0by25 AN ISN HUMAN RIGHTS INITIATIVE. Global Snapshot Human Subjects Application Template. Human Research Protections Program RESEARCH PLAN

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1 0by25 AN ISN HUMAN RIGHTS INITIATIVE Global Snapshot Human Subjects Application Template Human Research Protections Program RESEARCH PLAN 1. PROJECT TITLE Global Assessment of Acute Kidney Injury Incidence and Outcomes: Global Snapshot Version date: PRINCIPAL INVESTIGATOR 3. FACILITIES Medical centers across the world (hospital wards, ICU, emergency rooms, outpatient clinics, nursing homes, healthcare centers/dispensaries) 4. ESTIMATED DURATION OF THE STUDY 09/29/2014 to 11/09/2014 Providers will be asked to select a day (Index day) during this 6 week study period 5. LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) Acute Kidney Injury (AKI) is an important cause of mortality and morbidity worldwide. This is associated with a significant socioeconomic burden of AKI that is increasingly recognized as modifiable since this condition may be prevented and/or treated in a number of cases. The 0 by 25 project is an initiative sponsored by the International Society of Nephrology (ISN) with the main objective of Eliminate of preventable deaths from AKI by One of the first tasks toward accomplishment of this goal is this cross- sectional observational study called the Global Snapshot designed to draw a current picture of trends in AKI worldwide. Over a period of 3-4 weeks during the third quarter of 2014, patients will be enrolled at health care facilities across the world (hospital wards, ICU, outpatient clinics, nursing homes, healthcare centers) to draw a global picture of incidence, risk factors, resources available for treatment and prognosis of AKI. The aim is to identify trends in AKI risk, recognition, incidence, treatment and outcomes in different settings across the world. This information will be used to develop and implement educational tools and resources to prevent deaths from AKI by the year SPECIFIC AIMS Primary Objectives: 1. Establish incidence and outcomes of acute kidney injury (AKI) in different settings worldwide over a six week period. Secondary Objectives: 1. Compare risk factors, etiologies, diagnosis, management and outcomes of AKI in different countries 2. Determine resources available for recognition, non- dialytic and dialytic management and follow up of patients with AKI in different settings and countries 3. Evaluate barriers preventing access to the standard treatments of AKI across different countries. 7. BACKGROUND AND SIGNIFICANCE AKI is a complex disorder with a multitude of possible etiologies and clinical manifestations. Patients

2 may present with no a wide spectrum of symptoms ranging from being asymptomatic to completely anuric. It is associated with high mortality and co- morbidities such as chronic kidney disease or dialysis dependency. Incidence of AKI varies greatly according to patient risk factors or localization of population being studied (i.e.: hospital, ICU or community). There is a lack of knowledge of the region- specific (individual country and continent) characteristics of AKI. Little is known about the incidence, etiologies, resources and barriers to treatments of this condition in many parts of the world. In 2013, the International Society of Nephrology (ISN) and the International Federation of Kidney Foundations World Kidney Day was focused on AKI to with aims to raise awareness of this problem to eventually stimulate global discussion, education and policy development to prevent and treat AKI. The AKI Advisory Group for the American Society of Nephrology has published a meta- analysis evaluating world incidence of AKI. After including 154 studies (n=3,855,911) that met KDIGO definitions of AKI, they found the incidence of AKI to be as high as 21.6% in adults and 33.7% in children. The reported mortality rates were 23.9% in adults and 13.8% in children. This mortality rate was inversely related to country income and percentage of gross domestic product spent on total health expenditure. This study identified important gaps in worldwide AKI knowledge with very little or no data coming from regions where the expected incidence and mortality would be very high (Africa, South Asia, Southeastern Asia and Central Asia). 89% of the studies included in this meta- analysis came from countries in the Northern latitude (North America and Northern Europe). Another important point is that most of the data came from retrospective studies or post- hoc analysis.[2] Although these initiatives mentioned above were very insightful and identified important gaps in knowledge, more effort is required to understand this problem affecting all regions of the globe. The 0 by 25 initiative is sponsored by the ISN aiming to Elimination of preventable deaths from AKI by In order to eventually implement resources and tools to help prevent, diagnose and treat this AKI, we must first have an accurate picture of region- specific incidence, risk factors, available resources and barriers to diagnosis and treatment. This Global Snapshot cross- sectional observational study is the first step in identifying the true burden of AKI worldwide. This project aims to collect data on AKI cases seen in a 24- hour period across the world. The study is open to individual physicians across the world who agree to participate by providing de- identified clinical and lab data of patients with AKI that they care for on a designated day of their choice. 8. PROGRESS REPORT 9. RESEARCH DESIGN AND METHODS Study Design and protocol: The study is open to individual physicians across the world who agree to participate. Providers will be asked to select a day (Index day) during the 6- week study period (09/29/2014 to 11/09/2014) to record existing de- identified demographic, clinical, treatment and outcomes data on AKI patients. Patients who are under the care of the physician up to 3 days prior to the Index day will be screened as Suspected AKI case until they are Confirmed to have AKI based on available lab and clinical data up to 3 days from the Index day. Patient information will be recorded for the day AKI is confirmed and outcomes will be recorded at 1 week from the confirmation day (Figure 1) Page 2

3 Figure 1: Global Snapshot study design for enrollment and inclusion of patients Definitions: Suspected AKI: Oliguria (<200 ml/6 hours) and any AKI- related clinical signs or symptoms (see table 1) or urinalysis/dipstick abnormality. All suspected AKI cases must be confirmed prior to enrollment. Confirmed AKI: Meeting of at least one of the modified KDIGO Criteria [1] - Increase or decrease in serum creatinine >0.3 mg/dl from reference - Increase or decrease in serum creatinine > 50% from reference - Urine output < 400 ml/day Chronic Kidney Disease (CKD): Known diagnosis of chronic kidney disease; prior evidence of markers of kidney damage for 3 months (microalbuminuria, proteinuria >300mg/24 hrs or abnormalities in imaging tests) or the presence of glomerular filtration rate (GFR) <60 ml/min/1.73 m2 for 3 months calculated with MDRD (Modification of Diet in Renal Disease) equation, with or without other signs of kidney damage as described above. Reference creatinine: Most recent serum creatinine available in the last 12 months before presenting event De novo AKI: Evidence of AKI without prior evidence of kidney damage (normal urinalysis, normal imaging tests and calculated MDRD (Modification of Diet in Renal Disease) GFR is 90 ml/min/1.73m 2 ). AKI on CKD: Evidence of AKI with criteria of kidney damage as stated with CKD definition will be considered as AKI on CKD. AKI with previously unknown renal function status: Evidence of AKI without prior available serum creatinine or urinalysis values in patient chart Page 3

4 Inclusion Criteria: Suspected AKI patients seen by participating providers in centers across the world within 3 days or on index day Exclusion Criteria: Patients receiving Chronic dialysis (hemo or peritoneal dialysis) Renal transplant recipients Absence of AKI confirmation Outcomes: Dialysis requirement Renal recovery Mortality Follow up evaluation after AKI Measurements and data collection: In this observational study eligible patients who have met the study AKI criteria during the study period, will be identified by their participating health care providers. Existing data including clinical characteristics, lab results, dialysis procedure information and outcomes will be entered by the participating provider in web based Case Report Forms (attached). Since this is an observational study collecting pre- existing patient data, no additional laboratory samples will be required and interventions will be determined by the attending physicians and not influenced by the study personnel. Standard- of- care labs, vital signs and routine measurements will be performed in accordance with the usual and customary practices of each participating research site. All data entered in the database will be de- identified and there will be no contact with subjects and data or records. The following table identifies all the information that will be collected for each subject. No personal health information will be collected. Please refer to the attached Case Report Form for details. Screening day AKI confirmation day 7 days post AKI diagnosis Study ID number Age/Gender/Ethnicity Weight and height CKD status Number of kidneys Baseline creatinine Signs and symptoms associated with AKI* AKI diagnosis criteria met Timing of AKI screening day in regards to Index Day: - 3d, - 2d, - 1d or Index Day (see Case Report forms attached) Timing of AKI confirmation day in regards to Index Day: - Page 4

5 3d, - 2d, - 1d, Index Day, +1d, +2d or +3d (see Case Report forms attached) Location: Community (outpatient) vs Hospital (ER, ICU or ward) acquired AKI Creatinine and BUN at diagnosis Urinalysis and output Fluid balance status Risk factors and co- morbidities Suspected etiology Tools for diagnosis Treatment of AKI received Mortality and cause Hospital length of stay Disposition post hospital discharge Dialysis dependency status Last available creatinine Renal recovery status Renal biopsy results (if applicable) Planned follow up Table 1: Time- scheduled data that will be collected for each participating subject * Symptoms or signs associated with AKI (dehydration, diarrhea, vomiting, increased thirst, excessive sweating, fever, any infection, hypotension, weakness, shortness of breath, loss of weight, jaundice, pallor, allergic reaction, swelling, trauma, poisoning, animal/insect bite, pregnancy or delivery related symptoms) All the data will be collected and stored as digital Case Report Forms (CRF) using the open source, secure data platform KEEP (keep.distributedhealth.org). This application provides 2- factor user authentication with secure transmission and storage of fully encrypted data. The process of case reporting will be carried out by the registered providers (via 0by25.org) who will have access only to their own CRFs through an individual secured ID number and password. Each subject entered will be assigned a random 10 digit system identifier such that no personal health information is required. Providers will only have access to their entered subject s records. The study s principal investigator will have access to all the subjects CRF data with login via 2- factor authentication as above. The data collected will be restricted to de- identified, non- personal health information. 10. HUMAN SUBJECTS This study will record data from males and females of all ages including minorities, children and all races that meet the inclusion criteria and do not meet any exclusion criteria mentioned in section 9. Patients will be identified in the intensive care unit (ICU), on regular wards, emergency room, clinics and dispensers by their respective participating health care providers and will be enrolled in the study. The subjects in this study are not at greater than minimal risk as there are no study interventions and only non- PHI will be collected. The research will not affect the rights and welfare of the subjects. Page 5

6 It is expected that approximately 50 patients will be included at UCSD centers on index day. As this is a multi- center study, data on patients at other participating institutions will also be added to the secured 0 by 25 Initiative online data- recording website. The expected number of patients across all sites is approximately 10, RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH Patient Identification: All patients seen at a participating center and identified by all participating health care provider (nephrologists, intensivists, other physicians or allied health personnel treating AKI) as potential candidates for the study will be screened for eligibility. Participating providers will record patient information on the web- based Case Report Forms (see attached) that include information on the day AKI was confirmed and follow up on outcomes 7 days later. 12. INFORMED CONSENT We are requesting a waiver of consent for the following reasons: Consent Waiver Requirements: 1. The research is minimal risk: The nature of the data collected involves documentation of routinely measured clinical information, laboratory values, medication administration, procedural data, and outcomes of patient identified by their providers as having AKI on index day. The recorded data will be extracted from existing medical records and will not include any PHI. As the final dataset is de- identified, this review poses no more than minimal risk to those involved. 2. The waiver will not adversely affect the rights and welfare of the subjects. We will not report any results that might identify a subject and we have taken appropriate measures to secure the confidentiality of the patients, granting a waiver will not adversely affect privacy rights and welfare of the individuals whose records will be used. Since this is an observational study collecting routine patient data, no additional test or intervention is required. 3. The research could not practicably be conducted without a waiver: This is an international project designed to capture a snapshot of AKI across different settings and populations. Several patients may be unable to consent and require language interpreter or surrogate consent from a legally authorized representative. Given the short duration of the study, limited to a single day, it would be very difficult to obtain individual consent in all these settings. Patients who could not be consented would make it highly likely that the final sample would not be representative of the actual population who develop AKI. 4. Whenever appropriate, the subjects will be provided with additional pertinent information after participation: This study is not providing any feedback to the subjects. The treating physician is not using this information to guide patient care. 5. Breach of Confidentiality: The only record linking the subject and the research will be the randomly assigned 10 digit system identifier (such that no personal health information is required) and the principal risk would be potential harm resulting from a breach of confidentiality. The local providers will be the only ones able to associate the patients they entered with their 10 digit system identifiers, as they will be the only ones who maintain PHI at the source. No PHI will not be entered on the central database. HIPAA Waiver Requirements: 1. The disclosure of Protected Health Information involves no more than minimal risk: The data is available in the electronic medical record (EPIC) and is being collected manually on security- enabled website with encrypted data. Individual passwords to access the data will only available to those involved in the study and participating providers will only have access to the Page 6

7 information of the patients they enrolled. The nature of the data collected involves pre- existing non- PHI laboratory values, medication administration, procedural data, and outcomes of the subjects involved. As these variables are historical and the final dataset is de- identified, this review poses no more than minimal risk to those involved. 2. Granting of the waiver will not adversely affect privacy rights and welfare of the individuals whose records will be used. As mentioned previously all identifiers of patient data will not be collected to preserve privacy. Access to the data set will only be permitted to those listed in the initial application (see section 21). As mentioned, besides the principal investigator, participating providers will only have access to the information of the patients they registered. 3. The project could not practicably be conducted without a waiver: As previously stated above, this is an international project designed to capture a snapshot of AKI across different settings and populations. Given the short duration of the study limited to a single day, it would be very difficult to obtain individual consent in all these settings. Several patients may be unable to consent and require language interpreter or legally authorized representative making it highly likely that the final sample would not be representative of the actual population who develop AKI. 4. The project could not practicably be conducted without use of protected health information: This study involve the collection of many different lab values, medications, and their process- of- care, it is essential to perform a detailed review of the clinical information recorded in EPIC. 5. The privacy risks are reasonable relative to the anticipated benefits of research: The minimal privacy risk to which the subjects will be exposed is significantly outweighed by the beneficial information which will come from a better understanding of the incidence, risk factors and outcomes of acute kidney injury worldwide. 6. An adequate plan to protect identifiers from improper use and disclosure is included in the research proposal: Patient privacy will be maintained by optimizing de- identification of the records in the database. As mentioned previously, all the data will be collected and stored as digital Case Report Forms (CRF) using the open source, secure data platform KEEP (keep.distributedhealth.org). This application provides 2- factor user authentication with secure transmission and storage of fully encrypted data. The process of case reporting will be carried out by the registered providers (via 0by25.org) who will have access only to their own CRFs through an individual secured ID number and password. Each subject entered will be assigned a random 10- digit system identifier such that no personal health information is required. Providers will only have access to their entered subject s records. The study s principal investigator will have access to all the subjects CRF data with login via 2- factor authentication as above. No personal health information will be collected. 7. An adequate plan to destroy the identifiers at the earliest opportunity, or justification for retaining identifiers, is included in the research proposal: Once patients have been identified and data extracted from their chart, all personal identifiable information will be destroyed. No personal health information will be collected. For the purpose of reporting research findings, the data will be described as group data and it will be impossible to reveal the identity of individual subjects. Therefore, the use of disclosure of personal health information will involve no more than minimal risk. 8. Whenever appropriate, the subjects will be provided with additional pertinent information after participation: As mentioned above, if appropriate, the subjects will be given pertinent information if following a review, there is thought to be potential benefit to the subject. 9. The project plan includes written assurances that personal health information will not be re- used or disclosed for other purposes: The protected health information will only be used for the purposes outlined in this project application only. The data will not be used for any other Page 7

8 purpose. 10. Breach of Confidentiality: The only record linking the subject and the research will be the randomly assigned 10- digit system identifier (such that no personal health information is required) and the principal risk would be potential harm resulting from a breach of confidentiality. 13. ALTERNATIVES TO STUDY PARTICIPATION 14. POTENTIAL RISKS Standard- of- care labs, vital signs and routine measurements will be performed in accordance with the usual and customary practices of each participating research site. This is an observational study collecting pre- existing patient data, no additional laboratory samples or interventions will be required. Therefore there are limited risks for the participants. The potential risk is related to patient confidentiality. Patient privacy will be maintained by optimizing de- identification of the records in the database, secure access to the used for this study. No personal information will be used for any published information about this study. 15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES The only patient risk is confidentiality breach. Measures to prevent this incident are described in the following section 16. The participants will encounter no other risk, intervention or discomfort. Patients will receive treatment according to local standard medical practice. 16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT Patient confidentiality: Patient privacy will be maintained by optimizing de- identification of the records in the database. As mentioned previously, all the data will be collected and stored as digital Case Report Forms (CRF attached) using the open source, secure data platform KEEP (keep.distributedhealth.org). This application provides 2- factor user authentication with secure transmission and storage of fully encrypted data. The process of case reporting will be carried out by the registered providers (via 0by25.org) who will have access only to their own CRFs through an individual secured ID number and password. Each subject entered will be assigned a random 10 digit system identifier such that no personal health information is required. Providers will only have access to their entered subject s records. The study s principal investigator will have access to all the subjects CRF data with login via 2- factor authentication as above. The data collected will be restricted to de- identified, non- personal health information. Additionally, for the purpose of reporting research findings, the data will be described as group data and it will be impossible to reveal the identity of individual subjects. Therefore, the use of disclosure of personal health information will involve no more than minimal risk. 17. POTENTIAL BENEFITS There are no direct benefits to the patients whose data will be analyzed. Future patients with AKI may benefit from the findings, as the results will provide new knowledge to allow better characterization of the incidence of the disease and the special characteristics of AKI in different populations and will help guide further interventions to palliate to local needs in AKI prevention and treatment. Therefore, we anticipate that the privacy risks are reasonable relative to the anticipated global benefits of this research. 18. RISK/BENEFIT RATIO This study is an observational study and there are no risks associated with the study protocol. No changes will be made in the routine care of the patients. This study proposes to address several important issues in the prevention and treatment of patients with AKI. Confidentiality of participants will be guaranteed by optimizing de- identification of data of the records in the database, secure access to the database used for this study. Regarding possible benefits, we do not have knowledge of the geographical Page 8

9 incidence of acute kidney injury and its local risk factors. Little is also known about the resources available for treatments and barriers to implementation of new strategies. This lack of information makes it difficult to evaluate region- specific needs to intervene on AKI prevention and treatment. Overall the knowledge gain from the Global Snap Shot will identify help develop tools to palliate to the regional needs with the primary eventual aim of reducing and by 2025, eliminating mortality attributed to AKI. Future patients may benefit from the findings of this research. Therefore, we anticipate that the privacy risks are reasonable relative to the anticipated benefits of research. 19. EPENSE TO PARTICIPANT There will be no additional expense to the subject for participating in the study, e.g. hospitalization will not be prolonged and no extra costs will occur. 20. COMPENSATION FOR PARTICIPATION No compensation is offered for participation in the study. 21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES Role Last name First Name Degree Department Institution Investigator Investigator Investigator Investigator 22. BIBLIOGRAPHY 1. KDIGO Clinical Practice Guidelines for Acute Kidney Injury. KI suppl 1 vol 2 2. Susantitaphong, P (2013). World incidence of AKI: a meta- analysis. Clin J Am Soc Nephrol, 8(9), FUNDING SUPPORT FOR THIS STUDY This study is sponsored by the International Society of Nephrology (ISN) ( a non- profit organization. Dr Mehta is the Chair of the ISN Acute Kidney Injury Committee and is the designated Project leader for this worldwide study. There is no conflict of interest with the PI and ISN for this study. 24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 26. IMPACT ON STAFF This purely observational study is not anticipated to add any significant impact to nursing staff. 27. CONFLICT OF INTEREST None 28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER- RELATED STUDIES 29. OTHER APPROVALS/REGULATED MATERIALS 30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT (consent waiver) Page 9