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Maximal suppression of renin-angiotensin system in nonproliferative glomerulonephritis. Background Elimination of residual proteinuria is the novel target in renoprotrection; nevertheless, whether a greater suppression of renin-angiotensin system (RAS) effectively improves the antiproteinuric response in patients with moderate proteinuria remains ill-defined. Methods We evaluated the effects of maximizing RAS suppression on quantitative and qualitative proteinuria in ten patients with stable nonnephrotic proteinuria (2.55 ± 0.94 g/24 hours) due to primary nonproliferative glomerulonephritis (NPGN), and normal values of creatinine clearance (103 ± 17 mL/min). The study was divided in three consecutive phases: ( 1 ) four subsequent 1-month periods of ramipril at the dose of 2.5, 5.0, 10, and 20 mg/day; ( 2 ) 2 months of ramipril 20 mg/day + irbesartan 300 mg/day; and ( 3 ) 2 months of irbesartan 300 mg/day alone. Results Maximizing RAS suppression was not coupled with any major effect on renal function and blood pressure; conversely, a significant decrement in hemoglobin levels, of 0.8 g/dL on average, was observed during up-titration of ramipril dose. The 2.5 mg dose of ramipril significantly decreased proteinuria by 29%. Similar changes were detected after irbesartan alone (-28%). The antiproteinuric effect was not improved either by the higher ramipril doses (-30% after the 20 mg dose) or after combined treatment (-33%). The reduction of proteinuria led to amelioration of the markers of tubular damage, as testified by the significant decrement of α 1 microglobulin (α 1 m) excretion and of the tubular component of proteinuria at sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Conclusion In nonnephrotic NPGN patients, standard doses of either ramipril or irbesartan lead to significant reduction of residual proteinuria and amelioration of the qualitative features suggestive of tubular damage. The enhancement of RAS suppression up to the maximal degree does not improve the antiproteinuric response and is coupled with a decrement of hemoglobin levels.