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How Does Proteinuria Cause Progressive Renal Damage?

Mauro Abbate^*, Carla Zoja^* and Giuseppe Remuzzi^*,

^* Mario Negri Institute for Pharmacological Research and Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy

Address correspondence to: Dr. Giuseppe Remuzzi, "Mario Negri" Institute for Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy. Phone: +39-035-319-888; Fax: +39-035-319-331; E-mail: gremuzzi{at}marionegri.it

The possibility that proteinuria may accelerate kidney disease progression to end-stage renal failure has received support from the results of increasing numbers of experimental and clinical studies. Evidence indicating that this process occurs through multiple pathways, including induction of tubular chemokine expression and complement activation that lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis, is reviewed. Macrophages are prominent in the interstitial inflammatory infiltrate. This cell type mediates progression of renal injury to the extent that macrophage numbers in renal biopsy predict renal survival in patients with chronic renal disease. Chemoattractants and adhesive molecules for inflammatory cells are upregulated by excess ultrafiltered protein load of proximal tubular cells via activation of NF-B–dependent and NF-B–independent pathways. This mechanism is a potential target for therapeutic approaches, as shown by beneficial effects of manipulations with inhibitory molecules of NF-B activation or of chemokine receptors in experimental studies. Targeting complement synthesis or activation in proximal tubule might offer novel therapeutic opportunities. Finally, proximal tubular cell receptors for uptake of plasma proteins that are under investigation may provide activation signals on excess tubular protein handling.

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