Elsevier

The Lancet

Volume 354, Issue 9176, 31 July 1999, Pages 359-364
The Lancet

Articles
Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria

https://doi.org/10.1016/S0140-6736(98)10363-XGet rights and content

Summary

Background

Stratum 2 of the Ramipril Efficacy in Nephropathy (REIN) study has already shown that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, angiotensin-converting enzyme (ACE) inhibition reduced the rate of decline in glomerular filtration and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF) found in controls on placebo plus conventional antihypertensives. In REIN stratum 1, reported here, 24 h proteinuria was 1 g or more but less than 3 g per 24 h.

Methods

In stratum 1 of this double-blind trial 186 patients were randomised to a ramipril or a control (placebo plus conventional antihypertensive therapy) group targeted at achieving a diastolic blood pressure of less than 90 mm Hg. The primary endpoints were change in glomerular filtration rate (GFR) and time to ESRF or overt proteinuria (⩾3 g/24 h). Median follow-up was 31 months.

Findings

The decline in GFR per month was not significantly different (ramipril 0·26 [SE 0·05] mL per min per 1·73m2, control 0·29 [0·06]). Progression to ESRF was significantly less common in the ramipril group (9/99 vs 18/87) for a relative risk (RR) of 2·72 (95% CI 1·22–6·08); so was progression to overt proteinuria (15/99 vs 27/87, RR 2·40 [1·27–4·52]). Patients with a baseline GFR of 45 mL/min/1·73 m2 or less and proteinuria of 1·5 g/24 h or more had more rapid progression and gained the most from ramipril treatment. Proteinuria decreased by 13% in the ramipril group and increased by 15% in the controls. Cardiovascular events were similar. As expected, the rate of decline in GFR and the frequency of ESRF were much lower in stratum 1 than they had been in stratum 2.

Interpretation

In non-diabetic nephropathies, ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria.

Introduction

The Ramipril Efficacy In Nephropathy (REIN) trial1 was designed to test whether glomerular protein traffic and its modification by an angiotensin-converting enzyme (ACE) inhibitor, influenced disease progression in non-diabetic chronic nephropathies.2 The main endpoints are the rate of decline of glomerular filtration rate (GFR) and the time to end-stage renal failure (ESRF). Patients were stratified before randomisation by level of 24 h proteinuria (stratum 1, ⩾1 and <3 g; stratum 2, ⩾3 g). Treatment, with an ACE inhibitor (ramipril) or placebo plus conventional antihypertensive therapy, was targeted at the same blood-pressure control. At the second interim analysis, the slowing GFR decline in the ramipril group exceeded that expected from the degree of blood-pressure reduction in stratum 2, and at that point the independent adjudicating panel, following the protocol, advised that stratum 2 be stopped.3 These patients continued on ramipril or were switched to ramipril and entered the REIN follow-up study,4 which found GFR almost stabilised in patients originally randomised to ramipril and continuing that drug for more than 36 months. Patients in REIN stratum 1 continued in the trial as per protocol, and the results are reported here.

Section snippets

Patients and methods

The REIN study1, 3 was approved by the ethical committee and by the institutional review board of the 14 hospitals involved, and every patient gave written informed consent. An independent adjudicating panel monitored ethical, statistical, and safety issues. The panel was allowed to break the randomisation code if required for safety reasons.

Results

There were 186 patients in REIN stratum 1, 99 in the ramipril group (median follow-up 32·2 months [IQR 29·4–54·5]) and 87 in the conventional treatment group (31·4 months [27·6–49·4], figure 1). Baseline characteristics are shown in table 1. 175 patients (92 ramipril, 83 placebo) had at least three GFR evaluations including baseline, and the median number of measures was 8 (IQR 7–10).

Discussion

The main finding from REIN stratum 1 is that in patients with non-diabetic chronic nephropathies and baseline proteinuria of less than 3 g ramipril halved the risk of progression to ESRF and to persistent nephrotic range proteinuria, a strong predictor of rapidly declining GFR.3, 4 Most of the difference between the two treatment groups was due to an excess of events in conventionally treated patients after 48 months' follow-up, while no more events occurred in ramipril-treated patients. The

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