Inhibition of the renin–angiotensin–aldosterone system in early chronic kidney disease: do we know as much as we think we do?

Inhibitors of the renin–angiotensin–aldosterone system (RAAS) are the mainstay of pharmacological chronic kidney disease (CKD) management. First released in the 1980s, in people with impaired kidney function, RAAS inhibitors reduce blood pressure and proteinuria, slow the rate of GFR decline and reduce cardiovascular events. Evidence for the benefits of angiotensin-converting enzyme (ACE) inhibitors (and angiotensin receptor blockers [ARBs]) in the CKD population as a whole has been demonstrated in meta-analyses of randomised controlled trials examining cardiac and/or kidney outcomes.[1–3] RAAS inhibitors are, therefore, recommended by KDIGO for first-line management of hypertension in people with CKD G1–4, A2–3 (albuminuria ≥30 mg/g), with or without diabetes.[4] 

Despite accounting for the majority of people with kidney disease, the evidence base for RAAS inhibitors specific to those with mild to moderate CKD (who do not have diabetes) is limited. Research has tended to focus on more advanced CKD, with or without proteinuria, and few studies present subgroup results by CKD stage. Early treatment of CKD, with the aim of slowing GFR decline and reducing cardiovascular events, could, however, result in significant health and economic benefits on both a population and individual level. 

Although some of the efficacy of RAAS inhibition has been shown to relate to the severity of underlying disease (such as proteinuria), there is little reason to imagine that people with mild to moderate CKD (G1–3) should not benefit from the pleiotropic mechanisms of action of these drugs. On the other hand, it is possible that adverse effects in this population could outweigh the benefits, given the lower absolute rate of either kidney or cardiac events.

Cooper et al [5] set out to answer some of these questions in a Cochrane Review designed to determine the benefits and harms of RAAS inhibition in people with CKD G1–3 without diabetes (an updated review from 2011 [6]). Published in July 2023, the authors used the valuable Cochrane Kidney and Transplant Register of Studies to identify randomised controlled trials reporting outcomes following use of ACEi, ARB or ACEi plus ARB versus placebo, or ACEi versus ARB, in people with non-diabetic CKD G1–3. Studies in populations with a single kidney diagnosis were excluded, but the authors did not differentiate between trials that examined the use of RAAS inhibitors in hypertensive versus normotensive individuals. 

Remarkably, only six studies were found (total n=9379), and all were rated at high or unclear risk of bias. No studies included patients with CKD G1, and the source of the G2 data is unclear (I have queried this with the authors). Meta-analysis was challenging, as few outcomes were reported by more than one or two studies. In people with CKD G3, the authors reported, with low certainty, that ACE inhibitors versus placebo make little or no difference to death (any cause) or cardiovascular events, and may increase the risk of adverse events (RR, 1.33 [95% CI 1.26–1.41]). With very low certainty, they found ARBs versus placebo to have uncertain effects on death (any cause), rate of GFR decline, proteinuria or blood pressure. 

The authors concluded that there is currently insufficient evidence to determine the risks and benefits of RAAS inhibitor use in mild to moderate CKD.

So, what can we conclude from this well-conducted Cochrane Review? My take is that the clear benefits of ACE/ARB therapy that are present for patients with advanced CKD are not necessarily present in early–moderate CKD, but really the evidence base is not established. Aggregating patient-level data from trials including people with CKD G3 would allow us to assess the efficacy of ACE inhibitors and ARBs more accurately in this subgroup. People with CKD G1–2 have, however, less frequently been included in prior studies, probably due to challenges in identifying structural and functional kidney abnormalities, as well as adequately powering research in this lower risk population. So, is the question about RAAS inhibitor use in mild to moderate CKD important enough to deserve a new, dedicated, large-scale, randomised controlled trial, designed to overcome these barriers? 

Preventing progression of CKD at an early stage is certainly a priority. Given the remarkable cardiorenal protection that SGLT2 inhibitors appear to confer when added to RAAS inhibition in proteinuric and advanced CKD populations, perhaps the more relevant question now is what benefit might this drug combination demonstrate in the wider CKD population with less advanced disease.

A digest of the review can be read here.

References

1. Xie X, Liu Y, Perkovic V et al (2016) Renin-angiotensin system inhibitors and kidney and cardiovascular outcomes in patients With CKD: A Bayesian network meta-analysis of randomized clinical trials. Am J Kidney Dis 67: 728–41
2. Jafar TH, Schmid CH, Landa M et al (2001) Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med 135: 73–87
3. Zhang Y, He D, Zhang W et al (2020) ACE inhibitor benefit to kidney and cardiovascular outcomes for patients with non-dialysis chronic kidney disease stages 3-5: A network meta-analysis of randomised clinical trials. Drugs 80: 797–811
4. Cheung AK, Chang TI, Cushman WC et al (2021) Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int 99: 559–69
5. Cooper TE, Teng C, Tunnicliffe DJ, Cashmore BA et al (2023) Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database Syst Rev 7: CD007751
6. Sharma P, Blackburn RC, Parke CL (2011) Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database Syst Rev 10: CD007751