ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies

Background. Whether angiotensin-converting enzyme (ACE) gene polymorphism affects disease progression and response to ACE inhibitor therapy in nondiabetic proteinuric nephropathies is not clearly established. Methods. The relationship between insertion/deletion (IID) genotypes and proteinuria, rate of glomerular filtration rate decline (Delta GFR)-centrally evaluated by repeated measures of iohexol plasma clearance-and incidence of end-stage renal disease (ESRD) was prospectively evaluated in 212 patients with nondiabetic proteinuric chronic nephropathies enrolled in the Ramipril Efficacy in Nephropathy (REIN) trial, where patients were randomly assigned to ramipril or conventional treatment. Results. The Delta GFR +/- SEM (-0.38 +/- 0.09 vs. -0.50 +/- 0.08 vs. -0.36 +/- 0.06 mL/min/1.73 m(2) per month) and incidence of ESRD (19 vs. 22 vs. 25%) in the three subgroups with the II, ID, and DD genotypes, respectively, were comparable. Of note, Delta GFR (-0.28 +/- 0.07 vs. -0.43 +/- 0.09 mL/min/1.73 m(2) per month) and incidence of ESRD [14% vs. 36%, P = 0.04, RR (95% CI), 2.62 (1.02 to 6.71)] were lower in ramipril than in conventionally treated patients in the DD genotype, but not in the II and ID genotype. Either at univariate (P = 0.04) or at multivariate (P = 0.01) analysis, ramipril significantly predicted a lower incidence of events in DD, but not in II and ID patients. At three months, ramipril decreased proteinuria more effectively in DD (-38.2%) than in the II (-26.7%) or ID (-19.2%) genotype. In DD (but not in II or ID) ramipril-treated patients, a short-term reduction in proteinuria correlated with Delta GFR over the entire follow-up period (P = 0.02, r = -0.41). Conclusions. In nondiabetic proteinuric nephropathies, the ACE I/D polymorphism does not predict disease progression, but is a strong predictor of ACE inhibition-associated renoprotection in that proteinuria, Delta GFR, and progression to ESRD are effectively reduced in patients with the DD, but not in those with the II or ID genotype.