ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies

Background. Whether angiotensin-converting enzyme (ACE) gene polymorphism a ffects disease progression and response to ACE inhibitor therapy in nondiab etic proteinuric nephropathies is not clearly established. Methods. The relationship between insertion/deletion (IID) genotypes and pr oteinuria, rate of glomerular filtration rate decline (Delta GFR)-centrally evaluated by repeated measures of iohexol plasma clearance-and incidence o f end-stage renal disease (ESRD) was prospectively evaluated in 212 patient s with nondiabetic proteinuric chronic nephropathies enrolled in the Ramipr il Efficacy in Nephropathy (REIN) trial, where patients were randomly assig ned 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 conventionall y treated patients in the DD genotype, but not in the II and ID genotype. E ither at univariate (P = 0.04) or at multivariate (P = 0.01) analysis, rami pril significantly predicted a lower incidence of events in DD, but not in II and ID patients. At three months, ramipril decreased proteinuria more ef fectively in DD (-38.2%) than in the II (-26.7%) or ID (-19.2%) genotype. I n DD (but not in II or ID) ramipril-treated patients, a short-term reductio n 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 polymorp hism does not predict disease progression, but is a strong predictor of ACE inhibition-associated renoprotection in that proteinuria, Delta GFR, and p rogression to ESRD are effectively reduced in patients with the DD, but not in those with the II or ID genotype.