RAS inhibitors in CKD - Hold your nerve

Whilst we are (rightly) excited about the advent of the SGLT2 inhibitors as a drug class that can improve renal and cardiovascular outcomes in people with CKD, it’s important to remember that the SGLT2 inhibitors are indicated as an add-on to standard CKD treatment. One key component of that standard treatment is an ACE inhibitor or angiotensin receptor antagonist, collectively known as renin-angiotensin system (RAS) inhibitors. Of note, the trial data supporting SGLT2 inhibitors in CKD was based on people who were on maximally tolerated doses of RAS inhibitors. 

Yet a recent Drugs and Therapeutics Bulletin review (Drug and Therapeutics Bulletin 2025;63:54-58) highlights that ‘despite an extensive evidence base and decades of clinical experience, they (RAS inhibitors) remain underused, underdosed and frequently discontinued due to concerns about changes in kidney function and hyperkalaemia.’ The DTB reminds us that reductions in eGFR and rises in potassium are common, often to be expected due to the way the drugs work, and usually settle over time to give longer term renal benefits. 

RAS inhibitors are indicated for a number of reasons - hypertension, secondary prevention after MI, heart failure with reduced ejection fraction, but also for proteinuric CKD, with or without diabetes (see NICE CKD guideline NG203 for detail of CKD indications). At a renal level RAS inhibitors work by inhibiting the (angiotensin 2 mediated) vasoconstriction of the efferent arterioles (the outflow vessels from the glomerulus). This outflow vasodilation leads to an acute drop in intraglomerular pressure, and often a resultant drop in eGFR. It is estimated that 16% of people treated with RAS inhibitors will have an initial drop in eGFR of ≥15%. 

But for the vast majority of people this initial reduction in eGFR stabilises and ultimately leads to improved kidney function and reduced proteinuria. There is convincing evidence that RAS drugs improve renal and CVD outcomes in people with diabetic CKD, and that they reduce the risks of end stage kidney disease in people with proteinuric CKD even without diabetes. Reassuringly we also now have evidence from the STOP-ACEi trial that RAS inhibitors are safe in people with advanced CKD with eGFR <30. However, it is important to remember we should NOT use dual RAS inhibitors (I.e. ACEi and ARB) - this combination has been shown to cause clinically significant AKI risks and hyperkalaemia.

So, what changes in renal function and potassium can we tolerate when initiating or increasing the dose of RAS inhibitors? When do we need to stop (or reduce the dose) and when can we hold our nerve and continue? International guidance reassures us that we can tolerate probably much larger reductions in renal function than many of us might have thought. As long as the decrease in eGFR is <25% and creatinine increase <30% we can continue to titrate to a maximally tolerated dose. If the drop in renal function exceeds this we should review causes for AKI (e.g. intercurrent illness, dehydration etc), check BP, review concurrent medications that may have contributed (notably NSAIDs), and consider renal artery stenosis (a rare cause of substantial drops in eGFR on RAS inhibitor initiation). If there are no reversible causes we will need to consider stopping, or reducing the dose, of the RAS inhibitor. 

As for potassium we can tolerate serum K <5.5 mmol/L. In the context of a well patient and no signs of AKI, if mild hyperkalaemia develops (K 5.5-5.9 mmol/L) halve the dose, if moderate hyperkalaemia develops (K 6.0-6.4 mmol/L) stop the RAS inhibitor, and in both cases repeat the renal function/K within 1 week whist also looking for contributory causes (medication review, potassium rich foods including ‘lo-salt’ products) and considering if the initial result may have been an artefact (e.g. haemolysis, or a delay in sample processing - a common one to consider for us in primary care if the sample has been taken at the Practice). 

This guidance is very reassuring that in many cases we can hold our nerve with drops in renal function or rises in potassium when initiating or increasing doses of RAS inhibitors, whist reviewing for concurrent/mitigating causes.