Statins were found protective. PROMISS study (simvastatin was beneficial) 2010 a trial did not show any benefit of statins. Fenoldopam-selective D1 receptor antagonist.
Contrast induced acute kidney injury
Contrast-inducedAcute Kidney Injury DM Seminar Dr. Vishal Golay 16/11/11
• 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 45 Recognition of high risk groups. 40 35 30 25 20 Prevention 15 controversy 10 5 0 1960 1970 1980 1990 2000
• 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.
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 Radiology 250(1); January 2009 of CI-AKI after IA inj of either of the agents even in Iodixanol is not associated with a significantly reduced risk those with and without diabetes. of CIN compared with the LOCM pooled together.• Thus, either agent can be safely used for coronary interventions in patients with renal insufficiency Circulation. 2007;115:3189-3196
Left ventricular &-----: 30-45 mLaortic angiographyPCI-----------------------:150-200 mLCECT scan--------------:uses 100-150 mLIVU-----------------------: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 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
120 Risk factors contd…..100•80 Many risk factors are covariates rather than independent variables. This may account for reports 60 that fail to determine causality of independent variables. 40• Incidence increases proportional to the number of20 cosexisting risk factors. 0 0 1 2 3 4 number of risk factors Arch Intern Med 1990;150
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.
Course and Prognosis Creat rise Creat peak Return to baseline In a study on 200 patients undergoing PCI for acute MI, patients who developed CIN had a Non-oliguric 48hours longer hospital stay (13 ±7 days as compared 3-5 days 10-14days CIAKI with 8 ±3 days in subjects without CIN; p<0.001) and a more complicated clinical course, in Oliguric CIAKI 48 hours addition to a significantly increased risk of 5-10 days 14-21 days death. J Am Coll Cardiol 2004;44:1780 –1785• 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.
Oxidative stress Direct tubular toxicityContrast Induced AKI
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.
• 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.
Trials those who included patients with CKD2-4 as well asnormal renal function. 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
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-AKIthan recently reported, with important variation among differentCohorts There was a protective effect of sodium bicarbonate on therisk of CI-AKI, especially in patients who underwent coronaryprocedures and those with CKD, without effect on need for RRT ormortality. 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 ofsodium 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 inThe ambiguity the development of CI-AKI.have been due to preventing of these initial results couldmany factors. The main reasons could have been:• NAC induces glutathione1. The dose of NAC was low. synthesis. It also plays a role in counteracting vasoconstriction by ↑NO2. The ROS generation lasts much longer than anticipated.3. It is the peak levels of NAC during the procedure that is more• important. was reported by Tepel et al in 2000 in a trial First benefit published in NEJM. (NAC+hydration was compared with hydration with 0.45% NaCl alone).• Some other trial published after that showed ambiguous results.
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 trials the RAPPID study. J Am Coll Cardiol 2003;41:2114-8. Eur Heart J 2004;25: 206-11.
Current status of NACACT 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 withtheophylline use, and this reduction is comparable with that ofNAC.The main issue of theophylline use in patients with renalinsufficiency is its safety profileRole of highly selective A1 receptor antagonists should beevaluated
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 system Priming 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 was started (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 and maintained at the target value throughout the procedure and during the next 4 hours
Summary of the preventivestrategies Hydration remains the most imp strategy. Needs standardization of dosage Role of NAC & NaHCO3 Promising agents: unclear.Theophylline, statins, CIAKI Safety and low cost , can be ascorbic acid, PGs tried Additional studies are needed to clear the confusion
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.