nephsap volume 15, number 1 - hypertension - nefroinfo. nephs… · editorial 1 adiposity and blood...

NephSAPNephrology Self-Assessment Program

®

Volume 15 • Number 1 • March 2016

HypertensionDebbie L. Cohen, MD

Aldo J. Peixoto, MD

Co-Directors: Gerald Hladik, MDJerry Yee, MD

CO-DIRECTOR,NephSAPGerald A. Hladik, MDUniversity of North Carolina at Chapel HillChapel Hill, NC

CO-DIRECTOR,NephSAPJerry Yee, MD, FASNHenry Ford HospitalDetroit, MI

MANAGING EDITORGisela Deuter, BSN, MSAWashington, DC

ASSOCIATE EDITORSDebbie L. Cohen, MDUniversity of Pennsylvania School of MedicinePhiladelphia, PA

Richard J. Glassock, MDProfessor Emeritus, The David Geffen School ofMedicine at the University of CaliforniaLos Angeles, CA

Stanley Goldfarb, MDUniversity of Pennsylvania School of MedicinePhiladelphia, PA

Jay L. Koyner, MDUniversity of ChicagoChicago, IL

Holly J. Kramer, MDLoyola University Medical CenterMaywood, IL

Ruediger W. Lehrich, MDDuke UniversityDurham, NC

Kevin J. Martin, MBBChSt. Louis University School of MedicineSt. Louis, MO

John P. Middleton, MDDuke UniversityDurham, NC

Sankar D. Navaneethan, MD, MPHBaylor College of MedicineHouston, TX

Aldo J. Peixoto, MDYale UniversityWest Haven, CT

Asghar Rastegar, MDYale UniversityNew Haven, CT

Brad H. Rovin, MDOhio State University Medical CenterColumbus, OH

Manoocher Soleimani, MDUniversity of CincinnatiCincinnati, OH

Charuhas V. Thakar, MDUniversity of CincinnatiCincinnati, OH

John P. Vella, MDMaine Medical CenterPortland, ME

Alexander C. Wiseman, MDUniversity of Colorado at DenverDenver, CO

FOUNDING EDITORSRichard J. Glassock, MDEditor-in-Chief Emeritus

Robert G. Narins, MD

PrefaceNephSAP� is one of the premiere educational activities of the American Society ofNephrology (ASN). Its primary goals are self-assessment, education, and the provision ofContinuingMedical Education (CME) credits andMaintenance of Certification (MOC) pointsfor individuals certified by the American Board of Internal Medicine. Members of the ASNreceive NephSAP electronically through the ASN website by clicking on the NephSAP linkunder “Education and Meetings” tab.

EDUCATION: Medical and nephrologic information continually accrues at a rapid pace.Bombarded from all sides with demands on their time, busy practitioners, academicians, andtrainees at all levels are increasingly challenged to review and understand new and evolvingevidence. Each bimonthly issue of NephSAP is dedicated to a specific theme, i.e., to a specificarea of clinical nephrology, hypertension, dialysis, and transplantation, and consists of aneditorial, a syllabus, and self-assessment questions, to serve as a self-study device. Over thecourse of 24 months, all clinically relevant and key elements of nephrology will be reviewedand updated. The authors of each issue digest, assimilate, and interpret key studies publishedsince the release of the previous issues and integrate this new material with the body ofexisting information. Occasionally a special edition is produced to cover an area not ordinarilyaddressed by core issues of NephSAP.

SELF-ASSESSMENT:Thirty, single-best-answer questionswill follow the 80 to 100 pages ofsyllabus text. The examination is available online with immediate feedback. Those answering75% correctly will receive MOC and CME credit, and receive the answers to all the questionsalong with brief discussions and an updated bibliography. Members will find a new areareviewed every 2 months, and they will be able to test their understanding with our quiz. Thisformat will help readers stay up to date in developing areas of clinical nephrology,hypertension, dialysis, and transplantation, and the review and update will support thosetaking certification and recertification examinations.

CONTINUINGMEDICALEDUCATION:Most state and local medical agencies as well ashospitals are demanding documentation of requisite CME credits for licensure and for staffappointments. A maximum of 48 credits annually can be obtained by successfully completingthe NephSAP examinations. In addition, individuals enrolled in Maintenance of Certification(MOC) through the American Board of Internal Medicine may obtain points towardMOC bysuccessfully completing the self-assessment examination of NephSAP.

N This paper meets the requirements of ANSI/NISO Z39.48-1921 (Permanence of Paper),effective with July 2002, Vol. 1, No. 1.

NephSAP�

�2016 by The American Society of Nephrology

Editorial1 Adiposity and Blood Pressure Control: Implications

for Clinical PracticeSankar D Navaneethan, Adam Whaley-Connell

Syllabus7 NephSAP, Volume 15, Number 1, March

2016—HypertensionAldo J. Peixoto, Debbie L. Cohen

7 Learning Objectives

7 Update on the Epidemiology of Hypertension

7 Hypertension as a Mediator of CardiovascularDisease Burden

8 Hypertension Awareness, Treatment, and Control

11 Adverse Outcomes Related to Low DBP

13 Prognostic Relevance of Long–Term Visit to Visit BPVariability

14 Prehypertension and Risk of ESRD

15 Hypertension after AKI

15 Albuminuria and Hypertension: What ComesFirst?

16 Social Stress and Hypertension: The HousingForeclosures Story

16 Antiretroviral Therapy and Hypertension

17 And the Salt Debates Continues. . .

21 Update on the Mechanisms of Hypertension withRelevance to Clinical Practice

21 Unraveling the Effects of Dietary Potassium on BP

23 Pendrin Overexpression and Chloride-InducedHypertension

24 Proteolytic Activation of the ENaC

25 Vascular Smooth Muscle Cell Stiffness as a Mediatorof Arterial Stiffness in Hypertension

25 Aortic Stiffness and Risk of Renal Injury

26 Hypertension with Brachydactyly Is Caused bya Mutation in Phosphodiesterase-3A

28 Update on the Evaluation of the HypertensivePatient

28 Technological Updates on BP Measurement

28 Recommendations for Screening and Confirmation ofHigh BP in Adults

30 New ABPM Guidelines

31 ABPM and Home BP Monitoring: New PrognosticStudies in Hypertension

34 Orthostatic Hypotension

34 Objective Volume Assessment in the Evaluation ofHypertensive Patients with CKD

36 Secondary Hypertension: Obesity-RelatedHypertension

36 Physiologic Mechanisms

36 Effects of Bariatric Surgery

38 Sleep Apnea, Use of Continuous Positive AirwayPressure, and Effects on Hypertension

41 Primary Aldosteronism

42 Diagnosis of Primary Aldosteronism

42 ARR for Screening of Primary Aldosteronism

42 Adrenal Vein Sampling

43 Summary of the Consensus Statement on AdrenalVein Sampling (26)

43 Novel Testing for Primary Aldosteronism

44 Treatment of Primary Aldosteronism: Predictors ofBP Control after Adrenalectomy

44 Somatic Mutations in Primary Aldosteronism

44 Somatic Mutations and Left Ventricular Hypertrophy

44 Prorenin Levels

45 Pheochromocytoma

45 Clinical Studies in Pheochromocytoma andParaganglioma

46 Genetics of Pheochromocytoma and Paraganglioma

46 Fibromuscular Dysplasia

51 Atherosclerotic Renal Artery Stenosis

Volume 15, Number 1, March 2016

54 BP Guideline Updates

57 BP Goals in CKD

62 Update on the Treatment of Hypertension

62 Payments to Physicians and Practices to RewardHypertension Control

64 Self-Titration of Antihypertensive Therapy and theUse of Telemedicine in Hypertension

66 Pharmacogenetics to Predict Antihypertensive DrugResponse

67 Treatment of Mild Hypertension

67 Clinical Studies: Devices, Diets, Supplements, andCombination Therapy

67 Device-Guided Breathing for Hypertension

68 Effects of Vitamin D Supplementation on BP

68 Sodium-Glucose Transporter 2 Inhibitors Effect onLowering BP

69 Thiazides: Chlorthalidone Versus HCTZ—TheDebate Continues

69 Atenolol Versus Metoprolol in CKD

70 Azelnidipine—A New Calcium Channel Blocker

70 Medication Adherence and Use of Generic Drugs

70 Fish Oil and BP

70 Vegetarian Diets and BP

71 Dietary Nitrates and Hypertension

71 Combination Therapy

77 Renal Denervation Update

77 Update on the Symplicity HTN-1 Study

77 Symplicity HTN-3 Study Results

77 Possible Reasons Why the Symplicity HTN-3 StudyWas Negative and What Seems to PredictResponse to RDN

79 Twelve-Month Data from the Symplicity HTN-3Study

80 Other Renal Denervation Studies

80 Predicting RDN Response

80 RDN in Milder Resistant Hypertension

80 RDN in Isolated Systolic Hypertension

81 The Global Symplicity Registry

81 Safety of Renal Denervation

81 The Future of Renal Denervation

82 Other Approaches for Renal Denervation

82 Ethanol-Based Sympathicolysis of Renal Nerves

83 Extracorporeal High–Intensity Focused Ultrasound

83 Baroreflex Activation Therapy

84 The Effects of Chronic Aldosterone Infusion onBaroreflex Activation Therapy and RenalDenervation

84 Arteriovenous Fistula for Hypertension

87 Hypertension in the Elderly and Cognition

89 Stroke Update

92 Intra-Arterial Revascularization after IschemicStroke

93 Intracerebral Hemorrhage Associated with the Useof Anticoagulant Therapy

95 New Developments in the Treatment of SpecialPopulations

95 Outcomes According to Drug Class in Asians

95 Outcomes of Different Drug Classes According toBody Mass Index

96 Drug Choices and BP Targets in Polycystic KidneyDisease

97 Aliskiren and Coronary Atherosclerosis inPrehypertension

97 Treatment of Neurogenic Orthostatic Hypotension

98 Complications of Hypertension Treatment

98 LCZ696 (Valsartan/Sacubitril) and AlzheimerDisease Risk

98 Antihypertensive Medication Use and Risk of Falls inthe Elderly

CME Self-Assessment Questions100 NephSAP, Volume 15, Number 1, March

2016—Hypertension Examination


Upcoming IssuesPregnancy and the KidneyBelinda Jim, MD, Kate Bramham, MBBS, Sharon E. Maynard, MD,

and Michelle A. Hladunewich, MD

May 2016

Glomerular, Vascular, and Tubulointerstitial DiseasesRichard J. Glassock, MD and Brad H. Rovin, MD

July 2016

Renal Bone Disease, Disorder of Divalent Ions, andNephrolithiasisStanley Goldfarb, MD and Kevin J. Martin, MBBCh

September 2016

End-Stage Renal Disease and DialysisRuediger W. Lehrich, MD and John P. Middleton, MD

November 2016


The Editorial Board of NephSAP extends its sincere appreciation to the following reviewers. Their efforts and insights have helped to improvethe quality of this postgraduate education offering.

NephSAP Review PanelMustafa Ahmad, MD, FASNKing Fahad Medical CityRiyadh, Saudi Arabia

Kamal E. Ahmed, MD, FASNYuma NephrologyYuma, AZ

Sadiq Ahmed, MDUniversity of KentuckyLexington, KY

Nasimul Ahsan, MD, FASNNorth Florida/South GeorgiaVA Health SystemGainesville, FL

Jafar Al-Said, MD, FASNBahrain Specialist HospitalManama, Bahrain

Naheed Ansari, MD, FASNJacobi Medical Center/Albert EinsteinCollege of MedicineBronx, NY

Gopal Basu, MDChristian Medical CollegeVellore, Tamil Nadu, India

Mona B. Brake, MD, FASNRobert J. Dole VA Medical CenterWichita, KS

Chokchai Chareandee, MD, FASNUniversity of MinnesotaMinneapolis, MN

Bulent Cuhaci, MD, FASNAmerican HastanesiIstanbul, Turkey

Kevin A. Curran, MDFresenius Medical Care & US RenalCare Dialysis FacilitiesCanton, TX

Rajiv Dhamija, MDRancho Los Amigos NationalRehabilitation CenterDowney, CA

Mahmoud El-Khatib, MDUniversity of CincinnatiCincinnati, OH

Lynda A. Frassetto, MD, FASNUniversity of California atSan FranciscoSan Francisco, CA

Claude Mabry Galphin, MDNephrology AssociatesChattanooga, TN

Duvuru Geetha, MD, FASNJohns Hopkins UniversityBaltimore, MD

Carl S. Goldstein, MD, FASNRobert Wood JohnsonMedical SchoolNew Brunswick, NJ

Steven M. Gorbatkin, MD, PhDEmory University,Atlanta, GA

Ashik Hayat, MD, FASNTaranaki Base HospitalNewplymouth, Taranaki, NZ

Ekambaram Ilamathi, MD, FASNState University of New YorkStony Brook, NY

Talha Hassan Imam, MDKaiser PermanenteFontana, CA

Pradeep V. Kadambi, MDUniversity of ArizonaTucson, AZ

Sharon L. Karp, MDIndiana UniversityIndianapolis, IN

Amir Kazory, MD, FASNUniversity of FloridaGainesville, FL

Apurv Khanna, MDSUNY Upstate Medical UniversitySyracuse, NY

Nitin V. Kolhe, MD, FASNRoyal Derby HospitalDerby, Derbyshire, UK

Rahul Koushik, MDUniversity of TexasHealth Science CenterSan Antonio, TX

Lalathaksha Murthy Kumbar, MBBSHenry Ford HospitalDetroit, MI

Nicolae Leca, MDUniversity of WashingtonSeattle, WA

Paolo Lentini, MD, PhDSan Bassiano HospitalBassano del Grappa, Italy

Edgar V. Lerma, MD, FASNUniversity of Illinois at ChicagoCollege of MedicineChicago, IL

Orfeas Liangos, MD, FASNKlinikum CoburgCoburg, Bayern, Germany

Meyer Lifschitz, MDShaare Zedek Medical CenterJerusalem, Israel

Naveed Masani, MDWinthrop University HospitalMineola, NY

Hanna W. Mawad, MD, FASNUniversity of KentuckyLexington, KY

Kevin McConnell, MDJefferson Nephrology, LtdCharlottesville, VA

Pascal Meier, MD, FASNCentre Hospitalier du Valais RomandSion, Switzerland

Ashraf Mikhail, MBBChMorriston HospitalSwansea, Wales, UK

Lawrence S. Moffatt, Jr., MDCarolinas Medical CenterCharlotte, NC

Sumit Mohan, MDColumbia University College ofPhysicians and SurgeonsNew York, NY

Koosha Mortazavi, MDVista Del Mar Medical GroupOxnard, CA

Tariq Mubin, MDKern Nephrology Medical GroupBakersfield, CA

Thangamani Muthukumar, MDCornell UniversityNew York, NY

Macaulay A. Onuigbo, MD, FASNMayo ClinicRochester, MN

Kevin P. O'Reilly, MDOhio State UniversityColumbus, OH

Carlos E. Palant, MDWashington DC VA Medical CenterWashington, DC

Malvinder Parmar, MB, MS, FASNNorthern Ontario School of MedicineTimmins, ON, Canada


Pairach Pintavorn, MD, FASNEast Georgia Kidney and HypertensionAugusta, GA

James M. Pritsiolas, MD, FASNCarePoint Health Medical GroupBayonne and Chatham, NJ

Paul H. Pronovost, MD, FASNYale University School of MedicineWaterbury, CT

Mohammad A. Quasem, MDUniversal Health Services HospitalsBinghamton, NY

Wajeh Y. Qunibi, MDUniversity of TexasHealth Science CenterSan Antonio, TX

Pawan K. Rao, MD, FASNSt. Joseph HospitalSyracuse, NY

Bharathi V. Reddy, MDUniversity of ChicagoMedical CenterChicago, IL

Joel C. Reynolds, MD, FASNInternal Medicine ClinicMeridian, MS

Brian S. Rifkin, MDHattiesburg ClinicHattiesburg, MS

Helbert Rondon-Berrios, MD, FASNUniversity of PittsburghSchool of MedicinePittsburgh, PA

Bijan Roshan, MD, FASNKidney Associates of ColoradoDenver, CO

Mario F. Rubin, MD, FASNUniversity of ArizonaTucson, AZ

Ehab R. Saad, MD, FASNMedical College of WisconsinMilwaukee, WI

Mark C. Saddler, MBChBDurango Nephrology AssociatesDurango, CO

Mohammad G. Saklayen, MBBSWright State UniversityBoonshoft School of MedicineDayton, OH

Mohammad N. Saqib, MDLehigh Valley HospitalOrefield, PA

Henry L. Schairer, Jr., MD, FASNLehigh Valley Health NetworkAllentown, PA

Gaurang M. Shah, MD, FASNLong Beach VA Healthcare SystemLong Beach, CA

Nita K. Shah, MDSt. Barnabas Health CenterLivingston, NJ

Arif Showkat, MD, FASNUniversity of TennesseeMemphis, TN

Manish M. Sood, MD, FASNUniversity of ManitobaWinnipeg, MB, Canada

Susan P. Steigerwalt, MDSt. John Providence HospitalDetroit, MI

Ignatius Yun-Sang Tang, MDUniversity of Illinois Hospital andHealth Sciences SystemChicago, IL

Ahmad R. Tarakji, MD, FASNCollege of Medicine, King Saud UniversityRiyadh, Saudi Arabia

Hung-Bin Tsai, MDNational Taiwan UniversityHospitalTaipei, Taiwan

Anthony M. Valeri, MDColumbia UniversityNew York, NY

Allen W. Vander, MD, FASNKidney Center of SouthLouisianaThibodaux, LA

Juan Carlos Q. Velez, MDMedical University of SouthCarolinaCharleston, SC

Shefali Vyas, MDSt. Barnabas Health CenterLivingston, NJ

Nand K. Wadhwa, MDStony Brook UniversityStony Brook, NY

Sameer Yaseen, MDNephrology PCDes Moines, IA

Mario Javier Zarama, MDKidney Specialists ofMinnesota, PASaint Paul, MN

Program Mission and ObjectivesThe Nephrology Self-Assessment Program (NephSAP) provides a learning vehicle for clinical nephrologists to renew andrefresh their clinical knowledge, diagnostic, and therapeutic skills. This enduring material provides nephrologists challenging,clinically oriented questions based on case vignettes, a detailed syllabus that reviews recent publications, and an editorial on animportant and evolving topic. This combination of materials enables clinicians to rigorously assess their strengths andweaknesses in the broad domain of nephrology.

Accreditation StatementThe American Society of Nephrology (ASN) is accredited by the Accreditation Council for Continuing Medical Education toprovide continuing medical education for physicians.

AMA Credit Designation StatementThe ASN designates this enduring material for a maximum of 10 AMA PRA Category 1 Credits™. Physicians should claimonly the credit commensurate with the extent of their participation in the activity.

Original Release Date

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CME Credit Termination Date

February 28, 2018

Examination Available Online

On or before Monday, March 14, 2016

Estimated Time for Completion

10 hours

Answers with Explanations

• Provided with a passing score after the first and/or after the second attempt

• March 2018: posted on the ASN website when the issue is archived.

Target Audience

• Nephrology certification and recertification candidates

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Method of Participation

• Read the syllabus that is supplemented by original articles in the reference lists.

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Instructions to obtain American Board of Internal Medicine (ABIM) Maintenance of Certification(MOC) PointsEach issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria:

• Be certified by ABIM in internal medicine and/or nephrology and enrolled in the ABIM–MOC program

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• Enter your (ABIM) Candidate Number and Date of Birth prior to completing the examination.

• Take the self-assessment examination within the timeframe specified in this issue of NephSAP.

• Below your score, select “Click here to post to ABIM.”

MOC points will be applied to only those ABIM candidates who have enrolled in the MOC program. It is your responsibility tocomplete the ABIM MOC enrollment process.

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If you have difficulty viewing any of the pages, please refer to the ASN technical support page for possible solutions. If youcontinue having problems, contact ASN at [email protected].


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Disclosure InformationThe ASN is responsible for identifying and resolving all conflicts of interest prior to presenting any educational activity to learners to ensure thatASN CME activities promote quality and safety, are effective in improving medical practice, are based on valid content, and are independent of thecontrol from commercial interests and free of bias. All faculty are instructed to provide balanced, scientifically rigorous and evidence-basedpresentations. In accordance with the disclosure policies of the Accreditation Council for Continuing Medical Education (ACCME), individuals who arein a position to control the content of an educational activity are required to disclose relationships with a commercial interest if (a) the relation is financialand occurred within the past 12 months; and (b) the individual had the opportunity to affect the content of continuing medical education with regard to thatcommercial interest. For this purpose,ASNconsider the relationships of the person involved in theCMEactivity to includefinancial relationships of a spouseor partner. Peer reviewers are asked to abstain from reviewing topics if they have a conflict of interest. Disclosure information is made available to learnersprior to the start of any ASN educational activity.

EDITORIAL BOARD:Debbie L. Cohen, MD—Current Employer: University of Pennsylvania School of Medicine; Scientific Advisor or Membership: Editorial board:

Journal of Clinical Hypertension; Member, ASN Hypertension advisory groupGerald A. Hladik, MD—Current Employer: University of North Carolina at Chapel Hill; Scientific Advisor/Membership: Co-Director for NephSAP,

American Society of NephrologyAldo J. Peixoto, MD—Current Employer: Yale University School of Medicine; Honoraria: Society of Critical Care Medicine, Brown University,

University of Pennsylvania; Scientific Advisor or Membership: Associate Editor, Blood Pressure Monitoring; Editorial Board: CJASN, AmericanJournal of Nephrology, Brazilian Journal of Nephrology, Faculty of 1000 Prime; Society Committees: American Society of Hypertension: CMECommittee, Clinical Practice Committee; ASH Hypertension Centers Committee

Manoocher Soleimani, MD—Current Employer: University of CincinnatiCharuhas V. Thakar, MD—Current Employer: University of Cincinnati; Consultancy: AbbVie, Quark Pharmaceuticals; Research Funding:

Hospira, AbbVie, AstraZeneca; Honoraria: Yale University; University of New Mexico, Rush University/Perioperative Summit; CRRT;Scientific Advisor and Other Interests/Relationships: Co-editor; Textbook with Springer

Jerry Yee, MD, FASN—Current Employer: Henry Ford Hospital; Consultancy: Amgen, Vasc-Alert, Alexion, ZS Pharma; Ownership Interest:Merck, Gilead; Honoraria: Amgen, Alexion, Gerson, Drexel University, University of California at San Diego, ZS Pharma; Patents/Inventions: Vasc-Alert; Scientific Advisor/Membership: NKF: Editor-in-Chief of Advances in CKD (journal); Editorial Board: CJASN, American Journal of Nephrology,Co-Director for NephSAP; Other Interests/Relationships: Chief Medical Director, Greenfield Health Systems

EDITORIAL AUTHORS:Sankar D. Navaneethan, MD, MPH, FASN—Current Employer: Baylor College of Medicine; Consultancy: AbbVie, Boehringer Ingelheim (End-point adjudication committee member) Scientific Advisor or Membership: Editorial board: CJASN, AJKD, American Journal of Nephrology, ClinicalNephrology; American Society of Nephrology: CKD advisory group memberAdam Whaley-Connell, DO, MPH, FASN—Current Employer: Harry S. Truman Memorial Veterans Hospital

ASN STAFF:Gisela A. Deuter, BSN, MSA—Nothing to disclose

Commercial SupportThere is no commercial support for this issue.


EditorialAdiposity and Blood Pressure Control: Implications for Clinical Practice

Sankar D Navaneethan, M.D., M.S., M.P.H.*† and Adam Whaley-Connell, D.O., M.S.P.H.‡§k

*Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, BaylorCollege of Medicine, Houston, Texas; †Section of Nephrology, Michael E. DeBakey VeteransAffairs Medical Center, Houston, Texas; ‡Research Service, Harry S Truman Memorial VeteransHospital, Columbia, Missouri; and Divisions of §Nephrology and Hypertension, andkEndocrinology and Metabolism, Department of Medicine, Columbia School of Medicine,University of Missouri, Columbia, Missouri

Obesity and hypertension remain a public healthdilemma (1–3). In this context, more than one-third ofUS adults are obese and about 28.5% have high bloodpressure (1). The combination of obesity and hyper-tension promote cardiovascular and kidney disease. Ithas been estimated that the annual medical cost ofobesity was nearly US $147 billion in 2008 and,concurrent with hypertension, accounts for significanthealth care expenditure (4). Despite the economic andcomorbid burden, there is a significant lack of aware-ness regarding blood pressure and risk-factor controlamong individuals with hypertension and obesity, re-spectively (1,5). Currently, non-Hispanic blacks havethe highest age-adjusted rates of obesity, and thispopulation bears a disproportionate burden of hyper-tension and chronic kidney disease (CKD). Indeed,among those with CKD, the prevalence of hypertensionis much higher (6,7). Further, over two-thirds of individ-uals with CKD are either overweight or obese (8,9), andobesity is associated with further decline in kidneyfunction (10,11). It is clear that excess adiposity contrib-utes to the development of blood pressure elevation;however, it is unknown whether special considerationsshould be given (with respect to antihypertensive medi-cations) to those with obesity and hypertension. Theevidence supporting weight loss to optimize blood pres-sure and kidney function is important to clinical practice.

PathophysiologyExperimental models and studies propose mech-

anisms to explain obesity-related hypertension, andsome suggest hypertension by itself contributes to thedevelopment of obesity (12–15). A complex interplayof epigenetic (e.g.,environmental-,lifestyle-, diet-, and

behavior-related), genetic, and neurohormonal factorscontribute to the development of hypertension in thecontext of obesity. Changes in behavioral (less physicalactivity) and dietary (larger portion sizes and consump-tion of high-fat and high-fructose diets) factors thatcontribute to the obesity epidemic have also led tothe rise in hypertension rates. Obesity contributes toheightened sympathetic nervous system (SNS) andrenin-angiotensin-aldosterone system (RAAS) activityand drives obesity-related blood pressure elevations (16).There are a number of contributory mechanisms thatdrive excess SNS and RAAS activities in the setting ofobesity. In this vein, the findings of multiple preclinicalexperimental studies suggest that excess adiposity acti-vates intrarenal RAAS (13), but the clinical significanceof this remains unknown. Importantly, in the setting ofexcess fat, there is population-level data to suggest thataldosterone levels are higher and the observed increasesin blood pressure occur through aldosterone-mediatedagonism of mineralocorticoid and glucocorticoid recep-tors (17,18). To date, much of the clinical work suggeststhat excess aldosterone produces the bulk of treatment-resistant hypertension that is described (19).

In addition to excess RAAS activity, increases inadipokines (e.g., leptin) in overweight individuals withunderlying obstructive sleep apnea augment underlyingSNS perturbations and potentiate further blood pressurechanges (13,20). With regard to renal microcirculation,excess weight contributes to physical alterations in renalhemodynamics, resulting in glomerular hyperfiltrationand intraglomerular hypertension, thereby influencingtubuloglomerular feedback. However, alterations in tu-buloglomerular feedback are not the only mechanismsthat may influence blood pressure in individuals with

Nephrology Self-Assessment Program - Vol 15, No 1, March 2016

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obesity. The obese population is sensitive to dietarysodium intake, which is attributed to the combined effectsof hyperinsulinemia, hyperaldosteronism, and increasedactivity of the SNS on the renal tubule.

Obesity has also been linked to endothelial dys-function and arterial stiffness, which often precedes thedevelopment of hypertension (21). Although these hemo-dynamic and vascular effects are related more tovisceral fat in humans, there has been little mechanisticwork to dissect the processes that influence this relation-ship. There is increasing interest in alterations of the gutmicrobiome and the association of this with obesity andhypertension (22). Several previous reviews have dis-cussed in detail the individual mechanisms that linkobesity and hypertension (23–25). We anticipate the gutmicrobiome to remain an active area of interest for yearsto come. There have been multiple prospective clinicalstudies that support the association between obesity andhypertension for over 50 years (26). Although it is clearthat there is an association between hypertension andobesity, and there may be cause and effect, there is littleknown regarding the effect of weight-loss interventionson blood pressure parameters and kidney function.

Weight Loss, Hypertension, and Kidney FunctionEffects on Blood Pressure

Data from a pooled analysis of 25 clinical trialsenrolling 4874 participants without preexisting kidneydisease demonstrated significant systolic and diastolicblood pressure reductions after a 5.1 kg weight loss(27). A correlation between weight loss and bloodpressure reduction highlights the importance of weightloss for preventing and treating hypertension. Notably,the majority of studies did not include participantswith preexisting kidney disease. Studies examining theeffects of weight loss on blood pressure reduction inthose with existing kidney disease are limited. How-ever, most studies that have examined the effect ofvarious weight-loss modalities in CKD have reportedmodest improvements in systolic and diastolic bloodpressure (28–30). Although exercise and lifestyle in-terventions were also associated with improvements incardiorespiratory fitness, their effect on kidney diseaseprogression is unknown (31,32).

Look AHEAD Trial DataThere is sufficient data to support the contention

that lifestyle interventions, such as weight loss, theDietary Approaches to Stop Hypertension diet, and

tobacco cessation, improve blood pressure control inthe general population. What is not known is whetherlifestyle modification affects kidney function. Severalsmaller studies, and a subsequent meta-analysis oftheir results, have reported a beneficial effect of weightloss on blood pressure and other vascular stiffnessmarkers, such as pulse wave velocity (33). In a sec-ondary analysis of the Look AHEAD trial data, theeffects of intense lifestyle intervention on blood pres-sure, glycemic control, and kidney outcomes werestudied (34). Briefly, in the Look AHEAD trial, 5145overweight or obese individuals with type 2 diabetes wererandomly assigned to intensive lifestyle modification orstandard diabetes support and education at 16 clinicalsites in the United States. Mean weight loss was greaterin the intensive lifestyle intervention group versus thediabetes support and education group at one year (8.6%versus 0.7%). During a median follow-up of 9.6 years,weight loss in the intensive lifestyle group was 4 kg morethan the diabetes support and education group. Averagedover time, systolic blood pressure was lower, and antihy-pertensive medication use was less common in theintensive lifestyle modification group. Very high riskCKDwas defined as: (1) an eGFR,30ml/min per 1.73m2

irrespective of albuminuria, (2) an eGFR,45 ml/minper 1.73 m2 and albuminuria .30 mg albumin/g ofcreatinine, or (3) eGFR,60 ml/min per 1.73 m2 andalbuminuria .300 mg albumin/g of creatinine. Theincidence of very high risk CKD was lower withintensive lifestyle modification. When body weight,hemoglobin A1c, and systolic blood pressure wereadded to a multivariable model that predicts very high-risk CKD, the risk was attenuated, suggesting that theeffect of lifestyle on CKD is mitigated through these riskfactors. These data further underscore the sustainedeffects of weight loss on blood pressure and the potentialrenal benefit in people with obesity with preservedkidney function.

Weight-Loss Drugs in HypertensionA Cochrane meta-analysis pooled nine clinical

trials that enrolled adults with hypertension and com-pared weight-loss drugs such as orlistat and sibutramine(35). In patients with elevated blood pressure, orlistatand sibutramine reduced body weight, but orlistat re-duced blood pressure and sibutramine increased bloodpressure. In this analysis, there were no data regardingmortality and morbidity. It is important to note that dataon weight-loss drugs in the obese CKD population is

2 Nephrology Self-Assessment Program - Vol 15, No 1, March 2016

limited and acute kidney injury has been reported withorlistat use in the general population (36). Recently, theUS Food and Drug Administration approved newweight-loss-promoting drugs, but their role in CKD is unclear.

Choice of Antihypertensives and Their EffectsAccording to Body Size

Although antihypertensive medications are notdosed according to body mass index (BMI) in adults, itis not clear whether the effects of antihypertensivetherapy differ according to factors such as body sizeor BMI. Data from a prespecified secondary analy-sis of the Avoiding Cardiovascular Events throughCombination Therapy in Patients Living with SystolicHypertension (ACCOMPLISH) trial suggest thatbody size influences the cardiovascular outcomesof various treatment options for hypertension (37).ACCOMPLISH, a multicenter trial, aimed to comparethe effects of a combination of angiotensin-convertingenzyme-inhibition (ACEI) and a calcium channelblocker (CCB) with the effects of a combination ofACEI with a thiazide diuretic in those with hypertension.The composite primary endpoint (cardiovascular deathor non-fatal myocardial infarction or stroke) was 30.7 inpatients of normal weight, 21.9 in patients who wereoverweight, and 18.2 in patients with obesity (per 1000patient-years) in those allocated to ACEI and diuretic.The composite primary endpoint did not differ betweenthe three BMI groups among those allocated to ACEIand CCB. In this context, in patients with obesity,the primary event rates were similar between groups.However, rates were significantly lower with ACEI andCCB in overweight patients (hazard ratio, 0.76; 95%confidence interval [95% CI], 0.59 to 0.94; P¼0.03)and those of normal weight (hazard ratio, 0.57; 95% CI,0.39 to 0.84; P,0.01). These data may suggest thatdifferent mechanisms might mediate hypertension inpatients of normal weight and patients with obesity(e.g., SNS and RAAS). ACEI plus a CCB seem to beequally effective, irrespective of BMI, whereas ACEIplus a thiazide diuretic might not be effective in thosewho are lean and have hypertension. These data areapplicable only to those without preexisting kidneydisease, because diuretics are often indicated in patientswith kidney disease and CCBs could impair autoregu-lation in CKD (6).

The population-level data, discussed above, andexperimental data suggest that patients with obesityhave augmented RAAS activity, and this raises the

question of whether these patients will have incremen-tal benefits during RAAS blockade. In a post hocanalysis of the Ramipril Efficacy In Nephropathy trial,Mallamaci and colleagues examined whether beingoverweight or obese affects the response to ACEI(ramipril, n¼337) (38). Among patients treated withplacebo, the incidence rate of end-stage renal disease(ESRD) was substantially higher in patients withobesity than those with normal BMI (24 versus 10events per 100 person-years). ACEI reduced the rate ofrenal events in all BMI strata, but the effect was higheramong patients with obesity (incident rate reduction86% for ESRD) than patients who were overweight(incident rate reduction, 45%) or those with normalBMI, suggesting that the risk reduction conferred byACEI is larger among patients with obesity. This studycorroborated an interesting hypothesis and providedadditional evidence to support the use of ACEI in thosewho are obese.

Role of Aldosterone BlockadeAs discussed above, several studies have reported

higher circulating levels of aldosterone in individualswith obesity. Reduction in aldosterone levels withweight loss was first demonstrated over 30 years ago,and further studies demonstrated a favorable RAASprofile with weight loss in obesity (39,40). Usingmouse models, low-dose spironolactone was shownto attenuate vascular inflammation, oxidative stress,and possibly prevent development of arterial stiffeningsecondary to consumption of a Western diet. In oneprospective cohort that randomized 113 patients witha BMI .30 kg/m2, without comorbidities but with-impaired early diastolic mitral annular velocity, tothe mineralocorticoid receptor antagonist spironolac-tone 25 mg once daily or placebo for 6 months (41),results suggested that spironolactone improved leftventricular function and myocardial acoustic propertieseven in the absence of comorbidities, highlighting thebeneficial effects of spironolactone in obesity. Further,recent data suggest spironolactone to be the best add-onagent for the treatment of resistant hypertension inthose who are already on three different antihyperten-sive medications (42).

In a meta-analysis evaluating aldosterone recep-tor antagonists in preexisting CKD, a significant re-duction in both systolic and diastolic blood pressureswith the addition of a nonselective aldosterone antag-onist was reported (43). Even though aldosterone

Nephrology Self-Assessment Program - Vol 15, No 1, March 2016 3

antagonist therapy was associated with decreasingurinary protein excretion, its effect on kidney functiondecline remains unclear. Particularly, the risk of hyper-kalemia was two-fold higher in the treatment group.Despite its antifibrotic and beneficial effects reported inheart failure, a major concern for hyperkalemia anda lack of long-term data limited its clinical utility topopulations with resistant hypertension, particularly inthose with kidney disease (42,44,45). Recently, a 90-daytrial reported the beneficial effects of aldosterone antag-onism on urinary albumin excretion (46). The risks ofhyperkalemia leading to discontinuation in the finere-none 7.5-, 15-, and 20-mg/d groups were 2.1%, 3.2%,and 1.7%, respectively. Additional data establishing thelong-term effects and safety are warranted (47).

Obstructive Sleep Apnea, Hypertension, and KidneyDisease

Several studies support the link between sleep-disordered breathing and incident hypertension(20,48). Apart from increased SNS activity due tointermittent hypoxia, endothelial dysfunction, systemicinflammation, and abnormal autonomic function havebeen implicated in the development of obstructive sleepapnea (OSA)-induced hypertension (49). Further, pa-tients with OSA also experience nocturnal bloodpressure non-dipping that fosters a persistently elevatedblood pressure (50). In a large study, including over3 million US veterans, Molnar and colleagues reportedthat the risk of incident CKD was also significantlyhigher in patients with untreated (hazard ratio, 2.27;95% CI, 2.19 to 2.36) and treated (hazard ratio, 2.79;95% CI, 2.48 to 3.13) OSA, highlighting the effects onkidney function (51). Similar results were shown ina recent meta-analysis (n¼12 studies) that noted a 73%increased risk for diabetic kidney disease (52).

In the CKD and ESRD populations, underlyingvolume overload also produced upper airway edemaand worsening of OSA by circumferential trachealcompression (bidirectional relationship),which in turnaggravated hypertension (53). Unabated, this viciouscycle could lead to adverse cardiovascular outcomes.Recent clinical trials have demonstrated the benefits ofcontinuous positive airway pressure in those with OSA(54). It is important to note that most of these trials wereof short duration (,12 weeks), with 24-hour meanarterial blood pressure as the primary outcome mea-sure. Whether these data translate to improvements inlonger-term health outcomes regarding cardiovascular

and kidney disease warrants additional study. As weawait such studies, physicians treating patients withdifficult-to-control hypertension or obesity and hyper-tension should consider further evaluation and man-agement of underlying sleep-disordered breathing inthe CKD/ESRD population.

Obesity, Bariatric Surgery, and Blood PressureSeveral prospective studies and, more recently,

randomized, controlled trials have reported type 2diabetes remission in patients with morbid obesity afterbariatric surgery. Data from the Longitudinal Assess-ment of Bariatric Surgery Consortium (n¼2458),a multicenter, observational, cohort study, reportedremission of hypertension (defined as blood pres-sure ,140/90 mmHg without medication) in 38.2%of individuals undergoing gastric bypass and 17.4% ofthose undergoing gastric banding (55). These im-provements were in addition to improved glycemiccontrol. Similar results were also noted in a systematicreview that included 29 studies,which further concludedthat gastric bypass led to higher rates of remission ofdiabetes and hypertension compared with the gastricsleeve procedure (56). Although a few studies havereported the metabolic effects of bariatric surgery inpatients with kidney disease, its long-term effect onkidney disease progression is unclear (57,58). Further,the risks of acute kidney injury, higher in-hospitalcomplications, and development of kidney stones haveto be considered during referral (59,60).

ConclusionsObesity-related hypertension is a significant prob-

lem and multiple mechanisms explain the link betweenincreases in BMI and elevations in blood pressure.Lifestyle modification in patients with obesity is associatedwith improvements in blood pressure and may havea potentially beneficial effect on kidney function. Clini-cians should also evaluate for underlying OSA in high-riskpatients. Although aldosterone antagonism is promising forthose with obesity and treatment-resistant hypertension,additional studies that appraise their long-term benefits andsafety are justified for the CKD population.

Acknowledgments

S.D.N. is supported by R01DK101500. The content is solelythe responsibility of the authors and does not necessarilyrepresent the official views of the National Institutes of Health.


Disclosures

SDN serves on the event adjudication committee for clinicaltrials sponsored by Boeringher-Ingelheim (Rheim, Germany)and Abbvie (North Chicago, Illinois). The authors have norelevant financial interest in the study.

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SyllabusNephSAP, Volume 15, Number 1, March 2016—Hypertension

Aldo J. Peixoto, MD, FASN,* and Debbie L. Cohen, MD†

*Department of Medicine, Section of Nephrology, Yale University School of Medicine, NewHaven, Connecticut; and †Department of Medicine, Renal-Electrolyte and Hypertension Division,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

Learning Objectives1. To discuss updated information on the epide-

miology of hypertension, in particular therole of hypertension on the global burden ofcardiovascular disease

2. To examine clinically relevant mechanisms ofhypertension, especially mechanisms leadingto salt sensitivity and the role of potassium inBP regulation

3. To review recent developments in the use ofout of office BP monitoring in the care ofpatients who are hypertensive

4. To describe recent developments in second-ary hypertension, particularly in pheochromo-cytoma and primary aldosteronism

5. To analyze recent hypertension guidelinesand clinical trials guiding the care of patientswho are hypertensive

Significant advances have occurred since the lastissue of the Nephrology Self-Assessment Program(NephSAP) on hypertension (1). In this issue, we willreview a selection of clinically relevant developments in theepidemiology, mechanisms, clinical evaluation, and man-agement of hypertension. We will frequently reference thetwo previous issues of NephSAP on hypertension (1, 2).

Update on the Epidemiology of Hypertension

Hypertension as a Mediator of CardiovascularDisease Burden

Hypertension remains one of the major risk factorsfor cardiovascular disease and death. In the GlobalBurden of Disease 2010 Report (3), myocardial infarctionand stroke are the two major worldwide causes of death;first and third causes of lost life-years, respectively; and

first and fifth causes of disability–adjusted life years(DALYs; summary metric of years of life lost and yearslived with a disability or alternatively, a measure ofhealthy life lost), respectively. Given the strong relation-ship between hypertension and myocardial infarctionand stroke, the same report ranked hypertension as thenumber 1 risk factor for loss of healthy life aheadof other risk factors, such as tobacco smoking, airpollution, alcohol abuse, obesity, and diabetes. In thisanalysis of 187 countries, 291 diseases, and 67 riskfactors, hypertension was responsible for 173.5 millionof 2.48 billion DALYs observed worldwide in 2010(3). Of concern, hypertension rose from fourth to thefirst ranked risk factor between the 1990 and 2010reports. In these 20 years, the total number of world-wide DALYs decreased by 0.6% from 2.5 to 2.48 billion,whereas the hypertension-associated DALYs increasedby 26.7% from 137 to 173.5 million, emphasizing theimportance of aggressive efforts at hypertension iden-tification, treatment, and control worldwide.

This high burden of disease results in high costsof care related to hypertension. In the United States,the 2015 estimate for direct medical costs in the care ofcardiovascular disease is $358 billion (4). From this,$91.4 billion are directly linked to hypertension care,and $170.4 billion result from hypertension as a mediat-ing factor of coronary disease, heart failure, and stroke.Despite a projected increase in the prevalence of allcardiovascular disease and hypertension of only approx-imately 10% between 2010 and 2030, the projected costincrease is threefold (4), absent a change in current healthpolicy. Therefore, improved treatment strategies areessential to mitigate this large discrepancy betweenrates of change in prevalence and cost.

An analysis of the Cardiovascular Research UsingLinked Bespoke Studies and Electronic Health RecordsProgram, a British cohort of approximately 1.25 millionpatients aged $30 years old has produced data on the


7

relationship between hypertension and 12 differenttypes of cardiovascular events (5). Approximately33% of patients had BP.140/90 mmHg, and 20%were receiving treatment for hypertension. After 5.2years of follow-up, the investigators recorded 83,098events and provided estimates of lifetime risk relatedto specific events stratified by systolic BP (SBP) anddiastolic BP (DBP) (Figure 1). There were significantdifferences in the strengths of the relationship betweenSBP and DBP and their associations with specificcardiovascular diseases. Important differences in theoverall effect of systolic, diastolic, and systodiastolichypertension (SDH) on years of life lost related tohypertension (for each of the individual diseases andfor overall cardiovascular disease) are shown in Figure2. These data underscore that the lifetime burden ofhypertension remains substantial in a modern Westerncountry, despite widely available treatment. Addition-ally, they indicate the heterogeneity in associationswith BP components for the different types of cardio-vascular disease studied (5).

A report of the Chicago Heart AssociationDetection Project in Industry Study has providedinformation on the prognostic relevance of isolatedsystolic hypertension (ISH) and isolated diastolichypertension (IDH) in younger individuals (6). Thestudy enlisted 27,081 mostly white subjects ages 18–49 years old (mean, 33 years old) between 1967 and1973. At baseline, 48.8% of men and 25.5% of womenhad BP levels that fell into one of the hypertensivecategories (men: 25.3% ISH, 3.7% IDH, and 19.7%SDH; women: 12.9% ISH, 2.9% IDH, and 9.7%SDH). All were untreated and free of cardiovasculardisease. After mean follow-up of 31 years, SDH wasthe subtype associated with greatest risk for cardio-vascular events and mortality; however, cardiovas-cular risk was also significantly increased in IDH butnot ISH in men and ISH but not IDH among women(Figure 3) (6). Neither ISH nor IDH was associatedwith increased stroke risk in this group of youngerindividuals. The most significant limitations of thisstudy were the availability of a single supine BP atbaseline, which may have provided incorrect BPphenotyping, and the lack of updated BP and treat-ment data during follow-up. Nevertheless, this studyprovides relevant information on the long-term effectof different BP phenotypes, including the relevanceof IDH in men and ISH in women, adding further tothe growing recognition of these patterns as clinically

relevant and therefore, probably meritorious oftreatment.

Finally, the International Database on Ambula-tory Blood Pressure in Relation to CardiovascularOutcomes has produced important observations on theprognostic relevance of SBP and DBP subtypes on thebasis of 24-hour ambulatory BP monitoring profiles in8341 patients followed for a median of 11.2 years (7).According to the baseline 24-hour BP averages (using,130/80 mmHg as normal), 71% of patients werenormotensive, 5% had IDH, 11% had ISH, and 13%had SDH. During follow-up, a total of 329 cardiovas-cular events and 493 deaths (151 cardiovascular) oc-curred. Compared with normotension, ISH and SDHwere associated with increased rates in all outcomesassessed (coronary events, all cardiac events, stroke,cardiovascular death, and all-cause death), whereasIDH was associated only with increased nonfatalcoronary and cardiac events (coronary plus heartfailure). None of the patterns was associated withincreased noncardiovascular death. The authors alsoanalyzed the effect of age on the relative importance ofeach BP component (7). Not surprisingly, 24-hourDBP was a stronger predictor of risk among patients,50 years old, where every 1-SD (approximately5-mmHg) increase in DBP was associated with a 74%increased risk for all cardiovascular events and a four-fold increased risk of cardiovascular death. The SBPdid not add to risk prediction in this group. Amongthose ages $50 years old, however, SBP was thedriver of end points, with each 1 SD (approximately 9mmHg) resulting in a 39% increase in combinedcardiovascular events and a 51% increase in risk ofcardiovascular death. In this older subgroup, DBP hadno effect on outcomes (7).

Hypertension Awareness, Treatment, and ControlUpdated information on the rates of awareness,

treatment, and control of hypertension in the UnitedStates has been published on the basis of data from theNational Health and Nutrition Examination Survey(NHANES) 1999–2012 cohort (N¼37,005 individuals;12,262 with hypertension) (8). As depicted in Figure 4,82% of patients are aware of the diagnosis of hyper-tension, 75% are receiving treatment, and 51% arecontrolled (overall), whereas the rate of control amongthose receiving treatment is 69%. Differently fromprevious gains in all domains in the past, this currentupdate shows flat rates of awareness and slightly worse


rates of treatment and control compared with the 2009–2010 update. The authors observed that obesity (oddsratio, 1.44), lack of health insurance (odds ratio, 1.68),and fewer than two visits to a health care provider per

year (odds ratio, 4.24) were all significantly associatedwith lack of treatment of hypertension (8). Conversely,possession of health insurance (odds ratio, 1.69) andtwo or more health care visits per year (odds ratio, 3.23)

Figure 1. Relationship between BP and risk of development of 12 cardiovascular diseases in the Cardiovascular Research UsingLinked Bespoke Studies and Electronic Health Records cohort. Forest plot of hazard ratios (HRs) and 95% confidence intervals(95% CIs) per 20/10 mmHg increase in SBP (black) or DBP (grey) adjusted for age and sex. The vertical dashed linescorrespond to the associations of SBP (black) or DBP (grey) with total cardiovascular disease. Adjustments include age,quadratic age, and stratification by sex and primary care practice. Reprinted with permission from Rapsomaniki E, Timmis A,George J, Pujades-Rodriguez M, Shah AD, Denaxas S, White IR, Caulfield MJ, Deanfield JE, Smeeth L, Williams B, HingoraniA, Hemingway H: Blood pressure and incidence of twelve cardiovascular diseases: Lifetime risks, healthy life-years lost, andage-specific associations in 1�25 million people. Lancet 383: 1899–1911, 2014.


were associated with achieved BP control ,140/90mmHg (8). Unfortunately, data from the HealthSurvey for England, which includes insured patientsseen by general practitioners in England from 1999 to2011, indicate that availability of treatment and ratesof control may be dependent on factors other thaninsurance and health care visits (9). In this study,overall awareness of hypertension was 71%, treatmentwas 58%, and control to ,140/90 mmHg was just37%, largely a function of the low treatment rates, asonly 63% of those treated achieved control of hyper-tension (9).

A silver lining to this report of stagnant to worserates of BP treatment and control is the closing of the gapin rates of control among younger and older patients whoare hypertensive. Until recently, the largest portion ofpatients with uncontrolled BP was composed of olderindividuals with inadequately controlled SBP. A reportof the NHANES data focused on the differences in ratesof control among those ,60 or.60 years of age (10). Itshowed that, between 1988 and 2010, the numbers ofpatients achieving control to ,140/90 mmHg are nowsimilar among younger and older patients who arehypertensive (difference was 14.1% and is now 2.8%),

Figure 2. Relative roles of systolic and diastolic hypertension on years of life lost to cardiovascular disease up to 95 yearsof age associated with hypertension at index ages 30, 60, and 80 years old adjusted for sex, smoking, diabetes, and totaland HDL-cholesterol. Data from the Cardiovascular Research Using Linked Bespoke Studies and Electronic HealthRecords cohort. Reprinted with permission from Rodriguez M, Shah AD, Denaxas S, White IR, Caulfield MJ, DeanfieldJE, Smeeth L, Williams B, Hingorani A, Hemingway H: Blood pressure and incidence of twelve cardiovascular diseases:Lifetime risks, healthy life-years lost, and age-specific associations in 1�25 million people. Lancet 383: 1899–1911,2014.


a reflection of more frequent initiation of treatment andimproved antihypertensive therapy.

Hypertension awareness, treatment, andcontrol rates are stagnant. Distinct fromprevious improvements in other hyperten-sion domains of care, the most recentnational survey (2012) reveals a flat ratefor awareness of hypertension and slightlyworse rates of treatment and controlcompared with 2010 data.

Adverse Outcomes Related to Low DBPAlthough untreated BP carries a log–linear posi-

tive relationship with increasing risk of cardiovascular

disease and death, these relationships with treated BPare much more complex. One recurring controversy hasto do with the J curve or the association between lowBP levels, particularly DBP, achieved during treatmentand worse hypertension outcomes. It is (somewhat)accepted that, especially among older patients, exces-sive reductions in DBP to levels ,60–70 mmHg areassociated with adverse outcomes. Several recent co-hort studies from large populations of treated patientswho are hypertensive have shed further light on thiscontroversy.

In the previous issue of NephSAP on hyperten-sion, we reviewed the role of functional status (assessedas walking speed) to interpret the association betweenBP and mortality in patients ages $65 years old in theNHANES, suggesting that SBP has an incrementalassociation with death risk only among patients with

Figure 3. Sex–specific cumulative incidence rate of cardiovascular disease (CVD) mortality for each hypertensionsubtype in the Chicago Heart Association Detection Project in Industry Study. The definition of each color line isas follows: periwinkle, SDH (SDH; SBP.140 mmHg and DBP.90 mmHg); gold, IDH (SBP,140 mmHgand DBP.90 mmHg); violet, ISH (SBP.140 mmHg and DBP,90 mmHg); green, high-normal BP (SBP¼130–139 mmHg and DBP¼85–89 mmHg, SBP¼130–139 mmHg and DBP,85 mmHg, or SBP,130 mmHg andDBP¼85–89 mmHg); and salmon, optimal-normal BP (SBP,130 mmHg and DBP,85 mmHg). Reprinted withpermission from Yano Y, Stamler J, Garside DB, Daviglus ML, Franklin SS, Carnethon MR, Liu K, Greenland P,Lloyd-Jones DM: Isolated systolic hypertension in young and middle-aged adults and 31-year risk forcardiovascular mortality: The Chicago Heart Association Detection Project in Industry study. J Am Coll Cardiol65: 327–335, 2015.


higher functional status and that higher SBP andDBP are associated with decreased risk in those withsignificant physical limitations. In follow-up to theseobservations, Peralta et al. (11) analyzed the interactionbetween functional limitations in performing activitiesof daily living (ADLs) and walking and SBP and DBPlevels in mediating risk of cardiovascular events anddeath in elderly individuals .75 years old enrolled inthe Cardiovascular Health Study (N¼2459 without pre-vious cardiovascular events); 18% had a limitation in atleast one of the ADLs (11). The average age of patientswas 78 years old, 61% were women, baseline BP was137/70 mmHg, and 59% were taking antihypertensivedrugs. After 8.5 years of follow-up, fully adjustedmodels revealed a positive relationship between SBPand incident cardiovascular events in patients with andwithout ADL limitations (hazard ratio, 1.06; 95%confidence interval, 0.97 to 1.17 and hazard ratio, 1.08;95% confidence interval, 1.03 to 1.13 per 10-mmHg risein SBP, respectively), although only significant amongthose without ADL impairments. For DBP, the re-lationship was neutral for those without ADL limita-tions (hazard ratio, 1.0; 95% confidence interval, 0.93to 1.09 per 10-mmHg increase) and inverse (hazard

ratio, 0.85; 95% confidence interval, 0.73 to 1.00 per10-mmHg increase) for those with ADL limitations.Compared with patients with baseline DBP #65mmHg, those with DBP¼66–80 mmHg had 35% lowerrisk of events, and those with DBP$80 mmHg had51% lower risk (11). These results corroborate, ina different cohort of elderly individuals, the previousobservations that low DBP is associated with increasedrisk, particularly in those with impaired functionalstatus.

A report from the Framingham Heart Study exa-mined the role of low DBP and high pulse pressure(PP) on the risk of recurrent cardiovascular events inpatients with ISH (12). In this relatively small study,791 patients (average age ¼69 years old; 53% men)with ISH and a previous cardiovascular event within5 years of enrollment (coronary artery events, heartfailure, or stroke) were followed for an average of 8years, during which 54% had a recurrent event and 10%died. When comparing subjects with DBP,70 mmHgwith those with DBP between 70 and 89 mmHg, thelow DBP group had a 5.9-fold (P,0.001) increase inrisk for any recurrent cardiovascular event after adjust-ments for age, sex, body mass index, total cholesterol,smoking, and diabetes (12). Although these observa-tions held for both treated and untreated subjects, theindividual hazard ratios were surprisingly higher foruntreated patients. On further analyses, the authorsevaluated the role of low DBP in the presence orabsence of elevated PP (,68 or.68 mmHg), showingthat the rate of recurrent events was increased onlyamong those with low DBP and high PP (73%),whereas it was between 46% and 54% in the otherthree groups (high DBP/high PP, high DBP/low PP,and low DBP/low PP) (12). Unfortunately, these ob-servational data still do not help the clinician whois trying to decide if treatment should be intensifiedor relaxed in patients who remain with high SBP(.150 mmHg) but have low DBP (,60–70 mmHg).In these settings, management is still largely an artthat needs to be guided by how treatment is beingtolerated and severity of the SBP elevation.

The interaction between low DBP and high PP islikely to result from underlying arterial stiffness asa mediator of the increase in risk, especially in thecoronary bed, where it is postulated that impairedmicrovascular function and low diastolic perfusionpressure explain increased event rates. To explore thisrelationship in coronary artery disease, a study of

Figure 4. Hypertension prevalence, awareness, treatment,control, and proportion of treated patients controlled (control/treated) among adults $18 years of age in the NHANES1999–2012 at 2-year increments. All trend lines showeda significant increase over time (P#0.002) with the exceptionof prevalent hypertension (P¼0.32). Reprinted with permis-sion from Egan BM, Li J, Shatat IF, Fuller JM, Sinopoli A:Closing the gap in hypertension control between younger andolder adults: National Health and Nutrition ExaminationSurvey (NHANES) 1988 to 2010. Circulation 129: 2052–2061, 2014.


hypertensive patients with coronary artery diseaseundergoing coronary angiography evaluated the re-lationship between aortic DBP and myocardial perfu-sion pressure (MPP), defined as the intracoronary DBPdistal to coronary lesions (13). There was a strongpositive relationship between aortic DBP and MPP(r¼0.90; P,0.001). Based on findings that coronaryflow ceases when MPP is ,50 mmHg under restingconditions and ,40 mmHg under maximal vasodila-tion, the authors provided estimates of the likelihood ofhaving a resting MPP ,50 mmHg based on baselineaortic DBP (13). They estimated that, when the aorticDBP is,65 or,60 mmHg, 15.7% and 54.3%, respec-tively, of patients would have an MPP,50 mmHg andtherefore, would be at risk for significant myocardialischemia (13). Unfortunately, the investigators did notreport the relationships according to brachial DBP orthe relationship between brachial and aortic DBP intheir cohort. In general, however, the differences incentral and brachial BP are very significant for SBP, butaortic DBP values usually track well with brachialDBP measurements, thus rendering the results clini-cally applicable without having to resort to devices thatestimate aortic pressures.

Prognostic Relevance of Long–Term Visit to VisitBP Variability

Long–term visit to visit variability has beenincreasingly studied and proposed as an independentcardiovascular risk factor beyond average BP. Theconcept is that the size of BP fluctuation across officevisits over time (including isolated BP elevations)contributes to increased risk regardless of the prevailingaverage BP over time. Previously, such fluctuations hadbeen dismissed due to random variation around a pa-tient’s true underlying BP. This field has grown expo-nentially in the past 5 years, and the systematic reviewand meta-analysis by Diaz et al. (14) was a welcomeaddition to the literature. Diaz et al. (14) identified 37observational studies (28 of which were publishedbetween 2010 and 2014) that evaluated long–term visitto visit BP variability measured most commonly as theSD of BP (and its coefficient of variation) for eachindividual over time. There was wide variability acrossstudies with respect to type of population studied, cohortsize (N=144 to 58,228), duration of follow-up (median,6 months to 14 years), number of visits to definevariability (3–156), time interval between visits (every2–3 days in hemodialysis studies to every 3–4 years),

number of BP readings per visit (one to three), methodof BP measurement, and types of outcomes evaluated.This extensive heterogeneity significantly limited theability of the authors to perform extensive meta-analyses, so pooled risk estimates were typically basedon combined results from only four to seven cohorts.When evaluating the conclusions of each study, in-creased SBP variability was significantly associatedwith adverse outcomes in 58% of 312 analyses,whereas increased DBP variability was associated withworse outcomes in 32% of 188 analyses. Whenanalyzed as a continuous variable, every SD increasein SBP variability resulted in a 17% increased risk ofstroke (hazard ratio, 1.17; 95% confidence interval,1.07 to 1.28), 27% increased risk of coronary disease(hazard ratio, 1.27; 95% confidence interval, 1.07 to1.51), 22% increased risk of cardiovascular mortality(hazard ratio, 1.22; 95% confidence interval, 1.09 to1.35), and 20% increased risk of all-cause mortality(hazard ratio, 1.20; 95% confidence interval, 1.05 to1.36). For DBP variability, the results were relativelysimilar but only significant for coronary disease andcardiovascular mortality and not for stroke or all-causedeath (14). Despite the limitations of this meta-analysis,it confirms the positive relationship between increasedlong–term BP variability and adverse cardiovascularoutcomes, albeit of relatively small magnitude.

A large study (15) was published since the meta-analysis by Diaz et al. (14). In this post hoc analysis ofthe Antihypertensive and Lipid-Lowering Treatment toPrevent Heart Attack Trial (ALLHAT), detailed in-formation was available on 25,814 hypertensive pa-tients attending seven study visits between months 6and 28 of the study (i.e., after initial drug titration)using methodologically rigorous methods of BP mea-surement. These visits produced the metric of vari-ability that was then used to assess risk of adverseoutcomes during future follow-up. After 2.7–2.9 yearsof follow-up, higher SBP variability (long-term SD ofSBP) was associated with increased risk of fatal andnonfatal coronary disease events, stroke, and all-causedeath but not heart failure (adjusted hazard ratios, 1.30and 1.58). These were noted primarily among thequintile of patients with the highest SBP variability(.14.3 mmHg) in contrast to those with the leastamount of variability (,6.5 mmHg).

Of greater clinical relevance is the question ofwhether BP variability can be modified by any in-terventions. An analysis of data from the Trials of


Hypertension Prevention showed that weight loss andsalt restriction did not have any measurable impact onvisit to visit BP variability, despite effective BPreductions (16). Earlier studies (17–19) suggested thatcalcium channel blockers resulted in decreased long–term BP variability, that thiazides produced slightlyless significant effects, and that b-blockers were asso-ciated with increased BP variability. It was also sug-gested that increasing doses of amlodipine furtherdecreased variability, whereas titration of atenolol pro-duced the opposite effect (i.e., further increase in variabil-ity) (17). These observations have not been consistentlyreplicated. In a post hoc analysis of the Systolic Hyper-tension in Europe Trial, the changes in long-term vari-ability with nitrendipine were not different from thosewith placebo, despite significantly lower BP (20). Simi-larly, in the European Lacidipine Study on AtherosclerosisTrial, visit to visit variability was similar among patientsrandomized to receive the dihydropyridine calciumchannel blocker lacidipine or atenolol (21).

Wang et al. (22) published a meta-analysis of theeffects of different drugs among subjects enrolled intofive large clinical trials. Drug classes included calciumchannel blockers (amlodipine in all five trials), b-blockers(atenolol in one trial), thiazide diuretic (chlorthalidonein one trial), angiotensin–converting enzyme inhibitors(lisinopril in one trial and enalapril in two trials), andangiotensin II receptor blockers (losartan in one trial).Individual comparisons found amlodipine to be asso-ciated with lower visit to visit variability than atenolol(approximately 23% less) and angiotensin–convertingenzyme inhibitors (9%–22% less), but no difference wasfound compared with chlorthalidone or losartan (22).Results of a separate analysis of the ALLHAT noted anapproximately 10% decrease in long-term variabilityamong subjects randomized to chlorthalidone or amlo-dipine compared with lisinopril (23).

In absolute numbers, the differences in variabilityobserved in these studies were quite small (0.58–1.65 mmHg in the meta-analysis by Wang et al. [22]),raising questions about their clinical and prognosticrelevance. It was postulated that drug–induced decreasedvariability results in better outcomes. In the ALLHAT,there were generally no differences in outcome pre-diction based on visit to visit variability according todrug assignment (chlorthalidone versus lisinopril versusamlodipine) (15). However, in the quintile of patientswith highest variability, there were two interestingobservations: a 2.1-fold increase in risk of stroke only

for those randomized to chlorthalidone (not to lisinoprilor amlodipine) and a 52% increase in risk of fatal andnonfatal coronary events in the amlodipine group (notlisinopril or chlorthalidone). Although these findingsare interesting, they could have been due to chance inview of the multiplicity of comparisons performed aspart of the study. Further studies are required to definethe role of drug choice in reducing BP variability and itsnegative prognostic role.

BP lability is a frequent problem in clinicalpractice. Unfortunately, the recent developments in theunderstanding of BP variability that we have discussedhelp advance the science of hypertension but not itsclinical practice. It will be important to explore furtherwhat pathophysiological factors influence visit to visitvariability (stress, anxiety, endothelial function, arte-rial stiffness, extracellular volume status, etc.) so thattreatment interventions are hypothesis-driven rather thanthe result of statistical observations. The literature in thisfield has started to emerge, but is not yet sufficientlymature to guide management.

Prehypertension and Risk of ESRDDespite debate surrounding whether nonmalig-

nant hypertension can result in kidney injury and pro-gressive CKD, current observational evidence fromstudies that included adequate assessment of renaldisease at baseline indicates a dose-dependent relation-ship between baseline BP and long-term risk of CKDand ESRD, although the absolute risk is low. A recentmeta-analysis of six observational studies includingapproximately 1 million participants extended the topicfurther by exploring the risk of ESRD in adults withprehypertension (BP¼120–139/80–89 mmHg) (24).After follow-up of 8–26 years, 0.36% of subjectsdeveloped ESRD. Compared with those with optimalBP (,120/80 mmHg), prehypertension was associatedwith a 59% increased risk of ESRD (risk ratio [RR],1.59; 95% confidence interval, 1.39 to 1.91). This riskwas dose dependent within strata of prehypertension:44% (RR, 1.44; 95% confidence interval, 1.19 to 1.74)for low-range prehypertension (BP¼120–129/80–84mmHg) and twofold (RR, 2.02; 95% confidence in-terval, 1.70 to 2.40) for high-range prehypertension(BP¼130–139/85–89 mmHg). The association be-tween prehypertension and ESRD was not affected bysex, age group (.50 or,50 years old), ethnicity (Asianversus non-Asian), or presence of CKD at baseline.Unfortunately, the studies included were not uniform in


the methods used to evaluate kidney disease at baseline.Overall, these results confirm the relationship betweennonmalignant hypertension and progressive kidneydisease and extend it to levels that fall below the dia-gnosis of hypertension, similar to what is seen for otherhypertension–related cardiovascular end points. How-ever, the absolute risk is small, and there is no evidencethat BP treatment at these prehypertensive levels resultsin benefit. Instead, these data underscore the continuumof BP-related risk and the importance of lifestyleinterventions to decrease BP levels at the individuallevel and limit the relentless increase in the prevalenceof prehypertension and hypertension at the populationlevel.

Hypertension after AKIThe possible association between primary renal

injury and the development of de novo hypertensioncan be explored through the analysis of studies of AKIin patients with previously normal BPs. In children,several small studies showed a heterogeneous butmodestly consistent association between a history ofhemolytic-uremic syndrome and future development ofhypertension (25). Two recent studies enhanced theseobservations in children. A long–term cohort study ofyoung men in the Israeli armed forces showed a 51%increase in risk of hypertension among 264 recruits witha history of resolved childhood glomerular disease(13.6% versus 7.4% among 37,880 controls; adjustedRR, 1.51; 95% confidence interval, 1.07 to 2.11;P¼0.02) (26). Another study performed an 8.2-yearfollow-up of 169 children who had received extracor-poreal membrane oxygenation in the neonatal period,60% of whom also had AKI (27). During follow-upvisits, 21% of children had BP levels consistent withdiagnosis of hypertension, especially in those witha history of AKI during extracorporeal membraneoxygenation, which was also associated with a higherincidence of eGFR,90 ml/min per 1.73 m2 and pro-teinuria. There was no control group, but these estimatesindicate that AKI in the setting of severe respiratoryfailure in the neonatal period may be associated with anincreased risk of hypertension in adolescence.

To explore the possible relationship between AKIand future development of hypertension in adults, Hsuet al. (28) conducted a retrospective cohort study of2451 (from 43,611 eligible subjects) previously nor-motensive patients with a defined episode of AKI in theKaiser Permanente Northern California health system.

Most (71%) had stage 1 AKI; 5% had baseline eGFR,60 ml/min per 1.73 m2, and 32% had a history ofproteinuria prior to the AKI episode. The etiology ofAKI was not defined but likely represented mostlycases of prerenal azotemia and ischemic acute tubularnecrosis, the two most common causes of AKI in hos-pitalized patients in the United States. After 2 years offollow-up, patients with an episode of AKI had a 22%increase in the adjusted odds of having at least one BPmeasurement .140/90 mmHg that was obtained ina nonurgent ambulatory setting (46% in the AKI groupversus 41% in controls; adjusted odds ratio, 1.22; 95%confidence interval, 1.13 to 1.32; P,0.001). Thisseparation was already noticeable by 6 months post-discharge (31% in the AKI versus 23% in controls;adjusted odds ratio, 1.40; P,0.001). The mediannumber of postdischarge BP measurements was 11in the AKI group and nine in control subjects. Animportant caveat is that these measurements wereobtained in casual, not research clinical settings.Although this may have resulted in imprecision of themeasurements, the large sample size helps dilute thisbias. The investigators observed an increase in thestrength of the relationship according to the severity ofthe AKI. For example, compared with stage 1 AKI, theodds of elevated BP at 2 years were 45% higher inthose with stage 2 AKI and 82% higher in stage 3 AKI.The differences between patients with and without AKIheld up in separate analyses including only patientswho had at least two occasions of elevated BP, thusproviding greater likelihood that the elevation was indeedsustained and more likely to represent new hypertensionrather than an isolated high reading. Likewise, exclusionof patients with baseline eGFR ,60 ml/min per 1.73 m2

and those with a history of proteinuria did not alter theresults (28).

In summary, observations in children and adultslink episodes of AKI of different etiologies with futuredevelopment of hypertension. These results expand thehypothesis that subtle renal injury may drive futurehypertension by way of salt sensitivity, as previouslyshown by several experimental models (29).

Albuminuria and Hypertension: What ComesFirst?

Albuminuria is a known complication of pro-gressive hypertensive kidney injury. Along the samelines of the foregoing discussion on AKI, studies ofthe relationship between albuminuria and de novo


hypertension provide important insights on the impor-tance of subtle underlying renal disease and the devel-opment of hypertension. Several previously publishedcohort studies indicate a progressive, dose–dependentrelationship between albuminuria and risk of incidenthypertension of 50%–75% in patients in high albumin-uria groups compared with undetectable albuminuria(30). Two recent, large cohort studies add more cre-dence to these observations. In a large longitudinal anal-ysis of 4378 subjects from the Atherosclerosis Risk inCommunities Study, Huang et al. (31) observed a 28%greater risk of incident hypertension (hazard ratio, 1.28;95% confidence interval, 1.10 to 1.49) between sub-jects in the highest and lowest quintiles of baselinealbuminuria over 9.8 years of follow-up. Of relevance,these were largely values in the normal range, becausethe lower limit of albuminuria in the top quintile was9.1 mg/g. In this cohort with preserved renal function,eGFR was associated only with prevalent, not incidenthypertension. Xu et al. (32) followed 1051 elderly menfrom the Uppsala Longitudinal Study of Adult Men,574 of whom had longitudinal 24-hour ambulatory BPmeasurements over a 6-year follow-up period. Therewas a positive association between increasing levelsof albuminuria at baseline and increased ambulatory BPparameters at follow-up in patients with eGFR,60 ml/min per 1.73 m2 but not among those with higher eGFR.A similar trend was detected between baseline albumin-uria and incident hypertension analyzed as a binaryvariable. In aggregate, the results of these studiesconfirm the independent role of albuminuria as a medi-ator of risk of de novo hypertension and emphasizethe importance of close observation of BP trends inindividuals with albuminuria. The relationship betweenhypertension and albuminuria is certainly bidirectional:hypertension causes albuminuria and albuminuria pre-disposes to hypertension.

Social Stress and Hypertension: The HousingForeclosures Story

Psychosocial stress has been long linked tohypertension. The financial crisis of the last decadeunleashed a huge wave of home mortgage foreclosures.More than 6 million home mortgages were affectedbetween 2007 and 2010, and approximately 1.8 millionhomes (approximately 1.5% of all housing units in theUnited States) foreclosed in 2011 alone (33). Given themagnitude of the housing crisis, there has been intereston the effects of home foreclosures on cardiovascular

health of not only of those whose homes were foreclosed,but also those in the surrounding community.

A group of investigators matched data from theFramingham Offspring Study between 1987 and 2008and Massachusetts deed information that includedgeocoded and dated foreclosure information for thesame time period in order to evaluate the BP impactfrom home foreclosures near the sites of residence ofstudy subjects (33). They used 100 m to define thesurrounding zone of reference, typically covering twohomes to each side and homes across the street andbehind the homes of the study subjects. Over the21 years of the study, the prevalence of hypertension inthe cohort increased from 18.5% to 26.5%, and theaverage SBP increased from 124 to 129 mmHg. Fore-closures were observed within 100 m of participanthomes on 153 occasions (2.3%) in 133 unique studyparticipants (7.6%). Each additional foreclosed prop-erty located within 100 m of a participant’s home wasassociated with an increase of SBP of 1.71 mmHg(P¼0.03) after adjustment for individual- and area-levelconfounders, such as age, sex, ethnicity, antihypertensivedrug use, area poverty rate, municipal foreclosure rate,and housing unit density. Because the association withincreased SBP levels was of relatively small magni-tude, there was no association with increased risk ofincident hypertension when assessed as a binary vari-able. The relationship between SBP and nearby fore-closed properties was attenuated and became statisticallyinsignificant (1.39 mmHg; P,0.10) after adjustment foralcohol consumption and body mass index.

Why should we care? Although at the individuallevel, the net effect seems small and possibly notrelevant at the population level, this study raisesawareness to the possibility that system-wide eco-nomic and financial issues may have an impact even onthose not directly involved (as in the case of nearbyforeclosures). Thus, it is possible that policy decisionsregarding social, economic, and housing interventionsmay have untoward population health effects that mayrequire consideration by policymakers (34).

Antiretroviral Therapy and HypertensionHIV disease is associated with increasing fre-

quency of cardiovascular complications due to widelyavailable and effective antiretroviral therapy (ART)and long–term patient survival (35). An increasingprevalence of hypertension may be responsible for thisincreased cardiovascular risk. Therefore, it is important


to understand the risk of hypertension in HIV and anyrelationship that hypertension may have with ART.Studies addressing these questions have been conflict-ing, with some suggesting no independent relationshipbetween type or duration of ART and hypertension,whereas others suggest that longer duration (.2 years)of therapy represents increased risk. Moreover, somestudies specifically suggest that the use of proteaseinhibitors and nucleoside reverse transcriptase inhibitor(NRTI) use are neutral or pose a greater risk (perhapsdue to their adverse metabolic effects). Others contendthat non-NRTIs actually are protective. In view of theexisting inconsistencies, the results of three recentstudies provide important information on this issue.

In a contemporary cohort of 1182 Italian HIV-positive patients (71% men; mean age of 47 years old),the prevalence of hypertension was 29.3% (36). Althoughthe study did not have a control group, the authors makereference to other Italian population studies of similar ageand sex distribution with a prevalence of hypertension of29%–36% (36). The large Veterans Aging CohortStudy, a cohort of 81,026 patients (27,059 HIV positiveand 53,787 matched controls), showed that the preva-lence of hypertension in predominantly HIV-positivemen with an average age of 47 years old was 32.7%, anumber lower than controls, in which prevalence was41.7% (37). Finally, among 13,632 South CarolinaMedicaid patients (6816 HIV positive and 6816 matchedcontrols; 57% men; 71% African American; median ageof 38 years old), the risk of incident hypertension overa median follow-up of 5.8 years was equal among HIV-positive patients and HIV-negative controls (20.4% and20.7%, respectively) (38). Among HIV-positive pa-tients, women, nonwhite ethnicity, diabetes mellitus,obesity, and smoking were all independent risk factorsfor incident hypertension (38). Therefore, it seems thatthe prevalence and incidence of hypertension in HIV-positive patients in the Western world are high but nodifferent than expected based on other clinical and de-mographic factors.

In the Italian study, ART duration of exposure,was associated with an increased risk of prevalenthypertension, but there were no relationships betweentype of ART and the diagnosis of hypertension (36).The relationship between exposure to ART and risk ofincident (not prevalent) hypertension was explored infurther detail in an analysis of the South CarolinaMedicaid cohort. In extensively adjusted analyses, theauthors (38) showed a difference in risk of incident

hypertension according to duration and type of ARTused. Based on months of exposure to a given group ofagents, longer duration of exposure to protease inhibi-tors and non-NRTIs was associated with increased riskof hypertension (hazard ratio, 1.26; 95% confidenceinterval, 1.11 to 1.44 and hazard ratio, 1.52; 95% con-fidence interval, 1.32 to 1.75, respectively). These re-sults were surprising in that the large longitudinal analysisof the Data Collection of Adverse Events of Anti-HIVDrugs Study Group had previously identified a pro-tective effect of non-NRTIs, although that study waslimited by its short follow-up (2.3 years) and the factthat it was conducted over a decade ago (39). Datafrom South Carolina indicate significant shifts in drugchoices over time along with increasing use of multi-class combinations and increasing overall incidence ofhypertension from 1994 to 2011 (38). Therefore, it ispossible that there is a shifting relationship betweendrug types and hypertension that is modified by overallexposure and changing drug profiles. More work willclarify this issue.

Does the presence of hypertension in HIVpatients mediate cardiovascular risk? In the VeteransAffairs Aging Cohort Study, hypertension was equallypredictive of the risk of myocardial infarction during5.9 years of follow-up among HIV-positive and HIV-negative subjects. Among HIV-positive subjects, ARTexposure did not modify risk (37). Therefore, hyper-tension is as strong a risk factor for myocardialinfarction in HIV-positive men as it is in the generalpopulation. If one extrapolates from treatment effectsin the general population, one will deduce that hyper-tension in HIV-positive patients should be treateddiligently to mitigate this risk. In that sense, plenty ofwork must be done: 35% of Italian patients were un-aware of the diagnosis of hypertension, and only 33%were adequately controlled (36). Among United Statesveterans, about one half of hypertensive patients haduncontrolled BP (37).

And the Salt Debates Continues. . .The 2 years since the last issue of NephSAP on

hypertension have been quite interesting with respect todata and recommendations regarding dietary salt re-striction in the general population and for patientswith hypertension. Recommendations of leading organi-zations vary slightly. The World Health Organizationrecommends a maximal daily sodium intake of 2000 mg(5000 mg salt). The US Department of Health and


Human Services recommends ,2300 mg sodium perday for all and,1500 mg for those ages$51 years old,all African Americans, and individuals who have hy-pertension, diabetes, or CKD. Finally, the AmericanHeart Association recommends restriction to ,1500mg daily for the entire United States population. TheInstitute of Medicine now issued a report in which itreviewed the updated literature and its 2005 recom-mendations, and it concluded that reduction to 2300 mgsodium daily is safe and effective. The Institute ofMedicine stated that the possible benefits of reducing itto ,2300 mg (and particularly, ,1500 mg) are rela-tively minor and because of safety concerns raised bysome studies, not supported by available evidence (40,41). However, in an insightful commentary, Stromet al. (41) point out that the spirited debate on whether2300 or 1500 mg should be the target misses the pointthat these low targets currently apply to ,10% of theUnited States population, because .90% of the pop-ulation ingest .2300 mg/d. Instead, the focus shouldbe on public policy to limit sodium intake at a population-wide level, because this is likely to have significantpublic health effects. Because .75% of sodium intakeconsumed by the United States population comes fromprocessed and restaurant food, such an approachrequires systematic reductions in sodium use, a shiftthat will require joint efforts by all stakeholders, in-cluding food research and development, food manu-facturing groups and retailers, restaurant and foodservice operations, government legislative bodies andregulatory agencies, public health policy groups, thehealth care industry, and academia (42). To that effect,the American Heart Association sponsored a stakeholderconference, the proceedings of which provide a largebody of valuable information to the interested reader(42). Although there are many industries committed toprogressive, large–scale (25%) reductions in salt contentin their foods, empirical data from the United Statesmarket are less than encouraging. In a study comparingsodium contents of 402 products (processed and restau-rant foods) sampled at three different periods during thestudy (2005, 2008, and 2011), sodium content declinedby 3.5% over the 6 years of the study in processed foodsbut increased by 2.6% in restaurant foods (43). More-over, there was substantial variability in the amountof change, with some general categories fluctuatingeither up or down by as much as 27%, and individualproducts showing changes as large as 90% reductions ortwofold increases in sodium content (43).

An updated Cochrane meta–analysis sought toestablish the effects of dietary sodium reduction on BP,all-cause mortality, and cardiovascular morbidity andmortality (44). The analysis included randomizedclinical trials of at least 6 months in duration (eighttrials and 3776 subjects) with mean follow-up between6 and 36 months and analyzed data on outcomes at theend of each trial or the time of longest follow-up fortrials that had post-trial observations, while also strat-ifying the results based on the presence or absence ofhypertension among enrolled subjects. There were 753total deaths and 392 cardiovascular events duringfollow-up. As noted in Table 1, the average sodiumreduction was 27 mEq/d (34 mEq in normotensivesubjects and 20 mEq among hypertensives). This re-duction was associated with minimal BP changesamong normotensives (1.15/0.8 mmHg) and modestbut substantially larger reductions in those with hyper-tension (4.1/3.7 mmHg). No differences in outcomeswere noted for all studies combined, but there wereconsistent trends toward lower cardiovascular morbidityand mortality among hypertensive patients (44). Severalhigh–profile observational studies published during thereview period for this NephSAP on hypertension issuefurther confirm these observations and trends (45–48).

We contend that the clinical and public healthimplications of the controversies described above aredifferent. From a public health perspective, there ismuch to be gained by system-wide interventions tocurb populational salt intake. This is based on theobservations that the average daily sodium consump-tion in the United States is 3400 mg sodium and that.90% of the United States population ingests .2300mg sodium per day (40). Given the high prevalenceof hypertension among adults and the demonstrableeffects of sodium reduction on BP levels, it is notsurprising that statistical models predict a significantreduction in morbidity and mortality among UnitedStates adults, even if modest reductions in daily sodiumintake occur (45, 49). From a clinician’s perspective,the relationship is not so simple, because only a fractionof hypertensive patients is salt sensitive. The size of thisfraction varies across patient subgroups and comprisesthe majority of individuals who are elderly, havediabetes mellitus or CKD, or are African American.However, even for those in these subgroups, saltsensitivity is not necessarily the rule. Therefore, toolsto more easily identify salt sensitivity in clinical practiceare needed. Unfortunately, no such tool is readily


available today. Once these are developed, the guessinggame about sodium restriction will largely disappearfrom the care of hypertensive patients, at least fromthe perspective of BP reduction. The role of sodiumrestriction in decreasing cardiovascular risk beyond BPcontrol is speculated but not convincingly shown andwill require a substantial amount of future work.

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Update on the Mechanisms of Hypertension withRelevance to Clinical Practice

Unraveling the Effects of Dietary Potassium onBP

Epidemiological data demonstrate a relationshipbetween low potassium intake and hypertension. In theProspective Urban Rural Epidemiology (PURE) Study,a large multinational cohort study involving 112,216subjects from 18 countries, greater estimated sodiumintake from a single morning urine sample was asso-ciated with higher BP (2.1/0.8 mmHg/g sodium in-gested per day). Greater estimated potassium intakewas associated with lower BP (20.8/20.1 mmHg/gpotassium ingested per day) (1). These relationships forboth electrolytes were steeper for older patients andthose with hypertension. Moreover, an important in-teraction was observed between sodium and potassiumintake: at any level of sodium intake, higher potassiumintake was consistently associated with lower BP (Figure5). This effect is particularly apparent in individualswith higher sodium intake (2) and has been recentlyobserved not only in adults but also, in a longitudinalstudy of American children/adolescents, although theresults were of borderline significance (3).

Sodium and potassium intake are also relevantfrom a cardiovascular risk perspective. The PUREStudy investigators also reported on the risks of car-diovascular events and mortality according to urinarysodium and potassium excretion (4). They demonstratedU-shaped relationships between sodium excretion andrisk of cardiovascular events and all-cause death, withthe lowest risk at a daily sodium intake of approxi-mately 4000 mg (4). Daily potassium intake ,1500–2000 mg was associated with increased risk for alloutcomes. Potassium intake .2000 mg was associatedwith better outcomes without a dose effect, except forall-cause mortality, which was lower at the highest levelsof potassium intake. In contrast to the BP observations,there was no interaction between sodium and potassiumin risk modification (4). A meta-analysis of 11 cohortstudies of 127,038 subjects (the PURE Study not in-cluding) showed similar results, with a protective effect ofhigher potassium intake, although it only reached statis-tical significance for the reduction in stroke risk (5).

Data from clinical trials on the BP and other ef-fects of dietary potassium supplementation were sum-marized in a meta-analysis of 21 studies involving1606 subjects (5). Assignment to an increased potassium
















diet in adults resulted in lower BP (3.5/2.0 mmHg),with the effect restricted to hypertensive patients (5.3/3.1 mmHg). These data are relevant to practice becauseof the observation that Western populations typicallyhave high sodium intakes and poor potassium intakes,thus making modifications in potassium intake espe-cially desirable to improve the rates of hypertensionprevalence and control as well as limit the risk ofcardiovascular events and death.

Previous work identified potential mechanisms ofthe action of dietary potassium on BP lowering asrelated to decreased autonomic activation, direct vaso-dilatation, or a natriuretic effect. This latter componentbecomes relevant in states of dietary sodium excess.Recent work helps us understand the molecularswitches involved in the process. In mice, Sorensenet al. (6) demonstrated that oral ingestion of a highpotassium diet (2%) results in rapid downregulation ofthe sodium chloride cotransporter (NCC) in the distalconvoluted tubule, independent of aldosterone or theanion coadministered with potassium. The group dem-onstrated rapid dephosphorylation of NCC on potas-sium loading, and this can be interpreted as an earlydriving force to excrete potassium combined witha natriuretic effect. In addition, there was a late effect(.6 hours), presumably aldosterone dependent viaactivation of the epithelial sodium channel (ENaC),that maintains kaliuresis with less sodium loss.

An interesting model has advanced our under-standing of the physiological regulation of this process.Terker et al. (7) have demonstrated that, in the presenceof high sodium intake, high dietary potassium aspotassium chloride (2%) resulted in significant natriure-sis, kaliuresis, and BP reduction compared with apotassium-restricted diet. They demonstrated that NCCphosphorylation is significantly decreased by potassiumrepletion, and this was accompanied by reduction intelemetrically monitored BP (7). They extended theapplicability of these findings to humans by demon-strating that urine exosomes of volunteers exposed to4 days of a high sodium/high potassium diet showedsignificantly less phosphorylated NCC than exosomesobtained following 4 days of a high sodium/low potas-sium diet (7). To confirm that the above effects wererelated to extracellular or total body potassium levels, theinvestigators demonstrated that amiloride had a similareffect during a low potassium diet and during amiloride–induced potassium retention and increased plasma potas-sium (7). Finally, the novel contribution of the study byTerker et al. (7) is the identification of the importance ofmembrane potential and intracellular chloride concentra-tion as the key signal for the regulation of NCC phos-phorylation. As a potassium load increases extracellularpotassium content, intracellular chloride concentrationalso increases. Chloride is an inhibitor of with-no-lysinekinase 1, an important regulator of NCC phosphoryla-tion, thus completing the cycle of decreased NCCactivation with natriuresis and lower BP (Figure 6) (7).

Figure 5. Mean (A) SBP and (B) DBP according to urinarysodium and potassium excretion in the PURE Study. Dataadjusted for age, sex, geographic region, body mass index,educational level, and alcohol intake. Reprinted with permis-sion from Mente A, O’Donnell MJ, Rangarajan S, McQueenMJ, Poirier P, Wielgosz A, Morrison H, Li W, Wang X, Di C,Mony P, Devanath A, Rosengren A, Oguz A, Zatonska K,Yusufali AH, Lopez-Jaramillo P, Avezum A, Ismail N, LanasF, Puoane T, Diaz R, Kelishadi R, Iqbal R, Yusuf R,Chifamba J, Khatib R, Teo K, Yusuf S; PURE Investigators:Association of urinary sodium and potassium excretion withblood pressure. N Engl J Med 371: 601–611, 2014.


These results have important clinical implicationsand underscore the importance of low potassium dietsto promote salt sensitivity and hypertension in settingsof sodium excess, as is the typical Western diet. Theyalso indicate the relevance of potassium repletion tocorrect this risk and point to potential mechanismsmediating BP-lowering effects, although better

understanding of other extrarenal effects still remainsto be elucidated.

Pendrin Overexpression and Chloride-InducedHypertension

Chloride is an essential part of salt-induced hyper-tension. Animals (and humans) fed sodium accompanied

Figure 6. New insights into the roles of dietary potassium, plasma potassium, intracellular chloride, and membrane polarity on theregulation of sodium and potassium balance and BP (the adrenal-renal axis). In states of high potassium intake, plasma potassiumincreases, resulting in cell membrane depolarization accompanied by increased intracellular calcium in the adrenal and increasedintracellular chloride in the distal convoluted tubule (DCT). In the adrenal, this results in increased aldosterone secretion, whichwill act on connecting tubule/collecting duct (CNT/CD) to promote kaliuresis. In DCT, high intracellular chloride directly inhibitswith-no-lysine kinase 1 (WNK1), resulting in decreased phosphorylation of NCC and natriuresis. The net balance is one ofnatriuresis, kaliuresis, and lower BP. In states of low potassium intake, plasma potassium falls, leading to opposite effects onaldosterone production (decreased) and NCC phosphorylation. Therefore, the net result is sodium and potassium retention andincreased BP. Reprinted with permission from Terker AS, Zhang C, McCormick JA, Lazelle RA, Zhang C, Meermeier NP, SilerDA, Park HJ, Fu Y, Cohen DM, Weinstein AM, Wang WH, Yang CL, Ellison DH: Potassium modulates electrolyte balance andblood pressure through effects on distal cell voltage and chloride. Cell Metab 21: 39–50, 2015.


by other anions have significantly blunted BP res-ponses when compared with sodium chloride. Despitethis, the role of chloride transport in the kidney (in-dependent of sodium) as a mediator of hypertensionhas not been well studied.

Pendrin is a sodium–independent chloride/bicar-bonate exchanger required for chloride reabsorptionthrough b-intercalated and non–A-, non–B-intercalatedcells in the collecting duct. It modulates sodium avidityby enhancing abundance and activity of the ENaC vialocal changes in luminal bicarbonate and ATP concen-trations (8). Pendrin also works in tandem with thesodium–dependent chloride/bicarbonate exchanger andfacilitates electroneutral sodium absorption through thethiazide-sensitive NCC. Finally, pendrin is upregulatedby aldosterone and angiotensin II. In pendrin-null mice,the BP is lower after exposure to mineralocorticoidsthan in wild-type mice (8). In view of these factors,pendrin is a possible mediator of hypertension.

To capitalize on this concept, Jacques et al. (9)developed a transgenic mouse model of pendrin over-expression in the intercalated cells of the distal neph-ron. In this model, pendrin overexpression resulted inincreased chloride reabsorption and salt-sensitive hy-pertension when exposed to sodium chloride but notsodium bicarbonate, implicating chloride in the patho-genesis of hypertension. The hypertension was presentonly under very high sodium chloride intake (8% NaCldiet) and was characterized by slow accumulation ofsodium chloride. Both amiloride and hydrochlorothia-zide resulted in pronounced natriuretic responses inthis model, implicating increased activity of thesetransporters, but the authors did not present BP datafor these interventions (9). Taken together and mindfulof the limitations of this overexpression experiment,these results indicate that pendrin may be involved inthe pathogenesis of hypertension in the setting of highsalt intake. Whether this will have any treatment impactremains uncertain, particularly because amiloride andhydrochlorothiazide corrected the abnormal phenotype.

Proteolytic Activation of the ENaCProteolytic activation of the ENaC is a possible

mechanism of sodium retention and therefore, hyper-tension in patients with the nephrotic syndrome (10).This activation is mediated by filtered proteases, inparticular plasminogen. Filtered plasminogen is con-verted to plasmin (by urine urokinase), which in turn,proteolytically activates ENaC through cleavage of

the extracellular domain of the g-subunit. At lowurine plasmin concentrations, proteolytic cleavage byplasmin is mediated by glycosylphosphatidylinositol-anchored prostasin, and at higher concentrations, it ismediated by a direct action of plasmin. Although theinitial studies were performed in patients with nephro-sis, this effect has been studied in patients with lesserdegrees of proteinuria, such as preeclampsia (11) anddiabetic nephropathy without nephrotic range protein-uria (12), and diabetic patients with resistant hyperten-sion, especially if albuminuric (13).

In a study comparing patients with type 1 dia-betes with nephropathy (mean albumin-to-creatinineratio ¼960 mg/g) with normoalbuminuric type 1 dia-betic controls (11), those with nephropathy had signif-icantly higher levels of urine plasminogen, prostasin,and plasmin. In addition, urine exosomes revealed thatENaC units with furin-mediated proteolysis of ENaC(intracellular cleavage) were observed in both groups,but ENaC samples with cleavage of only its extracellulardomain were observed only in the proteinuric group.Therefore, it is apparent that different mechanisms ofENaC activation occur in the presence of proteinuriawhen plasmin(ogen) is available in the urine.

Because amiloride interrupts ENaC–mediatedsodium conductance in the setting of plasmin activa-tion, it is a potentially useful treatment approach. Thiswas tested in an open-label study of 80 patients (60completers) with type 2 diabetes and resistant hyper-tension (14). In this 8-week study, amiloride (5 mg/d)was added to previous background therapy. Mostpatients had improvements in BP, averaging 5.3/3mmHg for the 24-hour BP average (P,0.001). Therewere significantly decreased urine plasminogen andalbumin concentrations after amiloride and a modesttrend toward greater BP reductions in patients withgreater baseline albuminuria. The magnitude and con-sistency of these findings were modest, in particularbecause there was no placebo control for this trial. Ofrelevance, the participants of this study had all beenstudied in a placebo–controlled, randomized trial ofspironolactone in resistant hypertension (15). In thatstudy, spironolactone produced an average placebo–subtracted reduction in awake ambulatory BP of 8.9/3.7 mmHg. For the amiloride study, the authorscompared the BP reductions with amiloride with theresponses to spironolactone for 26 subjects who wereenrolled in both trials (14). In that analysis, the averageawake BP response to spironolactone was higher than


that to amiloride (9.5/5.2 versus 6.8/5.2 mmHg;P¼0.17 and P¼0.11, respectively) (14). In sum, therecontinues to be progress in the determination of theclinical value of ENaC blockade in patients withproteinuria and hypertension. However, at present,the effects are modest, and further studies are neededto establish which patients will best respond to ENaCblockade.

Vascular Smooth Muscle Cell Stiffness as aMediator of Arterial Stiffness in Hypertension

Aortic stiffness has been largely interpreted as theresult of changes in extracellular matrix proteins thatalter the mechanical properties of the arterial wall. Theaging process and several pathophysiological states, inparticular diabetes, kidney disease, and hypertension,amplify these changes, although epidemiologic studieshave provided conflicting results in trying to resolvethe chicken or egg relationship between hypertensionand arterial stiffness (16, 17). A novel approach to thisconcept is to consider the role of the stiffness ofvascular smooth muscle (VSM) cells themselves as amediator of arterial stiffness. In experiments testing thedeformation of VSM cells using atomic force micros-copy nanoindentation (i.e., the force curves, reflectingthe indentation of cultured VSM cells in response to theatomic force microscope probe), Sehgel et al. (18) haveshown that, compared with normotensive littermates,spontaneously hypertensive rats have 2.5-fold higherpulse wave velocities, 50% increased elastic stiffness(stress-strain relationship ex vivo), and approximatelythreefold increase in VSM cells stiffness based onnanoindentation. Further, they concluded that the in-creased VSM cell stiffness is mediated by the cyto-skeletal proteins actin and myosin light chain, becausethe use of targeted inhibitors of these two contractileresponse elements eliminated VSM stiffness (18).

The same group of investigators extended theseobservations by comparing the relative contributions ofchanges in extracellular matrix content and VSM cellstiffness to progression of arterial stiffness from agingand hypertension in rats (19). To test differences be-tween aging and hypertension, both spontaneoushypertensive rats at weeks 16 and 64 of life and theirnormotensive Wistar–Kyoto littermates at the sameages were evaluated. Aortic elastic stiffness (stress-strain relationship ex vivo) increased with age and wasamplified by hypertension. Aortic structure changedwith age, with a significant increase in collagen content

and density accompanied by decreased elastin contentand density. These age-related effects were not signif-icantly modified by the coexistence of hypertension.VSM cell stiffness, on the other hand, was significantlyaffected by the presence of hypertension. Not only werethe deflection forces in response to nanoindentationincreased by more than threefold in older hypertensiveanimals, but VSM cells had more than twice thenumber of adhesion events observed in vitro betweenthe cells and an atomic force microscope probe coatedwith fibronectin. (19). In summary, these resultsshowed that aging and hypertension have separateand additive effects that contributed to arterial stiff-ness. Aging is associated with both cellular stiffnessand extracellular matrix changes, but hypertensionmediates stiffness largely through its potent effects onVSM cell stiffness mediated by the cytoskeletalcontractile apparatus and adhesive properties ofVSM cells to the surrounding matrix. Isolated systolichypertension of the elderly is marked by arterialstiffening and notoriously difficult to treat. It isplausible that the identification of treatable targetsthat improve VSM cell stiffness may achieve better BPcontrol in these patients.

Aortic Stiffness and Risk of Renal InjuryArterial stiffening is associated with increased

pulsatility of the circulation (pulse pressure) due toabnormal patterns of forward and reflected pulsewaves. The brain and kidney are targeted for poten-tially increased risk of injury in the setting of increasedarterial stiffness because of greater transmission ofpulsatile forces to the microvascular beds due toimpedance matching. These vascular beds have, bynecessity, low impedance to accommodate the re-quirement for high blood flow to these organs (17).Simply, impedance matching is the equalization ofstiffness between elastic (proximal) and muscular(distal) vessels. Normally, the aorta and its majorbranches are compliant, whereas muscular arteries aresignificantly stiffer with greater impedance to flow.This impedance mismatch causes forward travelingpulse waves to reflect backward instead of progressingtoward the target organ. When the aorta stiffens,however, muscular arteries typically do not followsuit, thus leading to a similar level of stiffness. Oncethe stiffness gradient disappears, there is no furtherimpedance mismatch and greater risk of transmissionof pulsatile energy to the peripheral vasculature (17).


Animal studies in models where there is loss ofafferent arteriole autoregulation provide partial supportto this hypothesis (20). As detailed in previous issuesof NephSAP on hypertension, arterial stiffness is acommon complication of CKD and associated withworse outcomes in this population, including the morerapid loss of renal function, thus providing furtherclinical plausibility to this construct.

Woodard et al. (21) performed a series of proce-dures in 362 older adults in order to explore hemody-namic factors mediating renal injury related to aorticstiffening in humans. This cross-sectional study in-cluded tonometric assessment of aortic stiffness (carotid-femoral pulsewave velocity [cfPWV]), magnetic resonancemeasurements of aortic flow patterns, pulse wavevelocity, cardiac output, renal blood flow, and renalvascular resistance as well as the renal pulsatilityindex (amplitude of the renal flow waveform dividedby the mean flow in each renal artery). The mean agewas 79 years old, 40% of patients had iohexol GFR,60 ml/min per 1.73 m2, and approximately 75% werereceiving antihypertensive therapy. cfPWV and centralpulse pressure but not mean arterial pressure werepositively associated with pulsatility index and reno-vascular resistance and negatively associated with renalcortical arterial volume. In other words, a stiffer aortaresults in increased pulsatility of the renal circulation,increased resistance to flow, and decreased corticalflow. These functional changes had varying relation-ships with GFR and albuminuria. cfPWV, renal arterypulsatility index, and renovascular resistance all hadnegative associations with GFR, whereas cortical ar-terial volume was positively associated with it. Theassociation between cfPWV and GFR was no longersignificant after adjustments for pulsatility index, re-novascular resistance, and cortical arterial volume.Conversely, only mean arterial pressure was associated(positively) with albuminuria (21). Because of its cross-sectional design, the study had limited ability to addressdirectionality of the relationships, so the authors usedmediation analysis in order to dissect the relationshipbetween aortic stiffness (cfPWV) and GFR as related tothe pulsatility index, renovascular resistance, and cor-tical arterial volume (21). These analyses showed that34% of the relationship between cfPWV and GFR wasmediated by pulsatility index and that an additional20% or 36% of the relationship was mediated by lowercortical arterial volume or greater renovascular resis-tance, respectively, when proposed in the model as

mediators downstream from higher pulsatility index.This model, although not conclusive, is the first tosuggest that aortic stiffness may contribute to GFR lossthrough the transmission of increased pulsatile flowenergy to the renal microvasculature, which may, inturn, induce arteriolar constriction (increased renovas-cular resistance) and/or vascular rarefaction (decreasedcortical arterial volume) (21). This same model wasunable to link aortic stiffness to albuminuria. Hashimotoand Ito (22) made somewhat similar observations byultrasound assessments of aortic and renal artery flow.These investigators showed that an excessive reverseflow pattern in the aorta during diastole is a strongercorrelate of low eGFR and associated with decreasedintrarenal flow velocities (22). These results point toanother factor in aortic function during arterial stiff-ening (i.e., enhanced flow reversal) that worsens in-creased pulsatility as a mediator of impaired renal flowand low GFR in hypertension and/or CKD (22). Betterunderstanding of these relationships, validation inyounger populations, and easier and more precisemeasurement of these variables in clinical practice mayimprove the management of kidney functional loss inthe setting of stiff arteries, the norm in CKD.

Aging and hypertension have additive,separate effects that contribute to arterialstiffness. Aging is associated with cellularstiffness and extracellular matrix accumu-lation, whereas hypertension mediates stiff-ness largely through potent effects on VSMcells mediated by the cytoskeleton andadhesive properties of VSM cells to theirsurrounding matrix.

Hypertension with Brachydactyly Is Caused bya Mutation in Phosphodiesterase-3A

Hypertension with brachydactyly is a rare butwell described Mendelian syndrome of hypertension.This autosomal dominant disorder is characterized byshort stature, brachydactyly, and salt-independenthypertension that develops during early to midadult-hood and if untreated, is often complicated by stroke inthe absence of other target organ injury. Maass et al.(23) used whole-genome sequencing to identify mis-sense mutations in phosphodiesterase 3A (PDE3A), the


gene encoding PDE3A, as the cause of the disorder insix unrelated kindred with the syndrome from Turkey,France, South Africa, Canada, and the United States.The authors demonstrated that these gain-of-functionmutations increased phosphorylation of PDE3A byprotein kinase A in mesenchymal stem cell–derivedVSM cells and that PDE3A may mediate VSM pro-liferation and increased vascular tone (23). In addition,parathyroid hormone–related peptide downregulationwas documented, which may mediate the syndrome’sskeletal phenotype. The mechanisms of hypertension inthe syndrome are unclarified but seem related to in-creased systemic vascular resistance from a primaryvascular wall problem as implied by the lack of BPresponse to ganglionic blockers, robust response tonitroprusside, and increased effective aortic elastance(central aortic end-systolic BP divided by stroke volume)(24). No excess platelet activation or cardiac abnormali-ties were found in four subjects with the syndrome. Thisdiscovery has relevant implications to clinical care. First,it is the first example of Mendelian hypertension that isnot caused by abnormal renal sodium handling. Second, itprovides a possible mechanism of sustained increasedvascular resistance that may be targeted pharmacologi-cally to improve BP control and/or vascular proliferation.

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Update on the Evaluation of the HypertensivePatient

Technological Updates on BP MeasurementOffice BP measurements are often plagued by

poor technique, inaccurate instruments, measurementwithout allowing patients to rest, and failure to averagemultiple readings. Not surprisingly, such casual officeBP readings do not have good agreement with ambu-latory BP monitoring (ABPM) averages and are weaklyassociated with hypertensive complications. A recentsolution to the use of casual office BP is the avail-ability of automated office BP monitoring (AOBP)using a device that can be activated by the patient andthat obtains and averages several readings. Such amethod is associated with much closer agreement withABPM and displays good correlations with left ven-tricular mass and carotid intima-media thickness (1).Several devices are already available on the market.Using one of these devices (BpTRU; Bp TRU MedicalDevices, Coquitlam, BC, Canada), Armstrong et al. (2)obtained conventional office BP (COBP), AOBP (aver-age of five automated readings obtained by the patientin a waiting area), and 24-hour ABPM in 422 patientsreferred for ABPM. The main goal of the study was totest the use of the BpTRU device in a waiting arearather a designated examination room, with the goal ofassessing the generalizability of its use in a busyclinical practice setting. Similar to previous studies,they demonstrated that AOBP (141/83 mmHg) wasmuch closer to the awake ABPM (139/81 mmHg) thanthe COBP (155/90 mmHg) (2). However, the generalaccuracy of the agreement between the AOBP andABPM was about 73%; 18% of patients had discor-dant readings in the range of white coat hypertension(WCH; i.e., AOBP high with normal ABPM), and41% had disagreements in the masked hypertension(MH) range (AOBP normal with high ABPM). Inaddition, Edwards et al. (3) reported that AOBP resulted

in lesser rates of incorrect diagnosis of WCH (8% ofpatients versus 14% with COBP) but resulted in higherrates of incorrect classification of MH than COBP (20%versus 8%). Therefore, it seems that AOBP, although veryefficient in reducing the average office BP value and thus,decreasing the odds of incorrectly diagnosing WCH, mayresult in unacceptable rates of missing MH, a condition ofincreased vascular risk (see below). It seems that moreresearch that focuses on outcomes assessment usingAOBP is necessary prior to its more liberal recommen-dation as the primary method of office BP measurement.

Until recently, only 24-hour ABPM allowed themeasurement of nighttime BP. More recently, home BPdevices available in other countries have programmablefeatures that allow the patient to obtain self-measured BPsduring sleep. Ishikawa et al. (4) compared the measure-ment of nocturnal BP with one such device (OmronHEM-5001; Omron Healthcare, Kyoto, Japan) with thatof conventional ABPM in 50 hypertensive patients. Thehome BP monitor was programmed to obtain threereadings per night (2:00, 3:00, and 4:00 AM) for sevennights; these 21 readings were averaged to represent theself–monitored sleep BP. Overall, the nighttime BP valueswere similar between the home BP and ABPM methods(difference of 2.9/1.6 mmHg; P¼0.21 and P¼0.34,respectively), and the reduction observed using the homeBP method had stronger correlation with changes in leftventricular mass during follow-up (r¼0.39; P¼0.01) thanthose observed with ABPM (r¼0.25; P¼0.12) (4). Welook forward to the availability of these programmablemonitors in the United States market, because they willallow the frequent monitoring of nocturnal BP without thecosts and inconvenience of 24-hour ABPM.

Until recently, only 24-hour ambulatory BPmonitoring permitted the measurement ofnighttime BPs. More recently, home BPdevices, which are available in other coun-tries, have been outfitted with program-mable features that allow self-measuredBPs during sleep. Commercialization inthe United States is forthcoming.

Recommendations for Screening andConfirmation of High BP in Adults

A systematic review for the US Preventive ServicesTask Force (USPSTF) covered the important topics of




clinical relevance of screening for hypertension, appro-priate time interval between screenings, and best methodsto confirm the diagnosis of hypertension in those withelevated BP (5). The following statements summarize thesystematic review and the USPSTF recommendations(http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/high-blood-pressure-in-adults-screening).

Previous evidence of the impact of treatment ofhypertension on clinical outcomes had justifiedscreening in adults. This systematic review identifiedone study showing that screening was associated withfewer cardiovascular hospitalizations and myocardialinfarctions among elderly patients screened via a phar-macy-based program, thus providing additional, nowdirect support for screening for high BP. Accordingly,the USPSTF will continue to support the screening forhypertension among adults in the United States.

Based on 39 studies of hypertension incidence (Figure7), the USPSTF recommends annual screening foradults ages 40 years old and older and those who areat increased risk for high BP, such as those who havehigh-normal BP (130–139/85–89 mmHg), are over-weight or obese, or are African American. Each of

these groups has a two- to threefold greater incidenceof hypertension than control groups with normal BP,normal weight, and non–African-American ethnic-ities (5). Adults ages 18–39 years old with normal BP(,130/85 mmHg) who do not have other risk factorsshould be rescreened every 3–5 years.

The most practice changing of the USPSTF recom-mendations is that, if screening BPs using appropri-ate properly performed office BP measurement areelevated, the diagnosis of hypertension should beconfirmed with out of office BP monitoring. Thisrecommendation was based on two general lines ofevidence. First, there was the identification of 11studies (six rated as good quality and five rated asfair quality) showing that, after adjustment for officesystolic BP, 24-hour ambulatory systolic BP wasconsistently associated with increased risk of car-diovascular end points, particularly stroke (Figure8). A meta-analysis testing whether there were differ-ences in the predictive ability of 24-hour average,daytime, and nighttime BPs did not detect any sig-nificant differences among the hazard ratios usingthese different BP categories (5). Second, there wasthe determination that an analysis of 24 studies usingABPM (N¼18 studies) or home BP monitoring (N¼6

Figure 7. Scatterplot of studies of hypertension incidence according to screening interval. Note the progressive increase withrepeat screening and the increased incidence in studies testing a single screening visit, emphasizing the importance of repeatedmeasurements. The size of symbols represents sample size (N¼730–115,736). HTN, hypertension. Reprinted with permissionfrom Piper MA, Evans CV, Burda BU, Margolis KL, O’Connor E, Whitlock EP: Diagnostic and predictive accuracy of bloodpressure screening methods with consideration of rescreening intervals: A systematic review for the U.S. Preventive ServicesTask Force. Ann Intern Med 162: 192–204, 2015.


http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/high-blood-pressure-in-adults-screening



studies) as the gold standard for the diagnosis ofhypertension showed that elevated COBP could beconfirmed in only 35%–95% of cases, thus makingthe case for a more robust method of confirma-tion (than office BP) before embarking on long-term treatment. Interestingly, in its initial draft,the recommendation suggested the use of 24-hourABPM for diagnosis, but after public review, thefinal recommendation accepted the use of home BPas an alternative. The recommendation acknowledgesthat the predictive ability of home systolic BP wassimilar to 24-hour BP; however, because too fewstudies are available, firm conclusions could not bereached. This recommendation aligns with the UnitedKingdom’s guideline recommendations from 2011 (6).

These new recommendations have far-reaching im-plications. Because of the grade A recommendation

status, out of office BP will need to be covered by allinsurers for the diagnosis of hypertension without costsharing by patients (e.g., copayments, deductibles,and coinsurance) as dictated by the Affordable CareAct’s section 2173. This will likely require reimburse-ment reform, because the availability of ABPM remainslimited, largely due to low reimbursement rates (medianpayment of $52 per study among Medicare beneficia-ries undergoing studies between 2007 and 2010 [7]).Also, because of the size of the population at risk (asmany as 2%–5% annually of the adult population overthe age of 40 years old), the expected number could beenormous, thus requiring creative strategies to provideABPM and home BP monitoring services.

New ABPM GuidelinesThe European Society of Hypertension issued

updated guidelines for the clinical use of ABPM in 2014

Figure 8. Risk for cardiovascular and mortality outcomes based on a 10-mmHg increase in 24-hour ambulatory SBP afteradjustment for office SBP. 95% CI, 95% confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI,myocardial infarction. Reprinted with permission from Piper MA, Evans CV, Burda BU, Margolis KL, O’Connor E, WhitlockEP: Diagnostic and predictive accuracy of blood pressure screening methods with consideration of rescreening intervals: Asystematic review for the U.S. Preventive Services Task Force. Ann Intern Med 162: 192–204, 2015.


(8). These are summary guidelines in follow-up to a muchmore detailed document published in 2013 (9). Severalimportant practical recommendations have been proposed.

Because of the importance of nighttime BP on prog-nosis, the definitions of WCH and MH should bebased on ABPM averages that include nighttimemeasurements. Therefore, it is proposed that, insteadof using the awake averages, as previously done, the24-hour average of 130/80 mmHg be used as thecutoff for the diagnosis of WCH (office .140/90 mmHg and 24 hour ,130/80 mmHg) and MH(office,140/90 mmHg and 24 hour$130/80 mmHg).

Four general categories of compelling indications forABPM are described, including the identification ofWCH, the identification of MH, the identification ofabnormal circadian BP patterns, and the assessmentof treatment, including the identification of true resis-tant hypertension. These indications and additional

indications are listed in Table 2. Unfortunately, despitethese recommendations, lack of reimbursement remainsa major impediment to the widespread use of ABPM.

The definition of a satisfactory ABPM recording is un-defined. The current guidelines propose aminimum of 20awake and seven asleep readings with readings obtainedat least every 30 minutes throughout the 24-hour period.

Although openly acknowledging concerns about mon-itoring patients with atrial fibrillation, the guidelinesacknowledge that most monitors obtain accuratereadings in this population. Therefore, patients withatrial fibrillation may undergo ABPM. The guide-lines call for more research on outcomes assessmentin atrial fibrillation patients undergoing ABPM,because these patients have been traditionally ex-cluded from large observational studies.

ABPM and Home BP Monitoring: NewPrognostic Studies in Hypertension

Other than the updated review of prognosticstudies presented as part of the systematic reviewfor the USPSTF, a few additional studies regardingprognosis merit review in this update. Whereas pre-vious data supported the role of home BP to pre-dict target organ damage solely by evaluation of leftventricular hypertrophy, an updated meta-analysisprovided new information on the relationship betweenhome BP and albuminuria when compared with officeBP (10). The meta-analysis included four cross-sectional studies (N¼1726 patients) and demonstratedconsistently and significantly better correlation coef-ficients between home BP and albuminuria than officeBP (r¼0.31; 0.27–0.35 versus r¼0.19; 0.14–0.24,respectively). This update extends the role of homeBP as a better correlate of albuminuria than office BP.

There have been new studies extending the roleof home BP measurements to evaluate outcomes in thegeneral population. Two studies have addressed thisquestion through the evaluation of the prognosis of twoconditions identified by home BP monitoring: WCH(high office BP and normal home BP) and MH (normaloffice BP and high home BP). In the Finnish cohortstudy of home BP monitoring, Finn-Home, Hanninenet al. (11) enrolled 1540 patients from the generalpopulation and explored the prevalence of measures oftarget organ damage (electrocardiographic left ventric-ular hypertrophy, carotid intima-media thickness, andaortopopliteal pulse wave velocity [PWV]) at baselineaccording to BP status. Of the enrolled patients, 773

Table 2. Clinical indications for ABPM based on theEuropean Society of Hypertension practice guidelines

Reprinted with permission (with modification) from Parati G, Stergiou G, O’Brien E,Asmar R, Beilin L, Bilo G, Clement D, de la Sierra A, de Leeuw P, Dolan E, Fagard R,Graves J, Head GA, Imai Y, Kario K, Lurbe E, Mallion JM, Mancia G, Mengden T, MyersM, Ogedegbe G, Ohkubo T, Omboni S, Palatini P, Redon J, Ruilope LM, Shennan A,Staessen JA, vanMontfrans G, Verdecchia P, Waeber B, Wang J, Zanchetti A, Zhang Y;European Society of Hypertension Working Group on Blood Pressure Monitoring andCardiovascular Variability: European Society of Hypertension practice guidelines forambulatory blood pressure monitoring. J Hypertens 32: 1359–1366, 2014.


(50%) were normotensive, 233 (15%) had WCH, 122(8%) had MH, and 412 (27%) had sustained hyperten-sion. Similar to previous studies, this study revealedthat patients with MH had greater Cornell voltageproduct (19.0 versus 17.2 mm; P,0.01), prevalenceof left ventricular hypertrophy (10.8% versus 4.4%;P¼NS), and PWV (14.8 versus 13.2 m/s; P,0.05) thannormotensive subjects after multiple relevant adjustments,numbers that were similar to sustained hypertensives.There were no differences for carotid intima-mediathickness. Subjects with WCH, on the other hand, had anintermediate risk of having target organ damage, althoughthe Cornell voltage product was statistically higher inWCHsubjects than in normotensives (18.2 versus 17.2 mm;P,0.05), and the prevalence of left ventricular hypertrophywas numerically higher as well (8.9% versus 4.4%;P¼NS), thus representing a subgroup with risk that islower than MH, though numerically higher than normo-tension. In the evaluation of the prognosis of WCH andMH in the International Database of Home Blood Pressurein Relation to Cardiovascular Outcome, 6458 patientsfrom five different populations were followed for anaverage of 8.3 years (12). As shown in Table 3, WCH,MH, and sustained hypertension were all associated withsignificantly increased risk of cardiovascular eventsamong the 5007 untreated subjects. Among the 1451treated patients, only MH and sustained hypertension,not WCH, were associated with increased cardiovascularrisk. Other relevant findings included the demonstration ofincreased risk of controlled treated hypertension comparedwith untreated normotension and the lack of associationbetweenWCH and mortality in any of the subgroups (12).

These results point further to the intermediate risk posedby WCH when detected with home BP, although this riskis mitigated by antihypertensive treatment.

In the realm of hypertension in CKD, the SpanishABPM Registry has provided important information onthe assessment of BP control based on ABPM comparedwith COBP measurements in 5693 hypertensive patientswith CKD ranging from stage 1 to 5. Most had stage 3CKD (N¼3893), with 73% receiving antihypertensivetreatment (13). Using 140/90 mmHg in the clinic and130/80 mmHg for 24-hour average BP as the cutoffs forcontrol, the investigators reported that only 15% werecontrolled in the office and on ABPM (13); 49% wereuncontrolled in both settings, whereas the rates of WCHand MH were 29% and 7%, respectively. In a separatestudy, Minutolo et al. (14) evaluated 489 hypertensivepatients with CKD (average age ¼64 years old;eGFR¼45 ml/min per 1.73 m2) with both clinic and24-hour ABPM and followed them for a median of 5.2years to investigate the differential impact of BP control inthe clinic and/or ambulatory settings on cardiorenal out-comes. They classified patients according to level of BPcontrol using 140/90 mmHg for clinic BP and 135/85 and120/70 mmHg for average daytime and nighttime BPs,respectively (14). For all relevant end points (ESRD ordeath, cardiovascular events, ESRD, and all-cause death),patients with uncontrolled clinic and ABPM pressures hadthe worst outcomes (Figure 9, A and B). The results ofthese two studies and in particular, the adverse outcomesassociated with a masked effect in the study by Minutoloet al. (14) (15% of their cohort) underscore the relevanceof out of office BP monitoring in this population.

Table 3. Hazard ratios for cardiovascular events in the International Database on Home Blood Pressure in Relation toCardiovascular Outcome Database according to treatment status in patients with WCH, MH, and sustained hypertension

95% CI, 95% confidence interval; IDHOCO, International Database on Home Blood Pressure in Relation to Cardiovascular Outcome; HR, hazard ratio; HT, hypertension.Reprinted with permission (with modification) from Stergiou GS, Asayama K, Thijs L, Kollias A, Niiranen TJ, Hozawa A, Boggia J, Johansson JK, Ohkubo T, Tsuji I, Jula AM,Imai Y, Staessen JA; International Database on HOme blood pressure in relation to Cardiovascular Outcome (IDHOCO) Investigators: Prognosis of white-coat and maskedhypertension: International Database of HOme blood pressure in relation to Cardiovascular Outcome. Hypertension 63: 675–682, 2014.


Figure 9. Adverse cardiorenal outcomes in patients with CKD according to achieved BP control in the office and/or ambulatorysetting. (A) ESRD (in this study, defined as dialysis therapy initiation) or death, (B) fatal and nonfatal cardiovascular events, (C)ESRD, and (D) all-cause mortality in the four groups of patients. Group 1, patients with both clinic and ambulatory BPs at goal;group 2, patients with clinic BP not at goal and ambulatory BP at goal; group 3, patients with clinic BP at goal and ambulatoryBP not at goal; and group 4, patients with both clinic and ambulatory BPs not at goal. 95% CI, 95% confidence interval; CV,cardiovascular; HR, hazard ratio. Reprinted with permission from Minutolo R, Gabbai FB, Agarwal R, Chiodini P, Borrelli S,Bellizzi V, Nappi F, Stanzione G, Conte G, De Nicola L: Assessment of achieved clinic and ambulatory blood pressurerecordings and outcomes during treatment in hypertensive patients with CKD: A multicenter prospective cohort study. Am JKidney Dis 64: 744–752, 2014.


Orthostatic HypotensionOrthostatic hypotension (OH) is relatively com-

mon among patients with hypertension. It is estimatedthat up to one third of elderly patients with hyperten-sion also have OH, and OH is associated with in-creased risk of falls, coronary disease, stroke, heartfailure, and death (15). A recent study expanded ourknowledge of OH by performing a large cross–sectional analysis of the Irish population over the ageof 50 years old with a beat-to-beat BP monitor thatprovided detailed information on the behavior of BP onstanding as well as the overall adequacy of the hemo-dynamic adaption to orthostatic stress (16). The 4475subjects studied consisted of 52% women, had a meanage of 63 years old, and had 20% with a history of a fallin the preceding year, 39% with complaints of dizzinesson standing, 7.5% with diabetes, 35% receiving anti-hypertensive drugs, and 21% defined as having poly-pharmacy (more than five prescription medications).A large proportion of these individuals had someimpairment in orthostatic BP. With increasing decadeof life, the prevalence of OH increased from 4.2% in50- to 59-year-old subjects to 18.5% in those$80 yearsof age. Consistent with the reported rate of orthostaticsymptoms, initial OH, defined as a symptomatic BP fall.40/20 mmHg during the first 15 seconds of standing,was highly prevalent (30%–35%) and did not vary byage. The prevalence of impaired BP stabilization,defined as a lack of return to baseline BP at 40 secondson standing, occurred in 16% of subjects and increasedwith each decade, affecting 41% of those $80 years ofage. The study provides normative data for each of theage groups in detailed graphs and tables. This studydiffers from any previously published studies by itslarge sample size, representation of a community–basedmiddle–aged and elderly population, and the use of

a beat-to-beat monitor that allows clear mapping of theadaptation to standing, including the first 15 seconds,which are virtually never captured by routine sphyg-momanometry. Because early OH (within the first15 seconds) is an important cause of presyncopal symp-toms (and syncope), these findings highlight the im-portance of recognizing the existence of the problemand the fact that it cannot be diagnosed by routinemethods. Because of the high cost and limited avail-ability of beat-to-beat monitors, a pragmatic approachto this is to presume the diagnosis of early OH andprovide clear instructions to the patient on slow, step-wise standing (i.e., sit and then stand) and use of othernonpharmacologic approaches to OH, such as thecocktail party leg position and support stockings (typi-cally thigh high with or without a lower–abdominalpress component). Although we believe that thesefindings have relevance to the management of symp-tomatic patients, their impact to asymptomatic patientswith treated hypertension remains uncertain, and fur-ther work will be necessary to tease out the interactionsbetween OH, antihypertensive treatment changes, andBP-related outcomes, both low and high (cardiovascu-lar events, falls, and death).

Objective Volume Assessment in the Evaluation ofHypertensive Patients with CKD

Extracellular fluid (ECF) volume expansion is afrequent finding in hypertension, in particular in pa-tients with diabetes and/or CKD. A large body of datahas explored the use of objective measures of ECF,most commonly bioimpedance spectroscopy, to betterdefine dry weight in patients on hemodialysis. Tech-nological developments have made bioimpedancedevices easy to use and relatively inexpensive. Thetechnique applies multifrequency electric impulses

Figure 9. Continued.


through electrodes typically placed on one wrist andone foot. Estimates of total body water and extracel-lular water result. Hung et al. (17) studied 338 CKDpatients (average eGFR ¼28 ml/min per 1.73 m2) andshowed that 52% were overhydrated, defined as ECFexpansion by.7% of predicted for age, weight, height,and sex; 20% of patients had ECF expansion in theabsence of any clinical signs of volume overload. Thedegree of ECF expansion correlated with systolic BP(r¼0.31; P,0.001), PWV (r¼0.14; P,0.01), log ofN-terminal probrain natriuretic peptide (r¼0.54;P,0.001), eGFR (r¼20.15; P,0.001), and severalmarkers of malnutrition and inflammation.

Verdalles et al. (18) explored the use of bioimpe-dance to better design the management of 50 CKDpatients with resistant hypertension. Despite absenceof any clinical findings to suggest volume overload, 30of the 50 subjects had evidence of ECF expansion(.6.6% than predicted), and the presence of overhydra-tion occurred more commonly in those with moreadvanced CKD, diabetes, and more proteinuria. Patientswith ECF expansion were managed with diuretic in-tensification and experienced a significant decrease inoffice systolic BP (21.4 mmHg) at 6 months without anincrease in antihypertensive medications (from 3.9 to 3.7;P¼0.60). Conversely, patients without ECF expansionwere managed with other agents and as expected, had anincrease in antihypertensives (from 3.3 to 4.3; P,0.01)and a much lower systolic BP response (9.4 mmHg) (18).This was not a randomized trial, and it is possible thatpatients would have responded just as well with empiricalincrease in diuretic dosing. However, these data point tothe potential value of better phenotyping patients froma volume standpoint to better design antihypertensivetreatment. Further studies are encouraged.

References1. Myers MG: Eliminating the human factor in office blood pressure

measurement. J Clin Hypertens (Greenwich) 16: 83–86, 2014 PubMed2. Armstrong D, Matangi M, Brouillard D, Myers MG: Automated office

blood pressure - being alone and not location is what matters most.Blood Press Monit 20: 204–208, 2015 PubMed

3. Edwards C, Hiremath S, Gupta A, McCormick BB, Ruzicka M:BpTRUth: do automated blood pressure monitors outperform mercury?J Am Soc Hypertens 7: 448–455, 2013 PubMed

4. Ishikawa J, Shimizu M, Sugiyama Edison E, Yano Y, Hoshide S, EguchiK, Kario K; J-TOP (JapanMorning Surge-Target Organ Protection) StudyInvestigators Group: Assessment of the reductions in night-time bloodpressure and dipping induced by antihypertensive medication usinga home blood pressure monitor. J Hypertens 32: 82–89, 2014 PubMed

5. Piper MA, Evans CV, Burda BU, Margolis KL, O’Connor E, WhitlockEP: Diagnostic and predictive accuracy of blood pressure screeningmethods with consideration of rescreening intervals: A systematic review

for the U.S. Preventive Services Task Force. Ann Intern Med 162: 192–204, 2015 PubMed

6. National Institute for Health and Clinical Excellence: The ClinicalManagement of Primary Hypertension in Adults: Clinical Guideline127. NICE, 2011. Available at: http://www.nice.org.uk/guidance/cg127/evidence/cg-hypertension-full-guideline3. Accessed September 26, 2014

7. Kent ST, Shimbo D, Huang L, Diaz KM, Viera AJ, Kilgore M, Oparil S,Muntner P: Rates, amounts, and determinants of ambulatory bloodpressure monitoring claim reimbursements among Medicare beneficia-ries. J Am Soc Hypertens 8: 898–908, 2014 PubMed

8. Parati G, Stergiou G, O’Brien E, Asmar R, Beilin L, Bilo G, Clement D,de la Sierra A, de Leeuw P, Dolan E, Fagard R, Graves J, Head GA,Imai Y, Kario K, Lurbe E, Mallion JM, Mancia G, Mengden T, MyersM, Ogedegbe G, Ohkubo T, Omboni S, Palatini P, Redon J, RuilopeLM, Shennan A, Staessen JA, vanMontfrans G, Verdecchia P, Waeber B,Wang J, Zanchetti A, Zhang Y; European Society of HypertensionWorkingGroup on Blood Pressure Monitoring and Cardiovascular Variability:European Society of Hypertension practice guidelines for ambulatory bloodpressure monitoring. J Hypertens 32: 1359–1366, 2014 PubMed

9. O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, Clement D,de la Sierra A, de Leeuw P, Dolan E, Fagard R, Graves J, Head GA,Imai Y, Kario K, Lurbe E, Mallion JM, Mancia G, Mengden T, MyersM, Ogedegbe G, Ohkubo T, Omboni S, Palatini P, Redon J, RuilopeLM, Shennan A, Staessen JA, vanMontfrans G, Verdecchia P, WaeberB, Wang J, Zanchetti A, Zhang Y; European Society of HypertensionWorking Group on Blood Pressure Monitoring: European Society ofHypertension position paper on ambulatory blood pressure monitoring.J Hypertens 31: 1731–1768, 2013 PubMed

10. Fuchs SC, Mello RG, Fuchs FC: Home blood pressure monitoring isbetter predictor of cardiovascular disease and target organ damage thanoffice blood pressure: A systematic review and meta-analysis. CurrCardiol Rep 15: 413, 2013 PubMed

11. Hänninen MR, Niiranen TJ, Puukka PJ, Kesäniemi YA, Kähönen M, JulaAM: Target organ damage andmasked hypertension in the general population:The Finn-Home study. J Hypertens 31: 1136–1143, 2013 PubMed

12. Stergiou GS, Asayama K, Thijs L, Kollias A, Niiranen TJ, Hozawa A,Boggia J, Johansson JK, Ohkubo T, Tsuji I, Jula AM, Imai Y, Staessen JA;International Database on HOme blood pressure in relation to CardiovascularOutcome (IDHOCO) Investigators: Prognosis of white-coat and maskedhypertension: International Database of HOme blood pressure in relation toCardiovascular Outcome. Hypertension 63: 675–682, 2014 PubMed

13. Gorostidi M, Sarafidis PA, de la Sierra A, Segura J, de la Cruz JJ,Banegas JR, Ruilope LM; Spanish ABPM Registry Investigators:Differences between office and 24-hour blood pressure control inhypertensive patients with CKD: A 5,693-patient cross-sectionalanalysis from Spain. Am J Kidney Dis 62: 285–294, 2013 PubMed

14. Minutolo R, Gabbai FB, Agarwal R, Chiodini P, Borrelli S, Bellizzi V,Nappi F, Stanzione G, Conte G, De Nicola L: Assessment of achievedclinic and ambulatory blood pressure recordings and outcomes duringtreatment in hypertensive patients with CKD: A multicenter prospectivecohort study. Am J Kidney Dis 64: 744–752, 2014 PubMed

15. Shibao C, Lipsitz LA, Biaggioni I; American Society of HypertensionWriting Group: Evaluation and treatment of orthostatic hypotension. JAm Soc Hypertens 7: 317–324, 2013 PubMed

16. Finucane C, O’Connell MD, Fan CW, Savva GM, Soraghan CJ, NolanH, Cronin H, Kenny RA: Age-related normative changes in phasicorthostatic blood pressure in a large population study: Findings fromThe Irish Longitudinal Study on Ageing (TILDA). Circulation 130:1780–1789, 2014 PubMed

17. Hung SC, Kuo KL, Peng CH, Wu CH, Lien YC, Wang YC, Tarng DC:Volume overload correlates with cardiovascular risk factors in patientswith chronic kidney disease. Kidney Int 85: 703–709, 2014 PubMed

18. Verdalles U, de Vinuesa SG, Goicoechea M, Quiroga B, Reque J, Panizo N,Arroyo D, Luño J: Utility of bioimpedance spectroscopy (BIS) in themanagement of refractory hypertension in patients with chronic kidney disease(CKD). Nephrol Dial Transplant 27[Suppl 4]: iv31–iv35, 2012 PubMed







http://www.nice.org.uk/guidance/cg127/evidence/cg-hypertension-full-guideline3

http://www.nice.org.uk/guidance/cg127/evidence/cg-hypertension-full-guideline3













Secondary Hypertension: Obesity-Related Hypertension

Physiologic MechanismsObesity-related hypertension is mediated through

numerous physiologic mechanisms. Increased sympa-thetic nervous system activity and activation of therenin-angiotensin system have been well documented.Inappropriately low levels of natriuretic peptides havebeen observed in obese individuals in epidemiologicaland animal studies (1, 2); however, atrial natriureticpeptide (ANP) has limited clinical value due to itsshort half-life. Midregional proatrial natriuretic peptide(MRproANP) is the midregional epitope of the ANPprohormone, and it is released into the circulationtogether with ANP but is more stable with a longerhalf-life (1). Natriuretic peptides induce natriuresis,vasodilation, and suppression of the renin-angiotensin-aldosterone system. Therefore, low circulating levelsof ANP in morbidly obese patients may be associatedwith impaired natriuresis, thereby contributing tohypertension and salt sensitivity.

Other factors that contribute to salt sensitivityin obesity-related hypertension have been described.Increased expression of angiotensin I receptors in theproximal tubule contributes to impaired natriuresis insalt-sensitive hypertension (3,4). Volume expansioncharacteristic of salt-sensitive hypertension resultsin suppression of renin release. Serum aldosteronelevels, however, are higher than expected in obeseindividuals with salt-sensitive hypertension (5). Thisincrease is mediated by the release of aldosterone-releasing factors from adipose tissue. Fujita (6) hasdemonstrated a role for increased Rac1, a member ofthe Rho family of small guanosine-59-triphosphatenucleotide-binding proteins, in mediating hyperten-sion in obese hypertensive rats. Rac1 acts as a novelligand–independent modulator of increased mineralocor-ticoid receptor activity, further potentiating sodium re-tention in salt-sensitive hypertension.

Adiponectin has been linked as a possible causalmechanism in obesity-related hypertension. A meta-analysis analyzed plasma adiponectin levels in 48(nonprospective and prospective) studies that included17,598 adults (8220 with hypertension; mean age ¼19–69 years old; mean body mass index [BMI] ¼22–38 kg/m2) (7). Adults with hypertension had loweradiponectin levels than normotensive adults by 1.64mg/ml(95% confidence interval [95% CI], 22.07 to 21.21).For each 1-mg/ml adiponectin increase, there was a 6%

risk reduction for hypertension (95% CI, 0.92 to 0.97),and these findings were consistent across study designand age, sex, and BMI (P.0.05). This meta-analysissuggests that plasma adiponectin is a possible mediatorof obesity-related hypertension and may representa potential therapeutic target in this population.

Effects of Bariatric SurgeryIn the prior NephSAP, the effects of bariatric

surgery on hypertension were discussed, and the valueof surgical weight reduction in improving BP control inhypertensive patients with diabetes was confirmed. Thetrials also enrolled patients with mild to moderateobesity (BMI,35 kg/m2), raising awareness of thepotential value of bariatric surgery in patients withhypertension without morbid obesity.

The Longitudinal Assessment of Bariatric SurgeryConsortium conducted a multicenter observational co-hort study at 10 United States hospitals in six geo-graphically diverse clinical centers. Adults undergoingfirst–time bariatric surgical procedures were recruitedbetween 2006 and 2009 and followed until September of2012 (8). Three years after Roux-en-Y gastric bypass(RYGB) or laparoscopic adjustable gastric banding(LAGB), the percentage weight change from baselineand resolution of hypertension were assessed. Thestudy included 2458 participants with a median BMIof 46 kg/m2. There were 1738 participants who un-derwent RYGB, 610 participants who underwent LAGB,and 110 participants who underwent other procedures. Atbaseline, 68% of subjects had hypertension. Threeyears following surgery, the median actual weight losswas greater for RYGB versus LAGB (41 versus 20 kg,respectively). The majority of weight loss was evident1 year after surgery for both procedures (Figure 10).Remission of hypertension, specified as no requirementfor antihypertensive medication, occurred in 38% ofRYGB participants and 17% of LAGB participants.The incidence of new-onset hypertension was 13% inRYGB participants and 18% in LAGB participantsover 3 years. There were also significant improvementsin the incidence of diabetes and dyslipidemia, withgreater improvements for RYGB.

A recent study examined the effect of sodiumintake on 24-hour BP in obese subjects before and afterlaparoscopic Roux-en-Y gastric bypass (LRYGB) (9);12 hypertensive and 12 normotensive morbidly obesepatients who underwent an LRYGB procedure wereenrolled in the study. All participants had 24-hour


ambulatory BP (ABP), systemic hemodynamics, andMRproANP concentrations obtained presurgery and 6weeks and 12 months after surgery. The effect of highversus low sodium intake on 24-hour ABP was evaluatedbefore and 12 months after surgery. To determine theinfluence of sodium on BP and systemic hemodynamics,the patients were randomized to a low (90 mmol/d) orhigh salt (250 mmol/d) diet for 5 days by simplerandomization before and 12 months after the operation.Participants then resumed their regular diet during a 2-week washout period before crossing over to the oppositediet for another 5-day period. Six weeks after LRYGB,the average weight loss was 20 kg, with a further 21-kgweight loss 1 year after surgery. In hypertensive patients,24-hour ABP was significantly reduced at 6 weeks butdid not remain reduced by 1 year after surgery; however,antihypertensive medications were successively reducedfrom baseline to 1 year postsurgery. In patients who werenormotensive at baseline, there was no change in 24-hourABP 6 weeks postsurgery, but BP was non-significantlyreduced after 1 year (Figure 11). Plasma MRproANP

levels were subnormal presurgery in hypertensive patientsand increased after 1 year by 77%. In normotensivepatients, preoperative concentrations were normal andincreased only by 6% (Figure 12). High sodium intakeprovoked plasma volume expansion and increased strokevolume and cardiac output without an effect on 24-hourABP. This study demonstrated that LRYGB resulted ina significant 24-hour ABP reduction and a substantialincrease in MRproANP concentrations in hypertensive,

Figure 10. Observed and modeled percentage weight changesby time point. Lines indicate modeled weight changes; datamarkers are median values, and bars are interquartile ranges(IQRs). Reprinted with permission from Courcoulas AP,Christian NJ, Belle SH, Berk PD, FlumDR, Garcia L, HorlickM, Kalarchian MA, King WC, Mitchell JE, Patterson EJ,Pender JR, Pomp A, Pories WJ, Thirlby RC, Yanovski SZ,Wolfe BM; Longitudinal Assessment of Bariatric Surgery(LABS) Consortium:Weight change and health outcomes at 3years after bariatric surgery among individuals with severeobesity. JAMA 310: 2416–2425, 2013.

Figure 11. LRYGB alleviates hypertension in morbid obesepatients. MAP (millimeters Hg) before, 6 weeks after, and 12months after LRYGB in (A) obese hypertensive patients and(B) obese normotensive patients. Reprinted with permissionfrom Bonfils PK, Taskiran M, Damgaard M, Goetze JP,Floyd AK, Funch-Jensen P, Kristiansen VB, Støckel M,Bouchelouche PN, Gadsbøll N: Roux-en-Y gastric bypassalleviates hypertension and is associated with an increase inmid-regional pro-atrial natriuretic peptide in morbid obesepatients. J Hypertens 33: 1215–1225, 2015.


obese patients 6 weeks postsurgery, implying a possi-ble link between obesity-related hypertension andaltered release or degradation of cardiac natriureticpeptides.

These two studies highlight several importantpoints. (1) Bariatric surgery–associated weight losshas a favorable effect on BP reduction, with moreimpressive decreases in weight and BP reduction withan RYGB procedure compared with the less invasiveLAGB procedure. (2) LRYGB surgery results insignificant 24-hour ABP reductions and is accompaniedby enhanced ANP levels, which raises the possibility ofpathophysiological linkage between obesity-associatedhypertension and alteration of the release or degradationof ANP.

Sleep Apnea, Use of Continuous Positive AirwayPressure, and Effects on Hypertension

Obstructive sleep apnea (OSA), the use of con-tinuous positive airway pressure (CPAP), and itseffects on BP were discussed in the prior NephSAP.The effects of CPAP on BP reduction are modest, and thishas been shown in a number of prior studies (10–12). Thereare a number of new studies in the last 2 years that addsignificantly to the literature and will be discussed here.

OSA is common among patients with hyperten-sion, especially in resistant hypertension (13), and bothof these highly prevalent conditions contribute toincreased cardiovascular (CV) risk. Although OSAincreases the risk of CV disease through a number ofmechanisms, repetitive cycles of hypoxemia and re-oxygenation probably play a central role in increasingCV risk by increasing sympathetic nervous systemactivity, systemic inflammation, and oxidative stress(14). By supplementing nocturnal oxygen, CV riskmay be reduced compared with CPAP use. Gottliebet al. (15) evaluated the effects of nocturnal oxygensupplementation for CV reduction in OSA patients,enrolling 318 patients with CV disease or multiple CVrisk factors in a randomized, controlled trial (RCT).Participants were screened for OSA, and those who hadan apnea-hypopnea index (AHI) of 15–50 events perhour were randomly assigned to a control group toreceive education on sleep hygiene and healthy lifestylealone or sleep hygiene and lifestyle in addition to eitherCPAP or nocturnal oxygen supplementation. CV riskwas assessed at baseline and after 12 weeks, and theprimary outcome was 24-hour mean arterial pressure(MAP). ABP data was available for 281 (88%) partic-ipants at baseline and 12 weeks. The 12-week 24-hourMAP was lower in the CPAP group than in the controlgroup (22.4 mmHg; P¼0.04) or the group receivingsupplemental oxygen (22.8 mmHg; P¼0.02). Therewas no significant difference in the 24-hour MAPbetween the control group and the group receivingoxygen. These results showed that, in patients with CVdisease or multiple CV risk factors, treatment of OSAwith CPAP resulted in a significant BP reduction.However, nocturnal supplemental oxygen was ineffectivefor BP reduction. The average decrease in BP from CPAPadministration was modest as demonstrated in priorstudies (16,17), but additional BP reduction was seen inpatients already taking antihypertensive medications whohad well controlled hypertension at baseline. This study

Figure 12. RYGB is associated with an increase inMRproANP in morbidly obese patients. MRproANP (pico-moles per liter) before, 6 weeks after, and 12 months afterLRYGB in (A) obese hypertensive patients and (B) obesenormotensive patients. Reprinted with permission from BonfilsPK, Taskiran M, Damgaard M, Goetze JP, Floyd AK, Funch-Jensen P, Kristiansen VB, Støckel M, Bouchelouche PN,Gadsbøll N: Roux-en-Y gastric bypass alleviates hyperten-sion and is associated with an increase in mid-regional pro-atrial natriuretic peptide in morbid obese patients. J Hypertens33: 1215–1225, 2015.


does not support the clinical practice of providingsupplemental oxygen as salvage therapy for OSA inpatients in whom CPAP is problematic.

Another study by Chirinos et al. (18) randomized181 obese persons with moderate to severe OSA andserum C–reactive protein (CRP) levels .1.0 mg/L tothree groups for 24 weeks: weight loss, CPAP, or both.Of the 146 participants, those assigned to weight lossonly and the combined interventions had reductions inCRP levels, insulin resistance, and serum triglyceridelevels. None of these changes were observed in the CPAPgroup. At 24 weeks, BP fell in all three groups withoutsignificant between–group differences. In the 90 patientswho met prespecified criteria for adherence, the com-bined interventions of weight loss and CPAP resulted ina larger reduction in systolic BP (SBP; 14.1 mmHg) thanin the weight loss group (6.8 mmHg) and the CPAP alonegroup (3.0 mmHg) (Figure 13). This study showed that,in adults with obesity and OSA, CPAP plus a weight lossintervention did not reduce CRP levels more than eitherintervention alone; however, adherence to a regimen ofweight loss and CPAP resulted in incremental reductionsin BP compared with either intervention alone.

The Effect of Continuous Positive AirwayPressure (CPAP) Treatment in the Control of Re-fractory Hypertension Trial (the HIPARCO Ran-domized Clinical Trial) from Spain evaluated theeffects of CPAP on BP and its nocturnal dipping inresistant hypertension and moderate to severe OSA(19). One hundred ninety-four resistant hypertensionpatients with AHI$15 were randomized to CPAP orno therapy while maintaining their usual antihyper-tensive regimens. The primary end point was thechange in 24-hour MAP at 12 weeks. After 12 weeks,CPAP was associated with not only a 3-mmHg greaterreduction in 24-hour MAP than the no CPAP controlgroup (P¼0.02) but restoration of nocturnal dipping(Figure 14), with a significantly greater percentage ofdippers at the end of the study (35.9% CPAP versus21.6% control; adjusted odds ratio, 2.4; P¼0.02). CPAPreduced the proportion of risers (i.e., patients whose BPincreased during sleep, a group that is at particularlyhigh risk for CV events) (20) compared with baseline,whereas the percentage of risers remained unchanged inthe control group (Table 4). The number of hours ofCPAP administration correlated with the degree of BPimprovement, which may explain why the differenceswere further amplified when CPAP adherence wasconsidered in a per-protocol analysis. The effects of

CPAP on BP were more pronounced with use of CPAPfor more than 4 hours per night. This study demon-strated that CPAP therapy for those with OSA andresistant hypertension reduced the 24-hour MAP anddiastolic BP (DBP) by 12 weeks and showed improve-ment of nocturnal BP profiles associated with greaterCV risk.

Another large RCT also assessed the effect ofCPAP on nocturnal dipping in OSA (21). The studyincluded 298 cardiology patients who were random-ized to optimized medical management alone or incombination with either nocturnal supplemental oxy-gen or CPAP. There was a statistically significant 4%increase in the odds of nondipping SBP per 1-Uincrease in both AHI and oxygen desaturation index(ODI). At severe OSA levels, a 10% and a 4% increasein odds of nondipping DBP per 1-U increase in AHIand ODI were observed, respectively. There was nosignificant relationship between AHI and nondippingMAP; however, a 3% increase in the odds of non-dipping MAP per 1-U increase in ODI was observed(odds ratio, 1.03; 95% CI, 1.00 to 1.05). This studydemonstrated that increasing AHI and/or ODI wereassociated with greater odds of nondipping SBP andnondipping MAP in participants with moderate tosevere OSA and increased CV risk. More severe levelsof AHI and ODI also were associated with nondippingDBP. These results support the concepts that patientswith more severe OSA are more likely to haveabnormal nocturnal BP patterns and that ABP moni-toring may facilitate identification of patients at in-creased CV risk.

There were also two meta-analyses published inthis area. One meta-analysis analyzed the effects ofCPAP on BP in patients with resistant hypertensionand OSA (22). Six studies met the inclusion criteriafor pre-CPAP and post-CPAP analyses. The pooledestimates of mean changes after CPAP showed meanchanges for 24-hour ambulatory SBP and DBP of27.21 and 24.99 mmHg (P,0.001 for both), re-spectively. This meta-analysis demonstrated a favorablereduction of BP with CPAP treatment in patients withresistant hypertension and OSA, and the BP reductionswere larger than those previously reported in patientswith OSA without resistant hypertension. The otherstudy included 31 RCTs that compared CPAP witheither passive or active treatment (23). A random effectsmeta-analysis of active versus passive treatment (29RCTs; 1820 subjects) demonstrated a mean change in


Figure 13. Changes from baseline in the insulin sensitivity index, serum triglyceride levels, and SBP in the modified intention-to-treat and per-protocol populations. A shows changes in the insulin sensitivity index, B shows changes in serum triglyceridelevels, and C shows changes in SBP. I bars represent 95% CIs. P values without brackets are for the change from baseline ineach group. P values with brackets are for between-group differences at week 24. To convert the values for triglycerides tomillimoles per liter, multiply by 0.01129. Reprinted with permission from Chirinos JA, Gurubhagavatula I, Teff K, Rader DJ,Wadden TA, Townsend R, Foster GD, Maislin G, Saif H, Broderick P, Chittams J, Hanlon AL, Pack AI: CPAP, weight loss, orboth for obstructive sleep apnea. N Engl J Med 370: 2265–2275, 2014.


SBP of22.6 mmHg and a mean change in DBP of22.0mmHg, favoring treatment with CPAP (P,0.001).Among studies using 24-hour ABP monitoring, meandifferences in SBP and DBP were 22.2 and 21.9mmHg, respectively, during daytime and 23.8 and21.8 mmHg, respectively, during nighttime. In metare-gression analysis, a higher baseline AHI was associatedwith a greater mean net decrease in SBP. This meta-analysis showed that CPAP reduced BP modestly asshown in prior studies; however, patients with frequentapneic episodes seemed to benefit the most from CPAP.

These studies demonstrate that, in hypertensivepatients with OSA, there is no role for supplementaloxygen in patients with OSA who cannot tolerateCPAP and that combining weight loss together withregular use of CPAP improves BP control in obesepatients with OSA. Patients with resistant hyperten-sion and more severe OSA are more likely to haveabnormal nocturnal BP patterns that may increase CVrisk. Patients with OSA and resistant hypertension or

frequent apneic episodes are more likely to havea greater reduction in BP from use of CPAP.

Primary Aldosteronism

Primary aldosteronism (PA) accounts for approx-imately 10% of patients with hypertension and may bepresent in up to one third of patients with resistanthypertension. Most patients with PA do not havehypokalemia. Patients with PA have an increased riskof CV disease, CKD, and stroke disproportionate to thedegree of hypertension. The preferred screening testfor PA is the aldosterone renin ratio (ARR) that mustbe interpreted in the context of the antihypertensiveagents in use. There is now recognition of a number ofsomatic mutations that are associated with the de-velopment of PA as reviewed in the last NephSAPhypertension issue. Surgery or targeted medical therapywith mineralocorticoid antagonists is effective for bothhypertension management and reversal of the end

Figure 14. Correlation between changes in 24-hour mean BP, SBP, DBP, and number of hours of CPAP use. Correlation betweenCPAP use and change in BP in the patients of the CPAP group who finished the follow-up. Reprinted with permission fromMartínez-García MA, Capote F, Campos-Rodríguez F, Lloberes P, Díaz de Atauri MJ, SomozaM,Masa JF, GonzálezM, SacristánL, Barbé F, Durán-Cantolla J, Aizpuru F, Mañas E, Barreiro B, Mosteiro M, Cebrián JJ, de la Peña M, García-Río F, Maimó A,Zapater J, Hernández C, Grau SanMarti N, Montserrat JM; Spanish Sleep Network: Effect of CPAP on blood pressure in patientswith obstructive sleep apnea and resistant hypertension: The HIPARCO randomized clinical trial. JAMA 310: 2407–2415, 2013.

Table 4. Effect of CPAP treatment on prevalence of BP patterns

OR, odds ratio. Reprinted with permission (with modification) from Martínez-García MA, Capote F, Campos-Rodríguez F, Lloberes P, Díaz de Atauri MJ, Somoza M, Masa JF,González M, Sacristán L, Barbé F, Durán-Cantolla J, Aizpuru F, Mañas E, Barreiro B, Mosteiro M, Cebrián JJ, de la Peña M, García-Río F, Maimó A, Zapater J, Hernández C, GrauSanMarti N, Montserrat JM; Spanish Sleep Network: Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: The HIPARCOrandomized clinical trial. JAMA 310: 2407–2415, 2013.


organ damage effects of aldosterone excess. Multipleclinical studies that have been published in the last2 years will be summarized below.

Diagnosis of Primary Aldosteronism

ARR for Screening of Primary AldosteronismThe ARR is widely used to screen for PA and

recommended by the Endocrine Society (24). Currentguidelines recommend a cutoff value of 91 pmol/mUor 30 ng/ml per hour (24).

A study from The Netherlands prospectivelyassessed the characteristics of the ARR and the ef-fect of combination antihypertensive treatment in 178patients with persistent hypertension, despite the use ofat least two antihypertensives (25). Plasma renin andaldosterone levels were assessed twice within aninterval of 4 weeks, and all patients underwent anintravenous salt loading test. A post–test plasma al-dosterone exceeding 235 pmol/L was considered di-agnostic for PA. An ARR was repeated after 4 weeks ofstandardized treatment with a calcium channel blockerand/or an a-adrenergic receptor blocker. The preva-lence of PA was 15.2%, and the median ARR was35.0 pmol/mU in PA versus 7.1 pmol/mU in patientswith essential hypertension (P,0.001). Under randommedication, the ARR had 22.2% sensitivity and 98.7%specificity. On standardized treatment, the ARR rosefrom 9.6 to 21.4 (P,0.001). Multivariate regressionshowed that the angiotensin–converting enzyme in-hibitors (ACEIs) and angiotensin II receptor blockers(ARBs) were responsible for the lower ARRs duringrandom treatment. The authors concluded that ARRsensitivity for PA is low when the recommended cutoffis used and has poor reproducibility (25). Furthermore,the authors proposed the need for alternative screeningtests (25). Our opinion is that, despite issues with usingARR as a screening test, as long as the physician takesinto account the reasons for possible false–positiveand –negative results, the ARR is still a good initialscreening test and should not be disbanded. Thesereasons are well documented in the Endocrine SocietyGuidelines.

Adrenal Vein SamplingAdrenal venous sampling (AVS) is the definitive

evaluation for PA. AVS is used to document lateraliz-ing aldosterone hypersecretion in PA; however, thereare large discrepancies between institutions in thecriteria used to interpret its results. AVS also requires

a skilled operator to perform this procedure correctly.There are a number of new studies addressing differentissues related to AVS as well as a consensus statementfrom a group of experts for the use of AVS forsubtyping of PA (26). The clinical algorithm usuallyfollowed in PA is to obtain imaging in patients withelevated ARRs and then, proceed with AVS. AVS canbe done with cosyntropin stimulation or unstimulated.AVS is a technically difficult procedure, particularly incannulating the right adrenal vein. Consequently, theselectivity index (SI; the ratio of cortisol in right andleft adrenal veins compared with the inferior venacava) should be three or more to confirm correctcatheter placement and verify adequate sampling.Comparisons are made between left, right, and periph-eral aldosterone-to-cortisol (A/C) ratios to determinethe lateralization index (LI). If a sample is adequate, theLI is measured and should be at least more than two todetermine lateralization, which implies a beneficial re-sponse to surgery. Some centers use much higher ratios(for example, an SI of $5 and an LI of $4).

Two studies were published from the same groupin Australia in relation to AVS. The first reviewed1397 AVS procedures over a period of 34 years andfound in 2.6% of patients, despite adequate samplingas determined by SI, that bilateral A/C ratios were nogreater than peripheral ratios; 22 of 37 individuals inthis category underwent repeat AVS: 10 demonstratedunilateral aldosterone production, and eight of theseunderwent unilateral adrenalectomies that were histo-logically confirmed aldosterone–producing adenomas(APAs) resulting in cure (three) or improvement (five)of hypertension. Eight had bilateral aldosterone pro-duction. Four studies were inconclusive. Patients withinitial unsatisfactory AVS because of bilaterally lowA/C ratios had significantly (P¼0.02) more unilateraldisease (10 of 18 [55.6%] had satisfactory repeatstudies versus 326 of 1066 satisfactory initial studies[30.6%]) and a significantly higher (67.6% versus49.9%; P¼0.03) percentage of men. It is important toacknowledge this subgroup of patients and consideroffering the opportunity for repeat AVS; about onethird of these selected patients may ultimately benefitfrom adrenalectomy (27). Contralateral suppression(CS) is defined as A/C (adrenal) # A/C (peripheral) onthe unaffected side. Patients with one side clearlydominant (LI$2) but no CS are offered surgerysometimes. The same group included all patients whounderwent unilateral adrenalectomy for PA if AVS


was successful with SI$3, LI$2, and $6 months ofpostoperative follow-up; 80 patients were included,and 66 had CS (28). At postoperative follow-up, thosewith CS had a lower SBP of 128 versus 144 mmHg(P¼0.001), a greater proportion with cure or improve-ment of hypertension (96% versus 64%; P¼0.003),a greater proportion with biochemical cure of PA onfludrocortisone suppression testing (88% versus 44%;P¼0.002), and a smaller number of antihypertensivemedications (0 versus 1.5; P¼0.003). This study showedthat CS correlated with improved BP and biochemicaloutcomes from surgery and should be considered whenreferring a patient for adrenalectomy.

A retrospective analysis of all AVS proceduresdone for PA from a single high–volume institutionwith extensive experience was analyzed to determinewhether performing AVS prior to imaging could de-crease the use of imaging in the evaluation of PA (29).Of 235 patients analyzed, 63% (n¼148) were men,with a mean age of 55 years old. Imaging and AVSwere concordant in 52% (n¼123). AVS was non-lateralizing in 43% (n¼101), indicating that thesepatients might have avoided imaging with an AVS-first approach. In patients #40 years old (n¼23), 35%(n¼8) had no AVS lateralization and might haveavoided imaging in an AVS-first approach. Imagingand AVS were concordant in 52% (n¼12) of patients#40 years old and 52% (n¼111) of patients.40 yearsold (P¼0.99). This study introduces a new concept inthe current clinical paradigm: if AVS is performed first,43% of patients will not require computed tomography(CT) /magnetic resonance imaging (MRI) imaging. Theanalysis suggests that an AVS-first approach may re-duce unnecessary cross–sectional imaging studies.

Summary of the Consensus Statement on AdrenalVein Sampling (26)

(1) Patients with established PA should undergo AVSwhen adrenalectomy is considered, except in thefollowing circumstances: patients age ,40 yearsold with marked PA and a clear unilateral adrenaladenoma and a normal contralateral adrenal glandon computed imaging, patients who are poorsurgical candidates, and patients suspected of hav-ing an adrenocortical carcinoma.

(2) AVS should be performed by a multidisciplinaryteam in centers with extensive expertise.

(3) The pulsatile pattern of secretion of cortisol andaldosterone can generate time-related variability inhormone concentrations in adrenal vein blood, andcosyntropin stimulation and bilateral simultaneoussampling can minimize this time-related variabilitycompared with sequential sampling without cosyn-tropin stimulation.

(4) Cosyntropin stimulation during AVS facilitates theassessment of selective adrenal vein catheteriza-tion, but there is no conclusive evidence thatcosyntropin stimulation leads to a better outcomethan unstimulated AVS.

(5) Successful AVS should be determined by calculat-ing the SI; AVS studies that are not bilaterallysuccessful should not be used to establish laterali-zation. The cutoff value for the SI should be $2.0under unstimulated conditions, and the cutoff valuefor the SI should be $3.0 during cosyntropinstimulation.

(6) Lateralization of aldosterone secretion should bedetermined by the LI. Most centers used LIbetween 2.0 and 4.0 under unstimulated conditionsand between 2.6 and 4.0 during cosyntropinstimulation; 100% of centers used baseline, un-stimulated LI values $2.0.

(7) Appropriate training programs and certification ofradiologists proficient in AVS should be implemented.In experienced hands, AVS is a safe procedure witha very low complication rate; adrenal vein rupture isone of the main complications. Generally, there are nolong-term sequelae of complications.

Novel Testing for Primary AldosteronismAVS is currently the only reliable method to

distinguish unilateral from bilateral diseases in PA. Arecent study from Japan evaluated whether peripheralplasma levels of 18-oxocortisol and 18-hydroxycortisolfacilitated the differentiation of aldosteronoma andbilateral hyperaldosteronism in 234 PA patients (30).All patients had CT imaging and AVS, of which 113had aldosteronoma on CT and 121 had bilateral hyper-aldosteronism. All aldosteronomas were surgicallyresected, and the diagnosis was histopathologically con-firmed. The 18-oxocortisol and 18-hydroxycortisol levelswere measured by liquid chromatography tandem massspectrometry; 18-oxocortisol levels .6.1 ng/dl or analdosterone level .32.7 ng/dl were found in 95 of 113patients with aldosteronoma (84%) but 0 of 121 with


bilateral hyperaldosteronism, and 18-oxocortisol levels,1.2 ng/dl, the lowest in aldosteronoma, were found in43% patients with bilateral hyperaldosteronism. Furtheranalysis of 27 patients with CT-undetectable micro-aldosteronomas revealed that eight of these 27 patientshad CT–detectable contralateral adrenal nodules. Thehighest 18-oxocortisol and aldosterone concentrationswere 4.8 and 24.5 ng/dl, respectively, both below thecutoff levels indicated above. This study requiresfurther corroboration and may present an easier methodto distinguish unilateral from bilateral PA.

Treatment of Primary Aldosteronism: Predictors ofBP Control after Adrenalectomy

A retrospective cohort study of patients under-going adrenalectomy for PA was performed to assessBP control at long–term follow-up ($12 months) (31).Primary outcome was cure, defined as normotension offantihypertensives. Of 85 patients, 15.3% (n¼13) werecured, 54.1% (n¼46) were normotensive while remain-ing on antihypertensives, and 30.6% (n¼26) remainedhypertensive. Younger age (P¼0.01), women (P,0.001),lower BMI (P¼0.02), shorter duration of hypertension(P¼0.002), lower serum creatinine (P¼0.001), and fewerpreoperative antihypertensive medications (P,0.001)were associated with cure. Women, BMI#25 kg/m2,hypertension ,5 years, creatinine #0.8 mg/dl, andless than two antihypertensives were incorporatedinto a scoring system. For a score of 0–1 (n¼61),the cure rate was 3%; 100% of patients with a score of4–5 (n¼3) were cured. This scoring system performedcomparably with the Aldosterone Resolution Score,which has been used to evaluate short–term post-operative outcomes.

Somatic Mutations in Primary Aldosteronism

Somatic Mutations and Left VentricularHypertrophy

Aldosterone exerts detrimental CV effects. Patientswith APAs develop somatic mutations in the KCNJ5potassium channel and manifest higher plasma aldo-sterone concentrations than individuals without muta-tions. One hundred twenty-nine APA patients withKCNJ5 sequencing information and long–term follow-up data were compared for echocardiographic changesby presence (26%) or absence (74%) of KCNJ5 muta-tions (32). At baseline, the two groups had similar BP

levels and were maintained on a comparable numberof antihypertensive medications. Mutation-positivepatients had greater left ventricular mass index(LVMI; 59 versus 51 g/h2.7; P,0.05) and plasmaaldosterone concentration (49 versus 36 ng/dl;P¼0.05) than mutation-negative patients. Despitethe higher LVMI, mutation-positive patients hada similar BP decrease, plasma aldosterone level, andLVMI to mutation-negative patients following adre-nalectomy. This study delineates KCNJ5 mutations asa mediator of higher risk for CV damage. If diagnosedin a timely manner, patients are likely to benefit fromBP reductions and regression of left ventricular hyper-trophy postadrenalectomy.

A recent meta-analysis included 13 studies with1636 APA patients in whom somatic KCNJ5 mutationtesting was available (33). The mean age was 49 yearsold, and 55% were women. The overall prevalence ofKCNJ5 mutations was 43% (range, 12%–80%). Themutation rate was lower in Europe, the United States,and Australia (35%) compared with Japan and China(63%; P,0.003). This observation correlated (r¼0.60;P¼0.03) with mean daily urinary sodium excretion.KCNJ5 mutation–positive APA patients were youn-ger (45 versus 52 years old), had higher plasmaaldosterone concentrations (42 versus 33 ng/dl), hadlarger tumors (16.1 versus 14.9 mm), and were moreoften women (67% versus 44%; all P,0.05) whencompared with patients without the mutation. There-fore, the phenotypic features of APA patients withKCNJ5 mutations are usually younger, are morelikely women, and have larger tumors with greateraldosterone levels. There was no significant differencein BP or serum K levels.

Prorenin LevelsProrenin can be detected in plasma of hyperten-

sive patients and may participate in the developmentof PA. Plasma prorenin levels and expression of theprorenin receptor (PRR) were measured from specimensof normal human adrenocortical zona glomerulosa andAPAs of normotensive, hypertensive, and PA subjectsto investigate the functional effects of PRR activation inhuman adrenocortical cells. PA patients had detectableplasma levels of prorenin, and by real-time PCR, ratiosof PRR to porphobilinogen deaminase were elevatedfrom normal adrenal cortex and APAs. The presence ofdetectable plasma prorenin in PA patients and high-expression PRR from normal human adrenal cortex,


APA tissue, and CD56R aldosterone–producing cells,along with activation of cytochrome P450 11B2 syn-thesis and extracellular signal–regulated kinase 1/2(ERK1/2) phosphorylation, imply that circulating andlocally produced prorenin may contribute to the de-velopment and/or maintenance of human PAs (34).

Pheochromocytoma

New guidelines regarding the diagnosis andmanagement of pheochromocytoma (PCC) and para-ganglioma (PGL) were published in 2014 (35). Themain recommendations that are relevant to a hyperten-sion specialist are as follows.

(1) Initial biochemical testing for PCC/PGL should in-clude measurements of plasma free or urinary frac-tionated metanephrines. Consideration should begiven to factors leading to false-positive or -negativeresults and common interfering medications (Table 5).

(2) Initial imaging should be done by CT, but MRI isa better option if metastatic disease is present or ifradiation exposure must be limited.

(3) 123I-metaiodobenzylguanidine imaging is useful fordetection of metastatic PCC/PGL.

(4) All patients should undergo genetic testing. Patientswith PGL should be tested for succinate dehydro-genase (SDH) mutations, and those with metastaticdisease should be tested for succinate dehydroge-nase complex subunit B (SDHB) mutations.

(5) All patients with functional secreting tumors shouldundergo preoperative blockade to prevent perioper-ative complications.

(6) Laparoscopic adrenalectomy should be performedfor most PCC patients, and open resection shouldbe performed for most PGL patients.

(7) Lifelong follow-up is suggested to detect recurrentor metastatic disease.

Clinical Studies in Pheochromocytoma andParagangliomaA retrospective cohort study was conducted of 126patients who underwent initial adrenalectomy for PCCat a single institution (36). Patients were classified aseither identified by diagnostic workup for symptomsor being PCC identified by imaging performed forother indications. Of 126 patients, 47% (n¼59) wereincidentally identified and had more nonspecific symp-toms, including abdominal or back pain (39.0% versus6.0%; P,0.001), and lower rates of classic symp-toms, such as hypertension (54.2% versus 77.6%;P,0.01), palpitations or arrhythmias (18.9% versus50.0%; P¼0.001), flushing or diaphoresis (25.4%versus 46.3%; P¼0.02), and headache (20.3% versus44.8%; P¼0.004). Incidentally identified PCC hadlower 24-hour urine metanephrines (2102 versus7299 mg; P¼0.02) and normetanephrines (2253 versus4383 mg; P,0.01). Histopathology demonstrated nodifference in malignant traits, and malignancy rates

Table 5. Medications that are implicated in adverse reactions in patients with PCC and can precipitate a crisis

ACTH, Adrenocorticotropic hormone. Reprinted with permission (with modification) from Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH,Naruse M, Pacak K, Young WF Jr.; Endocrine Society: Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 99:1915–1942, 2014.


were equivalent (5.1% versus 6.0%; P¼0.86). In thisstudy, one half of the patients presenting for surgicalresection of PCC were identified incidentally but still hadequivalent rates of malignancy and therefore, requiredefinitive evaluation and early surgical referral.

There has been recognition of an associationbetween development of PCC/PGL in patients withcongenital cyanotic heart disease. The association’spathomechanism is postulated on the basis of chronichypoxia. A retrospective study identified patients withcongenital heart disease and PCC/PGL confirmed bypathology or biochemistry and imaging (37); 20 PCC/PGL cases were identified, 18 of which had congen-ital cyanotic heart disease, with mean duration ofcyanosis of 20 years (range ¼1–57 years) and a medianage at diagnosis of 31.5 years old. Biochemical analysisrevealed a noradrenergic biochemical phenotype similarto that reported in hypoxia–related PCC/PGL geneticsyndromes (e.g., SDH or von Hippel–Lindau mutations)but without clinical signs of such syndromes.

Genetics of Pheochromocytoma andParaganglioma

Genetics of PCC/PGL were discussed in the priorNephSAP but are worth reviewing, because it is nowapparent that PCC/PCGL is the most common solidtumor associated with an inherited susceptibility syn-drome. Up to 40% of PCC/PGL have a germlinemutation in one of 12 genes with known association forenhanced risk for development of PCC/PGL: RET, vonHippel–Lindau, neurofibromin 1, transmembrane protein127, MYC-associated factor X, hypoxia-inducible factor2A (HIF2A), and the SDH components SDHA, SDHB,SDHC, SDHD, and SDHFA2 (Figure 15) (38). Therehave also been an increasing number of somatic muta-tions described in patients with PCC/PGL, includingmutations in the HIF2A, ATRX, and H-RAS genes (39–41). Tumors with H-RAS mutations activate the RAS/RAF/ERK signaling pathway and are associated withmen with PCC having benign and sporadic diseasecharacteristics. Somatic ATRX mutations are associatedwith alternative lengthening of telomeres, and they arealso common in pancreatic neuroendocrine tumors andneuroblastomas andmay be important in the developmentof clinically aggressive PCC/PGL. Recent transcriptomesstudies have classified PCC/PGL tumors into two distinctgroups: cluster 1: harboring mutations in SDHx, vonHippel–Lindau, or HIF2A (characterized by a hypoxictranscriptional signature); and cluster 2: harboring muta-

tions in RET, neurofibromin 1, transmembrane protein127, and MYC-associated factor X (characterized by anactivation of the Phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin and Rat sarcoma/Rapidly accelerated fibrosarcoma/Extracellular-signal-regulated kinases (Ras/Raf/Erk) signaling pathways) asshown in Figures 16–18 (38, 42). Greater understandingof the genetics and tumor biology pathways will hope-fully lead to improved targeted therapies for these tumors.

Fibromuscular Dysplasia

A consensus statement on fibromuscular dyspla-sia (FMD) from the European consensus group waspublished with the following recommendations (43).

Figure 15. Timescale of genetic discoveries in PGL/PCC.Reprinted with permission from Gimenez-Roqueplo AP,Dahia PL, Robledo M: An update on the genetics ofparaganglioma, pheochromocytoma, and associated heredi-tary syndromes. Horm Metab Res 44: 328–333, 2012.

Figure 16. Expression analysis. Reprinted with permissionfrom Gimenez-Roqueplo AP, Dahia PL, Robledo M: Anupdate on the genetics of paraganglioma, pheochromocy-toma, and associated hereditary syndromes. Horm MetabRes 44: 328–333, 2012.


(1) The prevalence of symptomatic renal FMD inthe general population is approximately 0.4%,and cervicocephalic FMD is probably one half ascommon as renal FMD.

(2) FMD is defined as an idiopathic, segmental, non-atherosclerotic, and noninflammatory disease of themusculature of arterial walls, leading to stenosis ofsmall- and medium-sized arteries. The diagnosis ofFMD requires exclusion of renal artery spasm,arterial diseases of monogenic origin, and inflam-matory arterial diseases.

(3) There are three main histological types of renalFMD according to the most affected arterial walllayer: intimal FMD (5% of renal artery FMDcases), medial FMD (.85%), and perimedialFMD (10%). These categories are not mutuallyexclusive, because involvement of more than onelayer in the same diseased artery is not uncommon.Similar lesions have also been documented withcervical or intracranial FMD.

(4) Because FMD–related renal artery stenosis isnow usually treated by percutaneous transluminal

Figure 17. Cluster 1–pseudohypoxia pathway. Mutations in von Hippel–Lindau (VHL) SDH and HIF2A and at least in one caseeach in prolyl hydroxylase domain-containing protein 2 (PHD2) and fumarate hydratase (FH) occur in PCCs and PGLs and canlead to increased activation of HIF. HIF1a or HIF2a subunits heterodimerize with HIF1b and transactivate multiple target genesinvolved in angiogenesis, metabolism, and cell growth. HIF2A mutations lead to activated HIF–induced downstreamtranscription and resistance to degradation. VHL mutations impair proteasome-mediated HIF degradation. Mutations of SDHand FH result in the accumulation of their respective substrates, succinate and fumarate, which competitively inhibita-ketoglutarate (aKG) for activation of various classes of aKG-dependent dioxygenases (shown in blue), including PHDs,which promote HIF degradation; Jumonji–related histone demethylases (JMJDs), which demethylate histones; and the TETfamily of DNA hydroxylases (TETs), which demethylate DNA. Thus, inhibition of aKG-dependent dioxygenases collectivelyleads to HIF activation and global hypermethylation of target genes. HIF can also directly regulate the activity of some JMJDs.Proteins with mutations that lead to loss of function are shown in green, and proteins with activating mutations are shown in red.HIFa* represents either HIF1a or HIF2a, but only HIF2a is mutated in PCCs. PHD** represents PHD1, PHD2, and PHD3 (onePGL has been reported with a PHD2 mutation) and is colored in both green (loss-of-function mutation) and blue (aKG-targetenzyme). Reprinted with permission from Dahia PL: Pheochromocytoma and paraganglioma pathogenesis: Learning fromgenetic heterogeneity. Nat Rev Cancer 14: 108–119, 2014.


angioplasty (PTA) rather than surgery, histologicalverification is seldom available, and the angio-graphic classification has progressively replacedthe histological classification.

(5) Three angiographic types of renal artery FMD havebeen described: multifocal (string of beads appear-ance), unifocal (solitary stenosis,1 cm in length), andtubular (stenosis $1 cm in length) as seen in Figure19. Because the two last categories differ only by thelength of the diseased segment, it has been proposed togroup them under the general term unifocal.

(6) The string of beads aspect accounts for .80% ofcases, and its histological substrate is medial FMD.It affects mainly women between 30 and 50 years

of age; the lesions commonly involve the middle ordistal thirds of the main renal artery, and there isoften extension into the proximal portion of the first-level branches. Lesions are bilateral in 60% of cases.

(7) Screening for FMD is recommended in the follow-ing patients with hypertension: age ,30 years old,especially in women; grade 3 ($180/110 mmHg),accelerated, or malignant hypertension; resistanthypertension; small kidney without history of urop-athy; abdominal bruit without apparent atherosclero-sis; or FMD in at least another vascular territory.

(8) Screening for FMD of the cervicocephalic arteriesshould be considered in cases of retinal or cerebralischemic events, intracranial aneurysms, subarachnoid

Figure 18. Cluster 2–kinase signaling pathway. RET, neurofibromin 1 (NF1), transmembrane protein 127 (TMEM127), MYC-associated factor X (MAX), and more recently HRAS, when mutated, have been shown to lead to increased progrowth signalinginvolving the receptor tyrosine kinase and downstream pathways, including mammalian target of rapamycin (mTOR) and MYC.RET and other growth factor kinase receptors (GFRs), when activated, are internalized by endosomes (not shown) and initiatea cascade of events that lead to the activation of RAS and PI3K/AKT downstream signals, including mTOR activation. mTOR istranslocated from the cytoplasm to the lysosome to become activated. Active mTOR regulates cell growth through the synthesisof macromolecules, including protein (through inhibition of 4EBP1), nucleic acids, lipids and fatty acids, and increased glucoseuptake (through HIF activation). MYC binds to MAX to regulate transcription of multiple genes. In some cancers, MYCcooperates with mTOR to increase protein translation by inhibition of 4EBP1 and with HIF to increase glucose uptake andglycolysis. These pathways are held in check by various proteins: NF1, which inhibits RAS; MAX, which inhibits MYC; andTMEM127, which may inhibit mTOR (shown by dashed arrows to reflect the unclear mechanisms underlying this interaction).Multiple components of these pathways have been omitted for simplicity. Genes and proteins with activating mutations are shown inred, and those with loss-of-function mutations are shown in green. Reprinted with permission from Dahia PL: Pheochromocytomaand paraganglioma pathogenesis: Learning from genetic heterogeneity. Nat Rev Cancer 14: 108–119, 2014.


hemorrhage, cervical or intracranial dissections, orpulsatile tinnitus.

(9) In patients with renal artery FMD, screening isrecommended for asymptomatic cervicocephalic le-sions only if identification of lesions will alter futuremanagement. Hypertensive patients with cervicoce-phalic FMD should be screened for renal FMD. Inpatients with renal artery and/or cervicocephalicFMD, screening of other, less often involved vascu-lar beds should be considered in the presence ofsuggestive symptoms or medical history. Screeningfor FMD of the renal, iliac, and cervicocephalicarteries is also recommended in case of spontaneouscoronary artery dissection, particularly in the pres-ence of hypertension or other suggestive symptoms.

(10) It is recommended to ask a patient with FMD aboutwhether first-degree relatives have a history of early-onset hypertension, dissection, aneurysms, or cere-bral hemorrhage. If there is a positive answer to atleast one of these questions, the patient may informrelative(s) about the possibility of hereditary FMD.

(11) When there is a clinical suspicion of RAS, duplexultrasound remains a reasonable, first–line screen-ing test to detect RAS, and results should beconfirmed by another imaging technique in thecase of positive findings or if results are negativein the presence of high–level clinical suspicion.

(12) Magnetic resonance angiography (MRA) andpreferably, computed tomography angiography(CTA) are the recommended imaging techniquesfor confirmation of renal artery FMD. They arealso recommended as first–line screening tests in

the following circumstances: (1) when the resultsof duplex ultrasound are expected to be subopti-mal (obese patients, apnea difficult or impossible,low echogenicity, or poor local expertise) or (2)when the degree of suspicion of FMD is high and/ora diagnosis of FMDwould havemajor clinical impli-cations (very young age, malignant or complicatedhypertension, complications in another territory,and increase in plasma creatinine). One approachto FMD screening is displayed in Figure 20.

(13) It is recommended to perform renal DSA (1) incases of FMD confirmed by CTA or MRA,provided that revascularization is medically jus-tified, and (2) in cases of high clinical suspicion ofFMD-related stenosis when the diagnosis remainsuncertain after performing noninvasive tests.

(14) MRA and CTA are the recommended techniquesto establish the diagnosis of FMD of the cervico-cephalic arteries and detect associated intracranialaneurysms. Cervical artery digital subtractionangiography may be indicated in case of atypicalclinical presentation and in patients who mayrequire endovascular therapy.

(15) Smoking cessation should be strongly encouragedin patients with FMD.

(16) Revascularization of FMD-related lesions is rec-ommended only in cases of symptomatic FMDwith direct or indirect signs of organ ischemiadownstream of the lesion. The therapeutic decisionshould take into account symptomatology, type,localization, and extent of arterial lesions; pres-ence of associated aneurysms in the same or other

Figure 19. Angiographic classification of FMD of the renal arteries. String of beads appearance of multifocal FMD (left panel),unifocal FMD (center panel), and tubular FMD (right panel). Reprinted with permission from Persu A, Giavarini A, Touzé E,Januszewicz A, Sapoval M, Azizi M, Barral X, Jeunemaitre X, Morganti A, Plouin PF, de Leeuw P; ESH Working GroupHypertension and the Kidney: European consensus on the diagnosis and management of fibromuscular dysplasia. J Hypertens32: 1367–1378, 2014.


territories than the primary lesion; the experienceof the center; and age and patient preferences.Importantly, procedures should be performed bya multidisciplinary team with extensive experienceof the disease.

(17) In hypertensive patients with FMD-related RAS,revascularization is recommended in the follow-ing circumstances: (1) in the case of hypertensionof recent onset as a first-line treatment to normal-ize BP; (2) in cases of medical treatment failure(drug resistance or intolerance); (3) when renalinsufficiency or deterioration of renal functionoccurs, especially after ACEI, ARB, or directrenin inhibitor therapy; and (4) in case of renalsize reduction downstream of the stenosis.

(18) In patients with significant FMD-related RAS,renal PTA is the first–line revascularizationtechnique, and stenting after PTA is not re-commended, unless required for proceduraldissection.

(19) With significant FMD–related RAS, surgeryshould be contemplated in the following cases:(1) stenosis associated with complex aneurysm(s),(2) restenosis despite two unsuccessful attemptsof PTA, and (3) complex lesions of arterialbifurcations or branches (rare).

(20) It is recommended to revascularize only symp-tomatic carotid FMD lesions. The indicationshould take into account the severity of symp-toms, causality of the relation between lesions and

Figure 20. Proposed algorithm for establishing the diagnosis of FMD of the renal arteries. Renal duplex ultrasound remainsa reasonable first–line screening test to detect renal artery stenosis in most cases. However, CTA or MRA is recommended as thefirst screening test when the results of renal duplex are expected to be suboptimal (obese patients, apnea difficult or impossible,low echogenicity, or poor local expertise) and/or when the degree of suspicion is high or the diagnosis of FMD would havemajor clinical implications (very young age, malignant or complicated hypertension, complications in another territory, orincrease in plasma creatinine). CTA is preferable to MRA because of its higher spatial resolution, especially for distal lesions. Inpractice, the choice between CTA and MRA will take into account local expertise, individual risk of nephrotoxicity andirradiation, and patients’ preference. Reprinted with permission from Persu A, Giavarini A, Touzé E, Januszewicz A, SapovalM, Azizi M, Barral X, Jeunemaitre X, Morganti A, Plouin PF, de Leeuw P; ESHWorking Group Hypertension and the Kidney:European consensus on the diagnosis and management of fibromuscular dysplasia. J Hypertens 32: 1367–1378, 2014.


symptoms, experience of the center performing theprocedure, and patient preference.

(21) If revascularization does not seem justified in renalartery FMD patients with hypertension, clinical(monthly BP measurements until target BP valuesare reached and then at regular intervals) andbiological (annual assessment of plasma creati-nine) monitoring is recommended along withmonitoring of kidney length by annual dupleultrasonography.

(22) After revascularization of FMD-related RAS, it isrecommended to evaluate BP and GFR after 1 monthand check renal imaging at 6 months or earlier in thecase of BP or plasma creatinine elevation.

Atherosclerotic Renal Artery Stenosis

Atherosclerotic renal artery stenosis (ARAS) is in-creasingly frequent in an aging population. ARASaffects approximately 7% of individuals older than 65

years old and is present in about 50% of patients withdiffuse arterial disease; about 10%–15% of ARAScases lead to resistant hypertension and/or ischemicnephropathy (44), but the exact mechanism by whichARAS causes kidney tissue injury is unclear. Hemo-dynamic studies have shown that changes in pressuregradient and blood flow occur only with critical RAS(i.e.,$75% luminal stenosis). However, the severity ofARAS does not correlate with kidney function, declinein glomerular filtration, or improvement from revascu-larization. A newer imaging technique, blood oxygenlevel–dependent MRI was discussed previously inNephSAP on hypertension and measures tissue deox-yhemoglobin, which provides an assessment of tissueoxygenation in vivo. When used to evaluate patientswith preserved glomerular filtration and unilateralARAS, the technique has shown preserved corticaland medullary oxygenation despite a reduction inkidney size and blood flow, indicating that kidneyswith ARAS have preserved oxygenation during theearly stages of the ischemic nephropathy (45).

Figure 21. Kaplan–Meier survival plot for patients presenting with flash pulmonary edema. Dashed line, patients treated withpercutaneous renal angioplasty with bare-metal stenting; horizontal axis, time in months from diagnostic angiography; solidline, medically treated patients; vertical axis, event-free survival. Reprinted with permission from Ritchie J, Green D,Chrysochou C, Chalmers N, Foley RN, Kalra PA: High-risk clinical presentations in atherosclerotic renovascular disease:Prognosis and response to renal artery revascularization. Am J Kidney Dis 63: 186–197, 2014.


The management of ischemic nephropathy mayinclude medical therapy and/or revascularization. Pre-viously, revascularization was accomplished by a sur-gical bypass procedure or endarterectomy, with themorbidity and mortality associated with a major sur-gical procedure. During the last few decades, less in-vasive endovascular procedures, such as PTA withstent placement, have been performed. Newer antihy-pertensive and CV drugs have also been developed,which may obviate the need for revascularization. Theindications of each of these therapeutic options havechanged over time. The latest randomized clinicaltrials, including the Cardiovascular Outcomes in RenalAtherosclerotic Lesions Trial (reviewed previously inNephSAP) as well as a meta-analysis of these studies,have indicated that the best approach to ARAS ismedical therapy alone (46, 47), particularly in low–risk, stable ARAS (44). High-risk patients, however,may benefit from intervention, including those withflash pulmonary edema, rapidly declining kidney func-tion, and refractory hypertension. Medical therapy forpatients with adequate BP control, stable kidneyfunction, and no recurrent flash pulmonary edemashould include an ACEI or ARB, with addition ofother antihypertensive drugs to achieve good BPcontrol. Antiplatelet therapy, statins, antidiabetic ther-apy if indicated, and smoking cessation should beencouraged (44). There is no role for ARAS screeningin asymptomatic patients who have atherosclerosis andCKD or hypertension.

A single center from the United Kingdom retro-spectively analyzed 467 patients (who were includedin a prospective cohort study) with renal artery stenoses$50% who were managed according to clinical pre-sentation and physician/patient preference (48). Theyincluded patients with flash pulmonary edema (n¼537;7.8%), refractory hypertension (n¼5116; 24.3%), andrapidly declining renal function (n¼546; 9.7%) andcompared them with low–risk presentation patients withnone of these phenotypes (N¼5230; 49%) (48). Theycompared percutaneous revascularization that was con-ducted in 32% with flash pulmonary edema, 28% withrapidly declining renal function, and 28% with refractoryhypertension with a strategy of medical management(48). Results showed that, during a median follow-upof 3.8 years, 55% died, 33% had a CV event, and 18%reached ESRD. In medically treated patients, flashpulmonary edema was associated with increased riskof death (hazard ratio [HR], 2.2; P,0.001) and increase

in CV events (HR, 3.1; P,0.001) but no increase inESRD compared with the low-risk phenotype. Noincreased risk for any end point was observed inpatients presenting with rapidly declining renal func-tion or refractory hypertension. Compared with med-ical treatment, revascularization was associated withreduced risk of death (HR, 0.4; P¼0.01) but not withreduced CV events or ESRD rates in patients present-ing with flash pulmonary edema (Figure 21). Re-vascularization did not the reduce risk for rapidlydeclining renal function or refractory hypertension;however, when both rapidly declining renal functionand refractory hypertension were present (n¼531),revascularization was associated with reduced risk fordeath (P¼0.04) and CV events (P¼0.02). This studyis limited because it is a retrospective analysis of anobservational study, but it supports the recommenda-tion of flash pulmonary edema as an indication forrenal artery revascularization in ARAS. The combi-nation of rapidly declining kidney function and re-fractory hypertension represents another clinicalscenario that may benefit from revascularization andpotentially, a subgroup of further investigation inmore robust future trials.

There is evidence that revascularizationdoes not add benefit in low–risk stableARAS. High-risk patients may, however,benefit from intervention, including thosewith flash pulmonary edema, rapidly de-clining kidney function, and refractoryhypertension. Medical therapy should in-clude ACEIs or ARBs with addition ofother antihypertensive drugs to achievegood BP control, antiplatelet therapy, sta-tins, antidiabetic therapy if indicated, andsmoking cessation.

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BP Guideline Updates

Since the last NephSAP on hypertension, a num-ber of BP guidelines were published, resulting inconsiderable controversy regarding BP goals in specificpopulations. The 2014 Evidence-Based Guideline forthe Management of High Blood Pressure in Adults(Eighth Joint National Committee [JNC8]) was notfully published and not detailed in the last version (1).This section will provide a summary of the latestguidelines with a specific focus on BP goals in CKD.The preliminary results of the Systolic Blood PressureIntervention Trial (SPRINT) (2) were published justbefore this issue was set for publication and will becommented on briefly, but it will be discussed in greaterdetail in the next NephSAP.

The 2014 Evidence-Based Guideline for theManagement of High Blood Pressure in Adults Reportfrom the panel members appointed to the JNC8 basedtheir recommendations on a rigorous, evidence–basedapproach using randomized, controlled trials and grad-ing evidence quality and recommendations based ontheir effect on important outcomes (1). They publishednine recommendations as detailed in Table 6 (1). Themain recommendations included the following recom-mendations.

(1) In the general population age$60 years old, treat toa goal systolic BP (SBP) ,150 mmHg and a goaldiastolic BP (DBP) ,90 mmHg. If pharmacologictreatment results in SBP,140 mmHg and treatmentis well tolerated without adverse effects, treatmentdoes not need to be adjusted.

(2) In the general population ,60 years old, treat toa goal SBP ,140 mmHg and a goal DBP ,90mmHg.

(3) In patients with CKD, treat to a goal SBP ,140mmHg and a goal DBP ,90 mmHg.

(4) In patients with diabetes, treat to a goal SBP ,140mmHg and a goal DBP ,90 mmHg.

(5) In the general black population, including those withdiabetes, initial treatment should include a thiazide-type diuretic or calcium channel blocker.

(6) In patients with CKD, regardless of race or diabetes,initial (or add-on) treatment should include an


















angiotensin–converting enzyme inhibitor or angioten-sin II receptor blocker to improve kidney outcomes.

(7) If goal BP is not reached within 1 month oftreatment, the clinician should increase medicationand consider referral to a hypertension specialist ifgoal BP is not reached after adding a third drug.The recommendation also detailed an algorithm of

recommended antihypertensive agents to use as shownin Figure 22 (2014 Hypertension Guideline Manage-ment Algorithm) as well as a comparison of the differentBP goals and initial suggested drug therapy for adultswith hypertension as recommended by the differentsocieties and guideline groups as shown in Table 7.

These guidelines have produced significant de-bate, and there have been many editorials commentingon these guidelines, with some publications directlydisagreeing with these guidelines (3–8). Five membersof the JNC8 panel published a separate paper, stating

that, although they agreed with most of the recommen-dations, they disagreed with the recommendation toincrease the target SBP in persons $60 years oldwithout diabetes or CKD from 140 to 150 mmHg (5).They justified their disagreement for the followingreasons (5): increasing the target SBP will likely reducethe intensity of antihypertensive treatment in a largepopulation at high risk for cardiovascular disease(CVD); the higher SBP goal would also apply to somegroups at the highest cardiovascular (CV) risk (AfricanAmericans, hypertensive patients with multiple CVDrisk factors other than diabetes mellitus or CKD, andthose with clinical CVD); evidence supporting the SBPtarget increase from 140 to 150 mmHg in this pop-ulation was insufficient; and the higher SBP goal in thispopulation may reverse decades-long declines in CVD,particularly stroke mortality. They also commented thatthis particular guideline (5) was not in alignment with

Table 6. Guideline comparisons of goal BP and initial drug therapy for adults with hypertension

ACEI, angiotensin–converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; ESC/ESH, European Society of Cardiology/European Society ofHypertension; CHEP, Canadian Hypertension Education Program; ADA, American Diabetes Association; ISHIB, International Society on Hypertension in Blacks. Reprinted with permission (withmodification) from James PA, Oparil S, Carter BL, CushmanWC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr., Svetkey LP, Taler SJ,Townsend RR, Wright JT Jr., Narva AS, Ortiz E: 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the EighthJoint National Committee (JNC 8). JAMA 311: 507–520, 2014.


Figure 22. The 2014 hypertension guideline management algorithm. aAngiotensin–converting enzyme inhibitors (ACEIs) andangiotensin receptor blockers (ARBs) should not be used in combination. bIf BP fails to be maintained at goal, re-enter thealgorithm where appropriate based on the current individual therapeutic plan. CCB, calcium channel blocker.Reprinted withpermission from James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevreML, MacKenzie TD, Ogedegbe O, Smith SC Jr., Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr., Narva AS, Ortiz E: 2014evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to theEighth Joint National Committee (JNC 8). JAMA 311: 507–520, 2014.


guidelines from the European Society of Hypertension,the Canadian Hypertension Education Program, theNational Institute for Health and Clinical Excellence(NICE), and the American College of Cardiology/American Heart Association (9–12).

Navar-Boggan et al. (13) subsequently assessedthe proportion of United States adults who were potentiallyaffected by the 2014 Hypertension Guidelines. Using theNational Health and Nutrition Examination Survey(NHANES) data from 2005 and 2010, 16,372 partic-ipants were included, and the authors compared theJNC7 Guideline and the 2014 BP Guideline with respectto BP control and treatment (13). The newer guidelinerecommendations would substantially reduce the pro-portion of United States adults who would requiretreatment for hypertension, particularly among adultsolder than 60 years old, and there would be a decreasefrom 68.9% of participants who would require treat-ment for hypertension under JNC7 to 61.2% under the2014 BP Guideline. There would also be a substantialincrease in the proportion of adults considered to haveachieved goal BP; in older adults.60 years old, 40.0%would have been considered to have achieved goal BPusing JNC7 as opposed to 65.8% using the 2014 BPGuidelines.

Using the 2014 Hypertension Guidelines toclassify BP among United States adultscomparedwith JNC7would result in a sub-stantial reduction in the proportion ofUnited States adults who would requiretreatment for their hypertension (particu-larly among older adults .60 years old),and there would also be a substantial in-crease in the proportion of adults consid-ered to have achieved goal BP.

A joint American Heart Association/AmericanCollege of Cardiology/American Society of Hyperten-sion statement regarding BP goals made the followingrecommendations.

(1) BP goal ,140/90 mmHg in patients with hyper-tension and coronary artery disease (CAD).

(2) BP,130/80 mmHg in some individuals with CAD,previous myocardial infarction, stroke, or transientischemic attack or CAD risk equivalents (carotid

artery disease, peripheral arterial disease, or abdom-inal aortic aneurysm).

(3) In patients with an elevated DBP and CAD withevidence of myocardial ischemia, the BP should belowered slowly, and DBP should not be lowered,60 mmHg in patients .60 years of age or withdiabetes mellitus (14).

BP Goals in CKD

Patients with CKD are at particularly high risk for CVevents, and the rationale for treatment of hypertensionin CKD is to slow ongoing renal injury and retardprogression to ESRD. The recommendations from thevarious societies and agencies are shown in Table 8(15) and will be discussed in detail below.

The recommendations for BP goals in CKD from2014 BP Guidelines are based on three randomized,controlled trials: the Modification of Diet in RenalDisease (MDRD) Study; the African American Studyof Kidney Disease and Hypertension (AASK) Trial,and the Ramipril Efficacy in Nephropathy-2 (REIN-2)Trial (16–18) and subsequent meta-analyses based onthe same three trials (19–21). The MDRD Study, theAASK Trial, and the REIN-2 Trial all failed to show abenefit from lower BP goals (,140/90 versus 125–130/75–80 mmHg) in reduction of CV events, slowingprogression of CKD to ESRD, and reducing mortality.The AASK Trial prospectively included proteinuria asan end point, but lower BP targets did not show anybenefit on slowing progression of CKD (17). TheMDRD Study, however, did show a benefit in a posthoc analysis of lower BP goals in the setting ofproteinuria (more than 1 g/24 h) (21). There was,however, an unequal use of angiotensin–convertingenzyme inhibitor treatment in the different treatmentgroups. A systematic review and meta-analysis of the2272 participants of these three trials comparing lowversus high BP targets in adults with CKD also did notshow any conclusive evidence favoring a lower BPtarget of 125/75–130/80 versus 140/90 mmHg aftera mean follow-up of 2–4 years. There was a benefit forCKD patients with proteinuria of 300–1000 mg/d (20).Data disclosed a decreased incidence of stroke withlower BP goals (22), but there was also evidence of anincrease in CV morbidity and mortality with lower BPgoals from a recent veterans study (discussed below)(23). The Action to Control Cardiovascular Risk in


Diabetes (ACCORD) Trial, which randomized type 2diabetics to an SBP goal of,140 versus,120 mmHg,also failed to demonstrate CV protection from a lowerBP target, but the rate of stroke was decreased (24).Renal outcomes were not specifically addressed in the

ACCORD Trial, and serum creatinine levels and eGFRwere not improved with lower BP goals.

A recent retrospective study from a national CKDdatabase of United States veterans compared mortalityin CKD patients with a treated SBP of ,120 mmHg

Table 7. Recommendations for management of hypertension

Recommendations

Recommendation 1In the general population age $60 yr old, initiate pharmacologic treatment to lower BP at SBP,150 mmHg orDBP,90 mmHg and treat to a goal SBP ,150 mmHg and a goal DBP ,90 mmHg (strong recommendation—grade A)

Corollary recommendation: In the general population age$60 yr old, if pharmacologic treatment for high BP results in lowerachieved SBP (e.g., ,140 mmHg) and treatment is well tolerated and without adverse effects on health or quality of life,treatment does not need to be adjusted (expert opinion—grade E)

Recommendation 2In the general population ,60 yr old, initiate pharmacologic treatment to lower BP at DBP.90 mmHg and treat to agoal DBP ,90 mmHg (for ages 30–59 yr old, strong recommendation—grade A; for ages 18–29 yr old, expert opinion—grade E)

Recommendation 3In the general population ,60 yr old, initiate pharmacologic treatment to lower BP at SBP.140 mmHg and treat to a goalSBP ,140 mmHg (expert opinion—grade E)

Recommendation 4In the population age .18 yr old with CKD, initiate pharmacologic treatment to lower BP at SBP,140 mmHg orDBP,90 mmHg and treat to a goal SBP ,140 mmHg and a goal DBP ,90 mmHg (expert opinion—grade E)

Recommendation 5In the population age .18 yr old with diabetes, initiate pharmacologic treatment to lower BP at SBP.140 mmHg orDBP.90 mmHg and treat to a goal SBP ,140 mmHg and a goal DBP ,90 mmHg (expert opinion—grade E)

Recommendation 6In the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, CCB, ACEI, or ARB (moderate recommendation—grade B)

Recommendation 7In the general black population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic or CCB (for general black population, moderate recommendation—grade B; for black patients with diabetes,weak recommendation–grade C)

Recommendation 8In the population age.18 yr old with CKD, initial (or add–on) antihypertensive treatment should include an ACEI or ARB toimprove kidney outcomes; this applies to all CKD patients with hypertension, regardless of race or diabetes status(moderate recommendation—grade B)

Recommendation 9The main objective of hypertension treatment is to attain and maintain goal BP. If goal BP is not reached within 1 mo oftreatment, increase the dose of the initial drug or add a second drug from one of the classes in recommendation 6 (thiazide-type diuretic, CCB, ACEI, or ARB). The clinician should continue to assess BP and adjust the treatment regimen until goalBP is reached. If goal BP cannot be reached with two drugs, add and titrate a third drug from the list provided. Do not use anACEI and an ARB together in the same patient. If goal BP cannot be reached using only the drugs in recommendation6 because of a contraindication or the need to use more than three drugs to reach goal BP, antihypertensive drugs from otherclasses can be used. Referral to a hypertension specialist may be indicated for patients in whom goal BP cannot be attainedusing the above strategy or the management of complicated patients for whom additional clinical consultation is needed(expert opinion—grade E)

CCB, calcium channel blocker; ACEI, angiotensin–converting enzyme inhibitor; ARB, angiotensin II receptor blocker. Reprinted with permission (with modification) from JamesPA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr., Svetkey LP, Taler SJ, TownsendRR, Wright JT Jr., Narva AS, Ortiz E: 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the EighthJoint National Committee (JNC 8). JAMA 311: 507–520, 2014.


with patients with the currently recommended SBP of,140 mmHg (23). This study included 77,765 indi-viduals with GFR,60 ml/min per 1.73 m2 and un-controlled hypertension (received one or more BPmedications with evidence of a decrease in SBP). Ofthis cohort, 5760 patients had a treated SBP of ,120mmHg at follow-up, and 72,005 patients had a treatedSBP of 120–139 mmHg at follow-up. During a medianfollow-up of 6.0 years, 19,517 patients died (2380deaths in the SBP,120 mmHg group [death rate of80.9/1000 patient-years] and 17,137 deaths in the SBPof 120–139 mmHg group [death rate of 41.8/1000patient-years]; P,0.001). The mortality hazard ratioassociated with follow-up SBP ,120 versus 120–139mmHg was 1.70 (95% confidence interval, 1.63 to1.78). These results suggest that tighter SBP control isassociated with higher all–cause mortality in patientswith CKD. However, this is a retrospective observa-tional analysis and at risk for confounding.

The 2012 Kidney Disease Improving Global Out-comes (KDIGO) Clinical Practice Guideline for Man-agement of Blood Pressure in CKD (25) was the firstguideline to recommend a higher BP goal for patientswith CKD, and it was commented on in the previousNephSAP. This guideline recommended a BP goal of#140/90 mmHg in CKD patients without albuminuria.They also recommended a goal BP #130/80 mmHgin CKD patients with micro- or macroalbuminuria(albuminuria $30 mg/24 h) (25). KDIGO also recom-mended treatment with renin-angiotensin-aldosterone

system blockade in all CKD patients with an albuminexcretion rate of $30 mg/24 h.

Other guideline groups have also raised the BPtargets for patients with CKD, including the Amer-ican Diabetes Association (BP target ,140/80mmHg) (26), the Canadian Hypertension EducationProgram (BP target ,140/90 mmHg for CKD) (27),and the European Society of Cardiology/ EuropeanSociety of Hypertension (SBP target ,140 mmHg forCKD) (9). The NICE Guideline advised initiatingtreatment in those with CKD at BP$140/90 mmHgand treating to a target of 120–139/,90 mmHg (28, 29).The NICE Guidelines also recommended drug treatmentfor BP$130/80mmHg for albumin-to-creatinine ratio of$70 mg/mmol and a target of 120–129/,80 mmHg.

Although there is no consensus on BP targets forCKD, the majority of guidelines favor a BP,140/90mmHg in CKD without proteinuria; however, mostguidelines recommend maintaining a lower BP targetfor those with more severe proteinuria. This may betherapeutically challenging, because patients with ad-vanced CKD are more likely to have resistant hyper-tension and be taking multiple antihypertensive agents.In a recent NHANES analysis, more patients with CKDhad uncontrolled BPs compared with non-CKD pa-tients, even when using the recent higher BP targetssuggested by the 2014 BP Guidelines (BP,140/90mmHg) (Figure 23) (30).

A recent study of 651,749 mostly men withCKD who are United States veterans assessed the

Table 8. BP targets and treatment recommendations in CKD

Guideline SourceCKD without

Proteinuria,a mmHg CKD with Proteinuria, mmHg Recommended Agents

US JNC8 ,140/,90 ,140/,90 ACEI or ARBKDIGO ,140/,90 #130/#80 ACEI or ARBNICE ,140/,90 ,130/,80 ACEI or ARBb

CHEP ,140/,90 ,140/,90 ACEI; ARB if ACEI intolerantESC/ESH ,140 ,130 ACEI or ARBASH/ISH ,140/,90 ,140/,90c ARB or ACEIISHIB ,130/,80 ,130/,80 Diuretic or CCBACEI, angiotensin–converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CHEP, Canadian Hypertension Education Program; ESC/ESH, European Society ofCardiology/European Society of Hypertension; ASH/ISH, American Society of Hypertension/International Society of Hypertension; ISHIB, International Society onHypertension in Blacks; CCB, calcium channel blocker. Reprinted with permission (with modification) from Townsend RR, Taler SJ: Management of hypertension inchronic kidney disease. Nat Rev Nephrol 11: 555–563, 2015.aProteinuria definitions vary; the authors recommend using either 11 (by dipstick), .500 mg protein per 24 hours, or .200 mg albumin per 24 hours (or the equivalent ofthese values in a spot urine determination that uses a protein-to-creatinine or albumin-to-creatinine ratio).bThe NICE, The United Kingdom National Institute for Health and Clinical Excellence, recommendations in CG182 are to use ACEI or ARB when proteinuria is present;otherwise, the guidance is to follow general recommendations for BP control (CG127) when proteinuria is absent.cThe ASH/ISH guidelines acknowledge that some authorities still recommend ,130/,80 mmHg for CKD with proteinuria.


association of BP with death in patients with CKD(31). They examined all possible combinations of SBPand DBP from lowest (BP¼80/40 mmHg) to highest(BP¼210/120 mmHg) in 10-mmHg increments (31).The study revealed that patients with SBP of 130–159mmHg combined with DBP of 70–89 mmHg had thelowest adjusted mortality rates, and those in whom bothSBP and DBP were concomitantly very high or verylow had the highest mortality rates. Patients with mod-erately elevated SBP combined with DBP$70 mmHghad consistently lower mortality rates than did patientswith DBP ,70 mmHg. Results were consistent insubgroups of patients with normal and elevated albumin-to-creatinine ratios. Overall, the optimal BP in CKDpatients seemed to be 130–159/70–89 mmHg.

The prospective SPRINT study may finallyanswer the ongoing debate about what SBP goalclinicians should be targeting in patients with at highrisk for CVD and CKD (2). SPRINT is a largeNational Institutes of Health–sponsored multicenter,randomized, controlled trial that enrolled 9361 subjectswith an SBP of at least 130 mmHg. The primary goal ofSPRINT was to test whether reducing SBP to a lowergoal (SBP,120 mmHg) than currently recommen-ded (SBP,140 mmHg) would reduce the occur-rence of CVD and CKD events. Subjects enrolledwere 50 years of age or older with a SBP of 130 mmHgor higher and at least one of the following: a history ofCVD, stage 3 CKD (eGFR¼20–59 ml/min per 1.73m2), an intermediate to high risk for CVD other thanstroke, or age $75 years old. A subject was defined ashaving CVD if they had a prior myocardial infarction,percutaneous coronary intervention, coronary arterybypass grafting, carotid endarterectomy or carotidstenting, peripheral arterial disease with revasculariza-tion, acute coronary syndrome, abdominal aortic aneu-rysm$5 cm with or without repair, a coronary calciumscore .400, or left ventricular hypertrophy. A subjectwas defined as intermediate or high risk for CVD basedon the following: Framingham Risk Score for 10-yearCVD risk of 15% based on laboratory work donewithin the past 12 months for lipids. The primaryoutcome was a composite of CV events. The SPRINTStudy was terminated early after 3.26 years on advisoryof the data safety monitoring board. The results of theSPRINT Study showed a 25% reduction in the primarycombined CV outcome and a 27% reduction in mor-tality in the group randomized to an SBP,120 mmHg(2, 32). This obviously has important implications

for BP guidelines in this population. The baselinemean SBP and DBP were 139.7 and 78.1 mmHg. At 1year, the mean SBP was 121.4 mmHg in the intensivetreatment group and 136.2 mmHg in the standardtreatment group. In the SPRINT study, 28% of subjectshad CKD, 28% of subjects were .75 years old, 36%were women, and 20% of subjects had prior CVD. Thesample was diverse and included 29.9% black, 10.5%Hispanic, and 57.7% white subjects. Importantly,SPRINT excluded many patients with hypertension,including those with a history of prior stroke, diabetes,polycystic kidney disease, any secondary cause forhypertension, GFR,20 ml/min, .1 g proteinuria per24 hours, GN treated with immunosuppressive therapy,symptomatic heart failure within the last 6 months orleft ventricular ejection fraction ,35%, expected sur-vival ,3 years, cancer diagnosed within the last2 years, organ transplant, CV event, CV procedure,or hospitalization for unstable angina within the last3 months, and all patients ,50 years of age. Althoughthe SPRINT Study will provide important informationon managing SBP in older nondiabetic subjects withsubstantial CVD risk, it is important to remember thatthese results cannot be generalized to the other popula-tions outlined above. More detailed results and analysisfrom this study will be provided in the next NephSAP.

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29. Carville S, Wonderling D, Stevens P; Guideline Development Group:Early identification and management of chronic kidney disease inadults: Summary of updated NICE guidance. BMJ 349: g4507,2014 PubMed

30. Sakhuja A, Textor SC, Taler SJ: Uncontrolled hypertension by the 2014evidence-based guideline: Results from NHANES 2011-2012. J Hyper-tens 33: 644–651, 2015 PubMed

31. Kovesdy CP, Bleyer AJ, Molnar MZ, Ma JZ, Sim JJ, Cushman WC,Quarles LD, Kalantar-Zadeh K: Blood pressure and mortality in U.S.veterans with chronic kidney disease: A cohort study. Ann Intern Med159: 233–242, 2013 PubMed

32. Wright JT Jr., Williamson JD, Whelton PK, Snyder JK, Sink KM,Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, KimmelPL, Johnson KC, Goff DC Jr., Fine LJ, Cutler JA, Cushman WC,Cheung AK, Ambrosius WT: SPRINT Research Group: A randomizedtrial of intensive versus standard blood-pressure control. N Engl J Med373: 2103–2116, 2015

Update on the Treatment of Hypertension

Payments to Physicians and Practices to RewardHypertension Control

Despite variability in the available literature, it ispossible that monetary incentives, as rewards tophysicians who achieve better control of chronicconditions (e.g., BP in hypertension, glycated hemo-globin in diabetes, or LDL-cholesterol (LDL-C) inhyperlipidemia or coronary disease) may ultimatelyresult in better clinical outcomes and possibly lowercosts. Petersen et al. (1) performed a cluster-randomizedtrial in 12 Veterans Affairs (VA) medical centers in theUnited States to address this issue in the setting ofhypertension care. The intervention included financialincentives to those whose patients achieved guideline(Seventh Joint National Committee) –recommendedBP targets when there were interventions initiated tothose with uncontrolled BP and for treatment choicesthat were guideline driven. Centers were randomized to





















one of four interventions: payments only to physicians,payments to the entire practice team (divided amongphysicians and nonphysician members of the careteam), combined payments (both physician and prac-tice components), or no incentives (control group).After baseline data collection for 4 months, subjects(physicians) underwent four 4-month monitoring peri-ods, in which each physician had 40 of their hyperten-sive patients randomly selected for an evaluation of BPcontrol and use of guideline–concordant antihyperten-sive medications. After the end of the active period,there was a 12-month washout period to evaluatethe sustainability of the effects without incentives.

Throughout the active part of the study but not duringthe washout period, physicians received feedback onthe audits of their patients through a website designedto provide this information.

The maximum pay per record reviewed was$18.20 (US$9.10 per measure), and the average totalpayouts to individual study subjects were $4270,$2682, and $1648 for the combined, individual, andpractice-level interventions. As shown in Figure 24,baseline rates of BP control were high in all groups.Groups randomized to the individual (physician) -basedincentive had the only statistically significant increasein control rates during the study. The adjusted absolute

Figure 24. A and B show the unadjusted proportions of physician’s patients meeting the rewarded clinical measures in hypertensioncare by the study group (details in the text). The table presents modeled results of the effect of the intervention on the rewardedclinical measures. aP values compared with the control group. bModel adjusted for proportion of patients with diabetes, whether thephysician worked at a teaching hospital, and geographic location. cModel adjusted for proportion of patients with diabetes, mean ageof patients, whether the physician worked at a teaching hospital, and ceiling effects. Reprinted with permission from Petersen LA,Simpson K, Pietz K, Urech TH, Hysong SJ, Profit J, Conrad DA, Dudley RA, Woodard LD: Effects of individual physician-leveland practice-level financial incentives on hypertension care: A randomized trial. JAMA 310: 1042–1050, 2013.


difference in change between the proportion of thephysician’s patients achieving BP control or receivingan appropriate response for the individual incentivegroup and the control physicians was 8.36%. There-fore, a typical study physician in the individual groupwith a panel size of 1000 patients with hypertensionwould be expected to have about 84 additional patientsachieving BP control or receiving an appropriate re-sponse after 1 year of exposure to the intervention. Theinterventions did not reach statistical significance in thepractice and combined models. Additionally, the in-tervention did not result in greater use of guideline-concordant medications in any of the interventiongroups, although there was an across the board in-creased effect that included the control group, thusnullifying any effects of the intervention itself. Afterthe washout period, any effects observed during theintervention were no longer significant. In sum, theseresults suggest that financial incentives to physiciansresult in greater treatment intensification and better ratesof BP control. Furthermore, because the baseline rateswere already so high (75%–86%), as often seen in theVA system but not among the general hypertensivepopulation in the United States, it is conceivable thatsuch incentives may have an even greater effect outsideof the VA system, because there would not be sucha substantial ceiling effect. Decisions regarding financialincentives for good performance versus financial penal-ties for poor performance are in active flux in currenthealth policy development, and studies like this andfuture modeling or measurement of outcomes related tosuch interventions will help shape these important healthcare delivery decisions.

Self-Titration of Antihypertensive Therapy and theUse of Telemedicine in Hypertension

Home BP monitoring leads to greater patientinvolvement and better BP control. Newer adaptationsto the use of home BP monitoring to facilitate hyper-tension treatment are under active investigation. Two ofthese strategies include the use of health care providers(physician or nonphysicians) to titrate therapy via tele-medicine and the use of patient–initiated self–titration inresponse to observed values at home.

Home BP telemonitoring refers to the use ofa home BP monitor and a mechanism for transmittingthe values obtained back to clinicians by either remoteconnectivity with the monitors or an active upload bypatients themselves. Several trials describe the value of

home telemedicine to improve BP control. In a meta-analysis of 23 trials including 7037 patients, home BPtelemonitoring resulted in lower BP (4.7/2.5 mmHg;P,0.001), 16% greater likelihood of achieving BPcontrol, and more active hypertension treatment (0.4additional prescription medications) than patients re-ceiving usual care (2).

These interventions are effective in not onlypatients with uncomplicated hypertension (as was thecase of most studies in the meta-analysis above) butalso, high-risk patients. The Targets and Self-Managementfor the Control of Blood Pressure in Stroke and AtRisk Groups (TASMIN-SR) Trial was an open–label,randomized trial of 552 hypertensive patients witha history of stroke, coronary heart disease, diabetes,or CKD with baseline BP of at least 130/80 mmHgbeing treated at 59 United Kingdom primary carepractices (3). Study subjects randomized to the in-tervention received home BP monitors and instructionson medication self-titration based on BP values. Theprocess of education was delivered over two or three1-hour sessions, and the patients followed a protocolthat called for medication self-titration in the case ofsequential home BP readings target. There were presetwarning BPs (.180/100 or ,100 mmHg systolicBP [SBP]) that the patient should immediately contacthis/her primary care practice. The office BP targetwas 130/80 mmHg, and the home BP target was 120/75mmHg. As shown in Figure 25, the intervention wasassociated with a 9.2/3.2-mmHg lower BP at12 months, an effect that was observed across allsubgroups evaluated. As planned by the interven-tion, this was achieved through the use of a largeramount of medications (mean, 0.9 defined daily doseof antihypertensive agents at 12 months) (3). Animportant limitation of this trial is its generalizability;only a small portion of screenees (approximately 8%)was eligible for the study, and the investigators estimatethat only about 20% of hypertensive patients may besuitable to receive this self-titration intervention (3).

In health care systems with advanced populationhealth management programs, the use of clinicalpharmacists or other advanced health care professio-nals (nurse practitioners and physician assistants) canresult in improved hypertension management. TheHome Blood Pressure Telemonitoring and Case Man-agement to Control Hypertension (HyperLink) Studywas a cluster-randomized trial of 450 patients withhypertension and several comorbid conditions in 16


clinical sites of the HealthPartners Medical Group (4).Similar to the TASMIN-SR Study, the HyperLinkStudy was designed to test telemonitoring interven-tions in populations with associated comorbid con-ditions. Patients randomized to the intervention receiveda home BP monitor that transmitted home BPs topharmacists who adjusted BP medications basedon specified targets (140/90 mmHg for most and130/80 mmHg for diabetes or kidney disease). After12 months, 71% of patients in the intervention groupwere controlled compared with only 53% in the controlgroup (P,0.01). The study also established that theintervention had a durable effect on BP control rates6 months after termination of the trial (72% versus57%; P,0.01).

Maciejewski et al. (5) also analyzed the durability ofthe effects of telemedicine interventions up to 18 months

after the completion of a clinical trial. In the original study(6), all patients underwent home BP telemonitoring andwere randomized to receive a nursing education interven-tion, a nurse– and physician–administered medicationmanagement intervention, both, or neither (i.e., usualcare). The study showed that all interventions wereeffective compared with usual care in patients withuncontrolled BP. In the durability analysis based onBP values abstracted from the electronic medical record,patients in the three intervention groups demonstratedsustained improvements in BP control compared withpatients who received usual care (17%–20% greaterabsolute control rates) (5). Similar to the original trial,the magnitude of the late effects was also greater amongpatients with uncontrolled BP at baseline.

Telemedicine approaches that use practitioner–directed or patient–directed self–titration of medications

Figure 25. Differences in SBP between the self-titration and control groups in the TASMIN-SR Study. The overall differencewas 9.2 mmHg, and the intervention was effective across multiple subgroups. IMD, index of multiple deprivation. Reprintedwith permission from McManus RJ, Mant J, Haque MS, Bray EP, Bryan S, Greenfield SM, Jones MI, Jowett S, Little P,Penaloza C, Schwartz C, Shackleford H, Shovelton C, Varghese J, Williams B, Hobbs FD, Gooding T, Morrey I, Fisher C,Buckley D: Effect of self-monitoring and medication self-titration on systolic blood pressure in hypertensive patients at high riskof cardiovascular disease: The TASMIN-SR randomized clinical trial. JAMA 312: 799–808, 2014


are interesting interventions that can increase thetimeliness of BP adjustments and maximize patientconvenience, being of particular relevance to single-payer or capitated systems, where they can also de-crease costs and system overcrowding. Since Januaryof 2015, this may also have become of relevance tophysicians caring for Medicare patients in the UnitedStates, because Medicare started reimbursing nonfaceto face care to Medicare beneficiaries with 17 eligiblechronic conditions, one of which is hypertension(Chronic Care Management services at https://www.cms.gov). We believe that the lessons learned fromtelemedicine intervention studies have direct implica-tions to optimal hypertension care and the pursuit ofimproved rates of BP control.

Pharmacogenetics to Predict AntihypertensiveDrug Response

In his 2015 State of the Union address, PresidentObama announced the Precision Medicine Initiative.The mission of this initiative is to “enable a new era ofmedicine through research, technology, and policiesthat empower patients, researchers and providers towork together toward development of individualizedtreatments” (https://www.whitehouse.gov/precision-medicine) using approaches that acknowledge theindividuality of each patient and the impact that genes,environment, and lifestyle have on the presentation ofdisease and response to therapy. Accordingly, theNational Institutes of Health will support the assemblyof a large cohort of patients that will include genomic,behavioral, and personal health records data to allowexploration of myriad questions by independent in-vestigators (7). In certain areas of medicine, oncologyin particular, pharmacogenetics has been used toidentify genetic markers to predict treatment responsesto individual drugs, including measures of efficacyand toxicity. In the field of hypertension, pharmaco-genetic approaches have proven of little value. In thepast 3 years, several groups of investigators havestarted to use genome–wide association studies(GWASs) to evaluate markers of response to individualdrug classes. If successful, such an approach wouldallow precise identification of patients and individual-ized treatment plans that maximize drug efficacy andoptimize rates of BP control. However, the use of theGWAS approaches has not added much precision tohypertension management. Most studies are successfulat identifying alleles that significantly identify a higher

likelihood of BP response to a certain agent (or class).However, as summarized by Fontana et al. (8) andcompiled in the Pharmacogenomic Knowledge Basethrough 2014, the data indicate only moderate- (thia-zide diuretics) to low-level (all other classes) evidenceof effect in the case of BP-lowering drugs. This isbecause the majority of evidence for the magnitude ofeffects is relatively minor, has low allelic frequency inthe population, and has limited reproducibility of thefindings in validation cohorts (8).

The issue of limited reproducibility acrosscohorts was illustrated by the Genetics of DrugResponsiveness in Essential Hypertension (GENRES)Study, a four–way, double–blinded, placebo–controlled,cross–over GWAS trial. The aim of the GENRES Studywas to identify loci that influence the BP response todrugs from four antihypertensive classes (amlodipine,bisoprolol, losartan, and hydrochlorothiazide) (9). Thismethodologically rigorous study included 4 weeks ofexposure to each of the individual drugs followed by 4weeks of placebo washout between drugs. Treatmenteffects were evaluated by ambulatory BP monitoring.The authors present extensive associations betweensingle-nucleotide polymorphisms (SNPs) and BP reduc-tions with different agents (9). When one considers thedifferences that would be clinically relevant, arbitrarily.5 mmHg, there were five SNPs identified for bisopro-lol (all toward lower BP with allele frequencies between1% and 11%), two SNPs for hydrochlorothiazide (bothtoward higher BP with allele frequency of 3% for both),one SNP for amlodipine (toward lower BP with allelefrequency of 2%), and none for losartan. Replicationcould not be achieved in four other cohorts (9). This wasa well conducted study of 228 men. The investigatorsrecognize the limited size of the study and planned itin order to identify significant SNPs with an effectsize of 4 mmHg with a minor allele frequency of30% (9). They argued that, in future studies, there is“importance of even larger sample sizes” to detectsmaller effect sizes (9). Alternatively, we posit thatdetecting smaller effect sizes, while interesting froma mechanistic perspective, will not disclose a marker ofpharmacogenetic relevance for clinical decision mak-ing. Moreover, it is apparent that there are significantdifferences between drugs within the same class. Frauet al. (10) identified a specific polymorphism in theCAMK1D gene that encodes a protein involved in theregulatory pathway involved in aldosterone synthesisand mediates the response to losartan, with an effect size


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https://www.cms.gov

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of 5.5 mmHg. These findings were replicated in anothercohort using losartan with a very similar effect size butshowed no effect in another cohort receiving anotherangiotensin receptor blocker, candesartan. In our view,the state of the science and currently used approachessuggest that the viability of pharmacogenetic ap-proaches in hypertension remains in the distant future.

Treatment of Mild HypertensionUncertainty remains about the value of pharma-

cologic treatment of patients with early-stage hyper-tension (stage 1 or BP¼140–159/90–99 mmHg),especially in the absence of underlying cardiovascular(CV) disease. In the previous issue of NephSAP onhypertension, we reviewed the results and limitations ofa Cochrane review concluding that treatment of mildhypertension was not associated with clinical benefits.The Blood Pressure Lowering Treatment Trialists’Collaboration (BPLTTC) has since published a meta-analysis that updated the previous Cochrane review andadded individual patient data from the BPLTTC (11).This meta-analysis included trials where at least 80% ofsubjects had stage 1 hypertension, there was no pre-vious CV disease, and there were two arms thatcompared antihypertensive drug therapy with placeboor another control intervention. The total number ofpatients included was 15,266 from 13 trials, 95% ofwhom had participated in a placebo-controlled trial.After a median follow-up of 4.4 years, 661 (5.1%)developed a CV event. Active treatment resulted inlower risk of adverse outcomes for all six outcomesstudied (all CV events, coronary events, stroke, heartfailure, CV death, and all-cause death), although onlystroke, CV death, and all-cause death reached statisticalsignificance (relative risk, 0.72; 95% confidence in-terval [95% CI], 0.55 to 0.94; relative risk, 0.78; 95%CI, 0.67 to 0.92; and relative risk, 0.75; 95% CI, 0.57 to0.98, respectively) (11). A point of major importanceis that the patients added by the BPLTTC were diabeticin 96% of cases, a group in which treatment wouldbe expected to result in greater benefit. Although thedifferences in risk reduction were not statistically differ-ent, the individual estimates were consistently greater inthe subset of patients contributed by the BPLTTC thanthose from non-BPLTTC trials. Therefore, on the sur-face, this meta-analysis supports the treatment of patientswith stage 1 hypertension and no previous CV disease.Our interpretation of the data is that antihypertensivetreatment of diabetic patients with uncomplicated stage 1

hypertension should be carried out. For patients who donot have diabetes, this meta-analysis does not provideany new insights on the value of drug treatment of mildhypertension. For the practicing clinician, the decisioncontinues to be based on overall risk assessment (ac-knowledging the limited duration of follow-up of moststudies) and patient preferences regarding drug therapy.

Clinical Studies: Devices, Diets, Supplements, andCombination Therapy

Device-Guided Breathing for HypertensionThe recent American Heart Association (AHA)

Scientific Statement regarding the use of nonpharma-cological treatments for hypertension recommendsdevice-guided breathing to lower BP in patients withstage 1 hypertension (12). Device-guided breathingconsists of an interactive system that uses a belt aroundthe thorax to monitor the breathing rate. Real-timedata, corresponding to inspiration and expiration, istranslated to musical tones and heard by the patientthrough headphones. As the patient synchronizesbreathing with the tones, the device gradually prolongsthe exhalation tone (primarily) and slows the breathingrate to ,10 breaths per minute (slow breathing). Thephysiological origin of the hypotensive effects ofpaced breathing has traditionally been attributed torelaxation and possibly, increased baroreflex sensitivity(13). A meta-analysis of randomized studies of at least 4weeks in duration with a single- or double-blind designand an active control group was conducted (14). Theeffect of device-guided breathing on office SBP com-pared with music therapy or a sham device was 2.2mmHg (95% CI, 22.7 to 7.0) in favor of the controlgroup; device-guided breathing did not significantlylower office diastolic BP (DBP). All trials included inthe analysis had short follow-up periods. The meta-analysis showed that device-guided breathing did notsignificantly lower office BP compared with a shamprocedure or music therapy.

Another study evaluated the effects of device–guided breathing frequency on BP reduction in patientswith type 2 diabetes mellitus (T2DM) and hyperten-sion. This was a single–center, double–blind, sham–controlled trial in The Netherlands (15). Patientswere randomized to 15-minute sessions with eitherthe device-guided breathing (target ,10 breaths perminute) or a sham device with music for an 8-weekstudy period; 20 of the patients randomized to the


intervention group and 24 patients randomized to thecontrol group completed the study. There were nosignificant changes in office SBP and DBP. Based onthe meta-analysis and this study in type 2 diabetics, itseems that device-guided breathing does not seem tobe a viable nonpharmacologic option for hyperten-sion treatment, despite its AHA recommendation.

Effects of Vitamin D Supplementation on BPIn epidemiological analyses, low 25-hydroxyvitamin

D [25(OH)D] levels have been linked to incident andprevalent hypertension and CV disease (16,17). Therehave been a number of prospective trials publishedrecently assessing the effects of 25(OH)D supplemen-tation on BP reduction. The first study is the Vitamin Din Isolated Systolic Hypertension Trial, which re-cruited elderly patients with the following criteria:70 years old or older with isolated systolic hyperten-sion defined as SBP.140 mmHg and DBP,90 mmHgand baseline 25(OH)D levels,30 ng/ml (18). Subjectswere randomized to receive either 100,000 IU oralcholecalciferol or matching placebo every 3 months for1 year, and 159 subjects with a mean age of 77 yearsold, baseline SBP of 163/78 mmHg, and mean baseline25(OH)D levels of 18 ng/ml were randomized. In thetreatment group, 25(OH)D levels were significantlyincreased when compared with the placebo group;however, there was no significant effect on BP re-duction. There were no differences in adverse effectsbetween groups, and interestingly, the total number offalls was nonsignificantly lower in the treatment group.A subgroup analysis of the 75 subjects with orthostatichypotension (mean decrease in BP of 32/5 mmHg) atbaseline was also assessed for the role of 25(OH)Dsupplementation on orthostasis (19). Repeated meas-ures analysis showed no significant effect of 25(OH)Dsupplementation on orthostatic hypotension in elderlypatients with isolated systolic hypertension.

A larger prospective, double–blind, randomizedstudy enrolled 534 subjects with prehypertension andstage 1 hypertension at four sites in the United States.Subjects were 18–50 years of age with 25(OH)Dlevels ,25 ng/ml and SBPs in the range of 120–159mmHg, and they were randomized to either high-dose25(OH)D (4000 IU/d) or low-dose 25(OH)D (400IU/d) for 6 months. The median age was 38 years old,62% were men, and 48% were black, with a median25(OH)D level of 15 ng/ml; 72% (383) of subjectscompleted the full study. There were no significant

differences in office or ambulatory SBP or DBP at 1year. This study concluded that 25(OH)D supplemen-tation did not lower BP in 25(OH)D-deficient subjectswith mild to moderate hypertension. Finally, a meta-analysis of placebo–controlled, randomized trials of25(OH)D supplementation for a minimum of 4 weekswith reported BP data also showed no effect of25(OH)D supplementation on either SBP and DBPin 4541 subjects (20). Furthermore, subgroup analysesdid not show any baseline factor that predicted a betterresponse to therapy. In conclusion, there is no role for25(OH)D supplementation to lower BP in prehyper-tension or stage 1 or 2 hypertension in any age group.There is also no role for 25(OH)D supplementation ona population level as an intervention to lower BP.

There is no role for 25(OH)D supplemen-tation to lower BP in prehypertension orstage 1 or 2 hypertension in any age group.There is also no role for 25(OH)D supple-mentation on a population level as an in-tervention to lower BP.

Sodium-Glucose Transporter 2 Inhibitors Effecton Lowering BP

The sodium-glucose transporter 2 (SGLT2) in-hibitors are a novel class of oral antihyperglycemicagents for the treatment of T2DM (21). Dapagliflozinwas approved in the European Union in 2012, andcanagliflozin was the first agent in this class approvedin the United States in 2013. SGLT is a low–affinity,high–capacity transporter expressed exclusively in theS1 and S2 segments of the renal proximal tubule, where90% of glucose reabsorption occurs (22). In T2DM,inhibition of SGLT2 increases renal glucose excretionby reducing glucose reabsorption by the proximaltubule. A number of clinical trials have shown signifi-cant reductions in SBP and DBP following SGLT2inhibitor therapy (23,24). A meta-analysis included 27randomized, controlled trials (12,960 participants) ofSGLT2 inhibitor treatment of T2DM patients withreported changes in SBP and/or DBP (25). Subgroupanalyses were performed for placebo-controlled trialsand those with active controls. SGLT2 inhibitors signif-icantly reduced mean SBPs and DBPs from baseline by4.0 and 1.6 mmHg, respectively. Only canagliflozinshowed a significant dose-response relationship with


SBP (P,0.01). Significant reductions in body weightand hematocrit were also seen with the SGLTs. SGLTshad no significant effect on the incidence of orthostatichypotension (P.0.05). SGLT2 inhibitors may representan exciting new class of drugs for T2DM, with thepotential to reduce CV disease risk through improvedglycemic control and possible additional benefits ofweight loss, improved triglyceridemia, and lower BP.There are an increasing number of recent reports ofassociated ketoacidosis with the use of SGLT2 drugs.Long–term safety issues still need to be determined.

Thiazides: Chlorthalidone Versus HCTZ—TheDebate Continues

This ongoing debate was discussed in the priorNephSAP, with most studies showing greater efficacyof chlorthalidone compared with hydrochlorthiazide(HCTZ) and decreased CV event rate (26,27). Acontrary study assessing the use of chlorthalidone inolder adults, however, did not demonstrate a lowerrate of CV events or deaths than HCTZ, but there wasa greater incidence of electrolyte abnormalities, par-ticularly hypokalemia with chlorthalidone, comparedwith HCTZ (28). A study from The Netherlandsinvestigated the differences in risk of hyponatremiabetween chlorthalidone and HCTZ, adjusting fordaily dose received (29). Subjects from the DutchIntegrated Primary Care Information Database witha serum sodium ,130 mmol/L or hospitalization dueto hyponatremia were compared with age- and sex-matched controls. Hyponatremia in the 1033 casesidentified was more common with chlorthalidone thanwith HCTZ at equal dose per day: adjusted odds ratiowas 2.09 (95% CI, 1.13 to 3.88) for 12.5 mg/d and1.72 (95% CI, 1.15 to 2.57) for 25 mg/d. These resultsindicated that the risk of hyponatremia in users ofchlorthalidone is higher than in users of HCTZ whenused at the same milligrams per milligram dose butnot when used with equipotent doses (HCTZ, 25 mg/dversus chlorthalidone, 12.5 mg/d). There was no increasedrisk of hyponatremia observed with chlorthalidone whencompared with twice the dose of HCTZ per day, which isrequired to achieve similar BP reductions. Due to thepossible CV benefits with chlorthalidone, its longer dur-ation of action, and no increased risk of hyponatremia forsimilar dosing for efficacy, chlorthalidone does seem tobe the more favorable diuretic option.

Another population–based cohort study from TheNetherlands analyzed differences in thiazide-associated

hyponatremia over a 10-year period between men andwomen and between different categories of age, bodymass index (BMI), daily thiazide dose, and eGFR (30).The study included 13,325 individuals $45 years oldand showed that hyponatremia occurred in approxi-mately one third (32.4%) of participants who wereexposed to thiazide diuretics, and a thiazide wasassociated with nearly five times the risk of hypona-tremia than no exposure (hazard ratio, 4.95; 95% CI,4.12 to 5.96). Younger age and lower BMI butnot female sex (as previously shown) (31) significantlymodified the risk of thiazide-associated hyponatremia(P,0.05). This study reinforces the knowledge thatapproximately one third of patients will develop thia-zide-associated hyponatremia and that risk is increased inpatients who are younger with lower BMIs.

There is no increased risk of hyponatre-mia observed with chlorthalidone whencompared with twice the dose of HCTZper day, which is required to achievesimilar BP reductions. Due to the possi-ble CV benefits with chlorthalidone, itslonger duration of action, and no in-creased risk of hyponatremia for similardosing for efficacy, chlorthalidone asopposed to HCTZ does seem to be themore favorable diuretic option.

Atenolol Versus Metoprolol in CKDAtenolol and metoprolol tartrate are com-

monly prescribed b-blockers; however, atenolol isrenally excreted, whereas metoprolol tartrate is not.A population–based, matched, retrospective cohortstudy was conducted in older adults who wereprescribed either oral atenolol or metoprolol tartrate(32). There were 75,257 patients per group withmean age of 75 years old. CKD was present in 4.6%of patients (median GFR ¼38 ml/min per 1.73 m2).When compared with metoprolol tartrate, initiatingatenolol treatment was not associated with higher riskof hospitalization with bradycardia or hypotension;however, atenolol treatment initiation was associatedwith lower 90-day risk of mortality than metoprololtartrate (incidence, 0.97% versus 1.44%; relative risk,0.68; 95% CI, 0.61 to 0.74). Lower eGFR did not


modify either association (Figure 26). This study isretrospective and at risk for confounding, but despitethe authors’ initial hypothesis, atenolol was associatedwith a lower 90-day risk of mortality, regardless ofeGFR, with no difference in risk of hospitalizationattributable to bradycardia or hypotension comparedwith metoprolol tartrate (32).

Azelnidipine—A New Calcium Channel BlockerA recently developed calcium channel blocker,

azelnidipine, decreases heart rate while lowering BP,possibly by inhibiting sympathetic nerve activity asdemonstrated in animal models. A prospective, ran-domized, open–label, and cross–over study of 14 patientswas conducted to evaluate whether azelnidipine inhibitedsympathetic nerve activity compared with amlodipinein essential hypertension (33). BP, heart rate, andbaroreflex sensitivity were measured, and musclesympathetic nerve activity (MSNA) via microneurog-raphy was recorded after 8 weeks of treatment witheither azelnidipine or amlodipine. Although SBPs andDBPs did not differ between azelnidipine and amlo-dipine, the heart rate in the azelnidipine group wassignificantly decreased compared with that in theamlodipine group. MSNA was also significantly re-duced in the azelnidipine compared with the amlodi-pine group (47.7614.9 versus 61.5610.7 bursts per100 beats; P,0.05). There were no significant differ-ences observed in baroreflex control of heart rate orMSNA between the two groups. This is a small studythat needs to be replicated in a larger cohort, but itdoes demonstrate that azelnidipine, compared withamlodipine, exerted a favorable effect on sympatheticnerve activity without affecting baroreflex sensitivity inhypertensive patients. Azelnidipine might also be usefulfor treating hypertension complicated by heart failureand ischemic heart disease.

Medication Adherence and Use of Generic DrugsPhysicians are encouraged to prescribe generic

drugs due to the lower cost. A study from Italy comparedthe risk of discontinuing antihypertensive drug ther-apy in patients treated with monotherapy using eithera generic or brand-name agents. A large cohort(N¼101,618) of newly treated hypertensive patients$18 years old from a region in Italy were followeduntil the earliest date that treatment discontinuationoccurred or death, emigration, or 12 months aftertreatment initiation (34). Patients who started on

generics did not experience a different risk of discontin-uation compared with those starting on brand-nameagents (hazard ratio, 1.00). Discontinuation did not occurwith different rates during periods covered by generics orbrand-name agents (incidence rate ratio, 1.01) within thesame individuals. This study showed that generic prod-ucts are not responsible for the high rate of discontinu-ation from antihypertensive drug therapy, and therefore, ifone assumes therapeutic equivalence between brandedproducts and generics, this would favor the prescription ofgeneric drugs for their economic benefits.

Fish Oil and BPA meta-analysis on 70 randomized, controlled

trials examined the effects of eicosapentaenoic acid(EPA) and docosahexaenoic acid (DHA) without upperdose limits and including food sources on BP (35).Compared with placebo, EPA and DHA provisionshowed a minor reduction in SBP and DBP (21.52and 20.99 mmHg, respectively). The strongest effectsof EPA and DHA were observed among untreatedhypertensive subjects who showed a larger reductionin SBP and DBP (24.51 and 23.05 mmHg, respec-tively) (Figure 27). This meta-analysis indicates that useof fish oil reduced SBP, whereas DBP was only reducedwith intake of $2 g/d EPA and DHA (Figure 28).

Vegetarian Diets and BPA meta-analysis examined the association be-

tween vegetarian diets and BP (36). Vegetarian dietswere defined as dietary patterns that excluded or rarelyincluded meats; some vegetarian diets included dairyproducts, eggs, and fish. All vegetarian diets empha-sized foods of plant origin, particularly vegetables,grains, legumes, and fruits. Seven clinical trials and 32observational studies met the inclusion criteria. In theseven controlled trials (n¼311; mean age ¼44.5 yearsold), consumption of vegetarian diets was associatedwith a reduction in mean SBP (24.8 mmHg; P,0.001)and DBP (22.2 mmHg; P,0.001) compared with theconsumption of omnivorous diets. In the 32 observa-tional studies (a total of 21,604 participants; meanage ¼46.6 years old), consumption of vegetarian dietswas associated with lower mean SBP (26.9 mmHg;P,0.001) and DBP (24.7 mmHg; P,0.001) com-pared with the consumption of omnivorous diets. Thismeta-analysis indicates that vegetarian diets may beassociated with lower BP and could potentially bea useful nonpharmacologic means for reducing BP.


Dietary Nitrates and HypertensionSingle-dose administration of dietary inorganic

nitrate acutely reduces BP in normotensive healthyvolunteers via bioconversion to the vasodilator nitricoxide. A study assessed whether dietary nitrate mightprovide sustained BP lowering in patients with hyper-tension. A double–blind, placebo–controlled clinicaltrial randomized 68 hypertension patients to receivedaily dietary supplementation for 4 weeks with eitherdietary nitrate (250 ml beetroot juice daily) or placebo(250 ml daily as nitrate–free beetroot juice) after a2-week run–in period followed by a 2-week washout(37). The primary end points were changes in clinic,ambulatory, and home BPs compared with placebo.The results disclosed that daily supplementation withdietary nitrate versus placebo was associated withreduction in BP as measured by clinic BP (27.7/2.4mmHg; P,0.001 and P¼0.05, respectively), 24-hourambulatory BP (7.7/5.2 mmHg; P,0.001 for both),and home BP (8.1/3.8 mmHg; P,0.01 for both), withno evidence of tachyphylaxis over the 4-week period.Endothelial function was also improved by approxi-mately 20% (P,0.001), and arterial stiffness wasreduced by 0.59 m/s (0.24–0.93; P,0.01). Theintervention was well tolerated. These findings suggest

a role for dietary nitrate as an inexpensive adjunctivetreatment for management of mild hypertension.

Combination TherapyThe combination of two antihypertensive drugs

from different classes is likely to cause a greaterreduction in BP than would an increase in a mono-therapy dose (38). The use of antihypertensive fixed–dose combinations (FDCs) when compared with higherdoses of the monotherapy has been shown to improveBP control, lower rates of adverse events, and improvedrug adherence (39,40). An FDC therapy (polypill)combines antihypertensive medications in low doseswith a statin with or without aspirin into a single pill forCV disease prevention. A polypill has potential utilityin low-resource settings, because it increases adherenceat lower cost (41).

The Use of a Multidrug Pill In Reducingcardiovascular Events (UMPIRE) Study determinedwhether FDC therapy combining aspirin, simvastatin,and two antihypertensive drugs (lisinopril and eitherHCTZ or atenolol) versus usual care improved long-term adherence and lowered SBP and LDL-C (42).This randomized, open–label study included 2004participants with established CV disease or who were

Figure 26. Kidney function and population-based outcomes of initiating oral atenolol versus metoprolol tartrate in older adults.The 90-day all–cause mortality outcome with atenolol versus metoprolol tartrate stratified by the presence of a lower eGFR. Pvalue for interaction. Reprinted with permission from Fleet JL, Weir MA, McArthur E, Ozair S, Devereaux PJ, Roberts MA,Jain AK, Garg AX: Kidney function and population-based outcomes of initiating oral atenolol versus metoprolol tartrate in olderadults. Am J Kidney Dis 64: 883–891, 2014.


at risk of CV disease in India and Europe. Participantswere randomly assigned (1:1) to an FDC-based strategy(n¼1002) containing either (1) 75 mg aspirin, 40 mgsimvastatin, 10 mg lisinopril, and 50 mg atenolol or (2)75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and12.5 mg HCTZ or to usual care (n¼1002). At baseline,mean BP was 137/78 mmHg, LDL-C was 91.5 mg/dl,and 61.5% of the total participants reported use ofantiplatelet, statin, and two or more BP-loweringmedications. Median follow-up was 15 months. TheFDC group had improved adherence versus usual care(86% versus 65%; P,0.001), with concurrent reduc-tions in SBP (22.6 mmHg; P,0.001) and LDL-C(24.2 mg/dl; P,0.001) at the end of the study (Figure29). In the subgroup of 727 participants with loweradherence at baseline, adherence at the end of studywas 77% versus 23% (P,0.001), and SBP and LDL-Cwere reduced by 4.9 mmHg (P¼0.01) and 6.7 mg/dl(P¼0.11), respectively (Figure 30). There were nosignificant differences in serious adverse events orCV events in either group. There were only 85 CVevents overall, and there was insufficient power todetect meaningful differences between groups. Ifbeneficial changes in SBP, LDL-C, and aspirin ob-served in this trial were realized in a similar popula-tion, it has been estimated that there would be a 15%relative risk reduction in coronary artery disease andstroke (43). However, a clinical trial would need toobserve .1000 events to reliably detect a relative risk

reduction of 15% (44). This study demonstrates that,in patients with or at high risk of CV disease, an FDCstrategy that lowers BP and cholesterol in conjunctionwith antiplatelet therapy resulted in significantlyimproved medication adherence at 15 months anda small but statistically significant lowering in SBPand LDL-C.

A Cochrane review assessed the association ofpolypills on CV diseases (45) and was summarized inJAMA (46). Nine trials (N¼7047) included six differ-ent drug combinations. The three largest trials in-cluded 78% of all participants across the studies. Thefollow-up period was relatively short: 12 weeks or lessin six trials and 12–15 months in the remaining threetrials. Only two trials reported rates of all-causemortality (n¼3465) and fatal and nonfatal CV diseaseevents (n¼2479). Two trials included at least 10% ofparticipants with prevalent CV disease at baseline.The polypill versus comparator group was associatedwith decreases in SBP (13.4 versus 6.3 mmHg),decreases in total cholesterol (33.3 versus 4.3 mg/dl),and improved adherence at 15 months (86% versus65%). The polypill was associated with a higheradverse event rate versus the comparator group (29.7%versus 24.2%) (Table 9). The most commonly reportedadverse events in the intervention and comparatorgroups were abnormal liver function tests (7.8% versus7.6%), cough (6.4% versus 3.5%), and myalgias(4.0% versus 3.6%). All-cause mortality was low in

Figure 27. Results from meta-analyses of randomized, controlled trials examining the EPA and DHA provision and (A) SBPand (B) DBP among hypertensive subjects. Reprinted with permission from Miller PE, Van Elswyk M, Alexander DD: Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: A meta-analysis of randomizedcontrolled trials. Am J Hypertens 27: 885–896, 2014.


both study groups (,1.2%), and there was no associ-ation of decreased mortality in the intervention groupcompared with the comparator group. Fatal and non-fatal CV disease event rates were 4.0% in the in-tervention group versus 2.9% in the comparator group.No trials reported cost outcomes. Based on the avail-able data, it seems that polypills are associated withlower BP and cholesterol compared with usual care.This positive result is likely the product of increased

adherence, particularly in patients with low baselineadherence.

Lastly, a study assessed the efficacy and safety ofa fixed dose combination (FDC) of a vasodilatingb-blocker (nebivolol) and an angiotensin II receptorblocker (valsartan) in an 8-week randomized, controlledtrial in adults with hypertension; 4151 participants (age$18 years old) with hypertension (BP,180/110 mmHg)were randomly assigned by a 24-hour interactive web

Figure 28. Results from meta-analyses of randomized, controlled trials examining EPA and DHA and (A) SBP and (B) DBP byEPA and DHA dose category. The circle represents the pooled summary estimate across all studies within each dose category,with 95% CIs; n indicates the number of data points in each dose category, which may be greater than the number of individualstudies. Reprinted with permission from Miller PE, Van Elswyk M, Alexander DD: Long-chain omega-3 fatty acidseicosapentaenoic acid and docosahexaenoic acid and blood pressure: A meta-analysis of randomized controlled trials. Am JHypertens 27: 885–896, 2014

Figure 29. SBP and LDL-C levels by treatment group during follow-up. At the end of the study (median, 15 months), there wasa 2.6-mmHg difference (P,0.001) in SBP (FDC2 usual care) and a 4.2-mg/dl difference (P,0.001) in LDL-C (FDC 2 usualcare). Overall mean differences were obtained via repeated linear regression using a covariance matrix with a compoundsymmetry structure. Estimates combine all nonmissing values collected at months 12, 18, and 24. Model terms include treatment,month, treatment · month interaction, and baseline SBP or LDL-C level. Dashed lines indicate 95% CIs. Reprinted withpermission from Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, Grobbee DE, Bots ML, Reddy KS, Cidambi R,Bompoint S, Billot L, Rodgers A; UMPIRE Collaborative Group: Effects of a fixed-dose combination strategy on adherence andrisk factors in patients with or at high risk of CVD: The UMPIRE randomized clinical trial. JAMA 310: 918–929, 2013.


Figure 30. Primary outcomes of SBP and LDL-C by prespecified subgroups. The primary outcomes of SBP and LDL-C areshown by prespecified baseline subgroups. Error bars indicate 95% CIs, boxes are placed at the relative risk for and sizedproportional to the amount of information per subgroup, and vertical dashed lines show the overall effect for each outcome. Pvalues are for the test of homogeneity for each subgroup. CVD, cardiovascular disease. Reprinted with permission from Thom S,Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, Grobbee DE, Bots ML, Reddy KS, Cidambi R, Bompoint S, Billot L,Rodgers A; UMPIRE Collaborative Group: Effects of a fixed-dose combination strategy on adherence and risk factors inpatients with or at high risk of CVD: The UMPIRE randomized clinical trial. JAMA 310: 918–929, 2013.


response system to 4 weeks of double-blind treatmentwith nebivolol and valsartan FDC, nebivolol only,valsartan only, or placebo (47). Doses were doubledduring weeks 5–8. At week 8, the FDC of nebivolol andvalsartan (20 and 320 mg/d) group had significantlygreater reductions in DBP from baseline than nebivolol at40 mg/d or valsartan at 320 mg/d. All other comparisonswere also significant, favoring the FDCs (all P,0.001).All SBP comparisons were also significant (all P,0.01).At least one treatment–emergent adverse event wasexperienced by 30%–36% of participants in each group.This study showed better efficacy and comparabletolerability of the FDC compared with monotherapy.This is the first publication of combination therapy ofa b-blocker and angiotensin II receptor blocker.

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Renal Denervation Update

The concept of catheter ablation of the renalsympathetic nerves or renal denervation (RDN) for thetreatment of hypertension was discussed in the priorNephSAP. The positive results of the SymplicityHTN-1 (1) and the Symplicity HTN-2 (2) Studies werealso discussed. Because the results of the SymplicityHTN-3 Trial have been published with surprisinglynegative results (3), multiple publications addressedpossible reasons explaining why this trial was negativein the face of prior positive results of this device-basedtherapy that had been obtained primarily from Europeand Australia. There have also been a number ofpublished studies that evaluated whether specific sub-groups experienced a greater benefit from RDN.

Update on the Symplicity HTN-1 StudyThe Symplicity HTN-1 Study was a nonrandom-

ized proof-of-concept study of RDN in subjects withresistant hypertension. The 36-month follow-up resultsof the Symplicity HTN-1 Study have been published(4) and demonstrated complete follow-up BP data on88 of 153 participants. Results showed significantdecreases in systolic BP (SBP) and diastolic BP (DBP;232.0 and 214.4 mmHg, respectively) at 36 months.One subject required renal artery stenting, and threedeaths unrelated to RDN occurred during follow-up.This study revealed that BP reductions in the Sym-plicity HTN-1 Study were durable for at least 36months.

Symplicity HTN-3 Study ResultsThe Symplicity HTN-3 Study was the first RDN

trial to be performed in the United States. This trialwas different from the prior trials, in that there wasa sham procedure in the control group (3). The studyenrolled 535 patients who met strict entry criteria forresistant hypertension and were randomized in a 2:1fashion to either the RDN procedure or the shamprocedure. The trial did not meet its primary efficacyend point, which was defined as a superiority marginof 5 mmHg for the difference in office SBP changefrom baseline to 6 months in the RDN group comparedwith the sham control group. Using office-based SBPat 6 months, there were SBP reductions of 14.1 and11.7 mmHg in the RDN and control arms, respec-tively. Although each group’s BP reduction frombaseline was statistically significant, the between-groupdifferences were not statistically significant. BP wasalso assessed using 24-hour ambulatory BP (ABP)monitoring. The change in 24-hour ABP was 26.8mmHg in the denervation group and24.8 mmHg in thesham procedure group, which was not statisticallysignificant. There were no significant differences insafety between the two groups.

Possible Reasons Why the Symplicity HTN-3Study Was Negative and What Seems to PredictResponse to RDN

Several key variables as shown in Figure 31 havebeen identified post hoc that were predictive of SBPresponse to RDN, including total number of ablationattempts and energy delivery in a four-quadrant pattern,higher baseline office SBP $180 mmHg, use of analdosterone antagonist, preserved kidney function atbaseline, and nonuse of vasodilators. White patientswho underwent RDN had a significantly greater changein office SBP than those receiving sham: 215.2 and28.6 mmHg, respectively (P¼0.01) (5).

Further evaluation has also shown that conflictingresults from the three Symplicity Studies may be dueto a number of issues, including differences in studydesign, patient characteristics, medication adherence,or efficacy of the RDN procedure. Although theSymplicity HTN-2 and the Symplicity HTN-3 Studieswere randomized, controlled trials, the SymplicityHTN-2 Study had a less rigorous study design, becausepatients did not undergo a sham procedure. Unlike theprior studies, there was also the possibility of a potentplacebo or Hawthorne effect in the control group of the







Symplicity HTN-3 Study. Other factors included thelarge percentage of patients whose antihypertensivemedications were changed during the follow-up pe-riod. Specifically, there were slightly more increases indose or number of medications in the sham group andmore decreases in dose or number of medications inthe RDN group (5). The Symplicity HTN-3 Study wasalso performed in a United States cohort with a higherproportion of African Americans than that of other trials;however, there were no racial differences in response tothe RDN procedure in the Symplicity HTN-3 Study, butAfrican Americans had a more potent response to thesham procedure than non-African Americans, a findingthat warrants further exploration (5).

Another area of focus in explaining the variedresults of these trials pertains to the RDN procedure

and the anatomic distribution and density of sympa-thetic nerves within the renal artery wall. There isa greater concentration of nerves in the proximal andmiddle segments of the renal artery, and the nervesin the distal segment are closer to the lumen andtherefore, more susceptible to ablation (6, 7). Thecircumferential distribution of nerves along the renalartery is also not uniform, and there are more nerves inthe ventral than dorsal regions. Therefore, asymmetricdelivery of radiofrequency energy is necessary forcomplete ablation (Figure 32). In the Symplicity Trials,the RDN procedure was performed by starting in thedistal segment of the artery, with successive ablationsapplied to the wall after rotating the catheter tipcircumferentially and withdrawing proximally. In theSymplicity HTN-3 Study, only 19 patients received

Figure 31. Selected subgroup analyses. Shown are between-group differences in the change in office SBP from baseline to 6months in selected subgroups. The body mass index is the weight in kilograms divided by the square of the height in meters.95% CI, 95% confidence interval. Reprinted with permission from Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, FlackJM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL;SYMPLICITY HTN-3 Investigators: A controlled trial of renal denervation for resistant hypertension. N Engl J Med 370: 1393–1401, 2014.


ablations in all four quadrants bilaterally (5). In thissmall group of patients, BP reduction was similar to thatobserved in prior trials. Given the complicated networkof nerves, there is likely a certain minimum number ofablations for the procedure to be effective; in theSymplicity HTN-3 Study, the number of ablation at-tempts during the procedure was associated with a greaterBP response to RDN, and a higher number of ablationsdid not increase the risk of adverse events.

The knowledge of renal nerve distribution andreduction in sympathetic activity has been ascertainedin studies using a porcine model. One study usedunilateral RDN in pigs to assess if different regions ofthe renal artery responded differently to RDN asassessed with renal norepinephrine (NE) levels. Thepigs were divided into three groups receiving RDNnear the ostium, RDN in the main renal artery near thebifurcation, or RDN in the extrarenal branches of therenal artery. After 2 weeks, the pigs were euthanized,renal cortex tissue was collected for NE measurement,and histology of the renal arteries was performed.Renal NE decreased by 12% with RDN at the ostium,45% with RDN near the bifurcation in the main renalartery, and 74% when RDN was performed inextrarenal artery branches. The number of renalnerves was found to be greatest in extrarenal branchesand the main artery compared with the ostium. Theaverage distance from the lumen was greatest fornerves at the ostium and least at the branches. Thisstudy demonstrated that RDN lowered renal NE levelsto a greater extent when performed in branches of the

renal artery closer to the kidney, most likely due togreater numbers of nerves located in the distal renalartery and branch arteries (8). Another study in pigsusing a bilateral RDN procedure with a bipolar radio-frequency system to deliver energy and achieve de-nervation (9) showed that application of bipolarradiofrequency energy along the entire length of therenal artery using 4-mm staggered electrodes witha temperature-controlled algorithm led to sufficientrenal nerve injury to reduce sympathetic function, asshown by changes in renal NE and tyrosine hydrox-ylase immunostaining.

Another issue to consider is proceduralist expe-rience level. In the Symplicity HTN-3 Study, proce-duralists lacked hands-on experience with RDN priorto the trial, and the majority of interventionists in theSymplicity HTN-3 Study performed fewer than threeprocedures in the trial (5). However, operator experi-ence level was not related to the BP response.

Twelve-Month Data from the Symplicity HTN-3Study

There has been recent publication of the 12-month follow-up data from the Symplicity HTN-3Study (10); 12-month follow-up was available for 319of 361 RDN subjects and 48 of 101 noncross-oversubjects, and 6-month denervation follow-up was avail-able for 93 of 101 cross-over subjects. In the subjectsundergoing RDN, the decrease in office SBP wasgreater at 12 months than at 6 months (218.9 and215.5 mmHg, respectively; P¼0.03), but 24-hour ABP

Figure 32.Distribution and density of renal sympathetic nerves. Distribution of nerves stratified according to total number (eachgreen dot represents 10 nerves), relative number as a percentage per segment, and distance from the lumen in relative (A)proximal, (B) middle, and (C) distal locations. Reprinted with permission from Mahfoud F, Edelman ER, Böhm M: Catheter-based renal denervation is no simple matter: Lessons to be learned from our anatomy? J Am Coll Cardiol 64: 644–646, 2014.


data did not demonstrate a significant difference at 12months. The noncross-over group had a significantdecrease in SBP at 6 months of 232.9 mmHg, but thereduction was less at 12 months, with mean SBPreduction of 21.4 mmHg. The smaller BP reductionobserved in the noncross-over group was attributed topossible nonadherence with medication (10).

Other Renal Denervation Studies

Predicting RDN ResponseThe European Network Coordinating Research

on Renal Denervation Database has also publisheddata on predictors of response to RDN (11). Theyidentified 109 extreme BP responders (first quintile)and nonresponders (fifth quintile) to RDN, definedaccording to office or 24-hour ABP in their network(11). They compared the baseline characteristics andBP changes 6 months after RDN in both subsets(11). In extreme responders (defined according toABP), baseline BP and BP changes 6 months afterRDN were similar for office and out of the office BP.However, when extreme responders were definedaccording to office BP, there was a large white coateffect at baseline, with a dramatic decrease in effect at6 months. Extreme responders, when defined accord-ing to office BP, were more frequently women withgreater baseline office BPs and eGFRs in comparisonto nonresponders. By contrast, when consideringABP measures to define extreme responders andnonresponders, the single relevant difference betweenboth subsets was baseline ABP. This study suggeststhat ABP readings should be used as a baseline toselect the appropriate subjects for RDN studies due tothe large white coat effect when using office BP. Theauthors also suggest that a greater response in womenmay reflect drug adherence (11).

RDN in Milder Resistant HypertensionA randomized study from Europe assessed the

effects of RDN in 71 patients with resistant hyperten-sion with mean daytime ambulatory SBPs of 143–144mmHg (12). Patients were assigned to RDN versussham procedure. Data were analyzed for both theintention-to-treat (ITT) analysis (all patients who un-derwent randomization irrespective of treatment re-ceived or protocol adherence) and the per protocolanalysis (included all patients who completed the entiretrial according to the study protocol). The mean change

in 24-hour SBP in the ITT cohort was not significantlyreduced at 6 months in the RDN versus sham group(27.0 versus 23.5 mmHg, respectively; P¼0.15). Inthe per protocol cohort, 24-hour SBPs were signifi-cantly reduced at 6 months in the RDN versus shamgroup (28.3 versus23.5 mmHg, respectively; P¼0.04).RDNwas effective at reducing BP at 6 months in patientswith mild resistant hypertension who completed thetreatment protocol per study design.

Another recently published trial from France is theRenal Denervation for Hypertension Trial that assessed,by ABP, the efficacy, safety, and cost-effectiveness ofRDN in resistant hypertension when added to a stan-dardized stepped–care antihypertensive treatment com-pared with standardized stepped–care treatment alone(13). The standardized treatment consisted of use ofthe combination of a diuretic, angiotensin–convertingenzyme inhibitor (ACEI) or angiotensin II receptorblocker (ARB), and dihydropyridine calcium channelblocker (indapamide, 1.5 mg; ramipril, 10 mg [orirbesartan, 300 mg]; and amlodipine, 10 mg daily).Patients were recruited from 15 French tertiary carehypertension centers with physicians experienced inRDN using the Medtronic catheter. After 4 weeks ofstandardized triple therapy, 106 patients with ABP–confirmed resistant hypertension were randomly as-signed to the RDN (n¼53) or the control group(n¼53). After randomization, spironolactone at25 mg/d, bisoprolol at 10 mg/d, prazosin at 5 mg/d,and rilmenidine at 1 mg/d were sequentially added frommonths 2–5 in both groups if home BP was $135/85mmHg. At 6 months, the RDN group with standardizedtriple therapy had a significantly greater reduction ofdaytime and nighttime SBPs as measured by ABP(6 mmHg). The number of antihypertensive drugs anddrug adherence at 6 months were similar between thetwo groups. There were three minor RDN–relatedadverse events, including lumbar pain in two patientsand mild groin hematoma in one patient. A mild andsimilar decrease in eGFR from baseline to 6 monthswas observed in both groups.

RDN in Isolated Systolic HypertensionA study from Europe analyzed the effects of

RDN on isolated systolic hypertension (ISH) (14) in126 patients divided into 63 patients with ISH and 63patients with combined hypertension (CH) defined as bothelevated SBP and elevated DBP ($140/$90 mmHg).The subjects included were part of the Global Symplicity


Registry (GSR), a prospective study to assess safetyof RDN. Patients had office ABP measurements at 3,6, and 12 months. RDN significantly reduced officeSBP and DBP at 3, 6, and 12 months in both ISH andCH, but there was less reduction in the patients withISH at all time points. There were more nonresponders(change in office SBP ,10 mmHg) after 6 months inthe ISH group than in the CH group. Mean 24-hourABP was significantly reduced at all time points inCH; however, in ISH using ABP, the SBP was onlysignificantly reduced at 3 and 12 months, and it wasreduced only at 12 months for DBP. This studyconcluded that RDN did reduce office BP and ABPin patients with ISH; however, the reduction was lesspronounced compared with that in patients with CH.

The Global Symplicity RegistryThe GSR is a prospective, open–label, multicen-

ter registry of patients who underwent an RDN pro-cedure using the Symplicity catheter without anenrollment trial (15). The only inclusion criterion wasage$18 years old, and eligibility for RDN was definedby local regulations for use of the Symplicity RDNsystem. Data collected include office and 24-hour ABPs.Six-month follow-up data reported so far include998 patients with 323 in the severe hypertension group(office SBP $160 mmHg, 24-hour ABP $135 mmHg,and three or more antihypertensive medication clas-ses). Mean baseline office SBP was 163.5 mmHg forall patients and 179.3 mmHg for the severe hyper-tension group, with corresponding baseline 24-hourmean SBPs of 151.5 and 159 mmHg, respectively.At 6 months, changes in office and 24-hour ABPs were211.6 and 26.6 mmHg, respectively, for all patients(P,0.001 for both) and 220.3 and 28.9 mmHg,respectively, for those with severe hypertension(P,0.001 for both). For both office and 24-hour SBPs,the 6-month reduction was greater in patients withhigher baseline SBP values. The mean SBP reductionin the severe hypertension group of 20.3 mmHg after 6months was statistically significant and greater than thereduction observed in the Symplicity HTN-3 Study(15). The SBP reduction was accompanied by a smallbut significant reduction in antihypertensive medicationuse. The GSR also had low rates of adverse events fromRDN to 6 months with one new renal artery stenosis.70% and pseudoaneurysm and five patients requir-ing hospitalization for hypertensive emergency. Renalfunction was not affected by the RDN procedure. In the

GSR, 59% of the operators had performed .15 RDNprocedures even before the registry started in contrastto the Symplicity HTN-3 Trial, where 50% of operatorsperformed less than or equal to two RDN proceduresduring the study. The average number of complete 120-second ablations in the severe hypertension cohort inthe registry was 13.7, whereas it was only 9.2 in theSymplicity HTN-3 Trial. This may account for thedifferences in efficacy between the registry data andthe Symplicity HTN-3 Trial.

Safety of Renal Denervation

RDN in the hands of experienced operatorsseems to be safe. In the Symplicity HTN-3 Study,the study did meet its primary safety end point. Renalfunction was not adversely affected. Patients withpreexisting renovascular abnormalities have been ex-cluded from the Symplicity HTN Trials, but there havebeen a number of reports of de novo renal arterystenosis discovered during follow-up that were notoriginally reported in the results of the trials (16–18).

The Future of Renal Denervation

There are other catheter–based systems under-going evaluation, including the use of ultrasound ina thermal gel model to achieve RDN. There are at leastfour RDN studies underway using different technolo-gies and catheter designs but with almost identicalstudy designs. There will be off medication and onmedication groups in most of these ongoing studies.Subjects will be randomized to RDN versus a shamprocedure based on the Symplicity HTN-3 Trial design.Medtronic will be conducting the SPYRAL HTNGlobal Clinical Trial in the United States, Europe,Australia, and Japan. The trial will consist of tworandomized, sham–controlled trials, SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, and patientswill be followed for 3 years after RDN. The HTN-OFFMED Study is designed to isolate the BP-loweringeffect of the RDN procedure, and the HTN-ON MEDStudy will evaluate the effect of RDN in the presence ofa standardized antihypertensive medication regimenconsisting of a triple combination of an ACEI orARB, thiazide diuretic, and calcium channel blocker.These medications do not need to be prescribed atmaximal dosing. This study will also utilize a newer,multielectrode catheter (Spyral) to reduce procedure


duration and allow for the simultaneous and uniformdelivery of radiofrequency energy in four quadrants,and it has the ability to ablate both distal segments andbranch renal arteries (http://www.spyralhtntrials.com/us/trials/on-med/index.htm; http://www.spyralhtntrials.com/us/trials/off-med/index.htm). The trial will alsoinclude patients with more moderate hypertension withan entry office SBP of 150–180 mmHg in both the onand off medication groups. This is likely based on datafrom the two randomized, controlled trials that havedemonstrated a benefit of RDN in patients with lesssevere hypertension (12,13). The results of the BPresponses in RDN studies are shown in Figure 33 (19).A statement by Weber et al. (20) suggests that futurestudies should be guided by the established random-ized, controlled clinical designs used for the study ofantihypertensive drugs and other treatments for hyper-tension. They make the following suggestions whendesigning future RDN trials (20).

(1) The fundamental evaluation of RDN must be to testwhether the BP-lowering efficacy in hypertensivepatients is significantly greater than that of placebo(sham procedure in this case) and whether theprocedure is safe.

(2) Because the studies are trying to determine efficacyof RDN for BP reduction, patients included in thesestudies should have higher SBPs in the range of150–80 mmHg at baseline off medication.

(3) If subjects are randomized to sham, there should bea limited duration of this study period before theyare able to receive active medication to minimizecardiovascular risk. They suggest a period of 2months as reasonable (20).

(4) The primary end point of these trials should be thedifference in achieved SBPs between the interven-tion and control groups measured by ABP moni-toring after 2 months.

(5) After the important secondary end points are reachedat about 6 months of blinded follow-up, the study canbe unblinded, but patients who have received activedenervation must be followed for a considerable timeafterward to evaluate long-term safety.

(6) A sequence of drugs (that are added during the trialperiod) should be followed to minimize differencesin responses among patients of different ethnicities,ages, and dietary intake.

(7) Prior to enrollment in the study, patients in the onmedication arm could receive a standardized two– or

three–drug regimen. A two-drug regimen wouldlikely comprise an ACEI or an ARB in combinationwith a thiazide (or a calcium channel blocker). Thistwo-drug regimen should achieve control of BP inmost people with hypertension, including those withstage 2 hypertension. Thus, patients whose SBPsremain in the range of 150–180mmHg on this regimenlegitimately represent a challenge in hypertensivemanagement and possibly, an appropriate patientgroup for this type of trial. It is critical that the trialprotocol specifies exactly the two-drug regimen. Pref-erably, this therapy should be provided by the trialsponsor to investigators and patients to ensure treat-ment consistency and facilitate medication adherence.

(8) If a three-drug regimen is used, the agents should bean ACEI or ARB, a thiazide diuretic, and a cal-cium channel blocker in maximum doses. Ifa patient is taking such a regimen and SBP remainssignificantly elevated in the range of 150–180mmHg, this would meet the criteria for treatment-resistant hypertension. The proportion of treatment-resistant individuals would represent only a smallfraction (,10%) of the total hypertension population,and finding patients taking three-drug regimens in thecommunity who satisfy the entry criteria for sucha trial could prove difficult. Preferably, the trial shouldreplace medications with a standardized three–drugprotocol, preferably contained within a single tablet.

(9) It is essential that investigators and staff selectedto conduct these trials are experienced in hyper-tension research and that the interventionalistsperforming the denervation procedures have con-siderable experience performing coronary andperipheral artery interventions; they should re-ceive adequate training regarding the techniquesto be used in the trials.

Other Approaches for Renal Denervation

Ethanol-Based Sympathicolysis of Renal NervesA novel noncatheter–based approach has been devel-oped using image–guided transarterial circumferentialinjection of dehydrated ethanol around the renal arteryto achieve renal sympathetic denervation. Using anadult porcine model, a novel three–needle deliverydevice was introduced into the renal arteries usingfluoroscopic guidance. Ethanol was injected bilaterallywith one injection per artery using the three needlesinto the adventitial and periadventitial space using three


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different ethanol doses with saline injection as a shamcontrol. Three swine received ethanol, and sevenreceived saline injections. The mean renal parenchymalNE concentration at 2 weeks was reduced by 54%–88%in a dose-dependent manner. Histological examinationrevealed circumferential renal nerve injury at depthsof 2–8 mm from the intimal surface. There were nodevice-related or ethanol-induced injuries. Angiogra-phy at 45 days demonstrated normal–appearing renalarteries with no detectable stenoses (n¼8) (22).Streitparth and colleagues reported a case of refractoryhypertension in a 50-year-old man with ESRD treatedwith computed tomography–guided percutaneous peri-arterial ethanol sympathicolysis, with a decrease of29/14 mmHg in BP at 1 month. The procedure wasperformed without complications (23).

Extracorporeal High–Intensity FocusedUltrasound

Noninvasive RDN using extracorporeal high–intensity focused ultrasound has been tested in dogsusing a sham control. This technology did show reduc-tions in BP and noradrenaline concentrations comparedwith baseline, with no significant change observed in thesham control group. Histopathologic examination alsodemonstrated nerve fiber disruption at day 28 after RDN

(24). This technology (KonaMedical’s ultrasound-basedRDN) is now being tested in humans.

Baroreflex Activation Therapy

Previous trials have shown substantial BP reduc-tions using baroreflex activation therapy (BAT) inpatients with resistant hypertension (25, 26), but BAThas not been met with wide clinical enthusiasm. TheRheos Baroreflex Hypertension System is a device thatrequires bilateral surgeries with implantation of elec-trodes around both carotid arteries at the locationwhere the greatest response on stimulation is observed.The invasiveness of the procedure, the short batterylife, and the procedure complication rate make thisa potentially unattractive option for patients. A secondgeneration system of BAT (Barostim neo) has beendesigned and requires implantation of a single elec-trode at one carotid site, thereby reducing the surgicalprocedure and possible complications. The Barostimdevice also has a smaller battery with an extendedlifespan of about 3 years. A nonrandomized proof-of-concept study using this device enrolled 30 patientswith treatment-resistant hypertension and showeda 26/12.4-mmHg BP reduction at 6 months. Therewere three perioperative complications and one long–

Figure 33. Recent studies of the effects of RDN with various catheters on BP. ABPM, ambulatory BP monitoring; ACHIEVE,presented in abstract form see reference 21; ENCOREd, EuropeanNetwork Coordinating Research on Renal Denervation; EnligHTN1,multielectrode renal denervation system; RAPID, rapid renal sympathetic denervation for resistant hypertension using the MayaMedical OneShot ablation system; REDUCE-HTN, renal denervation using the Vessix renal denervation system for the treatment ofhypertension; TIVUS, Therapeutic Intravascular Ultrasound catheter System; TRH, Treatment Resistant Hypertension. Reprintedwith permission from Oparil S, Schmieder RE: New approaches in the treatment of hypertension. Circ Res 116: 1074–1095, 2015.


term procedure–related complication (27). There isa new study that is currently enrolling using the newdevice called the Barostim Hypertension Pivotal Trial(NCT01679132; http://www.cvrx.com/usa/healthcare/hypertension/clinical-trials/). A recently published studyexplored whether unilateral BAT stimulation wouldproduce comparable BP reductions as bilateral stim-ulation using the data from patients enrolled in theRheos Pivotal Trial (26). This trial enrolled treatment–resistant hypertensive patients who were randomizedto receive either immediate BAT or deferred BAT 6months after implantation. During the trial, parameterswere adjusted to achieve optimal baroreflex activation.Unilateral stimulation was applied unless bilateralstimulation resulted in a greater BP reduction. The6-month data were pooled for the group with imme-diate BAT, and the 12-month data were pooled for thegroup with deferred BAT. Data showed that 80patients were stimulated bilaterally and that 215patients had been stimulated on one side only (127at the right side and 88 at the left side) (28). Pooleddata results show that BP and heart rate did not differbetween the two groups at baseline; however, BP andheart rate were significantly lower in the unilateralthan in the bilateral group after the 6-month period.They also compared the effects of right-sided stimu-lation with the effects of either left-sided or bilateralstimulation (28). Right-sided stimulation was found tobe the most effective. The authors concluded that BATproduced a greater effect with unilateral than bilateralstimulation in treatment-resistant hypertension, withunilateral right–sided BAT seeming to be more effec-tive than bilateral or left-sided BAT (28). These datasuggest that the left and right carotid systems maybehave differently, and therefore, future research isneeded to assess whether both sides act in concert witheach other or independently. Another recent studyinvestigated whether there is concomitant carotidchemoreflex activation during BAT using the Rheossystem. Fifteen patients from a single center who hadthe device implanted underwent a standardized testwith high– and low–electric activation settings (thedevice was switched off for 2 hours while patientswere at rest, and the device was switched on at sixelectric settings of high and low frequencies andamplitudes), and cardiovascular and respiratory changeswere observed during each setting. Measures of forcedexpiratory volume in 1 second were also performedbefore and after turning off the device. There were no

changes in any respiratory measure, but the meanarterial pressure showed a highly significant decreaseduring electric activation (P,0.001), suggesting thatthere is no appreciable coactivation of carotid bodychemoreceptors during device therapy (29).

The Effects of Chronic Aldosterone Infusion onBaroreflex Activation Therapy and Renal Denervation

Despite the global and renal-specific suppression ofsympathetic activity with RDN and BAT, it is not clearwhich patients with resistant hypertension will respond tothese technologies. Many patients with resistant hyper-tension also have inappropriately high plasma levels ofaldosterone. A study was performed to investigate theeffects of BAT and surgical RDN in dogs with super-imposed hypertension induced by the chronic aldoste-rone infusion. During BAT or RDN alone, BP and NElevels were reduced; after 14 days of chronic aldosteroneinfusion (with increases of aldosterone levels from4.360.4 to 70.066.4 ng/dl) and simultaneous BAT,NE levels remained similarly reduced, but the fall in BPwas significantly diminished. RDN also did not reduceBP levels under these conditions. This is an interestingstudy invoking the suggestion that patients with aldoste-rone excess may have a diminished BP–lowering re-sponse to either BAT or RDN.

Arteriovenous Fistula for Hypertension

A novel mechanistic approach to BP reductionuses a self-expanding device that creates a 4-mmarteriovenous fistula (AVF) between the iliac arteryand vein and generates a sustained calibrated shuntvolume of approximately 800 ml/min within a shortperiod of time (30). This ROX Coupler System (ROXMedical Inc., San Clemente, CA) reduces vascularresistance and increases arterial compliance, resultingin immediate and substantial reduction of SBP andDBP (31). The system was originally developed fortreatment of chronic obstructive pulmonary diseasepatients and is commercially available for use inEurope. The proposed mechanism of action includesa reduction in total systemic vascular resistance,increase in cardiac volumes, and reduction in afterload,resulting in an overall reduction in cardiac work,despite increased cardiac output. Improvements inarterial oxygen content may accompany this increasein cardiac output, resulting in an increase in tissue


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oxygen delivery, thereby reducing the hypertensiveactions of a number of neurohumoral mechanisms,including peripheral and renal chemoreceptors thatdrive sympathetic overactivation. The reduction insystemic vascular resistance and decrease in effectivearterial volume seen after the system is implantedresult in improved vascular compliance with a reduc-tion in the reflected pulse wave that reduces cardiacwork (19). The potential mechanisms for the BPreduction are displayed in Figure 34. Initial positiveresults in COPD patients extended the indication topatients with COPD and superimposed arterial hyper-tension. BP was reduced in subjects with COPD;however, no BP reduction was seen in the normoten-sive patients with COPD. These data were derived froma subset of 24 hypertensive COPD patients with officeSBP $130 mmHg during antihypertensive treatmentwho had undergone the ROX procedure. The BP wassignificantly reduced from 145/86 mmHg at baseline to130/71 and 132/67 mmHg at 6 and 12 months, re-spectively (P,0.01) (30). Based on this retrospectiveanalysis, eight non-COPD patients with treatment-resistant hypertension underwent ROX Coupler Sys-tem therapy in a nonrandomized study. Baseline officeBP and the 24-hour ABP (175/87 and 158/74 mmHg,respectively) were significantly decreased at 6 months(152/82 versus 142/69 mmHg) (31). A prospective,nonblinded, randomized study from Europe called theMulticenter ROX CONTROL-HTN Study was per-formed in 100 non-COPD patients who had treatment-resistant hypertension on drug therapy. The trial alsoincluded patients who had failed RDN. Patients wererandomly assigned in a 1:1 ratio to undergo implan-tation of the AVF coupler device plus current an-tihypertensive medications versus maintenance ofantihypertensive therapy alone. The primary end pointwas the mean change from baseline in office BP and24-hour ambulatory SBP at 6 months. Analysis wasby modified ITT, with all patients remaining infollow-up at 6 months; 44 patients received the AVFcoupler therapy, and 39 were continued on usual care.Mean office SBP was reduced by 27 mmHg in theAVF coupler group (P,0.001) and 3.7 mmHg in thecontrol group (P¼0.31). Mean 24-hour ambulatorySBP was reduced by 13.5 mmHg (P,0.001) in theAVF coupler group and 0.5 mmHg (P¼0.86) in thecontrol group. The AVF coupler was associated withlate ipsilateral venous stenosis in 12 of the 42 patientstreated by venoplasty or stenting. Five admissions

occurred in three of the 39 patients in the control groupcompared with none in the arteriovenous coupler group(P¼0.02) (32). The ROX coupler represents a novelapproach to resistant hypertension when other treatmentoptions have been exhausted. The procedure is associ-ated with a fairly high incidence of complications at6 months. The long-term consequences of having achronic AVF require longitudinal evaluation.

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13. Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G, Delsart P, MidullaM, Mounier-Véhier C, Courand PY, Lantelme P, Denolle T, Dourmap-Collas C, Trillaud H, Pereira H, Plouin PF, Chatellier G; RenalDenervation for Hypertension (DENERHTN) investigators: Optimumand stepped care standardised antihypertensive treatment with orwithout renal denervation for resistant hypertension (DENERHTN): Amulticentre, open-label, randomised controlled trial. Lancet 385: 1957–1965, 2015 PubMed

14. Ewen S, Ukena C, Linz D, Kindermann I, Cremers B, Laufs U,Wagenpfeil S, Schmieder RE, Böhm M, Mahfoud F: Reducedeffect of percutaneous renal denervation on blood pressure inpatients with isolated systolic hypertension. Hypertension 65:193–199, 2015 PubMed

15. Böhm M, Mahfoud F, Ukena C, Hoppe UC, Narkiewicz K, Negoita M,Ruilope L, Schlaich MP, Schmieder RE, Whitbourn R, Williams B,Zeymer U, Zirlik A, Mancia G; GSR Investigators: First report of theGlobal SYMPLICITY Registry on the effect of renal artery denervationin patients with uncontrolled hypertension. Hypertension 65: 766–774,2015 PubMed

16. Bacaksiz A, Uyarel H, Jafarov P, Kucukbuzcu S: Iatrogenic renal arterystenosis after renal sympathetic denervation. Int J Cardiol 172: e389–e390, 2014 PubMed

17. Jaén Águila F, Mediavilla García JD, Molina Navarro E, Vargas HitosJA, Fernández-Torres C: Bilateral renal artery stenosis after renaldenervation. Hypertension 63: e126–e127, 2014 PubMed

18. Kaltenbach B, Id D, Franke JC, Sievert H, Hennersdorf M, Maier J,Bertog SC: Renal artery stenosis after renal sympathetic denervation. JAm Coll Cardiol 60: 2694–2695, 2012 PubMed

19. Oparil S, Schmieder RE: New approaches in the treatment of hyper-tension. Circ Res 116: 1074–1095, 2015 PubMed

20. Weber MA, Kirtane A, Mauri L, Townsend RR, Kandzari DE, Leon MB:Renal denervation for the treatment of hypertension: Making a newstart, getting it right. J Clin Hypertens (Greenwich) 17: 743–750,2015 PubMed

21. Zeller T, Andersson B, BohmM, Kuck KH, Sievert H, Graf T et al. TheParadise renal denervation system: initial clinical results from theACHIEVE study. EuroPCR 14A-OP205, 2014 PubMed

22. Fischell TA, Vega F, Raju N, Johnson ET, Kent DJ, Ragland RR, FischellDR, Almany SL, Ghazarossian VE: Ethanol-mediated perivascular renalsympathetic denervation: Preclinical validation of safety and efficacy ina porcine model. EuroIntervention 9: 140–147, 2013 PubMed

23. Streitparth F, Gebauer B, Nickel P, Reinke P, Freyhardt P, Wieners G,Hamm B, Günther RW: Percutaneous computer tomography-guidedethanol sympathicolysis for the treatment of resistant arterial hyperten-sion. Cardiovasc Intervent Radiol 37: 513–518, 2014 PubMed

24. Wang Q, Guo R, Rong S, Yang G, Zhu Q, Jiang Y, Deng C, Liu D,Zhou Q, Wu Q, Wang S, Qian J, Wang Q, Lei H, He TC, Wang Z,Huang J: Noninvasive renal sympathetic denervation by extracorporealhigh-intensity focused ultrasound in a pre-clinical canine model. J AmColl Cardiol 61: 2185–2192, 2013 PubMed

Figure 34. Potential mechanisms for the reduction in BP seen after the creation of a fixed central arteriovenous (AV)anastomosis using the ROX Coupler. ANP, atrial naturetic peptide. Reprinted with permission from Burchell AE, Lobo MD,Sulke N, Sobotka PA, Paton JF: Arteriovenous anastomosis: Is this the way to control hypertension? Hypertension 64: 6–12,2014.
















25. Scheffers IJ, Kroon AA, Schmidli J, Jordan J, Tordoir JJ, Mohaupt MG,Luft FC, Haller H, Menne J, Engeli S, Ceral J, Eckert S, Erglis A,Narkiewicz K, Philipp T, de Leeuw PW: Novel baroreflex activationtherapy in resistant hypertension: Results of a European multi-centerfeasibility study. J Am Coll Cardiol 56: 1254–1258, 2010 PubMed

26. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J,de Leeuw PW, Sica DA: Baroreflex activation therapy lowers bloodpressure in patients with resistant hypertension: Results from thedouble-blind, randomized, placebo-controlled rheos pivotal trial. J AmColl Cardiol 58: 765–773, 2011 PubMed

27. Hoppe UC, Brandt MC, Wachter R, Beige J, Rump LC, Kroon AA,Cates AW, Lovett EG, Haller H: Minimally invasive system forbaroreflex activation therapy chronically lowers blood pressure withpacemaker-like safety profile: Results from the Barostim neo trial. J AmSoc Hypertens 6: 270–276, 2012 PubMed

28. de Leeuw PW, Alnima T, Lovett E, Sica D, Bisognano J, Haller H,Kroon AA: Bilateral or unilateral stimulation for baroreflex activationtherapy. Hypertension 65: 187–192, 2015 PubMed

29. Alnima T, Goedhart EJ, Seelen R, van der Grinten CP, de Leeuw PW,Kroon AA: Baroreflex activation therapy lowers arterial pressurewithout apparent stimulation of the carotid bodies. Hypertension 65:1217–1222, 2015 PubMed

30. Faul J, Schoors D, Brouwers S, Scott B, Jerrentrup A, Galvin J, LuitjensS, Dolan E: Creation of an iliac arteriovenous shunt lowers bloodpressure in chronic obstructive pulmonary disease patients withhypertension. J Vasc Surg 59: 1078–1083, 2014 PubMed

31. Burchell AE, Lobo MD, Sulke N, Sobotka PA, Paton JF: Arteriovenousanastomosis: Is this the way to control hypertension? Hypertension 64:6–12, 2014 PubMed

32. Lobo MD, Sobotka PA, Stanton A, Cockcroft JR, Sulke N, Dolan E,van der Giet M, Hoyer J, Furniss SS, Foran JP, Witkowski A,Januszewicz A, Schoors D, Tsioufis K, Rensing BJ, Scott B, Ng GA,Ott C, Schmieder RE; ROX CONTROL HTN Investigators: Centralarteriovenous anastomosis for the treatment of patients with uncon-trolled hypertension (the ROX CONTROL HTN study): A randomisedcontrolled trial. Lancet 385: 1634–1641, 2015 PubMed

Hypertension in the Elderly and Cognition

Hypertension and cognitive impairment are prev-alent in the elderly. Hypertension is present in approx-imately 60% of adults older than 60 years old, anddementia affects 6%–8% of adults 60 years old or olderand about 25% of adults 85 years old or older (1). Mildcognitive impairment (MCI) that may herald the de-velopment of overt dementia is also common, with anestimated prevalence of 25% in adults 65 years old orolder (2). The results of studies on the associationbetween hypertension and dementia are contradictory.There is concern regarding lowering BP, diastolic BP(DBP) in particular, in the elderly and increasing risk ofdementia and MCI. There is some evidence to suggesta potential J– or U–shaped relationship between DBPand risk of cognitive impairment. There are a numberof recent studies assessing the effects of BP lowering,with a focus on systolic BP (SBP), DBP, and BPvariability and the effects of these on cognitive function.

One such study assessed both office and ambula-tory BP and the use of antihypertensive medicationsand whether this helped predict cognitive decline inelderly patients with baseline dementia or MCI (3).Subjects were recruited from two outpatient memoryclinics and had a median follow-up of 9 months.Cognitive decline was defined as a change in Mini-Mental State Examination score between baseline andfollow-up. The study included 172 elderly patients witha mean age of 79 years old. At baseline, 68% of patientshad dementia, and 32% had MCI; 70% of patientswere treated with antihypertensive medications.Patients in the lowest tertile of daytime SBP(SBP#128 mmHg) showed a greater Mini-MentalState Examination score change compared withpatients in the intermediate tertile (SBP¼129–144mmHg; P¼0.002) and patients in the highest tertile(SBP$145mmHg; P¼0.003). Low daytime SBP wasindependently associated with a greater progressionof cognitive decline in older patients with dementiaand MCI among those treated with antihypertensivemedications. This study shows that excessive loweringof SBP with the use of antihypertensive medicationmay be harmful for older patients with cognitiveimpairment and that use of ambulatory BP monitoringmay be helpful to avoid overtreatment of hypertensionin the elderly.

Another study also assessed 24-hour ambulatoryBP, office BP, and cognitive function in 319 community–living older adults (4). Cognitive function was assessedusing the Montreal Cognitive Assessment. The meanage was 72 years old, 66% were women, and 13% wereAfrican American. The authors performed linear re-gression with performance on the Montreal CognitiveAssessment as the primary outcome and 24-hour BPpatterns as the independent variable, adjusting forage, sex, race, education, and comorbidities (4).Greater nighttime systolic dipping (P¼0.05) andhigher 24-hour DBP (P¼0.02) were both signifi-cantly associated with better cognitive function.There was no association between cognitive functionand 24-hour SBP, BP variability, and ambulatoryarterial stiffness. The study showed that greaternighttime systolic dipping and higher 24-hour DBPwere associated with better cognitive function. Thestudy suggests that low 24-hour DBP and nondip-ping status may predict future cognitive impairment.

Another study assessed whether patients withtype 2 diabetes mellitus had a reduced risk of cognitive










decline and total brain volume at 40 months withintensive treatment for hypertension and combinationlipid therapy (statin plus fibrate) (5). This multicenterstudy included 2977 patients with type 2 diabetes(A1c,7.5%) and no baseline cognitive impairmentor dementia. Patients were randomized to SBP,140versus ,120 mmHg. Cognition was assessed at base-line and 20 and 40 months. A subset of 503 participantsunderwent baseline and 40-month brain magneticresonance imaging to assess for change in total brainvolume. Baseline mean A1c level was 8.3%; mean agewas 62 years old, and mean duration of type 2 diabeteswas 10 years. At 40 months, there was no difference incognitive function in the intensive BP–lowering arm;however, total brain volume had declined more inthe intensive versus standard BP–lowering group(P¼0.01). The authors concluded that intensive BPcontrol did not have any effect on cognitive decline at40 months; however, intensive BP control was associ-ated with greater decline in total brain volume at 40months (5).

The Prospective Study of Pravastatin in theElderly at Risk was conducted in the United Kingdomand Europe to assess the effects of BP variabilityon cognitive decline (6). The study enrolled 5461participants with mean age of 75.3 years old andincreased cardiovascular risk. BP was measured every3 months during an average of 3.2 years. Visit to visitvariability in BP was defined as the SD of BPmeasurements between visits. Participants with highervisit to visit variability in SBP had worse performanceon all cognitive tests, including attention, processingspeed, and immediate and delayed memory. HigherBP variability was also associated with lower hip-pocampal volume and cortical infarcts, and highervariability in DBP was associated with cerebralmicrobleeds (all P,0.05). The study showed thathigher visit to visit variability in BP independent ofmean BP was associated with impaired cognitivefunction in the elderly.

Excessive lowering of SBP with the useantihypertensive medication may beharmful for older patients with cognitiveimpairment, and use of ambulatory BPmonitoring may be helpful to avoid over-treatment of hypertension in the elderly.

An analysis of incident dementia from theHypertension in the Very Elderly Trial included 3845participants, of whom 263 developed incident de-mentia after a follow-up period of 2.2 years (7). Thisstudy included hypertensive patients (SBP¼160–199mmHg) of at least 80 years old who were randomizedto active treatment (indapamide sustained release of1.5 mg with or without perindopril at 2–4 mg) versusplacebo to attain a goal BP of 150/80 mmHg. Incidentdementia was a secondary end point and was notsignificantly different between the two treatment groups.However, after adjustment for various covariates,baseline DBP was inversely related to incident de-mentia (P,0.01). Achieved DBP did not predict laterdementia in the placebo group (P¼0.43) but didshow a U-shaped relationship in the active treatmentgroup (P¼0.02). SBP was not associated with in-cident dementia at baseline (P¼0.62) or duringfollow-up in the placebo and active treatment groups.Wider pulse pressure (PP), however, was associatedwith an increased risk of dementia in both treatmentgroups (placebo, P¼0.03; active, P,0.01) and forbaseline PP (P¼0.10) (Figure 35). Wider PP mayindicate an increased risk for dementia. Therefore,overtreatment of the elderly with overaggressiveDBP lowering may increase the risk of cognitivedecline and dementia.

Lastly, a prospective study from the Women’sHealth Initiative Memory Study investigated the re-lationship of hypertension, antihypertensive treatment,and sodium intake on cognitive decline in older women(8). The study enrolled 6426 cognitively intact womenages 65–79 years old with a median follow-up of 9.1years. Cognitive functioning was assessed annuallyby global cognitive screening and neurocognitiveand neuropsychiatric evaluations. Results of thestudy showed that women receiving antihyperten-sive treatment with uncontrolled BP (.140/90mmHg) had the highest risk for cognitive decline.Sodium intake did not modify the risk for cognitivedecline in women.

In summary, these studies reveal increased riskfor cognitive decline and dementia in the elderlywith uncontrolled BP. Using antihypertensive med-ication to excessively lower BP, particularly DBP,may be harmful in the elderly, and one study actu-ally demonstrated a U-shaped relationship with DBPand cognitive decline. Lower 24-hour DBP, greaterPP, and nondipping status are also predictive of


cognitive decline, and intensive BP lowering is notprotective and may actually result in structural brainchanges and lower total brain volumes. Also in-terestingly, higher visit to visit variability in SBPindependent of baseline BP resulted in poorer perfor-mance on cognitive testing as well as structural brainchanges. These studies seem to indicate from a clinicalviewpoint that the physician should be cautiousregarding overtreatment of the elderly by aggressiveDBP lowering, because this may increase risk ofcognitive decline and dementia. The ongoing SystolicBlood Pressure Intervention Trial will increase ourknowledge in this area (9). This study has enrolledapproximately 9300 subjects older than 50 years oldwith CKD or cardiovascular risk factors and random-ized subjects to an SBP goal of ,120 or,140 mmHg.Extensive cognitive testing and brain imaging are beingconducted over a 5-year period.

References1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP: The

global prevalence of dementia: A systematic review and metaanalysis.Alzheimers Dement 9: 63–75.e2, 2013

2. Ward A, Arrighi HM, Michels S, Cedarbaum JM: Mild cognitiveimpairment: Disparity of incidence and prevalence estimates. AlzheimersDement 8: 14–21, 2012 PubMed

3. Mossello E, Pieraccioli M, Nesti N, Bulgaresi M, Lorenzi C, Caleri V,Tonon E, Cavallini MC, Baroncini C, Di Bari M, Baldasseroni S, CantiniC, Biagini CA, Marchionni N, Ungar A: Effects of low blood pressure incognitively impaired elderly patients treated with antihypertensive drugs.JAMA Intern Med 175: 578–585, 2015 PubMed

4. Conway KS, Forbang N, Beben T, Criqui MH, Ix JH, Rifkin DE:Relationship between 24-hour ambulatory blood pressure and cognitive

function in community-living older adults: The UCSD AmbulatoryBlood Pressure Study. Am J Hypertens 28: 1444–1452, 2015 PubMed

5. Williamson JD, Launer LJ, Bryan RN, Coker LH, Lazar RM, GersteinHC, Murray AM, Sullivan MD, Horowitz KR, Ding J, Marcovina S,Lovato L, Lovato J, Margolis KL, Davatzikos C, Barzilay J, GinsbergHN, Linz PE, Miller ME; Action to Control Cardiovascular Risk inDiabetes Memory in Diabetes Investigators: Cognitive function and brainstructure in persons with type 2 diabetes mellitus after intensive loweringof blood pressure and lipid levels: A randomized clinical trial. JAMAIntern Med 174: 324–333, 2014 PubMed

6. Sabayan B, Wijsman LW, Foster-Dingley JC, Stott DJ, Ford I, BuckleyBM, Sattar N, Jukema JW, van Osch MJ, van der Grond J, van BuchemMA,Westendorp RG, de Craen AJ, Mooijaart SP: Association of visit-to-visit variability in blood pressure with cognitive function in old age:Prospective cohort study. BMJ 347: f4600, 2013 PubMed

7. Peters R, Beckett N, Fagard R, Thijs L, Wang JG, Forette F, Pereira L,Fletcher A, Bulpitt C: Increased pulse pressure linked to dementia:Further results from the Hypertension in the Very Elderly Trial -HYVET. J Hypertens 31: 1868–1875, 2013 PubMed

8. Haring B, Wu C, Coker LH, Seth A, Snetselaar L, Manson JE,Rossouw JE, Wassertheil-Smoller S: Hypertension, dietary sodium,and cognitive decline: results from the Women’s Health InitiativeMemory Study [published online ahead of print July 1 , 2015]. Am JHypertens PubMed

9. Ambrosius WT, Sink KM, Foy CG, Berlowitz DR, Cheung AK,Cushman WC, Fine LJ, Goff DC Jr., Johnson KC, Killeen AA, LewisCE, Oparil S, Reboussin DM, Rocco MV, Snyder JK, WilliamsonJD, Wright JT Jr., Whelton PK; SPRINT Study Research Group: Thedesign and rationale of a multicenter clinical trial comparing twostrategies for control of systolic blood pressure: The Systolic BloodPressure Intervention Trial (SPRINT). Clin Trials 11: 532–546,2014 PubMed

Stroke Update

Systolic BP (SBP) remains the most modifiablerisk factor for stroke (1). Having a stroke increases therisk for recurrent strokes (2). There have been several

Figure 35. Two-year dementia risk (percentage) versus baseline PP (left panel), follow-up PP in the placebo group (centerpanel), and follow-up PP in the active treatment group (right panel). The dots represent the risks in quartiles of the PP. Reprintedwith permission from Peters R, Beckett N, Fagard R, Thijs L, Wang JG, Forette F, Pereira L, Fletcher A, Bulpitt C: Increasedpulse pressure linked to dementia: Further results from the Hypertension in the Very Elderly Trial - HYVET. J Hypertens 31:1868–1875, 2013.










important publications that add to our knowledge ofBP and its association with stroke and stroke out-comes. Several newer studies examine the effects ofimmediate BP reduction after acute stroke (3–6), andothers assess the effects of discharge BP on outcomes at1 and 5 years poststroke (7, 8)

The benefits of BP lowering and primary strokeprevention are well established, but the effects oflowering BP immediately after acute ischemic strokeare not certain. The China Antihypertensive Trial inAcute Ischemic Stroke randomized 4071 patients withnonthrombolyzed ischemic stroke within 48 hours ofonset and elevated SBP to receive antihypertensivetherapy within 24 hours postrandomization versusdiscontinuation of all antihypertensive medications(3). The treatment group consisted of 2038 patientswho were randomly assigned to receive antihyperten-sive treatment aimed to lower SBP by 10%–25%within the first 24 hours and achieve a BP,140/90mmHg within 7 days with maintenance of this BPduring the hospitalization. A control group of 2033patients was randomized to discontinue all antihyper-tensive medications during the hospitalization. Theprimary outcome was a combination of death andmajor disability (modified Rankin Scale score $3) at14 days or hospital discharge. The Rankin score isa categorical scale that measures functional outcome,with scores ranging from zero (no symptoms) to six(death). Mean SBP was reduced from 166.7 to 144.7mmHg within 24 hours in the antihypertensive treat-ment group and from 165.6 to 152.9 mmHg in thecontrol group within 24 hours after randomization(absolute difference ¼29.1 mmHg; P,0.001). MeanSBP was 137.3 mmHg in the antihypertensive treat-ment group and 146.5 mmHg in the control group atday 7 after randomization (29.3 mmHg; P,0.001).Interestingly, the primary outcome did not differ be-tween treatment groups (683 events in the antihyper-tensive treatment versus 681 events in the controlgroup at 14 days or hospital discharge; P¼0.98).The secondary composite outcome of death andmajor disability at 3 months post–treatment fol-low-up also did not differ between treatment groups(500 versus 502 events, respectively; P¼0.93). Thisstudy prompted the debate as to how best to managethe early elevation of BP that commonly occurs in thesetting of cerebral ischemia. There are potentialadvantages for aggressive BP lowering, includingreduction of cerebral edema, which would lessen the

occurrence of hemorrhagic transformation of the cere-bral infarct and hasten the transition to long–termantihypertensive therapy. Conversely, there are alsoadvantages to completely refraining from early BPintervention and allowing for permissive hypertension,because BP lowering may diminish collateral flow andincrease the size of the cerebral infarct (9). This studyalso underscores that the management of BP in thesubacute period from 12 hours to 2 weeks afterischemic stroke does not matter that much, and thelikelihood of death and major disability at 14 days orhospital discharge did not differ in the different groups.An optimal strategy for management of BP may be toavoid BP-lowering agents during the first 12 hours afterstroke onset, when collateral circulation compromise isstill a substantial concern in most patients. Then, BPlowering should be implemented beginning in the12- to 36-hour period if there has not been any earlyneurologic worsening to help avert secondary injuryand finally, ensure that the patient will be transitionedto long–term antihypertensive therapy for secondaryprevention.

The Efficacy of Nitric Oxide Study randomlyassigned patients with acute ischemic or hemorrhagicstroke and SBP of 140–220 mmHg to 5 mg transdermalglyceryl trinitrate for 7 days or control (5). Patientsreceived glycerol trinitrate within 48 hours of strokeonset. A subset of patients who were taking antihyper-tensive drugs before their stroke was also randomlyassigned to continue or stop taking these drugs. Theprimary outcome was function as determined by a mod-ified Rankin Scale at 90 days. The study included 4011patients with a mean BP (MBP) of 167/90 mmHg atbaseline and median time of 26 hours after stroke onset.BP was significantly reduced on day 1 in 2000 patientsallocated to glyceryl trinitrate compared with 2011controls by 27.0/23.5 mmHg (both P,0.001) BP wasfurther reduced by29.5/25.0 mmHg (P,0.001) on day7 in 1053 patients allocated to continue antihypertensivedrugs compared with 1044 patients randomized tostop them. Functional outcome at 90 days did notdiffer in either treatment comparison. This studydemonstrated that, in patients with acute ischemic orhemorrhagic stroke and SBP.140 mmHg, transder-mal glyceryl trinitrate lowered BP and had acceptablesafety but did not improve functional outcome. Thisstudy reinforces the notion that antihypertensivedrugs can be safely stopped in the first few days afteran acute stroke.


This notion of low BP being harmful after strokewas reinforced with a study from the Czech Republiccomparing the relationship of admission, maximal,and discharge BP during hospitalization for the firstacute ischemic stroke with total mortality afterstroke in 532 patients with a median follow-up of66 weeks (6). In multivariate analysis, admissionMBP and discharge SBP quartiles were independentpredictors of mortality and outperformed otherparameters of BP. After multivariate adjustments,patients with admission MBP ,100 mmHg hada higher risk of death than those with MBP between100–110 and 110–121 mmHg, whereas the risk ofmortality did not differ from the group with admis-sion MBP .122 mmHg. Similarly, patients withdischarge SBP ,120 mmHg had an increased risk ofdeath compared with groups with SBP between 120–130 and 130–141 mmHg, whereas the risk of deathwas similar to that with discharge SBP.141 mmHg.This study demonstrated that risk of all-cause deathwas significantly increased in those with MBP,100mmHg on admission and SBP,120 mmHg ondischarge.

A recent Cochrane review reinforces thesedata. This review included randomized, controlledtrials of interventions to lower BP compared withcontrol within 1 week of acute ischemic or hemor-rhagic stroke (4). This included 26 trials involving17,011 participants (8497 participants were assignedactive therapy and 8514 participants received pla-cebo or control). Results showed that active lower-ing of BP did not reduce death or dependency bydrug class, stroke type, or time to treatment. Treat-ment within 6 hours of stroke seemed effective inreducing death or dependency (odds ratio [OR], 0.86;95% confidence interval [95% CI], 0.76 to 0.99) butnot death (OR, 0.70; 95% CI, 0.38 to 1.26) at theend of the trial. Although death or dependencydid not differ between people who continued pre-stroke antihypertensive treatment versus those whostopped it temporarily (worse outcome with continu-ing treatment; OR, 1.06; 95% CI, 0.91 to 1.24),disability scores at the end of the trial were worse inparticipants randomized to continue treatment. Theauthors concluded that lowering BP during theacute phase of stroke does not improve functionaloutcome and that it is reasonable to withhold BPmedications until patients are medically and neu-rologically stable, after which time drugs can then

be reintroduced, provided that there is suitable oralor enteral access(4).

Physiologic reasoning suggests that anoptimal strategy for management of BPmight be to avoid BP-lowering agentsduring the first 12 hours after strokeonset, when collateral circulation compro-mise is still a substantial concern in mostpatients, and then, implement BP loweringbeginning in the 12- to 36-hour period ifthere has not been any early neurologicworsening to help avert secondary injuryand finally, ensure that the patient will betransitioned to long–term antihypertensivetherapy for secondary prevention.

Another recent study of 3153 veterans withischemic stroke examined the effects of BP at dis-charge and 1 year poststroke and their associationswith treatment intensification (7). The study purposewas to determine the quality of hypertension carepoststroke via analysis of SBP trajectory, antihyperten-sive treatment intensification opportunities associatedwith medication intensifications and the associationbetween patient adherence, and treatment intensifica-tion. The authors examined the SBP stratified bydischarge SBP (#140, 141–160, or .160 mmHg)(7). Hypertension treatment opportunities were de-fined as outpatient SBP .160 mmHg or repeated SBPs.140 mmHg. Treatment intensification was defined asthe proportion of treatment opportunities with antihy-pertensive changes (range, 0%–100%, where 100%indicated that each elevated SBP always resulted inmedication change). Results showed that 38% ofpatients had one or more elevated outpatient SBPseligible for treatment intensification in the year follow-ing stroke; 30% of patients had a discharge SBP #140mmHg and an average of 1.93 treatment opportunities,and treatment intensification occurred in 58% of eligi-ble visits. Forty-seven percent of patients dischargedwith SBP¼141–160 mmHg had an average of 2.1opportunities for intensification, and treatment intensi-fication occurred in 60% of visits. Sixty-three percentof the patients discharged with an SBP.160 mmHghad an average of 2.4 intensification opportunities, andtreatment intensification occurred in 65% of visits.


The study demonstrated three main findings. (1)Among patients hospitalized for ischemic stroke, SBPtrajectory after stroke was highly influenced by dis-charge SBP (Figure 36). (2) Regardless of dischargeSBP, the ratio of medication intensification to oppor-tunities was 58%–65%. (3) There was no relationshipbetween poststroke medication adherence and treat-ment intensification, evidenced by the nearly 50% ofpatients with elevated SBP in the poststroke period withadherence level of ,80%. This finding suggests thatmany patients would benefit from adherence counsel-ing and that providers often do not account for or assessadherence when deciding to intensify treatment. Theauthors suggest three modifiable targets for improve-ment in stroke care (7). (1) Initiation or resumption ofhypertension treatment after the acute stroke period(24–48 hours) should occur in neurologically stablepatients with documented BPs of $140/90 mmHggiven the robust relationship between discharge SBPand SBP trajectory after stroke in this study. (2) Effortsto assure that patients are on the correct medicationsand titrate those medications should be implemented toavoid untreated or undertreated hypertension, particu-larly in those with resistant hypertension or blackpatients, two groups more likely to be uncontrolled inthe poststroke period. (3) In this study, 12% of patientswere discharged with SBP.160 mmHg, and many hadelevated BP in the year after stroke; this group ofpatients had no statistically significant difference intreatment intensification compared with patients whowere discharged with lower SBP. This finding suggeststhat the time to effect the most change in the poststrokeBP trajectory is predischarge. Secondary stroke pre-vention efforts should focus on initiation and review ofantihypertensive medications before discharge after anacute stroke, and patient counseling for medicationadherence is extremely important.

The North East Melbourne Stroke IncidenceStudy (NEMESIS) from Australia assessed whetherlow BP after stroke is associated with poorer out-comes. Participants from the NEMESIS were con-tacted at 5 years poststroke for a follow-up evaluation(8). A multivariable Cox proportional hazards regres-sion model was used to assess the association betweenSBP measurements 5 years poststroke and outcomesup to 10 years poststroke (death, acute myocardialinfarction, or recurrent stroke). In participants whosurvived 5 years from the time of stroke, a lower SBPof ,120 mmHg was associated with a greater risk of

acute myocardial infarction and death (hazard ratio,1.61; P¼0.02) compared with an SBP of 131–141mmHg. Interestingly, when compared with an SBP of131–141 mmHg, there were no differences in outcomesin patients with SBP¼121–130 mmHg or 142–210mmHg (Figures 37 and 38). These findings were notmodified when adjusting for prescription of antihyper-tensive medications. This study demonstrated that therewas a greater risk of poor outcome in long-term survivorsof stroke with low SBP, indicating that the ideal BP forlong-term survivors of stroke may require reassessment.

Intra-Arterial Revascularization after Ischemic Stroke

A recent study examined the effects of intra-arterial treatment for emergency revascularization inpatients with acute ischemic stroke caused by a prox-imal intracranial arterial occlusion (10). Five hundredpatients from The Netherlands were randomly assignedto intra-arterial treatment plus usual care or usualcare alone. Eligible patients had a proximal arterialocclusion in the anterior cerebral circulation that wasconfirmed on vessel imaging that could be treatedintra-arterially within 6 hours after symptom onset.The primary outcome was the modified RankinScale score at 90 days; 233 patients were assigned to

Figure 36. SBP trajectory in the year after stroke. Quadraticmodel adjusted for sex, race, Charlson Score, number ofantihypertensive drugs at discharge, and interactions fordischarge BP by time. Reprinted with permission fromRoumie CL, Zillich AJ, Bravata DM, Jaynes HA, MyersLJ, Yoder J, Cheng EM: Hypertension treatment intensifi-cation among stroke survivors with uncontrolled bloodpressure. Stroke 46: 465–470, 2015.


intra-arterial treatment, and 267 patients were assignedto usual care alone. The mean age was 65 years old,and 89.0% of patients were treated with intravenousalteplase before randomization. Retrievable stents wereused in 81.5% of patients assigned to intra-arterialtreatment. The adjusted common OR was 1.67 (95%CI, 1.21 to 2.30). There was an absolute difference of13.5% (95% CI, 5.9 to 21.2) in the rate of functionalindependence (modified Rankin score, 0–2) in favor ofthe intervention (32.6% versus 19.1%). There were nosignificant differences in mortality or the occurrenceof symptomatic intracerebral hemorrhage. This studydemonstrated that, in patients with acute ischemicstroke caused by a proximal intracranial occlusion of theanterior circulation, intra-arterial treatment administeredwithin 6 hours after stroke onset was effective and safe.

Intracerebral Hemorrhage Associated with the Useof Anticoagulant Therapy

A retrospective study from Germany assessedhow to treat oral anticoagulant (OAC) –associatedintracerebral hemorrhage, the effects of anticoagulationreversal on hematoma enlargement, and when to re-sume use of OAC (11). The study included 1176individuals for analysis of long–term functional out-come: 853 for analysis of hematoma enlargement and719 for analysis of OAC resumption. Hemorrhage

enlargement occurred in 307 of 853 patients (36.0%).Reduced rates of hematoma enlargement were associ-ated with reversal of international normalized ratio(INR) levels ,1.3 within 4 hours after admissionversus INR of $1.3 (19.8% versus 41.5%; P,0.001)(Figure 39) and SBP after 4 hours ,160 versus $160mmHg (33.1% versus 52.4%; P,0.001). The combi-nation of INR reversal,1.3 within 4 hours and SBP of,160 mmHg at 4 hours was associated with lower ratesof hematoma enlargement (18.1% versus 44.2%;P,0.001) and lower rates of in-hospital mortality(13.5% versus 20.7%; P¼0.03). OAC was resumed in172 of 719 survivors (23.9%). Interestingly, OAC re-sumption showed fewer ischemic complications (OAC,5.2% versus no OAC, 15.0%; P,0.001), and hemor-rhagic complications were not significantly differentbetween the groups (8.1% versus 6.6%; P¼0.48).Propensity–matched survival analysis in patients withatrial fibrillation who restarted OAC showed a de-creased hazard of 0.26 (P,0.001) for long-term mor-tality (Figure 40). Functional long–term outcome wasunfavorable in 786 of 1083 patients (72.6%). Althoughthese results are encouraging, this was a retrospectiveanalysis and requires replication in the context ofa prospective trial before changing clinical practice.

References1. Kannel WB, Wolf PA, McGee DL, Dawber TR, McNamara P, Castelli

WP: Systolic blood pressure, arterial rigidity, and risk of stroke. TheFramingham study. JAMA 245: 1225–1229, 1981 PubMed

2. Hong KS, Yegiaian S, Lee M, Lee J, Saver JL: Declining stroke andvascular event recurrence rates in secondary prevention trials over the

Figure 37. Cumulative hazard of composite end point ofdeath or nonfatal vascular event after 5 years after theNEMESIS entry. Adjusted for age, sex, socioeconomicstatus, history of high cholesterol, disability, and domicile.Years refer to the number of years between 5 and 10 yearsafter stroke. Reprinted with permission from Kim J, Gall SL,Nelson MR, Sharman JE, Thrift AG: Lower systolic bloodpressure is associated with poorer survival in long-termsurvivors of stroke. J Hypertens 32: 904–911, 2014.

Figure 38. Forest plot of SBP quartile hazard ratios. Adjustedfor age, sex, socioeconomic status, history of high cholesterol,disability, and domicile. Reprinted with permission from KimJ, Gall SL, Nelson MR, Sharman JE, Thrift AG: Lowersystolic blood pressure is associated with poorer survival inlong-term survivors of stroke. J Hypertens 32: 904–911, 2014.



past 50 years and consequences for current trial design.Circulation 123:2111–2119, 2011 PubMed

3. He J, Zhang Y, Xu T, Zhao Q, Wang D, Chen CS, Tong W, Liu C, XuT, Ju Z, Peng Y, Peng H, Li Q, Geng D, Zhang J, Li D, Zhang F, GuoL, Sun Y, Wang X, Cui Y, Li Y, Ma D, Yang G, Gao Y, Yuan X,Bazzano LA, Chen J; CATIS Investigators: Effects of immediateblood pressure reduction on death and major disability in patients withacute ischemic stroke: The CATIS randomized clinical trial. JAMA311: 479–489, 2014 PubMed

4. Bath PM, Krishnan K: Interventions for deliberately altering bloodpressure in acute stroke. Cochrane Database Syst Rev 10: CD000039,2014 PubMed

5. Bath PM, Woodhouse L, Scutt P, Krishnan K, Wardlaw JM, BereczkiD, Sprigg N, Berge E, Beridze M, Caso V, Chen C, Christensen H,Collins R, El Etribi A, Laska AC, Lees KR, Ozturk S, Phillips S, PocockS, de Silva HA, Szatmari S, Utton S; ENOS Trial Investigators: Efficacyof nitric oxide, with or without continuing antihypertensive treatment,for management of high blood pressure in acute stroke (ENOS): A

partial-factorial randomised controlled trial. Lancet 385: 617–628,2015 PubMed

6. Wohlfahrt P, Krajcoviechova A, Jozifova M, Mayer O, Vanek J,Filipovsky J, Cifkova R: Low blood pressure during the acute periodof ischemic stroke is associated with decreased survival. J Hypertens33: 339–345, 2015 PubMed

7. Roumie CL, Zillich AJ, Bravata DM, Jaynes HA, Myers LJ, Yoder J,Cheng EM: Hypertension treatment intensification among strokesurvivors with uncontrolled blood pressure. Stroke 46: 465–470,2015 PubMed

8. Kim J, Gall SL, Nelson MR, Sharman JE, Thrift AG: Lower systolicblood pressure is associated with poorer survival in long-term survivorsof stroke. J Hypertens 32: 904–911, 2014 PubMed

9. Saver JL: Blood pressure management in early ischemic stroke. JAMA311: 469–470, 2014 PubMed

10. Berkhemer OA, Majoie CB, Dippel DW: Intraarterial treat-ment for acute ischemic stroke. N Engl J Med 372: 1178–1179,2015 PubMed

Figure 39. Association of timing and extent of INR reversal with hematoma enlargement. Logistic regression model usinggeneralized estimating equations to visualize the association of optimal INR reversal (INR,1.3 versus INR$1.3 on firstmonitoring after reversal treatment) with hematoma enlargement over time. Hematoma enlargement was defined as relativevolume increase of .33% on follow-up imaging. The thick blue line represents a regression of OR estimates generated every12 minutes. Each OR estimate included available data covering612 minutes (actual data started at 0024 hours; i.e., the first ORestimate was calculated at 0036 hours and included all available data from 0024 to 0048 hours). Data markers represent the meanof those five OR estimates that encompassed full hours (e.g., the OR estimate at hour 1 represents a mean of the five included ORestimates at 0036 hours [i.e., all data 0024–0048 hours], at 0048 hours [i.e., all data 0036–0100 hours], at 0100 hours [i.e., alldata 0048–0112 hours], at 0112 hours [i.e., all data 0100–0124 hours], and at 0124 hours [i.e., all data 0112–0136]). Each ORwas weighted according to available data points within each time interval, and generation included the method of movingaverages (binning of five subsequent ORs). The vertical dashed line indicates the last significant OR estimate at 0412 hours. Weonly included those patients for analysis (n¼496) for whom the first INR value obtained after initiation of reversal treatment wasavailable within the assessed time frame (0024–0636 hours). Error bars indicate 95% CIs. Reprinted with permission fromKuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, Flechsenhar J, Neugebauer H, Jüttler E, Grau A, PalmF, Röther J, Michels P, Hamann GF, Hüwel J, Hagemann G, Barber B, Terborg C, Trostdorf F, Bäzner H, Roth A, Wöhrle J,Keller M, Schwarz M, Reimann G, Volkmann J, Müllges W, Kraft P, Classen J, Hobohm C, Horn M, Milewski A, ReichmannH, Schneider H, Schimmel E, Fink GR, Dohmen C, Stetefeld H, Witte O, Günther A, Neumann-Haefelin T, Racs AE, NueckelM, Erbguth F, Kloska SP, Dörfler A, Köhrmann M, Schwab S, Huttner HB: Anticoagulant reversal, blood pressure levels, andanticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 313: 824–836, 2015.











11. Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, SobeskyJ, Flechsenhar J, Neugebauer H, Jüttler E, Grau A, Palm F, Röther J,Michels P, Hamann GF, Hüwel J, Hagemann G, Barber B, Terborg C,Trostdorf F, Bäzner H, Roth A, Wöhrle J, Keller M, Schwarz M,Reimann G, Volkmann J, Müllges W, Kraft P, Classen J, Hobohm C,Horn M, Milewski A, Reichmann H, Schneider H, Schimmel E, FinkGR, Dohmen C, Stetefeld H,Witte O, Günther A, Neumann-Haefelin T,Racs AE, Nueckel M, Erbguth F, Kloska SP, Dörfler A, Köhrmann M,Schwab S, Huttner HB: Anticoagulant reversal, blood pressure levels,and anticoagulant resumption in patients with anticoagulation-relatedintracerebral hemorrhage. JAMA 313: 824–836, 2015 PubMed

New Developments in the Treatment of SpecialPopulations

Outcomes According to Drug Class in AsiansA meta-analysis evaluated the effect of different

drug classes on outcomes in hypertensive patients of

Asian origin (1). The search strategy used the termsAsian, Chinese, and Japanese to identify Asian pop-ulations and included 10 clinical trials comparingdifferent drug classes (calcium channel blockers,angiotensin–converting enzyme [ACE] inhibitors, an-giotensin receptor blockers, thiazide diuretics, andb-blockers) in .18,000 subjects. In separate analysesfor mortality (cardiovascular and all cause), myocardialinfarction, stroke, and heart failure, no particular drugclass was superior to another. This meta-analysisreassures clinicians of the general equivalence of agentsin this population.

Outcomes of Different Drug Classes According toBody Mass Index

In the previous issue of NephSAP on hyperten-sion, we discussed a post hoc analysis of the Avoid-ing Cardiovascular Events through CombinationTherapy in Patients Living with Systolic Hypertension(ACCOMPLISH) Trial according to body weight. Theresults indicate that, among patients treated with com-bination benazepril/hydrochlorothiazide, there wasless cardiovascular protection for those with normalbody mass index (BMI) compared with obese indi-viduals. No such differences were observed for thebenazepril/amlodipine group (2). To further define theextent of these findings, the Blood Pressure LoweringTreatment Trialists’ Collaboration (BPLTTC) performeda meta-analysis of 22 trials including .135,000 subjects(3). In the main analysis using categorical distribu-tions of BMI, there was no evidence of a differentialeffect of any particular drug class on cardiovascularevent rates by BMI categories as demonstrated by thehigh P values for all trends (Figure 41). As a secondstep, the investigators analyzed the effects of drugclasses on cardiovascular outcomes using BMI asa continuous variable (3). ACE inhibitors wereassociated with greater protection with increasingBMI compared with thiazide diuretics and calciumchannel blockers. It is possible that the significantlygreater proportion of diabetics in higher BMI rangesexplained this effect. Lastly, they performed an anal-ysis using the same approach as the ACCOMPLISHTrial; the observations from the ACCOMPLISH Trialcould not be replicated in the BPLTTC dataset (3). Itappears that ACE inhibitors are slightly more pro-tective with increasing BMI, but there seems to be noother interactions between drug class and BMI. Thelimited efficacy of diuretics in patients with normal

Figure 40.Kaplan–Meier survival rates of patients with atrialfibrillation with and without OAC resumption. Kaplan–Meiersurvival curves of the propensity-matched cohort (whichincluded only patients who were discharged alive) com-paring patients with atrial fibrillation who restarted OACversus those who did not restart OAC. Survival is presentedfrom index intracerebral hemorrhage (ICH) until 1 year offollow-up and analyzed by log-rank, Breslow, and Tarone–Ware testing. Reprinted with permission from KuramatsuJB, Gerner ST, Schellinger PD, Glahn J, Endres M,Sobesky J, Flechsenhar J, Neugebauer H, Jüttler E, GrauA, Palm F, Röther J, Michels P, Hamann GF, Hüwel J,Hagemann G, Barber B, Terborg C, Trostdorf F, Bäzner H,Roth A, Wöhrle J, Keller M, Schwarz M, Reimann G,Volkmann J, MüllgesW, Kraft P, Classen J, Hobohm C, HornM, Milewski A, Reichmann H, Schneider H, Schimmel E,Fink GR, Dohmen C, Stetefeld H, Witte O, Günther A,Neumann-Haefelin T, Racs AE, Nueckel M, Erbguth F,Kloska SP, Dörfler A, Köhrmann M, Schwab S, HuttnerHB: Anticoagulant reversal, blood pressure levels, and antico-agulant resumption in patients with anticoagulation-relatedintracerebral hemorrhage. JAMA 313: 824–836, 2015.



BMI could not be reproduced in a much largerdatabase.

Drug Choices and BP Targets in Polycystic KidneyDisease

Hypertension is a common complication ofautosomal dominant polycystic kidney disease andoften develops prior to the appearance of low GFR.Important advances in the management of hypertensionin autosomal dominant polycystic kidney disease re-sulted from the publication of the main results of theHalt Progression of Polycystic Kidney Disease Study(4,5). The first study (early disease) enrolled 558patients ages 15–49 years old with baseline eGFR.60 ml/min per 1.73 m2 and randomized them usinga 2·2 factorial design to either a standard BP target (120/70–130/80 mmHg) or a low BP target (95/60–110/75 mHg) and either an ACE inhibitor (lisinopril) plus anangiotensin receptor blocker (telmisartan) or lisinoprilplus placebo (4). The change in magnetic resonanceimaging–measured total kidney volume over 60 months

was the primary end point; other end points includedchanges in eGFR, albuminuria, and left ventricular mass.After up to 96 months of follow-up, dual blockade withlisinopril and telmisartan was not superior to lisinoprilalone for any of the end points. In the BP goal com-ponent of the analysis, there was a substantial 13.4-mmHg difference between the standard and low BPgroups. The low BP group required a median of two BPmedications, whereas the median for the standardBP group was one drug. The low BP target resulted ina smaller fractional annual increase in total kidneyvolume (5.6% versus 6.6%; P,0.01), greater annualdecline in left ventricular mass index (21.17 versus20.57 g/m2 per year; P,0.001), and less albuminuria(23.77% per year; 95% confidence interval, 25.71 to21.78 versus 2.43% per year; 95% confidence interval,0.48 to 4.41; P,0.001). There were no overall differ-ences in eGFR during follow-up, but the low BP grouphad a greater slope of loss of eGFR early on, whereas theslope of GFR loss in the late phase of the study wassteeper in the standard group. Although statisticallysignificant, the magnitude of the results of this study

Figure 41. Effect of different BP–lowering regimens on total major cardiovascular events according to baseline BMI. ACE,angiotensin-converting enzyme; 95% CI, 95% confidence interval; DBP, diastolic BP; SBP, systolic BP. Reprinted withpermission from Ying A, Arima H, Czernichow S, Woodward M, Huxley R, Turnbull F, Perkovic V, Neal B; Blood PressureLowering Treatment Trialists’ Collaboration: Effects of blood pressure lowering on cardiovascular risk according to baselinebody-mass index: A meta-analysis of randomised trials. Lancet 385: 867–874, 2015.


was small and affected only surrogate outcomes relatedto kidney disease progression. However, the low BPtarget was generally well tolerated and could beachieved with relative ease. Therefore, many haveadopted the approach of treating younger patients withpreserved eGFR more aggressively, targeting BP levels,110/75 mmHg.

The second study (5), including 486 patients withmore advanced disease (eGFR¼25–60 ml/min per1.73 m2), did not have different BP goals, and allpatients were treated to a goal of,130/80mmHg. Patientswere randomized simply to dual (lisinopril plus telmi-sartan) versus single blockade of the renin-angiotensinsystem (lisinopril alone). As in the study of early disease,dual blockade did not confer any advantage over singleblockade for any of the study end points.

Aliskiren and Coronary Atherosclerosis inPrehypertension

Another negative study on the effect of the renininhibitor aliskiren on cardiovascular outcomes wasrecently published. The Aliskiren Quantitative Athero-sclerosis Regression Intravascular Ultrasound Studyenrolled patients with coronary artery disease and BPlevels in the prehypertension stage (systolic BP ¼125–139 mmHg) to evaluate the effect of aliskiren orplacebo on the progression of coronary atherosclerosisbased on measured atheroma volume on sequentialintravascular ultrasound of the coronary arteries duringcardiac catheterization in 458 subjects (6). Comparedwith placebo, aliskiren decreased brachial (2.1/1.5mmHg) and aortic BP (5.4/0.5 mmHg) but had nosignificant impact on percentage of atheroma regres-sion (difference of 0.43% favoring aliskiren; P¼0.08),change in atheroma volume (2.04 mm3 favoringaliskiren; P¼0.18), or proportion of patients showingregression of atheroma volume (57% aliskiren versus49% placebo; P¼0.08). These differences were notstatistically significant and not clinically relevant.These results add to the list of studies that demonstratethe absence of effect of aliskiren on cardiovascularoutcomes, which was previously delineated for heartfailure and diabetes/kidney disease, as discussed in theprevious issue of NephSAP on hypertension. It isunlikely that any further studies on renin inhibition,as either an alternative or an addon to ACE inhibitors orangiotensin II receptor blockers, will ever be con-ducted. It is likely that renin inhibitors will remain in

use solely as a fourth- or fifth-choice antihypertensivein patients intolerant to other drug classes.

Treatment of Neurogenic Orthostatic Hypotension

Neurogenic orthostatic hypotension (NOH) causedby conditions, such as primary or secondary autonomicneuropathies, Parkinson disease, and multiple systemsatrophy, is commonly seen by hypertension specialists,because it is complicated by supine hypertension in50%–60% of cases. The most disabling symptomassociated with NOH is orthostatic dizziness, which istypically managed with a combination of lifestylemodifications, supportive garments, and a combinationof vasoconstrictor therapy (most commonly mido-drine) and fludrocortisone. A new vasoconstrictoroption, droxidopa, is now available for the treatmentof NOH after approval by the US Food and DrugAdministration (FDA) in 2014.

Droxidopa (L-threo-3,4-dihydroxyphenylserine)is an orally administered artificial amino acid that isconverted to norepinephrine both centrally and pe-ripherally by the widely expressed enzyme aromaticamino acid decarboxylase (7). Most of the effectsdownstream from the increased norepinephrine levelsare related to increased vasoconstriction and increasedcentral a–adrenergic output, although other effects,such as increased b–adrenergic myocardial stimula-tion and b-adrenergic–mediated vasodilation, are alsopossible and not well studied (7). Previous positiveresults from small studies were recently confirmed bya phase 3 trial of 263 patients with symptomaticnondiabetic NOH, most of whom had Parkinsondisease, of whom 162 (62%) responded to open-labeltreatment with droxidopa and were randomized todroxidopa or placebo (8). Treatment response wasdefined as an improvement of at least one point in the10–item Orthostatic Hypotension Questionnaire(OHQ) and a $10-mmHg increase in standing BPduring open-label therapy. After a 7-day washout, the162 responders received droxidopa at the highesteffective dose during the open-label period or placebofor 7 days. At day 7, treatment with droxidopa ata mean of 430 mg thrice daily resulted in a 0.73-pointreduction in the overall OHQ score (approximately13% improvement) and a 1.3-point reduction in thedizziness/lightheadedness score (approximately 20%reduction), both statistically and modestly significant.Twice as many droxidopa patients had improvements


.3 U in the dizziness lightheadedness score (27%versus 11%; P¼0.02). Standing BP increased by11.2 mmHg with droxidopa and 3.9 mmHg with placebo(P,0.001), and there was no effect on heart rate. Severesupine hypertension (systolic BP .180 mmHg) wasobserved in 4.9% of droxidopa and 2.5% of placebopatients (8).

A second study took a slightly different ap-proach. Investigators enrolled 181 subjects with non-diabetic NOH, 101 of whom (56%) responded toopen-label therapy (9). Responders continued on open-label treatment at their optimal dose (mean ¼390 mgthree times daily) for 1 week and then were ran-domized to continued blinded droxidopa or with-drawal to placebo for 2 weeks. OHQ scores andstanding BP improved significantly during the open-label phase, but there was no difference betweendroxidopa and placebo during the randomized (with-drawal versus continuation) period. All elements ofthe OHQ numerically favored droxidopa as did thefinal standing BP, with a trend that was not statisticallysignificant for most end points. This study outlines theexistence of a significant placebo effect in NOH andquestions the actual superiority of droxidopa overplacebo. One could entertain a possible carryovereffect of droxidopa during the 2 weeks of treatmentwithdrawal in the placebo group, but this wouldbe unexpected given the short half-life of the drug(2–3 hours) (9).

Future studies will be necessary to help tease outsome of the critical issues about the use of droxidopa,including confirmation of its efficacy, evaluation of thelong-term sustainability of its effects, comparison of itseffects with other vasoconstrictors (especially mido-drine), evaluation of its safety in patients withtachyarrhythmias (especially atrial fibrillation), andevaluation of its use in additional populations, partic-ularly those with autonomic dysfunction associatedwith diabetes mellitus. One such additional populationthat has been studied in a phase 2 trial is patients onhemodialysis who are prone to intradialytic hypotension.In a 4-week study of 85 patients, 600 mg droxidopagiven 1 hour prior to dialysis resulted in improvedpostdialysis mean arterial pressure (14.8 mmHg) com-pared with further decrease with placebo (24.4 mmHg;P¼0.02) and significant decreases in hypotension-related termination of dialysis (10). Corroboration ofthese findings and comparisons with midodrine and/orcool dialysate will be of interest.

Complications of Hypertension Treatment

LCZ696 (Valsartan/Sacubitril) and AlzheimerDisease Risk

LCZ696, a drug that combines valsartan andsacubitril, a neprilysin inhibitor, is an effective antihy-pertensive agent and has been approved by the FDA forthe treatment of heart failure with left ventricular dys-function given its superiority to enalapril (11). Neprilysinis a neutral endopeptidase that is ubiquitously distrib-uted and has a broad range of substrates (12). Froma cardiovascular perspective, neprilysin degrades natri-uretic peptides, so its inhibition has value in maximizingnatriuretic peptide activity. On the other hand, neprilysinis the most effective protease for b-amyloid degradation,the amyloid protein involved in the formation of neuro-fibrillary plaques in Alzheimer disease. Neprilysin-de-ficient mice develop Alzheimer–like brain lesions, andthe infusion of neprilysin inhibitors in the brains ofrabbits and mice increases b-amyloid concentrations(12). Consequently, there has been interest in the use ofneprilysin to treat Alzheimer disease and concern thatthe use of neprilysin inhibitors (such as LCZ696) mayresult in an increased risk for disease progression (13).Nonpeer-reviewed communications indicate that LCZ696has not been associated changes in cognition in patientswith heart failure, but other ongoing studies are con-ducting serial measures of cognition to formally addressthis question (14). The availability of LCZ696 in heartfailure and by default, hypertension, is an importantrecent development. Ruling out a potential detrimentaleffect with respect to cognition will be equally important.

Antihypertensive Medication Use and Risk ofFalls in the Elderly

Previous evidence suggested an increased risk offalls among elderly patients receiving antihypertensiveagents. Because previous studies had several meth-odological limitations, Tinetti et al. (15) performeda study of 4961 elderly Medicare beneficiaries (all.70 years old; mean age of 80.2 years old; 61%women; all community-dwelling) specifically assessingthe risk of serious fall injuries over a 3-year follow-upperiod; 9% of subjects had a serious fall injury.Receiving antihypertensive drugs in moderate intensity(0.2–2.5 defined daily doses) was associated witha 40% (adjusted hazard ratio, 1.4; 95% confidenceinterval, 1.03 to 1.90) increased risk of injury related toa fall. This risk was most prominent among those with


a previous history of falls and adjusted for multiplerelevant factors, including the most recently measuredBP. These results are not surprising but remind us of theimportance of integrating an assessment of fall riskwhen treating elderly patients with hypertension.

References1. Yano Y, Briasoulis A, Bakris GL, Hoshide S, Wang JG, Shimada K,

Kario K: Effects of antihypertensive treatment in Asian populations: Ameta-analysis of prospective randomized controlled studies (CARdio-vascular protectioN group in Asia: CARNA). J Am Soc Hypertens 8:103–116, 2014 PubMed

2. WeberMA, Jamerson K, Bakris GL,Weir MR, Zappe D, Zhang Y, DahlofB, Velazquez EJ, Pitt B: Effects of body size and hypertension treat-ments on cardiovascular event rates: Subanalysis of the ACCOMPLISHrandomised controlled trial. Lancet 381: 537–545, 2013 PubMed

3. Ying A, Arima H, Czernichow S, Woodward M, Huxley R, Turnbull F,Perkovic V, Neal B; Blood Pressure Lowering Treatment Trialists’Collaboration: Effects of blood pressure lowering on cardiovascular riskaccording to baseline body-mass index: A meta-analysis of randomisedtrials. Lancet 385: 867–874, 2015 PubMed

4. Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, SteinmanTI, Winklhofer FT, Brosnahan G, Czarnecki PG, Hogan MC, MiskulinDC, Rahbari-Oskoui FF, Grantham JJ, Harris PC, Flessner MF, Bae KT,Moore CG, Chapman AB; HALT-PKD Trial Investigators: Bloodpressure in early autosomal dominant polycystic kidney disease. NEngl J Med 371: 2255–2266, 2014 PubMed

5. Torres VE, Abebe KZ, Chapman AB, Schrier RW, Braun WE,Steinman TI, Winklhofer FT, Brosnahan G, Czarnecki PG, HoganMC, Miskulin DC, Rahbari-Oskoui FF, Grantham JJ, Harris PC,Flessner MF, Moore CG, Perrone RD; HALT-PKD Trial Investigators:Angiotensin blockade in late autosomal dominant polycystic kidneydisease. N Engl J Med 371: 2267–2276, 2014 PubMed

6. Nicholls SJ, Bakris GL, Kastelein JJ, Menon V, Williams B, ArmbrechtJ, Brunel P, Nicolaides M, Hsu A, Hu B, Fang H, Puri R, Uno K,Kataoka Y, Bash D, Nissen SE: Effect of aliskiren on progression ofcoronary disease in patients with prehypertension: The AQUARIUSrandomized clinical trial. JAMA 310: 1135–1144, 2013 PubMed

7. Ross AJ, Stewart JM: Prospects for droxidopa in neurogenic orthostatichypotension. Hypertension 65: 34–35, 2015 PubMed

8. Kaufmann H, Freeman R, Biaggioni I, Low P, Pedder S, Hewitt LA,Mauney J, Feirtag M, Mathias CJ; NOH301 Investigators: Droxidopafor neurogenic orthostatic hypotension: A randomized, placebo-controlled, phase 3 trial. Neurology 83: 328–335, 2014 PubMed

9. Biaggioni I, Freeman R, Mathias CJ, Low P, Hewitt LA, Kaufmann H;Droxidopa 302 Investigators: Randomized withdrawal study of patientswith symptomatic neurogenic orthostatic hypotension responsive todroxidopa. Hypertension 65: 101–107, 2015 PubMed

10. Vannorsdall MD, Hariachar S, Hewitt LA: A randomized, placebo-controlled, phase 2 study of the efficacy and safety of droxidopa inpatients with intradialytic hypotension. Postgrad Med 127: 133–143,2015 PubMed

11. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, RizkalaAR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR;PARADIGM-HF Investigators and Committees: Angiotensin-neprilysininhibition versus enalapril in heart failure. N Engl J Med 371: 993–1004, 2014 PubMed

12. Vodovar N, Paquet C, Mebazaa A, Launay JM, Hugon J, Cohen-SolalA: Neprilysin, cardiovascular, and Alzheimer’s diseases: The therapeu-tic split? Eur Heart J 36: 902–905, 2015 PubMed

13. Galli A, Lombardi F: Neprilysin inhibition for heart failure. N Engl JMed 371: 2335, 2014 PubMed

14. McMurray JJ, Packer M, Solomon SD: Neprilysin inhibition for heartfailure. N Engl J Med 371: 2336–2337, 2014 PubMed

15. Tinetti ME, Han L, Lee DS, McAvay GJ, Peduzzi P, Gross CP, Zhou B,Lin H: Antihypertensive medications and serious fall injuries ina nationally representative sample of older adults. JAMA Intern Med174: 588–595, 2014 PubMed

















Hypertension

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NephSAP, Volume 15, Number 1, March 2016—Hypertension Examination

1. A 35-year-old man is referred to you for theevaluation of persistently elevated diastolic BP de-spite lifestyle changes over the past 6 months. Hefeels well and has no other comorbid conditionsother than the fact that he is overweight (BMI¼27.6kg/m2). His father and grandfather had myocardialinfarctions before age 50. He is worried about hiscardiovascular risk. His BP is 130/102 mmHg andhis exam is otherwise normal. A homeBP log showsa home BP average of 126/97 mmHg. A basicevaluation for secondary causes of hypertension isnegative. His diastolic BP has remained elevateddespite a 6-month trial of lifestyle modification.In addition to ongoing lifestyle modification,which ONE of the following options wouldrepresent your BEST recommendation to him?

A. You should reassure him that his elevateddiastolic BP does not have adverse prog-nostic implications because his systolic BPis normal

B. You should inform him that although hiscardiovascular risk is increased, isolateddiastolic hypertension does not requiretreatment

C. You should inform him that his cardiovas-cular risk is less than patients with systo-diastolic hypertension and that you wouldnot treat him until his home diastolic BPsare .100 mmHg

D. You should inform him that his cardiovas-cular risk is increased and that you recom-mend that he start drug treatment

2. You are asked to make a public health presentationabout the current state of hypertension prevalence,diagnosis, and treatment in the United States at alocal community fair.Which ONE of the following statementsregarding the epidemiology of hypertensionis CORRECT?

A. ,50% of hypertensive adults are awarethat they have hypertension

B. About 50% of people with hypertensionare receiving treatment

C. About 75% of people with hypertensionare controlled and this rate is steadilyimproving

D. About 50% of people with hypertensionare controlled

E. The prevalence of hypertension has steadilyincreased over the past decade

3. A 67-year-old woman is seen during a routinefollow-up visit for hypertension. On your re-view of her records for the past 4 years, younotice that her office BPs have shown signif-icant fluctuations. Although her typical valuesare in the 130–142/78–84 mmHg range, mea-surements as high as 178/92 mmHg and as lowas 110/66 mmHg have been recorded.Which ONE of the following statements isCORRECT with regard to her long-term BPvariability?

A. Increased long-term BP variability is asso-ciated with an increased risk of cardiovas-cular events despite adequate BP controlon most visits

B. Increased long-term BP variability is associ-ated with increased cardiovascular risk onlyin the presence of consistently elevated BP

C. Beta-blockers decrease long-termBPvariabilityD. Long-term BP variability has no relationship

to cardiovascular events

4. Which ONE of the following statementsis CORRECT regarding potassium intake,hypertension, and cardiovascular risk?

A. High potassium intake results in lower BPlevels exclusively in individuals with lowsodium intake

B. Low potassium intake is associated withan increased risk of cardiovascular but notall-cause mortality

C. High dietary potassium results in natriuresisand lower BP by decreasing aldosteronesecretion

D. Low dietary potassium promotes hyperten-sion by increasing the activity of the sodium-chloride cotransporter (on a high sodium diet)

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E. Dietary potassium has no significant role inBP regulation

5. A 56-year-old man with type 2 diabetes mellitusis referred for the management of proteinuriaand resistant hypertension. His antihyperten-sive medications include chlorthalidone, lisino-pril, diltiazem, and doxazosin. Spironolactonehad been tried with a favorable BP response,but he experienced significant gastrointestinalside effects and stopped taking it. Home BPreadings average 148/90 mmHg. On physicalexamination, his BP is 160/92 mmHg, hispulse rate is 60/min, and there is 11 legedema. Laboratory studies show an eGFR(Chronic Kidney Disease Epidemiology Col-laboration [CKD-EPI]) of 78 ml/min per1.73 m2, a serum potassium level of 3.8 mEq/L,and a urine albumin/creatinine ratio of 1182 mg/g.Which ONE of the following is the MOSTappropriate treatment?

A. Add atenololB. Add minoxidilC. Add clonidineD. Add amiloride

6. You are seeing a 32-year-old black woman for ahealth-maintenance visit in a primary care practice.She is asymptomatic. Her BP is 128/80 mmHg,her BMI is 30 kg/m2, and her physical examina-tion is negative.Which ONE of the following is the MOSTappropriate time for her to have her bloodpressure rechecked according to recom-mendations of the U.S. Preventive ServicesTask Force?

A. In 6 monthsB. In 1 yearC. In 3–5 yearsD. As needed, according to her symptoms

7. A 56-year-old woman is referred for furtherevaluation and management of hypertension.She has had several elevated office BPs forthe past year despite dietary sodium reduction,increased physical activity, and weight loss.She is otherwise well and is on no medica-tions. Home BP readings average 134/85mmHg. On physical examination, her BP is152/94 mmHg.

In addition to continued monitoring of her BP,which ONE of the following is the MOSTappropriate next step in management?

A. No change in managementB. Obtain 24-hour ambulatory BP monitoringC. Obtain an echocardiogramD. Start drug treatment

8. A 45-year-old man with hypertension is referredto you for the evaluation of treatment resistance.His antihypertensive medications include amlo-dipine 10 mg daily, valsartan 320 mg daily,chlorthalidone 25 mg daily, and metoprolol50 mg twice daily. He has been adherent totherapy. A physical examination shows a BP of160/98 mmHg. His body mass index is 30 kg/m2.His pulse rate is 60/min. The remainder of theexamination is normal. Laboratory studies showa serum potassium level of 4.2 mEq/L and a serumcreatinine (SCr) level of 0.8 mg/dl. The urinalysisis normal, and the urine albumin/creatinine ratio is28 mg/g. You decide to order a 24-hour ambula-tory BP monitoring study to confirm treatmentresistance. Results of this study show the follow-ing average BPs.24-hour: 134/83 mmHgDaytime (awake): 140/87 mmHgNighttime (sleep): 122/78 mmHgWhich ONE of the following is the MOSTappropriate management?

A. No change in managementB. Add doxazosinC. Increase the dose of metoprololD. Add spironolactone

9. Which ONE of the following statements isCORRECT regarding strategies for population-based management of hypertension?

A. Use of self-monitored BP at home resultsin worse BP control rates

B. Home BP tele-monitoring supervised bya health care provider results in higherrates of BP control than usual care

C. Self-treatment titration on the basis of homeBP readings is suitable for more than 75%of hypertensive patients

D. Self-treatment titration on the basis ofhome readings is safe for uncomplicatedhypertensive patients, but not for patientswith comorbid conditions


E. Financial incentives to physicians do notresult in any measurable improvement inBP control rates

10. You are seeing a 31-year-old woman with auto-somal dominant polycystic kidney disease. She isasymptomatic and feels well. She has liver cysts,but no other known extrarenal manifestations ofautosomal dominant polycystic kidney disease.She is on no medications. On physical examination,her BP is 132/80 mmHg. Her home BPmonitoringshows readings that average 130/82 mmHg.Laboratory studies show an eGFR (CKD-EPI)of 82 ml/min per 1.73 m2 and a potassium levelof 4.1 mEq/L.Which ONE of the following is the MOSTappropriate target BP to attenuate increases intotal kidney volume in this patient?

A. 140/80 mmHgB. 130/80 mmHgC. 120/75 mmHgD. 110/75 mmHg

11. A 70-year-old man with multiple system atrophyis referred to you for assistance in the managementof orthostatic hypotension complicated by supinehypertension. He has poor orthostatic toleranceand has had multiple episodes of syncope. A trialof fludrocortisone had been terminated because ofexcessive edema and supine hypertension (BPapproximately 200/110 mmHg). Midodrinecaused pruritus and a severe headache, requiringdiscontinuation. He is taking no vasoactive med-ications. His supine BP is 152/86 mmHg. Hisstanding BP is 80/52 mmHg (measured 3 minutesafter standing), and is accompanied by significantdizziness. Laboratory studies are all normal.In addition to usual nonpharmacologicmeasures, which ONE of the following is theMOST appropriate treatment recommenda-tion to improve his orthostatic hypotension?

A. DroxidopaB. PyridostigmineC. ClonidineD. ErythropoietinE. A caffeinated beverage with each meal

12. A 64-year-old woman with essential hypertensionis evaluated in routine follow-up. She has seeninformation about the new BP guidelines pub-lished by the Joint National Committee (JNC) in

2014 and she is worried that her BP may be toolow. She feels well and is asymptomatic. She doesnot have diabetes mellitus or coronary arterydisease. Her medications include lisinopril 10 mgdaily and hydrochlorothiazide (HCTZ) 12.5 mgdaily. Her current BP is 132/74 mmHg. Theremainder of the findings from the examinationare unremarkable. Laboratory studies show a SCrlevel of 0.7 mg/dl.Which ONE of the following is the MOSTappropriate management of her hypertension,according to the Eighth JNC 2014 evidence-based guidelines for the management of highblood pressure in adults?

A. Discontinue lisinopril and HCTZB. Discontinue lisinoprilC. Discontinue HCTZD. Make no changes to the current regimen

13. A 56-year-old black woman is evaluated forinadequately controlled hypertension. She hasstage 3 CKD, but does not have diabetes mellitus.Her home blood pressure readings range between150–170/80–95 mmHg. She is currently onlytaking enalapril 40 mg daily. On physical exam-ination, her body mass index (BMI) is 20 kg/m2

and her blood pressure is 165/95 mmHg. There istrace pretibial edema. The remainder of the exam-ination is normal. Laboratory studies disclosedthe following values: sodium 138 mEq/L, potas-sium 3.9 mEq/L, chloride 106 mEq/L, total CO2

22 mmol/L, SCr 1.9 mg/dl, and an eGFR of44 ml/min per 1.73 m2. You decide tostart a thiazide diuretic, and consider the risk ofhyponatremia during your discussion of potentialside effects of this intervention with the patient.Which ONE of the following factors is associ-ated with the greatest risk of thiazide-associatedhyponatremia for this patient?

A. Female sexB. Her eGFRC. Use of chlorthalidone over HCTZ at

equipotent dosingD. Her BMI

14. Which ONE of the following MOST likelycontributes the most to the pathogenesis ofsalt-sensitive hypertension in obese individuals?

A. Decreased expression of angiotensin 1receptors in the proximal tubule


B. Increased serum renin levelsC. Inappropriately low atrial natriuretic peptide

levelsD. Decreased renal expression of Rac1

15. A 66-year-old obese man is evaluated for poorlycontrolled hypertension. Ambulatory BP moni-toring shows a mean daytime BP of 160/94mmHg, and a mean nighttime BP of 152/92mmHg without nocturnal dipping. He has sleepapnea, but finds it difficult to use the continuouspositive airway pressure machine. His medica-tions include lisinopril 40 mg daily, amlodipine10 mg daily, and chlorthalidone 25 mg daily. Aphysical examination shows a BMI of 40 kg/m2,a BP of 162/94 mmHg, and a pulse rate of 68/min.His abdomen is obese. The remainder of theexamination is unremarkable.In addition to weight loss, which ONE ofthe following is the MOST effective non-pharmacologic intervention to lower BPfurther and improve the nocturnal BPpattern?

A. Nocturnal oxygen supplementationB. PsychotherapyC. Device-guided breathingD. Regular use of continuous positive airway

pressure for at least 4 hours per night

16. A 34-year-old white woman is referred forevaluation of recent-onset severe hypertension.She is asymptomatic. She does not have witnessednocturnal choking or gasping, headaches, palpita-tions, or sweating. There is no family historyof hypertension. Her regular medications are:losartan 100 mg daily, felodipine 10 mg daily,metoprolol 100 mg twice daily, and chlortha-lidone 25 mg daily. A physical examinationshows a BMI of 24 kg/m2, a BP of 172/102mmHg without arm discrepancy or posturalchanges, and a pulse rate of 60/min. There isno radiofemoral delay. No abdominal bruitsare detected. The remainder of the examina-tion is normal. Laboratory studies disclose thefollowing values: serum sodium 138 mEq/L,potassium 3.5 mEq/L, chloride 99 mEq/L,total CO2 29 mmol/L, BUN 12 mg/dl, SCr1.2 mg/dl, TSH 2.0 U/L, supine plasma aldo-sterone 18 ng/dl per hour (reference range, 2–5ng/dl per hour), and standing plasma renin

activity 12 ng/ml per hour (reference range, 0.6–3.0 ng/ml per hour). An MRI of the abdomenshows no adrenal or kidney abnormalities.Which ONE of the following is the MOSTappropriate next step in the diagnostic evalu-ation of this patient?

A. Measure plasma metanephrinesB. Refer for adrenal vein samplingC. Refer for polysomnographyD. Order a CT angiogram

17. A 55-year-old man has severe resistant hyper-tension and is referred for further evaluation. Hehas no other medical problems. A physicalexamination shows a BP of 164/88 mmHg, apulse rate of 72/min, and a BMI of 29 kg/m2.Laboratory studies show a SCr level of 1.0 mg/dland potassium level of 3.9 mEq/L. You perform anappropriate workup for secondary hypertension.His plasma renin activity is 0.3 ng/ml per hour(reference range, 0.6–3.0 ng/ml per hour) and hisplasma aldosterone level is 44 ng/dl (referencerange, 2–5 ng/dl). He had an abdominal CT scanthat is shown below (Figure 1)Which ONE of the following is the MOSTappropriate next step in the management ofthis patient?

A. Refer for surgeryB. Add spironolactone 50 mg dailyC. Add amiloride 5 mg twice dailyD. Refer for adrenal vein sampling

Figure 1. Original image provided courtesy of Dr. DebbieL. Cohen, Renal, Electrolyte and Hypertension Division,Perelman School ofMedicine at the University of Pennsylvania,Philadelphia, PA.


18. Which ONE of the following indices best iden-tifies individuals with primary aldosteronismwho are MOST likely to benefit from surgery?

A. An aldosterone/renin ratio of 40B. A selectivity index of 6C. A lateralization index of 6D. Contralateral suppression of aldosteroneE. A low peripheral venous aldosterone/cor-

tisol ratio19. A 26-year-old man develops an acute and severe

elevation in BP to 220/140 mmHg during electivesurgery for a hernia repair. The surgery isabandoned because of persistently high anduncontrolled BP. He has no prior history ofhypertension, but does have a family history ofhypertension.Which ONE of the following is the MOSTappropriate diagnostic test to order next?

A. Aldosterone/renin ratioB. PolysomnographyC. CT angiographyD. Plasma metanephrinesE. Plasma catecholamines

20. A 44-year-old man with paroxysmal hypertensionhas recently been diagnosed with an 8 cm para-aortic paraganglioma in the organ of Zuckerkandlobserved on computed tomography imaging.His plasma catecholamines and metanephrinesare ten times above the upper limit of thereference range. He is referred for surgicalmanagement.In addition to adequate preoperative combinedalpha- and beta-blockade before surgery,which ONE of the following is the next MOSTappropriate step in management?

A. 123-I-metaiodobenzylguanidinescintigraphy

B. Fluorodeoxyglucosepositron emissiontomography

C. Genetic testingD. Urine catecholamines

21. A 72-year-old man with a history of poorlycontrolled hypertension is evaluated 3 monthsafter a left-sided middle cerebral artery stroke.He wants advice about the optimal BP for whichhe should aim in order to prevent a future stroke.On physical examination, his BP is 156/80 mmHg.He does not have carotid bruits or a cardiac

murmur. He has decreased strength in the rightarm graded at 5-/5. The remainder of the exam-ination is normal. Review of a magnetic reso-nance imaging/angiography study of the brainperformed during his hospitalization 3 monthsago shows no evidence of large vessel diseaseand an infarct in the distribution of the left middlecerebral artery.Which ONE of the following is associated withthe highest 5-year risk of stroke, acute myo-cardial infarction, and death for this patient?

A. A discharge systolic BP of .140 mmHgB. Maintenance of his systolic BP at ,140

mmHgC. Maintenance of his systolic BP at ,130

mmHgD. Maintenance of his systolic BP at ,120

mmHg

22. A 65-year-old woman with hypertension andatrial fibrillation is evaluated in the emergencydepartment for acute onset of headache, right-sided weakness, and lethargy. A CT scan of herhead reveals a left-sided frontal lobe hemorrhage.She has been adherent with warfarin anticoagu-lation, and her admission international normal-ized ratio (INR) is 2.4. A physical examinationshows a BP of 184/88 mmHg. A neurologicexamination shows lethargy, a dense right-legparesis, and decreased strength in the right arm.In addition to discontinuing warfarin, whichONE of the following is the MOST appropri-ate in the management of this patient?

A. Reversal of INR to ,2.0 within 4 hoursB. Reversal of INR to ,1.3 within 4 hoursC. Reversal of INR to ,1.3 plus lowering of

systolic BP ,160 mmHg within 4 hoursD. Reversal of INR to ,1.3 plus lowering of

systolic BP ,140 mmHg within 4 hours

23. An 84-year-old woman with hypertension isevaluated during a routine follow-up visit.Her daughter is concerned that her memoryhas gradually declined over the past year. Shehas been on a stable antihypertensive regimenover the past 10 years that includes lisinopril,amlodipine, and chlorthalidone. A physical exam-ination shows a BP of 138/76 mmHg and a pulserate of 66/min. She has no edema. The findingsof the examination are otherwise unremarkable.


Ambulatory BP monitoring shows a mean day-time BP of 140/80 mmHg, and a mean nighttimeBP of 136/84 mmHg without nocturnal dipping.The results of a 24-hour urine test shows 130 mEqof sodium excretion.Which ONE of the following findings is MOSTpredictive of cognitive decline in this woman?

A. Her diastolic BPB. Her systolic BPC. Her dietary sodium intakeD. The absence of nocturnal dipping

24. A 72-year-old white man with a history of CKD isreferred for evaluation of resistant hypertension.His average blood pressure is 170/95 mmHg ona regimen that includes optimally dosed valsartan,amlodipine, carvedilol, and chlorthalidone. Aphysical examination shows a BMI of 24 kg/m2,and a BP of 172/96 mmHg without arm discrep-ancy. He has grade 2 hypertensive retinopathyand an S4 gallop. He does not have edema. Theremainder of the examination is unremarkable.Laboratory studies show a stable SCr level of 2.1mg/dl (eGFR, 38 ml/min per 1.73 m2).Which ONE of the following is MOST likely tobe associated with resistant hypertension inthis man?

A. His BMIB. Underlying CKDC. His ageD. His race

25. Which ONE of the following is the expectedoutcome resulting from the implementation ofthe 2014 JNC Hypertension Guidelines asopposed to the JNC 7 guidelines?

26. A 55-year-old woman with hypertension, hyper-lipidemia, and active smoking is evaluated in

follow-up for hypertension. She asymptomatic.She is currently taking lisinopril 40 mg daily andchlorthalidone 25 mg daily for her hypertension.Her office BP is 139/78 mmHg in the seatedposition and 135/76 mmHg after standing for 2minutes. The findings from her physical exami-nation and laboratory tests are unremarkable.Based on the findings of the Systolic BloodPressure Intervention Trial (SPRINT), whichONE of the following would be the MOSTappropriate next step in her management?

A. Continue the same treatmentB. Decrease the dose of lisinopril to allow her

systolic BP to increase above 140 mmHgC. Add amlodipine, targeting a systolic BP of

,140 mmHgD. Add amlodipine, targeting a systolic BP of

,120 mmHgE. Stop lisinopril and substitute amlodipine

27. The SPRINT study compared a systolic BP targetof 140 mmHg with a target of 120 mmHg inpatients without diabetes who had hypertensionand a high risk for cardiovascular disease.Which ONE of the following statements iscorrect about SPRINT?

A. The study results were difficult to interpretbecause the separation of systolic BPbetween the two groups was only 4 mmHg(130 mmHg versus 126 mmHg)

B. The low BP target (120 mmHg) was asso-ciated with acute kidney injury in 20% ofpatients

C. The low BP target (120 mmHg) resulted ina 38% reduction in the risk of heart failure

D. The standard BP target (140 mmHg)resulted in a 14% reduction in the risk ofmyocardial infarction

E. Among study subjects older than 75 years,randomization to the low BP target(120 mmHg) group resulted in a 22%-higher rate of cardiovascular events

28. A 28-year-old woman is referred to you for theevaluation of hypertension that has been present forthe past 6 months. She has no significant medicalproblems and is taking no medications. On physicalexamination, her BP is 150/98 mmHg. There areno other relevant findings. As part of her evalua-tion, a computed tomography angiogram shows

Item

Proportion of USAdults RequiringTreatment forHypertension

Proportion ofUS AdultsAchievingGoal BP

A No change No changeB Decreased DecreasedC Decreased IncreasedD Increased IncreasedE Increased Decreased


a segment of multifocal left main renal arterystenosis, consistent with medial fibroplasia.Which ONE of the following is the MOSTappropriate next step in her management?

A. Start losartan, aspirin, and atorvastatinB. Obtain a renal scintigraphy scan with

captoprilC. Refer for percutaneous renal angioplastyD. Refer for percutaneous renal angioplasty

and stentingE. Refer for renal artery bypass

29. Which ONE of the following statements about25-hydroxyvitamin D (25OHD) deficiency andhypertension is correct?

A. 25OHD deficiency is associated withhigher rates of hypertension in individu-als below age 50 but not among olderpatients

B. 25OHD replacement in elderly patientswith 25OHD deficiency and isolatedsystolic hypertension effectively lowerssystolic BP compared with placebo

C. 25OHD replacement is an effective therapyfor orthostatic hypotension

D. 25OHD treats the white-coat effect inpatients with white-coat hypertension, butdoes not lower ambulatory BP

E. 25OHD replacement has no effect on BP inhypertensive patients with 25OHDdeficiency

30. One of your patients with hypertension,who iscurrently treated with amlodipine and benazepril,informs you that he would like to start drinkingbeetroot juice on the basis of what he has read onthe Internet. He asks you for your opinion on itssafety and efficacy with regard to hypertension.Which ONE of the following options is correctabout the effects of beetroot juice on BP?

A. Beetroot juice lowers BP by decreasingaldosterone production

B. Beetroot juice has an acute BP-loweringeffect over the first 4–7 days, but tachy-phylaxis develops after this initial period

C. Beetroot juice lowers ambulatory BP byabout 8/5 mmHg compared with placebo

D. Beetroot juice increases pulse wavereflection

E. Beetroot juice is a well known cause ofhypertension and should be avoided


nephsap volume 15, number 1 - hypertension - nefroinfo. nephs… · editorial 1 adiposity and blood...

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