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Chronic Progression of Tubulointerstitial Damage in Proteinuric Renal Disease Is Mediated by Complement Activation: A Therapeutic Role for Complement Inhibitors?

Stephen I-Hong Hsu^*,, and William G. Couser

*Institute of Prevention and Research, National Kidney Foundation of Singapore; Department of Medicine, Faculty of Medicine, National University of Singapore; Genome Institute of Singapore, Singapore; and Division of Nephrology, University of Washington, Seattle, Washington.

Correspondence to Dr. Stephen I. Hsu, Department of Medicine, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074. Phone: 65-6874-8882; Fax: 65-6779-4112;

ABSTRACT. The mechanisms by which increased urinary protein concentrations lead to nephrotoxic injury are certain to be multifactorial and involve complex interactions between numerous pathways of cellular damage mediated by both cellular and humoral pathways. These may include a major role for the podocyte in glomerular diseases leading to chronic renal failure, the loss of microvascular endothelium, the albumin-induced upregulation of renal cytokines and growth factors that promote tubulointerstitial injury by inflammation and fibrogenesis, and the role of complement-mediated tubulointerstitial injury due to proteinuria. This review will focus on the last mechanism, and emphasize recent studies implicating a primary role for activation of complement in proteinuric urine as the principal mediator of tubulointerstitial damage and progressive renal disease in various experimental animal models of nephrosis. It will be our contention that intraluminal activation of the terminal complement cascade leading to the formation of the C5b-9 membrane attack complex is the principal mediator of chronic progressive interstitial damage and progressive renal failure irrespective of the type of primary glomerular injury. This paradigm has important implications for the potential therapeutic role of complement inhibitors that are currently being developed. E-mail: mdchsus@nus.edu.sg

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