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Impact of angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and protein excretion in patients with overt proteinuria

OBJECTIVE:Proteinuria is the hallmark of renal disease. In essential hypertension the onset of de novo proteinuria is associated with faster rate of progression of disase. Observations on the association between the ACE gene polymorphism and hypertension have been inconsistent, which might be due to ethnic and geographical variations. It may also have different effects on the reduction of proteinuria by ACE inhibitors in patients with proteinuria. In this study was to investigated the relationship between ACE gene polymorphism and antiproteinuric effect of ACE inhibitors (ramipril) and to evaluate the possible association between I/D polymorphism and hypertension. DESIGN AND METHODS: We recruited 66 hypertensive patients (male 42, female 24) with overt proteinuria (urinary protein excretion over 500 mg/day). Patients were classified into three groups in accordance with ACE genotypes (17 DD ; 35 ID ; 14 II). They were treated with ramipril and prospectively followed up for one year.Various clinical parameters including age, body mass index (BMI), 24-h urine protein, creatinine, creatinine clearance (Ccr), systolic and diastolic blood pressure (SBP and DBP), mean arterial pressure (MAP) were measured in the pre- and post-treatment periods. The ACE gene insertion/deletion(I/D) polymorphisms in intron 16 were determined by PCR. RESULTS: There were no significant differences in the clinical parameters such as age, gender, serum creatinine, Ccr, SBP, DBP, MAP, and daily urinary excretion of protein among three groups (P>0.05). ID genotype patients were found to have lower BMI (p=0.031). The majority of patients had glomerulonephritis (GN): focal segmental glomeruosclerosis in 27%, membranous GN in 21%, IgA nephropathy in 19.7%, crescentic GN in 3%, minimal change disease (MCD) in 1.5%, lupus nephritis in 3% and chronic GN in 6% cases. Tubulointerstitial nephritis was found in 3% cases, vascular disease and diabetic nephropathy in 3% case and nephroangiosclerosis in 6% case. ACE inhibition significantly reduced proteinuria in all genotype groups (p<0.05). The percentage reductions of 24-h urinary excretion of protein were significantly different between the genotype groups (p=0.042) and for DD genotype were significantly greater than in ID (79.2+/-28.9% vs 49.2+/-64.8%, P=0.015). The slope of SBP was the main factor related to the slope of the percentage reduction of proteinuria, however, a significant negative correlation coefficient between these parameters was found ( rs=-0.382, p=0.002). We failed to find significant difference in outcomes of treatments with ACE inhibitor between male and female according the I/D polymorphism of the ACE gene. CONCLUSIONS: D allele in the ACE genotype could be a useful genetic marker with important clinical, therapeutic and prognostic implications in recognizing patients with proteinuria that are at greater risk of renal damage.

ACE-genotype; ACE inhibitors; antiproteinuric effect; arterial hypertension; proteinuria

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