Dual RAAS Inhibition and Risk of Hyperkalemia

Dual renin-angiotensin-aldosterone system (RAAS) blockade involves therapy with a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), direct renin inhibitors (DRIs), or mineralocorticoid receptor antagonists (MRAs). Researchers have hypothesized that dual RAAS blockade would result in more complete inhibition of the RAAS cascade.

Results of large clinical trials of dual RAAS inhibition in patients with diabetic kidney disease (DKD) have shown an increased risk of acute kidney injury (AKI) and hyperkalemia with no additional benefit in mortality, cardiovascular events, or progression of chronic kidney disease, compared with RAASA inhibitor monotherapy.

According to Reid Whitlock, MSc, and colleagues, the development of newer, more selective nonsteroidal MRAs has resulted in a new opportunity for dual RAAS inhibition in patients with DKD. The researchers conducted a systematic review and meta-analysis of the risk of AKI and hyperkalemia with the use of dual RAAS blockade in that patient population. Results were reported online in Nephrology Dialysis Transplantation [doi.org/10.1093/ndt/gfad101].

The review included randomized controlled trials published from 2006 to May 30, 2022. The study population was adult patients with DKD receiving dual RAAS blockade. Thirty-one randomized controlled trials representing 33,048 patients were included in the review. Random effects were calculated using pooled risk ratios and 95% CIs.

There were 208 AKI events in 2690 patients on ACEi plus ARB versus 170 in 4264 patients receiving ACEi or ARB monotherapy (pooled risk ratio [RR], 1.48; 95% CI, 1.23-1.39). There were 304 hyperkalemia events in 2818 patients on ACEi plus ARB versus 208 in 4396 patients on ACEi or ARB monotherapy (pooled RR, 1.97; 95% CI, 1.32-2.94).

There was no increase in the risk of AKI with use of a nonsteroidal MRA plus ACEi or ARB compared with ACEi or ARB monotherapy. However, there was a two-fold increase in the risk of hyperkalemia, with 953 events in 7837 patients receiving dual therapy versus 454 events in 6895 patients receiving monotherapy (pooled RR, 2.05; 95% CI, 1.84-2.28). There was a five-fold higher risk of hyperkalemia with use of a steroidal MRA plus an ACEi or ARB, with 28 events in 245 patients at risk in dual therapy versus five events in 248 patients at risk in monotherapy (pooled RR, 5.42; 95% CI, 2.15-13.67).

In conclusion, the researchers said, “Dual therapy with RAASi is associated with an increased risk of AKI and hyperkalemia compared to RAASi monotherapy. Conversely, dual therapy with RAAS inhibitors and nonsteroidal MRAs have no additional risk of AKI but a similar risk of hyperkalemia, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs.”