Expired PA-13-143: Acute Kidney Injury in Older Adults (R21)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Aging (NIA)
Funding Opportunity Title	Acute Kidney Injury in Older Adults (R21)
Activity Code	R21 Exploratory/Developmental Research Grant Award
Announcement Type	New
Related Notices	NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 3, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications. May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.
Funding Opportunity Announcement (FOA) Number	PA-13-143
Companion Funding Opportunity	PA-13-141, R01 Research Project Grant PA-13-142, R03 Small Grant Program
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.866
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) invites applications that propose basic, clinical, translational and outcomes research on acute kidney injury (AKI) in older persons. The R21 mechanism is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research. Applications may focus on the 1) epidemiology, etiology and risk factors for AKI in older adults, 2) pathophysiology of AKI in the aging kidney and its impact on chronic kidney disease (CKD) and other organ disease 3) early detection, diagnosis and monitoring of AKI, and 4) prevention, treatment and management strategies of AKI in older patients with the goal of improving short- and long-term outcomes including morbidity, mortality, progression of CKD, functional independence and quality of life. Research supported by this initiative should enhance knowledge of the increasing incidence of AKI in older persons and its consequences and provide evidence-based guidance in the diagnosis, prevention, and treatment of AKI in this expanding segment of the population. Studies in both human subjects and animal models are appropriate under this FOA as warranted by the study questions.

Key Dates

Posted Date	March 14, 2013
Open Date (Earliest Submission Date)	May 16, 2013
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Standard AIDS dates apply.
Scientific Merit Review	Standard dates apply.
Advisory Council Review	Standard dates apply.
Earliest Start Date	Standard dates apply.
Expiration Date	May 8, 2016
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

Among all age groups, older adults are the most vulnerable to develop acute kidney injury (AKI), defined as a precipitous decline in glomerular filtration rate (GFR). Overall AKI incidence has increased over the past decades, and the rate has grown fastest in those over 75 years old, who also comprise the most rapidly expanding age group in the U.S. population. Several factors likely contribute to this rise in AKI incidence including more aggressive surgical and medical treatments, increasing numbers of chronic and comorbid illnesses, greater use of nephrotoxic medications and imaging agents, aging of the population, and longer exposure to chronic diseases and nephrotoxins, all of which may be associated with direct or vascular-related kidney injury. Older adults are particularly vulnerable to most of these insults, which, in addition to age-related changes in kidney structure and function, renders these individuals highly susceptible to both AKI onset and the most adverse associated outcomes. Compared to younger AKI patients, older persons who develop AKI have higher rates of short- and long-term mortality, subsequent chronic kidney disease (CKD) including end-stage renal disease (ESRD), prolonged hospital stays, transitions to sub-acute care facilities, AKI-related morbidity, functional decline and related health-care costs. These data, mainly derived from cohorts that may underdiagnose AKI in seniors and have limited follow-up, likely underestimate the magnitude of this trend. Clarification of epidemiologic trends, etiology, additional risk factors, impact of CKD on AKI, as well as identification of high-risk groups and predictors of short- and long-term outcomes of AKI in older adults may lead to earlier and improved prevention, diagnostic and treatment strategies.

Although AKI describes a general scenario where GFR is acutely compromised, its phenotypes in older adults are approximately divided between changes in vascular or pre-renal perfusion (30%), direct kidney injury (most frequently acute tubular necrosis) (40%) and/or post-renal obstruction (25%). Several etiologies are more commonly associated with these AKI subtypes, or combinations of them, in seniors, including sepsis (the most common), pre-existing CKD, new onset and/or chronic NSAID use, and contrast agents used in imaging studies.

Acute kidney injury results from a reduction of renal autoregulatory mechanisms superimposed on decreased functional reserve, which limit the kidney’s appropriate reparative response to stressors. The specific age-related alterations in kidney structure and function which render the older adult more susceptible to AKI need further investigation to identify preventative and therapeutic targets and strategies. Additionally, elucidation of the mechanisms underlying AKI, especially those related to cellular senescence and inflammation, on short-term and long-term renal function, as well as AKI-related morbidity (impact on distant organs such as lungs, brain, liver, heart and bone marrow) and mortality may identify at risk populations and guide prevention and management strategies to improve renal and overall outcomes.

The heterogeneous etiology and pathophysiology of AKI complicates its diagnosis, for which the current gold standard remains an abrupt rise in serum creatinine (SCr). Measurement of SCr is particularly problematic in older adults as SCr levels depend on both GFR and creatinine formation, which is influenced by muscle mass, nutritional status and catabolic/anabolic state, and volume of distribution, all of which may be altered with advancing age. The diagnosis of AKI by SCr is also challenging in seniors by the age-related decline in GRF which may affect SCr baseline as well as its rate of rise and fall. Lastly, creatinine is relatively slow to accumulate in the serum after AKI, thus identification and validation of earlier GFR change markers would accelerate AKI diagnosis and treatment.

Acute kidney injury increases in-hospital death 3-8 fold and raises long-term mortality rate, more so in older compared with younger AKI patients. Similarly, AKI increases the risk of CKD including ESRD, again more in older than in younger patients. Further investigation is needed to determine if, and in what settings, transient hemodialysis or hemofiltration, which are used less frequently in older AKI patients, may improve outcomes. Additionally, little is known about the short-term and long-term impact of AKI on outcomes meaningful to older patients and their families and caregivers including quality of life (QOL), physical function and independence, health-related quality of life (HRQOL) and cognitive function. Risk identification tools that encompass age, multimorbidities, patient-preferences, underlying renal function and specific AKI mechanisms in older patients may predict such outcomes necessary to guide patient-centered preventative and therapeutic strategies.

Strategies to rectify pre-renal and post-renal AKI causes as well as supportive strategies including dialysis remain the only available treatment options for AKI at present. Some preventive strategies, including pre-hydration prior to stressors, use of non-ionic contrast agents, avoidance of nephrotoxic agents, performing off-pump coronary artery bypass grafting surgery are helpful, but often overlooked in seniors because of the under appreciation of elevated AKI risk and/or underlying renal compromise. Novel strategies for AKI as well as validation of the efficacy of current preventative/supportive AKI therapies that reduce the associated morbidity and mortality in seniors are needed.

Management of the older AKI patient is complex and requires multidisciplinary coordination. Guideline-suggested management is rarely applicable to older patients with underlying renal compromise, coexisting morbidities and comparatively reduced lifespans. Aggressive therapies such as hemodialysis/hemofiltration, invasive or diagnostic radiology procedures and/or renal transplant are often not considered or offered to older patients, possibly due to lack of evidence of their potential usefulness or unclear age-related risk/benefit ratio. Patient-centered decision support tools are needed to assist in this process as evidence becomes more available. Certain aspects of age-related patient management also warrant study including increased sensitivity to salt and fluid balance and redistribution, nutritional assessment and replenishment during AKI, cardio-renal and reno-cardiac syndromes, prophylactic strategies to prevent falls, skin breakdown, frailty/functional decline, pain (if NSAIDs are withdrawn), delirium and potential toxicities of renally cleared medications.

The NIA and NIDDK participated in a workshop aimed at reviewing current knowledge of and identifying research opportunities for AKI in older adults. The need and direction of future research on AKI in older adults addressed at this workshop contributed to this FOA. The main workshop themes are summarized in Anderson, S. et al. J Am Soc Nephrol 22:28-38, 2011.

Scope of Research

This FOA invites mechanistic and clinical research applications in both animal models and in humans, addressing the etiology and risk factors, pathophysiology, diagnosis, prevention, treatment and/or consequences of AKI in older patients. The R21 mechanism is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research. Areas of interest include, but are not limited to, the following:

Epidemiology, Etiology and Risk Factors

Development and validation of AKI risk assessment tools incorporating age, underlying renal function, and comorbidities.
Identification of age-associated changes, specific medications, morbidities, nephrotoxic agents, hemodynamic pre-renal and post-renal factors, or other etiologies of AKI in seniors, their associated cellular, molecular, signaling or multifaceted mechanisms and site of AKI to determine potential preventive and therapeutic targets.
Studies leading to insights into ethnic or racial disparities of increased AKI incidence in older adult populations.
Role of chronic and/or superimposed acute oxidative stress in the predisposition of older adults or animal models to AKI and its short and long term sequelae.
Contributions of underlying cellular senescence in the aging kidney and its role in predisposing older adults or animal models to renal, systemic and distant organ stress (including cellular senescent stress-related upregulation of p16(INK4A), telomere shortening, Dicer-associated microRNAs, heme oxygenase-regulated autophagy, Chordin 1 regulated expression of bone morphogenic protein and injury and repair/regenerative capacity).

AKI Pathophysiology and Impact on CKD and other Organs

Identification of specific mechanisms underlying AKI reduction in renal functional capacity including reduction in vessel density, regenerative capacity, natriuretic and medullary responses, and influence of age-related kidney changes on AKI pathophysiology.
Potential differences in mechanisms of AKI pathophysiology, injury and recovery between older and younger patients or animal models.
Relationship of co-morbidities and/or age-related changes in other organs to the development and outcomes of AKI in older adults or animal models.
Factors influencing increased salt-sensitive hypertension, volume redistribution and salt and fluid handling in AKI in older patients or animal models.
Understanding how AKI increases long-term ESRD and mortality risk.
Factors leading to AKI renal functional recovery in older patients or animal models.
Mechanisms underlying impact of AKI on distant organ pathophysiology (lung-vascular congestion, increased permeability, alveolar hemorrhage; brain-astrocyte inflammation, glial fibrillary acidic protein upregulation, altered cellular junctions/electrical conductivity/endothelial cells in blood-brain-barrier; GI, liver, bone marrow and heart).
Elucidation of role of chronic and/or superimposed acute inflammatory changes, including specific inflammatory markers, cytokines and pathways, that are upregulated in aging and/or AKI and their role in AKI and distant organ pathophysiology in older adults or animal models.
Role of AGE, AGE-R1 and reactive oxygen species and endothelial function in AKI and its outcomes.
Pathophysiology of contrast-induced nephropathy (CIN) and mechanism of increased vulnerability of older adults or animal models to CIN.

Early Detection and Diagnosis

Development and validation of new methods or biomarkers for accurate, reliable and efficient detection and monitoring of AKI in older adults, and that account for underlying age-related renal dysfunction, nutritional status, catabolic state, volume status and co-morbidities.
Development of strategies to measure AKI in older adults with earlier detection capability and higher sensitivity and specificity than serum creatinine.
Possible role of cystatin C, NGAL, IL-18, KIM-1 and L-FABP as detection and/or therapeutic monitoring biomarkers for AKI in older humans.
Sepsis-induced mechanisms of AKI in older adults or animal models.

Prevention and Treatment Strategies

Specific fluid hydration strategies for older patients before invasive or diagnostic procedures to prevent AKI.
Early recognition and preventative monitoring of post-renal AKI causes for those at risk to prevent AKI episodes.
Role of hemodialysis and/or hemofiltration, criteria for initiation/cessation, and risk vs. benefit in treatment and/or supportive care of AKI in older adults.
Development of novel therapeutic strategies for AKI in older patients including potential role of erythropoietin or atrial natriuretic peptide.

Management and Improved Outcomes of AKI in Older Adults

Management of multi-morbidities, polypharmacy and volume redistribution in older AKI patients.
Strategies to prevent delirium, falls, functional decline, cognitive changes, skin breakdown and development of additional morbidities during AKI in older adults.
Determination of nutritional status and needs during AKI in older patients and development of appropriate nutritional provision and monitoring during AKI accounting for renal function, sarcopenia, catabolic and inflammatory states and alterations in volume distribution.
Assessment and management of fluid and salt management in older AKI patients.
Management strategies for pain during AKI in patients in whom NSAIDS have been discontinued, such as narcotic dosing and complementary or alternative approaches.
Application of geriatric assessment tools to evaluate and monitor older adults at risk for, or during, AKI events.
Comprehensive, multidisciplinary strategies to reduce long-term increased incidence of morbidities, CKD, ESRD and mortality in older AKI patients after hospital discharge.
Development of patient-centered decision making support tools to assist older AKI patients and/or their surrogates in care options.

Specific age ranges for older patients or aged animals are not specified for this FOA. Age ranges and groups should be selected to address the study hypotheses and effectively utilize the demographic composition of available patient groups, study cohorts, or data sets. Applications may address changes across a span of ages as appropriate for the study questions, and younger age groups may be included for comparison purposes.

Resources that may be useful for researchers developing applications for this FOA include longitudinal datasets designed for the study of older populations, administrative datasets with medical information, and datasets from large observational or intervention studies in specific diseases or conditions. Datasets may be augmented through data linkage or by collection of additional information targeted toward specific study questions. Some potential study populations that focus on aging are listed in NIA's Population Studies Database, at http://nihlibrary.ors.nih.gov/nia/ps/niadb.asp. Large longitudinal and epidemiological studies that focus on factors related to cognitive and emotional health/impairment in the adult are listed in the NIH Cognitive and Emotional Health Project database at http://trans.nih.gov/cehp (specifically, http://trans.nih.gov/cehp/hbq/search.asp). Information on another potential study population, the Chronic Renal Insufficiency Cohort (CRIC) Study, can be accessed through the NIDDK website at http://www.niddk.nih.gov/patient/cric/cric.htm

Section II. Award Information

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	The combined budget for direct costs for the two year project period may not exceed $275,000. No more than $200,000 may be requested in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined two-year award period.
Award Project Period	The maximum project period is 2 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education
Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Hispanic-serving Institutions
Historically Black Colleges and Universities (HBCUs)
Tribally Controlled Colleges and Universities (TCCUs)
Alaska Native and Native Hawaiian Serving Institutions
Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

Small Businesses
For-Profit Organizations (Other than Small Businesses)

Governments

State Governments
County Governments
City or Township Governments
Special District Governments
Indian/Native American Tribal Governments (Federally Recognized)
Indian/Native American Tribal Governments (Other than Federally Recognized)
Eligible Agencies of the Federal Government
U.S. Territory or Possession

Other

Independent School Districts
Public Housing Authorities/Indian Housing Authorities
Native American Tribal Organizations (other than Federally recognized tribal governments)
Faith-based or Community-based Organizations
Regional Organizations
Non-domestic (non-U.S.) Entities (Foreign Institutions)

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

SF424(R&R) Cover