Contrast Nephropathy AKI

CONTRAST INDUCED AKI

Presenter : Manish Kumar SinglaClinical Nephrology and transplant fellowUniversity of TorontoModerator : Dr Ron WaldJune 17th 2014

CONTRAST NEPHROPATHY / CI AKI 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.

CI-AKI OR CINDefinition: New onset acute kidney injury (absolute Cr rise 0.5

mg- 1 mg/dl or relative, 25%-50% from baseline) after contrast administration and in the absence of other etiology

Time course of CI-AKI: Occurs after 24-48 hrs of contrast Cr peaks in 3-5days and normalizes in 7-10 days(70%) In 30%, 3 weeks to return baseline or progress to CKD Predominantly non-oliguric AKI and with mild

proteinuria

RISK FACTORS FOR CIN Patient-related

Renal insufficiency Diabetes mellitus* Intravascular volume depletionReduced cardiac outputConcomitant nephrotoxins

Procedure-related↑ volume of radiocontrastMultiple procedures w/i 72 hours Intra-arterial administrationType of radiocontrast

}

* Diabetes alone not strong risk factor

additive risk

Class 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

CONTRAST AGENTS

Left ventricular &-----: 30-45 mLaortic angiographyPCI-----------------------:150-200 mLCECT scan--------------:uses 100-150 mL IVU-----------------------:100-mL bolus of a 50%–60%

FFA uses Na fluorescein and not assoc with CIN

0 1 2 3 40

20

40

60

80

100

120

number of risk factors

Arch Intern Med 1990;150

INC

IDEN

CE in

%

CONTRAST INDUCED AKI PATHOPHYSIOLOGY How contrast agents cause AKI ?

Contrast Induced AKI

Direct tubular toxicity

Oxidative stress

Vasoconstricti

on

A temporary increase in renal transport work in the thick ascending limb of Henle's loop

(­ in oxygen consumption)+

Constriction of medullary capillaries (¯ in medullary oxygen delivery)

LEAD TO

MEDULLARY ANGINA

A temporary increase in renal transport work in the thick ascending limb of Henle's loop

(­ in oxygen consumption)+

Constriction of medullary capillaries (¯ in medullary oxygen delivery)

LEAD TO

MEDULLARY ANGINA

CONTRAST MEDIA INDUCE MEDULLARY HYPOXIA

Solomon, et al. Kidney Int 1998; 230-242Solomon, et al. Kidney Int 1998; 230-242

PATHOPHYSIOLOGY OF CIN

Radiocontrast Administration

CIN

Medullary Hypoxia

Generation of ROS

IntrarenalVasoconstriction

DirectCytotoxicity

RheologicEffects

OsmoticLoad

UNIQUENESS OF CONTRAST INDUCED AKI Universally iatrogenic Risk factors well characterised Time of insult largely predictable

Make it amenable to prevention

PREVENTIVE STRATEGIES

CCB Loop diuretics* Mannitol* Dopamine* Fenoldopam* ANP Hemodialysis*

NAC Theophylline Aminophyllin

e Ascorbic acid Statins Hemofiltratio

n

• IVF

Ineffective EffectiveUnclear benefit

* Possibly harmful

PREVENTIVE STRATEGIES FOR CIN

HEMODIALYSIS: 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 of procedure and one study even reports a detrimental effect.

ROLE OF EXTRACORPOREAL THERAPIES

NAC FOR CIAKI (N=83)

Tepel M, et al. N Engl J Med 2000; 343:180-184

0%

5%

10%

15%

20%

25%

% C

IN (

Scr

↑

0.5

mg/

dL

@ 4

8h)

Control

2%

21%

P=0.01

NAC

 Publication of this study was followed by a proliferation of clinical trials evaluating NAC

most NAC trials enrolled small numbers of patients on the basis of large postulated effect sizes, used small changes in kidney function as the primary endpoint, and did not systematically track longer-term sequelae of CI-AKI.

The inconclusive and contradictory results of these trials also led to multiple meta-analyses with conflicting conclusions

NAC Meta-analysis

Citing these results, 2011 guidelines issued by the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions state that NAC is not useful for the prevention of CI-AKI and recommend against its administration 

NAC - SUMMARY Protective effect unclear Many studies to date have

methodological flaws Cheap and benign (in oral form) Should not be used in lieu of other

measures

CLINICAL TRIALS OF VOLUME EXPANSION

1994 → present Provide clinical basis for:

Protective effect of IVF Deleterious effect of furosemide Superiority of isotonic IVF Superiority of IVF to pt-directed oral

fluids Potential benefit of oral NaCl

Rate of CIN: 11% 28% 40%

Solomon R, Werner C, Mann D, D’Elia J, Silva P. N Engl J Med. 1994;331:1416-1420.

ISOTONIC V. HYPOTONIC SALINE

Mueller C, et al. Arch Int Med. 2002; 162:329-336

P=0.04

P=0.35

P=0.93

SALINE VS. BICARBONATE IV FLUID

13.6%

1.7%

0%

2%

4%

6%

8%

10%

12%

14%

NaCl (n=59) NaHCO3(n=60)

rate of CIN

(8/59)

(1/60)

Merten et al. JAMA 2004;291:2328-2334

P = 0.02

IMPORTANT LIMITATIONS OF THIS STUDY Presumed effect size -67%, allowed the

study with small sample size of 260. (33% would have needed 1300

Switch of one patient would have resulted in statistically negative study

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

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

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

Power curve: the relationship between trial size and power.

Hiremath S , and Brar S S Nephrol. Dial. Transplant. 2010;ndt.gfq279

© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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.

------CLINICAL EQUIPOISE--------

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

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

SUMMARY OF PREVENTION NAC – of unclear benefit

Can use 1200 mg po bid x 2 days IV fluids beneficial – isotonic >>

hypotonic? Superiority of NaHCO3Abbreviated regimen OK – 1 hr pre and 4-6

hr post

WHAT IS OPTIMAL HYDRATION?

Dal lake, Kashmir, India

WHAT IS OPTIMAL HYDRATION?

WHAT IS OPTIMAL HYDRATION? Volume? Duration ?

Very little is known about the optimal rate and duration of fluid administration around the time of contrast exposure.

So far, no trial has directly compared volume expansion with isotonic saline at different rates or durations in at risk populations

Not unexpectedly, these uncertainties might explain, in part, the non-uniform adoption of volume expansion strategies.

POSEIDON Trial

POSEIDON

Poseidon is one of the twelve Olympian deities of the pantheon in Greek mythology.

His main domain is the ocean, and he is called the "God of the Sea".

Additionally, he is referred to as "Earth-Shaker“ due to his role in causing earthquakes, and has been called the "tamer of horses

POSEIDON

AIM Aimed to investigative different rates of

fluid administration guided by the left ventricular end-diastolic pressure

STUDY DESIGN AND PARTICIPANTS

Between Oct 10, 2010, and July 17, 2012,

All consecutive patients referred to the cardiac catheterization laboratory at the Kaiser Permanente Medical Center in Los Angeles, CA, USA

Funded by Kaiser Permanente Southern California regional research committee grant

INCLUSION CRITERIA eGFR of 60 mL/min or lower age 18 years or older and at least one of the following:

diabetes mellitushistory of congestive heart failurehypertensionage older than 75 years

EXCLUSION CRITERIA inability to obtain consent from participants emergency cardiac catheterisation Renal replacement therapy exposure to radiographic contrast media within the

previous 2 days allergy to radiographic contrast media acute decompensated heart failure severe valvular heart disease mechanical aortic prosthesis left ventricular thrombus history of kidney or heart transplantation change in estimated GFR of 7.5% or more per day or

a cumulative change of 15% or more during the preceding 2 or more days

STUDY PROTOCOL Eligible patients randomized in a 1:1

ratio to either left ventricular end-diastolic pressure-guided therapy or a standard fluid administration protocol

Randomization was stratified by diabetes mellitus status and N-acetylcysteine use.

This study was partly blinded

STUDY PROTOCOL Creatinine was measured at baseline

and twice afterward between day 1 and 4.

Commercially available 0.9% sodium chloride used in all patients

A bolus infusion at 3 mL/kg for 1 h was given to all patients before the procedure

STUDY PROTOCOL Before the administration of contrast media, LVEDP

was measured by placing an angled 5 or 6-French pigtail catheter in the mid-cavity of the left ventricle.

Fluid rate was adjusted according to the LVEDP as follows: 5 mL/kg/h for LVEDP lower than 13 mm Hg, 3 mL/kg/h for LVEDP of 13–18 mm Hg, and 1.5 mL/kg/h for LVEDP higher than 18 mm Hg.

The control group was hydrated at 1.5 mL/kg per h. Infusion was continued for the duration of the

procedure, and for 4 h post-procedure in both groups

OUTCOMESPrimary outcome

Primary endpoint was increase in the serum creatinine of greater than 25% or 0.5 mg/dL from baseline

Secondary endpoints components of the

primary endpoint occurrence of major

adverse events at 30 days and 6 months :- composite of all-

cause mortality myocardial infarction or renal replacement

therapy

STATISTICAL ANALYSIS Analyses were done with Stata version

12.0 and R version 2.15.3. All tests were two-tailed, with

differences reported as significant if the p value was less than 0.05

BASELINE CHARACTERISTICS OF STUDY POPULATION

BASELINE CHARACTERISTICS OF STUDY POPULATION

RESULTS total mean (SD) volume of NS

administered was 1727 ml in LVEDP group vs 812 ml in control group

RESULTS Overall incidence of CI AKI was 11.4% - it was 6.7 % in LVEDP group vs 16.3% in control group (p = 0.005) Relative risk was 0.41 (95% CI 0.22–0.79)NNT 11

RESULTS IN OTHER PRE-SPECIFIED GROUPS

RESULTS Patients who received larger volumes of

normal saline had a lower rate of contrast-induced acute kidney injury than did those given smaller volumes

Among patients with LVEDP > 18, incidence of CI AKI was 5.3% (8/152) in the treatment group versus 14.4% (21/146) in the control group (relative risk 0.37, 95% CI 0.17–0.80; p=0.008)

Moreover, the odds of contrast-induced acute kidney injury decreased by 9% for every additional 100 mL of normal saline administered (odds ratio 0.91 p = 0.01)

MAJOR ADVERSE CLINICAL EVENTS

MAJOR ADVERSE EVENTS

DISCUSSION First randomised trial to compare different rates of volume expansion with normal

saline for the prevention of CI AKI Clinical assessment of a patient’s

intravascular volume status without hemodynamic data , and thus their ability to tolerate high rates of fluid administration, is difficult and imprecise

LVEDP guided fluid administration protocol provides a framework for targeted intravascular volume expansion.

Through linkage of the rate of fluid administration to the LVEDP, the treatment group was able to receive roughly twice the volume with a similar rate of fluid termination than the control group

This resulted in a significant 68% relative reduction (a 9.5% absolute reduction) in the primary endpoint of CI AKI and a significant 59% relative reduction (a 6.4% absolute reduction) in major adverse clinical events.

DISCUSSION There was continued accrual of more

major adverse events in the control group than in the LVEDP-guided therapy group beyond 30 days in context of CI AKI, suggested in other studies as well

These findings emphasise the importance of longer term follow-up CI AKI prevention trials

CONCLUSIONS LVEDP guided iv saline administration

is well tolerated and could substantially reduce chances of CI AKI and subsequent adverse outcomes

CRITIQUEInternal validation

Patient population : comparable between the two groups except

CHF & PCI Randomization ( blocks of 4)

Treatment : higher volumes received by LVEDP group

Follow up: 10-15% excluded from primary analysis

(creatinine) but no loss on follow up Outcomes

Long term outcomes measured

CRITIQUEExternal validation

Patient population Quite similar : high risk*

Treatment short protocol- logistically feasible, ambulatory

procedures (longer protocols may be more effective)

Control group fluid rate- almost standard Follow up

Can be done easily Outcomes

CI AKI 25 %rise ( vs KDIGO) Sustained loss / Progression to CKD

LIMITATIONS

More aggressive volume expansion is not suitable for all patients (ADHF, VHD)

LVEDP measurement is invasive and not always available

Randomisation in blocks of four Only partially blinded CHF prevalence & PCI rate was different

in two groups

PRESERVE TRIAL

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