Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy

Summary

Background

In diabetic nephropathy, angiotensin-converting-enzyme (ACE) inhibitors have a greater effect than other antihypertensive drugs on proteinuria and the progressive decline in glomerular filtration rate (GFR). Whether this difference applies to progression of non-diabetic proteinuric nephropathies is not clear. The Ramipril Efficacy In Nephropathy study of chronic non-diabetic nephropathies aimed to address whether glomerular protein traffic influences renal-disease progression, and whether an ACE inhibitor was superior to conventional treatment, with the same blood-pressure control, in reducing proteinuria, limiting GFR decline, and preventing endstage renal disease.

Methods

In this prospective double-blind trial, 352 patients were classified according to baseline proteinuria (stratum 1: 1–3 g/24 h; stratum 2: ≥3 g/24 h), and randomly assigned ramipril or placebo plus conventional antihypertensive therapy targeted at achieving diastolic blood pressure under 90 mm Hg. The primary endpoint was the rate of GFR decline. Analysis was by intention to treat.

Finding

At the second planned interim analysis, the difference in decline in GFR between the ramipril and placebo groups in stratum 2 was highly significant (p=0·001). The Independent Adjudicating Panel therefore decided to open the randomisation code and do the final analysis in this stratum (stratum 1 continued in the trial). Data (at least three GFR measurements including baseline) were available for 56 ramipril-assigned patients and 61 placebo-assigned patients. The decline in GFR per month was significantly lower in the ramipril group than the placebo group (0·53 [0·08] vs 0·88 [0·13] mL/min, p=0·03). Among the ramipril-assigned patients, percentage reduction in proteinuria was inversely correlated with decline in GFR (p=0·035) and predicted the reduction in risk of doubling of baseline creatinine or endstage renal failure (18 ramipril vs 40 placebo, p=0·04). The risk of progression was still significantly reduced after adjustment for changes in systolic (p=0·04) and diastolic (p=0·04) blood pressure, but not after adjustment for changes in proteinuria. Blood-pressure control and the overall number of cardiovascular events were similar in the two treatment groups.

Interpretation

In chronic nephropathies with proteinuria of 3 g or more per 24 h, ramipril safely reduces proteinuria and the rate of GFR decline to an extent that seems to exceed the reduction expected for the degree of blood-pressure lowering.

Introduction

In most forms of proteinuric chronic renal disease, glomerular filtration rate (GFR) continues to decline even when the initial insult has been removed.1, 2 Of the various mechanisms that contribute to renal-function deterioration, hypertension has an important role. In animals, the limitation of systemic and glomerular hypertension reduces urinary protein excretion and prevents renal-function deterioration.3, 4 In human insulin-dependent diabetes, normalisation of systemic blood pressure limits renal-disease progression,5, 6 but, with similar blood-pressure control, angiotensin-converting-enzyme (ACE) inhibitors are better than more conventional drugs,7, 8 and reduce the risk of terminal renal failure.⁹ In nearly all studies, renoprotective properties of ACE inhibitors were accompanied by a decrease in the rate of urinary protein excretion.10, 11 This effect is not surprising, since ACE inhibitors have beneficial effects on the permeability and size-selective function of the glomerulus; these effects would lead to limited ultrafiltration of macromolecules and proteins.12, 13, 14 Whether the effect of ACE inhibitors of reducing protein traffic explains the protection they offer against endstage renal failure in diabetes remains unclear. Given the evidence that filtered proteins have an intrinsic renal toxicity,15, 16, 17, 18, 19 however, it is a subject worth investigating. In nondiabetic renal disease, some studies showed that ACE inhibitors slowed the rate of GFR decline more than other antihypertensive drugs at similar levels of blood-pressure control.20, 21 Other studies did not share this finding.22, 23 In studies that found a lower risk of doubling of baseline serum creatinine in patients on ACE inhibition therapy than in controls²⁴ the GFR was not measured. Thus, whether ACE inhibitors are superior to other antihypertensives in slowing the rate of GFR decline in non-diabetic renal disease has not yet been established.

The Ramipril Efficacy In Nephropathy (REIN) study—carried out in 352 patients with chronic non-diabetic nephropathies—was a randomised, double-blind, placebo-controlled trial designed to test the hypothesis that glomerular protein traffic, and its modification by an ACE inhibitor, influences renal-disease progression.²⁵ We also wanted to clarify the extent to which this effect is dependent on the degree of blood-pressure control. To accomplish these aims, we devised a prestratification strategy for two values of proteinuria (stratum 1: 1·0–2·9 g/24 h and stratum 2: ≥3·0 g/24 h) in patients otherwise randomly assigned ACE inhibitor or conventional therapy. Treatment aimed to achieve the same blood-pressure control in both study groups during the study period. Rate of renal-function decline—which was assessed by repeated measures of true GFR—was the principal endpoint of the study.

Here we report our main results in the 166 patients of stratum 2.