Dual RAAS inhibitor therapy tied to increased risk of acute kidney injury in diabetic kidney disease patients

"Although RAAS (renin-angiotensin-aldosterone system) inhibition has been reported to preserve kidney function, and dual RAAS inhibition improves proteinuria reduction, there appears to be a point at which further RAAS blockade may have harmful effects on the kidney," the researchers wrote.

Conversely, Navdeep Tangri, University of Manitoba. Winnipeg, Manitoba, Canada, and colleagues showed that dual therapy with non-steroidal MRAs (mineralocorticoid receptor antagonists) and RAAS inhibitors have no additional AKI risk but a similar hyperkalemia risk, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs.

"MRA addition to an ACEi or ARB (angiotensin-receptor blockers) was not tied to an increase in acute kidney injury compared to ACEi or ARB monotherapy," the researchers reported.

Dual RAAS blockade involves dual therapy with a combination of ACE inhibitors, direct renin inhibitors (DRIs), angiotensin-receptor blockers, or mineralocorticoid receptor antagonists. It is hypothesized that dual RAAS inhibition would lead to a more complete blockade of the RAAS cascade. However, large clinical trials on dual RAAS inhibition have revealed an increased risk of hyperkalemia and AKI without additional benefit on CKD (chronic kidney disease) progression, cardiovascular events, or mortality compared to RAAS inhibitor monotherapy in DKD patients.

The development of newer, more selective non-steroidal mineralocorticoid receptor antagonists as cardiorenal protective therapies has created a new opportunity for dual RAAS inhibition. Dr Tangri and colleagues conducted a systematic review and meta-analysis of the hyperkalemia and AKI risks with dual RAAS blockade in patients with diabetic kidney disease.

They conducted a systematic review and meta-analysis of the RCTs (randomized controlled trials) published from 2006 to 2022. The study population included adult DKD patients receiving dual RAAS blockade. The systematic review included 31 RCTs and 33 048 patients. Pooled risk ratios (RRs) were calculated using random effects.

The researchers reported the following findings:

• There were 208 AKI events in 2690 patients on ACEi + ARB versus 170 in 4264 patients with ACEi or ARB monotherapy (pooled RR 1.48).
• There were 304 hyperkalemia events in 2818 patients on ACEi + ARB versus 208 in 4396 patients with ACEi or ARB monotherapy (pooled RR 1.97).
• A non-steroidal MRA + ACEi or ARB showed no increase in the risk of AKI (pooled RR 0.97) compared to ACEi or ARB monotherapy but had a 2-fold higher risk of hyperkalemia with 953 events in 7837 patients in dual therapy versus 454 events in 6895 patients in monotherapy (pooled RR 2.05).
• A steroidal MRA + ACEi or ARB had a 5-fold higher risk of hyperkalemia with 28 events in 245 at risk in dual therapy versus five events in 248 at risk in monotherapy (pooled RR 5.42).

"The research showed that dual RAS blockade with an ACEi and ARB was tied to a 50% increase in the risk of an AKI compared to ACEi or ARB monotherapy," the researchers wrote. "In contrast, the addition of an MRA to an ACEi or ARB was not associated with an increase in AKI compared to ACEi or ARB monotherapy."

"These findings highlight that there may be important differences in the benefits and risks when implementing dual RAAS combination therapies for the treatment of diabetic kidney disease," they concluded.

Reference:

Whitlock, R., Leon, S. J., Manacsa, H., Askin, N., Rigatto, C., Fatoba, S. T., Farag, Y. M., & Tangri, N. 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. Nephrology Dialysis Transplantation. https://doi.org/10.1093/ndt/gfad101