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Chronic Proteinuric Nephropathies. II. Outcomes and Response to Treatment in a Prospective Cohort of 352 Patients: Differences Between Women and Men in Relation to the ACE Gene Polymorphism

PIERO RUGGENENTI^*,, ANNALISA PERNA^*, CARMINE ZOCCALI, GIULIA GHERARDI^*, ROBERTO BENINI^*, ALESSANDRA TESTA, GIUSEPPE REMUZZI^*, and THE "GRUPPO ITALIANO DI STUDI EPIDEMIOLOGICI IN NEFROLOGIA"(GISEN)^,a

^* Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases "Aldo e Cele Daccò" Villa Camozzi, Ranica, Italy
Unit of Nephrology, Ospedali Riuniti, Azienda Ospedaliera, Bergamo, Italy
Unit of Nephrology, Center of Clinical Physiology of the "Consiglio Nazionale delle Ricerche," Reggio Calabria, Italy.

Correspondence to Dr. Piero Ruggenenti, Clinical Research Center "Aldo e Cele Daccò" Villa Camozzi, "Mario Negri" Institute for Pharmacological Research, Via Gavazzeni 11, 24125, Bergamo, Italy. Phone: + 39 35 319 888; Fax: + 39 35 319 331; E-mail: ruggenenti{at}irfmn.mnegri.it

Abstract. In the Ramipril Efficacy in Nephropathy study, ramipril decreased the rate of GFR decline (GFR) and progression to end-stage renal disease (ESRD) in 352 patients with proteinuric chronic nephropathies. This study investigated whether in these patients disease outcome and response to treatment were affected by gender or insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. GFR (0.43 ± 0.05 versus 0.48 ± 0.08 ml/min per 1.73 m²) and incidence of ESRD (23 and 22%, respectively) were comparable in male and female patients. However, compared to conventional treatment, ramipril decreased GFR (-52% versus -19%) and progression to ESRD (-74% versus -40%) more effectively in women than in men. Thus, the relative risk (95% confidence interval [CI]) of events (ESRD) between conventional and ramipril treatment was 5.52 (1.59 to 19.17, P = 0.003) in women, but only 1.80 (1.08 to 2.97, P = 0.02) in men. This gender-related effect of ramipril was associated with more reduction in proteinuria (-7.8 ± 4.2% versus -21.9 ± 5.7%, P = 0.05) and was still evident even after correction for potentially confounding factors such as baseline GFR, daily sodium intake, ramipril dose, BP control, and concomitant treatment with diuretics or dihydropyridinic calcium channel blockers (adjusted RR [95% CI]: women, 5.07 [1.26 to 20.38], P = 0.02; men, 1.44 [0.85 to 2.44], P = 0.17). Ramipril uniformly decreased GFR and incidence of ESRD in women with either DD (-39% and -100%) or II + ID (-71% and -82%) genotype, and in men (-25% and -50%) with the DD genotype, but had no beneficial effect in men with the II + ID genotype (+18% and +34%). Thus, the relative risk of events (ESRD) between conventional and ramipril-treated men was higher in subjects with the DD genotype (1.85; 0.69 to 4.94) and lower in those with the II ± ID genotype (0.71; 0.28 to 1.80). Again, in parallel with GFR and events, proteinuria decreased in women with DD (-23.3 ± 8.0%) or II + ID (-16.0 ± 9.5%) genotype and in men with the DD genotype (-14.8 ± 7.0%), but did not change in men with II + ID genotype (+1.0 ± 7.8%). Of note, the ACE genotype-related effect of ramipril was still evident even after correction for the above potentially confounding factors (adjusted RR [95% CI]: DD, 2.52 [0.83 to 7.63], P = 0.10; II + ID, 0.35 [0.12 to 1.01], P = 0.05). Thus, among patients with chronic proteinuric nephropathies, men are at increased risk of progression due to their lower response to ACE inhibitor treatment. ACE inhibition is uniformly renoprotective in women regardless of the ACE polymorphism, and in men with the DD genotype, but is virtually devoid of beneficial effects in men with the II or ID genotype. This information may help to guide therapeutic interventions in clinical practice and to interpret the results of prospective trials in chronic renal disease.

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