Management of hypertension in advanced kidney disease

Abstract

Purpose of review:

To present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD).

Recent findings:

In the AMBER trial, compared with placebo, the potassium-binder patiromer mitigated the risk of hyperkalemia and enabled more patients with uncontrolled resistant hypertension and stage 3b/4 CKD to tolerate and continue spironolactone treatment; add-on therapy with spironolactone provoked a clinically meaningful reduction of 11–12 mmHg in unattended automated office systolic blood pressure (SBP) over 12 weeks of follow-up. In the BLOCK-CKD trial, the investigational non-steroidal mineralocorticoid-receptor-antagonist (MRA) KBP-5074 lowered office SBP by 7–10 mmHg relative to placebo at 84 days with minimal risk of hyperkalemia in patients with advanced CKD and uncontrolled hypertension. The CLICK trial showed that the thiazide-like diuretic chlorothalidone provoked a placebo-subtracted reduction of 10.5 mmHg in 24-hour ambulatory SBP at 12 weeks in patients with stage 4 CKD and poorly controlled hypertension.

Summary:

Enablement of more persistent spironolactone use with newer potassium-binding agents, the clinical development of novel non-steroidal MRAs with a more favorable benefit-risk profile and the recently proven BP-lowering action of chlorothalidone are 3 therapeutic opportunities for more effective management of hypertension in high-risk patients with advanced CKD.

INTRODUCTION

Hypertension is the most common comorbidity in patients with chronic kidney disease (CKD) and it can be either the cause or a consequence of kidney damage [1]. The burden of hypertension travels hand-in-hand with the severity of CKD [2], with an increasing prevalence of high blood pressure (BP) from 67% in patients with preserved kidney function up to 92% in those with an estimated-glomerular-filtration-rate (eGFR) <30 ml/min/1.73m² [3]. Furthermore, independent of eGFR, albuminuria is directly associated with the severity of hypertension [4;5]. Compared to those without CKD, despite the more aggressive treatment of hypertension in patients with advanced CKD, BP often remains inadequately controlled [6]. The prevalence of resistant hypertension, defined as uncontrolled BP despite treatment with 3 antihypertensives in optimal doses that include a diuretic, is 2 to 3 times higher in stage 3b/4 CKD than in the general population [7–9]. Compared to controlled hypertension, true resistance to antihypertensive treatment is associated with an increased risk for adverse cardiovascular events and incident kidney failure [10;11]. There is therefore a critical unmet need for more effective BP control in this high-risk patient population.

The purpose of this article is to present recent developments in the field of pharmacotherapy of hypertension in advanced CKD. We discuss evidence from recently completed randomized trials and provide directions for future research in this important scientific area.

ENABLEMENT OF PERSISTENT SPIRONOLACTONE USE FOR RESISTANT HYPERTENSION IN ADVANCED CKD

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 multi-way 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 hyperkalemia were not eligible in PATHWAY-2 trial. Accordingly, guidelines discourage the use of spironolactone when the levels of eGFR are <45 ml/min/1.73m² or when the levels of serum potassium are >4.5 mmol/L [13]. In such patients, the addition of spironolactone to background therapy with an ACEI or an ARB is associated with 2-fold higher incidence of hyperkalemia [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 hyperkalemia [17;18].

The AMBER (Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease) trial tested the hypothesis whether concomitant treatment with an agent that binds potassium in the gut can mitigate the risk of hyperkalemia 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/1.73m² 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 hyperkalemia [between-group difference: 19.5%; 95% confidence interval (CI): 10.0% to 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 systolic BP was −11.7 mmHg (95% CI: −14.1 to −9.3). The corresponding systolic BP change in the placebo group was −10.8 mmHg (95% CI: −13.2 to −8.3). The difference in the systolic BP 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/1.73m². 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 5 patients needed to be treated with patiromer to enable the use of spironolactone in 1 more patient [19]. Despite the lack of a significant between-group difference in the change of unattended automated office systolic BP, 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, since the recruitment rate was much lower than expected due to the Covid-19 pandemic [20].

NON-STEROIDAL MRAs

The observation that the use of currently available steroidal MRAs in daily clinical practice is associated with intolerable side effects, such as with an increased risk of hyperkalemia, has led to the discovery and development of non-steroidal MRAs with the aim to maintain the potent and selective inhibition of the mineralocorticoid receptor with a more favorable safety profile [21;22]. Agents that belong to the novel class of non-steroidal MRAs and have progressed into an advanced stage of clinical development are the following: finerenone, esaxerenone and KBP-5074. Differences in clinical efficacy among non-steroidal MRAs, such as BP-lowering action, appear to exist, but the superiority of one agent over the other remains unclear in the absence of trials to provide direct head-to-head comparisons [21;22].

Based on firm evidence from the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) trial [23], the US Food and Drug Administration recently approved finerenone for use in daily clinical practice with the indication of cardiorenal protection in patients with CKD and type 2 diabetes. Whether this recently approved non-steroidal MRA is also effective in improving BP control in the subset of patients with uncontrolled or resistant hypertension and CKD remains unanswered. In the FIDELIO-DKD trial [23], finerenone provoked a placebo-subtracted reduction of 2–3 mmHg in office systolic BP. This modest BP-lowering effect contrasts with the reduction of 11–12 mmHg in unattended automated office systolic BP seen with spironolactone over the course of the AMBER trial [19]. Whether finerenone is a safer substitute for spironolactone in the subgroup of patients with moderate-to-advanced CKD and uncontrolled resistant hypertension warrants further investigation.

On the basis of evidence from a large phase 3 trial demonstrating a potent BP-lowering action of esaxerenone [24], this novel selective non-steroidal MRA received regulatory approval in Japan for the treatment of essential hypertension [25]. The safety and BP-lowering efficacy of esaxerenone was investigated in 2 multicenter, open-label, non-randomized, dose-escalation studies that included patients with hypertension and moderate kidney dysfunction (eGFR ≥30 and <60 ml/min/1.73m²) [26]. Esaxerenone was administered at an initial dose of 1.25 mg/day that was up-titrated to 2.5 and then 5 mg/day. Over a follow-up period of 12 weeks, monotherapy with esaxerenone was accompanied by a reduction of 18.5/8.8 mmHg in sitting office BP. When esaxerenone was administered as add-on therapy to patients already treated with an ACEI or an ARB, a similar reduction of 17.8/8.1 mmHg in sitting office BP was observed [26]. Hyperkalemia (defined as serum potassium ≥5.5 mEq/L) was not seen with monotherapy, but occurred in 7 out of 58 patients (12.1%) who received add-on therapy with esaxerenone.

In the ESAX-DN [Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria] trial [27], 455 patients with type 2 diabetes and high albuminuria (urinary albumin-to-creatinine ratio of 45 to <300 mg/g and eGFR ≥30 ml/min/1.73m²) receiving background treatment with an ACEI or an ARB were randomized to esaxerenone (1.25–2.5 mg/day) or placebo over 52 weeks of follow-up. As compared with placebo, esaxerenone significantly increased the proportion of patients who achieved remission of albuminuria (between-group difference: 18%; 95% CI: 12.0% to 25.0%) [27]. The BP-lowering efficacy of esaxerenone in patients with mild-to-moderate CKD was also confirmed. Over the course of the ESAX-DN trial, a median reduction of 10 mmHg in sitting office systolic BP was observed in the esaxerenone group, but not in the placebo group. As expected, hyperkalemia occurred more commonly with active-treatment than with placebo, but these events were easily manageable either with reduction of the dose of esaxerenone or with transient drug discontinuation [27]. A subsequent single-arm interventional study showed that therapy with esaxerenone was associated with a 54.6% reduction in urinary albumin-to-creatinine ratio in 56 patients with type 2 diabetes and very high albuminuria [28]. Whether this positive benefit/risk ratio of esaxerenone persists in patients with more advanced CKD requires investigation in future trials.

KBP-5074 is an investigational non-steroidal MRA with higher selectivity and stronger binding affinity to the mineralocorticoid receptor as compared with spironolactone and eplerenone [29;30]. Pharmacokinetic studies showed that KBP-5074 exhibits a prolonged plasma half-live of ~60 hours that is suggestive of a potent and sustained hemodynamic effect [31]. BLOCK-CKD (Study of KBP-5074 in Subjects With Uncontrolled Hypertension and Advanced Chronic Kidney Disease) was a phase 2b trial aiming to explore the safety and BP-lowering efficacy of this agent in 162 patients with stage 3b/4 CKD and inadequately controlled hypertension [32]. Over 84 days of follow-up, as compared with placebo, the addition of KBP-5074 0.25 mg/day to standard treatment provoked a mean change of −7.0 mmHg in office systolic BP. The placebo-subtracted change in office systolic BP provoked by KBP-5074 0.50 mg/day was −10.2 mmHg [32]. The incidence of hyperkalemia was comparable between active-treatment and placebo group [32]. Based on these positive preliminary data, a phase 3 trial with a randomized withdrawal period (NCT04968184) has been designed to explore the safety, efficacy, and durability of BP-lowering action of KBP-5074 in 600 patients with stage 3b/4 CKD and poorly controlled hypertension.

CHLOROTHALIDONE FOR POORLY CONTROLLED HYPERTENSION IN ADVANCED CKD

International guidelines recommend the use of thiazide diuretics for the treatment of hypertension in patients with eGFR ≥30 ml/min/1.73m² [33]. For those with more advanced CKD, most guidelines recommend the use of loop diuretics, because thiazide/thiazide-like diuretics are considered much less effective or ineffective when eGFR is reduced to levels <30 ml/min/1.73m² [1;13;34]. However, in 2014, a pilot, single-arm interventional study enrolling 12 patients with eGFR of 20–45 ml/min/1.73m² and uncontrolled hypertension showed that the addition of the long-acting thiazide-like diuretic chlorothalidone (at a starting dose of 25 mg/day) to the background antihypertensive regimen was accompanied by a clinically meaningful reduction of 10.5/3.1 mmHg in 24-hour ambulatory BP [35]. These provocative data provided the rationale for the design of CLICK (Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease), a larger phase 2 clinical trial aiming to investigate whether chlorothalidone is an effective BP-lowering medication in patients with advanced CKD [36].

In CLICK, 160 patients with eGFR of ≥15 to <30 ml/min/1.73m² and uncontrolled hypertension, as confirmed by the “gold-standard” method of 24-hour ambulatory BP monitoring, were randomly assigned in a 1:1 ratio to chlorothalidone (at a starting dose of 12.5 mg/day) or placebo [37]. Over 12 weeks of follow-up, chlorothalidone provoked a placebo-subtracted change of −10.5 mmHg (95% CI: −14.6 to −6.4) in 24-hour systolic BP and a change of −3.9 mmHg (95% CI: −6.3 to −1.5) in 24-hour diastolic BP [37]. Improvement in hypervolemia was the predominant mechanism that mediated the BP-lowering action of chlorothalidone. The treatment-induced reduction in ambulatory BP was accompanied by a parallel decrease in body weight, body volume, and N-terminal pro-brain natriuretic peptide levels. Furthermore, chlorothalidone lowered by 50% (95% CI: 37% to 60%) the urinary albumin-to-creatinine ratio as compared with placebo, preliminary evidence that this agent may offer cardiorenal protection [37].

The impressive benefits of chlorothalidone on ambulatory BP and albuminuria in CLICK challenge the current “dogma” that thiazide-like diuretics are generally ineffective and should not be used when the levels of eGFR are <30 ml/min/1.73m². However, treatment with chlorothalidone in patients with advanced CKD should be sensible and with careful monitoring of the patients for the prevention of side effects [38]. Over the course of CLICK trial [37], hypokalaemia, hyperglycemia, hyperuricemia, dizziness and reversible increases in serum creatinine levels were adverse events that occurred more commonly with chlorothalidone than with placebo. Incidence of these adverse events may be even higher in daily clinical practice, if treatment with chlorothalidone is more aggressive (i.e. with higher doses than those used in CLICK) [38]. Notably, treatment with a higher dose of chlorothalidone may aggravate the risk for adverse events without any clinically meaningful benefit on BP control. In CLICK [37], most of the BP-lowering action of chlorothalidone was exerted over the first 4 weeks of therapy, when the study drug was administered at the initial dose of 12.5 mg/day. Furthermore, the risk for adverse effects, particularly the risk for a reversible increase in serum creatinine, appeared to be higher in the subgroup of patients who were concomitantly receiving therapy with a loop diuretic [38]. In such patients, a lower dose of chlorothalidone (i.e. 12.5 mg three times per week) may be similarly effective but safer than the stating dose of 12.5 mg/day that was used in CLICK [37].

CONCLUSION

In conclusion, enablement of more persistent use of spironolactone with the administration of newer agents that bind potassium in the gut, the clinical development of non-steroidal MRAs with sustained BP-lowering action and a more favorable side-effect profile as well as the recently proven BP-lowering efficacy of the thiazide-like diuretic chlorothalidone are 3 novel therapeutic opportunities for more effective management of hypertension in advanced CKD. Larger phase 3 clinical trials are clearly warranted to fully elucidate whether these therapeutic strategies can also improve kidney failure and cardiovascular outcomes in this high-risk patient population.

KEY POINTS.

• The prevalence of resistant hypertension in advanced CKD is 2–3 higher than in the general population, but the use of spironolactone is rescricted by the risk of hyperkalemia.

• Newer potassium-binding therapies can mitigate the risk of hyperkalemia to enable the more persistent use of spironolactone for the treatment of resistant hypertension in advanced CKD.

• Esaxerenone is a non-steroidal MRA that is approved for the treatment of essential hypertension in Japan and a phase 3 trial sugested a possible renoprotective effect of esaxerenone in patients with type 2 diabetes, high albuminuria and mild-to-moderate kidney dysfunction.

• KBP-5074 is an investigational non-steroidal MRA with prolonged duration of action and a recent phase 2b trial showed that among patients with advanced CKD and uncontrolled hypertension, this agent is effective in improving BP control with minimal risk of hyperkalemia.

• A recent phase 2 trial demonstrated that among patients with stage 4 CKD and poorly controlled hypertension, chlorothalidone provoked a placebo-subtracted reduction of 10.5 mmHg in 24-hour ambulatory systolic BP, evidence that oppose the currently established “status quo” that thiazide-like diuretics are generally ineffective when eGFR is reduced to levels <30 ml/min/1.73m².