Medline ® Abstract for Reference 20

of 'Epidemiology, etiology, and course of chronic kidney disease in children'

20
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Progression in chronic kidney disease.
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Eddy AA
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Adv Chronic Kidney Dis. 2005;12(4):353.
 
The pathogenic mechanisms that lead to chronic kidney disease (CKD) converge on a common pathway that results in progressive interstitial fibrosis, peritubular capillary loss with hypoxia, and destruction of functioning nephrons because of tubular atrophy. Interstitial recruitment of inflammatory leukocytes and myofibroblasts occurs early in kidneys destined to develop fibrosis. Circulating monocytes are recruited by locally secreted chemoattractant molecules, facilitated by leukocyte adhesion molecules. Functionally heterogeneous macrophages secrete many fibrosis-promoting molecules, but under some circumstances they may also serve a protective scavenging role. Excessive extracellular matrix production occurs primarily within interstitial myofibroblasts, a population of cells that appears to have more than 1 origin, including the resident interstitial fibroblasts, trans-differentiated tubular epithelial cells, and bone marrow-derived cells. Impaired activity of the endogenous renal matrix-degrading proteases may enhance interstitial matrix accumulation, but the specific pathways that are involved remain unclear. Tubules, inflammatory cells, and myofibroblasts synthesize the molecules that activate the fibrogenic cascades, the most important of which is transforming growth factor beta (TGF-beta). TGF-beta may direct cells to assume a pro-fibrotic phenotype or it may do so indirectly after stimulating synthesis of other fibrogenic molecules such as connective tissue growth factor and plasminogen activator inhibitor-1. Reduced levels of antifibrotic factors that are normally produced in the kidney such as hepatocyte growth factor and bone morphogenic protein-7 may accelerate fibrosis and its destructive consequences. Development of new therapeutic agents for CKD looks promising, but several agents that target different components of the fibrogenic cascade will almost certainly be necessary.
AD
Division of Nephrology, University of Washington and Children's Hospital and Regional Medical Center, Seattle, WA 98105, USA. allison.eddy@seattlechildrens.org
PMID