Biochemical and Reno-protective Effects of Remote Ischemic Pre-conditioning on Contrast-induced Acute Kidney Injury
Phase: NA
Conditions: Contrast-induced Acute Kidney Injury
Sponsor: Oladipupo Olafiranye, MD, MS

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Clinical Trial Protocol  
Biochemical and Reno-Protective Effects of Remote Ischemic Preconditioning on 
Contrast-Induced Kidney Disease (BRICK) Trial 
 
 
Version 
Date 
Main reason for changes 
1 
12/20/2017 
Not applicable 
2 
02/26/2019 
Addition of a second trial 
site   
 
 
1. Background  
Acute kidney injury (AKI) is a common complication of intravenous, iodinated 
contrast media, that is widely used for cardiac catheterization and percutaneous 
coronary intervention (PCI) in patients with coronary artery disease (CAD).1,2 In the 
United States, CAD remains the number one cause of death in both men and women 
despite improvement in the care of patients over the last decade. Although PCI 
restores blood flow to the heart, the contrast media used for the procedure can cause 
AKI, possibly mediated by contrast–induced vasoconstriction of renal blood vessels 
and free radical–mediated direct renal tubular toxicity. The incidence of AKI is 
estimated to range between 10 and 40% in patients undergoing cardiac catheterization 
with higher rates in patients with acute myocardial infarction.1,2 In the United States, 
approximately 1.4 million cardiac catheterization procedures are performed each year, 
and this estimate is expected to increase exponentially in the next few decades. With 
increasing use of contrast media, the prevalence of AKI is also expected to rise. AKI 
predicts elevated risk of heart attack, longer in-hospital stay, more complicated 
hospitalization course, and higher in-hospital mortality. Unfortunately, there is no 
effective prophylactic regimen to prevent AKI. 
 
Remote ischemic pre-conditioning (RIPC), elicited by application of one or more 
brief episodes of ischemia and reperfusion of a limb, is a promising therapy for 
preventing or attenuating AKI. Given that renal ischemic injury and tubular toxicity 
are the most common pathophysiological concepts of AKI, it stands to reason 
that RIPC may prevent AKI via nitrite-induced vasodilation and damage 
associated molecular protein -mediated renal cell protection. Our preliminary data 
suggest that RIPC provides renal protection and indicate a connection between 
RIPC-induced changes in protective molecules (nitrite, cyclic guanosine 

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monophosphate [cGMP)], tissue inhibitor of metalloproteinases 2 [TIMP-2], and 
insulin-like growth factor–binding protein 7 [IGFBP7] and organ protection. 
However, the effect of RIPC on AKI in patients with CAD undergoing cardiac 
catheterization is not well-established, and the underlying mechanism of such effect 
remains unclear.  
 
2. Study Design and Objective 
This is a prospective, double-blinded, two-center, randomized, sham-controlled 
clinical trial. The primary aim of this study is to determine whether remote ischemic 
preconditioning (RIPC) reduces the incidence of acute kidney injury (AKI) in high-
risk patients undergoing coronary angiography and/or PCI. The secondary aim is to 
study the effect of RIPC on renal (TIMP-2 X IGFBP7) and vascular (cGMP) 
biomarkers, major adverse cardiac events (MACE), and major adverse kidney events 
(MAKE) during a 6-month follow-up period in high-risk patients undergoing 
coronary angiography.  
 
3. Patient 
Eligible male and female patients over the age of 18 years with unstable angina or 
non-ST elevation myocardial infarction (NSTEMI) who are at high risk for AKI and 
undergoing coronary angiography and/or PCI. The trial will be conducted at two 
tertiary hospitals in the United States, the University of Pittsburgh Medical Center and 
the affiliated Veterans Affairs Pittsburgh Healthcare System. AKI risk will be 
determined by a modified version of Mehran’s risk score. The scoring system contains 
different risk factors, including patient characteristics, comorbidities and contrast 
volume. At the time of enrollment and prior to coronary angiography, the lowest range 
of contrast volume (1-100) in the scoring system will be utilized for calculation of 
modified Mehran risk score as shown in Table 1.3 After coronary angiogram, the 
actual volume of contrast used during the procedure will be utilized to calculate post-
angiography Mehran risk score. A score of 11 or higher will be used to define patients 
at high risk for AKI as shown in Table 2.3 Patients with inability to provide informed 
consent, acute ST elevation myocardial infarction, unstable blood pressure (BP) 
(systolic BP > 200 or <90 mmHg), peripheral vascular disease, contrast allergy, renal 
disease requiring dialysis, or placement of arteriovenous fistula graft will be excluded.  
 

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Table 1: Scoring System for Predicting Acute Kidney Injury  
Risk Factors 
 Score 
Age > 75 
4 
Diabetes mellitus 
3 
NYHA Class III/IV Heart failure 
5 
Anemia (male: HCT<39, female: 
HCT<36) 
3 
Hypotension (SBP<80mmHg or >1hr 
inotropic support) 
5 
Intra-aortic balloon pump placement  
5 
Estimated GFR < 20ml/min 
6 
Estimated GFR  20-40 ml/min 
4 
Estimated GFR  40-60ml/min 
2 
Contrast volume (1-100cc) 
1 
Contrast volume (101-200cc) 
2 
Contrast volume (201-300cc) 
3 
Contrast volume (301-400cc) 
4 
Contrast volume (401-500cc) 
5 
 
Table 2:  Risk Score and Predicted Risk of Acute Kidney Injury and Dialysis 
Mehran Risk Score 
Risk of AKI 
Risk of Dialysis 
≤ 5 
7.5% 
0.04% 
6-10 
14% 
0.12% 
11-16 
26.1% 
1.09% 
>16 
57.3% 
12.6% 
 
 

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Inclusion Criteria 
Adult patients over the age of 18 years  
Diagnosis of non-ST elevation myocardial infarction or unstable angina 
Referral for invasive coronary angiogram and/or percutaneous coronary intervention 
Acute kidney injury risk score of ≥11 
 
Exclusion Criteria 
Inability to give informed consent 
Unstable blood pressure (systolic blood pressure > 200 or <90 mmHg) 
History of allergy to contrast media 
Peripheral vascular disease of upper limb 
Renal disease requiring dialysis 
Placement of arteriovenous fistula and arteriovenous graft 
  
4. Randomization and Blinding 
A total of 110 patients will be randomized to the RIPC (55) treatment group or the 
Sham-RIPC (55) control group on a 1:1 basis. Randomization will be computer-
generated using the REDCap data management application system. Unblinded 
statistician will set up a pre-defined allocation table with variable block sizes of 2 to 
4, and stratification by site. Unblinded research staff will perform randomization and 
application of RIPC and sham-RIPC. Patients will be blinded by the use of Sham-
RIPC in the control group. Investigators, cardiologist performing coronary 
angiography, clinical outcome assessors, and data analysts will be unaware of 
treatment assignment. 
 
5. Procedures, blood and urine sampling and analysis 
All patients will undergo coronary angiography and/or PCI using the standard 
technique. The decision to perform PCI, choice of guidewires, balloons, stent types, 
and characteristics will be made by the interventional cardiologist according to 
common laboratory practice and guideline for coronary angiography and 
interventions. All patients will receive standard medical therapy and hydration for 
coronary angiography and PCI. We will extract data on patient demographic and 
medical history including gender, age, race, comorbidities, and coronary angiography 

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findings from the electronic medical record.  
 
After randomization, we will perform RIPC or Sham-RIPC approximately 1-4hrs 
before coronary angiography. The patients assigned to RIPC will undergo 3 cycles of 
5-minute inflation of a standard blood-pressure cuff to 200 mmHg, followed by 5-
minute cuff deflation. In patients assigned to the control group, sham-RIPC will be 
induced using 3 cycles of 5-minute blood pressure cuff inflation to a pressure of 10 
mmHg, followed by 5-minute cuff deflation.  
 
For the primary aim outcome of AKI, blood samples will be drawn at baseline and 
then at 24hrs and 48hrs after coronary angiography for measurement of serum 
creatinine using the standard laboratory protocol. Urinary insulin-like growth factor-
binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases 2 (TIMP-2), 
both inducers of G1 cell cycle arrest, are implicated in AKI and serve as biomarkers to 
predict it. 4 The product of urinary TIMP-2 and IGFBP7 concentrations, (TIMP-
2) × (IGFBP7), will be measured with the NephroCheck Test. We will measure 
urinary TIMP-2 × IGFBP7 from samples obtained at baseline, immediately after three 
cycles of RIPC but before coronary angiography, 24hrs, and 48hrs after coronary 
angiography. These assays will be performed at the Center for Critical Care 
Nephrology core laboratory at the University of Pittsburgh according to the standard 
manufacturer’s specification. Plasma concentration of cyclic guanylate 
monophosphate (cGMP) will be measured using blood samples obtained at baseline, 
immediately after 3 cycles of RIPC but before coronary angiography, 24hrs, and 48hrs 
after coronary angiography. These assays will be performed at the Center for 
Microvascular Research laboratory at the University of Pittsburgh using the standard 
enzyme immunoassay kit. 
 
6.  Outcomes 
The primary end point is the occurrence of AKI, defined as a relative increase in 
serum creatinine of ≥ 0.3mg/dl compared with baseline creatinine within 48 hours 
after coronary angiography according to the Kidney Disease: Improving Global 
Outcomes guideline.5 Secondary biomarker endpoints include the product of urinary 
concentrations of TIMP-2 and IGFBP7 and plasma concentration of cGMP.  
Other secondary clinical outcomes are 1) major adverse cardiovascular and 

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cerebrovascular events (MACCE) including rehospitalization for myocardial 
infarction, repeat revascularization, hospitalization for heart failure, stroke, and 
cardiac death and 2) major adverse kidney events (MAKE) including use of renal 
replacement therapy and all-cause death during the 6-month follow up. 
 
7.  Statistical analysis 
Sample size and power analysis for the primary outcome: Limited data are available 
for estimation of sample size for the effect of RIPC on incidence of AKI in high-risk 
patients with unstable angina or NSTEMI undergoing coronary angiography or PCI. 
Assuming an estimated incidence rate of AKI of 36-40% in high-risk study population 
as documented in prior studies, and considering absolute risk reduction (ARR) of 26-
28% as reported in trials performed in patients at moderate to high risk for AKI,6,7 a 
sample size of 100 patients (50 RIPC and 50 Sham-RIPC) will provide 88% power to 
detect a 25% ARR in the RIPC group (i.e. incidence of AKI is 35% in controls and 
10% in RIPC group). Relative powers for different levels of effect sizes for our  
estimated sample size (N=100) are shown in the Table 1 below. We will enroll 110 
patients to allow for up to 10% loss to follow up.  
 
Table 1: Estimated Power with N=100 at Various Effect Sizes 
 
AKI Incidence (RIPC Arm) 
10% 
15% 
20% 
AKI Incidence 
(Sham-RIPC) 
30% 
73% 
44% 
21% 
35% 
88% 
65% 
39% 
40% 
95% 
81% 
59% 
 
Descriptive Statistics: Baseline socio-demographic and clinical characteristics will be 
summarized using mean and standard deviation when normally distributed, and 
median and interquartile range when not normally distributed. Categorical variables 
will be summarized using relative frequencies and percentages.  
Primary outcome: the goal is to determine whether RIPC reduces the rate of AKI in 
high-risk patients undergoing coronary angiography and/or PCI. As this is a 
categorical variable with an expected reduction in AKI rate, the hypothesis will be 
tested using risk ratio to determine if the difference in incidence of AKI is 
significantly lower in RIPC group compared to the Sham-RIPC group. We will 
explore baseline variables for univariable associations with AKI and examine for 
independent association of RIPC with AKI using logistic regression. The primary 

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analyses will be based on intention-to-treat principle.   
Secondary outcomes (biomarkers): the goal is to characterize changes in the product 
of TIMP2 and IGFBP7 and plasma cGMP following RIPC in patients with CAD 
undergoing coronary angiogram. We will test the association of RIPC with levels of 
each molecule (RIPC vs. non-RIPC groups) using parametric statistics (t-test, 
confidence intervals for differences) when levels were normally distributed 
(expected), or using transformed levels if not. If distributions are very unbalanced, 
nonparametric tests will be used. The extent of protocol violations and missing 
outcome data will be quantified overall and by random assignment. All statistical 
analyses will be performed using SPSS.  
    
8. Ethics 
The written informed consent form, and overall study protocol and materials will be 
reviewed and approved by the IRB before the initiation of this trial. A Data and 
Safety Monitoring Board (DSMB) will be created to review this study. The DSMB 
will meet after initial approval with plan for quarterly meeting. However, the follow-
up meeting frequency of the DSMB will be determined during the first meeting. An 
emergency meeting of the DSMB will be called at any time by the Chairperson should 
questions of patient safety arise. 
 
9. Informed consent 
All study patients will be provided with an easily understandable informed consent 
form approved by the IRB. The patients will be enrolled after signing the informed 
consent form. The informed consent form will be kept as an important document of 
the clinical trials for future reference. 
 
 
 
 
 
 
 
 
 

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