Full Text DK-94-014


NIH GUIDE, Volume 23, Number 1, January 7, 1994

RFA:  DK-94-014

P.T. 34

  Treatment, Medical+ 

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  March 15, 1994
Application Receipt Date:  April 12, 1994


The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invites investigators to submit:  (1) innovative research
grant applications that could provide a critical insight into
fundamental factors and/or mechanisms leading to progression of renal
disease, such as IgA nephropathy in childhood, and (2) clinical
research applications for pilot studies in IgA nephropathy. The
latter will assess the efficacy and safety of innovative therapeutic
strategies aimed at preventing and/or controlling renal disease
progression in children, adolescents, and young adults with IgA


The 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. Potential applicants may obtain
a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).


Applications addressing the fundamental research aspects of this
solicitation may be submitted by domestic and foreign for-profit or
nonprofit organizations, whether public or private, such as
universities, colleges, hospitals, laboratories, units of State or
local governments, and eligible agencies of the Federal Government.
Applications addressing the clinical pilot aspect of this
solicitation may be submitted only by domestic for-profit and
nonprofit organizations, as described above.

Minority individuals and women are encouraged to submit as Principal

Note: Foreign institutions are ineligible for the R29 award.


Support of this program will be through the NIH grant-in-aid research
project (R01) and FIRST (R29) grant awards. Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant.  Awards will be administered under
Public Health Service (PHS) grants policy as stated in the PHS Grants
Policy Statement.

This RFA is a one-time solicitation for applications for new awards.
Generally, future unsolicited competing continuation applications for
either the fundamental research or the clinical component of this
solicitation will compete with all investigator-initiated
applications and will be reviewed according to the customary peer
review procedures.  The total requested project period for
applications submitted in response to this RFA, addressing either the
fundamental research aspects of this solicitation or the clinical
aspect of this RFA, may not exceed a total of five years.  A maximum
of three years may be requested for foreign awards.

The earliest possible award date will be September 30, 1994.


For FY 1994, $2,000,000 will be committed to fund applications
submitted in response to this RFA; however, this funding level is
dependent upon the receipt of a sufficient number of applications of
high scientific merit.

It is anticipated that 5-6 awards will be made to support
applications addressing the fundamental research aspects of this
solicitation, and 3-4 awards will be made to support applications
addressing the clinical aspect.  Applications must limit their
requests to not more than $160,000 direct costs for the initial
budget period.

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.


This comprehensive research initiative is intended to (a) stimulate
innovative fundamental research work utilizing state-of-the-art
methodology including molecular and cell biology and genetic
approaches that could provide critical insights into fundamental
factors/mechanisms leading to renal disease progression in general,
and to the establishment of IgA nephropathy in particular, in
children and young adults; (b) identify and pilot test possible
treatment intervention protocols that should result in control of
renal disease progression in IgA nephropathy, once the diagnosis has
been made.  The pilot protocols will test the efficacy and safety of
innovative therapeutic interventions aimed at preventing and/or
controlling disease progression in children, adolescents and young
adults affected with IgA nephropathy.


Chronic renal insufficiency and end-stage renal disease (ESRD) in the
pediatric patient represent a significant problem.  This constitutes
a unique pathophysiologic entity in which the multi-system effects of
uremia adversely affect the growth and development of most organ
systems and the individual.  There is universal agreement that there
are renal disorders unique to the pediatric age group that are
clearly different in pathogenesis, management, and prognosis from
renal disorders in adults.  It is also recognized that, even though
renal failure is more frequent in adults, the majority of the
disorders observed in adults have their onset in childhood.
Therefore, a reduction in the major causes of kidney diseases that
start in infancy or childhood and efforts directed at the
understanding of the most basic mechanisms underlying renal disease
progression, minimizing complications and improving clinical outcome,
constitute the mainstay of the long-range research plan for pediatric
nephrology within the NIDDK.

IgA nephropathy was first described over 20 years ago and is
considered to be the most common primary glomerular disease
throughout the world.  In southern Europe, Asia and Australia the
incidence is calculated at 30-40 percent; in northern Europe and the
United States it is calculated at 20 percent of all primary
glomerular diseases.  The different estimates may reflect differences
in screening practices and in indications for renal biopsy.  The
diagnostic hallmark of IgA nephropathy is the finding of mesangial
deposition of IgA by immuno-fluorescence microscopy of biopsy
specimens.  This test is, therefore, essential for the correct
diagnosis of the disease.

There are strong suggestions that IgA nephropathy has a genetic
predisposition; nevertheless, the pathogenesis remains an enigma, and
different mechanisms have been ascribed.  It affects the pediatric as
well as the adult patient population, and the clinical course and
prognosis varies greatly.  The course of IgA nephropathy ranges from
a small percentage of cases (estimated at 4 percent) with a benign
course and with regression of symptoms without any treatment
intervention, or a clinically progressive course with frequent
recurrence of gross hematuria and a continuous deterioration of renal
function (estimated at 50 percent), to a pathological deterioration
in renal function leading to ESRD or death.

There is no proven treatment for IgA nephropathy.  Some regimens
involve steroids with varying doses, varying schedules (daily vs.
alternate days), and varying length of treatment.  Other protocols
involve azathioprine/chlorambucil, Cyclosporine, plasma exchange and
antiplatelet agents alone or in combination.  These different
treatment regimens have been proposed and tested in small series;
however, as of today, the results are openly controversial.

Therefore, there is a need to learn more about the pathogenesis,
genetics, natural history, true epidemiology, and effective treatment
interventions for IgA nephropathy before ESRD ensues.


It is NIH policy that women and minorities must be included in
clinical study populations unless there is a good reason to exclude
them. The study design must seek to identify any pertinent gender or
minority population differences.


NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample and must be appropriate for the scientific
objectives of the study.  This information must be included in the
form PHS 398 (Rev. 9/91) in Item 4 (Research Design and Methods) of
the Research Plan AND summarized in Item 5, Human Subjects.
Applicants/offerors are urged to assess carefully the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States racial/ethnic minority populations; i.e., Native
Americans [including AmeriCan Indians or Alaskan Natives],
Asian/Pacific Islanders, Blacks, Hispanics.

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention [and preventive strategies], diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and reflected
in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these


Prospective applicants are asked to submit, by March 15, 1994, 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 subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NIDDK staff to estimate the potential review
workload and to avoid 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
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 594-7515
FAX:  (301) 594-7503


The research grant application form PHS 398 (rev. 9/91) must be used
in applying for these grants.  The grant application kits are
available from most institutional business offices or may be obtained
from the Office of Grants Information, Division of Research Grants,
National Institutes of Health, 5333 Westbard Avenue, Room 449,
Bethesda, MD 20892, telephone 301/710-0267.

The RFA label available in the 9/91 revision of form PHS 398 must be
affixed to the bottom of the face page.  Failure to use this label
could result in delayed processing of your application such that it
may not reach the review committee in time for review.  In addition,
the RFA title and number must be typed on line 2a 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

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892

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

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

Applications must be received by April 12, 1994.  If an application
is received after that date, it will be returned to the applicant.
The DRG will not accept any application in response to this
announcement that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending
application.  However, it is allowable to submit the same project as
both an R01 and as a component project of a program project (P01).
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. Such
applications must not only include an introduction addressing the
previous critique but also be responsive to this RFA.

Applicants from institutions which 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 could be included
the application.

For investigators applying for support through the FIRST award
mechanisms (R29), three letters of references must be submitted with
the application.  An applicant submitting a revised application in
response to this RFA must again submit reference letters.


Upon receipt, applications will be reviewed by the Division of
Research Grants (DRG) for completeness.  Incomplete applications will
be returned to the applicant without further consideration.
Evaluation for responsiveness to the program requirements and
criteria stated in the RFA is an NIDDK staff function.  If the
application is not responsive to the RFA, NIDDK staff will contact
the applicant to determine whether it should be returned to the
applicant or held until the next regular receipt date and reviewed in
competition with all other applications.

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by the appropriate peer review group convened by the NIDDK.  If
the number of applications is large compared to the number of awards
to be made, a triage of the applications may be conducted.
Applications judged to be not competitive for the award will be
withdrawn from further review.  The NIDDK will notify the applicant
and institutional
official of this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the NIH peer review
procedures by an initial review group specifically convened for this
RFA.  Following this review, the applications will be given a
secondary review by the National Diabetes and Digestive and Kidney
Diseases Advisory Council unless not recommended for further
consideration by the initial review group.

Review Criteria

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

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; and

o  if an application involves and could have an adverse effect upon
humans, animals, or the environment, the adequacy of the proposed
means for protecting against or minimizing such effects.

Additional Criteria for Review of Applications from Foreign
Institutions Include:

o  uniqueness of research such that it can only be performed outside
of the United States.

Additional Criteria for Review of Pilot Clinical Study Applications

o  familiarity with and experience in recruiting participants for
participation in clinical studies;

o  documentation of access to IgA patients.


The anticipated date of award is September 30, 1994.  Applications
will compete for available funds with all other approved applications
submitted in response to this RFA.  The following will be considered
in making funding decisions:

o  quality of the proposed work as determined by peer review;
o  availability of funds;
o  program balance among research areas of the RFA; and
o  how the proposed research relates to, or integrates with, ongoing
research activities included in collaborator's laboratories;


Written and telephone inquiries concerning this RFA are encouraged.
Inquiries regarding programmatic issues should be directed to:

Gladys H. Hirschman, M.D.
Chronic Renal Diseases Program and Pediatric
Division of Kidney, Urologic and Hematologic Diseases,
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A-07
Bethesda, MD  20892
Telephone:  (301) 594 7584
FAX:  (301) 594 7501

Inquiries regarding fiscal matters should be directed to:

Aretina D. Perry
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 639
Bethesda, MD  20892
Telephone:  (301) 594-7543


Letter of Intent:        March 15, 1994
Application Receipt:     April 12, 1994
Initial Review:          June-July, 1994
Second Level Review:     September 20-21, 1994
Anticipated Award:       September 30, 1994


This program is described in the Catalog of Federal Domestic
Assistance No. 93.849.  Awards are 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


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