Contrast-induced Acute Kidney Injury

DM Seminar

Dr. Vishal Golay16/11/11

• Iodinated contrast medium was first used in 1954.

• Association of contrast use with renal impairment was first made with use of iodopyracet, a di-iodinated pyridine derivative ≥ 50yrs ago

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Prevention

Recognition of high risk groups.

controversy

• It is one of the common causes of AKI hospitalized patients.

• CI-AKI was reported to be the third most common cause of AKI in hospitalized patients.

Nash et al. AJKD 2002;39:930-6.

• Reported incidence varies from 1.7-2% of patients without predisposing factors and up to 10-45% of patients with predisposing factors.

All agents are chemical modifications of a 2,4,6-tri-iodinated benzene ring.

Contrast agentsClass Agents Osmolality

(msom)Osmolality (compared to plasma)

High-osmolar

Ionic monomers

Iothalamate (conray)Diatrizoate (hypaque)Metrizoate

1400-2000 5-8

Low-osmolar

Non-ionic monomers

Iohexol (omnipaque)Ioversol (optiray)IopamidolIopromide

600-800 2-3

Ionic dimer Ioglaxate

Iso-osmolar Nonionic dimer

Iodixanol(visipaque)Iotrolan

300 1

CIN consensus working panel(2006)

• Consensus statement 6: In patients at increased risk for CIN undergoing intra-arterial administration of contrast, ionic high-osmolality agents pose a greater risk for CIN than low-osmolality agents. Current evidence suggests that for intra-arterial administration in high-risk patients with chronic kidney disease, particularly those with diabetes mellitus, nonionic, iso-osmolar contrast is associated with the lowest risk of CIN.

• Consensus statement 7: Higher contrast volumes (>100 mL) are associated with higher rates of CIN in patients at risk. However, even small (30 mL) volumes of iodinated contrast in very high-risk patients can cause CIN and acute renal failure requiring dialysis, suggesting the absence of a threshold effect.

• Consensus statement 8: Intra-arterial administration of iodinated contrast medium appears to pose a greater risk for CIN above that with intravenous administration.

CARE Study• It was a multicenter, randomized, double-blind

comparison of iopamidol and iodixanol in patients (414 pts) with chronic kidney disease (eGFR, 20 to 59 mL/min) who underwent cardiac angiography or PCI.

• There was no statistical difference in the development of CI-AKI after IA inj of either of the agents even in those with and without diabetes.

• Thus, either agent can be safely used for coronary interventions in patients with renal insufficiency

Circulation. 2007;115:3189-3196

Radiology 250(1); January 2009

Iodixanol is not associated with a significantly reduced risk of CIN compared with the LOCM pooled together.

Left ventricular &-----: 30-45 mLaortic angiographyPCI-----------------------:150-200 mLCECT scan--------------:uses 100-150 mL IVU-----------------------:100-mL bolus of a 50%–60% (weight-to-volume ratio) contrast material.FFA uses Na fluorescein and not assoc with CIN

Definition

• In 2008, contrast-induced acute kidney injury (CIAKI) was proposed as the consensus name for what was formerly termed ‘contrast-induced nephropathy’

Arch. Intern. Med. 168, 1325–1332 (2008).

Defined by a fixed (0.5 mg/dl [44 μmol/L]) or proportionate (25 %) rise in serum creatinine levels assessed 48 hours after exposure to the contrast medium, in the absence of any other

apparent cause.

Risk factors

Patient related factors:

• Renal insufficiency.• Diabetic Nephropathy.• Advanced age (>75 yrs).• Effective volume depletion-

– Dehydration.– CHF.– CLD– Nephrotic syndrome– Hypotension

• Concomitant exposure to nephrotoxins

• Myeloma• Male gender.• Hypertension• Transplanted kidney• Hyperuricemia• Proteinuria• Anemia

Risk factors contd…..

Procedure related factors:• Type of radiocontrast medium (HOCM>LOCM/IOCM).• Dose of contrast used.• Repeated exposure to radiocontrast material within 72

hours.• Mode of administration (IA>IV)• Primary coronary intervention for acute MI

Risk factors contd…..

• Many risk factors are covariates rather than independent variables. This may account for reports that fail to determine causality of independent variables.

• Incidence increases proportional to the number of cosexisting risk factors.

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number of risk factors

Arch Intern Med 1990;150

INCI

DEN

CE in

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Renal insufficiency & risk of CI-AKI

• The risk of CIAKI increases marked when CCl<60ml/min & rises further when other risk factors are present.

• Reduced GRF makes the functioning nephrons secrete greater load of contrast.

• Lack of functional reserve to buffer acute losses in glomerular filtration.

• Studies show that risk dramatically increases at lower GFR.

Evaluation of risk

• Proper history and physical examination is imperative.

• Various risk-prediction models have been developed for pts undergoing PCI.

• Serum creatinine at baseline should be checked if the contrast is being given IA or any risk factors are present. GFR should be calculated.

• Always consider alternate imaging techniques in those with risk factors.

N Engl J Med 2006;354:379-86.

Course and Prognosis

• 1% may need dialysis & in those with severe involvement, 30% may have residual renal impairment..

• At 1 year after PCI, the mortality rate in patients undergoing dialysis had increased to 45.2%, compared with 35.4% in patients with CIN not requiring dialysis and 19.4% in patients who did not develop CIN.

Creat rise Creat peak Return to baseline

Non-oliguric CIAKI

48hours 3-5 days 10-14days

Oliguric CIAKI 48 hours 5-10 days 14-21 days

In a study on 200 patients undergoing PCI for acute MI, patients who developed CIN had a longer hospital stay (13 ±7 days as compared with 8 ±3 days in subjects without CIN; p<0.001) and a more complicated clinical course, in addition to a significantly increased risk of death.

J Am Coll Cardiol 2004;44:1780 –1785

Pathogenesis

Contrast Induced AKI

Direct tubular toxicity

Oxidative stress

Vasoconstriction

Vasoconstriction

• CIAKI is primarily an ischemic form of AKI caused by the vasoconstrictive properties of contrast media.

• Animal studies show a biphasic response after contrast injection. There is an initial renal vasodilation followed by intense and prolonged (3 hrs) vasoconstriction.

• There is a selective decrease in the medullary blood flow and oxygen saturation due to an imbalance between vasodilators and vasoconstrictors

• The principal vasoconstrictors are Adenosine and Endothelin.

• Contrast media seem to reduce renal blood flow directly through afferent arteriole vasoconstriction via activation of adenosine receptor A1.

• In concert, contrast agents also disrupt the vasodilatory systems like NO and prostaglandins bringing about an intense vasocontriction and reduced medullary bloos supply

Oxidative stress

• The intense vasoconstriction and loss of autoregulatory capacity can contribute to additional renal injury through the release of reactive oxygen species (eg, superoxide [OH].).

• Damage is due to overwhelming of the anti-oxidant factors by the excess generation of ROS.

• Underlying diseases like CKD and Diabetes already have high ROS and thus predisposes for CIN.

• Benefit of anti-oxidants gives an indirect clue.

Direct tubular toxicity

• Marked osmotic diuresis is observed following contrast administration.

• “osmotic nephrosis”

• The most common histopathologic features of this disorder include intense focal or diffuse vacuolization of the proximal tubules or overt tubular necrosis.

Prevention of CI-AKI

• Only 40% of patients with GFR <60ml/min receive any form of preventive measures.

• Even when they do so, the strategy is not a standardized one.

Hydration

• The benefit of hydration in prevention was detected by retrospective analysis, and trials on benefit of hydration is limited by absence of controls.

• However, it remains the most efficient method of prevention of CI-AKI.

• IV crystslloids are given @1-1.5ml/kg/hr, beginning 12 hrs before the procedure and continuing up to 6-24 hrs after it.

Hydration contd….

The mechanisms by which IV hydration decreases the risk of CI-AKI are:

• IV half-normal (0.5 N) saline may cause an increase in free water excretion, leading to dilution of the contrast agents within the tubule lumen.

• 0.9% saline was found better probably due to increased delivery of sodium to the distal nephron, leading to reduced activation of the RAS via the macula densa.

• Intravenous volume expansion would also minimize reductions in the renal production of nitric oxide.

Hydration contd….

• Mueller et al compared hydration with 0.45% and 0.9% NaCl in 1620 patients who were undergoing cardiac catheterization. The incidence of CIN was 2% and 0.7% respectively (p=0.04). The benefit was more in those with diabetes.

Arch. Intern. Med. 162, 329–336 (2002).

• Two small studies suggest that sustained fluid administration within 12 h before and within 12 h after administration of contrast medium is superior to bolus administration at the time of contrast administration

Clin. Nephrol. 62, 1–7 (2004).J. Invasive Cardiol. 15, 699–702 (2003).

Hydration contd….

• In an emergency situation full preprocedure volume expansion is not possible, and there is a lack of published evidence to guide clinicians about appropriate alternatives.

• The CIN Consensus Working Panel agreed that in emergency situations, where the potential benefit from an urgent investigation outweighs the risks of waiting, the procedure can be undertaken without knowledge of renal function, which precludes risk stratification according to renal function.

• Hence, clinical judgment is needed.• Appropriate postprocedure intravenous fluids should be

given.

Sodium bicarbonate

• The beneficial role of sodium bicarbonate was first studied by Merten et al. (RCT of 119 patients). Significant reduction in CIN with NaHCO3 as compared to NaCl infusion.

JAMA 291, 2328–2334 (2004)

.• NaHCO3 is given at a dose of 3ml/kg/hr infusion for 1

hr before procedure of a 154mEq/L NaHCO3 solution which is continued post procedure @ 1mL/kg/hr for 6 hours.

Sodium bicarbonate contd…

• The role of bicarbonate is unclear and controversial. It might be related to an increase in tubular fluid pH level and prevent the formation of free radicals.

• But bicarbonate is a pro-oxidant specially in the presence of ROS.

• In vitro studies also showed that although NAC and ascorbic acid prevented contrast induced apoptosis of tubular cells, bicarbonate failed to do so.

1. This metanalysis highlights that the perceived benefit of sodium bicarbonate is largely driven by small, underpowered RCTs with extreme treatment effects and wide CIs.

2. Among the large randomized trials there was no evidence of benefit for hydration with NaHCO3 compared with NaCl for the prevention of CI-AKI.

Clin J Am Soc Nephrol 4: 1584–1592, 2009

Trials those who included patients with CKD2-4 as well as normal renal function.

1. Although the summary of the published data favours bicarbonate but this is due the effect of the smaller, poorer quality trials .

2. In summary this metanalaysis concluded that the benefit of bicarb may be over-estimated and the routine clinical use recommendation maybe still premature

This meta-analysis demonstrated a higher incidence of CI-AKI than recently reported, with important variation among different Cohorts

There was a protective effect of sodium bicarbonate on the risk of CI-AKI, especially in patients who underwent coronary procedures and those with CKD, without effect on need for RRT or mortality.

Due to the borderline statistical significance, the relative lowquality of the individual studies, heterogeneity and publication bias, only a limited recommendation can be made in favour of the use of sodium bicarbonate.

N-Acetylcysteine

• Due to the role of ROS in the pathogenesis of CI-AKI it was postulated that NAC, an antioxidant may be helpful in preventing the development of CI-AKI.

• NAC induces glutathione synthesis. It also plays a role in counteracting vasoconstriction by ↑NO

• First benefit was reported by Tepel et al in 2000 in a trial published in NEJM. (NAC+hydration was compared with hydration with 0.45% NaCl alone).

• Some other trial published after that showed ambiguous results.

The ambiguity of these initial results could have been due to many factors. The main reasons could have been:1. The dose of NAC was low.2. The ROS generation lasts much longer than anticipated.3. It is the peak levels of NAC during the procedure that is more

important.

This MA failed to provide conclusive proof of benefit in favor of NAC

N Engl J Med 2006;354:2773-82.354 consecutive patients undergoing primary angioplasty

were randomized to one of three groups: 1. 116 patients were assigned to a standard dose of NAC (a

600-mg intravenous bolus before primary angioplasty and 600 mg orally twice daily for the 48 hours after angioplasty),

2. 119 patients to a double dose of NAC(a 1200-mg intravenous bolus and 1200 mg orally twice daily for the 48 hours after intervention),

3. 119 patients to placebo.

• The serum creatinine concentration increased 25 % or more from baseline after primary angioplasty in 39 of the control patients (33%), 17 of the patients receiving standard-dose N-acetylcysteine (15 %), and 10 patients receiving highdose N-acetylcysteine (8%, P<0.001).

• NAC has a dose dependent reduction in the risk of developing CI-AKI with a p<0.001 for this dose-trend.

• Similar findings were also confirmed by 2 earlier trialsthe RAPPID study. J Am Coll Cardiol 2003;41:2114-8.

Eur Heart J 2004;25: 206-11.

Current status of NAC

ACT Trial (Circulation. 2011;124:1250-1259)• RCT on 2308 patients undergoing an intravascular angiographic

procedure with at least 1 risk factor for CIAKI randomized to NAC 1200 mg or placebo.

• The incidence of CIAKI (primary end point) was 12.7% in the NAC group and 12.7% in the control group (relative risk, 1.00; 95% CI 0.81 to 1.25; P=0.97).

• A combined end point of mortality or need for dialysis at 30 days was also similar in both groups.

• Consistent effects were observed in all subgroups analyzed, including those with renal impairment.

Conclusions—NAC does not reduce the risk of CIAKI or other clinically relevant outcomes in at-risk patients undergoing coronary and peripheral vascular angiography.

Adenosine receptor antagonists• Adenosine induced vasoconstriction has been shown to be

an important pathogenetic mechanism in the development of CIAKI.

• When given before contrast media, oral or IV administered theophylline, a nonselective adenosine-receptor antagonist, have been shown to reduce the incidence of CIAKI in many studies.

• Trials have used theophylline in doses of 5 mg/kg iv, 2.88 mg/kg orally, and 165 mg iv.

There was a trend towards reduction in CIAKI use with theophylline use, and this reduction is comparable with that of NAC.The main issue of theophylline use in patients with renal insufficiency is its safety profile Role of highly selective A1 receptor antagonists should be evaluated

Other agents

Role of extracorporeal therapiesHEMODIALYSIS:• Contrast medium is dialyzable and there were initial reports

that HD was beneficial in preventing CIAKI.

• Later studies showed that in patients not previously on RRT, HD had no preventive role even if given within 1 hr or periprocedural and one study even reports a detrimental effect.

• However, CIN Consensus working Panel agreed that in patients with severe renal impairment (eGFr <20 ml/min) who require contrast-medium administration, hemodialysis should be undertaken if CIAKI develops.

Role of extracorporeal therapies contd….

HEMOFILTRATION:

• Single study on patients with Cr>2mg/dl or GFR <50 ml/min with continuous HF starting 6 hrs before till 24 hrs after the procedure showed HF to be protective.

• However, the fact that HF is not an effective contrast media removing modality, interruption of HF during the procedure, good intensive care management of pts on HF and concomitant medications makes this study difficult to interpret and HF remains an investigative tool. Requiring further studies

N. Engl. J. Med. 349, 1333–1340 (2003).

REMEDIAL trials 1&2

• REMEDIAL I trial, demonstrated that the combined strategy of volume supplementation with NaHCO3 & NAC was superior to the administration of NS & NAC alone or a combination of NS, ascorbic acid, and NAC in preventing CI-AKI in patients at low to medium risk.

Circulation. 2007;115:1211–1217.

• Investigators of REMEDIAL II trial used furosemide and justified its use by results of the PRINCE trial and theoretical principles.

Circulation. 2011;124:1260-1269

REMEDIAL trial II contd…

• It was a multicentric RCT, included pts with GFR<30 mL/min/1.73 m2 and/or a risk score 11.

• They were randomly assigned to NaHCO3 & NAC(control group) or hydration with saline and NAC controlled by the RenalGuard System and furosemide (RenalGuard group).

• Conclusion—RenalGuard therapy is superior to sodium bicarbonate and N-acetylcysteine in preventing AKI in high-risk patients.

Renal Guard systemPriming hydration of 250 ml

was given followed by furosemide (0.25 mg/kg) iv to achieve an optimal urine flow of 300 mL/h.

As soon as the urine flow reached the target value, the patient wasmoved into the catheterization laboratory, and the procedure wasstarted (procedural phase).

Controlled hydration by the RenalGuard system continued during the procedure and for 4 hours after the procedure (postprocedural phase). Urine flow was monitored andmaintained at the target value throughout the procedure and duringthe next 4 hours

Summary of the preventive strategies

CIAKI

Hydration remains the

most imp strategy.

Needs standardization of dosage

Role of NAC & NaHCO3 unclear.

Safety and low cost , can be

tried

Additional studies are

needed to clear the confusion

Promising agents:

Theophylline, statins,

ascorbic acid, PGs

Take home message

• CI-AKI is one of the most common cause of Aki in hospitalized patients.

• It is a preventable condition if the risk factors are vigilantly detected.

• The pathogenesis and preventive measures remain unclear and controversial.

• Of all the modalities of prevention, good hydration remains the only proven methodology.

THANK YOU