Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria

Patients, methods, and results

Forty four normotensive patients with insulin dependent (type I) diabetes and persistent microalbuminuria (30-300 mg/24 h) were enrolled as previously described in detail.1 The treatment group (n=21) was given captopril (100 mg/24 h) and bendrofluazide (2.5 mg/24 h). The 23 remaining patients were left untreated. Diabetic nephropathy was defined as albuminuria persistently >300 mg/24 h. Glomerular filtration rate was measured annually with Crom EDTA plasma clearance over 4 hours.1

After 4 years two patients in each group were excluded because they did not attend follow up sessions. Four of the patients in the control group started antihypertensive treatment with diuretics, βblockers, or a calcium channel blocker. Three patients in the treatment group were changed from bendrofluazide to frusemide because of oedema or diastolic blood pressure >95 mm Hg. After 8 years 16 of the 21 patients in the treatment group and two patients from the control group were subsequently investigated after a treatment pause of 2 months.

The proportion of patients who progressed to diabetic nephropathy was 40% (9/23) in the control group and 10% (2/21) in the captopril group (survival analysis P=0.019). In the captopril group there was a significant increase in urinary albumin excretion (P<0.001) during the treatment pause. In six (38%) of the 16 patients albuminuria exceeded 300 mg/24 h.

Glomerular filtration rate in the captopril group declined from 126 (24) at baseline to 114 (23) ml/min after 8 years but rose again to 126 (21) during the pause in treatment (table). Follow up values of glomerular filtration rate measured during the treatment pause were therefore used whenever available. The decline in mean glomerular filtration rate (ml/min) was 11.8 (95% confidence interval 1.2 to 22.0; t test P value 0.03) and 1.4 (−4.9 to 7.7; P=0.65) in the control and captopril group, respectively (P=0.09 between the groups). The fall in glomerular filtration rate during the 8 year study period in the eight control patients who developed nephropathy was 27.3 (3.7 to 51.0; P=0.03) while glomerular filtration rate increased by 3.8 (−3.5 to 11.0) in the six patients treated with captopril with urinary albumin excretion >300 mg/24 h during the treatment pause (P=0.02 between the groups). Haemoglobin A1c and blood pressure did not differ between the two groups at any time during the study.

Comment

Our study has shown that the beneficial effect of angiotensin converting enzyme inhibition in the prevention of diabetic nephropathy is long lasting and associated with preservation of normal glomerular filtration rate. To obtain a valid determination of the rate of decline in glomerular filtration rate the applied glomerular filtration rate method should have a good accuracy and precision and the observation period should exceed 2 years.4 These requirements have been fulfilled in our study in contrast with previous studies.2^–3 The second part of the study showed a return in glomerular filtration rate to the values before treatment after 2 months of withdrawal of antihypertensive treatment. The temporary fall in glomerular filtration rate in the intervention group was therefore regarded as a reversible haemodynamic phenomenon. Patients with persistent microalbuminuria at follow up had a stable normal glomerular filtration rate.5 The clinically significant effect of angiotensin converting enzyme inhibition on preservation of normal glomerular filtration rate was related to prevention of progression from microalbuminuria to diabetic nephropathy in patients with insulin dependent diabetes.