• changes from baseline in urinary protein excretion [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  

• change from baseline in serum CRP, creatinine and estimated creatinine clearance, as well as urinary NAG, TNF-alpha and MCP-1 [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  

Drug: pentoxifylline
The dose for pentoxifylline will be 1,200 mg/day (400 mg three times a day) for 1 year.

Pentoxifylline (PTX) is a phosphodiesterase inhibitor that is used clinically to treat patients with peripheral vascular disorders. In addition to its hemorheologic activity, PTX possesses potent anti-inflammatory and immunomodulatory properties. In vivo, PTX has shown its ability to attenuate nephrotic syndrome secondary to membranous glomerulonephritis and lupus nephritis, and to reduce subnephrotic proteinuria of early and advanced diabetic nephropathy. However, the anti-proteinuric effect of PTX has been traditionally attributed to down-regulation of TNF-alpha. Whether or not other inflammatory mediators are also affected by PTX has never been studied. Our previous works have shown that PTX can inhibit cytokine or albumin-induced MCP-1 production in vitro, and attenuate proteinuria in association with suppression of renal MCP-1 mRNA expression in experimental glomerulonephritis. More recently, we have found that PTX lowers proteinuria by modulating renal MCP-1 production in a subgroup of human glomerular diseases. In this study, we aim to investigate whether combination of PTX and corticosteroids results in additive reduction in proteinuria, and higher remission rates in patients with primary nephrotic syndrome. The secondary objective is to study whether PTX monotherapy can be effective in patients with primary nephrotic syndrome not suitable for or intolerant of corticosteroid therapy.

The part A study is a prospective, open-labeled, comparative study including primary nephrotic patients randomized into 2 groups. Group A receives oral pentoxifylline plus oral prednisolone, whereas group B receives oral prednisolone alone. The treatment duration is 1 year for both subgroups. The dose for pentoxifylline will be 1,200 mg/day for 1 year. The dose for prednisolone will be 1 mg/kg/day for the initial 3 months, then the dose will be gradually tapered, thus by 6 months the dose will be 0.5 mg/kg/day, and at 12 months the dose will be reduced to around 5-10 mg/day. Part B of the study consists of primary nephrotic patients not considered suitable for (eg., chronic HBV or HCV infection), or intolerance of (eg., concomitant diabetes mellitus, active peptic ulcer disease) standard corticosteroid therapy. Pentoxifylline 1,200 mg/day will be administered to these patients for a total of 1 year. For either part of the study, serum and urine specimens will be collected before initiation of therapy (day 0), and at month 1, 3, 6, and 12 after the commencement of therapy. Glomerular filtration rates will be calculated by Cockcroft-Gault and simplified MDRD formula. Urinary protein excretion will be quantitated by spot urine protein/creatinine ratio and 24-hour urinary protein measurement. All biochemical and immunological analyses will be performed by the Department of Laboratory Medicine, National Taiwan University Hospital. Serum and urine samples will be measured for inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, MCP-1, CX3CL1 (fractalkine), IL-8 by using commercial ELISA kits.