Full Text DK-97-007
NIH GUIDE, Volume 26, Number 2, January 17, 1997
RFA:  DK-97-007
P.T. 34, AA


National Institute of Diabetes and Digestive and Kidney Diseases
Letter of Intent Receipt Date:  March 18, 1997
Application Receipt Date:  April 18, 1997
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) recognizes the need to enhance research activities in
Pediatric Nephrology.  The Division of Kidney, Urologic and
Hematologic Diseases (DKUHD) of the NIDDK invites Exploratory
Research Project Grant Applications (R21s) to encourage and
facilitate studies designed to develop and/or apply new promising
experimental tools to the understanding of the pathophysiology and
pathogenesis of events resulting in chronic renal failure and its
complications, in children.
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  Exploratory Grants in Chronic Renal Failure in
Children, 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).
Applications may be submitted by domestic for-profit and non-profit
organizations, public or private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and
eligible agencies of the Federal Government. Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
Support of this program will be through the National Institutes of
Health (NIH) Exploratory/Developmental Research Project Grant (R21)
Award.  The total requested project period for applications submitted
in response to this RFA may not exceed two years.  The requested
budgets may not exceed $50,000 (Direct Costs) per 12-month budget
period.  The anticipated award date will be September 30, 1997.  This
RFA is a one-time solicitation.  If the NIDDK determines that there
is a sufficient continuing program need, a request for applications
will be announced.  Future unsolicited competing continuation
applications will compete with all investigator-initiated
applications and will 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
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.
A total of $500,000 in total costs for each of two years will be
committed by the NIDDK to fund applications submitted in response to
this RFA.  It is anticipated that approximately five 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.
The primary objective of this solicitation is to invite Exploratory
Research Project Grant Applications from members of the diverse
pediatric research community with research interest, technology,
tools and strategies that could be brought to bear on problems
relevant to chronic renal failure in children.  In order to meet
these objectives, this solicitation is put forward to encourage and
facilitate the development of exploratory research protocols focused
on the pathophysiology and pathogenesis of chronic renal failure in
children.  The final aim is directed towards the enhanced
understanding of the underlying mechanisms leading to chronic renal
failure and its complications in children in a combined effort to
reduce or eliminate its causes, control disease progression and
provide pediatric patients with new and optimal management and
Chronic renal disease (CRD) and renal failure in pediatric patients
represent a significant problem; the clinical care and attendant
services required to manage these patients are the most difficult,
time consuming and frustrating endeavors for patients, their
families, and treating pediatric nephrologists.  Furthermore, when
renal replacement therapies are needed, these must be individually
tailored to each patient and continuously adapted to meet the special
requirements of the growing and developing patient.
Progressive renal disease occurs in all age groups resulting from
varying underlying causes, recognized as distinct according to the
different age-categories involved.  Congenital structural
malformations, including vesicoureteral reflux, obstruction,
hypoplasia and dysplasia, represent the principal underlying causes
of end-stage renal disease (ESRD) particularly in the very young
child.  Added to these, older children also develop chronic renal
failure (CRF) resulting from glomerular and tubulointerstitial
disease, immune complex disease, hemolytic uremic syndrome, IgA
nephropathy, focal segmental sclerosis,  hereditary nephropathies,
etc.  The majority of these disease entities remain mechanistically
mysterious.  Diabetic nephropathy, so frequently underlying ESRD in
the adult population, does not result in CRF in childhood.
Nevertheless, most patients with diabetes who develop ESRD in their
20s and 30s, are those whose diabetes presented during childhood or
early adolescence.
In children, as in adults, renal disease progression occurs even when
the primary renal insult has been corrected, treated, or become
inactive.  Adaptive mechanisms may play an important role in the
ongoing process.  The similar histologic appearance of chronic renal
diseases, which is independent of the initial lesion, represents
further evidence that such progressive pathway may be common to all.
Regardless of where in the kidney the insult occurs, the structural
hallmark of progressive failure is the development of scar tissue,
through fibrinogenesis.  The biologic mediators of scar formation in
the glomerulus have been actively examined and some of the biological
mediators which regulate these processes are currently under active
investigation.  Research continues to focus on growth factors and
cytokines which mediate mesangial cell proliferation and the
production of extracellular matrix.  Treatment of experimental models
with agents that block these growth factors have provided new
insights into disease pathogenesis and future management.
During the past decade, dramatic developments have unfolded in the
field of molecular genetics and allied disciplines, allowing for the
application of powerful tools and strategies to the investigation of
kidney diseases.  These same tools need to be more forcefully applied
to research focused on renal diseases affecting children.  A few
selected examples are listed to highlight research progress and
opportunities.  Included, among many others, are the following recent
o  Specific mutations have been demonstrated in the collagen COL4A5
gene in patients with Alport's Syndrome.
o  Molecular alterations associated with the alpha 3 chain of type IV
collagen are implicated in the development of Goodpasture's Syndrome,
in humans.
o  The Wilm's tumor suppressor gene WT1, has been identified.
Germline WT1 mutations predispose to Wilm's tumor and are often
associated with urogenital anomalies.
o  The cystinuria gene has been mapped to chromosome 2, subregion
2p21, and three distinct phenotypes for cystinuria have been
described.  The identification of four novel mutations shall serve to
complement the measurements of cystine excretion in the selection of
patients with high risk of nephrolithiasis, for anticipatory
o  The congenital nephrotic syndrome (CNS) locus has been assigned to
chromosome 19q12-q13.1 on the basis of linkage analysis in Finnish
families; the linkage of the CNS locus to the same chromosomal region
was also confirmed in non-Finnish CNS families.  CNS is inherited as
an autosomal recessive trait and it has been postulated that the
primary defect could be a structural and functional defect in the
glomerular basement membrane.
o  In IgA nephropathy, a deletion (D) polymorphism of a fragment of a
287-bp fragment of intron 16 of the angiotensin converting enzyme
(ACE) gene, has been recently found to have a significant association
with progressive deterioration of renal function.  The association of
hypertension and mild initial reduction of renal function, as risk
factors for progression, suggest that the presence of the DD ACE
genotype may shift IgAN from mild to severe, and nephropathy from
subclinical to overt.  It is suggested that the presence of
proteinuria may act as a risk factor for disease progression and
renal failure, conceivable because proteinuria and progression share
the same genetic risk factor, namely the D polymorphism of the ACE
o  Concerning complications resulting from CRF, in recent years, the
treatment option of recombinant human GH (rhGH) has been successful
in stimulating growth in children with various degrees of CRF.
Despite this treatment, growth retardation remains one of the major
obstacles to successful rehabilitation of children and adolescents
with CRF.  The pathogenesis of uremic growth failure is only
partially understood and it is viewed as resulting from several
interrelated processes, all contributing to growth impairment in the
uremic child. Recombinant human growth factor (rhIGF-I) has been used
in combination with rhGH, and has shown a synergistic effect,
improving total nitrogen retention in calorically deprived subjects
and stimulating linear growth in children with GH receptor defects.
This growth factor may offer promise in the treatment of selective
growth disorders and protein catabolic states.
o  The Final Report of the Growth Failure in Children with Renal
Disease Study has been published.  The data confirmed that once
glomerular filtration rate (GFR) falls to less than 50% of normal, an
elevated serum PTH level can be expected; both calcitriol and
dihydrotachysterol were found to be equally potent in suppressing PTH
Despite research progress and the evidence of the level of
productivity and opportunities, many fundamental aspects of the
pathogenesis and pathophysiology of the underlying conditions as well
as the adaptation to CRF are incompletely understood, unknown, or
remain unexplored in pediatrics and require immediate research
attention.  Therefore, research efforts should continue, and
application of the most up to date research tools must be encouraged
to be able to make a difference in the overall prevention of renal
disease progression as well as in improving the management of the
severe complications resulting from CRF in children.  This is the
focus of the present RFA.
Research Goals and Scope
It is the intent of this solicitation to invite applications from
investigators of the diverse pediatric research community with
research interest, technology and specific strategies, who wish to
apply their expertise: (i) to elucidate and enhance the current
understanding of the pathogenesis and pathophysiology of CRF in
children, focusing primarily on events occurring at the cellular and
molecular levels; (ii) to identify, characterize, or develop
experimental models, faithful to pediatric chronic renal disease, to
help in the understanding of the fundamental events leading to renal
disease progression and CRF; (iii) to identify interventions that
could lead to improvements in the management and outcome of CRF in
This special program should encourage interdisciplinary collaboration
in the basic disciplines to stimulate and facilitate fundamental
research work; 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 CRF and its complications in
Examples of pediatric CRF-related topics illustrating areas which
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  Studies addressing the biology of kidney development and
differentiation with emphasis on molecular events resulting in
abnormalities which may lead to the development of CRF.
o  Investigation of the inflammatory and immunologic processes and
the genetic environment factors responsible for glomerular or
tubulointerstitial injury perceived as contributors to the
development of progressive renal disease and CRF in children.
o  Identification and characterization of experimental models
faithful to pediatric chronic renal disease and CRF.  These
experimental models should be ideally suited for the detailed
evaluation of events occurring at the cellular, molecular or genetic
levels, responsible for the ultimate development of CRF.
o  Elucidation of the pathogenesis and pathophysiology of  relevant
complications resulting from, or inherent to CRF in children.
o  Identification and characterization of early markers of renal
disease severity in children.
o  Identification of novel approaches to improve the immediate and
long-term outcome of pediatric CRF.
It is hoped that a better understanding of events occurring at the
cellular and molecular levels with new technologies and investigative
approaches, which have already proven extraordinarily useful in
genetics, immunology, and allied disciplines, should enhanced the
understanding of the pathophysiologic events, should result in a
better understanding of the basic mechanisms leading to chronic renal
disease, in pediatrics and help in the development of preventive
strategies to prevent or improve the management and outcome of CRF in
Investigators are not limited to the above examples of research
focus, and are encouraged to propose other approaches that are
appropriate to Exploratory Research Grants, and to the requirements
of this RFA.
It is the policy of the NIH that women and members of minority groups
and their 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
Prospective applicants are asked to submit, by March 18, 1997, 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-F - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594 8885
FAX:  (301) 480 3505
The research grant application form PHS-398 (rev. 5/95) is be used in
applying for these grants.  Application kits are available at most
institutional offices of sponsored research and may be obtained from
the Division of Extramural Outreach and Information Resources,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone (301) 435-0714, e-mail:
The RFA label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the application.
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 the YES box
must be marked.
Submit a signed, typewritten original of the application, including
the Checklist plus three signed, exact photocopies, in one package
BETHESDA, MD  20892-7710
BETHESDA, MD 20817 (for express/courier service)
At time of submission, two additional copies of the application must
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-F - MSC 6600
Bethesda, MD  20892-6600
Applications must be received by April 18, 1997.  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.
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.  Incomplete applications will be returned to the
applicant without further consideration.  If the application is not
responsive to the RFA, DRG staff may contact the applicant to
determine whether to return the application to the applicant or
submit it for review in competition with unsolicited applications, at
the next review cycle.
As part of the initial merit review, all applications will receive a
written critique and may undergo a process in which only those
applications deemed to have the highest scientific merit will be
discussed, assigned a priority score, and receive a second level
review by the national advisory council.  Applications determined to
be non-competitive will be withdrawn from further consideration and
the principal investigator and the official signing for the applicant
organization will be notified.
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.
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.
The anticipated date of award is September 30, 1997.  Award criteria
will include the scientific merit of the application as determined by
peer review, availability of funds, and programmatic priorities.
Letter of Intent Receipt Date:  March 18, 1997
Application Receipt Date:       April 18, 1997
Initial Review:                 July 1997
Second Level Review:            September 17-18, 1997
Anticipated Award:              September 30, 1997
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
FAX:  (301) 480-3510
Email:  gladys_hirschman@nih.gov
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:  perrya@ep.niddk.nih.gov
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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