COMMENTARY

Resistant Hypertension

Hypertension is an important problem in patients with chronic kidney disease (CKD). Bakris and colleagues (1) have argued that it is “a marriage that should be prevented”. 

Hypertension in CKD patients is multifactorial (2); causes include, excessive activation of the renin-angiotensin system, extracellular volume expansion, increased activity of the sympathetic nervous system, increased endothelin production, decreased availability of endothelium-derived vasodilators and structural changes of the arteries, renal ischemia, and sleep apnea. 

A sub-set of CKD patients with hypertension (≈25-40%, (3)) have resistant hypertension (RHTN). In the current issue of CJASN, Raymond Townsend does a nice job in reviewing the topic as part of a new feature called “Attending Rounds” (4).

In the past couple of months there have been a series of papers discussing the prevalence and risk factors for resistant hypertension. The most notable have been the papers by Persell (5) in Hypertension (June 2011) and a paper by Egan and co-workers (6) Circulation (August 2011).  

The Joint National Committee 7 defines RHTN as failure to achieve goal BP (<140/90 mm Hg for the overall population and <130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) when a patient adheres to maximum tolerated doses of 3 antihypertensive drugs including a diuretic. In the AHA Scientific Statement: Resistant Hypertension: Diagnosis, Evaluation, and Treatment (7), Calhoun and colleagues define it as “high blood pressure (BP) requiring >4 antihypertensive medications, whether controlled or uncontrolled”.

The prevalence of RHTN is unknown. Extrapolating data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study some have estimated the prevalence to be 20-30%, because at the end of the 5-year treatment period in the study, 34% of subjects never achieved BP control and 27% of subjects were receiving >=3 antihypertensive medications (8). Another approach is to use community-based observational studies, such as NHANES, to estimate the prevalence of RHTN. The RHTN prevalence in these studies is estimated to be 20-30%. Persell (5) applied the American Heart Association definition of RHTN of needing >=4 medications to the 2005–2008 NHANES data to estimate the prevalence of RHTN to be 8.9% of all US adults with hypertension and 12.8% of treated hypertensive subjects. As well most drug-treated adults with uncontrolled hypertension were receiving medications from only 1 or 2 pharmaceutical classes.

Based on these figures and current estimates of there being 68-million hypertensive adult Americans, Ahmed and Calhoun in an editorial (9) accompanying Persell’s paper estimate that  approximately 6.1 million Americans have RHTN. Egan and co-workers evaluating NHANES data from 1988 to 1994, 1999 to 2004, and 2005 to 2008 point to the problem of RHTN getting worse -- prevalence of RHTN increasing from 15.9% (1998-2004) to 28.0% (2005-2008) of treated patients (P<0.001).

Consistent with other reports, Persell reports that compared with patients with controlled hypertension, subjects with RHTN were more likely obese, older, black, and more likely to have diabetes mellitus and chronic kidney disease. Increased cardiovascular risk was reflected in greater rates of coronary heart disease, heart failure, and stroke.

An approach to resistant hypertension is shown below.

1. Measure BP accurately

–     “Persons should be seated quietly for 5 minutes with feet on the floor and the arm supported at heart level”

–     Cuff must be appropriately sized (cuff bladder must encircle 80% of the arm)

–     Check both arms and a leg (or palpate pulses carefully)

2. Consider “White Coat Hypertension” (WCH)

–     Home and Ambulatory BP Monitoring (ABPM)

3. Consider “pseudoresistance”

–     Pseudohypertension (calcification of the arteries resulting in failure of the BP cuff to compress and occlude flow)

–     Non-adherence (may account for up to 50% of resistant cases)

–     Inadequate Regimen

–     Interfering medicines and substances also need to be considered

o   NSAIDs

o   Excessive Alcohol, Caffeine, or Tobacco

o   Excessive Salt Intake

o   Oral contraceptives

o   Sympathomimetic agents (nasal decongestants, anorectic pills, cocaine, amphetamine-like stimulants

o   Glucocorticoids

o   Anabolic steroids

o   Erythropoietin,

o   Cyclosporine

o   Black licorice

o   Herbal supplements (e.g., ma huang and ginseng)

4. Consider secondary causes

–     Obstructive Sleep Apnea

–     Obesity (Metabolic Syndrome)

–     Endocrinopathies

·      Hyperaldosteronism, thyroid problems, pheochromocytoma

–     Kidney Disease

·      Renal Insufficiency and Renal Artery Stenosis

So what are the key therapeutic issues that nephrologists need to consider in treating RHTN, particularly in the CKD population:

1.    Treat subtle or clinically apparent extracellular volume expansion. Since a suboptimal dosing regimen or inappropriate antihypertensive drug combinations is the most common cause of resistant hypertension, the first step in management is to review the medication regimen. The most important intervention is to either add a diuretic agent, or increase the dose of the diuretic, or changing the diuretic class based on kidney function. A thiazide diuretic is preferred if the patient’s estimated GFR (eGFR) is >50 ml/min/1.73 m². Persell points out that despite the well-established superiority of chlorthalidone compared with hydrochlorothiazide in reducing BP (10), the majority of patients with RHTN (55%) continue to receive hydrochlorothiazide as their diuretic. Switching to a loop diuretic, such as furosemide or bumetanide is recommended once the eGFR falls <50 ml/min/1.73 m². Persell and colleagues report that 33% of subjects with a GFR <30 mL/min and RHTN were not being treated with a loop diuretic.

2.    Consider adding an aldosterone antagonist. Only 3% of patients with RHTN based on Persell’s paper were receiving either spironolactone or eplerenone. Obviously in patients with CKD, use of an aldosterone antagonist is a thorny issue if the patient has a history of hyperkalemia or a high-normal serum potassium. Patients with advanced CKD are unlikely candidates for this reason, although some smaller studies have reported the use of low dose spirinolactone in RHTN in CKD patients (11). However, very judicious use (and with close follow-up), of an aldosterone antagonist is worth thinking about in patients with milder CKD.

3.    The patient should be on a renin-angiotensin blocker along with a calcium antagonist. Options for a fourth agent include a vasodilator, beta-blocker or a peripheral alpha-blocker. Adding a complementary calcium channel blocker (e.g., adding diltiazem to nifedipine XL) has also been recommended. On the other hand, dual blockade with both an angiotensin receptor blocker and an ACE inhibitor does not result in additive BP reduction and may actually be harmful.

4.    Work up the patient for sleep apnea and treat it. There is now a fairly substantial literature demonstrating that sleep apnea and hypertension are common partners in the CKD population (12).

References

1. Bakris GL, Ritz E; World Kidney Day Steering Committee. The message for World Kidney Day 2009: hypertension and kidney disease--a marriage that should be prevented. J Hypertens. 2009 Mar;27(3):666-9. PubMed PMID: 19262237

2. Campese VM, Mitra N, Sandee D. Hypertension in renal parenchymal disease: why is it so resistant to treatment? Kidney Int. 2006 Mar;69(6):967-73. Review.

PubMed PMID: 16528245.

3. De Nicola L, Borrelli S, Gabbai FB, Chiodini P, Zamboli P, Iodice C, Vitiello S, Conte G, Minutolo R. Burden of resistant hypertension in hypertensive patients with non-dialysis chronic kidney disease. Kidney Blood Press Res.2011;34(1):58-67. Epub 2011 Jan 4. PubMed PMID: 21212686.

4. Townsend RR. Attending rounds: a patient with drug-resistant hypertension. Clin J Am Soc Nephrol. 2011 Sep;6(9):2301-6. Epub 2011 Aug 18.

5. Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation. 2011 Aug 30;124(9):1046-58. Epub 2011 Aug 8.

6. Persell SD. Prevalence of resistant hypertension in the United States,2003–2008. Hypertension. 2011; 57; 1076–1080.

7. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM; American Heart Association Professional Education Committee. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008 Jun 24;117(25):e510-26. PubMed PMID:18574054.

8. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, Black HR, Hamilton BP, Holland J, Nwachuku C, Papademetriou V, Probstfield J, Wright JT, Alderman MH, Weiss RJ, Piller L, Bettencourt J, Walsh SM, for the ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering and Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens. 2002; 4: 393–404.

9. Ahmed MI, Calhoun DA. Resistant hypertension: bad and getting worse. Hypertension. 2011; 57: 1045–1046.

10. Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJG, Phillips BB, Zimmerman MB, Bergus GR. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006; 47: 353–358.

11. Abolghasmi R, Taziki O. Efficacy of low dose spironolactone in chronic kidney disease with resistant hypertension. Saudi J Kidney Dis Transpl. 2011 Jan;22(1):75-8. PubMed PMID: 21196617

12. Sim JJ, Rasgon SA, Derose SF. Sleep apnea and hypertension: prevalence in chronic kidney disease. J Clin Hypertens (Greenwich). 2007 Nov;9(11):837-41. PubMed PMID: 17978590.