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

In patients with insulin dependent diabetes, angiotensin converting enzyme inhibition delays the progression from microalbuminuria to diabetic nephropathy, but previous studies have been too short to show a preservation of kidney function.^1–3 We assessed the effectiveness of angiotensin converting enzyme inhibition on preservation of kidney function in an 8 year prospective, randomised controlled trial.

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, β blockers, 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 A_1c 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.

Table.

Mean glomerular filtration rates (ml/min) in normotensive patients with insulin dependent diabetes at baseline, after 8 years’ follow up, and during pause in treatment in captopril and control groups

Patient No	Captopril group				Control group
	Baseline	8 Years	8 Years + pause		Baseline	8 Years	8 Years + pause
1	100	101	120		141	157*	135*
2	129	125	131		156	131	—
3	153	—	—		131	123	—
4	96	75	—		96	39*	47*
5	114	99	122*		87	84	—
6	112	98	116*		132	106*	—
7	105	105*	112*		154	68*	—
8	127	145*	140*		151	143	—
9	140	127	144		150	161	—
10	108	70	102*		117	106	—
11	169	—	—		111	—	—
12	144	120	121		148	144	—
13	117	104	—		118	119	—
14	110	100	97		108	94*	—
15	96	108	—		126	141	—
16	171	151	166		142	168	—
17	164	156	161*		145	130	—
18	128	106	103		146	140	—
19	104	116	105		122	—*	—
20	130	135	146		117	91*	—
21	132	122	128		120	112*	—
22	—	—	—		136	130*	—
23	—	—	—		120	118	—
Mean(SD)	126 (24)	114 (23)	126 (21)		129 (18)	119 (32)†	—

^*Patient developed diabetic nephropathy during 8 years of follow up or during treatment pause. 

^†Difference from baseline significant at P=0.03.