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CONTRAST INDUCED NEPHROPATHY

By, AYESHA FAREED PHARM D.

Definition:Any internally administered substance

that has a different opacity from soft tissue on radiography or computed tomography; includes barium, used to opacify parts of the gastrointestinal tract; water-soluble iodinated compounds, used to opacify blood vessels or the genitourinary tract is called a Radiocontrast agent or Radiocontrast medium (RCM).

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Iodine Contrast Agents: Diatriazoate, Iodipamide Iothalamite, Metrizoate, Iohexol, Iopamidol, Iomersol, Iomeprol,Iopromide, Iptrolan, Ipodate, Iodixanol, etc.

Types of Radiocontrast agents:

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Iodinated contrast agents are usually tri iodo benzoic acid derivatives of sodium or meglumine salts.

Either salt used alone has a serious risk of ventricular fibrillations, thus used as mixture. PARAMETER SODIUM MEGLUMINE

Solubility Less BetterTolerance Less BetterBBB Effect Crosses NotVascular effects

More Less

Viscosity Low HighOpacification Better LessBronchospas

mNo Yes

Non iodinated contrast agents:

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Barium Sulphate (Used in X- ray and GIT imaging)

Gadolinium contrast agents (used in MRI scan)

Gadoterate (Dotarem)Gadodiamide (Omniscan)Gadobenate (MultiHance)Gadopentetate (Magnevist)Gadoteridol (ProHance)Gadofosveset (Ablavar, formerly Vasovist)Gadoversetamide (OptiMARK)Gadoxetate (Eovist)Gadobutrol Gadavist)

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Mangafodipir(Teslascan) – MRI withdrawn from market in 2012.

Rubidium-82 chloride (Myocardial perfusion imaging)

Technetium (99mTc) fanolesomab (NeutroSpec) – formerly used in diagnosis of appendicitis, suspended from the market in 2005 owing to life threatening adverse effects.

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Used in Ultrasound:Microspheres of human albumin(ALBUNEX),

galactose, phospholipids.Poly Lactic co glycolic acid (PLGA) particles

comprising of liquid perfluorocarbon and a metal have been suggested for use in ultrasound.

Optison™ (GE Healthcare Systems) is FDA-approved protein-shelled microbubble contrast agent which contains a perfluoropropane (perflutren) gas core.

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Alzheimer’s disease and amyloid beta PET imaging:

Florbetaben (18F) [NEURACEQ]Florbetapir (18F)Flutemetamol (18F)

ADVERSE REACTIONS OF RCM:

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• Nausea, vomiting Altered taste, Sweating, Cough, Itching, Rash, hives Warmth (heat) ,Pallor, Nasal stuffiness Headache Flushing Swelling eyes, face Dizziness Chills Anxiety Shaking

MILD • Tachycardia/bradycardia ,Hypotension Bronchospasm, wheezing, Hypertension,Dyspnea Laryngeal edema ,Pronounced cutaneous reaction, Pulmonary edema.

MODERATE • Hypersensitivity and

anaphylactoid reactions, Laryngeal edema, Profound hypotension Unresponsiveness (severe or progressive) Convulsions Cardiopulmonary arrest , arrhythmias

SEVERE

Based on mechanism:

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1. Chemotoxic reactions: which include organ specific reactions like nephrotoxicity, cardiovascular toxicity, neurotoxicity, vasovagal reactions and also associated with thyroid function abnormalitie, rarely thyrotoxicosis.

2. Anaphylactoid/Hypersensitivity reactions: Immediate hypersensitivity reactions –

develop within 5 minutes to one hour of contrast administration.

Delayed hypersensitivity reactions – develop from one hour to several days after contrast administration.

Treatment of Contrast Reactions:

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Post Contrast Acute KidneyInjury (PC – AKI)

and Contrast Induced Nephropathy (CIN)

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Post-contrast acute kidney injury (PC-AKI) is a general term used to describe a sudden deterioration in renal function that occurs within 48 hours following the intravascular administration of iodinated contrast medium.

PC-AKI may occur regardless of whether the contrast medium was the cause of the deterioration. PC-AKI is a correlative diagnosis.

Contrast-induced nephropathy (CIN) is a specific term used to describe a sudden deterioration in renal function that is caused by the intravascular administration of iodinated contrast medium; therefore, CIN is a subgroup of PC-AKI . CIN is a causative diagnosis.

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Contrast induced nephropathy is a sudden deterioration is renal function within 48 to 72 hours of contrast administration in patients without other attributable factors for renal insufficiency.

It is a condition with impairment in renal function defined as an increase in SCr by more than 25% within three days following intravenous administration in the absence of an alternative etiology.

Incidence: The frequency of CIN has decreased in the past decade from a general incidence of 15 to 7% [2013].

The overall incidence of PC-AKI in studies of cardiac angiography is higher than it is in studies of patients who receive IV iodinated contrast medium.

RISK FACTORS FOR CIN:

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PATHOPHYSIOLOGY OF CIN:

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DIAGNOSIS:

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There are no standard criteria for the diagnosis of PC-AKI or CIN.

One of the most commonly used criteria has been an absolute increase of 0.5 mg/dL over a baseline serum creatinine.

The diagnosis of AKI is made according to the AKIN (Acute Kidney injury network) criteria if one of the following occurs within 48 hours after a nephrotoxic event (e.g., intravascular iodinated contrast medium exposure)

1) Absolute serum creatinine increase ≥0.3 mg/dL (>26.4 µmol/L).

2) A percentage increase in serum creatinine ≥50% (≥1.5-fold above baseline).

3) Urine output reduced to ≤0.5 mL/kg/hour for at least 6 hours.

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Serum creatinine is limited as a measure of renal function in that it is impacted by gender, age, and muscle mass and nutritional status.

An alternative method for evaluating renal function is estimating creatinine clearance using the Cockcroft-Gault formula or GFR which is estimated by the Modification of Diet in Renal Disease (MDRD) formula.

The Cockcroft-Gault equation:[(140-age) X Actual Body Weight (kg) / (Serum Cr X 72)] multiply the result by 0.85 for females

GFR (mL/min/1 .73m2) = 175 x (SCr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African American)

SCREENING:

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1. Age > 65 years2. Diabetes treated with insulin or other prescribed 3. Receiving chemotherapy or aminoglycoside within

the past one month.4. Diagnosis of a collagen vascular disease 5. Diagnosis of a paraproteinemia syndrome6. History of a kidney transplant, renal tumor, renal

surgery, or single kidney7. History of end stage liver disease 8. History of severe congestive heart failure9. Metformin or metformin-containing drug

combinations

Following risk factors require a serum creatinine measurement within 1 month of the proposed dose of contrast:

Risk assessment and prophylactic strategies are based on eGFR rather than the absolute level of SCr :

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eGFR ≥ 60 mL/min: very low risk for CIN. These patients require no specific prophylaxis or follow up.

eGFR 45- 59 mL/min: low risk for CIN. In the absence of additional risk factors patients receiving IV CM requireno specific prophylaxis or follow up. For patients receiving IA CM preventative measures are recommended.

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eGFR < 45 mL/min: moderate risk of CIN, preventive measures are recommended. IV hydration recommendedfor patients receiving intra-arterial contrast. For intravenous administration, either oral or IV hydration could be used; IV hydration being preferred if eGFR < 30 mL/min.

Patients with unstable renal function, an acute illness and/or acute renal failure: GFR calculation in thesepatients is unreliable. They are thought to be at particular risk, full preventative measures, including intravenoushydration and follow up are recommended.

The American College of Radiology provides the following recommendations for holding Metformin:

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Category 1 : For patients with eGFR ≥ 45 mL/min without liver dysfunction, alcohol abuse, cardiac failure, myocardial or peripheral muscle ischemia, sepsis or severe infection:Do not hold metformin or check creatinine after contrast administration.

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Category 2: For patients with eGFR ≥ 45 mL/min with liver dysfunction, alcohol abuse, cardiacfailure, myocardial or peripheral muscle ischemia, sepsis or severe infection:Hold metformin for 48 hours. The procedure for assessing renal function and time to restart metformin will be determined by the radiologist and practitioner and communicated to the patient.

Category 3: For patients with impaired renal function, eGFR < 45 mL/min:Hold metformin at the time of contrast administration and follow renal function untilmetformin can be re-instituted safely.

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PREVENTION AND MANAGEMENT OF CIN

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1. Avoid dehydration.

2. Alternative imaging not requiring CM should be considered if the alternate imaging can adequately address the diagnostic questions.

3. CM volume and frequency of administration should be minimized while still maintaining satisfactory image quality. Avoid repeat CM injection within 72 hours.

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4. High osmolar CM should be avoided, as iso-osmolar and low-osmolar CM have been proven safer.

5. Nephrotoxic medications should be discontinued 48 hours prior to contrast administration.

6. Metformin should be discontinued on the day of the proposed CM administration, withheld for the subsequent 48 hours and recommenced after renal function has been re-evaluated and found to have returned to baseline.

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1. Choice of Iodinated Contrast Media: A meta-analysis of literature concerning high osmolar (HOCM) and low osmolar contrast media (LOCM) by Barreett and Carlisle concluded that LOCM are less nephrotoxic than HOCM in patients with underlying renal insufficiency.

A 2009 meta-analysis using data pooled from 25 trials found no difference in the rate of PC-AKI between iodixanol (iso-osmolar IOCM) and low osmolality agents after intravenous administration.

DIFFERENT STRATEGIES:

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2. Volume Expansion / Hydration: The ideal infusion rate and volume is unknown, but isotonic fluids are preferred (Lactated Ringer’s or 0.9% normal saline).

One possible protocol would be 0.9% saline at 100 mL/hr, beginning 6 to 12 hours before and continuing 4 to 12 hours after, but this is only practical in the inpatient setting.

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Solomon et al studied adult patients with chronickidney disease who underwent cardiac angiography. The reported incidence of PC-AKI was decreased byperiprocedural IV volume expansion (0.45% or 0.9% saline, 100 mL/h, 12 hours before to 12 hours afterintravascular contrast medium administration).

In another study, IV volume expansion with 0.9% saline was superior to IV volume expansion with 0.45% saline in PC-AKI risk reduction.

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Current data does not support the routine use of isotonic sodium bicarbonate infusions for the prevention of CIN.

Bicarbonate infusions should not be administered to patients with pulmonary edema, uncontrolled hypertension (SBP>160 or DBP >100, or patient at high risk for severe fluid overload.

Some studies and meta-analyses of patients undergoing cardiac angiography have shown intravenous volume expansion with sodium bicarbonate to be superior to 0.9% saline in reducing the risk of PC-AKI but the results are not considered definitive.

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N-acetylcysteine (NAC) is a thiol compound with antioxidant and vasodilatory properties. A possible mechanism of benefit in CIN involves minimizing both vasoconstriction and oxygen free radical generation after radio contrast administration.

Dose: Preferred oral dose is 1200mg twice daily on the day before and on the day of procedure to patients at risk of CIN.

Patients requiring emergent coronary angiography or procedures, in whom preventive therapy with oral NAC cannot be given the day before, has been treated with IV acetylcysteine.

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Effiacy of NAC to reduce the incidence of CIN is controversial.

There is evidence that it reduces serum creatinine in normal volunteers without changing cystatin-C which raises the possibility that NAC might be simply lowering serum creatinine without actually preventing renal injury.

NAC should not be considered a substitute for appropriate pre-procedural patient screening and adequate volume expansion.

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DIURETICS: Solomon et al reported no benefiial

effects from the osmotic diuretic mannitol when it was added to IV saline solution in patients with or without diabetes mellitus.

There was an exacerbation of renal dysfunction when the loop diuretic furosemide was used in addition to IV saline solution.

Neither mannitol nor furosemide is recommended for CIN risk reduction.

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3. Contrast volume and frequency: Minimize amount of contrast administered (< 2 ml/kg or max of 150 mL)

Lowest rates of CIN were seen in patients receiving less than 100 to 140 mL.

CM volumes in excess of 5mL/kg strongly predict nephropathy requiring dialysis.

A significantly increased risk of CIN has also been demonstrated among patients who received a second dose of CM within 48 hours

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4. RENAL DIALYSIS: CM can be easily removed with hemodialysis,

however there is no evidence that this removal reduces the risk of CIN.

Since the CM would reach the kidneys within one or two cardiac cycles and subsequent removal of CM is unlikely to stop the cascade of renal injury, which would have already begun.

Patients receiving dialysis are also at theoretical risk from the osmotic load imposed by intravascular iodinated contrast medium because they cannot readily clear the excess intravascular volume which may result in pulmonary edema and anasarca.

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In patients at risk for fluid overload, low osmolality or iso-osmolality contrast media should be employed with dosing as low as necessary to achieve a diagnostic result.

Most low-osmolality iodinated contrast media are not protein-bound, have relatively low molecular weights, and are readily cleared by dialysis.

Unless an unusually large volume of contrast medium is administered, or there is substantial underlying cardiac dysfunction, there is no need for urgent dialysis after intravascular iodinated contrast medium administration.

Alternative to Iodinated Contrast:

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Any appropriate non iodinated contrast agents may be used as alternative to iodinated contrast.

For example, Gadolinium agents are recommended as alternatives to iodinated contrast agents especially for coronary angiography.

Gadolinium-based contrast media (GBCM) have been approved for parenteral use since the late 1980s.

GBCM are extremely well tolerated by the vast majorityof patients in whom they are injected.

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Adverse effects: Most reactions are mild and physiologic, including coldness, warmth, or pain at the injection site; nausea, vomiting; headache; paresthesias; and dizziness.

GBCM administered to patients with acute kidney injury or severe chronic kidney disease can result in a syndrome of nephrogenic systemic fibrosis (NSF).

Nephrogenic systemic firosis (NSF) is a firosing disease, primarily involving the skin and subcutaneous tissues but also known to involve other organs, such as the lungs, esophagus, heart, and skeletal muscles.Initial symptoms typically include skin thickening and/or pruritis.

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NOVA(Noninvasive Optimal Vessel Analysis), a noninvasive MRI study that is noncontrast-based invented by Dr. Fady Charbel, head of the department of neurosurgery at the University of Illinois at Chicago, approved by FDA in 2001.

NOVA is a flow analysis system that works with magnetic resonance imaging to produce a 3-D model of the vasculature and quantify vessel blood flow. It is used to diagnose conditions such as stroke and aneurysms.

REFERENCES:

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1. ACR Manual on Contrast media Version 10.1, 2015. Page 33-45, 79,83.

2. Owen RJ, Hiremath S, Myers A, Fraser-Hill M, Barrett B. Canadian association of radiologists. Consensus guidelines for the prevention of contrast induced nephropathy. June 17 2011

3. Vijay SK, Tiwari BC, Singh AK. Contrast induced nephropathy: Pathophysiology and prevention. Heart India 2013;1:39-45.

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4. David J. Spinosa, MD John A. Kaufmann, MD Gary D. Hartwell, DSc – Gadolinium chelates in angiography and interventional radiology, Radiology 2002; 223:319–325

5. Molecular Imaging: Principles and Practice, Mark A. Borden, Shenping Qin, and Katherine W. Ferrara Ultrasound Contrast Agents Pg 425,429.

6. VasSol NOVA vassolinic.com7. Jessica B. Robbins, Myron A. Pozniak,

Contrast Media Tutorial, radiolody.wisc.edu 2010.

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