Management of Hypertension in Advanced Kidney Disease

Panagiotis I. Georgianos; Rajiv Agarwal


Curr Opin Nephrol Hypertens. 2022;31(4):374-379. 

In This Article

Enablement of Persistent Spironolactone use for Resistant Hypertension in Advanced Chronic Kidney Disease

International guidelines recommend the use of the steroidal mineralocorticoid receptor antagonist (MRA) spironolactone as fourth-line therapy for patients with resistant hypertension.[12,13] This guidance was based largely on the results of the PATHWAY-2 (Spironolactone versus placebo, bisoprolol and doxazosin to determine the optimal treatment for drug-resistant hypertension), a multiway cross-over trial, which demonstrated that spironolactone was more effective as compared with placebo or active-treatment with an α or β-blocker in lowering BP in patients with resistant hypertension.[14] All patients in this trial received background therapy with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB), calcium channel blockers and a diuretic in maximal tolerated doses. However, patients with moderate-to-advanced CKD or hyperkalaemia were not eligible in PATHWAY-2 trial. Accordingly, guidelines discourage the use of spironolactone when the levels of eGFR are less than 45 ml/min/1.73 m2 or when the levels of serum potassium are higher than 4.5 mmol/l.[13] In such patients, the addition of spironolactone to background therapy with an ACEI or an ARB is associated with two-fold higher incidence of hyperkalaemia.[15] Large population-based studies showed that the prevalence of resistant hypertension in advanced CKD is high, but the use of spironolactone is sparse,[6,16] mainly because treatment with this agent is restricted by the associated risk of hyperkalaemia.[17,18]

The AMBER (Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and CKD) trial tested the hypothesis whether concomitant treatment with an agent that binds potassium in the gut can mitigate the risk of hyperkalaemia to enable the more persistent use of spironolactone.[19] In this phase 2b study, 295 patients who had uncontrolled resistant hypertension and eGFR of 25–45 ml/min/1.73 m2 were randomized to spironolactone (at an initial dose of 25 mg/day) in addition to double-blind treatment either with the potassium-binder patiromer (8.4 g/day) or with placebo. Over 12 weeks of follow-up, compared with placebo, patiromer enabled more patients to remain on spironolactone treatment with less severe hyperkalaemia [between-group difference: 19.5%; 95% confidence interval (95% CI): 10.0–29.0].[19] The primary efficacy endpoint of the AMBER trial was met.

A key secondary objective was to investigate the BP-lowering efficacy of this therapeutic strategy. In the patiromer group, the change from baseline to study-end in unattended automated office SBP was -11.7 mmHg (95% CI: -14.1 to -9.3). The corresponding SBP change in the placebo group was -10.8 mmHg (95% CI: -13.2 to -8.3). The difference in the SBP reduction between the patiromer and placebo groups was not statistically significant.[19] It has to be noted that this unexpected finding was attributable to the altered pharmacokinetic properties of spironolactone. This issue was illustrated with the evaluation of urinary excretion of spironolactone metabolites over the course of the AMBER trial.[19] It was shown that spironolactone is a prodrug with biologically active metabolites that have long half-lives and accumulate over time, particularly in patients with an eGFR of 25–45 ml/min/1.73 m2. The accumulation of biologically active metabolites resulted in a prolonged BP-lowering action that persisted even 2 weeks after withdrawal of spironolactone at trial completion.[19]

Taken together, the AMBER trial provided evidence that newer potassium-binding therapies can enable the more persistent use of spironolactone for the management of resistant hypertension in patients with stage 3b/4 CKD. Just five patients needed to be treated with patiromer to enable the use of spironolactone in one more patient.[19] Despite the lack of a significant between-group difference in the change of unattended automated office SBP, add-on therapy with spironolactone was accompanied by a clinically meaningful improvement in BP control.[19] Whether this therapeutic strategy confers a downstream benefit on end-organ protection that is translated into a long-term reduction in the risk for 'hard' clinical outcomes is a crucial research question that will remain unanswered in the foreseeable future. The DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) trial was originally designed to explore the effect of patiromer-enabled optimization of renin-angiotensin-aldosterone-system inhibitor therapy on time to cardiovascular death or first cardiovascular-related hospitalization in patients with heart failure with reduced ejection fraction.[20] Unfortunately, the primary outcome in DIAMOND was reappraised, as the recruitment rate was much lower than expected due to the Covid-19 pandemic.[20]