RAAS inhibition combinations and risk of acute kidney injury and hyperkalaemia in diabetic kidney disease
Diabetic kidney disease (DKD) contributes nearly half of all cases of kidney failure that require replacement therapy. One of the cornerstones of DKD treatment is the single-agent renin–angiotensin–aldosterone system (RAAS) blockade. Several trials have demonstrated that angiotensin-converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) reduce the progression of kidney disease.
Dual inhibition of the RAAS involves therapy with a combination of ACEis, ARBs, direct renin inhibitors (DRIs) or mineralocorticoid receptor agonists (MRAs). While it is plausible that dual therapy can achieve a more complete inhibition of the RAAS, and thereby confers greater cardiovascular and kidney protection, trials have shown increased risk of adverse events, such as hyperkalaemia and AKI, without additional benefit on mortality or CKD progression. However, the more recent development of non-steroidal MRAs, such as finerenone, has created a new opportunity for dual inhibition of RAAS in terms of kidney protection.
In the present study, investigators conducted a systematic review and meta-analysis of the risk of AKI and hyperkalaemia with dual RAAS blockade in people with DKD. In total, 31 trials were selected for the review, with 33,048 adults included in the meta-analysis.
In the 2690 people receiving ACEi/ARB dual therapy, there were 208 AKI events versus 170 events in the 4264 receiving ACEi or ARB monotherapy (pooled RR, 1.48). There were 304 hyperkalaemia events in 2818 people on ACEi/ARB versus 208 in 4396 on ACEi or ARB monotherapy (pooled RR, 1.97).
With dual therapy with a non-steroidal MRA plus ACEi or ARB, there was no increase in the risk of AKI (pooled RR, 0.97) versus ACEi or ARB monotherapy. There was, however, an increased risk of hyperkalaemia, with 953 events in 7837 individuals receiving dual therapy versus 454 events in 6895 receiving monotherapy (pooled RR, 2.05). A steroidal MRA plus ACEi or ARB produced a 5-fold greater risk of hyperkalaemia compared with monotherapy, with 28 events in 245 at risk versus 5 events in 248 at risk (pooled RR, 5.43).
The authors conclude that, in people with DKD, combination therapy with non-steroidal MRAs and RAAS inhibitors was not associated with an additional AKI risk, but an increased risk of hyperkalaemia compared to ACEi or ARB monotherapy. The hyperkalaemia risk is lower than that for dual therapy with ACEi/ARBs and steroidal MRAs.
The findings highlight that there may be important differences in the risks and benefits of choice of combination therapy for the treatment of DKD.
The full study can be read here.
