Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study

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Abstract
Objective: To evaluate the concept that an insertion/deletion polymorphism of the angiotensin converting enzyme gene predicts the therapeutic efficacy of inhibition of angiotensin converting enzyme on progression of diabetic nephropathy. Design: Observational follow up study of patients with insulin dependent diabetes and nephropathy who had been treated with captopril for a median of 7 years (range 3-9 years). Setting: Outpatient diabetic clinic in a tertiary referral centre. Patients: 35 patients with insulin dependent diabetes and nephropathy were investigated during captopril treatment (median 75 mg/day (range 12.5 to 150 mg/day)) that was in many cases combined with a loop diuretic. 11 patients were homozygous for the deletion allele and 24 were heterozygous or homozygous for the insertion allele of the angiotensin converting enzyme gene. Main outcome measures: Albuminuria, arterial blood pressure, and glomerular filtration rate according to insertion/deletion polymorphism. Results: The two groups had comparable glomerular filtration rate, albuminuria, blood pressure, and haemoglobin A1c concentration at baseline. Captopril induced nearly the same reduction in mean blood pressure in the two groups—to 103 (SD 5) mm Hg in the group with the deletion and 102 (8) mm Hg in the group with the insertion—and in geometric mean albumin excretion—573 (antilog SE 1.3) μg/min and 470 (1.2) μg/min, respectively. The rate of decline in glomerular filtration rate (linear regression of all glomerular filtration rate measurements during antihypertensive treatment) was significantly steeper in the group homozygous for the double deletion allele than in the other group (mean 5.7 (3.7) ml/min/year and 2.6 (2.8) ml/min/year, respectively; P = 0.01). Multiple linear regression analysis showed that haemoglobin A1c concentration, albuminuria, and the double deletion genotype independently influenced the sustained rate of decline in glomerular filtration rate (R2 (adjusted) = 0.51). Conclusion: The deletion polymorphism in the angiotensin converting enzyme gene reduces the long term beneficial effect of angiotensin converting enzyme inhibition on the progression of diabetic nephropathy in patients with insulin dependent diabetes. Determination of the insertion/deletion polymorphism of the angiotensin converting enzyme gene can identify patients with accelerated progression in diabetic nephropathy Inhibition of angiotensin converting enzyme frequently combined with diuretics reduces blood pressure, arrests the progressive rise in albuminuria, and reduces the rate of decline in glomerular filtration rate in diabetic nephropathy The deletion polymorphism in the angiotensin converting enzyme gene reduces the long term beneficial effect of angiotensin converting enzyme inhibition on progression of diabetic nephropathy Patients with diabetic nephropathy who are homozygous for the deletion polymorphism should be offered earlier and more aggressive antihypertensive treatment with angiotensin converting enzyme inhibitors in addition to strict glycaemic control