ACEI/ATRA therapy decreases proteinuria by improving glomerular permselectivity in IgA nephritis

It has been postulated that angiotensin-converting enzyme inhibitor/angiotensin receptor antagonist (ACEI/ATRA) may decrease proteinuria in patients with glomerulonephritis by its action on the glomerular basement membrane. We therefore studied the relationship between the response of patients with IgA nephritis (IgAN) to ACEI/ATRA therapy by decreasing proteinuria and its effect on the selectivity index (SI) in these patients.

Forty-one patients with biopsy-proven IgAN entered a control trial, with 21 in the treatment group and 20 in the control group. The entry criteria included proteinuria of 1 g or more and/or renal impairment. Patients in the treatment group received ACEI/ATRA or both with three monthly increases in dosage. In the control group, hypertension was treated with atenolol, hydrallazine, or methyldopa. The following tests were performed at three monthly intervals: serum creatinine, total urinary protein, SI, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and low molecular weight (LMW) proteinuria.

After a mean duration of therapy of 13 +/- 5 months, in the treatment group, there was no significant change in serum creatinine, proteinuria, or SI, but in the control group, serum creatinine deteriorated from 1.8 +/- 0.8 to 2.3 +/- 1.1 mg/dL (P < 0.05). Among the 21 patients in the treatment group, 10 responded to ACEI/ATRA therapy determined as a decrease in proteinuria by 30% (responders), and the other 11 did not respond (nonresponders). Among the responders, SI improved from a mean of 0.26 +/- 0.07 to 0.18 +/- 0. 07 (P < 0.001), indicating a tendency toward selective proteinuria. This was associated with an improvement in serum creatinine from mean 1.7 +/- 0.6 to 1.5 +/- 0.6 mg/dL (P < 0.02) and a decrease in proteinuria from a mean of 2.3 +/- 1.1 to 0.7 +/- 0.5 g/day (P < 0. 001). After treatment, proteinuria in the treatment group (1.8 +/- 1. 6 g/day) was significantly less than in the control group (2.9 +/- 1. 8 g/day, P < 0.05). The post-treatment SI in the responder group (0. 18 +/- 0.07) was better than that of the nonresponder group (0.33 +/- 0.11, P < 0.002). Eight out of 21 patients in the treatment group who had documented renal impairment had improved renal function compared with two in the control group (chi2 = 4.4, P < 0. 05). Of the eight patients in the treatment group who improved their renal function, three normalized their renal function compared with one from the control group.

Our data suggest that ACEI/ATRA therapy may be beneficial in patients with IgAN with renal impairment and nonselective proteinuria, as such patients may respond to therapy with improvement in protein selectivity, decrease in proteinuria, and improvement in renal function. ACEI/ATRA therapy probably modifies pore size distribution by reducing the radius of large unselective pores, causing the shunt pathway to become less pronounced, resulting in less leakage of protein into the urine.