Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease

Background

Chronic kidney disease (CKD) is a long term condition that occurs as a result of damage to the kidneys. Early recognition of CKD is becoming increasingly common due to widespread laboratory estimated glomerular filtration rate (eGFR) reporting, raised clinical awareness, and international adoption of Kidney Disease Outcomes Quality Initiative (K/DOQI) classification. Early recognition and management of CKD affords the opportunity not only to prepare for progressive kidney impairment and impending renal replacement therapy, but also for intervening to reduce the risk of progression and cardiovascular disease. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are two classes of antihypertensive drugs that act on the renin-angiotensin-aldosterone system. Beneficial effects of ACEi and ARB on renal outcomes and survival in people with a wide range of severity of renal impairment have been reported; however, their effectiveness in the subgroup of people with early CKD (stage 1 to 3) is less certain.

Objectives

This review aimed to evaluate the benefits and harms of ACEi and ARB or both in the management of people with early (stage 1 to 3) CKD who do not have diabetes mellitus.

Search strategy

In March 2010 we searched The Cochrane Library, including The Cochrane Renal Group's specialised register and The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. Reference lists of review articles and relevant studies were also checked. The search was conducted using the optimally sensitive strategy developed by the Cochrane Collaboration for the identification of randomised controlled trials (RCTs) with input from an expert in trial search strategy.

Selection criteria

All RCTs reporting the effect of ACEi or ARB in people with early (stage 1 to 3) CKD who did not have diabetes mellitus were selected for inclusion. Only studies of at least four weeks duration were selected. Authors, working in teams of two, independently assessed the retrieved titles and abstracts, and whenever necessary the full text of these studies were screened to determine which studies satisfied the inclusion criteria.

Data collection and analysis

Data extraction was carried out by two authors, independently, using a standard data extraction form and cross checked by two other authors. Methodological quality of included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross checked by another author. When more than one study reported similar outcomes, data were pooled using the random-effects model, but a fixed-effect model was also analysed to ensure the robustness of the model chosen and to check susceptibility to outliers. Heterogeneity was analysed using a Chi(2) test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I-2 test. Where data permitted, subgroup analysis was used to explore possible sources of heterogeneity. The quality of the evidence was analysed.

Main results

Four RCTs enrolling 2177 participants met our inclusion criteria. Of these, three compared ACEi with placebo and one compared ACEi with ARB. Two studies had an overall low risk of bias, and the other two were considered to be at moderate to high risk of bias. Low to moderate quality of evidence (from two studies representing 1906 patients) suggested that ACEi had no impact on all-cause mortality (RR 1.80, 95% CI 0.17 to 19.27, P = 0.63) or cardiovascular events (RR 0.87, 95% CI 0.66 to 1.14, P = 0.31) in people with stage 3 CKD. For all-cause mortality, there was substantial heterogeneity in the results. One study (quality assessment: low risk of bias) reported no difference in the risk of end-stage kidney disease in those with an eGFR > 45 mL/min/1.74 m(2) treated with ACEi versus placebo (RR 1.00, 95% CI 0.09 to 1.11, P = 0.99). The (high risk of bias) study that compared ACEi with ARB reported little difference in effect between the treatments when urinary protein, blood pressure or creatinine clearance were compared. No published studies comparing ARB with placebo or ACEi and ARB with placebo were identified.

Authors' conclusions

Our review demonstrated that there is currently insufficient evidence to determine the effectiveness of ACEi or ARB in patients with stage 1 to 3 CKD who do not have diabetes mellitus. We have identified an area of significant uncertainty for a group of patients who account for most of those labelled as having CKD.