Abstract
Chronic kidney disease (CKD) in children is irreversible. It is associated with renal failure progression and atherosclerotic cardiovascular (CV) abnormalities. Nearly 60% of children with CKD are affected since birth with congenital or inherited kidney disorders. Preliminary evidence primarily from adult CKD studies indicates common genetic risk factors for CKD and atherosclerotic CV disease. Although multiple physiologic pathways share common genes for CKD and CV disease, substantial evidence supports our attention to the renin angiotensin system (RAS) and the interlinked inflammatory cascade because they modulate the progressions of renal and CV disease. Gene polymorphisms in the RAS-cytokine pathway, through altered gene expression of inflammatory cytokines, are potential factors that modulate the rate of CKD progression and CV abnormalities in patients with CKD. For studying such hypotheses, the cooperative efforts among scientific groups and the availability of robust and affordable technologies to genotype thousands of single nucleotide polymorphisms (SNPs) across the genome make genome-wide association studies an attractive paradigm for studying polygenic diseases such as CKD. Although attractive, such studies should be interpreted carefully, with a fundamental understanding of their potential weaknesses. Nevertheless, whole-genome association studies for diabetic nephropathy and future studies pertaining to other types of CKD will offer further insight for the development of targeted interventions to treat CKD and associated atherosclerotic CV abnormalities in the pediatric CKD population.
Highlights
Adjusted mortality rates since 1991 among the pediatric end-stage renal disease (ESRD) population increased by 5% to 26.6 per million general population in 2005; and cardiovascular (CV) mortality among pediatric ESRD patients has increased from 17.7 deaths per 1,000 patient years at risk in 1991 to 23.4 in 2005 [3]
Multiple physiologic pathways share common genes for Chronic kidney disease (CKD) and CV disease, substantial evidence [10, 25,26,27,28] supports our attention to the renin angiotensin system (RAS) and the interlinked inflammatory cascade because they modulate the progression of renal and CV disease
In the case of CKD, genetic polymorphisms in the RAS–cytokine pathway may be responsible for the intraindividual variation in renal and cardiac progression in patients with CKD and may offer new targets for drug therapy
Summary
ACE angiotensin converting enzyme, AGT angiotensin, AT1R angiotensin II type 1 receptor, DCCT Diabetes Control and Complications Trial, EDIC Epidemiology of Diabetes Interventions and Complications, ESRD end-stage renal disease, ARIC Arthrosclerosis Risk in Communities, HEMO hemodialysis, VUR vesicoureteral reflux, HD hemodyalysis, SLE systemic lupus erythematosus, MI myocardial infarction a The gene and gene polymorphism of interest b Study population is given to indicate potential for population stratification and type of CKD population (name of cohort study)/study type by: cross-sectional, cohort, or case control c In the study by Hsu et al, 3,449 subjects had AGT genotyping, whereas 3,381 subjects had both AGT and AT1R genotyping stem from adult studies that involve a significantly larger prevalent population. A proposed solution for studies with insufficient power are to: (1) emphasize replication and obtain data to determine biologic plausibility; (2) synthesize results of individual studies for meta-analysis; or (3) obtain data on individual subjects from several studies to perform a pooled analysis [125]
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