Nephrol Dial Transplant, 2023, 38, 2694–2703

https://doi.org/10.1093/ndt/gfad118
Advance access publication date: 24 June 2023

Hypertension in chronic kidney disease—treatment

TREATMENT STANDARD

standard 2023
Panagiotis I. Georgianos1 and Rajiv Agarwal 2

1
2nd Department of Nephrology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
2
Division of Nephrology, Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center,
Indianapolis, IN, USA
Correspondence to: Rajiv Agarwal; E-mail: ragarwal@iu.edu

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ABSTRACT
Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood
pressure (BP) measurement is the essential first step in the diagnosis and management of hypertension. Dietary sodium restriction is
often overlooked, but can improve BP control, especially among patients treated with an agent to block the renin–angiotensin system.
In the presence of very high albuminuria, international guidelines consistently and strongly recommend the use of an angiotensin-
converting enzyme inhibitor or an angiotensin receptor blocker as the antihypertensive agent of first choice. Long-acting dihydropy-
ridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options. For patients with treatment-
resistant hypertension, guidelines recommend the addition of spironolactone to the baseline antihypertensive regimen. However, the
associated risk of hyperkalemia restricts the broad utilization of spironolactone in patients with moderate-to-advanced CKD. Evidence
from the CLICK (Chlorthalidone in Chronic Kidney Disease) trial indicates that the thiazide-like diuretic chlorthalidone is effective
and serves as an alternative therapeutic opportunity for patients with stage 4 CKD and uncontrolled hypertension, including those
with treatment-resistant hypertension. Chlorthalidone can also mitigate the risk of hyperkalemia to enable the concomitant use of
spironolactone, but this combination requires careful monitoring of BP and kidney function for the prevention of adverse events.
Emerging agents, such as the non-steroidal mineralocorticoid receptor antagonist ocedurenone, dual endothelin receptor antagonist
aprocitentan and the aldosterone synthase inhibitor baxdrostat offer novel targets and strategies to control BP better. Larger and
longer term clinical trials are needed to demonstrate the safety and efficacy of these novel therapies in the future. In this article, we
review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and
management of hypertension in patients with CKD.

Keywords: chlorthalidone, chronic kidney disease, hypertension, RAS blockade, spironolactone

INTRODUCTION The first critical step is the accurate measurement of office BP

(Box 2). Most data that guide our therapeutic decisions are derived
Hypertension and chronic kidney disease (CKD) commonly coex-
from clinical trials that incorporated a standardized BP measure-
ist and the interrelation between these two pathophysiological
ment methodology in the office. As an example, SPRINT (Systolic
states is bidirectional [1, 2]. Persistently high blood pressure (BP)
Blood Pressure Intervention Trial) was a landmark trial demon-
can accelerate the progression of CKD and the progressive decline
strating that among non-diabetic adults at high cardiovascular
in the estimated glomerular filtration rate (eGFR) can conversely
risk, as compared with <140 mmHg, targeting a systolic BP (SBP)
interfere with the achievement of adequate BP control [2]. The
<120 mmHg lowered by 25% the relative risk of cardiovascular
coexistence of uncontrolled hypertension and CKD substantially
morbidity and mortality [9]. The protocol of SPRINT specified a
magnifies the risk of cardiovascular disease, which is the most im-
5-min seated rest period followed by three automated office BP
portant cause of morbidity and mortality in patients with CKD [3].
(AOBP) recordings taken without the presence of an observer in a
Although clinical trials have failed to demonstrate that intensive
quiet room [9]. A diagnostic test study explored the relation of this
BP lowering results in a lower rate of kidney function decline [4–
research-grade technique to routine office BP in 275 patients with
6], interventions to lower BP are generally believed to be effective
CKD [10]. Compared with routine measurement, research-grade
in attenuating the risk of adverse cardiovascular outcomes and
office SBP was 12.7 mmHg lower [10]. However, this comparison
all-cause mortality in the CKD population [7–9].
provides only an estimate of the mean difference between these
In this article, we review the current standards of treatment
two techniques at a population level. The 95% limits of agreement
and discuss novel developments in the pathophysiology, diagno-
were wide, indicating that individual patients may have differ-
sis, outcome prediction and management of hypertension in CKD
ences from routine office SBP ranging from 46.1 mmHg lower up
(Box 1).
to 20.7 mmHg higher [10]. Therefore, there is no single correction
factor to convert a routine BP value into a research-grade BP value
TREATMENT STANDARDS [11]. To implement intensive BP-lowering in daily clinical practice,
An overview of currently available guidelines for the assessment the minimum requirement is the adoption of the research-grade
and management of hypertension in CKD is depicted in Fig. 1. BP measurement methodology in our daily practices.

Received: April 20, 2023; Editorial decision: June 5, 2023

Published by Oxford University Press on behalf of the ERA 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.
 P. I. Georgianos and R. Agarwal | 2695

• In patients who are concomitantly treated with a loop

Box 1. “In a nutshell.” diuretic, chlorthalidone can be administered at a lower
starting dose (i.e. 12.5 mg every other day) in the hope of
• Research grade BP measurement is no longer for re- improving BP control with fewer adverse events.
search alone but for everyday practice. • β-blockers are not recommended by guidelines as first-
• Dietary Na restriction can improve BP in individuals and line therapies, but this drug category is useful for the
provide low-cost public health benefits. treatment of hypertension is CKD patients with specific
• ACEIs or ARBs remain the first-line choice in pharma- indications (i.e. heart failure with reduced ejection frac-
cotherapy of hypertension in patients with CKD and very tion or after an acute myocardial infarction).
high albuminuria.
• Spironolactone is the standard-of-care treatment of re-
sistant hypertension, but the associated risk of hyper- The diagnosis of hypertension can be improved with the use
kalemia limits its broad utilization in patients with of ambulatory BP monitoring (ABPM), considered as the refer-
moderate-to-advanced CKD. ence standard [12]. ABPM is typically performed over 24 h and
• The thiazide-like diuretic chlorthalidone is effective BP is recorded every 15–20 min during daytime and every 30 min

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in improving BP control in patients with an eGFR during nighttime [13]. Therefore, a unique advantage of ABPM is
<30 mL/min/1.73 m2 and serves as an alternative thera- that this technique enables the diagnosis of nocturnal hyperten-
peutic option for managing resistant hypertension in ad- sion and abnormal diurnal variation of BP (i.e. non-dipping and
vanced CKD. reverse-dipping BP pattern). These abnormalities in 24-h BP pro-
• Discontinuation of ACEIs or ARBs in patients with ad- files are frequently diagnosed in patients with CKD and are asso-
vanced and progressive CKD nearing the initiation of ciated with faster progression of kidney injury and increased risk
dialysis does not result in stabilization of the long-term of cardiovascular morbidity and mortality [12]. Home BP monitor-
decline in kidney function. ing (HBPM) is another method to assess BP outside of the office.
• Newer BP-lowering medications, such as the non- In this technique, patients are trained to obtain standardized BP
steroidal MRA ocedurenone, the aldosterone synthase measurements at home (two recordings in the morning and two
inhibitor baxdrostat and the dual endothelin receptor recordings at bedtime) for at least 3 days, and preferably 7 days,
antagonist aprocitentan, are currently under investiga- using validated automated BP monitors [14]. In a similar fashion
tion in clinical trials, offering hope for improved BP con- to ABPM, cohort studies showed that 1-week averaged home BP
trol with fewer adverse events and better treatment tol- is of superior predictive value as compared with office BP in pa-
erability in the near future. tients with CKD [15, 16]. However, home BP recording is less re-
producible than ABPM and in people with CKD, does not aid in
making a diagnosis of masked uncontrolled hypertension (MUCH)
[17]. Nevertheless, an advantage of HBPM is also the fact that this
technique is more broadly available and can be repeatedly used
Box 2. Strategies for the individualization of to monitor the BP-lowering response to antihypertensive therapy
antihypertensive treatment. over long-term periods of follow-up [14] and therefore surmount
therapeutic inertia [18].
• The initiation and intensification of antihypertensive The 2021 Kidney Disease: Improving Global Outcomes (KDIGO)
therapy should be guided at least by BP measurements guidelines recommend that dietary sodium intake should be re-
taken under standardized conditions, as recommended stricted to levels <90 mmol of sodium per day as an effective non-
by guidelines. pharmacological intervention for the treatment of hypertension
• Dietary Na restriction is an important component of in people with CKD [19]. Support for this guidance was provided by
management of hypertension, especially among patients an updated Cochrane meta-analysis showing that among patients
with CKD. with CKD, a mean reduction of 73.51 mmol/day in dietary sodium
• Choice of the appropriate antihypertensive agent should intake is associated with an average reduction of 6.91/3.91 mmHg
take into consideration the presence and severity of al- in office BP and with a 36% reduction in albuminuria [20]. Post hoc
buminuria. In CKD patients with very high albumin- analyses of clinical trials showed that dietary sodium restriction
uria, in the absence of contraindications, ACEIs or ARBs enhances the albuminuria-lowering action of renin–angiotensin
are recommended as the antihypertensive agents of first system (RAS) blockers in patients with albuminuric CKD [21].
choice. Larger and longer-term clinical trials are warranted to elucidate
• For patients with moderate-to-advanced CKD and resis- whether these benefits on intermediate endpoints are translated
tant hypertension who cannot tolerate add-on therapy into a long-term improvement in “hard” cardiorenal outcomes.
with spironolactone, the administration of a potassium- With respect to the dietary potassium intake, a recent open-label,
binding polymer can mitigate the risk of hyperkalemia cluster-randomized trial involving 20 995 people who had a his-
to enable the more persistent use of spironolactone. tory of prior stroke or were 60 years of age or older and had a
Whether this strategy results in greater regression of history of hypertension showed that as compared with regular
hypertension-related target-organ damage or in im- salt consumption (100% NaCl), the use of a potassium-containing
proved cardiorenal outcomes is currently unknown. salt substitute (75% NaCl and 25% KCl) lowered by 14% the risk of
• The thiazide-like diuretic chlorthalidone is an alterna- stroke, by 13% the risk of major adverse cardiovascular events and
tive choice for managing resistant hypertension in pa- by 13% the risk of all-cause mortality [22]. However, these results
tients with advanced CKD, but its use requires careful from trials conducted in the general population may not be gen-
monitoring of BP, serum electrolytes and kidney function eralizable to patients with CKD. An earlier systematic review of
for the prevention of adverse events. 11 observational studies incorporating data from 49 573 patients
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Figure 1: Summary of recent guideline recommendations for the assessment and management of hypertension in patients with CKD. *The use of
spironolactone as fourth-line therapy is discouraged in patients with eGFR <45 mL/min/1.73 m2 or with a serum potassium concentration of
>4.5 mmol/L. AHA/ACC: American Heart Association/American College of Cardiology; ESC: European Sociaty of Cardiology; ESH: European Society of
Hypertension; ISH: International Society of Hypertension.

with CKD revealed that the use of diets rich in potassium is not as- minuria is less persuasive and the preferential initiation of an
sociated with a lower rate of kidney function decline [23]. In con- ACEI or an ARB as first-line therapy in this setting is not strongly
trast, short-term clinical trials showed that among patients with recommended by guidelines [19]. Furthermore, the combination
moderate-to-advanced CKD, dietary potassium supplementation of an ACEI with an ARB is contraindicated. In Veterans Affairs
raises the risk of hyperkalemia [24]. Nephropathy in Diabetes, as compared with monotherapy, the in-
When BP remains uncontrolled, the administration of antihy- creased risk of hyperkalemia and acute kidney injury with the
pertensive therapy is the next step in the management of hy- combination of an ACEI and an ARB led to the premature termina-
pertension. Information with respect to doses, precautions and tion of the trial [29]. The Aliskiren Trial in Type 2 Diabetes Using
side effects of most commonly prescribed antihypertensive med- Cardiorenal Endpoints trial also was stopped early, because the
ications is provided in Table 1. For patients with high BP, CKD addition of the direct renin inhibitor aliskiren to standard treat-
and very high albuminuria, the 2021 KDIGO guidelines provide a ment with a RAS blocker increased the risk of hyperkalemia and
strong (Level 1B) recommendation that an angiotensin-converting hypotension [30].
enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) Most patients with CKD require multiple medications to
should be the antihypertensive agent of first choice [19]. The use achieve adequate BP control. Accordingly, second-line therapy
of RAS blockade as first-line therapy in albuminuric CKD is consis- can include either a long-acting dihydropyridine calcium channel
tently supported by all major hypertension guidelines on the basis blocker (CCB) or a diuretic [25, 26], with the latter being a more
of robust clinical trial evidence [25, 26]. The RENAAL (Reduction of appropriate option for patients with clinical signs or symptoms
Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) of volume excess. Third-line therapy in the algorithm completes
trial showed that among 1513 patients with type 2 diabetes (T2D) the combination of a RAS blocker, a dihydropyridine CCB and a
and albuminuric CKD, losartan improved by 16% the composite diuretic [25, 26]. The use of single-pill combinations is preferable;
outcome of doubling of serum creatinine, end-stage kidney dis- reducing pill burden simplifies treatment and associates with an
ease (ESKD) or death relative to placebo [27]. In the Irbesartan Di- improvement in treatment adherence and better BP control rates
abetic Nephropathy Trial [28], irbesartan was superior to placebo [31]. With respect to diuretic therapy, higher doses are typically
or active treatment with amlodipine in retarding the progression necessary to achieve a therapeutic effect in patients with CKD. Of
of kidney injury to ESKD in 1715 patients with albuminuric CKD the loop diuretics, torsemide may be preferable over furosemide,
associated with T2D. The AASK (African American Study of Kidney because it can be dosed once daily and its BP effect in people with
Disease and Hypertension) trial showed that among 1094 African- CKD is similar to twice-daily furosemide [32, 33]. In addition, most
Americans with hypertensive nephrosclerosis, ramipril provoked of guidelines released over the past years recommend the use of
relative risk reductions of 22% and 38% in the composite outcome a loop diuretic when the eGFR is <30 mL/min/1.73 m2 [25, 26],
of ≥50% decline in GFR from baseline, ESKD or death as compared because thiazide or thiazide-like diuretics were generally consid-
with metoprolol and amlodipine, respectively [6]. In contrast, the ered as ineffective in patients with advanced CKD. This estab-
evidence basis for a kidney protective effect of RAS blockade in lished therapeutic approach has been recently challenged by the
non-diabetic patients with CKD and moderately increased albu- results of the CLICK (Chlorthalidone in Chronic Kidney Disease)
Table 1: Commonly prescribed antihypertensive drugs, usual drug doses, precautions and side effects.

Drug class and druga Usual dose Common side effects Potential contraindications Additional considerations

ACEIs
Lisinopril 10–40 mg/day Cough; angioedema; hyperkalemia; Hyperkalemia; pregnancy; First-line antihypertensive agents
Perindopril 2–8 mg/day leucopenia; anemia bilateral renal artery in patients with severely
Ramipril 5–10 mg/day stenosis increased albuminuria
Trandolapril 0.5–4 mg/day
ARBs
Candesartan 8–32 mg/day Cough (less commonly than with Hyperkalemia; pregnancy; First-line antihypertensive agents
Irbesartan 75–300 mg/day ACEIs); angioedema; bilateral renal artery in patients with severely
Losartan 50–100 mg/day hyperkalemia; anemia stenosis increased albuminuria
Olmesartan 10–40 mg/day
Telmisartan 40–80 mg/day
Valsartan 80–320 mg/day
Dihydropyridine CCBs
Amlodipine 5–10 mg/day Lower-extremity edema; gingival; Worsening of albuminuria
Felodipine 5–10 mg/day hypertrophy
Manidipine 10–20 mg/day
Non-dihydropyridine CCBs
Verapamil 180–360 mg/day Constipation; gingival hyperplasia 2nd or 3rd degree heart Reduction in albuminuria; increase
Diltiazem 180–360 mg/day block the levels of calcineurin and
mTOR inhibitors; drug
interactions (i.e. β-blockers,
statins)
Thiazide or thiazide-like diuretics
Hydrochlorothiazide 12.5–25 mg/day Hyperuricemia; hypercalcemia; Hyponatremia; The thiazide-like diuretic
Chlorthalidone 12.5 mg/day hyponatremia; hypokalemia; hypokalemia; chlorthalidone is effective in
Metonazole 2.5 mg/day hyperglycemia hypercalcemia; volume lowering BP in patients with
depletion stage 4 CKD and poorly
controlled hypertension
Loop diuretics
Furosemide 40–80 mg/day Hearing loss; hypokalemia; Volume depletion Torsemide has better bioavailability
Torsemide 20 mg/day hypocalcemia; hyponatremia and longer elimination half-life
as compared with furosemide
Steroidal MRAs
Spironolactone 25–50 mg/day Hyperkalemia; metabolic acidosis; Hyperkalemia Spironolactone is useful in
Eplerenone 50–100 mg/day gynecomastia resistant hypertension as
fourth-line therapy
β-adrenergic receptor blockers
Atenolol 25–100 mg/day Bradycardia; hyperkalemia; fatigue; Bradycardia; asthma; β-blockers are recommended for
Bisoprolol 2.5–10 mg/day depression; sexual dysfunction chronic obstructive the management of
Carvedilol 12.5–25 mg twice daily pulmonary disease; 2nd hypertension in patients with
Metoprolol 50–100 mg twice daily or 3rd degree heart block specific cardiovascular
Nebivolol 2.5–10 mg/day indication for their use
P. I. Georgianos and R. Agarwal

a
This is a list of selected medications from each antihypertensive drug category; the use of antihypertensive agents may differ from country to country.
mTOR: mammalian target of rapamycin.
| 2697

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2698 | Nephrol Dial Transplant, 2023, Vol. 38, No. 12

trial [34]. In CLICK, 160 patients with stage 4 CKD and uncontrolled chlorthalidone is also associated with adverse events and requires
hypertension were randomized to receive the thiazide-like di- careful monitoring of BP, serum electrolytes and kidney function
uretic chlorthalidone (at a starting dose of 12.5 mg/day) or placebo [45].
for 12 weeks. Relative to placebo, chlorthalidone provoked a re- β-blockers are not recommended by guidelines for use as
duction of 10.5 mmHg in 24-h ambulatory SBP [34]. This potent BP- monotherapy or as first-line agents in pharmacotherapy of un-
lowering effect was paralleled with a placebo-subtracted reduc- complicated hypertension [25, 26]. However, this drug category is
tion of 50% in albuminuria, preliminary data supporting a poten- proven to be efficacious and should be considered for the treat-
tial cardiorenal protective action of chlorthalidone [34]. However, ment of hypertension in patients with specific cardiovascular in-
the use of this agent in advanced CKD requires careful monitor- dications for β-blocker use, such as in patients with heart failure
ing of the patients for the prevention of adverse events. In CLICK, with reduced ejection fraction, angina and atrial fibrillation, or af-
hypokalemia, reversible deterioration of kidney function, hyper- ter an acute myocardial infarction [46]. Furthermore, β-blockers
glycemia, orthostatic hypotension, dizziness and hyperuricemia may be useful for the treatment of resistant hypertension, when
occurred more commonly with chlorthalidone than with placebo, spironolactone is either contraindicated or not tolerated [26]. In
particularly in the subgroup of patients receiving concomitant the aforementioned PATHWAY-2 trial [37], bisoprolol was not as
treatment with a loop diuretic [34]. In such patients, we recom- effective as spironolactone, but it was superior to placebo in re-

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mend starting chlorthalidone at a lower dose (i.e. 12.5 mg every ducing home BP when added to the background antihypertensive
other day) in the hope of lowering the risk of adverse events [35]. regimen.
Patients whose BP remains uncontrolled despite adherence to
maximally tolerated doses of a RAS blocker, a CCB and a diuretic
fulfill the diagnostic criteria of resistant hypertension [36]. In such NEW DEVELOPMENTS
patients, the spironolactone versus placebo, bisoprolol, and dox- Pathogenesis
azosin to determine the optimal treatment for drug-resistant hy-
Population-based studies show that the prevalence of hyperten-
pertension (PATHWAY-2) trial demonstrated that the addition of
sion increases in parallel with worsening stage of CKD [39, 47].
spironolactone to the baseline antihypertensive regimen is supe-
These epidemiological data generate the impression that the
rior to placebo as well as superior to doxazosin or bisoprolol in
severity of hypertension travels with the progressive eGFR decline.
reducing home SBP over 12 weeks [37]. However, PATHWAY-2 ex-
However, accumulated evidence suggests that albuminuria plays
cluded patients with eGFR <45 mL/min/1.73 m2 [37]. Based largely
an even more important role. As examples, a cross-sectional study
on these clinical trial data, spironolactone is recommended by
explored the association of 17 risk factors for hypertension with
guidelines as the fourth-line agent for the treatment of resistant
the levels of SBP in 232 US Veterans with CKD. In multivariate
hypertension, but the use of spironolactone is discouraged in pa-
models, it was the urinary protein-to-creatinine ratio the factor
tients with an eGFR <45 mL/min/1.73 m2 and a serum potassium
that was more strongly associated with SBP regardless of the tech-
concentration of >4.5 mmol/L [26].
nique of BP measurement [48]. As compared with standardized or
Despite the fact that the prevalence of resistant hypertension
routine office recordings, the association between proteinuria and
is 2- to 3-fold higher in patients with moderate-to-advanced CKD
SBP was stronger when hypertension was assessed using ABPM
than in the general population [38–40], the available therapeu-
or HBPM. In sharp contrast, eGFR was not an independent deter-
tic options for this particular subgroup of high-risk patients are
minant of SBP by any technique [48]. A subsequent analysis of
few. A 2020 Cochrane meta-analysis showed that among patients
336 US Veterans with or without CKD who underwent 24-h ABPM
with albuminuric CKD, the use of spironolactone in combination
showed that as compared with the stage of CKD, proteinuria was
with an ACEI or an ARB (or both) is associated with a 2.17-fold
a stronger determinant of a disrupted circadian BP rhythm [49].
higher incidence of hyperkalemia and a 5.14-fold higher risk of
Compared with eGFR decrements, even small increments in the
gynecomastia [41]. Since hyperkalemia acts as a barrier and lim-
levels of proteinuria had a more dramatic impact on the mean
its the broad utilization of spironolactone [42, 43], the AMBER
levels of ambulatory BP [49]. The mechanisms through which pro-
(Spironolactone With Patiromer in the Treatment of Resistant Hy-
teinuria and hypertension are closely interrelated remain unclear.
pertension in Chronic Kidney Disease) trial randomized 295 pa-
Proteinuria may simply reflect the presence of more severe kidney
tients with eGFR ranging from 25 to ≤45 mL/min/1.73 m2 and
damage or reflect worse endothelial dysfunction [50].
uncontrolled resistant hypertension to receive spironolactone in
addition to double-blind treatment either with the potassium-
binding polymer patiromer or with placebo [44]. Patiromer en- Diagnosis
abled more patients to maintain on spironolactone treatment as MUCH is diagnosed in patients who are being treated for hy-
compared with placebo. However, even with the simultaneous ad- pertension, when they have a normal office BP but high out-of-
ministration of a potassium-binding polymer, approximately one- office BP [26, 37]. The phenotype of MUCH is identified more com-
third of patients who received spironolactone developed hyper- monly in patients with CKD than in the general population [51].
kalemia over 12 weeks of follow-up [44]. Among 333 US veterans with CKD and a normal office BP, the
Taking into consideration the associated risk of hyperkalemia prevalence of MUCH depended on how hypertension was defined.
and the general underutilization of spironolactone, an alternative MUCH was prevalent in 27% of the patients when daytime am-
therapeutic option for the management of resistant hypertension bulatory BP ≥135/85 mmHg was used to diagnose hypertension.
in advanced CKD could be the administration of chlorthalidone. It was 33% when hypertension was defined as a 24-h ambula-
A subgroup analysis of the CLICK trial incorporating data from tory BP ≥130/80 mmHg and increased to 56% when either day-
113 patients with resistant hypertension at baseline showed that time ambulatory BP ≥135/85 mmHg or nighttime ambulatory BP
as compared with placebo, chlorthalidone provoked a reduction ≥120/70 mmHg was used [17]. The prevalence of MUCH is progres-
of 13.9 mmHg in 24-h ambulatory SBP at Week 12 [45]. Unlike sively increased with increasing levels of office BP. Patients with
spironolactone, the risk of hyperkalemia with chlorthalidone is repeatedly low BP in the office are unlikely to have MUCH. In con-
practically nonexistent. However, as mentioned above, the use of trast, the suspicion of MUCH should be raised when office BP is
 P. I. Georgianos and R. Agarwal | 2699

within the prehypertensive range. Among patients with office SBP pared with placebo, in the BrigHTN trial, a 1-mg dose lowered sys-
of 130–139 mmHg, MUCH is diagnosed in two in three, and among tolic AOBP 8.1 mmHg [95% confidence interval (CI) 2.8–13.5], and
patients with office SBP of 120–129 mmHg MUCH is prevalent in a 2-mg dose lowered systolic AOBP 11 mmHg (95% CI 5.5–16.4).
one in three [17]. The accuracy of HBPM in diagnosing MUCH is not Treatment-induced elevations in serum potassium levels were
superior to the diagnostic accuracy of standardized office BP [17]. observed in only two patients, but hyperkalemia did not recur
ABPM is therefore necessary for the confirmation of the diagnosis after transient withdrawal and re-initiation of active-treatment
of MUCH. [54]. However, this trial excluded patients with CKD stage 3b
or higher—eGFR was about 85 mL/min/1.73 m2 at baseline—
New antihypertensives and comparison of therefore, safety is difficult to establish in this 12-week study.
existing antihypertensives Published in 2022, a dual endothelin antagonist, aprociten-
There has been a resurgence in interest to lower BP in people with- tan, was tested in the parallel-group, phase 3 study with aproci-
out and with CKD. Additional agents are currently under clinical tentan in subjects with resistant hypertension (PRECISION) trial
investigation, offering promise for more effective management of over 4 weeks in patients with resistant hypertension at doses of
resistant hypertension through blocking unique targets or more 12.5 mg and 25 mg [55]. Of the 730 patients enrolled in this trial,
only 162 (22.2%) patients had an eGFR <60 mL/min/1.73 m2 at

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safely blocking existing pathways in the future [52] (Box 3).
baseline. PRECISION followed a unique trial design that included:
(i) a 4-week, double-blind, placebo-controlled, treatment phase;
Box 3. Key developments and future opportunities in (ii) a 32-week, single-blind, active-treatment phase; and (iii) a
pharmacotherapy of hypertension. 12-week, double-blind, placebo-controlled withdrawal phase. The
primary endpoint was the change in systolic AOBP from base-
• Among patients with stage 3b/4 CKD and uncontrolled line to 4 weeks. Compared with placebo, a 12.5-mg dose lowered
hypertension, the non-steroidal MRA ocedurenone low- systolic AOBP 3.8 mmHg (95% CI 0.8–6.8), and a 25-mg dose low-
ered systolic AOBP at Day 84 with a minimal associated ered systolic AOBP 3.7 mmHg (95% CI 0.8–6.7) [55]. For the 12.5-
risk of hyperkalemia. mg dose, 24-h ambulatory SBP was lowered by 4.2 (95% CI 2.1–
• Among patients with resistant hypertension, as com- 6.2 mmHg) and for the 25-mg dose by 5.9 (95% CI 3.8–7.9 mmHg)
pared with placebo, the aldosterone synthase inhibitor [55]. This BP-lowering action was maintained until the completion
baxdrostat lowered unattended automated office SBP in of the single-blind, active-treatment phase of the trial at Week
a dose-dependent manner over 12 weeks of treatment. 40. Notably, subgroup analyses showed numerically greater re-
No deaths, serious adverse events and signs of adreno- ductions in standardized office SBP in patients who had very high
cortical insufficiency were observed over the course of albuminuria or stage 3–4 CKD [55]. The most frequently reported
the trial. adverse event was the development of mild-to-moderate edema
• In patients with resistant hypertension, the dual en- with aprocitentan, and seven patients stopped treatment with
dothelin receptor antagonist aprocitentan was superior aprocitentan [55]. Given the risk of heart failure with endothelin
to placebo in reducing systolic AOBP at Week 4 and receptor antagonists [56, 57], longer-term studies are needed to
this BP-lowering action was sustained at Week 40. Mild- confirm safety, especially with respect to heart failure in people
to-moderate edema was the most frequent treatment- with CKD.
related adverse event. Sodium-glucose co-transporter type 2 (SGLT-2) inhibitors have
• SGLT-2 inhibitors and the non-steroidal MRA finerenone been initially introduced as hypoglycemic drugs, but it was there-
are novel therapies that improve kidney and cardiovas- after discovered that cardiorenal protection is the main thera-
cular outcomes in patients with albuminuric CKD. Indi- peutic effect of these agents. A triad of landmark phase 3 clini-
rect comparisons show that finerenone provokes a more cal trials (canagliflozin and renal events in diabetes with estab-
potent reduction in ambulatory BP as compared with lished nephropathy clinical evaluation, dapagliflozin and preven-
SGLT-2 inhibitors, implying that BP lowering might play a tion of adverse outcomes in chronic kidney disease and the study
differential role in mediating the cardiorenal protection of heart and kidney protection with empagliflozin) demonstrated
afforded by these two drug categories. that SGLT-2 inhibitors safely and effectively attenuate the pro-
gression of CKD and improve cardiovascular outcomes in patients
with albuminuric CKD, irrespective of the presence or absence of
Published in 2021, a non-steroidal mineralocorticoid receptor T2D [58–60]. Finerenone, a highly selective non-steroidal MRA, is
antagonist (MRA), ocedurenone (formerly known as KBP-5074), also proven to be effective in improving cardiorenal outcomes in
was tested over 12 weeks in 162 patients with stage 3b/4 CKD patients with diabetic kidney disease [61]. In the finerenone in
with uncontrolled hypertension in doses of 0.25 mg and 0.5 mg chronic kidney disease and type 2 diabetes: combined FIDELIO-
[53]. The primary endpoint in the phase 2b study of KBP-5074 in DKD and FIGARO-DKD trial programme analysis pooled analysis
subjects with uncontrolled hypertension and advanced chronic of data from 13 026 patients with T2D and a broad spectrum of
kidney disease trial was the change in systolic AOBP from base- CKD, as compared with placebo, finerenone retarded the progres-
line to Week 12. Compared with placebo, a 0.25-mg dose lowered sion of diabetic kidney disease and reduced the risk of hospitaliza-
systolic AOBP 7 mmHg [standard error (SE) 3.37, P = .04]. A 0.5-mg tion for heart failure, cardiovascular death and myocardial infarc-
dose lowered systolic AOBP 10.2 mmHg (SE 3.32, P = .003). The tion [62]. Although treatment with finerenone was well tolerated,
incidence of mild hyperkalemia (serum potassium concentration the risk of hyperkalemia was more common with finerenone than
≥5.6 to <6.0 mmol/L) was low and comparable among groups, with placebo [62]. Post hoc analyses indicate that the combined
but the trial is too short to establish safety [53]. therapy with a SGLT-2 inhibitor and finerenone may be superior
In 2022, an aldosterone synthase inhibitor, baxdrostat, was to either monotherapy by reducing the risk of hyperkalemia [63]
tested over 12 weeks in 248 patients with resistant hypertension in patients who are already receiving standard-of-care treatment
in doses of 0.5, 1 and 2 mg [54]. BP averaged 148/88 mmHg. Com- with a RAS blocker [64, 65].
2700 | Nephrol Dial Transplant, 2023, Vol. 38, No. 12

Although neither SGLT-2 inhibitors nor finerenone are in- [77]. Similarly, a recent nationwide observational study showed
dicated for their antihypertensive effects, the magnitude and that among patients with advanced CKD, stopping RAS inhibitors
presence of these BP-lowering effects should be noted. In a is associated with a lower absolute risk of initiating dialysis, but
meta-analysis of seven trials involving 2381 patients with T2D, higher absolute risks of adverse cardiovascular events and all-
SGLT-2 inhibitor therapy for 4–12 weeks provoked a placebo- cause mortality [78]. A more conclusive answer to this crucial
subtracted reduction of 3.61 mmHg in 24-h ambulatory SBP [66]. question was provided by the multicentre randomized controlled
This effect was similar that seen using ABPM with 12.5-25 mg trial of angiotensin-converting enzyme inhibitor/angiotensin re-
hydrochlorothiazide [66]. This modest BP-lowering effect of ceptor blocker withdrawal in advanced renal disease (STOP-ACEi)
SGLT-2 inhibitors contrasts with the reductions in ambulatory BP trial [79]. In this trial, 411 patients with advanced and progressive
seen with finerenone in a recent sub-analysis of the mineralocor- CKD were randomized either to stop or to continue RAS inhibitor
ticoid receptor antagonist tolerability study–diabetic nephropa- therapy. Over 3 years of follow-up, there was no difference in the
thy (ARTS-DN) trial. In ARTS-DN, 823 patients with T2D and rate of eGFR decline between the discontinuation and continu-
albuminuric CKD were randomized to placebo or finerenone, ation groups [80]. Although the proportion of patients who pro-
administered at doses of 1.25–20 mg once daily in the morning gressed to ESKD or initiated kidney replacement therapy did not
for 90 days [67]. A subset of 240 patients underwent 24-h ABPM significantly differ between the two groups, there was a trend to

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at screening, Day 60 and Day 90 [68]. Relative to placebo, the worse outcome in those who discontinued RAS inhibitors (hazard
reduction in 24-h ambulatory SBP at Day 90 was 8.3 mmHg with ratio 1.28; 95% CI 0.99–1.65). Therefore, although observational
finerenone 10 mg/day, 11.2 mmHg with finerenone 15 mg/day studies favor the intervention of stopping ACEIs or ARBs in ad-
and 9.9 mmHg with finerenone 20 mg/day [68]. This indirect vanced CKD, the STOP-ACEi trial showed that discontinuation of
comparison suggests that the BP-lowering properties of SGLT-2 RAS blockade does not lead to stabilization of the long-term de-
inhibitors and finerenone might substantially differ. Accordingly, cline in kidney function and does not delay the initiation of dial-
the significance of BP lowering as a mediator of the improvement ysis [80]. In fact, a trend toward earlier dialysis was noted.
in cardiorenal outcomes also may not be similar for these two
novel drug categories.

SUMMARY
Renal denervation
In summary, research-grade BP measurement methodology must
Although the interest for device-based treatment of hyperten-
move from research to clinics. The diagnosis of hypertension can
sion dampened after the neutral results of the renal denerva-
be also improved when BP is measured outside of the clinic either
tion in patients with uncontrolled hypertension trial in 2015 [69],
using HBPM or ABPM. Dietary Na restriction is often overlooked,
more recent studies support the antihypertensive efficacy, tolera-
but effective strategy to manage poorly controlled hypertension.
bility and safety of catheter-based renal denervation [70–72]. Pub-
ACEIs and ARBs remain the first-line agents in pharmacotherapy
lished in 2022, a prespecified analysis of the long-term efficacy
of hypertension in patients with CKD, particularly in those with
and safety of renal denervation in the presence of antihyperten-
very high albuminuria [19]. Patients with uncontrolled BP despite
sive drugs trial provided evidence in favor of a long-lasting BP-
adherence to triple therapy with maximally tolerated doses of a
lowering action of this intervention showing that as compared
RAS blocker, a dihydropyridine CCB and a diuretic have by defi-
with the sham control procedure, renal denervation provoked a
nition resistant hypertension [36]. In such patients, the addition
clinically meaningful reduction of 10/5.9 mmHg in 24-h ambu-
of spironolactone to the baseline antihypertensive regimen is the
latory BP at 36 months of follow-up [73]. This persistent reduc-
pharmacological intervention of choice [26]. Since hyperkalemia
tion in ambulatory BP was independent of concomitant use of
is a disadvantage of spironolactone that limits its broad utilization
antihypertensive medications and was not counteracted by in-
for the management of resistant hypertension in moderate-to-
creased risk of adverse events [73]. Since sympathetic activity
advanced CKD, the thiazide-like diuretic chlorthalidone serves
is markedly increased in patients with CKD, there is biologically
as an alternative therapeutic option in this subgroup of high-risk
plausibility that renal denervation may confer an even greater
patients [45]. Chlorthalidone can mitigate the risk of hy-
benefit in this particular patient population. Small uncontrolled
perkalemia, enabling in this way the co-administration of
interventional studies showed remarkable reductions in BP with
spironolactone. However, the combination of chlorthalidone and
renal denervation in patients with stage 3–4 CKD, whereas other
spironolactone requires careful monitoring of the patients for
observational studies suggested that renal denervation is also as-
the prevention of adverse events, such as the episodes of acute
sociated with regression of albuminuria and a slower rate of eGFR
kidney injury [35]. Newer BP-lowering medications [53–55], such
decline [72, 74, 75]. Properly designed, sham-controlled clinical tri-
as the non-steroidal MRA ocedurenone, the aldosterone synthase
als are needed to demonstrate the safety and efficacy of this inter-
inhibitor baxdrostat and the dual endothelin receptor antagonist
vention in moderate-to-advanced CKD, since patients with eGFR
aprocitentan, are at different stages of clinical development,
<45 mL/min/1.73 m2 were systematically excluded from the cur-
offering promise for more effective BP control in the future. Renal
rently available renal denervation trials.
denervation is also anticipated to receive approval by regulatory
agencies as an adjunct interventional strategy to medications for
Stopping or continuing RAS inhibitors in patients who select one-time procedures instead of intensified
advanced CKD antihypertensive drug therapy.
Whether RAS blockers should be continued or stopped in patients
with advanced CKD who are nearing the initiation of dialysis re-
mains an area of controversy [76]. In such patients, an earlier
DATA AVAILABILITY STATEMENT
observational study suggested that discontinuation of ACEIs or
ARBs is associated with better preservation of kidney function Not applicable.
 P. I. Georgianos and R. Agarwal | 2701

CONFLICT OF INTEREST STATEMENT Renal Insufficiency Cohort (CRIC) study. J Am Soc Nephrol
2020;31:2609–21. https://doi.org/10.1681/ASN.2020030236
R.A. reports personal fees and nonfinancial support from Bayer
13. Parati G, Stergiou G, O’Brien E et al. European Society of Hyper-
Healthcare Pharmaceuticals, Akebia Therapeutics, Boehringer In-
tension practice guidelines for ambulatory blood pressure moni-
gelheim, Eli Lilly, Relypsa, Vifor Pharma and Diamedica; is a mem-
toring. J Hypertens 2014;32:1359–66. https://doi.org/10.1097/HJH.
ber of data safety monitoring committees for Vertex and Chinook;
0000000000000221
has served as an associate editor of the American Journal of Nephrol-
14. Parati G, Stergiou GS, Bilo G et al. Home blood pressure monitor-
ogy and Nephrology Dialysis Transplantation, and has been an author
ing: methodology, clinical relevance and practical application:
for UpToDate; and has received research grants from the National
a 2021 position paper by the Working Group on Blood Pressure
Institutes of Health and the US Veterans Administration. P.I.G. has
Monitoring and Cardiovascular Variability of the European So-
nothing to disclose.
ciety of Hypertension. J Hypertens 2021;39:1742–67. https://doi.
org/10.1097/HJH.0000000000002922
FUNDING 15. Agarwal R, Andersen MJ. Blood pressure recordings within and
outside the clinic and cardiovascular events in chronic kidney
R.A. is supported by the National Heart Lung and Blood Institute disease. Am J Nephrol 2006;26:503–10. https://doi.org/10.1159/

Downloaded from https://academic.oup.com/ndt/article/38/12/2694/7207411 by guest on 03 December 2023

(grant R01 HL126903). 000097366
16. Agarwal R, Andersen MJ. Prognostic importance of clinic and
home blood pressure recordings in patients with chronic kidney
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Received: April 20, 2023; Editorial decision: June 5, 2023

Published by Oxford University Press on behalf of the ERA 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.