Prospective trial of combined therapy with heparin/warfarin and renin-angiotensin system inhibitors in progressive IgA nephropathy.

We previously reported that a combined therapy with heparin/warfarin and renin-angiotensin system (RAS) inhibitors dramatically reduces proteinuria for prolonged periods in advanced IgA nephropathy (IgAN). In the present study, we prospectively analyzed whether the combined therapy can inhibit the progressive decline in renal function of patients with progressive IgAN. Patients who had a marked linearity of decline in loss of glomerular filtration rate (GFR), assessed by reciprocal serum creatinine plots vs. time for more than one year, were recruited in this study if they were histologically diagnosed as IgAN at this point of declining renal function. Twelve patients were eligible for trial entry; reciprocal serum creatinine plot suggested end-stage renal failure within 5 years. All patients were treated with continuous intravenous infusion of heparin for 8 weeks, followed by oral administration of warfarin, ACE inhibitors and/or angiotensin II receptor blockers and dypiridamole. Eight patients were further given corticosteroid for 2 years because of the presence of acute glomerular lesions such as cellular crescent or angionecrosis. All patients were followed-up for at least 12 months, and the mean follow-up period was 34 +/- 20 (range 12-79) months. After the combined therapy, urinary protein excretion was significantly reduced from 2.4 +/- 1.5 g/day at baseline to 0.7 +/- 0.5 g/day at final observation, while the mean serum creatinine was not significantly different. Of note, the mean slope of 1/serum creatinine significantly increased from -0.009 to +0.0002 dl/mg/week (p < 0.05). Moreover, histological analysis of a repeat kidney biopsy which was performed in 5 patients at 2 years after the institution of the combined therapy revealed that the percentage of cellular/fibrocellular crescent and the degree of mesangial matrix expansion were significantly attenuated (19-->0.1% and 1.6-->0.6 score, respectively) while the percentage of global sclerosis and tubulointerstitial lesion did not increase. These results indicate that our combined therapy with heparin/warfarin and RAS inhibitors can inhibit the progressive decline in renal function Combined Heparin/Warfarin and RAS Inhibitors in Progressive IgAN 115 of patients with progressive IgAN through its marked antiproteinuric and anti-inflammatory effects.