Resistant Hypertension in CKD

Introduction

Resistant hypertension is defined as BP that remains above goal despite the use of three antihypertensive medications at optimal doses of different classes, typically including a calcium channel blocker, a renin-angiotensin system (RAS) blocker, and a diuretic (1). Studies typically report apparent resistant hypertension (due to lack of information on medication dosing, adherence, and out of office BP). Apparent resistant hypertension is common in patients with CKD and is a high-risk phenotype for adverse cardiovascular and kidney outcomes (2). Increased salt and water retention, excessive RAS activation, and increased sympathetic activation contribute to uncontrolled BP in these patients. In this article, we describe our approach to management of resistant hypertension in CKD.

The Patient

A 60-year-old man with CKD, coronary artery disease, type 2 diabetes mellitus, and strong family history of hypertension is seen for uncontrolled hypertension. Seated office BP is 155/85 mm Hg, with heart rate of 50 beats per minute; he is not orthostatic, and his weight is 230 lbs. (body mass index of 34 kg/m²). Physical examination is notable for audible S4 and mild arteriolar narrowing on fundoscopy; there is no peripheral edema or vascular bruit. His antihypertensive medications include hydrochlorothiazide 25 mg daily, valsartan 320 mg daily, amlodipine 10 mg daily, long-acting metoprolol 100 mg daily, and clonidine 0.2 mg three times daily. His laboratory parameters are hemoglobin 12 g/dl, potassium 4.5 mEq/L, eGFR 35 ml/min per 1.73 m², urine albumin-creatinine ratio 500 mg/g, and hemoglobin A1c 7%. Echocardiogram showed moderate left ventricular hypertrophy and normal ejection fraction.

Pseudoresistance

Blood Pressure Measurement

Accurate BP measurement is imperative—it is important to exclude the “white coat effect” (transient elevation in office BP due to alerting effect in patients with treated hypertension); use of automated devices that take multiple consecutive BP readings with the patient resting alone can decrease white coat response compared with single manual measurements (3). Guidelines regarding proper technique should be followed (4). Out of office BP measurements with 24-hour ambulatory BP monitoring (ABPM) or home BP monitoring are recommended to verify in-office measurements (4).

Medication Adherence

Potential barriers to medication adherence should be addressed, including complex regimens, cost, side effects, and limited insight into illness.

Management

Stepwise evaluation and nonpharmacologic therapy are detailed in Figure 1.

Figure 1.

Evaluation and management of resistant hypertension. ABPM, ambulatory BP monitoring; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; CCB, calcium channel blocker; NSAID, non-steroidal anti inflammatory drugs; RAS, renin-angiotensin system.

Pharmacologic Therapy

A long-acting thiazide-like diuretic like chlorthalidone is favored over hydrochlorothiazide because of longer t_1/2 and higher potency (5). Although it is often the practice to switch to loop diuretics when eGFR is <30 ml/min per 1.73 m², there is some evidence that thiazide-like diuretics can still effectively lower BP in advanced CKD (6). When used, longer-acting loop diuretics, like torsemide, with more consistent absorption and advantage of once daily dosing are favored. Furosemide and bumetanide are short acting and should be dosed at least twice daily. Higher doses of loop diuretics may be required at lower levels of eGFR. RAS blockers are particularly useful in patients with albuminuria. Dual RAS blockade is currently not recommended (4,7). There are pharmacokinetic differences between various drugs within the same class, which may affect efficacy. For example, losartan has a shorter t_1/2, and other agents in this class have better BP-lowering efficacy. Aldosterone antagonists are effective in patients with resistant hypertension (8), with additional benefit in lowering proteinuria. Their major limiting side effect is hyperkalemia, especially when added to RAS blockers. Concurrent use of potassium binding agents may allow continuation of spironolactone (9); β-blockers should be first-line therapy in those with compelling indications (heart disease or heart failure). We favor the use of β-blockers with vasodilatory effects (like carvedilol or nebivolol) if started for hypertension management. Additional antihypertensive medications, including central sympatholytics, α-blockers, or direct vasodilators, should be considered on a case-by-case basis depending on tolerability (1).

Although combination therapy promotes adherence, a practical concern is the difficulty in identifying the inciting agent in patients who have drug sensitivity or experience drug reactions.

Although there is increasing research interest in device-based interventions, such as renal denervation and baroreflex amplification therapy, they remain investigational and are not currently Food and Drug Administration-approved for clinical use.

Our Patient

The goal BP for this patient is office BP <130/80 mm Hg. BP was checked with an automated device, which provides an average of five seated readings; for new patients, we check BP in both arms. Standing BP is routinely checked. Our nurses and medical assistants are trained in proper office BP measurement technique, with biannual competency assessments.

The patient had a home BP monitor but had not used this regularly. ABPM confirmed sustained hypertension, with average daytime (awake) BP of 150/85 mm Hg and average nighttime (sleep) BP of 140/80 mm Hg. The patient initially reported adherence to medications, but on further questioning, noted that he occasionally missed doses of clonidine. He denied use of any over-the-counter medications or illicit drugs. He reported headaches, fatigue, and excessive daytime sleepiness. Although aware of the need to follow a low-sodium diet, he consistently ate fast food for lunch and thought his diuretic would help counteract the high sodium. He drank alcohol only on occasion; he denied binge drinking. He reported no regular physical activity. Screening indicated high risk for obstructive sleep apnea.

The patient was educated on lifestyle modifications, he was instructed on home BP monitoring with an arm cuff, and his home BP device was checked for accuracy. A sleep study confirmed severe obstructive sleep apnea, and continuous positive airway pressure therapy was started. Evaluation for secondary causes was negative.

The following medication changes were implemented: hydrochlorothiazide was changed to chlorthalidone 25 mg daily; we continued valsartan, amlodipine, and metoprolol at the same doses; and we began weaning off clonidine (which could contribute to his fatigue, and inconsistent use of clonidine would also potentially cause rebound hypertension). His home BP readings were reviewed on a regular basis. He reported improved fatigue and daytime sleepiness. Repeat laboratory tests 1 month after instituting the above medication changes indicated potassium 4 mEq/L and eGFR 34 ml/min per 1.73 m².

His office BP at 3 months was 135/80 mm Hg, with heart rate of 65 beats per minute; a repeat ABPM showed average daytime BP of 130/75 mm Hg and average nighttime BP of 125/85 mm Hg. Continuous positive airway pressure therapy adherence was confirmed. At this point, we elected to continue the same regimen, with continued focus on lifestyle modifications. His office BP at 6 months was 138/80 mm Hg, with heart rate of 68 beats per minute; his average home BP reading was 135/75 mm Hg. His weight was 220 lbs. We added spironolactone 25 mg daily, with instructions to follow a low-potassium diet. Laboratory tests 1 month later indicated potassium 4.4 mEq/L and eGFR 32 ml/min per 1.73 m². His office BP at 9 months was 128/80 mm Hg, and his average home BP reading was 125/75 mm Hg. Laboratory tests at this time indicated potassium 4.7 mEq/L and eGFR 35 ml/min per 1.73 m². We continue to emphasize lifestyle modifications, with review of home BP readings on bimonthly basis and 6-month office visits.

Apparent resistant hypertension is common in CKD and presents a challenge for management. Assessment for pseudoresistance, including out of office BP monitoring, should be done. Evaluation for secondary causes of hypertension should be considered. Nonpharmacologic measures should be reinforced, along with optimizing pharmacologic therapy. Careful monitoring of kidney function along with electrolytes is necessary. A stepwise approach to evaluation and management may help in identifying contributory factors and achieving BP control.

Disclosures

M. Rahman reports employment with Case Western Reserve University; receiving research funding from Bayer Pharmaceuticals and Duke Clinical Research Institute; receiving honoraria from Reata and Relypsa; serving as an Associate Editor of CJASN and an Editorial Board member of American Journal of Nephrology; and other interests/relationships with Medical Advisory Board, Kidney Foundation of Ohio. G. Thomas reports employment with Cleveland Clinic and receiving honoraria from UpToDate.

Funding

None.