The study of kidney diseases endemic to children requires interdisciplinary research among a wide range of scientific investigators who will use complementary and integrated approaches. To facilitate this, the Division of Kidney, Urologic, and Hematologic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established Centers of Research Excellence in Pediatric Nephrology in 2001.
This consortium of research centers approaches the study of disease processes with the extensive collaboration of investigators in the clinical and basic sciences, including cell biology, molecular biology, immunology, virology, genetics, epidemiology, biochemistry, physiology, and pathology. Studies are designed to foster and extend the development of new approaches into the causes, early diagnoses, improved treatment, and, where possible, prevention of these diseases and disorders.
Kidney Disease in Children
Kidney disease is a major cause of illness and death in infants, children, and adolescents, who make up approximately 25 percent of the U.S. population. Both incidence and prevalence rates have increased moderately in the pediatric population since 1990, with rates continuing to be highest in adolescents 15 to 19 years of age, with particularly high rates- three times those of Caucasian Americans-in African American children of both genders. In the pediatric population, an estimated 14,000 children have kidney disease; 5,000 have kidney failure and are on dialysis or have a kidney transplant; and, of these, about 60 percent are 12 years of age or younger. As a consequence, the financial cost to the American taxpayer is enormous.
Developmental disorders of the kidney account for about one-third of all childhood cases. Investigators are beginning to perform molecular and genetic analyses to link specific gene products to normal growth and development of the kidney and human kidney diseases. For example, in congenital nephritic syndrome, a glomerular disease in infants that is characterized by massive amounts of protein in the urine and progressive kidney failure, researchers have recently identified mutations in a glomerular protein called nephrin. This disorder often progresses to the point that dialysis or kidney transplantation is required during infancy. Other disorders in the very young patient include renal dysplasia(s) and hypoplasia(s), cystic malformations, polycystic kidney disease (PKD), tubulointerstitial diseases, and congenital structural abnormalities (i.e., obstructive uropathy, vesicoureteral reflux, and the resulting reflux nephropathy).
Older children often develop end-stage renal failure from conditions such as immune complex disease, hereditary nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, and hemolytic uremic syndrome. The basic cellular and molecular mechanisms of most of these disorders are poorly understood. Progression often occurs even when health care providers consider the primary disease process to be adequately treated and when the disorder appears to have become inactive.
Several diseases that lead to chronic kidney disease and end-stage renal disease (ESRD) in adults often have their origin in childhood; notable examples are diabetes and hypertension. Up to one third of children who develop Type 1 (insulin-dependent) diabetes will develop ESRD in their twenties or thirties.
Strategies to prevent kidney disease ideally should begin in childhood or late adolescence; therefore, a great need exists to better understand the pathogenesis of these conditions, with the ultimate aim of prevention of complications or the development of improved therapies. In kidney disease, children face special growth and developmental challenges; strategies to address this are another urgent need.
Program Aims
Interrelated, basic research subprojects, each with high scientific merit and clear research objectives, have provided the traditional framework of the Centers of Excellence in Pediatric Nephrology program. In the aggregate, the subprojects will continue to be directed to the development of fundamental knowledge leading to the understanding of kidney disease processes in childhood and the design of curative or preventive strategies.
A new dimension to the centers program is the inclusion of research development and pilot and feasibility project(s). The aims of this project are as follows:
- Continue to attract new scientific expertise into the study of the basic mechanisms of kidney diseases and disorders among infants, children, and adolescents
- Encourage multidisciplinary research focused on the causes of these diseases
- Explore new basic areas that may have clinical research application
- Design two-year developmental research pilot and feasibility studies that will lead to new and innovative approaches to the study of kidney diseases in children and the eventual submission of competitive investigator-initiated R01 research grant applications
Strategies of Research
Representative, but not all-inclusive, areas of research appropriate for investigation include
- Studies of kidney disorders of genetic and congenital origin that may lead to progressive loss of renal function or cause severe metabolic imbalances in children, including hyperoxaluria, and that include the use of gene-targeting and transgenic technologies in addressing Bartter's, Gitelman's, and Liddle's syndromes during development and congenital nephrogenic diabetes insipidus
- Further identification and study of genes and gene mutations and molecular events involved in renal and urogenital morphogenesis and differentiation
- Studies of events involved in cellular signaling in renal morphogenesis in health and disease, including the definition of events involved in cellular communication and mechanisms by which growing cells influence and are influenced by extracellular matrix
- Immune-mediated disorders, including such diseases as post-infectious glomerulonephritis, human immunodeficiency virus (HIV), immunoglobulin A (IgA) nephropathy, Goodpasture's syndrome, and Wegner's granulomatosis
- Studies to understand the molecular mechanisms underlying the renal hypertension in infants and children
- Studies addressing the short and long-term effects of anti-hypertensive agents in infants and children
- Identification of risk factors and predisposing factors contributing to kidney disease progression in infants and children
- Studies addressing the etiology, pathophysiology, and treatment strategies for ESRD in infants and young children, including determinants of abnormal growth and development, the development of animal models to quantitate [quantify?] the contribution of selective variables in growth retardation in chronic renal failure, the effects of exogenous recombinant hormones, and the role of uremia in protein synthesis in young growing infants
- Cellular and molecular studies underlying the development and progression of glomerulonephritis in children, including the molecular changes affecting the glomeruli, alterations of the basement membrane, mechanisms leading to proteinuria, and the biochemistry of the nephron during pathological states
NIDDK/KUH Project Officer: Marva Moxey-Mims, M.D., 301-594-7717.
