In patients with diabetic kidney disease, use of 2 classes of renin-angiotensin-aldosterone system inhibitors (RAASi) can increase the risk for hyperkalemia and sometimes acute kidney injury (AKI) compared with RAASi monotherapy, a new study finds.

RAAS blockade includes a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin-receptor blockers (ARBs), direct renin inhibitors (DRIs), or mineralocorticoid receptor antagonists (MRAs).

Navdeep Tangri, MD, PhD, of the Chronic Disease Innovation Centre, Seven Oaks General Hospital, Winnipeg, Manitoba, Canada, and colleagues conducted a systematic review and meta-analysis of 31 randomized controlled trials testing these combinations in 33,048 patients with diabetic kidney disease.

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Hyperkalemia risk significantly increased 5.4-fold with combined use of a steroidal MRA such as spironolactone or eplerenone plus either an ACEi or ARB compared with ACEi or ARB monotherapy, the investigators reported in Nephrology Dialysis Transplantation. Hyperkalemia risk significantly increased 2.1-fold when ACEi or ARB was combined with a nonsteroidal MRA such as finerenone or esaxerenone. It significantly increased 2.0-fold with combined use of ACEi and ARB compared with ACEi or ARB monotherapy. Hyperkalemia risk significantly increased 1.4-fold when DRI was combined with ACEi/ARB compared with ACEi or ARB monotherapy.

AKI risk increased significantly (by 1.5-fold) only when ACEi and ARB were used in combination vs monotherapy, the investigators reported.

“Although RAAS inhibition has been shown to preserve kidney function, and dual RAAS inhibition improves proteinuria reduction, there appears to be a point at which further RAAS blockade may have deleterious effects on the kidney,” Dr Tangri’s team wrote.

Among the review’s limitations, drug doses were not always available, study durations differed across trials, and definitions of hyperkalemia and AKI varied.

Disclosure: This research was supported by Bayer US. Please see the original reference for a full list of disclosures.


Whitlock R, Leon SJ, Manacsa H, et al. The association between dual RAAS inhibition and risk of acute kidney injury and hyperkalemia in patients with diabetic kidney disease: a systematic review and meta-analysis. Nephrol Dial Transplant. Published online June 12, 2023. doi:10.1093/ndt/gfad101