Urinary Stone Disease Research Network: Scientific Data Research Center (USDRN-SDRC) (Collaborative U01)

RFA-DK-15-005
Urinary Stone Disease Research Network: Scientific Data Research Center (USDRN-SDRC) (Collaborative U01) stones--cc--rkramer62
Department of Health and Human Services
National Institutes of Health

Section I. Funding Opportunity Description

This FOA invites collaborative U01 cooperative agreement applications to establish a multi-center, multi-disciplinary group of investigators to be known as the Urinary Stone Disease Research Network (USDRN). The Scientific Data Research Center applications submitted under this FOA are linked to RFA-DK-15-004, which will support the USDRN clinical centers.

Background

Urinary Stone Disease (USD) is an important healthcare problem affecting about 1 out of 11 Americans, causing pain and suffering for the patient and a financial burden for the Nation. The prevalence of USD in the US has nearly doubled in the last 15 years, and is increasing in both adults and children. According to the Urological Diseases in America (UDA) project funded by the NIDDK, the annual cost of USD is estimated at $10 billion making it the most expensive non-malignant urologic condition in the U.S. A recent study estimates that the impact of obesity, diabetes and population rates will increase costs of USD to $1.24 billion/year by 2030. An acute symptomatic episode of USD is generally extremely painful and frequently results in Emergency Department (ED) care. ED visit rates for USD have doubled between 1992 and 2009. Computed tomography use for evaluation of USD in ED has tripled during the same time period and use of drugs has also increased. Cross sectional analyses show that about 10% of ED visits for USD are for repeat encounters. The intangible costs to the affected individual and the family, such as pain, diminished quality of life (QoL), time-off from work or school, and professional risks caused by a renal colic are enormous.

The treatment of USD has advanced over the last 30 years. New endourologic approaches allowed most stones to be treated endoscopically without the need for a skin incision. Technical advances have improved surgical USD treatment strategies. Improved optic lens systems and fiberoptic light sources have enabled better visualization. Increased instrument flexibility and miniaturization along with effective energy sources for stone disintegration led to the development of percutaneous nephrolithotomy and ureteroscopic lithotripsy. Extracorporeal shock wave lithotripsy (SWL) was developed for stone fragmentation without invasive instrumentation of the body. Although SWL and endourologic approaches are commonly used for the treatment of an USD episode, there is a major trend towards more frequent use of ureteroscopy (URS). Medical management has also advanced to a certain extent; however the prevalence of USD continues to increase both in adults and children. Despite these advances the limited state of knowledge for USD is reflected in several clinical management guidelines that have been published by the American Urological Association (AUA), and European Association of Urology (EAU) using systematic reviews and data extraction. Only 1 of 27 and 3 of 17 recommendations were based on Level 1 evidence.

USD is often recurrent.  Data from the National Health and Nutrition Examination Survey (NHANES) show that 35% of participants had experienced 2 or more distinct episodes of urinary stones. Other epidemiologic data show that recurrence rates of first time stone formers at 2, 5, 10, and 15 years were 11%, 20%, 31%, and 39%, respectively. Thus prevention of USD recurrence could substantially reduce its public health burden.

Ureteral stenting is a common prophylactic procedure after URS to mitigate peri-operative complications. Stenting the ureter is also performed in conjunction with SWL, and after complicated percutaneous nephrolithotomy (PCNL). Ureteral stenting is also used for therapeutic purposes such as obstructive pyelonephritis, bilateral obstructing stones or an obstructing stone in a solitary kidney. However; ureteral stents cause considerable patient discomfort such as pain, dysuria, urinary frequency, incontinence and hematuria.

The goals outlined in this FOA were developed in part, from the NIDDK sponsored workshop “Urinary Stone Disease: Research Challenges and Opportunities” held on April 1-2, 2015.

Research Objectives

This FOA will establish a network of investigators to design and conduct clinical research studies in adults and children with USD. The network is expected to include a wide range of expertise including but not limited to adult and pediatric urologists, adult and pediatric nephrologists, pediatricians, ED physicians, clinical trialists, nutritionists, behavioral scientists and radiologists. All studies proposed in the applications will be a starting point for discussions regarding the research undertaken by the network. USDRN investigators will devise studies that will be reviewed by a Protocol Review Committee (PRC) and approved by the NIDDK, then recruit stone forming patients for the collaborative studies. The final study protocol will be designed by the Clinical Center, and Scientific Data Research Center Program Directors/Principal Investigators and approved by the Steering Committee. Network study results are expected to provide evidence for management approaches to USD.

USD has different causes, and there have been many studies to understand the mechanisms of stone formation and prevention of new episodes of USD. In contrast, there is scant information about recurrent episodes of USD.  Available evidence suggests a high (about 35%) and unchanging rate of recurrence. Most urinary stones are primarily composed of calcium. There is a need to identify the underlying causes and to improve methods to prevent calcium USD recurrences. Increasing fluid intake and urinary volume, and medical therapies with potassium citrate and/or thiazide or thiazide analog diuretics are the recommended measures for recurrent calcium stone prevention based on moderate quality of evidence.

Although increasing fluid intake is generally recommended for stone-forming patients, a Cochrane review found no studies of increased fluid intake for the primary prevention of USD, and only one study for secondary prevention (to reduce recurrence). A more recent systematic review and meta-analysis including observational studies demonstrated that increased fluid intake significantly reduced incident and recurrent stones. Adherence and safety data were limited. Thus there is a need for a definitive randomized clinical trial (RCT) to evaluate the impact of increased fluid intake on urinary stone recurrence. However, increasing fluid intake and maintaining a daily urine volume of at least 2.5 liters is very challenging in children and adults. There are no reliable recommendations on fluid intake in children. Reluctance to drink increased amounts of water, urinary symptoms due to higher urine volumes, environmental circumstances for bathroom breaks, potential hyponatremia causing altered mental status, confusion, and even seizures, and difficulties in behavior change are some of the impediments for uninterrupted and sustained high fluid intake. The use of wearable devices, smartphone applications and incentives to encourage fluid intake, methods to monitor urine volume, pH and specific gravity are some of the new methods that can be used to facilitate fluid intake. A RCT with sufficient power is needed to determine how to maintain high fluid intake, and then show whether increasing and maintaining urinary volume decreases the urinary stone recurrences in adults and children. Investigators are encouraged to think broadly on incorporating mobile health technology, behavioral economics and/or other innovative strategies to maintain long-term fluid intake. Applicants are also encouraged to propose innovative trial methodologies such as adaptive and pragmatic trial designs, and use of surrogates for stone recurrence.

Ureteral stents are commonly used for therapeutic or prophylactic purposes. Their use is frequently based on clinical judgment of the surgeon to improve stone passage and/or prevent complications rather than evidence. Despite their clinically utility, ureteral stents can cause significant patient pain and discomfort. Years of research by academia and industry to reduce patient discomfort by different stent designs, developing drug-coated stents, and using different stent materials, have not completely eliminated stent related symptoms. Some of the pain and stent related symptoms can be controlled or reduced by medications. Studies are needed to provide evidence for appropriate stent use of ureteral stents during common procedures for stones (SWL, URS, and PCNL), identify patients who will likely experience stent related pain and symptoms, and to mitigate those symptoms. These questions may be answered by establishing new patient cohorts, randomized clinical trials, pragmatic clinical trials or by using other novel clinical study methodologies. Applicants may propose integrated approaches such as an observational study for event rate and risk identification, and a RCT to reduce ureteral stent use and/or mitigate stent pain and symptoms.

The long-term goal of USDRN is to inform clinical practice by a) providing evidence on the effects of fluid intake on urinary stone recurrence, b) understanding and reducing pain and suffering from the use of ureteral stents in USD patients, and c) to create data and biological specimen resources for USDRN investigators and other future researchers.

General Information

Document Type: Grants Notice
Funding Opportunity Number: RFA-DK-15-005
Funding Opportunity Title: Urinary Stone Disease Research Network: Scientific Data Research Center (USDRN-SDRC) (Collaborative U01)
Opportunity Category: Discretionary
Funding Instrument Type: Cooperative Agreement
Category of Funding Activity: Food and Nutrition
Health
Category Explanation:
Expected Number of Awards: 2
CFDA Number(s): 93.847 — Diabetes, Digestive, and Kidney Diseases Extramural Research
Cost Sharing or Matching Requirement: No
Posted Date: Aug 24, 2015
Creation Date: Aug 24, 2015
Original Closing Date for Applications: Nov 18, 2015  
Current Closing Date for Applications: Nov 18, 2015  
Archive Date: Dec 19, 2015
Estimated Total Program Funding: $4,000,000
Award Ceiling: $700,000
Award Floor:

Eligibility

Eligible Applicants:
Native American tribal governments (Federally recognized)
City or township governments
Nonprofits having a 501(c)(3) status with the IRS, other than institutions of higher education
Native American tribal organizations (other than Federally recognized tribal governments)
Public and State controlled institutions of higher education
Private institutions of higher education
Independent school districts
Small businesses
Special district governments
County governments
State governments
Nonprofits that do not have a 501(c)(3) status with the IRS, other than institutions of higher education
For profit organizations other than small businesses
Public housing authorities/Indian housing authorities
Others (see text field entitled “Additional Information on Eligibility” for clarification)
Additional Information on Eligibility: Other Eligible Applicants include the following: Alaska Native and Native Hawaiian Serving Institutions; Asian American Native American Pacific Islander Serving Institutions (AANAPISISs); Eligible Agencies of the Federal Government; Faith-based or Community-based Organizations; Hispanic-serving Institutions; Historically Black Colleges and Universities (HBCUs); Indian/Native American Tribal Governments (Other than Federally Recognized); Non-domestic (non-U.S.) Entities (Foreign Organizations); Regional Organizations; Tribally Controlled Colleges and Universities (TCCUs) ; U.S. Territory or Possession.

Additional Information

Agency Name: National Institutes of Health
Description: This Funding Opportunity Announcement (FOA) invites cooperative agreement applications to establish a multi-center, multi-disciplinary group of investigators to be known as the Urinary Stone Disease Research Network (USDRN). This FOA solicits applications for the Scientific Data Research Center (SDRC) and runs in parallel with a separate FOA that invites applications for the Clinical Centers (CCs) (RFA-DK-15-004). The USDRN will a) design and conduct a randomized clinical trial (RCT) to investigate the impact of increased fluid intake and increased urine output on the rate of recurrence of urinary stones in adults and children, b) conduct clinical research to understand and mitigate ureteral stent-related pain and symptoms, and c) provide data and collect biological samples from the studies to create a resource for future researchers. RFA-DK-15-004 will support USDRN Clinical Centers.
Link to Additional Information: http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-15-005.html
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