Mesangial hypercellularity predicts antiproteinuric response to dual blockade of RAS in primary glomerulonephritis

The greater antiproteinuric efficacy of converting enzyme inhibitor and angiotensin II receptor blocker combination (CEI+ARB), versus monotherapy with either drug, is not a consistent finding. We evaluated the clinicopathologic predictors of response to CEI+ARB in 43 patients with primary glomerulonephritis (GN), never treated with immunosuppressive drugs, and with persistent proteinuria after CEI alone. Main histological lesions were analyzed by obtaining on 557 glomeruli and 165 arteries formal score of mesangial cellularity, glomerulosclerosis, tubulointerstitial damage, mononuclear cell infiltration, arteriosclerosis, and arteriolar hyalinosis. Duration of CEI and CEI+ARB therapy was similar (4.7+/-2.4 and 5.0+/-1.5 months). Proteinuria (g/day) decreased from 3.5+/-2.9 to 2.4+/-2.3 after CEI, and to 1.5+/-1.3 after CEI+ARB (P<0.0001). Reduction of proteinuria after CEI+ARB was greater in proliferative versus non-proliferative GN (-63.3+/-23.4 versus 42.4+/-23.7%, respectively; P=0.006). When patients were categorized in responders and non-responders to CEI+ARB, no difference between the two groups was detected in any demographic or clinical variable, whereas histology showed in responders a greater prevalence of proliferative GN (71.4 versus 31.8%, P=0.009) and higher score of mesangial cellularity (1.76+/-0.53 versus 1.20+/-0.22, P<0.0001). At multiple regression analysis (r(2)=0.476, P=0.001), response to CEI+ARB resulted independently related only to mesangial cellularity (P<0.0001). In conclusion, the best independent predictor of antiproteinuric efficacy of CEI+ARB in patients with primary GN is the degree of mesangial cellularity. This finding supports the experimental evidence that high angiotensin II contributes to proliferation of mesangial cells.