Full Text DK-96-007

HEMOLYTIC UREMIC SYNDROME: PATHOPHYSIOLOGY AND TREATMENT
INTERVENTIONS

NIH GUIDE, Volume 24, Number 35, October 6, 1995

RFA:  DK-96-007

P.T. 34

Keywords: 
  Blood Diseases 
  Pathophysiology 
  Treatment, Medical+ 


National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  January 18, 1996
Application Receipt Date:  February 22, 1996

PURPOSE

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD),
jointly with the Division of Digestive Diseases and Nutrition (DDDN),
of the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) invites investigator-initiated research project
grant applications (R01s and R29s) and Interactive Research Project
Grant (IRPG) groups, to encourage and facilitate studies designed to
develop and/or apply new, promising experimental tools to the
understanding of the pathogenesis and pathophysiology of events
resulting in kidney lesions in the Hemolytic Uremic Syndrome (HUS);
to formulate experimental models of HUS; and to identify possible
therapeutic interventions to improve the management and outcome of
HUS.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Hemolytic Uremic Syndrome:  Pathophysiology
and Treatment Interventions, is related to the priority area of
chronic disabling diseases and food safety.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone (202) 512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Applications may be submitted by single institutions or by a
consortium of institutions.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as
Principal Investigators.  Foreign institutions are not eligible for
First Independent Research Support and Transition (FIRST) (R29)
Awards.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of
Health (NIH) research project grant (R01) award,
investigator-initiated interactive research project grant (IRPG)
groups, and FIRST (R29) Award.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all
investigator-initiated applications and be reviewed according to the
customary peer review procedures.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that
of the applicant.  Because the nature and scope of the research
proposal in response to this RFA may vary, it is anticipated that the
size of the awards will also vary; however, requested budgets must
not exceed the NIDDK average grant size of $160,000 (direct costs)
for the initial budget period for both R01s and the individual IRPG.
However, the lead IRPG may include a request for up to an additional
$50,000 direct costs for shared resources (The revised program
announcement (PA) for IRPGs, including SPECIAL INSTRUCTIONS FOR
PREPARING APPLICATIONS FOR INVESTIGATOR-INITIATED IRPGs, is published
in this (Vol. 24, No. 35 October 6, 1995) issue of the NIH Guide and
may be requested from the program staff listed under INQUIRIES)

The total requested project period for an application submitted in
response to this RFA may not exceed five years.  FIRST Awards must be
for five years and the total direct cost award for the five year
period may not exceed $350,000.  The anticipated award date will be
September 30, 1996.

FUNDS AVAILABLE

For FY 1996, $1.5 million in total costs per year for five years will
be committed by the NIDDK to fund applications submitted in response
to this RFA.  It is anticipated that approximately six to seven
awards will be made.  However, this funding level is dependent upon
the receipt of a sufficient number of applications of high scientific
merit.  Although this program is provided for in the financial plans
of the NIDDK, the award of grants pursuant to this RFA is also
contingent upon the availability of funds for this purpose.

Projects with substantial scientific merit that are not funded by the
NIDDK may be eligible for support by the American Digestive Health
Foundation (ADHF).  Applicants will be responsible for forwarding
copies of their Summary Statements and applications to the ADHF for
consideration for this award mechanism.  Support by the ADHF will be
determined by project scope; duration of funding will be limited to
two years.  No funds for indirect costs will be provided.

RESEARCH OBJECTIVES

The Hemolytic Uremic Syndrome (HUS) is a severe life-threatening
disease.  It represents the most common cause of acute renal failure
in infants and children but it can also affect neonates, adolescents
and adults.  It is a heterogeneous syndrome characterized by the
sudden onset of hemolytic anemia, thrombocytopenia and acute renal
failure, with central nervous system compromise occurring in an
important number of patients.  It commonly affects previously healthy
children.  The onset is sudden and it often follows an episode of
acute gastroenteritis with or without bloody diarrhea.  Common
findings are extreme pallor or jaundice; petechiae or mucosal
bleeding; and manifestations of acute renal failure, hypertension,
edema and congestive heart failure, accompanied by weakness and
lethargy.  Because it is a heterogeneous syndrome, the initial
diagnosis is often difficult and only the development of the systemic
symptomatology guides the diagnosis.

Hemolytic Uremic Syndrome (HUS) may occur sporadically or in
epidemics; it can be idiopathic, or secondary to infections or other
causes.  It can be a relapsing process with no prodromal diarrhea, or
apparently be familial or inherited as an autosomal recessive or
dominant form.  Different agents have been implicated as responsible,
but circulating verotoxin/shiga-like toxin (E. coli, predominantly
serotype 0157) and Shiga-toxin (Shigella dysenteriae) are strongly
implicated in the most common forms of HUS.  In North America, the
most common cause, in recent studies, have been the E. coli 0157:H7.
The hallmark of HUS is vascular endothelial cell injury in renal
microvessels resulting in increased thrombogenicity and local
intravascular coagulation, leukocyte adhesion, and production of
mediators.

Epidemiologic data on the true incidence and prevalence are limited;
however, it is continuously reported in different parts of the world
and seasonal variations are a common occurrence.  In Argentina, for
example, the prevalence is estimated at 26 per 100,000 children.
Mortality during the acute phase of HUS has declined from 40 percent
to 10-15 percent with improved general management and availability of
short term dialysis.  Complete recovery, however, occurs in only two
thirds of cases.  Information is not available on morbidity resulting
from long-term follow up under standardized treatment protocols.
Treatment interventions are several but, unfortunately, their value
has not yet been prospectively evaluated.

At present, HUS-associated with diarrhea seems to be emerging as an
important clinical and public health problem, with evidence that the
incidence is increasing mostly in young children.  There is evidence
that HUS is associated with substantial morbidity, based on evidence
of occult nephropathy on long-term follow up.  Some patients develop
hypertension and/or other complications that may impact in adult
life, while other patients show progress to end-stage renal disease
earlier in life.

The common denominator in all forms of HUS is vascular endothelial
cell injury and dysfunction.  This results in increased
thrombogenicity, leukocyte adhesion, and release of inflammatory
mediators.  Research progress has been steady in addressing these
issues and in the understanding of inflammatory processes and immune
mechanisms that contribute to vascular inflammation and injury to the
glomeruli and tubulo-interstitium.  The intent of this RFA is to
build on the remarkable progress that has been recently attained.

This initiative is part of a coordinated trans-NIH effort with the
lead role carried by NIDDK.  This special program will encourage
interdisciplinary collaboration in the basic disciplines with the aim
to stimulate and facilitate fundamental research work. Nevertheless,
research applications can also be more narrowly focussed from one
predominant discipline.  Highly encouraged is the application of
promising new experimental tools to the understanding of mechanisms
and events leading to end-organ compromise in HUS.

It is the intent of this solicitation to invite applications from
investigators with diverse research interests, who wish to apply
their expertise: (a) to elucidate and enhance the current
understanding of the pathogenesis and pathophysiology of HUS,
focusing primarily on events occurring at the cellular and molecular
levels, and (b) to identify interventions that could lead to
improvements in the management and outcome of HUS in children and
adults.

Examples of HUS-related research topics illustrative of areas that
would be considered within the intent of this solicitation, and
therefore responsive to this RFA, are listed.  These examples are
meant only to provide a broad direction and should not be considered
restrictive:

o  Identification and characterization of experimental models of HUS;

o  Inflammatory and immune processes relevant to HUS which contribute
to glomerular thrombotic microangiopathy;

o  Role of the vascular endothelium in antigen recognition and in
eliciting, effecting, and modulating local and systemic immunologic
and inflammatory responses, both in the gastrointestinal tract and
the kidney;

o  Studies of cytokines and the various inflammatory mediators in
eliciting communication signals between the renal and
gastrointestinal vascular endothelium and leukocytes;

o  Role of genetic and environmental factors in the pathogenesis of
immune and inflammatory responses resulting in renal and
gastrointestinalvascular injury;

o  Studies of cytokines that evoke proinflammatory and prothrombotic
effects on endothelial cells;

o  Role of coagulation and fibrinolytic systems in the induction and
maintenance of endothelial injury;

o  Role of endothelium-derived relaxing factor (EDRF), prostacyclin,
endothelin, platelet activating factor (PAF), etc., relevant to the
pathogenesis and pathophysiology of HUS glomerulopathy and
gastrointestinal disease;

o  Toxin-endothelial cell interaction, mediators, and resulting
glomerular endothelial or gastrointestinal injury;

o  Early markers of intestinal injury or gangrene;

o  Early markers of HUS;

o  Early markers of disease severity; and

o  Identification of treatment interventions to improve the immediate
and long-term outcome of HUS.

It is hoped that a better understanding of events occurring at the
cellular and molecular levels in HUS and the availability of newer
molecular biology tools, which have already enhanced the
understanding of the pathophysiologic events, should result in
further improvements in the management and outcome of HUS.

Investigators are not limited to the above examples of research
focus, and are encouraged to propose other approaches that are
appropriate to the investigator-initiated R01, IRPGs, and FIRST Award
(R29) mechanisms, and to the requirements of this RFA.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator should be included
with the application.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and sub-populations must be included in all NIH supported biomedical
and behavioral research projects involving human subjects, unless a
clear and compelling rationale and justification is provided that
inclusion is inappropriate with respect to the health of the subjects
or the purpose of the research.  This new policy results from the NIH
Revitalization Act of 1993 (Section 492B of Public Law 103-43) and
supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations) which have been in effect since
1990.  The new policy contains some provisions that are substantially
different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
subjects in Clinical Research", which have been published in the
Federal Register of March 20, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS Volume 23, Number 11, March
18, 1994.

Investigators may also obtain copies from these sources or from the
program staff or contact person listed under INQUIRIES.  Program
staff may also provide additional relevant information concerning the
policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 18, 1996, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the
information that it contains allows NIDDK staff to estimate the
potential review workload and avoid possible conflict of interest in
the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, Room 6AS 37-E, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, 6701 Rockledge Drive, Room 3034, MSC
7762, Bethesda, MD 20892-7762, telephone 301/710-0267, email:
[email protected].

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page.  Failure to use this label
could result in delayed processing of the application such that it
may not reach the review committee in time for review.  In addition,
the RFA title and number must be typed under item 2 of the face page
of the application form and check the YES box.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package
to:

DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At time of submission, two additional copies of the application must
also be sent under separate cover to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, Room 6AS 37-E, MSC 6600
Bethesda, MD  20892-6600

Applications must be received by February 22, 1996.  If an
application is received after that date, it will be returned to the
applicant.  The Division of Research Grants (DRG) will not accept any
application in response to this RFA that is essentially the same as
one currently pending initial review, unless the applicant withdraws
the pending application.  The DRG will not accept any application
that is essentially the same as one already reviewed.  This does not
preclude the submission of substantial revisions of applications
previously reviewed, but such applications must include an
introduction addressing the previous critique.

FIRST Award Applicants must adhere to the R29 Administrative
Guidelines (rev. February 1994) for eligibility, budget and period of
award.  FIRST (R29) Award applications must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award applications submitted without the required
reference letters will be considered incomplete and will be returned
without review.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG,
and for responsiveness by the NIDDK. Incomplete applications will be
returned to the applicant without further consideration.  In
addition, if NIDDK staff find that the application is not responsive
to the RFA, it will be returned without further consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIDDK in accordance with NIH peer review
procedures.  As part of the initial merit review, all applications
will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the National Diabetes and Digestive and Kidney Diseases
Advisory Council.

Review Criteria

o  Scientific and technical merit criteria specific to the objectives
of the RFA

o  Scientific, technical, or medical significance and originality of
proposed research

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research

o  Qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research

o  Availability of resources necessary to perform the research

o  Appropriateness of the proposed budget and duration in relation to
the proposed research

o  Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for recruitment and retention of subjects will also be
evaluated

o  For applications involving activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed means for protecting against or minimizing such effects

o  For foreign applications, availability of special opportunities
for furthering research programs through the use of unusual talent,
resources, populations, or environmental conditions not readily
available in the United States or that provide enhancement of
existing U.S. resources, must be addressed.

AWARD CRITERIA

The anticipated date of award is September 30, 1996.

Award criteria will include the scientific merit of the application
as determined by peer review, availability of funds, and programmatic
priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Inquiries regarding programmatic issues may be directed to:

Gladys H. Hirschman, M.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, Room 6AS-13, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
Email:  [email protected]

Frank Hamilton, M.D., M.P.H.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, Room 6AN-12B, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8877
Email:  [email protected]

Inquiries regarding fiscal matters may be directed to:

Aretina D. Perry
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, Room 6AN-38B, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8862
Email:  [email protected]

Schedule

Letter of Intent Receipt Date:  January 18, 1996
Application Receipt Date:       February 22, 1996
Initial Review:                 July 1996
Second Level Review:            September 1996
Anticipated Date of Award:      September 30, 1996

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.849 and 93.848.  Awards are made under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.

.

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