Adding a mineralocorticoid receptor antagonist (MRA) to renin-angiotensin-system (RAS) inhibitors is associated with an increased risk of hyperkalemia in patients with chronic kidney disease, according to a recent meta-analysis.

Gemma Currie, MD, and Alison H.M. Taylor, MD, of the Glasgow Cardiovascular Research Center in the United Kingdom, performed an updated meta-analysis of 19 randomized trials on MRA therapy conducted 1947 to 2014 (including unpublished data), involving 1646 non-dialysis chronic kidney disease (CKD) patients. Treated groups received an MRA (spironolactone or eplerenone) either alone or in addition to an ACE inhibitor and /or angiotensin II receptor blocker. Spironolactone was administered at 25 to 50 mg and eplerenone at 25 to 100 mg daily. Studies lasted anywhere from 8 to 52 weeks.

MRA added to RAS inhibitor therapy reduced systolic blood pressure (BP) by 5.7 mm Hg, diastolic BP by 1.7 mm Hg, and glomerular filtration rate by 3.2 mL/min/1.73 m2, the investigators reported in BMC Nephrology (2016:17:127). MRA therapy also lowered average protein/albumin excretion by 38.7%. Patients taking an MRA in addition to RAS inhibitors, however, had a 3.21 times greater risk of trial withdrawal due to hyperkalemia. In patients prescribed MRA, average potassium increased moderately by 0.19 mmol/L from baseline.

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“It is essential to consider that this does not necessarily equate to risk of developing clinically significant hyperkalaemia requiring treatment, rather of developing a serum potassium level above the predefined study upper limit, which in many trials was 5.5–6 mmol/L, the investigators wrote.

Based on clinical trials reporting at least 1 case of hyperkalemia, the researchers calculated that 10 patients would need to be treated for a year for 1 case of hyperkalemia to develop.

It remains feasible that the benefits of MRA add-on therapy outweigh the risks of hyperkalemia and decline in kidney function, according to the investigators.

The investigators found no difference in hyperkalemia risk between those with diabetic and non-diabetic CKD. Due to small numbers, the researchers were unable to assess hard clinical endpoints, such as cardiovascular events, the need for renal replacement therapy, and mortality.

“In conclusion, in patients with CKD, with persistent proteinuria despite RAS inhibition, addition of MRA represents a promising treatment strategy for reducing BP and proteinuria with a quantifiable risk of hyperkalaemia,” Dr Currie, Dr Taylor, and colleagues stated.

Future studies are needed to assess whether MRA added to RAS inhibition reduces cardiovascular risks and the need for renal replacement therapy.

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1.   1. Currie G, Taylor AHM, Fujita T, et al. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis. BMC Nephrology (2016) 17:127; doi: 10.1186/s12882-016-0337-0.