According to the 2002 USRDS Annual Data Report, the incidence in the United States of end-stage renal disease (ESRD) in young people ages 0 - 19 years is 15 per million people. The primary etiologies vary with age, but structural anomalies predominate. Data in the most recent report from the Chronic Renal Insufficiency arm of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) indicate that about two-thirds of the patients on the registry had some type of structural anomaly.
Numerous metabolic derangements occur in chronic kidney disease (CKD), and they have a significant impact on the overall well-being of affected children. Of the negative effects of pediatric renal disease, growth impairment is the best documented and studied, but very little systematic information is available about the magnitude of other developmental problems. In fact, large-scale prospective studies of pediatric chronic kidney disease have not been done.
The Prospective Study of Chronic Kidney Diseases in Children was established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Child Health and Human Development (NICHD), to determine the following in children with CKD:
- Risk factors for decline in renal function
- Incidence of, and risk factors for, impaired neurocognitive development and function
- Prevalence of risk factors for cardiovascular disease
- Long-term effects of growth failure and its treatment
The clinical coordinating centers for the study are Johns Hopkins University (Susan Furth, PI) and Children's Mercy Hospital , Kansas City (Bradley Warady, PI). The data coordinating center is Johns Hopkins University (Alvaro Munoz, PI). The study is currently in the planning stages and is slated to be completed in 2008. The information obtained from this study will establish natural history and outcome measures for intervention/prevention trials.
Structural Anomalies and Metabolic Disturbances
Short stature is one of the more commonly recognized effects of CKD, first recognized over a century ago. The height deficits are greatest for younger patients and the risk for growth failure has been documented as highest in patients developing CKD at birth or early in infancy. The degree of renal failure, and particularly a GFR < 25 ml/min/1.73m2, has been touted as critical to poor growth. Recent data also link poor growth to increased morbidity and mortality.
When CKD develops during the neonatal period or in early infancy, significant problems with neurocognitive development occur. Some studies suggest an incidence of severe neurodevelopmental delay as high as 60 percent to 85 percent in this subpopulation. Growth in head circumference is uniformly subnormal. Gross motor delay, along with global developmental retardation and a lack of maturation on electroencephalography are common. Myoclonic seizures and cerebellar dysfunction have also been described in infants. However, virtually no information exists on the impact of a decrease in renal function that develops later in childhood. Overall, the impact of renal disease and uremia on neurocognitive development has been the subject of little systematic evaluation.
Both the nature and magnitude of impaired neurocognitive development in pediatric patients with renal failure is unknown. Renal failure, however commonly affects both the central and peripheral nervous systems. Chronic uremic encephalopathy is associated with problems in learning and memory. These symptoms are believed to result from altered metabolic states in the CNS with ionic changes and possibly impaired synaptic function. Renal failure may also be accompanied by neuropathy and involvement of large diameter axons. There is substantial uncertainty in the renal community about whether earlier institution of renal replacement therapy offers advantages for the child's development.
The incidence of hypertension in children with CKD is reported at 38 percent to 78 percent. As a general rule, hypertension is infrequent in congenital renal disease, but it is almost universal in primary glomerular disease and renal injury caused by systemic disease. In addition, uremic cardiomyopathy can be seen in pediatric patients with advanced CKD or ESRD and may be associated with congestive heart failure. A recent report indicates that hyperhomocysteinemia is found in children with CRF, but it is unclear whether treatment of hyperhomocysteinemia in children decreases the risk for future atherosclerosis.
Hyperhomocysteinemia has been identified as a risk factor for development of atherosclerosis in adults with CRF. Cardiovascular disease is a major problem in the adult nephrology patient population, but the incidence and types of cardiovascular disease present in children are unknown. For patients who have kidney failure starting in childhood, the incidence of risk factors for cardiovascular disease needs to be clearly delineated.
Research Scope and Goals
The primary goals of this program are to recruit a cohort of 600 children with mild to moderately impaired kidney function and to follow these children in a prospective fashion for five years in order to define factors that impact on their well-being. Possible areas of research are listed below; however they were intended only to provide a broad direction for research.
- Determination of the risk factors for accelerated decline in renal function.
- Determination of the incidence of, and risk factors for, impaired neurocognitive development and function
- Determination of the nature (sensory, motor, visual and temporal processing; learning and memory; attention; social cognition and affect), and magnitude of neurocognitive impairment in pediatric CRF
- To establish brain structure/function correlates of neurocognitive impairment in pediatric CRF (imaging, behavioral and psychophysiological methodologies)
- Examination of genetic contributions to disease
- Determination of the implications of growth failure and its treatment on morbidity and mortality
- Determination of the prevalence of risk factors for cardiovascular disease
NIDDK/KUH Program Officer: Marva M. Moxey-Mims, M.D., (301) 594-7717.