Therapeutic efficacy of pentoxifylline on proteinuria and renal progression: an update

Abstract

Blood pressure control with renin-angiotensin system (RAS) blockade has remained the gold standard for treating patients with proteinuric chronic kidney disease (CKD) up to date. Nevertheless, RAS blockade slows but does not halt the progression of kidney disease, thus highlighting the need to search for additional therapeutic approaches. The nonselective phosphodiesterase (PDE) inhibitor pentoxifylline (PTX) is an old drug that exhibits prominent anti-inflammatory, anti-proliferative and anti-fibrotic activities both in vitro and in vivo. Studies in human subjects have shown that PTX monotherapy decreases urinary protein excretion, and add-on therapy of PTX to background RAS blockade additively reduces proteinuria in patients with CKD of various etiology. More recent studies find that PTX combined with RAS blockade delays the decline of glomerular filtration rate in diabetic patients with mild to moderate CKD, and reduces the risk of end-stage renal disease in diabetic and non-diabetic patients in late stage of CKD with high proteinuria levels. In this review, we update the clinical trial results of PTX as monotherapy, or in conjunction or in comparison with RAS blockade on patients with proteinuria and CKD, and propose a mechanistic scheme explaining the renoprotective activities of this drug.

Keywords: CKD; ESRD; Pentoxifylline; Proteinuria; Renin-angiotensin system.

Fig. 1

Possible mechanisms mediating PTX’s renal effects. AC, adenylate cyclase; aPKA, active protein kinase A; α-SMA, α-smooth muscle actin; ATP, adenosine triphosphate; cAMP, cyclic adenosine-3,5-monophosphate; CRE, cAMP response element; CREB, cAMP-response element binding protein; CTGF, connective tissue growth factor; CX3CL1, fractalkine; FN, fibronectin; GPCP, G-protein-coupled receptor; Grb2, growth factor receptor-bound protein 2; ICAM-1, intercellular adhesion molecule-1; IκB, inhibitory protein of NF-κB (p65/p50 heterodimer); IKK, IκB kinase; iPKA, inactive protein kinase A; MAPK, mitogen activated protein kinase; MCP-1, monocyte chemoattractant protein-1; P, phosphorylation; PDE, phosphodiesterase; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; Sos, son of sevenless; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor-α; PTX, pentoxifylline; TRADD, TNFR1-associated death domain protein; TRAF2, TNF receptor-associated factor 2; U, ubiquitination. Dash lines denote inhibitory pathways initiated by PTX from the leftmost side