Personalized Recommendations for Acute Kidney Injury (AKI) Care Using a Kidney Action Team: A Randomized Trial
Phase: NA
Conditions: Acute Kidney Injury
Sponsor: Yale University

Personalized Recommendations for Acute Kidney 
Injury (AKI) Care Using a Kidney Action Team:  A 
Randomized Trial 
 
NCT04040296 
Protocol Document 
Document Date: 7 May 2024 

CLINICAL STUDY PROTOCOL
Protocol Title: Personalized 
Recommendations for Acute Kidney Injury 
(AKI) Care Using a Kidney Action Team: A 
Randomized Trial
Principal Investigator
Francis Wilson
Protocol Version
7 May 2024
version 4
 
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REVISION HISTORY:
Revision #
Version Date
Original
October 1, 2021
V2
February 24, 2023
Update to 7.5 Data Collection
V3
April 5th, 2023
Update 5.3.2 Eligibility Criteria
V4
May 7th, 2024
Update to 5.2.2 Secondary 
Outcomes and 7.5 Data 
Collection
 
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Study Personnel
Principal Investigator
Francis Wilson
Email: francis.p.wilson@yale.edu
 
Key Study Personnel:
Melissa Martin
Email: melissa.martin@yale.edu
Abinet Aklilu
Email: Abinet.Aklilu@yale.edu
 
 
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Synopsis
Primary Objective
This is a clinical trial designed to determine whether personalized recommendations for 
the workup and treatment of patients with Acute Kidney Injury (AKI) will improve the rates 
of AKI best practices and reduce the rates of inpatient dialysis, inpatient mortality and AKI 
progression in a hospitalized population.
Study Duration
We anticipate approximately 36 months in which patients are randomized and data is 
collected, followed by 6 months of data analysis activities and publication.
Study Design
This is a randomized, controlled, single-blind, multicenter clinical trial.
Study Population
Adult inpatients within the Yale New Haven Health System who meet the following criteria:
Inclusion Criteria:
1.
Adults ≥ 18 years admitted to a participating hospital
2.
Stage 1 Acute Kidney Injury as defined by KDIGO creatinine criteria:
a.
0.3 mg/dl increase in inpatient serum creatinine over 48 hours OR
b.
50% relative increase in inpatient serum creatinine over 168 hours
Exclusion Criteria:
1.
Admission to hospice service or comfort measures only order
2.
Recipient of a solid organ transplant
3.
Immediate dialytic indication determined by the following:
a.
K ≥7 meq/L
b.
Acute ingestion of dialyzable toxin
c.
Refractory volume overload
d.
BUN > 150 mg/dL
e.
pH < 7.15 despite ventilatory support
4.
Pre-existing CKD stage 5 or ESKD
5.
Initial hospital creatinine > 4.0 mg/dl
6.
Nephrology already consulted
7.
Status post nephrectomy (partial or radical) during index admission
 
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Number of Participants
The study will enroll 4,000 individuals.
Number of Study Sites
The study will occur across two health systems and 7 study sites.  
1) The Yale New Haven Health System, comprising five hospitals in Connecticut and 
Rhode Island: Yale New Haven Hospital, Bridgeport Hospital, Greenwich Hospital, 
Lawrence and Memorial Hospital, and Westerly Hospital.
2) Two hospitals in the Johns Hopkins Hospital System: Johns Hopkins Medical Center 
and Johns Hopkins Bayview
Primary Outcome Variables
The primary outcome will be a composite of progression of AKI, Dialysis, and death at 14 
days post randomization or at hospital discharge, whichever comes first.  Progression of 
AKI is defined as a higher KDIGO-creatinine stage than that present at the time of 
randomization.  Dialysis is defined by the receipt of hemodialysis, continuous renal 
replacement therapy, or peritoneal dialysis.  Isolated ultrafiltration treatments for the 
purpose of volume removal will not be included. 
Secondary and Exploratory Outcome Variables (if applicable)
Several secondary outcomes will be assessed as follows:
-Inpatient mortality rate within 14 days
-Inpatient dialysis rate within 14 days
-Inpatient progression of AKI within 14 days
-The percent of discrete recommendations followed within 24 hours of randomization
-The rate of kidney consult within 14 days
-Rates of discharge to hospice care
We will also perform an assessment of heterogeneity of treatment effect across the study 
sites, as it is possible that the benefit of the KAT depends not only on patient 
characteristics, but upon local resources and practices.
 
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1 - Introduction
1.1 Introductory Statement
This is a clinical trial designed to determine whether personalized recommendations for the 
workup and treatment of patients with Acute Kidney Injury (AKI) will improve the rates of AKI 
best practices and reduce the rates of inpatient dialysis, inpatient mortality and AKI 
progression in a hospitalized population.
 
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2 - Background
2.1 Clinical Experience
Acute Kidney Injury (AKI), defined as an abrupt loss in kidney function, is common, occurring 
in 5-20% of hospitalized patients, and carries a significant and independent risk of inpatient 
mortality of up to 20% in some studies, even with small increases in serum creatinine 
concentration.1-6 If left untreated, AKI may significantly increase the risk of chronic kidney 
disease, the need for dialysis, and long-term mortality.7-9 
Despite such effects on morbidity and mortality, the incidence of AKI is increasing and 
clinical trials have yet to find an intervention that can be broadly implemented as an AKI 
treatment.10-11  Thus, international guidelines for the treatment of AKI focus on "best 
practices" that include appropriate management of drug dosing, the avoidance of kidney-
toxic exposures, and careful assessment of fluid and electrolyte balance.2  Management 
relies on three pillars of care: recognition, diagnostic workup, and a patient-specific 
treatment plan.  Early recognition of AKI and early nephrologist involvement may improve 
clinical outcomes.3  However, AKI, which is often asymptomatic, is frequently overlooked in a 
variety of hospital settings.1,12-13  In a previous study, we showed that only 43% of patients at 
a tertiary care academic hospital had documentation of their AKI in the medical record, and 
that missed documentation was associated with increased mortality after adjusting for 
admission type and severity.14  Perhaps more concerning, our group and others have shown 
that patients often continue to be exposed to kidney-toxic medication after AKI onset.15-16  
Other AKI  "best practices", such as urinalysis and further laboratory work-up, occur 
inconsistently and in a small minority of patients with AKI.17-19 
Previous studies by our group have focused extensively on increasing provider awareness 
and recognition of AKI.  Our group conducted a randomized clinical trial testing the efficacy 
of electronic alerts for AKI.20-21 This trial randomized 2,373 patients with AKI to usual care, or 
to an alert group in which a single alert was sent to the patient's primary provider.  This alert 
was to make providers aware of the presence of AKI, however, it did not describe or offer 
specific actions a provider could take in response to the alert.  We demonstrated clinical 
equipoise regarding the effectiveness of such alerting, as there was no improvement in the 
rates of AKI progression, dialysis or mortality among those in the alert group.
Rather than simply making providers aware of AKI, it may be beneficial to provide them with 
actionable items to aid in the care of their patients.  Because of the heterogeneity of both the 
AKI patient population and AKI etiology, diagnostic and treatment plans must be highly 
individualized.  Such plans must consider many facets of care, including changes to and 
careful monitoring of prescribed medications, optimization of hemodynamics, and 
management of complications.  Despite the apparent complexity, we believe that 
individualized plans are amenable to highly protocolized interventions that can be delivered 
in a timely manner.  Our aim in this study is to determine, through a randomized multicenter 
clinical trial, if personalized recommendations for the work-up and treatment of AKI will 
improve patient outcomes.  Patients with AKI will be identified in real-time, upon which a 
"Kidney Action Team" will be alerted.  The Kidney Action Team will be composed of an 
 
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advanced practitioner and a pharmacist, and overseen by a nephrologist, and trained to 
provide real-time recommendations for AKI work-up and management within one hour of AKI 
onset.  Patients will be randomized to either receive usual care, or to an active intervention 
group in which the recommendations of the Kidney Action Team are delivered to the 
patient's primary care team.  Our primary outcome will be a composite of AKI progression, 
dialysis and death at 14 days post-randomization, while process outcomes will focus on the 
amount of recommendations implemented within 24 hours of delivery.  The highly 
protocolized and objective nature of AKI recommendations will allow for multiple 
independent Kidney Action Teams across multiple study sites, and, should this intervention 
prove successful, will provide a highly generalizable model for easy integration into other 
health systems.  Further, because of their highly algorithmic nature, the recommendations 
are amenable to automation, and our results may warrant future research to create and 
validate an automated clinical decision support system that will efficiently identify AKI 
patients and provide highly individualized and timely treatment plans without the need for a 
Kidney Action Team.
2.2 Background/prevalence of research topic
Rapid response teams have proliferated, but no rapid response team for AKI has been 
evaluated. In 2008, the Joint Commission National Safety Goal required hospitals to 
implement systems to enable staff to directly request the aid of specially trained individuals 
when a patient's clinical appearance is worsening.22 The concept of the "rapid response 
team" was quickly adopted, with most hospitals in the US enacting at least some of the 
principles. Goals of the team are generally to prevent clinical deterioration, avoiding out-of-
ICU intubation or cardiac arrest. Meta-analyses suggest that in that capacity, they have been 
successful, though whether they decrease overall mortality is unclear.23-24 To date, no rapid 
response teams focused on AKI have been developed, though some small studies looking at 
early renal consult (within 24 hours) suggest some benefit.3,25 To be able to provide true 
rapid response for AKI (i.e. within 30 minutes), an automated AKI detection system and a 
well-trained "Kidney Action Team" needs to be in place. We have pioneered the use of 
automated AKI alerts, and have a highly accurate electronic monitoring system in place 
across the study hospitals. In contrast to conventional rapid response teams, Kidney Action 
Teams can operate remotely, greatly expanding their reach and reducing associated costs. 
This may be of particular benefit in rural healthcare settings, where access to nephrology 
expertise is limited.
 
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3 - Rationale/Significance
3.1 Problem Statement
It is unclear whether early, personalized recommendation for AKI diagnosis and treatment 
will meaningfully improve clinical outcomes among hospitalized patients.
3.2 Purpose of Study/Potential Impact
The purpose of this study is to evaluate the impact of a Kidney Action Team - a remote 
group of individuals who, by receiving real-time AKI alerts, can provide personalized initial 
recommendations for treatment and management. If the teams are shown to be successful, 
health systems may consider adopting this approach to mitigate the devastating downstream 
effects of AKI which include chronic kidney disease, dialysis, and death.
3.3 Potential Risks and Benefits
3.3.1 Potential Risks
We consider the study to be minimal risk, as we are synthesizing information already 
available to providers in the medical record and offering recommendations for care that 
would already otherwise be available to the patient. These recommendations are not 
experimental, and represent best practices for AKI care.  Potential risks are as follows:
•
Inattention to AKI: A general risk of providing recommendations in a randomized 
fashion is the possibility that providers, who care for multiple patients each day 
regardless of randomization status, will become accustomed to receiving 
recommendations for their AKI patients and thus become inattentive to those patients 
in the control arm for whom they receive no recommendations.  We will mitigate this 
effect by reminding providers in the recommendation note that this is part of a 
randomized trial and that recommendations are not sent for all patients who develop 
AKI.  Pre-trial and periodic provider outreach will also be conducted to emphasize 
this point. 
•
Overtreatment:  If the delivery of personalized recommendations affects physician 
behavior, then patients randomized to the intervention arm may be more likely to 
undergo certain tests or interventions, such as additional testing, than those in the 
control arm.  While these interventions fall into the standard of care, the 
recommendations are made by a Kidney Action Team without direct patient 
interaction.  Therefore, it is possible that some interventions may not be appropriate, 
may not benefit the patient, and may incur additional costs to the patient. We will 
make clear in the Kidney Action Team note that none of the recommendations are 
mandated, and that the providers clinical decisions should be paramount to any 
recommendation. Treating physicians are to use their own clinical judgement when 
making clinical decisions about these interventinos. 
•
Undertreatment/lack of follow up: Patients randomized to the intervention group may, 
based on recommendations, have certain kidney-toxic medications discontinued.  It 
is possible that in some unique situations, discontinuation of medication may 
engender more risk (for example, discontinuation of a proton pump inhibitor in a 
 
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patient at high risk for gastrointestinal bleeding).  Further, it may be incorrectly 
assumed by the primary care teams that the Kidney Action Team will follow up with 
further recommendations or with test results, and thus not follow up themselves.  We 
will attempt to prevent this through our pre-trial and periodic educational efforts 
where we will remind primary providers of the nature of the trial, that it is still best to 
use their own clinical judgement when deciding to follow recommendations, and that 
recommendations only occur once, with no follow up from the Kidney Action Team. 
This will also be made clear in the Kidney Action Team note, which will indicate that 
the KAT will not follow-up on results of tests, and if more assistance is needed a 
formal renal consult should be called.
•
As with all studies where PHI is collected, loss of privacy is at risk for subjects.  We 
will limit this risk through our use of an entirely electronic data collection system and 
our data security plan. To minimize loss of privacy to subjects, all patient data will be 
kept on a secure, HIPAA-compliant server with 2-factor authentication, accessible 
only from within the Yale firewall, or via VPN protocols, and only by study personnel.  
In addition, at the time of data acquisition, a unique study ID number will be assigned 
to each patient.  All PHI will be linked to this study ID number in a database that is 
separate and distinct from the primary dataset which includes clinical information.  
This linking dataset will be maintained on a separate HIPAA-compliant server and will 
only be accessible by the study investigators.
3.3.2 Potential Benefits
Subjects may directly benefit from participation in the study because their care teams may 
be more acutely aware of their medical condition and may provide more personalized, 
attentive care based on recommendations delivered from the Kidney Action Team.  Should 
our paradigm of personalized treatment plans prove successful in improving patient 
outcomes, a broader implementation could provide benefits to society at large.
 
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4 - Study Objectives
4.1 Hypothesis
A composite of progression of AKI, dialysis, and death will be significantly lower among 
patients randomized to receive Kidney Action Team recommendations compared to those 
randomized to usual care.
4.2 Primary Objective
This is a clinical trial designed to determine whether personalized recommendations for the 
workup and treatment of patients with Acute Kidney Injury (AKI) will improve the rates of AKI 
best practices and reduce the rates of inpatient dialysis, inpatient mortality and AKI 
progression in a hospitalized population.
 
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5 - Study Design
5.1 General Design Description
This is a randomized, controlled, multicenter clinical trial to determine the efficacy of the 
delivery of personalized recommendations for the treatment of AKI in reducing clinical 
outcomes of AKI progression, dialysis, and death in hospitalized patients.  Patients who 
develop AKI will be identified in real time and randomized to either usual care or to the active 
intervention group, in which the primary care team receives individualized recommendations 
for AKI treatment from a trained Kidney Action Team.
5.1.1 Study Date Range and Duration
We anticipate approximately 36 months in which patients are randomized and data is 
collected, followed by 6 months of data analysis activities and publication. The entire study 
will take place over the course of 4 years.
5.1.2 Number of Study Sites
The study will occur across two study sites.  
1) The Yale New Haven Health System, comprising five hospitals in Connecticut and Rhode 
Island
2) Two hospitals within the Johns Hopkins University Hospital System: Johns Hopkins 
Medical Center and Johns Hopkins Bayview.
5.2 Outcome Variables
5.2.1 Primary Outcome Variables
Composite of progression of AKI, dialysis, and death at 14 days post randomization or at 
hospital discharge.  Progression of AKI is defined as a higher KDIGO-creatinine stage than 
that present at the time of randomization.  Dialysis is defined by the receipt of hemodialysis, 
continuous renal replacement therapy, or peritoneal dialysis.  Isolated ultrafiltration 
treatments for the purpose of volume removal will not be included. 
5.2.2 Secondary and Exploratory Outcome Variables (if applicable)
Several secondary outcomes will be assessed as follows:
-Inpatient mortality rate within 14 days
-Inpatient dialysis rate within 14 days
-Inpatient progression of AKI within 14 days
-The percent of discrete recommendations followed within 24 hours of randomization
-The rate of kidney consults within 14 days
-Rates of discharge to hospice care
-All documentation of clinical care related to the study, including procedures performed, 
medications administered, and laboratory tests ordered during hospitalization
 
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We will also perform an assessment of heterogeneity of treatment affect across the study 
sites, as it is possible that the benefit of the KAT depends not only on patient characteristics, 
but upon local resources and practices.
5.3 Study Population
We will enroll adult inpatients in the Yale New Haven Health System and Johns Hopkins 
University Health System who develop Stage 1 AKI based on KDIGO creatinine criteria and 
who meet all inclusion and exclusion criteria described below.
Yale health system hospitals include Yale New Haven Hospital, Bridgeport Hospital, 
Greenwich Hospital, Lawrence and Memorial Hospital, and Westerly Hospital.  Johns 
Hopkins sites include Johns Hopkins University Hospital and Johns Hopkins Bayview 
Campus. Sites will use a central IRB (BRANY). 
5.3.1 Number of Participants
We determined the overall sample size of this study based on the clinical composite 
outcome of progression of AKI, Dialysis, and Death. The baseline rate of this outcome is 
21% based upon our preliminary data, and we felt that a relative 20% improvement (to 
16.8%) would represent a clinically meaningful difference. In order to have 90% power to 
detect such a difference (or greater) if it exists at an alpha of 0.05, we would need to enroll 
1,824 patients in each group, for a total of 3,648 in the study. Given concerns about 
contamination across the study arms (see III.J.9), we have increased this recruitment target 
by approximately 10% to a total of 4000 individuals. Enrollment of 4000 individuals will also 
allow us to detect a difference in the rate of adherence to recommendations of 10% of one 
standard deviation at an alpha of 0.05, which is ample power to determine if the provision of 
these recommendations change provider behavior.
5.3.2 Eligibility Criteria/Vulnerable Populations
Adult inpatients within the Yale New Haven Health System who meet the following criteria:
Inclusion Criteria:
1.
Adults ≥ 18 years admitted to a participating hospital
2.
Stage 1 Acute Kidney Injury as defined by KDIGO creatinine criteria:
a.
0.3 mg/dl increase in inpatient serum creatine over 48 hours OR
b.
50% relative increase in inpatient serum creatinine over 168 hours
Exclusion Criteria:
1.
Admission to hospice service or comfort measures only order
2.
Recipient of a solid organ transplant
3.
Immediate dialytic indication determined by the following:
a.
K ≥7 meq/L
b.
Acute ingestion of dialyzable toxin
 
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c.
Refractory volume overload
d.
BUN > 150 mg/dL
e.
pH < 7.15 despite ventilatory support
4.
Pre-existing CKD stage V or ESRD
5.
Initial hospital creatinine > 4.0 mg/dl
6.
Nephrology already consulted
7.
Status post nephrectomy (partial or radical) during index admission
 
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6 - Methods
6.1 Treatment - Device
6.1.1 Intended use for the device
Kidney Action Team Recommendations
Dedicated and trained Kidney Action Teams (KATs) will each consist of an advanced 
practitioner and a pharmacist and will be supervised by a nephrologist.  KATs will be 
available 24 hours a day, 7 days a week, barring extenuating circumstances. The KAT will 
be notified, in real-time, of all randomized patients at their site who meet enrollment criteria 
via an automated electronic health record system.  The KAT will be tasked with providing 
individualized recommendations for AKI workup and treatment based on best practices 
identified within several kidney domains.  Recommendations will be created for each 
randomized patient, however, they will only be delivered to the primary care teams of those 
patients who have been randomized to the active intervention group.  This strategy allows 
for both the blinding of the KAT as well as a comparison in the proportion of 
recommendations implemented between the control and intervention groups.  
Recommendations for those in the intervention group will be made and delivered within one 
hour of AKI alert via a specialized note (Appendix 1) that is entered into the patient's chart 
and flagged for cosigning by the covering primary physician (i.e., the person signed on to 
EPIC as the patient’s covering provider for that shift).
We have designed the recommendations to be limited to specific domains of AKI diagnosis 
and treatment in order to minimize the variability in recommendations across members of the 
Kidney Action Teams and to allow for timely recommendations to be made. These domains 
include potassium management, acid/base management, fluid management, drug redosing 
and cessation, and diagnostic work-up.  We have also included a set of universal 
recommendations that will be delivered to all patients randomized to the intervention group, 
as we feel these to be a necessary component of a standard work-up for any AKI patient. 
Universal AKI recommendations will be recommended if not yet performed in the 48 hours 
prior to randomization and include:
•
Obtaining a urinalysis
•
Obtaining a urine sodium, potassium, chloride, creatinine measurement
•
Obtaining a post-void residual measurement or renal ultrasound to rule out 
obstruction
•
Avoiding new nephrotoxic exposures
•
Measuring serum creatinine at least every 24 hours during the inpatient stay
•
Strict measurement of fluid input and output
Recommendations in the other domains will be personalized and may include the following:
Potential Recommendations for Potassium Management
 
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•
No recommendation
•
Administer loop diuretic:
o
Furosemide 40mg IV x 1 dose
o
Furosemide 60mg IV x 1 dose
o
Furosemide 80mg IV x 1 dose
o
Furosemide 120mg IV x 1 dose
o
Furosemide 160mg IV x 1 dose
o
Administer metolazone 30 minutes prior to loop diuretic
•
Other (specify)Low (2g) potassium diet
•
Potassium binder (such as sodium polystyrene sulfate, patiromer, or sodium 
zirconium cyclosilicate)
•
Lactated Ringer Bolus of 500ml
•
Recheck potassium within 6 hours
•
Recheck potassium within 2 hours
•
Calcium Gluconate 9meq IV
•
Insulin 5 units IV, with or without 50% dextrose
•
Insulin 10 units IV, with or without 50% dextrose (1 amp IV)
•
Nephrology Consult
•
Telemetry Monitoring
•
Other (specify)
Potential Recommendations for Acid/Base Management
•
No recommendation
•
Order ABG or VBG
•
Check toxic alcohols
•
Check lactate, beta-hydroxybutyrate
•
Give 1L of isotonic sodium bicarbonate
•
Start oral sodium bicarbonate (specify dose)
•
Other (specify)
Potential Recommendations for Diagnostic Testing
•
No recommendation
•
Order urinalysis
 
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•
Order CK, Haptoglobin and LDH
•
Consider renal consult
•
Other (specify)
Potential Recommendations for Fluid Management
•
No recommendation
•
1L Ringer's lactate bolus
•
Albumin 25g x 1
•
Albumin 50g x 1
•
Caution with IV fluids if concern for respiratory compromise
•
Check orthostatic vitals
•
Re-assess volume status prior to further volume resuscitation 
•
Avoid IV fluids 
•
Obtain chest x-ray
•
Obtain transthoracic echocardiogram 
•
Other (specify)
Potential recommendations for medication management:
•
No medications to stop or dose adjust
•
Stop NSAID
•
Stop ACEi/ARB/mineralocorticoid antagonist/Renin Inhibitor
•
Stop Proton Pump Inhibitor
•
Stop other nephrotoxic medication (specify)
•
Adjust the dose of this medication (specify)
Monitor the level of this medication (specify)Recommendations will only be made once for 
each patient (within one hour of AKI onset) and with no follow-up on results from these 
recommendations.  We will clearly communicate this with all exposed physicians during our 
educational outreach.  This ensures no post-randomization unblinding and will also increase 
generalizability by decreasing the burden on the Kidney Action Teams. 
6.1.2 Device administration and schedule
The Kidney Action Team will provide personalized recommendations within 1 hour of the AKI 
alert being generated. This will be the sole interaction between the KAT and the study 
patient. No follow-up of recommendations will be performed.
6.1.3 Method of Assignment/Randomization
 
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Randomization will be performed within REDCap using a computer-generated randomization 
table which will use permuted blocks (of 4, 6 and 8 individuals). Randomization will be 
stratified by study hospital.
The Kidney Action Team will create recommendations for all patients that meet eligibility 
criteria, regardless of randomization status, which will preserve their blinding. 
(Recommendations will only be delivered to patients in the intervention group).  Providers 
and patients will not be blinded.  Study investigators and analysts will be blinded to 
randomization status.
6.1.4 Concomitant therapy
There are no restrictions on concomitant therapy in this trial.
6.2 Assessments
6.2.1 Safety/Pregnancy-related policy
Pregnant women and those who are of child-bearing age are not excluded from this study.
6.3 Study Procedures
6.3.1 Informed Consent
Due to the nature of the study, it is not feasible to consent subjects, as it would severely 
contaminate the exposure of interest. For example, a control subject who was sought out for 
consent might indicate to his/her provider that they were enrolled into the study and would 
reveal their AKI diagnosis.  Further, it would be infeasible to consent patients in a timely 
manner (at the onset of AKI) that is needed for quick delivery of recommendations to the 
primary care team.  To avoid these issues, we could obtain informed consent from every 
patient on admission to the hospital.  However, given the incidence of AKI is approximately 
15% of admissions, this would be impractical as well as unnecessary for the vast majority of 
patients, exposing roughly 85% of patients never deemed eligible for the trial to the risks of 
loss of confidentiality present in all research with human subjects.  Given that the proposed 
research presents no more than minimal risk to subjects and that no procedures are being 
performed that require consent outside of the research paradigm, we request a waiver of 
informed consent for this study. Waiver of consent and HIPAA authorization from the 
BRANY IRB for all sites, including JHU and YNHH  hospitals under their own potential IRB. 
6.3.2 Screening
Screening of potential participants will be completed by an electronic AKI "sniffer" algorithm, 
already in place at the study hospitals. The algorithm will flag patients with AKI as defined in 
the inclusion criteria, and evaluate whether inclusion / exclusion criteria are met.  The patient 
information will then be passed, in real time, to the Kidney Action Team who will assess 
eligibility for enrollment into this trial.  The KAT will be able to complete a brief screening 
assessment prior to their formal evaluation to ensure that the patient is truly eligible as well.
6.3.3 Recruitment, Enrollment and Retention
As this study will be conducted under a waiver of informed consent, recruitment is automatic.  
We do note that the study hospitals have an "opt out" option for research that uses the 
electronic health record. These patients will not be enrolled in this study. 
 
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Patients will be followed electronically throughout their hospitalization. There are no formal 
study visits.
6.3.4 On Study Visits
There are no formal study visits.
6.3.5 End of Study and Follow-up
Follow-up will conclude at the time of discharge from the hospitalization in which the patient 
was randomized.
6.4 Statistical Method
6.4.1 Statistical Design
We will compare rates of the primary outcome of progression of AKI, dialysis and death 
using the Cochrane-Mantel-Haenszel chi-square test, accounting for stratification by 
hospital. We will average proportion of recommendations followed within 24 hours between 
the intervention and control group using the Van Elteren test to account for stratification by 
hospital.
6.4.2 Sample Size Considerations
We determined the overall sample size of this study based on the clinical composite 
outcome of progression of AKI, Dialysis, and Death. The baseline rate of this outcome is 
21% based upon our preliminary data, and we felt that a relative 20% improvement (to 
16.8%) would represent a clinically meaningful difference. In order to have 90% power to 
detect such a difference (or greater) at an alpha of 0.05, we would need to enroll 1,824 
patients in each group, for a total of 3,648 in the study. Given concerns about contamination 
across the study arms (see III.L.9), we have increased this recruitment target by 
approximately 10% to a total of 4000 individuals. Table 2 shows a breakdown of recruitment 
by study site. Given the fact that this trial will operate under a waiver of informed consent, 
and our prior track record in this space, we expect full accrual across both sites within 3 
years. Enrollment of 4000 individuals will also allow us to detect a difference in the rate of 
adherence to recommendations of 10% of one standard deviation at an alpha of 0.05, which 
is ample power to determine if the provision of these recommendations change provider 
behavior.
6.4.3 Planned Analyses
6.4.3.1 Primary Analyses
The primary analysis will compare the proportion of patients experiencing the primary 
outcome (progression of AKI, Dialysis, or Death) at 14 days after randomization. We will 
compare the difference using the Cochrane-Mantel_Haenszel chi-square test, accounting for 
stratification by study hospital. 
6.4.3.2 Analysis of Subject Characteristics
We will compare the baseline characteristics of subjects in the two study groups using chi-
square tests (for categorical variables) and Wilcoxon Rank Sum tests (for continuous 
variables). 
 
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7 - Trial Administration
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization
The study will be conducted under a waiver of informed consent.
Due to the nature of the study, it is not feasible to consent subjects, as it would severely 
contaminate the exposure of interest.  For example, a control subject who was sought out for 
consent might indicate to his/her provider that they were enrolled into the study and may 
subsequently affect provider behavior.  Further, it would be infeasible to consent patients in 
a timely manner, at the onset of AKI, that is required for rapid delivery of recommendations 
to the primary care team.  To avoid these issues, we could obtain informed consent from 
every patient on admission to the hospital.  However, given the incidence of AKI is 
approximately 15% of admissions, this would be impractical as well as unnecessary for the 
vast majority of patients, exposing roughly 85% of patients never deemed eligible for the trial 
to the risks of loss of confidentiality present in all research with human subjects.  Given that 
the proposed research presents no more than minimal risk to subjects and that no 
procedures are being performed that require consent outside of the research paradigm, we 
request a waiver of informed consent from the IRB.
Subjects will not be informed of their participation in the trial at a later date. Informing 
patients to the presence of AKI, which may be unfamiliar to most, may engender significant 
stress without offering any tangible benefit or guideline-based follow-up or intervention to 
pursue.  Patients may also incorrectly assume that AKI is an iatrogenic condition caused by 
poor medical care, or that they were not receiving the full extent of medical care available in 
the absence of the recommendations when assigned to the control group.  However, our 
study is simply synthesizing already available data from the electronic medical record and 
recommending a plan of care that is already available for physicians to utilize.  We will, 
however, update all clinicians with the results after trial completion.  While no data will be 
linked to any specific provider, we will be able to relay broader generalizations (e.g. 
personalized recommendations decrease the use of certain nephrotoxins).
7.2 Institutional Review Board (IRB) Review
The protocol will be submitted to the IRB for review and approval. Approval of the protocol 
must be obtained before initiating any research activity. Any change to the protocol or study 
team will require an approved IRB amendment before implementation as well as appropriate 
submission to the FDA.
The IRB will conduct continuing review at intervals appropriate to the degree of risk, but not 
less than once per year. A study closure report will be submitted to the IRB after all research 
activities have been completed. Other study events (e.g. data breaches, protocol deviations) 
will be submitted per the IRB's policies.
7.3 Subject Confidentiality
Data collected in the course of the study will be de-identified and stored on REDCap and on 
a secure HIPAA-compliant central server within the Clinical and Translational Research 
 
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Accelerator. The server is only accessible from within the Yale intranet (or via VPN remotely) 
and additionally requires separate logon username and password. No PHI will be included in 
analysis or publication.  All analyses will proceed on this server alone.
We will maintain a linking file in a separate location that will allow for future linking of de-
identified data to protected health information (PHI) for the purpose of potential future 
studies.  Studies that require the use of PHI (for example, linking patient info to national 
outcomes databases) will require approval the investigators.
7.4 Deviations/Unanticipated Problems
If the study team or monitor becomes aware of an unanticipated problem (e.g. data breach, 
protocol deviation), the event will be reported by the Investigator to the reviewing IRB 
according to their requirements and to the Sponsor within 10 business days. Within 10 
business days of the receipt of this information, the Sponsor will notify in writing other 
reviewing IRBs, the study monitor (if not already involved), and the FDA in accordance with 
applicable regulations. Protocol deviations will be identified through the review of the CRFs 
and collected data by the Sponsor-Investigator after each subject is enrolled. The Sponsor-
Investigator will also have a formal discussion with the study investigator after each case to 
assess for any potential protocol deviation. The study Monitor will also review each case and 
assess for protocol deviations.
7.5 Data Collection
•
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the investigators electronically (e.g., laboratory data). The 
investigators are responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF.
Data will be obtained from the electronic health record via Yale’s Joint Data Analytics 
Team (JDAT) as raw flat files from Clarity, the relational database from Epic.  These 
files will then be transferred to our server via secure FTP.  A deidentified dataset will 
be constructed by the study team using the Safe Harbor method of the HIPAA 
Privacy Rule, namely the removal of all 18 HIPAA identifiers.
Non PHI elements of this data pull will include the following (looking back a minimum 
of 10 years):
o
Full patient medical history
o
All available clinical care information during index encounter 
o
All available information from follow-up encounters following index 
hospitalization
o
Provider type/class and location of treatment for all follow-up encounters 
following index hospitalization
o
Patient coverage status
•
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
 
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•
The investigators are responsible for the data management of this study including 
quality checking of the data.
•
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for five years after study completion unless 
local regulations or institutional policies require a longer retention period.
7.6 Access to Source
•
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator's site.
•
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.
•
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
7.7 Data or Specimen Storage/Security
No specimens will be collected in the course of this study. Data Protection
•
Participants will be assigned a unique identifier by the investigators.
7.8 Retention of Records
Records will be retained for at least 5 years after the end of the study.
7.9 Study Monitoring
The study will be monitored by the internal team as well as a dedicated external Data and 
Safety Monitoring Board.
The DSMB will meet at least twice a year to review data and will have a formal meeting to 
assess the interim analysis results.
7.10 Data Safety Monitoring Plan
Data and Safety Monitoring Board
•
Participant safety will be continuously monitored by the external DSMB, which 
includes safety signal detection at any time during the study
•
Case unblinding may be performed for above reviews if necessary.
 
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The DSMB may unblind the intervention assignment for any participant with an SAE. If the 
SAE requires that an expedited regulatory report be sent to one or more regulatory 
agencies, a copy of the report, identifying the participant's intervention assignment, may be 
sent to investigators in accordance with local regulations and/or sponsor policy.
7.11 Study Modification
Study modifications will be implemented upon approval from the IRB.
7.12 Funding Source
This study is funded by a grant from the Association of Healthcare Research and Quality.
7.13 Publication Plan
•
The results of this study may be published or presented at scientific meetings.
•
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
 
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References
1. Bihorac A, Yavas S, Subbiah S, et al. Long-term risk of mortality and acute kidney injury 
during hospitalization after major surgery. Ann Surg. 2009; 249 (5):851-858. 
2. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. 
KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int.  2012; 2 (Suppl.):1-
138. 
3. Balasubramanian G, Al-Aly Z, Moiz A, et al. Early nephrologist involvement in hospital-
acquired acute kidney injury: a pilot study. Am J Kidney Dis. 2011; 57(2):228-234. 
4. Chertow GM, Soroko SH, Paganini EP, et al. Mortality after acute renal failure: models for 
prognostic stratification and risk adjustment. Kidney Int. 2006; 70(6):1120-1126. 
5. Lombardi R, Nin N, Lorente JA, et al. An assessment of the Acute Kidney Injury Network 
creatinine-based criteria in patients submitted to mechanical ventilation. Clin J Am Soc 
Nephrol. 2011; 6(7):1547-1555. 
6. Nin N, Lombardi R, Frutos-Vivar F, et al. Early and small changes in serum creatinine 
concentrations are associated with mortality in mechanically ventilated patients. Shock. 
2010; 34(2):109-116. 
7. Coca SG, King JT, Jr., Rosenthal RA, Perkal MF, Parikh CR. The duration of 
postoperative acute kidney injury is an additional parameter predicting long-term survival in 
diabetic veterans. Kidney Int. 2010; 78(9):926-933. 
8. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a 
systematic review and meta-analysis. Kidney Int.  2012; 81(5):442-448. 
9. Coca SG, Yusuf B, Shlipak MG, Garg AX, Parikh CR. Long-term risk of mortality and 
other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. 
Am J Kidney Dis.  2009; 53(6):961-973. 
10. Ejaz AA, Martin TD, Johnson RJ, et al. Prophylactic nesiritide does not prevent dialysis 
or all-cause mortality in patients undergoing high-risk cardiac surgery. J Thorac Cardiovasc 
Surg. 2009; 138(4):959-964. 
11. Tumlin JA, Finkel KW, Murray PT, Samuels J, Cotsonis G, Shaw AD. Fenoldopam 
Mesylate in Early Acute Tubular Necrosis: A Randomized, Double-Blind, Placebo-Controlled 
Clinical Trial. . American Journal of Kidney Diseases. 2005; 46(1):26-34. 
12. Grams ME, Waikar SS, MacMahon B, Whelton S, Ballew SH, Coresh J. Performance 
and limitations of administrative data in the identification of AKI. Clin J Am Soc Nephrol.  
2014; 9(4):682-689. 
13. Vlasschaert ME, Bejaimal SA, Hackam DG, et al. Validity of administrative database 
coding for kidney disease: a systematic review. Am J Kidney Dis. 2011; 57(1):29-43. 
14. Wilson FP, Bansal AD, Jasti SK, et al. The impact of documentation of severe acute 
kidney injury on mortality. Clinical nephrology. 2013. 
 
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15. Chertow GM LJ, Kuperman GJ, et al. Guided medication dosing for inpatients with renal 
insufficiency. JAMA 2001; 286(22):3829-2844. 
16. Salomon L DG, Jaudon MC, et al. Medication misuse in hospitalized patients with renal 
impairment. . Int. J. Qual. Health Care. 2003; 15(4):331-335. 
17. Tawadrous D, Shariff SZ, Haynes RB, Iansavichus AV, Jain AK, Garg AX. Use of clinical 
decision support systems for kidney-related drug prescribing: a systematic review. Am J 
Kidney Dis.  2011; 58(6):903-914. 
18. Weisbord SD MM, Resnick AL, Hartwig KC, Sonel AF, Fine MJ, Palevsky PM. 
Prevelance, Incidence, and Outcomes of Contrast-Induced Acute Kidney Injury. Arch Intern 
Med. 2008; 168(12):1325-1332. 
19. Finlay S BB, Lewington AJ, Hunter-Rowe CT, Banerjee A, Atkinson JM, Jones MC. 
Identification of risk factors assciated with acute kidney injury in patients admitted to acute 
medical units. Clinical Medicine.  2013; 13(3):233-238. 
20. Wilson FP, Shashaty M, Testani J, et al. Automated, electronic alerts for acute kidney 
injury: a single-blind, parallel-group, randomised controlled trial. Lancet. 2015. 
21. Wilson FP, Reese PP, Shashaty MG, et al. A trial of in-hospital, electronic alerts for 
acute kidney injury: design and rationale. Clin Trials. 2014; 11(5):521-529. 
22. Jones DA, DeVita MA, Bellomo R. Rapid-response teams. New England Journal of 
Medicine. 2011; 365(2):139-146. 
23. Chan PS, Jain R, Nallmothu BK, Berg RA, Sasson C. Rapid response teams: a 
systematic review and meta-analysis. Archives of internal medicine. 2010; 170(1):18-26. 
24. Maharaj R, Raffaele I, Wendon J. Rapid response systems: a systematic review and 
meta-analysis. Critical Care.  2015; 19(1):254. 
25. Ponce D, Zorzenon CdPF, Santos NYd, Balbi AL. Early nephrology consultation can 
have an impact on outcome of acute kidney injury patients. Nephrology Dialysis 
Transplantation 2011; 26(10):3202-3206. 
 
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Appendix 1: Kidney Action Team Note Template
Kidney Action Team Recommendation Note
Date:              Time:
The Kidney Action Team is a group of clinicians designed to provide personalized 
recommendations for the diagnosis and treatment of patients with Acute Kidney Injury (AKI).
We have been notified that this patient has developed AKI within the past hour.  We have 
reviewed the patient’s chart and, based on the patient’s current status and medical history, 
make the specific recommendations listed below.
***For all AKI patients, we recommend continued follow-up of serum creatinine and 
avoiding nephrotoxic exposures.***
KIDNEY ACTION TEAM PERSONALIZED RECOMMENDATIONS FOR YOUR AKI 
PATIENT:
❖Obtain urinalysis (if not already obtained)
❖Avoid new nephrotoxic exposures
❖Follow creatinine at least every 24 hours
❖Rule out obstruction via PVR or ultrasound
❖Provide bicarbonate supplementation
❖Stop PPI
❖Consider Renal Consult
Please note: This patient is part of a randomized clinical trial designed to test the efficacy of 
personalized recommendations for the diagnosis and treatment of Acute Kidney Injury.  You 
will NOT receive this recommendation note for all patients who develop AKI.
The Kidney Action Team has not seen or examined this patient.  Our recommendations are 
based on chart review only.  It is your choice to follow these recommendations using 
your own clinical judgement and your examination of the patient and his/her medical 
history.  Should you choose to follow any of the recommendations, the Kidney Action Team 
will not follow up on test results or provide any further recommendations. If you need 
assistance with AKI management, please consider a formal kidney consult. Medication 
recommendations are based on currently prescribed medications. Please reach out to your 
floor pharmacist if any further questions about starting renally cleared medications. 
Please cosign to acknowledge receipt of the recommendations.
Signed By:
Date:
 
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