REMEDIAL II
REnal Insufficiency Following Contrast MEDIA
Administration II TriaL
RenalGuard system in high risk patients for contrast
induced acute kidney injury
Carlo Briguori, MD, PhD
Laboratoy of Interventional Cardiology
Clinica Mediterranea, Naples - Italy
Disclosure Statement of Financial Interest
I, Carlo Briguori DO NOT have a financial
interest/arrangement or affiliation with one or more
organizations that could be perceived as a real or
apparent conflict of interest in the context of the
subject of this presentation.
Background
 Contrast-induced acute kidney injury (CI-AKI) is a
powerful predictor of unfavorable early and late
outcome1-3
 Several studies showed the advantages of the prophylaxis
by
 sodium bicarbonate solution 4-5
 N-acetylcysteine (NAC) 6-7
 However, in high risk patients the rate of CI-AKI is still high
1. McCullough PA. J Am Coll Cardiol 2008;51:1419-28
2. Solomon R. et al. Clin J Am Soc Nephrol 2009;4:1162-1169
3. Briguori C, et al. Circulation 2010;121:2117-2122.
4. Merten GJ et al. JAMA 2004;291:2328-2334
5. Briguori C, et al. Circulation 2007;115:1211-1217.
6. Tepel M et al. N Engl J Med 2000;343:180-184.
7. Trivedi H, et al. Am J Med 2009;122:874 e9-15
High risk patients
Hypotension
5
IABP
5
Risk
Score
Risk of
CIAKI
Risk of
Dialysis
CHF
5
5
7.5%
0.04%
Age > 75 years
4
Anemia
3
6 to 10
14%
0.12%
Diabetes
3
11 to 16
26.1%
1.09%
16
57.3%
12.6%
Contrast media volume
Serum creatinine >1.5 mg/dl
OR
eGFR <60 mlmin1.73 m2
1 for each 100 cc3
4
2 for 40-60
4 for 20-60
6 for <20
Mehran R et al J Am Coll Cardiol 2004; 44:1393-9
Background
 Creating and maintaining a high urine output is beneficial
to prevent kidney damage. This high urine flow rate,
indeed, should allow the body to rapidly eliminate
contrast, reducing its toxic effects.
 Data from the PRINCE study indicate that increasing the
urine flow rate (≥150 ml/h) reduces the toxic effect of
contrast media 1
 A forced diuresis regime is usually achieved by high dose
of furosemide which may be deleterious, potentially due
to a negative fluid balance 2,3
1. Stevens MA et al. J Am Coll Cardiol 1999;33:403-411
2. Weinstein JM et al. Nephron 1992;62:413-415
3. Solomon R, et al. N Engl J Med 1994;331:1416-1420.
Background
The
RenalGuardTM
automated
hydration matching system (PLC
Medical System, Inc.) was developed
in order to achieve precise real-time
high volume fluid balance using a
closed loop hydration monitoring
and infusion system
RenalGuard system
Resnic F. et al. J Am Coll Cardiol 2009 53: A36
RenalGuard System
RenalGuard System
closed loop fluid management system
high volume fluid pump
high accuracy dual weight measuring system
single use intravenous set; urine collection
system that interfaces with a standard Foley
catheter
real-time display of urine and hydration fluid
volume
user set net fluid gain and fluid bolus
administration for patients that require rehydration prior to and during the procedure
automatic battery back-up
automatic priming of infusion set
timely alerts to drain urine bag or to replace
the hydration fluid bag.
Purpose
We performed a prospective, randomized study
comparing the prophylactic effectiveness of 2
different strategies for preventing CI-AKI:
Sodium Bicarbonate plus N-Acetylcysteine
(Control Group)
Hydration
with
RenalGuard
system
(RenalGuard Group)
REMEDIAL II
• DESIGN: Prospective, randomized, double-arm,
multicenters clinical study
Elective contrast media administration in patients at high risk for CI-AKI
(risk score ≥11 and/or eGFR≤30 ml/min/1.73 m2)
RenalGuard
group
Control group
CI-AKI
(sCr ≥0.3 mg/dL at 48 h)
Sample size
• Hypothesis:
— Reduction in the primary endpoint from 25% in the Control group to
10% in the RenalGuard group
• Sample size:
– A total of 266 patients (133 each group) will be necessary to gave the
study 90% power and a significance level <0.05
Inclusion criteria

Age 18 y

Chronic kidney disease

High risk for CI-AKI:

eGFR ≤30 ml/min/1.73 m2 and/or

Mehran score ≥ 11
Exclusion criteria
• Primary or rescue PCI

Pregnancy

Recent (≤ 7 days) contrast media exposure

Chronic dialysis and/or history or previous dialysis

multiple myeloma

pulmonary edema

acute myocardial infarction

Administration of theophylline, dopamine, mannitol, or fenoldopam or sodium
bicarbonate.
REMEDIAL II trial
Sodium Bicardonate &
Acetylcysteine
Hydration by sodium bicarbonate
(3 ml/Kg i.v. 1 h before
and 1 ml/kg for 6 h after)
&
NAC 1200 mg BID x 2 &
1.5 g e.v. during the procedure
RenalGuard group
Hydration with normal saline
(urine flow ≥ 300 ml/h)
&
NAC (1.5 g/L)
&
limited (0.25 mg/kg) furosemide dose
RenalGuard group
Pre-procedure
Procedure
Post- procedure
Biomarkers:
sCr = baseline, 2, 6, 12, 24 and 48 hours
sCyC = baseline, 2, 6, 12, 24 and 48 hours
NGAL = baseline, 2, 6, 12, 24 and 48 hours
Furosemide (0.25 mg/kg)
500
300
200
RenalGuard system
Prime (≤250 mL)
400
Foley Catheter
Urine flow rate (ml/h)
600
Continuous real-time matched
replacement fluid
100
0
0
30
60
90
Patient ready for
procedure when
urine flow rate
is ≥300 ml/h
120 150
180
210 240 270
Time (minutes)
300 330
360
400
RenalGuard System
Endpoints
• Primary endpoint:
– Rate of CI-AKI, defined as a serum creatinine (sCr) increase 0.3
mg/dLat 48 hours
• Secondary endpoints:
– an increase in the sCr concentration 25% and 0.5 mg/dl at 48
hours after contrast exposure
– changes in the serum cystatin C (sCyC) concentration at 24 and
48 hours after contrast exposure
– the rate of acute renal failure requiring dialysis
– the rate of in-hospital, and 1 month major adverse events
(MAE), including a) death, b) renal failure requiring dialysis, and
c) acute pulmonary edema
– changes in the serum and urine NGAL concentrations at 2, 6, 12,
24 and 48 hours after contrast exposure
Enrollement
Assessed for eligibility ( n= 806)
Exclusion (n = 512)
Not meeting inclusion/exclusion criteria (n = 485 )
Refused to partecipate (n = 27)
Allocation
Patients allocated in the Control group (n = 147)
Received allocated treatment (n = 146)
Did not receive the allocated treatment (n= 1)
Patients lost at follow-up (n = 0)
Discontinued treatment (n = 2)
Patients lost at follow-up (n = 0)
Discontinued treatement (n = 0)
Patients analized ( n = 146)
Patients excluded from analysis (n = 0)
Patients analized ( n = 146)
Patients excluded from analysis (n = 0)
Analysis
Patients allocated in the RenalGuard group (n = 147)
Received allocated treatment (n = 146)
Did not receive the allocated treatment (n =1)
Follow-up
Randomized (n = 294)
Clinical Characteristics
Age, yrs (mean  SD)
Male, %
BMI (kg/m2)
Blood pressure (mm Hg)
Systolic
Diastolic
Mean
LVEF, % (mean  SD)
LVEDP (mm Hg)
Diabetes mellitus
Hypertension, %
Drugs:
ACE inhibitor
Calcium channel blocker
Angiotensin II receptor inhibitor
Diuretics
 blocker
Statins
Control
Group
(N=146)
RenalGuard
Group
(N=146)
P
75  9
76  8
0.31
103 (70.5%)
88 (60.5%)
0.065
29 5
28  5
0.16
152±27
78±10
103±13
48  10
14±7
104 (71%)
144 (98%)
152±27
77±13
102±15
46  11
14±7
101 (69%)
143 (98%)
0.99
0.76
0.85
0.10
0.81
0.51
0.95
67 (46%)
44 (30%)
45 (31%)
85 (58%)
88 (60%)
111 (76%)
70 (48%)
36 (25%)
42 (29%)
93 (64%)
92 (63%)
108 (74%)
0.77
0.37
0.77
0.36
0.66
0.73
Biochemical Characteristics
eGFR (ml/min/1.73 m2)
GFR ≤ 30
Serum Urea Nitrogen (mg/dL)
Baseline
after 48 h
Control
Group
(N=146)
32  7
62 (44%)
RenalGuard
Group
(N=146)
32  9
69 (48.5%)
0.83
0.41
78  31
70 ± 30
80  35
71±35
0.57
0.84
140  5
139± 6
140  3
140 ± 5
0.37
0.87
4.7  0.7
4.3 ± 0.6
4.6  0.7
4.2 ± 0.6
0.55
0.17
P
Serum Sodium (mEq(L)
Baseline
after 48 h
Serum Potassium (mEq/L)
Baseline
after 48 h
Procedural Characteristics
Control
Group
(N=146)
Performed procedure
coronary angiography
PCI
coronary angiography & PCI
peripheral procedure
Volume of contrast media (ml)
Contrast ratio >1
RenalGuard
Group
(N=146)
P
0.36
60 (41%)
58 (40%)
17 (11%)
11 (6%)
51 (35%)
71 (49%)
11 (7.5%)
13 (9%)
145  79
35 (24%)
135  76
28 (19%)
0.29
0.32
Distribution of the Risk score
120
Number of patients
100
72.5%
80
60
40
20
2%
13%
≥5
≥6-10
12.5%
0
≥11-15
Risk score
≥16
Urine Volume at 24 hours
3000
p <0.001
2500
2000
1500
1000
500
0
Control Group
RenalGuard group
RenalGuard group
Pre-procedure
Procedure
7 h & 54 minutes (4.7-11.5 h)
400
Foley Catheter
300
200
Furosemide (14±8mg; range = 0-50)
500
RenalGuard system
Prime (223±45 mL; range = 50-300)
600
Urine flow rate (ml/h)
Post- procedure
100
Biomarkers:
sCr = baseline, 2, 6, 12, 24 and 48 hours
sCyC = baseline, 2, 6, 12, 24 and 48 hours
NGAL = baseline, 2, 6, 12, 24 and 48 hours
Continuous real-time matched
replacement fluid
0
0
30
60
90
Time to reach
Target urine flow rate
58±19 min (30-120)
120 150
180
210 240 270
Time (minutes)
300 330
360
400
RenalGuard Group
4000
Volume (ml)
3500
3000
2500
infusion
2000
1500
urine
1000
500
0
15
45
75
105
135 165 195 225 255 285 315 345 375
Time (minutes)
RenalGuard Group
900
Mean urine flow rate:
352±131 ml/h
Urine flow rate (ml/h)
800
700
600
Target reached in 93%
of patients (416±19 ml/h)
500
400
300
Below the target in 7%
of patients (117±48 ml/h)
200
100
0
15
45
75
105
135
165
195
225
Time (minutes)
255
285
315
345
375
sCr kinetic
serum creatinine (median)
2.4
2.2
2.0
1.8
1.6
1.4
1.2
Control group
p = 0.008; F = 4.97
RenalGuard group
1.0
Baseline
24
Time (hours)
48
Primary endpoint
25
Odds ratio = 0.47; 95% CI= 0.24-0.92
p = 0.025
20.5%
20
CI-AKI (%)
30/146
15
11%
10
16/146
5
0
Control group
RenalGuard group
Secondary endpoints
Control group
(n= 146)
RenalGuard group
(n= 146)
P
30 (20.7%)
22 (15%)
19 (13%)
11 (7.5%)
16 (11%)
9 (6%)
4 (2.7%)
1 (0.7%)
0.025
0.003
0.001
0.003
21 (15.5%)
33 (24%)
23 (17%)
14 (10%)
11 (8.5%)
22 (16%)
17 (12%)
5 (3.5%)
0.07
0.13
0.29
0.04
29 (21%)
47 (34%)
35 (25.5%)
23 (17%)
16 (12%)
29 (22%)
21 (16%)
11 (8.5%)
0.045
0.027
0.050
0.039
Changes in creatinine at 48 hours
Increase ≥0.3 mg/dL
Increase ≥0.5 mg/dL
Increase ≥25%
Increase ≥50%
Changes in cystatin C at 24 hours*
Increase ≥0.3 mg/dL
Increase ≥10%
Increase ≥15%
Increase ≥25%
Changes in cystatin C a 48 hours*
Increase ≥0.3 mg/dL
Increase ≥10%
Increase ≥15%
Increase ≥25%
sCyC kinetic
2.4
serum cystatin C (median)
2.2
2.0
1.8
1.6
1.4
1.2
Control group
p = 0.004; F = 5.52
RenalGuard group
1.0
Baseline
24
Time (hours)
48
Secondary endpoint
Events rate at 1-month
p = 0.52
10
9
8
7
6
% 5
4
3
2
1
0
9.6
6.8
p = 0.031
p = 1.0
4.8
4.1 4.1
p = 0.62
2.1
0.7
Dialysis
0.7
Pulmonary
Edema
Control Group
Death
Cumulative
RenalGuard Group
Conclusions
The RenalGuard therapy, including hydration with
normal saline plus high dose of NAC controlled by the
RenalGuard system in combination with limited (0.25
mg/kg) dose of furosemide, is an effective
renoprotective strategy for patients at high- risk for CIAKI.
REMEDIAL II Investigators
• Clinica Mediterranea, Naples
–
–
–
–
C. Briguori (P.I.)
A. Focaccio
G. Visconti
B. Golia
• Multimedica IRCCS, Milan
–
–
–
–
F. Airoldi
D. Tavano
S. Di Biase
S. Bertoli
• University of Ferrara, Ferrara
– M. Valgimigli
– R. Ferrari
• University of Modena, Modena
– G.M. Sangiorgi
– M. G. Modena