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CJASN ePress. Published on November 28, 2016 as doi: 10.2215/CJN.06180616 In-Depth Review

Recognition and Management of Resistant

Branko Braam, Sandra J. Taler, Mahboob Rahman, Jennifer A. Fillaus, Barbara A. Greco, John P. Forman, Efrain Reisin, Debbie L. Cohen, Mohammad G. Saklayen, and S. Susan Hedayati

Abstract Despite improvements in hypertension awareness and treatment, 30%–60% of hypertensive patients do not achieve BP targets and subsequently remain at risk for target organ damage. This therapeutic gap is particularly important to nephrologists, who frequently encounter treatment-resistant hypertension in patients with CKD. Due to the number of Data are limited on how best to treat patients with CKD and resistant hypertension, because patients with CKD contributing authors, have historically been excluded from hypertension treatment trials. First, we propose a consistent definition of the affiliations are resistant hypertension as BP levels confirmed by both in-office and out-of-office measurements that exceed provided in the appropriate targets while the patient is receiving treatment with at least three antihypertensive , Supplemental including a diuretic, at dosages optimized to provide maximum benefit in the absence of intolerable side effects. Material. Second, we recommend that each patient undergo a standardized, stepwise evaluation to assess adherence to Correspondence: dietary and lifestyle modifications and antihypertensive medications to identify and reduce barriers and discon- Dr. Branko Braam, tinue use of substances that may exacerbate hypertension. Patients in whom there is high clinical suspicion should University of Alberta Hospital, Department be evaluated for potential secondary causes of hypertension. Evidence-based management of resistant hyper- of Medicine, Division tension is discussed with special considerations of the differences in approach to patients with and without CKD, of and including the specific roles of diuretics and receptor antagonists and the current place of Immunology, 11-132 emerging therapies, such as renal denervation and baroreceptor stimulation. We endorse use of such a systematic CSB Clinical Sciences approach to improve recognition and care for this vulnerable patient group that is at high risk for future and Building, Edmonton, AB, Canada T6G 2G3. cardiovascular events. Email: branko.braam@ Clin J Am Soc Nephrol ▪: ccc–ccc, 2016. doi: 10.2215/CJN.06180616 ualberta.ca

Introduction contribution of instituting appropriate lifestyle prac- Global recognition of hypertension, the number of tices to achievement of BP control may be underesti- treated patients, and the proportion achieving recom- mated or considered too time consuming to address. mended BP targets have improved over the past Third, overdiagnosis of rHTN could lead to specialty several decades (1,2). Nevertheless, many patients do referral of a large proportion of patients who could not reach BP goals and are labeled as having resistant otherwise be cared for by primary providers and in- hypertension (rHTN) (3), which is particularly com- crease health care costs. This paper proposes a step- mon among patients with CKD (4). Importantly, pa- wise approach for the evaluation and identification of tients with uncontrolled hypertension are more likely rHTN on the basis of the available literature and to develop target organ damage, including progres- where direct evidence is lacking, observational data. sive CKD and ESRD. Such patients are likely to be Special considerations regarding the evaluation and referred to a nephrologist for care, and treatment to management of rHTN in the patient with concomi- achieve BP goals may be challenging. Early recogni- tant CKD are also reviewed. tion of rHTN using a standardized definition and adoption of a consistent approach to evaluation and Definitions of rHTN management may increase the chance of successful In 2008, the American Association issued a implementation of therapeutic approaches that com- scientific statement that defined rHTN as BP that bine medical treatment and lifestyle changes to pre- remained above goal despite the concurrent use of vent adverse outcomes. three antihypertensive agents of different classes. The Accurate recognition and effective management of statement suggested that, ideally, one of three agents rHTN are problematic, because available consensus should be a diuretic and that all agents be prescribed guidelines are inconsistent, even in their definitions of at optimal dosages. In addition, patients whose BP rHTN (3,5,6). First, varied definitions render it diffi- was controlled but required four or more medications cult to accurately estimate prevalence and associa- were also considered resistant to treatment (3). This tions with outcomes. Second, inappropriate labeling definition did not address other relevant factors, such may discourage providers from performing evalua- as ensuring accurate BP measurement, reinforcement tions to establish whether the patient’s hypertension of lifestyle modifications and antihypertensive medi- is truly resistant, searching for reversible causes, and cation adherence, adequate dosing and frequency, pursuing more effective combination therapies. The elimination of prescription and over the counter www.cjasn.org Vol ▪▪▪▪,2016 Copyright © 2016 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology

medications that may interfere with BP control, and exclu- definition for rHTN that includes important factors, such sion of secondary causes (Table 1). In addition, the impor- as diuretic prescription and appropriate dosing. Conse- tance of out-of-office BP measurement as a part of quently,thetrueprevalenceofrHTNmaybelowerthan hypertension evaluation has been increasingly recognized reported. A prevalence rate in the range of 2%–10% in the and deserves consideration (7). Assessment requirements general population and primary care settings is a reason- as listed in Table 1 are necessary add ons to the definition able estimate. The prevalence is substantially higher in to make a clear distinction between apparent rHTN, in patients with CKD, estimated to be 40% of hypertensive which all of these requirements are not necessarily fulfilled, participants in the Chronic Renal Insufficiency Cohort and true rHTN. In the latter case, a thorough and complete (CRIC) Study. Approximately 50% had BP that was not assessment is required. at target on three or more medications, and the other one half had BP that was at target on four or more medica- tions.Olderage,men,blackrace,diabetesmellitus,and Epidemiology and Outcomes of rHTN higher body mass index were independently associated Epidemiologic studies report a highly variable preva- with higher likelihood of having apparent treatment- – lence for rHTN that ranges between 2% and 40% (1,4,7 15) rHTN (17). Similar findings were reported in a smaller fi depending on how rHTN was de ned. Unfortunately, epi- study from The Netherlands (18). demiologic cohorts generally do not incorporate detailed Despite differences in definitions, a consistent body of information regarding dosing, treatment evidence supports the concept that rHTN is associated adherence, appropriate use of diuretics, and other clini- with an increased risk of adverse long–term cardiovas- cal factors that may affect BP. Hence, the term apparent cular and kidney outcomes (9,14,19). In the ALLHAT, fi treatment-rHTN is used de ned as BP not at goal (usually participants with apparent treatment-rHTN were at $ 140/90 mmHg) when the patient is prescribed three or higher risk for coronary heart disease (hazard ratio more classes of antihypertensive medication or at goal af- [HR], 1.44; 95% confidence interval [95% CI], 1.18 to ter prescription of four or more classes. The variability in 1.76), stroke (HR, 1.57; 95% CI, 1.18 to 2.08), all-cause prevalence may also be related to differences in the pop- mortality (HR, 1.30; 95% CI, 1.11 to 1.52), heart failure ulations studied, and it is higher in patients with CKD and (HR, 1.88; 95% CI, 1.52 to 2.34), peripheral disease – (7,8,10). In the 2005 2008 US Na- (HR, 1.23; 95% CI, 0.85 to 1.79), and ESRD (HR, 1.95; 95% tional Health and Nutrition Examination Survey, the prev- CI, 1.11 to 3.41) compared with those without rHTN (12). alence of apparent treatment-rHTN was estimated to be In the CRIC Study, participants with CKD and apparent 11.8% among individuals with hypertension (1), similar treatment-rHTN had a 38% higher risk of cardiovascular to what was reported from the Antihypertensive and events or all-cause mortality and a 28% higher risk of Lipid-Lowering Treatment to Prevent Heart Attack Trial ESRD or 50% decline in GFR (17). (ALLHAT), in which 12.7% of patients had apparent treatment-rHTN (12). However, a large retrospective review of 468,000 hypertensive patients reported a prevalence of Stepwise Evaluation and Approach to rHTN 32%, but only one half of the patients categorized as resis- A systematic approach to evaluating the patient with tant were prescribed optimal antihypertensive regimens suspected rHTN is illustrated in Figure 1. rHTN should be (16). Data from a large health maintenance organization in- viewed as a diagnosis of exclusion. First, the accuracy of dicated that only 2.2% of patients with uncontrolled BP were BP measurements using optimal technique needs to be es- taking diuretics and two or more classes of antihyperten- tablished (20). Common pitfalls include improper patient po- sive medications at maximal recommended doses, with sitioning, wrong cuff size, poor timing of measurements, and 39.5% classified as having uncontrolled hypertension (4). equipment-related error. Ambulatory BP monitoring (ABPM) These examples illustrate the importance of a consistent is an important component of the evaluation of a patient with

Table 1. Definitions and assessment requirements for resistant hypertension diagnosis

Definition of rHTN (adapted from ref. 3) BP confirmed by out-of-office measurements exceeding the patient’s individualized target while receiving treatment with at least three antihypertensive medications, including a diuretic, maximized to optimal doses in the absence of intolerable side effects Assessment requirements Confirm accuracy of BP by out-of-office measurements Assess adherence to a healthy lifestyle and diet and reduce barriers Confirm discontinuation of substances that can cause high BP Recognize and address hypervolemic state Address nonadherence, tolerability, and dosing (intervals and up titration) of antihypertensive medications Consider evaluation for secondary causes of hypertension if there is high clinical suspicion Definition of controlled rHTN BP controlled to the patient’s individualized target while receiving treatment with at least four antihypertensive medications, including a diuretic, maximized to optimal doses in the absence of intolerable side effects

rHTN, resistant hypertension. Modified from ref. 3, with permission. Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Resistant Hypertension, Braam et al. 3

rHTN to assess BP variability and diurnal and nocturnal pat- apparent rHTN were adherent to all prescribed medica- terns, and it can identify masked and white coat hyperten- tions, that 16% did not take any prescribed medications, sion. The US Preventive Services Task Force recommends and that 37% took ,25% (28). In another study of newly ABPM as the standard for confirmation of a hypertension referred, already treated, and thoroughly evaluated pa- diagnosis outside of the clinical setting (21). It is important tients with rHTN, 10% were completely nonadherent, to detect nondipping, defined as ,10% nocturnal drop in BP, and 52% were partially or completely nonadherent (29). in assessing overall BP control and for prognostic significance Nonadherence may be more common among hypertensive (22). Importantly, nondipping occurs in 49%–82% of hyper- patients with CKD than those with normal kidney func- tensive patients with CKD and is associated with progression tion (30,31). This is possibly related to the increased cost of CKD (23–25). When ABPM is not feasible, home BP mon- and complexity of medical regimens needed to treat CKD- itoring may be substituted and has been shown to correlate related conditions or may be a contributing cause for CKD. closely with daytime ABPM readings (26), although it will Other causes of nonadherence include socioeconomic bar- not provide information about nocturnal patterns. Finally, riers, medication side effects, motivation, and cognitive automated office measurements can reduce the white coat dysfunction (32). Unfortunately, questionnaires have lim- effect but will miss masked hypertension. Thus, even in the ited value in recognizing nonadherence in apparent rHTN setting of goal office measurements, it might be useful to (33). Tools to identify adherence problems include noncon- pursue ABPM, such as when disproportionate target organ frontational face-to-face interview, review of pharmacy re- damageispresent.TheimportanceofaccurateBPassessment cords for timing of prescription refills, pill counts, phone was stressed in a recent statement by the American Society of calls between office visits, use of a clinical pharmacist Hypertension about rHTN (27). within the practice, or medication event monitoring sys- Second, nonadherence deserves special attention to tems that electronically document each time the patient identify and address adherence barriers effectively. One opens a pill bottle. Although not readily available in study screened patients’ urine samples with mass spec- most clinical settings, medication event monitoring sys- troscopy and found that only 47% of 76 patients with temswereshowntobereliableindicatorsofandmay

Figure 1. | A systematic approach to the patient with suspected resistant hypertension. 4 Clinical Journal of the American Society of Nephrology

improve adherence (34). In extreme cases, observed med- but without CKD should be further studied using renal ication dosing in a controlled clinical setting may unmask artery imaging by computed tomography or conventional nonadherence (35). A thorough approach to the patient angiography on the basis of clinical suspicion. Presence with rHTN should include proactive assessment of bar- and management of renovascular disease in patients riers for adherence. Urine screens with mass spectroscopy with concomitant CKD are discussed further in Special for detection of antihypertensive medications can be con- Considerations in the Patient with CKD below. sidered if available. Obstructive (OSA) is a common cause of Third, other factors contributing to or exacerbating secondary hypertension. Screening tools, such as the Berlin hypertension should be considered and addressed. These questionnaire, can be useful (37) followed by overnight include lifestyle practices (excessive salt and intake, oximetry and polysomnography for confirmation. Several sedentary lifestyle, and lack of exercise) and use of studies showed a high prevalence of OSA among patients recreational drugs and some prescription and nonprescrip- with CKD ranging from 22% to 33%, and OSA is tion medications (including complementary and alterna- considered a contributing factor to rHTN (38). Treatment tive medications) that exacerbate hypertension (Table 2) of OSA with continuous positive airway pressure (CPAP) (3). Evaluation of salt intake and volume status is further was shown to reduce BP, although to a limited degree. In a discussed in Special Considerations in the Patient with trial of 40 patients with moderate to severe OSA and CKD below. rHTN, a combination of CPAP and medical therapy versus Fourth, the diagnosis of rHTN requires that the patient is medical therapy alone resulted in a significant improve- treated with a diuretic. As detailed below (Pharmacologic ment in BP at 6 months: mean daytime ambulatory BP Treatment and Special Considerations in the Patient with decreased by 7/5 mmHg in the CPAP group and increased CKD), dose and dosing frequency should be critically by 3/2 mmHg in the control group (39). However, BP re- considered. duction was not consistent across trials of CPAP treatment Fifth, workup for secondary hypertension should be and is usually modest, with an average lowering of 3/2 mmHg considered (Table 3). The initial evaluation should include reported in a recent meta-analysis of 29 trials (40). A com- measurement of electrolytes, eGFR, urinalysis, urine pro- bination of CPAP and weight loss may result in greater BP tein assessment, and kidney imaging. In subjects with a reduction (41). family history of autosomal dominant polycystic kidney Several endocrine causes of secondary hypertension disease and normal serum creatinine, a renal ultrasound should be considered on the basis of clinical presentation. should be obtained. The addition of Duplex Doppler can Although is classically associated with provide quantitative information on velocities metabolic alkalosis and , normokalemia to improve detection of renovascular disease. Because sev- should not preclude the diagnosis or deter further testing eral studies suggest that angioplasty alone may improve in patients with a high pretest probability (32). Measure- BPandevencurehypertensioninyoungpersonswith ment of the serum concentration-to-plasma fibromuscular dysplasia (36), a young patient with rHTN renin activity ratio, which had a sensitivity of 89% and a

Table 2. Common prescription and nonprescription drugs that can raise BP

Prescription Drugs Nonprescription Drugs

Anabolic Anabolic steroids Antidepressants Caffeine Monoamine oxidase inhibitors Cocaine Selective serotonin reuptake inhibitor Ethanol (in excess) Selective uptake inhibitors Glycyrrhizic acid (contained in some licorice, cough drops, and chewing tobacco) Norepinephrine transporter inhibitors NSAIDs Calcineurin inhibitors Sympathomimetic and illicit drugs Cyclosporin Amphetamines Tacrolimus Cocaine Sympathomimetic nonprescription medications (decongestants) Erythropoietin Nasal sprays Contraceptives a-Adrenergic herbal supplements Estrogen containing (Ma-Huang) Progesterone containing Caulophyllum thalictroides (blue cohosh) NSAIDs Citrus aurantium Sympathomimetics Synephrine, N-methyltyramine (bitter orange) VEGF inhibitors 1,3-Dimethylamylamine Tyrosine kinase inhibitors Amphetamines (in context of ADHD)

NSAID, non-steroidal anti-inflammatory drugs; VEGF, vascular endothelial growth factor; ADHD, attention-deficit hyperactivity disorder. Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Resistant Hypertension, Braam et al. 5

Table 3. Potential causes of secondary hypertension

Cause Diagnostic Testing

Evaluate in all patients Parenchymal Basic blood chemistry, including creatinine, sodium, potassium, bicarbonate; urinalysis with microscopic examination, urine protein-to-creatinine and/or albumin to-creatinine ratio, kidney ultrasound Secondary causes to be considered Renal artery Kidney ultrasound with Duplex Doppler, magnetic resonance Atherosclerotic imaging, computed tomography angiography, conventional angiography Berlin questionnaire, overnight oximetry, polysomnography High-aldosterone states Serum sodium and potassium concentration, serum aldosterone Primary hyperaldosteronism concentration-to-plasma renin activity ratio, BP response to Adrenal adenoma mineralocorticoid receptor antagonist, genetic testing Bilateral adrenal hyperplasia Secondary hyperaldosteronism Renin-secreting tumor remediable aldosteronism Cushing syndrome Dexamethasone suppression test, 24-h urine excretion, salivary cortisol Congenital adrenal hyperplasia Clinical diagnosis Apparent mineralocorticoid excess Clinical diagnosis, aldosterone and renin levels, electrolytes Liddle syndrome Clinical diagnosis, family history, aldosterone and renin levels, Gordon syndrome serum electrolytes Plasma-free metanephrines, 24-h urine metanephrines and Hyper- or Thyroid-stimulating Aortic coarctation BP measurements in both arms and legs, echocardiogram, thoracic CTA or MRA

CTA, computed tomography angiogram; MRA, magnetic resonance angiography.

specificity of 71% in one study, can be useful as initial studied in any of the included trials (50). Long–term out- screening (42), even for patients taking antihypertensive come studies of weight loss by bariatric using gas- medications, except for aldosterone receptor blockers, tric banding revealed mixed results (51). In the Swedish which should be stopped 4–6 weeks before testing. Testing Obese Subjects Study, after a transient lowering of BP in for thyroid disease or pheochromocytoma should be con- the first postoperative years, BP was similar in subjects sidered on the basis of clinical suspicion (Table 3). who underwent surgery compared with controls (52,53). After the stepwise evaluation as depicted in Figure 1 has Data regarding gastric bypass surgery indicate better been completed to confirm that the hypertension is actu- long–term outcomes. In a small series of hypertensive ally resistant, the provider can formulate a therapeutic obese subjects, gastric bypass surgery was associated plan. with persistent hypertension in only 20% after 10 years. Similar data were reported by the Longitudinal Assess- Nonpharmacologic Approaches to Management ment of Bariatric Surgery Consortium, a multicenter obser- Evidence-based studies are sparse regarding nonphar- vational cohort study of ten United States hospitals in six macologic modification of lifestyle and diet as part of geographically diverse locations (54). Three years after management for rHTN in patients with and without CKD surgery, remission of hypertension occurred in 269 of (43). Several nonpharmacologic interventions have rela- 605 patients with hypertension at baseline who underwent tively well established efficacy in reducing BP in patients Roux-en-Y gastric bypass surgery (38.2%) and 43 of247 pa- with prehypertension and primary hypertension. Use in tients with hypertension who received laparoscopic adjust- treatment of rHTN is primarily extrapolated from these able gastric banding (17.4%) (54). Of note, gastric bypass as trials. The Dietary Approaches to Stop Hypertension opposed to gastric banding may also result in endocrine (DASH) Study provides the best evidence for BP-lowering changes that affect BP regulation, such as an increase in atrial effectiveness of dietary sodium restriction and weight loss natriuretic peptide levels (55). Evidence is currently lacking in those with prehypertension, with more pronounced ef- whether such differences translate into different clinical re- fects in those with hypertension (44–49). sponses in patient with rHTN with and without CKD. A Cochrane review summarized the effects of modest Accumulating evidence supports the beneficial effects of weight loss (24kgover6–36 months) by dietary interven- involving nurses and pharmacists in education, treatment, tion to reduce BP. However, hard outcomes were not and monitoring of hypertension (56). A recent randomized, 6 Clinical Journal of the American Society of Nephrology

controlled trial of 110 diabetic subjects with uncontrolled knowledge gap could benefit from trials specifically aimed hypertension revealed that home BP telemonitoring com- at lifestyle modifications in carefully selected patients with bined with automated support improved BP control over rHTN and CKD. home BP monitoring alone, with 51% of intervention par- ticipants achieving BP target compared with 31% of con- Pharmacologic Treatment trols (P,0.05) (57). A randomized trial of 401 participants Given the reported high nonadherence rates as assessed with uncontrolled hypertension showed that an interven- using mass spectroscopy in patients with apparent and tion using telemonitoring under primary care clinician su- confirmed rHTN (28,29), a comprehensive therapeutic pervision and optional patient decision support improved strategy is needed. Such a strategy would aim to (1) assure daytime ambulatory BP by 4.3/2 mmHg compared with that the prescribed medications are selected and dosed usual care (58). appropriately, (2) determine whether the instituted ther- Insight on the value of multiple simultaneous lifestyle apy causes a measurable BP response, and (3) verify the interventions for rHTN is the subject of the TRIUMPH Trial presence of and address barriers to adherence. Using pri- (Clinicaltrials.gov no. NCT02342808) (59) to be completed in mary hypertension treatment algorithms (63), a patient 2019, which evaluates the efficacy of a center–based lifestyle with rHTN would likely be treated with at least three intervention using exercise training, sodium reduction, DASH antihypertensive agents of different classes, including a diet, and weight management compared with standardized renin-angiotensin system blocker, a calcium antagonist, a education and physician advice for improving BP control in diuretic, and possibly, a b-blocker. As will be described, patients with rHTN (59). Patients with CKD are included if there are data to support the addition of a mineralocorti- the eGFR is .45 ml/min per 1.73 m2. Evidence is lacking coid receptor antagonist as an add-on fourth or fifth agent regardingtheBP-reducingefficacy of other individual non- if a high aldosterone state has been confirmed by labora- pharmacologic interventions, including exercise, reduced al- tory measurements. cohol intake, and nondietary, nonpharmacologic treatments Optimization of intravascular volume status is essential referred to as alternative approaches (60) in patients with in the management of the patient with rHTN (30), partic- rHTN. Table 4 summarizes efficacious lifestyle modifications ularly in those with CKD (64). Inadequate volume control in hypertensive patients that are not specifictorHTNorCKD was reported even in patients being treated with diuretics (47,61). (65). –type and atrial natriuretic peptide levels were To educate and engage patients about lifestyle changes, higher in 279 consecutive patients with rHTN (uncon- communication is key. Communication with patients about trolled and using three or more antihypertensive medica- cardiovascular risk requires dedicated effort and recogni- tions) compared with 53 controls (normotensive or BP tion of barriers to achieving effective changes (62). Even controlled by less than three antihypertensive medica- in a research study setting, it is difficult for participants to tions). Interestingly, 85% of those with rHTN were being maintain long–term lifestyle modifications (47). Develop- treated with a thiazide diuretic. ing effective public health strategies that can be feasibly Selection of a specific diuretic, titration of dose, and implemented and lead to sustained lifestyle modifications dosing frequency must each be considered for effective remains a challenge (61). Because data about the effective- management of volume. For example, furosemide has a ness of weight loss, diet adaptations, and other nonphar- half-life of 30 minutes to 2 hours in patients with normal macologic interventions in rHTN are limited, the current kidney function and would need to be dosed two to three

Table 4. The effect of nonpharmacologic approaches to manage hypertension

Modification Description Systolic BP Reduction

Weight reduction To attain normal weight (i.e., BMI,25) 5–20 mmHg/10-kg weight loss DASH Diet Rich in fruits, vegetables, low- dairy, 8–14 mmHg reduced saturated and total fat, and reduced sodium Reduced dietary sodium To 65–100 mmol/d (1.5–2.4 g Na+ or 3.8–6 2–8mmHg gNaCl) Increased physical activity Regular aerobic exercise 30 min/d most 4–9mmHg days of week Moderate alcohol intake Limit to #2drinksa per day for men and #1 2–4mmHg drink per day for women and those with lighter weight Increased potassium intake 120 mmol/d (4.7 g/d; also included in Variable DASH Diet) Alternative approaches Meditation, yoga, other relaxation Variable up to 2–10 mmHg therapies, biofeedback, device-guided breathing, and acupuncture

BMI, body mass index; DASH, Dietary Approaches to Stop Hypertension. aOne drink is equivalent to 12 oz beer, 5 oz wine, or 1.5 oz 80-proof liquor, each representing, on average, 14 g ethanol. Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Resistant Hypertension, Braam et al. 7

times daily (66). Additional discussion regarding choice of Assessment of volume status and salt intake is particu- diuretic and dosing in the setting of CKD is presented in larly relevant in the patient with CKD, although formal Special Considerations in the Patient with CKD below. measurements of salt excretion and volume using bioim- Plasma aldosterone levels, aldosterone-to-renin ratios, pedance or labeled red blood cell techniques may be and 24-hour urine aldosterone levels are reported to be technically challenging or unavailable. Extracellular fluid higher in those with rHTN compared with normotensive volume expansion is prevalent and increases with the subjects and subjects with controlled hypertension (65). severity of CKD (71). In 338 patients with stages 3–5CKD, Moreover, a low dose of decreased BP in 52% were fluid expanded as assessed by bioimpedance patients with rHTN by 17/7, 24/10, and 26/11 mmHg at (72). Several small trials, including studies of patients 1, 3, and 6 months after starting the drug, respectively (67). with rHTN and CKD, suggest that measurement of hemo- Two recent trials support the efficacy of mineralocorticoid dynamic parameters and volume status using thoracic bio- inhibition in rHTN. The first confirmed the efficacy of impedance may be an efficacious approach to guide 25 mg spironolactone (versus placebo) to decrease BP and medication selection and dosing (65,72–76). Until more reach the prespecified target systolic BP of ,140 mmHg data become available to support the standard use of (73% versus 41% in spironolactone versus placebo groups) such techniques in practice, reduction in salt intake and (68). The second compared the BP-lowering effect of the monitoring weight may serve as surrogates of volume sta- addition of spironolactone, doxazosin, bisoprolol, or pla- tus. Sodium intake can be estimated by 24-hour urinary cebo as add-on therapy to the participant’s baseline antihy- sodium excretion for an individual in steady state or pertensive medications. Spironolactone (25–50 mg) was the using a validated salt calculator, a survey of about 25 most effective and reduced home systolic BP by 14 mmHg, questions (77). Patients with CKD should be instructed about 9 mmHg more than placebo and 5–6 mmHg more to monitor their weight regularly. than doxazosin or bisoprolol (69). One of 285 treated pa- Secondary causes for hypertension are more common in tients experienced a serum potassium concentration patients with CKD and apparent rHTN. Although CKD per .6 mmol/L. These trials support mineralocorticoid inhibi- se could be responsible for rHTN (due to underlying renal tion with spironolactone as an effective addition to rHTN parenchymal disease), the presence of CKD should not treatment. Eplerenone, as a more specific aldosterone re- discourage investigation for other causes if clinical suspi- ceptor antagonist, remains a desirable alternative for pa- cion exists. OSA is frequent in the patient with CKD and tients with clinically significant side effects, such as particularly relevant in CKD, because fluid overload may gynecomastia or breast tenderness. contribute to swelling of the hypopharynx, palate, and Beyond optimizing diuretic dosage and addition of a nasal cavities and result in OSA exacerbation. mineralocorticoid antagonist, it may be necessary to add Special consideration is required regarding renovascular additional antihypertensive agents. Direct vasodilators, hypertension. On the basis of the results of the benefitof a-blockers, and central sympathetic agonists should be re- STent placement and and lipid-lowering served for the most resistant or those intolerant of other for the prevention of progression of renal dysfunction agents due to more significant associated side effects. caused by Atherosclerotic ostial stenosis of the Renal ar- tery (STAR) Trial (78), the STent for Renal Artery Lesions Special Considerations in the Patient with CKD (ASTRAL) Trial (79), and the Cardiovascular Outcomes in In addition to considerations already discussed for the Renal Atherosclerotic Lesions (CORAL) (80) Trial, which patient with rHTN, special attention should be given to suggested that renal angioplasty/stenting does not confer patients with rHTN and concomitant CKD with respect to additional benefit above optimal medical therapy in pa- the definition, stepwise evaluation, and particularly, dif- tients with stable CKD, routine screening for atheroscle- ferences in hypertension management. rotic renal artery disease should be discouraged (78–80). Whether the definition of rHTN in the setting of CKD The CORAL Trial emphasized the safety and efficacy of should include more specific criteria has not been clearly angiotensin receptor blockers in patients with unilateral or delineated. For example, patients with CKD are more likely bilateral renal artery stenosis. Medical therapy in patients to present with sodium retention and excess volume among suspected of having underlying atherosclerotic renal ar- other features, such as unopposed activity of the renin- tery disease should, therefore, include maximal tolerated angiotensin-aldosterone system (RAAS). Therefore, opti- doses of one of these agents before defining treatment re- mization of volume status, including attention to diuretic sistance. In contrast, patients who fail optimal medical selection and adequacy of dosage and dosing frequencies therapy, especially those with severe hypertension or re- as well as consideration for use of RAAS inhibitors, should current episodes of acute (flash) pulmonary edema, refrac- be addressed before a patient with CKD is labeled with true tory heart failure, recurrent AKI after treatment with rHTN. angiotensin receptor blockers or angiotensin–converting en- Special considerations for the systematic approach to the zyme inhibitors, or deterioration of kidney function, may patient with rHTN and CKD include confirmation of office benefit from percutaneous angioplasty and stenting, because elevated BP readings and interpretation of 24-hour ABPM. such patients were excluded from the three trials (81). In particular, questions remain regarding interpretation of With respect to nonpharmacologic approaches for man- nocturnal hypertension if high 24-hour ABPM readings are agement, rHTN is more common and salt sensitivity of BP limited to nighttime or in instances where BP is at target is well established in patients with CKD (43). The Kidney except for the presence of a nondipping pattern. There is a Disease Improving Global Outcomes guideline for man- need for additional studies on the utility of chronotherapy agement of BP in CKD advises limiting sodium intake to in the patient with CKD and rHTN. (70) 2 g/d for hypertensive patients not on dialysis (82). 8 Clinical Journal of the American Society of Nephrology

Nevertheless, recommendations regarding sodium restric- Catheter–based sympathetic renal denervation (RDN) tion in patients with CKD are on the basis of observational derives its pathophysiologic basis from the observation data, and interventional studies are needed to determine that bidirectional renal sympathetic nerve trafficking con- the optimal amount of sodium restriction in patients with tributes significantly to BP regulation (90). Surgical sym- CKD. One small randomized, controlled trial assessed so- pathectomy was at one time one of the few therapies that dium restriction for rHTN in 12 participants with CKD could provide treatment for hypertension when drug ther- (83) in a 4-week crossover design. Sodium excretion rates apy was not widely available (91). The renal artery can were 252 and 46 mmol/d during the high– and low– now be less invasively approached using radiofrequency sodium intake periods, respectively. The low–sodium intake ablation (92). In 2009, a small uncontrolled trial reported phase was accompanied by a substantially lower systolic striking reductions of 22/11 and 27/17 mmHg in office BP and diastolic BP (223/9 mmHg) (83). In addition, caution 6 and 12 months, respectively, after application of this and close monitoring should be used when considering the technique in 45 subjects with rHTN (92). Subsequently, a DASH diet for patients with advanced CKD or those being small nonblinded, randomized, controlled trial reported treated with RAAS inhibitors given the increased risk of that RDN decreased BP by 25/10 mmHg after 12 months hyperkalemia. (93). The SIMPLICITY-3 Trial was the first sham treatment– Discussion of pharmacologic treatment of the patient controlled trial using this approach, but it failed to confirm with CKD and rHTN comes with several considerations. earlier findings (94) Potential explanations included tech- Because of decreased GFR, higher doses of diuretics are nique issues (operator related and catheter related) and required in patients with CKD compared with those with trial design (better treatment adherence in both the control normal kidney function (84). Regarding thiazide or thiazide- and intervention groups). Although a recent paper report- like diuretics, there is evidence that chlorthalidone is more ed BP-lowering effect of RDN added to a stepped care potent in lowering BP, possibly because of a longer half- approach using antihypertensive medications (compared life, than hydrochlorothiazide (85). Moreover, recent meta- with stepped care alone), there was no sham operation analyses reported that chlorthalidone and other thiazide–like control (95). In the context of RDN, other techniques are diuretics were more efficacious in preventing cardiovascular now being developed with externally delivered focused events than hydrochlorothiazide and other thiazide–type ultrasound (96), which may offer safer adjunct treatment diuretics (86,87). The longer half-life and duration of ac- options. tion of chlorthalidone may be particularly valuable in pa- Although the negative SIMPLICITY-3 Trial substantially tients with variable medication adherence (88). Although decreased interest in RDN, studies using RDN in patients there is a widespread belief that thiazides are not ef- with heart failure are ongoing and may provide more fective for patients with CKD and eGFR,30 ml/min per insight. Furthermore, favorable clinical effects reported for 1.73 m2,arecentstudyshowedbenefit (89). To date, RDN, such as improvements in insulin sensitivity (97), mi- hydrochlorothiazide remains the most commonly used croalbuminuria (98), and apnea/hypopnea index (99), may thiazide, particularly in combination tablets. Taken to- be offset by safety concerns, such as renal artery stenosis gether, although there are no head to head outcomes tri- (100). Subsequent occurrence of reinnervation must also be als, it seems preferable to use chlorthalidone in the considered. Larger studies with longer durations are treatment of rHTN in patients with CKD. With advanced needed to address these issues before RDN can be consid- CKD (eGFR,20–30 ml/min per 1.73 m2), a loop diuretic ered for clinical use. canbeeffectivelyusedtomanagehypertensionwithcon- Another emerging technique is electrical carotid sinus sideration of dosing interval. Torsemide may be preferred, baroreceptor stimulation using implantable devices. Such because it has greater and more consistent bioavailability devices implanted chronically led to significant reductions and can be generally dosed once daily compared with in mean systolic BP of 26 and 35 mmHg after 6 and 12 months, furosemide or bumetanide, which would both require respectively (101). Importantly, the safety end point was not twice daily dosing. Diuretics in general and thiazides in met; issues were related to surgery (nerve damage and particular are associated with hyperuricemia, but this wound healing) and uncontrolled BP. Unfortunately, robust should not discourage their use in patients with CKD given sham–controlled studies are not available. Moreover, carotid the frequent presence of . In rare situations, body stimulation has not been associated with the favor- the combination of a thiazide and a loop diuretic to aug- able metabolic effects observed for RDN. Of note, neither ment diuresis may be considered; however, this approach catheter–based sympathetic RDN nor electrical carotid sinus can cause extreme natriuresis and must be titrated and baroreceptor stimulation are Food and Drug Administration– monitored carefully. approved therapies. A word of caution is needed about the application of mineralocorticoid inhibitors for patients with CKD; they Summary are frequently already treated with an inhibitor of the The lack of consensus around a unified definition for renin-angiotensin system and would be more prone to rHTN has challenged efforts to define prevalence of the develop hyperkalemia with a combination of medications condition and outcomes. A systematic approach to evalu- targeting the RAAS. ation will improve identification of factors contributing to poor control rates and facilitate efforts directed at better Role of Emerging Therapies control through modifying these factors, which include but In recent years, several novel therapies were investigated are not limited to nonadherence to lifestyle and dietary as potential complimentary or alternative treatments to modification or medications, use of substances that may antihypertensive medications. exacerbate high BP, suboptimal dosing of antihypertensives, Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Resistant Hypertension, Braam et al. 9

lackofuseorinadequatedosing of a diuretic as a cornerstone 8. Bangalore S, Fayyad R, Laskey R, Demicco DA, Deedwania P, of management, and failure to perform appropriate diagnostic Kostis JB, Messerli FH; Treating to New Targets Steering Com- mittee and Investigators: Prevalence, predictors, and outcomes testing to exclude secondary causes. We propose that rHTN fi in treatment-resistant hypertension in patients with coronary be de ned more restrictively as a BP that exceeds the disease. Am J Med 127: 71–81.e1, 2014 individualized BP target while the patient is receiving 9. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, treatment with at least three antihypertensive medications, Grimm RH, Black HR, Hamilton BP, Holland J, Nwachuku C, including a diuretic, at dosages optimized for maximum Papademetriou V, Probstfield J, Wright JT Jr., Alderman MH, fi Weiss RJ, Piller L, Bettencourt J, Walsh SM; ALLHAT Collabo- bene t with absence of intolerable side effects. In addition to rative Research Group: Success and predictors of blood pres- fi fi – of ce BP measurement, con rmation by above target out-of- sure control in diverse North American settings: The office measurements should be required. Treatment of rHTN antihypertensive and lipid-lowering treatment to prevent heart includes attention to dietary and lifestyle modifications and attack trial (ALLHAT). J Clin Hypertens (Greenwich) 4: 393– adjustments to the antihypertensive regimen, including con- 404, 2002 10. De Nicola L, Gabbai FB, Agarwal R, Chiodini P, Borrelli S, tinued vigilance to adherence barriers and avoidance of sub- Bellizzi V, Nappi F, Conte G, Minutolo R: Prevalence and stances that may cause high BP. For patients with CKD, drug prognostic role of resistant hypertension in chronic kidney class effect, dose escalation, optimization of dosing interval, disease patients. J Am Coll Cardiol 61: 2461–2467, 2013 and drug tolerability require additional attention, with spe- 11. Gupta AK, Nasothimiou EG, Chang CL, Sever PS, Dahlo¨fB, cial emphasis on volume assessment and treatment of hyper- Poulter NR; ASCOT investigators: Baseline predictors of re- sistant hypertension in the Anglo-Scandinavian Cardiac Out- volemia. The role and safety of emerging novel therapies need come Trial (ASCOT): A risk score to identify those at high-risk. additional exploration before their use in clinical practice. J Hypertens 29: 2004–2013, 2011 12. Muntner P, Davis BR, Cushman WC, Bangalore S, Calhoun DA, Acknowledgments Pressel SL, Black HR, Kostis JB, Probstfield JL, Whelton PK, The authors thank all members of the American Society of Ne- Rahman M; ALLHAT Collaborative Research Group: Treatment- resistant hypertension and the incidence of cardiovascular phrology (ASN) Hypertension Advisory Group (George L. Bakris, disease and end-stage renal disease: Results from the Anti- fi Ellen D. Burgess, Lance D. Dworkin, Karen A. Grif n, James M. hypertensive and Lipid-Lowering Treatment to Prevent Heart Luther, Julie Ingelfinger, Velvie A. Pogue, Jennifer S. Pollock, George Attack Trial (ALLHAT). Hypertension 64: 1012–1021, 2014 Thomas, Peter N. Van Buren, and Matthew R. Weir) for their valuable 13. Persell SD: Prevalence of resistant hypertension in the United advice and contributions. The ASN Hypertension Advisory Group States, 2003-2008. Hypertension 57: 1076–1080, 2011 14. Smith SM, Gong Y, Handberg E, Messerli FH, Bakris GL, Ahmed would also like to thank Grant Olan, Senior Policy and Government A, Bavry AA, Pepine CJ, Cooper-Dehoff RM: Predictors and Affairs Associate of the ASN, and Rosie Hernandez for their assis- outcomes of resistant hypertension among patients with coronary tance during the preparation of this manuscript. artery disease and hypertension. 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Branko Braam 1, Sandra J. Taler 2, Mahboob Rahman 3, Jennifer A. Fillaus 4, Barbara A. Greco 5, John P. Forman 6, Efrain Reisin 7, Debbie L Cohen 8, Mohammad G. Saklayen 9, and S. Susan Hedayati 10

1 Division of Nephrology and Immunology, Dept. Medicine and Dept. Physiology, Univ. of Alberta, Edmonton, AB, Canada 2 Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA 3 University Hospitals Case Medical Center, Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Ohio, USA 4 Division of Nephrology, Dept. Medicine, Univ. of Nebraska Medical Center, Omaha, Nebraska, USA 5 Renal Division, Baystate Medical Center, Renal and Transplant Associates of New England, Springfield, Massachusetts, USA 6 Renal Division, Department of Medicine, and Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 7 Section of Nephrology and Hypertension, Louisiana State University Health Science Center, New Orleans, USA. 8 Univ. of Pennsylvania, Renal, Electrolyte and Hypertension Division, Pennsylvania, USA 9 Dayton VA Medical Center, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA 10 Division of Nephrology, Dept. of Internal Medicine, Univ. of Texas Southwestern Medical Center and VA North Texas Health Care System, Dallas, Texas USA