Ci aki for nst 2015

CONTRAST INDUCED
ACUTE KIDNEY INJURY
ARKOM NONGNUCH, MD.
RENAL UNIT, DEPARTMENT OF MEDICINE, FACULTY OF MEDICINE,
RAMATHIBODI HOSPITAL, MAHIDOL UNIVERSITY

OUTLINE
• Deﬁnition and epidemiology of CI-AKI

• Pathophysiology, natural history, and differential
diagnosis of CI-AKI

• Population at risk for CI-AKI

• Prevention strategies of CI-AKI

• Future direction for prevention of CI-AKI

RIFLE VS AKIN
Critical Care 2007, 11:R31Arkom Nongnuch, Renal Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University

Definition of CI-AKI
Parameters Prior 2007 After 2007*
↑SCr 0.5 0.3 or 1.5 time
↓eGFR 25% 25%
Timing within 48 hrs within 48 hrs
Urine volume not stated
<0.5 ml/kg/hour for 6
hours
Critical Care 2013, 17:204
*Staged for severity according to the AKIN criteria

#
The cause of AKI should be determined whenever possible

Epidemiology of CI-AKI (In-Hospital)
American Journal of Kidney Diseases, Vol 39, No 5 (May), 2002: pp 930-936
Cause Episodes Mortality (%)
↓Renal perfusion 147 13.6
Medications 61 15
Contrast media 43 14
Postoperative 35 2.8
Sepsis 25 76
Arkom Nongnuch, Renal Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University

CI-AKI as a risk of death
In-HospitalMortality(%)
0
10
20
30
40
No AKI AKI Dialysis
35.7
7.1
1.1
Am J Med 1997; 103: 368-375.
P<0.0000001

Reduce nephron mass vulnerable to injury (CKD)

DM, poor renal perfusion, nephrotoxic drugs
Contrast enters renal vasculature

Adenosine release
from macula dense

Endothelin release
Prostaglandin
dysregulation
Sustain intrarenal vasoconstriction (hours/days)

Prolonged contrast transit time in kidney

Medullary hypoxia

Osmotic injury and ATN Ischemic injury and ATN
AKI
Pathophysiology of CI-AKI
Arkom Nongnuch, Renal Unit, Department of Medicine, Faculty of
Medicine, Ramathibodi Hospital, Mahidol University

CI-AKI VS Cholesterol emboli
Parameters CI-AKI Cholesterol emboli
Risk Hypotension, CHF, CKD CVD risks
Route Intra-arterial or venous Intra-arterial
Exposure High volume of radio contrast Thrombolytic or anticoagulant
Onset of AKI 24 hr Week
Reversible Mostly within 1-2 week Rarely
Others signs None signs of embolic and vasculitis
complement
level
normal low C3 and/or C4
UA Bland Bland/proteinuria/microscopic
hematuriaPrevention Yes No
Prognosis Good Poor

“Risk comes from not knowing
what you're doing.”

―Warren Buffett

Clin Exp Nephrol. 2013 Aug;17(4):441-79
DM and CKD considered high risk for CI-AKI

Risk factors of CI-AKI
Eur Radiol (2011) 21:2527-2541

CI-AKI risk scoring system
JACC Vol. 44, No. 7, 2004
*Formula for eGFR: 186 × (serum creatinine [mg/dL])−1.154× (age)−0.203× (0.742 [for women]) × (1.21 [for African Americans]).
Risk factor Score
SBP<80 mmHg for >1 h and requiring inotropic of IABP support within 24 h of procedure 5
Use of IABP 5
Heart failure, NYHA class III/IV and/or history of pulmonary edema 5
Age >75 years 4
Hct <39 % for men, <36 % for women 3
Diabetes 3
Contrast media volume 1 (for each 100 ml)
Serum creatinine > 1.5 mg/dL or 4
eGFR* <60 mL/min/1.73m
2(GFR40-60),
4(GFR20-40),
6(GFR<20)

JACC Vol. 44, No. 7, 2004
Total risk score SCr >25% or 0.5 mg/dL (%) Require dialysis (%)
≤ 5 7.5 0.04
6-10 14.0 0.12
11-16 26.1 1.09
≥ 16 57.3 12.6
CI-AKI risk scoring system

Prevention strategies of CI-AKI
Non-pharmacological

• Dose of contrast media

• Route of administration

• Type of contrast media
Pharmacological

• Volume expansion
(Nacl VS NaHCO3 VS
oral ﬂuid)

• NAC

• Others agents



Adenosine release
from macula dense

Endothelin release
Prostaglandin
dysregulation


Medullary hypoxia

AKI
Pathophysiology of CI-AKI
Arkom Nongnuch, Renal Unit, Department of Medicine, Faculty
of Medicine, Ramathibodi Hospital, Mahidol University



Endothelin release


Medullary hypoxia

AKI
↓Dose of CM

Intravenous route
↓Osm of CM
Volume expansion
Prostaglandin
dysregulation
NAC
Adenosine release
from macula dense


Type of contrast media
Type Agent
Osmolality

(mOsm/kgH2O)
Iodine content

(mg I/mL)
Ionization
High-osmolar
Ioxathalamate 2130 350 Ionic monomer
Diatrizoate 2000 370 Ionic monomer
Low-osmolar
Iobitridol 915 350 Non ionic monomer
Iopamidol 796 370 Non ionic monomer
Iohexal 780 350 Non ionic monomer
Iopromide 770 370 Non ionic monomer
Ioxaglate 600 320 Ionic dimer
Iso-osmolar
Iotrolan 320 300 Non ionic dimer
Iodixanol 290 320 Non ionic dimer

Dose of contrast media (grams iodine)
and the risk of CI-AKI
Acta Radiol 2008 49: 658
CI-AKI(%)
0
7.5
15
22.5
30
Grams iodine/eGFR ratio
<1 ≥1
25
3

Dose of contrast media (Volume) and the
risk of CI-AKI
J Am Coll Cardiol 2007; 50: 584-590
97% used iso and low osmolar : Average Iodine 350 mg/ml

Less (iodine) is More (protection)
• In all patients, only the minimum amount of contrast
medium necessary to answer the clinical diagnostic
question should be used.

• Use the lowest possible dose of contrast medium in
patients at risk for CI-AKI.

Route of administration
Clin Exp Nephrol. 2013 Aug;17(4):441-79Arkom Nongnuch, Renal Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University

Route of administration
Journal of Nephrology, vol. 25, no. 3, pp. 290-301, 2012.
1
RR 0.68; 95% CI 0.50-0.92; 𝑃 = 0.01
RR 0.75; 95% CI 0.44-1.26; 𝑃 = 0.27
11 randomized controlled trials (RCTs) including 2,210 patients with intra-arterial route

7 RCTs including 919 patients with intravenous route
Use low osmolality
contrast media
Intravenous route
Intra-arterial route

High Osm VS Low Osm contrast agent
RelativeRiskofCIN 0.0
0.3
0.6
0.9
1.2
High Osm Low Osm
0.64
1.00
Radiology 1993; 188: 171- 178.
• Meta-analysis

• High Osm VS Low Osm

• 39 Trials - 5146 patients

• CI-AKI = ↑ SCr>0.5 at 24-48 hrs

• RR of low osm = 0.64 (CI= 0.48-0.8)

Patients with DM and SCr 1.3-3.5 mg/dL who underwent
coronary or aortofemoral angiography
Iso-osm, non-ionic Iodixanol
(Visipaque), N=74, mean
contrast volume= 163 ml,
PTCA 17%
Low-osm, non-ionic Iohexol
(Omnipaque), N=65, mean
contrast volume= 162 ml,
PTCA 25%
N Engl J Med 2003, 348:491-499.
• Randomized, double blind, prospective, multicenter

• Primary endpoint: peak increase in serum creatinine concentration at 3 days after angiography

NEPHRIC Study Endpoint
N Engl J Med 2003, 348:491-499.
DifferenceofSCratD3
0
0.15
0.3
0.45
0.6
Iodixanol (Iso-Osm) Iohexol (Low-Osm)
0.55
0.13
P=0.001

418 DM with CKD (eGFR <50 mL/min) patients who underwent
CAG ± PCI
Iso-osm, non-ionic Iodixanol,
N=215
Low-osm, non-ionic Iopamidol,
N=213
• Randomized, double blind, prospective, multicenter

• Primary endpoint: CI-AKI= SCr >0.5 at D3
Am Heart J. 2009 Nov;158(5):822-828.e3Arkom Nongnuch, Renal Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University

• No beneﬁcial
effect of iso-osm
over low-osm in
high risk CI-AKI
patients
Am Heart J. 2009 Nov;158(5):822-828.e3
P=NS
P=NS

Inconsistent beneficial effect of

iso-osmolarity over low-osmolarity contrast agent
Evidence-Based Nephrology 2009. Edited by D. A. Molony and J. C. Craig.

Meta-analysis did not show beneficial effect of

iso-osmolarity over low-osmolarity contrast agent
An increase of at least 25% in serum creatinine level

RR=0.8 (CI 0.61-1.04)
An increase of at least 0.5 mg/dL in serum creatinine level

RR=0.75 (CI 0.44-1.26)
Radiology: Volume 250: Number 1︱January 2009Arkom Nongnuch, Renal Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University

Recommendation from ESUR and KDIGO
• Using of CM with low or iso-osmolarity in patients
with risk factors for CIN.

!
• Using either iso-osmolar or low-osmolar iodinated
contrast media, rather than high-osmolar iodinated
contrast media in patients at increased risk of CI-
AKI

Trials of prophylactic fluid therapy for
prevention of CI-AKI
Evidence-Based Nephrology 2009. Edited by D. A. Molony and J. C. Craig.
• No beneﬁcial effect of oral ﬂuid or 0.45%NSS for

JAMA, 2004;291:2328-2334
Patients With Baseline Serum Creatinine >1.8 mg/dl

who Underwent Contrast Exposure (Iopamidol in All)

N=137
5% Dextrose Sodium
Chloride Hydration (154
mEq/L of Sodium Chloride)

N=68
4.25% Dextrose Sodium
Bicarbonate Hydration (154
mEq/L of Sodium Bicarbonate)

N=69
Primary endpoint: increase in serum creatinine ≥25% within 2 days post-exposure
Rate IV :Bolus of 3 mL /kg per hour for 1 hour before iopamidol contrast, fol-
lowed by an infusion of 1 mL/kg per hour for 6 hours after the procedure.


Endpoints
Sodium Chloride

N=59
Sodium Bicarbonate

N=60
P value
Incidence of CI-AKI (%) 13.6 1.7 0.02
Change in eGFR (%) -0.1 8.5 0.02
JAMA, 2004;291:2328-2334

Saline + NAC
N=118
Saline+NAC+vitC
N=116
7 excluded
NaCl rate 0.5-1 ml/kg/hr 12 hrs before and after procedure

NaHCO3 rate 3 ml/kg/hr 1 hr before and 1 ml/kg/hr 6 hrs after procedure
9 excluded9 excluded
107 included
into analysis
108 included
into analysis
111 included
into analysis
Circulation. 2007;115:1211-1217
Patients with eGFR< 40 ml/min/1.73m2
,N=393
Excluded, N=42
Randomized, N=351
Bicarbonate + NAC
N=117

Incidence(%)
0
3
6
9
12
Increase SCr ≥ 25% Increase SCr ≥ 0.5 mg/dL Decrease eGFR ≥ 25%
10.3
11.2
10.3
0.90.9
1.9
9.2
10.8
9.9
Saline+NAC Bicarb+NAC Saline+NAC+vit C
Circulation. 2007;115:1211-1217
P=0.01 P=0.026 P=0.018

• Beneﬁcial effect of Isotonic bicarbonate over isotonic
saline remains inconclusive
Curr Opin Nephrol Hypertens 19:539–549
Trials of prophylactic fluid therapy for prevention
of CI-AKI (isotonic bicarb VS isotonic saline)

Meta-analysis of NaCl VS NaHCO3
Ann Intern Med. 2009;151:631-638.

• Either volume expansion regimen may be used.

• Isotonic NaCl intravenous regime of 1.0-1.5 ml/kg/h for at least 6 h
before and after contrast medium administration.

• Isotonic NaHCO3 3 ml/kg/h for 1 h before contrast medium followed
by 1 ml/kg/h for 6 h after.

• I.V. volume expansion with either isotonic sodium chloride or sodium
bicarbonate solutions, rather than no i.v. volume expansion, in patients at
increased risk for CI-AKI.

• Not using oral ﬂuids alone in patients at increased risk of CI-AKI.


N-acetylcysteine (NAC) in CI-AKI

• In theory, NAC may have vasodilator and antioxidant
effects.

• Adverse reaction are mild including anaphylactoid
reaction.

• Dosage for prevention CI-AKI are very low
comparing to dosage for acetaminophen intoxication.



Adenosine release
from macula dense

Endothelin release


Medullary hypoxia

AKI
↓Dose of CM

Intravenous route
↓Osm of CM
Volume expansion
Prostaglandin
dysregulation
NAC

N Engl J Med. 2000 Jul 20;343(3):180-4.
83 Patients with CKD (SCr 2.4±1.3 mg/dL) undergoing CT
scan with low osmolality contrast
41 patients received NAC 600
bid 2 days (oral) + 0.45%Nacl
1ml/kg/hr 12 hrs before and
after procedure
42 patients received 0.45%Nacl
1ml/kg/hr 12 hrs before and
after procedure
Endpoint : Change in SCr at 48 hrs

Incident of CI-AKI (↑SCr>0.5 mg/dL in 48 hrs)

N Engl J Med. 2000 Jul 20;343(3):180-4.
-7.5
0
7.5
15
22.5
30
Change in SCr at 48 hrs (mg/dL) CI-AKI
21
0.2
2
-0.4
Nac+hydration Hydration
P=0.01
P<0.001

N Engl J Med 2006;354:2773-82.
354 Patients admit for STEMI undergoing angioplasty
Control: 119 patients
received 0.9% NaCl
0.5-1 ml/kg/hr for
12 hrs
Standard NAC: 115
patients received 0.9%
NaCl 0.5-1 ml/kg/hr
for 12 hrs + NAC 600
mg IV before and NAC
600 mg oral bid for 48
hrs after CAG

( Total NAC 3000 mg)
High dose NAC: 118
patients received 0.9%
NaCl 0.5-1 ml/kg/hr
for 12 hrs + NAC 1200
mg IV before and NAC
1200 mg oral bid for 48
hrs after CAG

( Total NAC 6000 mg)

Incident(%)
0
10
20
30
40
Increase SCr ≥ 25% Increase SCr ≥ 50% RRT Mortality
3
1
3
8
4
2
6
15
11
5
18
33
NaCl
Standard NAC
High dose NAC
N Engl J Med 2006;354:2773-82.
P<0.001
P<0.001
P=0.04 P=0.007

Endpoint : ↑SCr ≥ 25% or 50% in 72 hrs

Incident of CI-AKI (↑SCr>0.5 mg/dL in 72 hrs)
J Am Coll Cardiol 2007;49:1283-8
111 Patients admit for ACS undergoing angioplasty
5% glucose isotonic NaHCO3 +
NAC 2400 mg IV 5 ml/kg/hr
for 1 hr before and NaHCO3
1.5 mg/kg/hr for 12 hrs +
NAC 600 mg oral bid for 1
day (N=56)
0.9% NaCl 1 mg/kg/hr 12 hrs
+ NAC 600 mg oral bid for 1
day after procedure (N=55)

Incident(%)
0
10
20
30
40
Increase SCr ≥ 25% Increase SCr ≥ 50% CI-AKI
21.8
14.5
30.9
1.8
0
1.8
HCO3+NAC NaCl+NAC
J Am Coll Cardiol 2007;49:1283-8
P<0.0001
P=0.003 P=0.0009

Trials of prophylactic NAC therapy for

Meta-analysis NAC for CI-AKI
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 11, 2009

Other agents (not show benefits)
• Theophylline : Adenosine antagonist

• Fenoldopam : Selective dopamine A1 agonist

• Statin : Antioxidant and inﬂammation effects

• Hemodialysis and hemodiaﬁltration : remove
radiocontrast agents

• Efﬁcacy of NAC and other drugs in reducing the incidence of
CIN remains unproven and their use cannot be recommended.

!
• Using oral NAC, together with i.v. isotonic crystalloids, in
patients at increased risk of CI-AKI.

• Not using theophylline, fenodopam, and statin to prevent CI-AKI

• Not using prophylactic intermittent hemodialysis (IHD) or
hemoﬁltration (HF) for contrast-media removal in patients at
increased risk for CI-AKI

Future Directions !!!

Personal with fluid administration
• Bioimpedance vector analysis
(BIVA). JACC Vol. 63, No. 14, 2014

• RenalGuard System. REMEDIAL
IItrial, Circulation.
2011;124:1260-1269

• Left ventricular end-diastolic
pressure-guided volume expansion.
POSEIDON trial, Lancet 2014; 383:
1814-23

Calculate eGFR, access risk of CI-AKI
eGFR<30 mi/min

eGFR 30-59 mi/min

eGFR>60 mi/min

Hold Metformin, NSAID, ± ACEI or ARB, Continue statin
• Isotonic NaCl or HCO3

✦1-1.5 ml/kg/hr for
3-12 hrs pre and 6-24
hrs post

• Low osmolal contrast
(Iso osmolal if high risk)

• Limited contrast volume

• Consider NAC 600-1200
mg PO bid pre and post
procedure 24 hr

• Isotonic NaCl or HCO3

✦1-1.5 ml/kg/hr for
3-12 hrs pre and 6-24
hrs post

• Low osmolal contrast
(Iso osmolal if high risk)

• Limited contrast volume

• Consider NAC 600-1200
mg PO bid pre and post
procedure 24 hr

• Nephrology consultation

Best clinical practice

• Monitor SCr at 48-72
hrs

• Deﬁne cause of AKI
(not just contrast)

• Rechallenge ACEI or
ARB, metformin

!

Take Home Message
• Rethinking before using radio contrast

• Recognise patients at risk and evaluate risk of CI-AKI
is crucial step of care

• Hydration when appropriated and may add NAC for
prevention CI-AKI

• CI-AKI is common, differential diagnosis with
cholesterol emboli

Ci aki for nst 2015

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