Contrast Induced Acute Kidney Injury

Contrast-induced nephropathy (CIN) is generally a reversibleform of acute kidney injury (AKI) that occurs soon after theadministration of radiocontrast media.

Sandler CM. Contrast-agent-induced acute renal dysfunction – is iodixanol the answer? N Engl J Med.

2003;348(6):551–3.

Mehran R, Nikolsky E. Contrast-induced nephropathy: definition, epidemiology, and patients at risk.Kidney Int Suppl. 2006(100):S11–5.

an absolute increase in serum creatinine of ≥0.5 mg/dL or a ≥25% relative increase

in serum creatinine from

the baseline value

at 48–72 hours after exposure

to contrast agent, peaks at

3–5 days

in the absence of alternative

causes for acute kidney

injury

Definition:

KDIGO Definition

CI-AKI is defined by the Kidney Disease Global Outcomes

(KDIGO) guidelines as an “increase in serum creatinine of 0.3

mg/dL or greater within 48 hours of contrast use or a 50% or

greater increase from baseline serum creatinine within 7 days”

• or an increase in cystatin C >10%

From Kidney disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group.

KDIGO CLINICAL PRACTICAL GUIDELINES FOR ACUTE KIDNEY INJURY.

Kidney Int 2012;Suppl 2:1 -138;

Is relative increase in serum creatinine more important than absolute increase in serum creatinine, does it matter much?

1 2 3 4 Weeks

SerumCreatinine

In most cases, the decline in renal

function is mild andtransient

S. Cr. usually returns

to the baseline value

after 1–3 weeks

Some patients have

a persistent decline

in renal function and

require RRT

(in patients with CINrisk factors)

CI -AKI Cholesterol Embolization

INCIDENCE 2% (14.5%) 0.15% (usually underestimated)

At risk CKD, DM2 Abdominal aortic aneurysm,

Diffuse atherosclerosis

Prediction Risk score Episodic HTN, eosinophilia

Signs Usually asymptomatic Signs of peripheral

embolization (livedo reticularis,

abdominal foot pain, purple

toes

Decreased urine output

Course Develops within in 24-48 hrs Develops slowly over weeks to

months.

Returns to baseline in 1-3

weeks

Progress to frank renal failure

(50%)

Renal replacement therapy -

dialysis

Usually not needed (2%) Half of the patient progress to

frank renal failure requiring

dialysis

Incidenceof CIN

RiskFactors

ContrastDose

Type of Radiologic procedure

ContrastType

According to the FDA, the incidence of renal failure aftercontrast administration, ranged from 0.6% to 2.3%.

However, rates of CIN may be as high as 50%, depending onthe presence of well characterized risk factors, the mostimportant of which are baseline chronic renal insufficiencyand DM.

Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after

percutaneous coronary intervention. Circulation. 2002;105(19):2259–2264.

Impact:

• Radiographic contrast media is the third most common causeof hospital acquired renal failure (after decreased renalperfusion and nephrotoxic medications), accounting for 11%of cases.

• In-hospital mortality rate of CIN: as high as 14%.

• Differential diagnosis: cholesterol embolism : can be difficultto distinguish: in elderly men, may have cutaneous signs.

Nash et al. Am J Kidney Dis 2002

Mortality Risk:

• Rihal et al. 2002, in a retrospective study of 7,586 patients noted a CINincidence of 3.3% and a 22% vs. 1.4% in-hospital mortality for patientswith CIN.

• McCullough et al. 1997 reported a mortality rate of 7.1% for CIN, 35.7% ifpatient required HD, vs. 1.1% for no CIN. 2 year mortality was 81.2% forHD patients.

• Significant association was found between >25% Creatinine increase andone year mortality (Gruberg et al, 2000).

How to Assess Renal Function?

Abbreviated Modification of Diet in Renal Disease equations (MDRD) equation:

eGFR, ml/min/1.73 m2= 186 x (Serum Creatinine [mg/dL]) -1.154 x (Age-0.203x (0.742 if female) x (1.210 if African American)

(140- age) x Body Weight [kg]*Creatinine Clearance, ml/min =

* Multiple by 0.8 in female

Cockcroft-Gault equation:

Serum Creatinine mg/dL] x 72

Pathophysiology:

• Poorly understood, complex syndrome, little known about underlyingcellular mechanism.

• Available contrast media: diverse family (ionic, nonionic, high/low/iso-osmolar)

• Biphasic response or immediate vasoconstriction (dose dependent) andreduction of renal blood flow (up to 50%, lasting for hours).

• Subsequent stasis of contrast causes:

– direct tubular injury and death (osmotic nephrosis - intense focal or diffusevacuolization of the proximal tubules - or overt tubular necrosis.

– vasoconstriction through Ca influx causing regional cortico-medullary andouter medullary blood flow reduction

• Endothelins (if contrast >150 ml), adenosine (prolongedvasoconstriction, A1 receptors) and angiotensin II releasedcausing vasoconstriction.

• Nitric oxide production reduced (in proportion to osmolalityof agent), reactive oxygen species production (due tohypoperfusion) increased.

• Iron plays a role in oxidative injury in CIN - ?role of ironchelation therapy.

• Chronic Kidney Disease (CKD) predisposes to the developmentof contrast-induced acute kidney injury (AKI).

• Any superimposed insult such as sustained hypotension,microshowers of atheroembolic material from catheterexchanges, use of IABP, or a bleeding complication can amplifythe injury processes occurring in the kidney.

Factors Involved In CIN Pathogenesis

In the presence of a reduced nephron mass, the remaining nephrons are vulnerable to injury. Iodinated contrast, after causing a brief (minutes) period of

vasodilation, causes sustained (hours to days) intrarenal vasoconstriction and ischemic injury. The ischemic injury sets off a cascade of events largely driven by

oxidative injury causing death of renal tubular cells. If a sufficient mass of nephron units are affected, then a recognizable rise in serum creatinine will occur

Risk Factors:

To assess the cumulative risk of several variables on renalfunction, a simple CIN risk score that could be readily applied wasdeveloped.

Predicting the Risk of CIN after PCIMehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after

percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393-9.

CIN

• There is no specific treatment once CI-AKI develops, andmanagement must be as for any cause of ATN, with the focus onmaintaining fluid and electrolyte balance.

• The best treatment of contrast-induced kidney injury isprevention.

Prevention

Imaging studies not requiring• Consider alternate contrast medium.

• The use of lower doses of low or iso-osmolal nonionic contrastagents and avoidance of repetitive studies that are closely spaced(within 48 to 72 hours).

• Avoidance of volume depletion.

Contrast agents:

• A decreased incidence of contrast nephropathy appears to beassociated with nonionic agents, which, are either low osmolal(500 to 850 mosmol/kg) or iso-osmolal (approximately 290 mosmol/kg).

Lautin EM, Freeman NJ, Schoenfeld AH, et al. Radiocontrast-associated renal dysfunction: a comparison of lowerosmolality and conventional high-osmolality contrast media. AJR Am J Roentgenol 1991;157:59.

IODIXANOL vs. LOCM

• NEPHRIC trial: iodixanol vs iohexol: diabetics, serum creatinine -1.5 -3.5 mg/dl (3% vs. 26%, p=0.02).

NEJM 2003;348(6):491-9.

• RECOVER trial: iodixanol vs ioxaglate: (7.9% vs. 17%, p=0.021), in patients with severe CKD (12.5% vs. 53.3%), diabetics (10.4% vs 26.5%).

JACC 2006;48(5):924-30.

• CARE trial: iopamidol: contrary findings: moderate to severe CKD patients, no difference in CIN (6.7% vs. 4.4% p=0.39)

Circulation 2007;115(25);3189-96.

• VALOR trial: ioversol: (21.8% vs.23.8%).

Am H J 2008;156(4);776-82.

IMAPCT trial, PREDICT trial, ACTIVE trial: no difference in nephrotoxicity.

• LOCM vs. IOCM: meta-analysis of 16 studies with 2763 patients.

• No difference when IOCM compared to LOCM collectively.

• Iodixanol (IOCM) had lower incidence of CIN when compared to ioxaglate and iohexol (Omnipaque) separately.

• No difference when compared to other agents.

• Most of the studies indicate that the higher volume of CM isespecially deleterious in the presence of other risk factors, withlower doses of contrast being safer, but not free of risk.

• Even relatively low doses of contrast (less than 100 ml) can inducepermanent renal failure and the need for dialysis in patients withchronic kidney disease.

• Intra-arterial administration is associated with higher rate of CINand LOCM is more beneficial over HOCM than with intravenoususe.

Vlietstra RE, Nunn CM, Narvarte J, Browne KF. Contrast nephropathy after coronary angioplasty inchronic renal insufficiency. Am Heart J 1996; 132: 1049–1050.

Studies in 1990’s calculated the dose of contrast to be given to the patients at risk for CIN:

< 5ml/kg / S. Creatinine (Max. 300 ml)

A ratio of <3.7 for the volume of contrast media to creatinine clearance has also been proposed as a stricter limit.

• Concomitant nephrotoxic drugs such as NSAID and nephrotoxicantibiotics, ACEI and diuretics should be discontinued 48 hoursprior to contrast administration.

• Metformin should be discontinued on the day of the proposedCM administration and for the subsequent 48 hours.

Goals of Hydration

• Maintain of sufficient intravascular volume to increase renalperfusion.

• Establishment of adequate diuresis prior to contrast media.

• Avoidance of hypotension.

• Solomon et al. (1994 NEJM) published that 0.45% NS wasmore effective in preventing CIN than IV mannitol orfurosemide (11% vs 28% vs 40%)

• Isotonic saline is superior to one-half isotonic saline since isotonic saline is a more effective volume expander.

• In a study by Mueller et al, intravenous administration of isotonicsaline was found to be superior, compared with half-isotonicsaline, in reducing the rates of CIN after percutaneous coronaryintervention (0.7% versus 2%, respectively).

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;162(3):329–336.

Since alkalinization may protect against free radical injury, the possibility that sodium bicarbonate may be superior to isotonic saline has been examined in a number of randomized trials and meta-analyses.BOSS (Bicarbonate or Saline Study): TCT 2013, no difference in the incidence of CIN in patients with CKD 3,4,5 undergoing CAG.

• The results were conflicting as some showed a significantly lower rate of contrast-induced nephropathy with sodium bicarbonate, while others found equivalent rates.

• 10 clinical trials in the past 5 years (largest trial 502 patients).• 6 had lower incidence of CIN in the NaHCO3 group, 4 showed no significant

benefits

• 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; 115:1211.

• Vasheghani-Farahani A, Sadigh G, Kassaian SE, et al. Sodium bicarbonate plus isotonic saline versus saline for prevention of contrast-induced nephropathy in patients undergoing coronary angiography: a randomized controlled trial. Am J Kidney Dis 2009; 54:610.

• IVF = 1 mL/kg/hr (Max 100 ml/hr) 12 hours pre & 12 hours post contrast

• CHF or left ventricular ejection fraction (LVEF) < 40%?

0.5 ml/kg/hr (Max 50 ml/hr) 12 hrs pre & postcontrast

• Emergent procedure? (suggested regimen):

Fluid bolus of 3ml/Kg prior to procedure. Hydration during procedure and 12 hrs after if possible (dependent on clinical status)

• Given that an increasing number of individuals receive contrast asoutpatients, this trial has evaluated the effectiveness of oral hydration inpreventing contrast nephropathy.

• 53 patients were randomly assigned to either unrestricted oral fluids orto normal saline at 1 mL/kg per hour for 24 hours beginning 12 hoursprior to the scheduled catheterization. AKI was significantly morecommon with oral hydration (35 versus 4 %).

IVF = 150 meq of sodium bicarbonate in 850 ml of D5W

3 ml/kg bolus (Max 300 ml) 1 hour prior to procedure and 1 mL/kg/hour (Max 100 ml/hr) during and for 6 hours post-procedure.

Glycemic control issues (including patients with diabetes)? Consider mixing sodium bicarbonate in 1 liter of sterile water instead of D5W

• There are great heterogeneity and conflicting resultsavailable clinical trials and meta-analyses examining

in the the

in the prevention of contrasteffectiveness of acetylcysteinenephropathy .

• Being a precursor for glutathione synthesis, NAC has the potentialto diminish oxidative stress by directly scavenging superoxideradicals and increasing intracellular glutathione.

Drager LF, Andrade L, Barros de Toledo JF, Laurindo FR, Machado Cesar LA, Seguro AC. Renal effects of Nacetylcysteine in patients at risk for contrast nephropathy: decrease in oxidant stress-mediated renal tubularinjury. Nephrol Dial Transplant. 2004;19(7):1803–7.

N acetyl Cysteine

• This trial studied 83 patients with chronic renal insufficiency whowere undergoing computed tomography.

• Patients were randomly assigned either to receive the antioxidantacetylcysteine (600 mg orally twice daily) and 0.45 percent salineintravenously, before and after administration of the contrastagent, or to receive placebo and saline.

• Conclusion:

Prophylactic oral administration of acetylcysteine, along withhydration, prevents the reduction in renal function induced by thecontrast.

• 2308 patients undergoing angiography received eitheracetylcysteine (1200 mg orally twice daily) or placebo on the daybefore and after angiogram.

• Patients had at least one of the following risk factors: age >70years, CKD, diabetes mellitus, heart failure or LV ejection fraction<45 percent, or shock.

• There was no difference in the development of CI-AKI (12.7percent in both groups).

Since the agent is potentially beneficial, well tolerated, and relatively inexpensive, 2012KDIGO guidelines that suggest administration of acetylcysteine to patients at high risk.

Acetylcysteine Dosing

Tolerating PO intake?600-1200 mg capsules PO Q12h X 4 doses2 doses pre-contrast and 2 doses post-contrast isoptimalEmergent Procedure?

1 dose before and 3 doses post cath or procedure is acceptable (Q12h x 4 doses total)IV Acetylcysteine?

600-1200 mg IV x 1 over 15 minutes, then 600-1200 mg PO/PT q12h x 4 dosespost-procedure: For a high risk patient undergoing cardiac catheterization orPE protocol CT scan with no POaccess

• Statins may improve endothelial function, reduce arterial stiffness, and reduce inflammation and oxidative stress.

• There are no sufficient data to support the use of statins solely for the prevention of contrast nephropathy.

Sugiyama M, Ohashi M, Takase H, et al. Effects of atorvastatin on inflammation and oxidative stress.

Heart Vessels 2005; 20:133.

Statins

• 2998 patients with type 2 diabetes and CKD were assigned to receiverosuvastatin or to a control group prior to a diagnostic angiogram withor without percutaneous intervention.

• Patients assigned to rosuvastatin received 10 mg daily two days priorand three days after the scheduled procedure.

• Contrast-induced was less common among patients assigned torosuvastatin compared with control (2.3 versus 3.9 percent,respectively).

• A prospective, single-center study of 304 patients with baselineestimated creatinine clearance <60 ml/min were randomized to receiveatorvastatin 80 mg/day or placebo for 48 hours before and 48 hoursafter contrast medium administration.

• All patients received intravenous saline hydration and oral N-acetylcysteine 1,200 mg 2 times/day.

• CIN occurred in 31 patients, 16 (11%) in the placebo group and 15 (10%)in the atorvastatin group (no benefit of atorvastatin compared withplacebo).

• PRATO-ACS Trial: Benefit seen.

• Systematic review (Xhang, Am J Nephrol, 2011) found 6 cohort studies and6 RCTs. Heterogeneity found among studies.

• 4/6 cohort studies found chronic statin therapy beneficial

• Most RCTs failed to show benefit.

• Chronic statin therapy may be more beneficial than only around the timeof administration

• Dose of beneficial statin uncertain

• Low-dose dopamine failed to show a protective effect on renal functionin patients undergoing contrast media exposure, and was evenassociated with a deleterious effect on the severity of renal failure andits duration.

Gare M, Haviv YS, Ben-Yehuda A, et al. The renal effect of low-dose dopamine in high-risk patientundergoing coronary angiography. J Am Coll Cardiol. 1 999;34(6):1682–1688.

Dopamine

• Fenoldopam is a specific dopamine-1 receptor agonist that augments renal plasma flow while decreasing systemic vascular resistance.

• A prospective randomized trial (CONTRAST) assessed the effectivenessof fenoldopam in 315 patients undergoing a cardiovascular procedurewho had CKD with an estimated creatinine clearance <60 mL/min.

• Unfortunately it also fails to reduce CIN incidence in CKD patients.

Vasoactivedrugs

• In a retrospective series of 285 patients, Weisz et al. reported a 71%decreased in CIN incidence with local fenoldopam therapy (0.05–0.8μg/kg/min).

Weisz G, Filby SJ, Cohen MG, Allie DE, Weinstock BS, Kyriazis D, et al. Safety and performance of targeted renal therapy: the Be- RITe! Registry. J Endovasc Ther. 2009;16(1):1–12.

Theophylline

• The clinical benefit of the competitive adenosine antagonisttheophylline is debated.

• In a randomized study by Huber et al, prophylactic intravenousadministration of theophylline 200 mg reduced the incidence of CIN in100 patients at risk, as compared with placebo (4% versus 16%).

• However, in other randomized studies, administration of theophyllinedid not provide any benefit in reduction of CIN rates compared withplacebo.

Huber W, Ilgmann K, Page M, et al. Effect of theophylline on contrast material-nephropathy in patients withchronic renal insufficiency: controlled, randomized, double-blinded study. Radiology. 2002; 223(3):772–779.

• Shammas NW, Kapalis MJ, Harris M, McKinney D, Coyne EP. Aminophylline does not protect against radiocontrastnephropathy in patients undergoing percutaneous angiographic procedures. J Invasive Cardiol. 2001;13(11):738–740.

Prostaglandins E1

• A 20 ng/kg/min PGE1 infusion has a significant protective effect on post-PCI SCr elevation.

• But higher infusion rates are not associated with increased benefits, probably due to the associated decrease in systemic blood pressure.

Koch JA, Plum J, Grabensee B, Modder U. Prostaglandin E1: a newagent for the prevention of renal dysfunction in high risk patients caused by radiocontrast media? PGE1 Study Group. Nephrol DialTransplant. 2000;15(1):43–9.

Calcium channel Blockers

• In a small, randomized, placebo controlled study of 35patients, eGFR was preserved in patients treated withnitrendipine but decreased in patients that received placebo.Neumayer HH, Junge W, Kufner A, Wenning A. Prevention of radiocontrast-media-inducednephrotoxicity by the calcium channel blocker nitrendipine: a prospective randomisedclinical trial.Nephrol Dial Transplant. 1989;4(12):1030–1036.

• By contrast, in three other studies, the change in serumcreatinine level did not differ significantly with calciumantagonists.

Carraro M, Mancini W, Artero M, et al. Dose effect of nitrendipine on urinary enzymes andmicroproteins following non-ionic radiocontrast administration. Nephrol Dial Transplant.1996;11(3):444–448.

Atrial Natriuretic Peptide:

• Morikawa et al. (JACC 2009) single center RCT ANP+IVF or IVF alone

• ANP at 0.042 mcg/kg/min 4-6 hours prior and 48 hours past

• eGFR at 24, 48 hours, 1 week and 1 month

• Slight benefit of ANP in Creatinine, no benefit in HD/ Hospital rateadmission

• Prior studies were negative, but this one had lower ANP dose for longertime

• No conclusive evidence yet, would need larger trials.

Methods to guide fluid repletion

Left ventricular end-diastolic pressure

RenalGuard System

Brar SS, Aharonian V, Mansukhani P, et al. Haemodynamic-guided fluid administration for the prevention of contrast-induced acute kidney injury: the POSEIDON randomised controlled trial. Lancet 2014; 383:1814.

Briguori C, Visconti G, Focaccio A, et al. Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II):RenalGuard System in high-risk patients for contrast-induced acute kidney injury. Circulation 2011; 124:1260.

Left ventricular (LV) end-diastolic pressure

• A randomized trial tested the benefit of a fluid replacement protocolguided by LV end-diastolic pressure among patients with CKD and otherrisk factors for CIN.

• In this trial, 350 patients were assigned to LV end-diastolic pressure-guided fluid management or to a control group.

• All patients received intravenous isotonic saline 3 mL/kg for one hourprior to cardiac catheterization. LV end-diastolic pressure wasdetermined in all patients prior to administration of contrast.

• Both groups received intravenous fluid throughout and for four hours following the procedure.

IV infusion rate

LV end-diastolicpressure

<13 mmHg

5 mL/kg/hour

13 - 18 mmHg

3 mL/Kg/hour

>18 mmHg

1.5 mL/Kg/hour

Control 1.5 mL/kg/hour

Contrast-induced AKI occurred less

frequently in the LV end-diastolic

pressure group, compared with

control (6.7 versus16.3, respectively).

RenalGuard system

Forced diuresis (RenalGuard System):

Treatment protocol for the RenalGuard System. Source: Reproduced with permission from PLC Medical Systems.

• Contrast-induced acute kidney injury occurred in 16 of 146 patients in the RenalGuard group (11%) and in 30 of 146 patients in the control group (20.5%).

• Conclusion:RenalGuard therapy, including hydration with normal saline plus high doses of NAC in combination with a limited (0.25 mg/kg) dose of furosemide, seems to be an effective renoprotective strategy for patients at high risk for CI-AKI.

The CI-AKICOR System

Comprises an 11Fr coronary sinus aspiration catheter that is inserted through the jugular vein. On activation,it exerts a vacuum effect and removes contrast from the coronary sinus.

Hemodialysis

• Iodinated contrast agents are readily dialyzable.

• The plasma clearance of most modern contrast media is 50–70 mL/ min,with more than 80% removed from the plasma within 4–5 hours ofhemodialysis.

• However, Reduction of CIN with dialysis is also not biologically plausiblesince the CM would reach the kidneys within one or two cardiac cycle.

• Subsequent removal of CM is unlikely to stop the cascade of renalinjury, which would have already begun.

Dawson P. Contrast agents in patients on dialysis. Semin Dial. 2002;15(4):232–236.

Hemofiltration

• In patients with chronic renal failure who are undergoingpercutaneous coronary interventions, periproceduralhemofiltration given in an ICU setting appears to be effective inpreventing the deterioration of renal function due to CIN and isassociated with improved in-hospital and long-term outcomes.

Marenzi G, Marana I, Lauri G, et al. The prevention of radiocontrast-agent-induced nephropathy by

hemofiltration. N Engl J Med 2003; 349:1333.

• A 2012 meta-analysis that included eight studies of hemodialysisand three studies of hemofiltration/hemodiafiltration showed nobenefit of RRT.

• Routine hemofiltration or hemodialysis for the prevention of contrast nephropathy in patients with CKD is not recommended.

Cruz DN, Goh CY, Marenzi G, et al. Renal replacement therapies for prevention of radiocontrast-induced nephropathy: a systematic review. Am J Med 2012; 125:66.

Novel Approaches:

Large studies of Oral/ Intravenous antioxidants (Deferiprone).

Intrarenal infusions of renal vasodilators using flow directedcatheters.

Systemic Cooling.

Novel, less toxic forms of radio - opaque contrast agents.

Take Home Message !!