Current issues of ACP Journal Club are published in Annals of Internal Medicine


Ramipril reduced the rate of progression to end-stage renal disease and overt proteinuria in nondiabetic nephropathy


ACP J Club. 2000 Jan-Feb;132:18. doi:10.7326/ACPJC-2000-132-1-018

Source Citation

Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in nondiabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999 Jul 31;354:359-64. [PubMed ID: 10437863]



In patients with nondiabetic chronic nephropathy and nonnephrotic proteinuria (1 to 2.9 g/24 h), does ramipril reduce the rate of disease progression?


Randomized (unclear allocation concealment*), blinded (patients and clincians),* placebo-controlled trial with median follow-up of 31 months (Ramipril Efficacy in Nephropathy [REIN] trial).


14 clinical centers in Italy.


186 adults (mean age 50 y, 74% men) with chronic nephropathy and persistent proteinuria (1 to 2.9 g/24 h). Exclusion criteria were use of angiotensin-converting enzyme (ACE) inhibitors in the previous 2 months and use of corticosteroids, nonsteroidal anti-inflammatory drugs, or immunosuppressive drugs in the previous 6 months; urinary tract infections; or overt heart failure. Follow-up was 94%.


After a 1-month run-in period, patients were allocated to increasing doses of ramipril, starting with 1.25 mg/d (n = 99) or placebo (n = 87). Study drugs were increased or other antihypertensive drugs were added or increased every 2 weeks to achieve a diastolic blood pressure (BP) < 90 mm Hg. All patients were asked to limit sodium intake and to eat 0.6 to 0.8 g protein/kg of body weight per day.

Main outcome measures

Change in glomerular filtration rate (GFR) and time to end-stage renal failure. Secondary outcomes were degree of proteinuria, major cardiovascular complications, and mortality.

Main results

Analysis was by intention to treat. Fewer patients in the ramipril group reached end-stage renal failure (P = 0.01) or overt proteinuria (P = 0.005) than did patients in the placebo group (Table). The groups did not differ for change in GFR (0.26 for ramipril group vs 0.29 mL/min per mo in the placebo group, P = 0.6), mortality, nonfatal cardiovascular events, BP, or adverse effects (12% for ramipril vs 7% for placebo {P = 0.3}†).


Ramipril reduced the rate of end-stage renal failure and overt proteinuria in patients who had nondiabetic nephropathy with nonnephrotic proteinuria.

*See Glossary.

P value calculated from data in article.

Source of funding: Hoechst Marion Roussel Clinical Research Institute.

For correspondence: Dr. P. Ruggenenti, Clinical Research Center for Rare Diseases “Aldo a Cele Daccò” Villa Camozzi, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. FAX 39-035-514-503.

Table. Ramipril vs placebo for nondiabetic nephropathy with nonnephrotic proteinuria‡

Outcomes at median 31 mo Ramipril Placebo RRR (95% CI) NNT (CI)
End-stage renal failure 9.1% 20.7% 56.1% (9 to 79) 9 (5 to 69)
> 3 g/24 h proteinuria 15.1% 31.0% 51.2% (15 to 72) 6 (4 to 27)

‡Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Urinary protein excretion is a marker of progressive renal disease and predicts the effect of BP control on the decline of GFR in patients with proteinuria > 1 g/d. ACE inhibitors have shown benefits in patients with chronic nephropathies and hypertension (1, 2). But in most of the early trials, BP was lower in ACE-inhibitor groups than in control groups.

The REIN study was designed to explore the effect of ramipril on progressive renal disease in patients with treated hypertension or normal BP compared with patients with equally controlled BP. Patients were stratified by level of proteinuria because a previous trial that studied ramipril had shown a decrease in the slope of GFR decline for patients with proteinuria > 3 g/d (3). The results for the second stratum of patients (proteinuria 1 to 2.9 g/d) are now available. Despite the lack of significant changes in the slope of GFR decline, ramipril halved the risk for end-stage renal disease without substantial adverse effects. These results support the overall conclusions that, first, ACE inhibition is beneficial in patients with chronic nephropathies and proteinuria and that, second, the extent of the benefit on progressive renal disease is proportional to the protein excretion rate. These converging results should help to convince specialists as well as general practitioners that strict control of BP is a major therapeutic goal in chronic renal disease and that ACE inhibitors are the drugs of choice in patients with proteinuria.

Maurice Laville, MD
Hôpital Edouard-Herriot
Lyon, France


1. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456-62.

2. Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Ann Intern Med. 1997;127:337-45.

3. The GISEN Group. 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. Lancet. 1997;349:1857-63.