronary intervention, which also

promotes the development of atheroemboli promotes the development of atheroemboli High total dose of contrast agent High total dose of contrast agent Multiple myeloma (with older contrast agents) Multiple myeloma (with older contrast agents)

Dose-dependent risk Dose-dependent risk

lower doses of contrast are safer (but not free of lower doses of contrast are safer (but not free of risk) risk)

Low dose has been variably defined as Low dose has been variably defined as less than 70 mL,less than 70 mL, less than 125 mL, or less than 125 mL, or less than 5 mL/kg [to a maximum of 300 mL] divided less than 5 mL/kg [to a maximum of 300 mL] divided

by the plasma creatinine concentration.by the plasma creatinine concentration.

However, diabetic patients with a plasma However, diabetic patients with a plasma creatinine concentration above 5 mg/dL may be creatinine concentration above 5 mg/dL may be at risk from as little as 20 to 30 mL of contrast. at risk from as little as 20 to 30 mL of contrast.

Clinical CharacteristicsClinical Characteristics The renal failure induced by contrast agents begins The renal failure induced by contrast agents begins

within the first 12 to 24 hours after the contrast study. within the first 12 to 24 hours after the contrast study. The renal failure is nonoliguric for the vast majority of The renal failure is nonoliguric for the vast majority of

patients.patients. In almost all cases, the decline in renal function is mild In almost all cases, the decline in renal function is mild

and transient, with recovery of renal function typically and transient, with recovery of renal function typically beginning within three to five days beginning within three to five days

Some patients, however, have a peak rise in the plasma Some patients, however, have a peak rise in the plasma creatinine that exceeds 5 mg/dL, occasionally requiring creatinine that exceeds 5 mg/dL, occasionally requiring dialysis; this is most likely to occur when the baseline dialysis; this is most likely to occur when the baseline plasma creatinine is greater than 4 mg/dL.plasma creatinine is greater than 4 mg/dL.

Persistent renal failure has been primarily described in Persistent renal failure has been primarily described in patients with preexisting advanced underlying disease, patients with preexisting advanced underlying disease, particularly in diabetics particularly in diabetics

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS AND DIFFERENTIAL DIAGNOSISDIAGNOSIS   

The diagnosis of radiocontrast-induced The diagnosis of radiocontrast-induced nephropathy is based upon the nephropathy is based upon the characteristic rise in plasma creatinine characteristic rise in plasma creatinine concentration beginning with the first 12 to concentration beginning with the first 12 to 24 hours. 24 hours.

The differential diagnosis includes, but is The differential diagnosis includes, but is not limited to, ischemic acute tubular not limited to, ischemic acute tubular necrosis, acute interstitial nephritis, and necrosis, acute interstitial nephritis, and renal atheroemboli. renal atheroemboli.

Prevention of Contrast Prevention of Contrast NephropathyNephropathy

There is no specific treatment once There is no specific treatment once contrast-induced acute renal failure contrast-induced acute renal failure develops, and management must be as for develops, and management must be as for any cause of acute tubular necrosis, with any cause of acute tubular necrosis, with the focus on maintaining fluid and the focus on maintaining fluid and electrolyte balance.electrolyte balance.

The best treatment of contrast-induced The best treatment of contrast-induced renal failure is prevention. Avoid contrast if renal failure is prevention. Avoid contrast if possible!possible!

Prevention con’tPrevention con’t The use of lower doses of contrast and avoidance of The use of lower doses of contrast and avoidance of

repetitive studies that are closely spaced (within 48 to 72 repetitive studies that are closely spaced (within 48 to 72 hours).hours).

Very small amounts of contrast (<10 mL) have been Very small amounts of contrast (<10 mL) have been safely used in patients with advanced kidney disease for safely used in patients with advanced kidney disease for examination of poorly maturing arteriovenous fistula. examination of poorly maturing arteriovenous fistula.

Avoidance of volume depletion or nonsteroidal Avoidance of volume depletion or nonsteroidal antiinflammatory drugs, both of which can increase renal antiinflammatory drugs, both of which can increase renal vasoconstriction. vasoconstriction.

The administration of intravenous saline or possibly The administration of intravenous saline or possibly sodium bicarbonate. sodium bicarbonate.

The administration of the antioxidant acetylcysteine. The administration of the antioxidant acetylcysteine. The use of low or iso-osmolal nonionic contrast agents. The use of low or iso-osmolal nonionic contrast agents.

Nonionic low osmolal agentsNonionic low osmolal agents    There appears to be little or no advantage in the There appears to be little or no advantage in the

prevention of contrast nephropathy when compared to prevention of contrast nephropathy when compared to ionic hyperosmolal agents in patients with normal renal ionic hyperosmolal agents in patients with normal renal function.function.

In studies of patients with moderate renal insufficiency In studies of patients with moderate renal insufficiency (serum creatinine concentration between 1.4 and 2.4 (serum creatinine concentration between 1.4 and 2.4 mg/dL) some nonionic, low osmolality agents have been mg/dL) some nonionic, low osmolality agents have been associated with a reduced incidence of a mild to associated with a reduced incidence of a mild to moderate decline in renal function moderate decline in renal function

Iodixanol, the only currently available iso-osmolal Iodixanol, the only currently available iso-osmolal nonionic contrast agent (approximately 290 mosmol/kg), nonionic contrast agent (approximately 290 mosmol/kg), may be associated with a lower risk of nephropathy than may be associated with a lower risk of nephropathy than low osmolal agents, particularly among diabetic patients low osmolal agents, particularly among diabetic patients with renal insufficiency with renal insufficiency

Preventive TreatmentPreventive Treatment

Hydration – beneficial in the majority of studies. IV Hydration – beneficial in the majority of studies. IV hydration is more beneficial than oral hydration.hydration is more beneficial than oral hydration.

Isotonic BiCarb> NS> 1/2NSIsotonic BiCarb> NS> 1/2NS Mannitol: no benefitMannitol: no benefit Diuretics: no benefitDiuretics: no benefit Acetylcysteine : conflicting results in the available clinical Acetylcysteine : conflicting results in the available clinical

trials and meta-analyses trials and meta-analyses The most commonly studied dose is 600 mg orally twice daily. The most commonly studied dose is 600 mg orally twice daily.

However, studies comparing 600 mg and 1200 mg twice daily However, studies comparing 600 mg and 1200 mg twice daily suggested slightly better outcomes with the higher dose.suggested slightly better outcomes with the higher dose.

no benefit to therapy with intravenous acetylcysteineno benefit to therapy with intravenous acetylcysteine

Prophylactic hemofiltration and Prophylactic hemofiltration and hemodialysishemodialysis   

Hemofiltration : expensive, logistically Hemofiltration : expensive, logistically cumbersome and associated with cumbersome and associated with significant riskssignificant risks its effectiveness compared to other less its effectiveness compared to other less

expensive strategies is not well established,expensive strategies is not well established, reported benefits are “implausible “reported benefits are “implausible “

Prophylactic dialysis : Studies show no Prophylactic dialysis : Studies show no benefit and a suggestion of possible harmbenefit and a suggestion of possible harm

SummarySummary Optimal therapy to prevent contrast-induced acute renal failure Optimal therapy to prevent contrast-induced acute renal failure

remains uncertain. Patients with near-normal renal function are at little remains uncertain. Patients with near-normal renal function are at little risk and few precautions are necessary other than avoidance of risk and few precautions are necessary other than avoidance of volume depletion. volume depletion.

We recommend the following preventive measures for patients at We recommend the following preventive measures for patients at increased risk of contrast nephropathy, which is defined a serum increased risk of contrast nephropathy, which is defined a serum creatinine ≥1.5 mg/dL (132 µmol/L) or an estimated glomerular creatinine ≥1.5 mg/dL (132 µmol/L) or an estimated glomerular filtration rate <60 ml/1.73 m2, particularly in patients with diabetes. filtration rate <60 ml/1.73 m2, particularly in patients with diabetes.

Avoid contrast if possible (i.e. MRI, non-contrasted CT scans, U/S Avoid contrast if possible (i.e. MRI, non-contrasted CT scans, U/S modalities)modalities)

We recommend NOT using high osmolal agents (1400 to 1800 We recommend NOT using high osmolal agents (1400 to 1800 mosmol/kg)mosmol/kg)

We suggest the use of iso-osmolal agents (approximately 290 We suggest the use of iso-osmolal agents (approximately 290 mosmol/kg) rather than low osmolal agents (500 to 850 mosmol/kg) rather than low osmolal agents (500 to 850 mosmol/kg) in high risk patientsmosmol/kg) in high risk patients

Use lower doses of contrast and avoid repetitive, closely spaced Use lower doses of contrast and avoid repetitive, closely spaced studies (eg, <48 hours apart)studies (eg, <48 hours apart)

Hydration with a BiCarb gtt +/- AcetylcysteineHydration with a BiCarb gtt +/- Acetylcysteine

Works CitedWorks Cited

Interventional Fellows InstituteInterventional Fellows Institute Up to DateUp to Date