Volume 13 • Number 2 • March 2014

NephSAP
®

Nephrology Self-Assessment Program

Hypertension
Co-Editors:
Raymond R. Townsend, MD
Aldo J. Peixoto, MD
 Preface
EDUCATION DIRECTOR, MAINTENANCE OF
CERTIFICATION (MOC)
Gerald A. Hladik, MD
University of North Carolina at Chapel Hill NephSAPÒ is one of the premiere educational activities of the American Society of
Chapel Hill, NC
Nephrology (ASN). Its primary goals are self-assessment, education, and the provision of
DEPUTY EDUCATION DIRECTOR, Continuing Medical Education (CME) credits and Maintenance of Certification (MOC) points
NephSAP for individuals certified by the American Board of Internal Medicine. Members of the ASN
Jerry Yee, MD, FASN receive NephSAP electronically through the ASN website by clicking on the NephSAP link
Henry Ford Hospital
Detroit, MI under “Education and Meetings” tab.
MANAGING EDITOR EDUCATION: Medical and nephrologic information continually accrues at a rapid pace.
Gisela Deuter, BSN, MSA Bombarded from all sides with demands on their time, busy practitioners, academicians, and
Washington, DC trainees at all levels are increasingly challenged to review and understand new and evolving
ASSOCIATE EDITORS evidence. Each bimonthly issue of NephSAP is dedicated to a specific theme, i.e., to a specific
Michael J. Choi, MD area of clinical nephrology, hypertension, dialysis, and transplantation, and consists of an
Johns Hopkins University School of Medicine editorial, a syllabus, self-assessment questions, and core nephrology questions to serve as
Baltimore, MD
a self-study device. Over the course of 24 months, all clinically relevant and key elements of
Linda F. Fried, MD, MPH
University of Pittsburgh
nephrology will be reviewed and updated. The authors of each issue digest, assimilate, and
Pittsburgh, PA interpret key studies published since the release of the previous issues and integrate this new
Richard J. Glassock, MD material with the body of existing information. Occasionally a special edition is produced to
Professor Emeritus, The David Geffen School of
Medicine at the University of California cover an area not ordinarily addressed by core issues of NephSAP.
Los Angeles, CA
SELF-ASSESSMENT: Thirty single-best-answer questions will follow the 40 to 50 pages of
Stanley Goldfarb, MD
University of Pennsylvania Medical School syllabus text. The examination is available online with immediate feedback. Those answering
Philadelphia, PA 75% correctly will receive MOC and CME credit, and receive the answers to all the questions
Ruediger W. Lehrich, MD along with brief discussions and an updated bibliography. Members will find a new area
Duke University
Durham, NC reviewed every 2 months, and they will be able to test their understanding with our quiz. This
Kevin J. Martin, MBBCh format will help readers stay up to date in developing areas of clinical nephrology,
St. Louis University School of Medicine hypertension, dialysis, and transplantation, and the review and update will support those
St. Louis, MO
John P. Middleton, MD taking certification and recertification examinations.
Duke University
Durham, NC
CONTINUING MEDICAL EDUCATION: Most state and local medical agencies as well as
Patrick T. Murray, MD hospitals are demanding documentation of requisite CME credits for licensure and for staff
University College Dublin appointments. A maximum of 48 credits annually can be obtained by successfully completing
Dublin, Ireland
the NephSAP examinations. In addition, individuals enrolled in Maintenance of Certification
Patrick H. Nachman, MD
University of North Carolina at Chapel Hill
(MOC) through the American Board of Internal Medicine may obtain points toward MOC by
Chapel Hill, NC successfully completing the self-assessment examination of NephSAP.
Aldo J. Peixoto, MD
Yale University N This paper meets the requirements of ANSI/NISO Z39.48-1921 (Permanence of Paper),
West Haven, CT effective with July 2002, Vol. 1, No. 1.
Asghar Rastegar, MD
Yale University
New Haven, CT
Manoocher Soleimani, MD
University of Cincinnati
Cincinnati, OH
NephSAPÒ
Charuhas V. Thakar, MD
University of Cincinnati
Ó2014 by The American Society of Nephrology
Cincinnati, OH
Raymond R. Townsend, MD
University of Pennsylvania Medical School
Philadelphia, PA
John P. Vella, MD
Maine Medical Center
Portland, ME
Alexander C. Wiseman, MD
University of Colorado at Denver
Denver, CO

FOUNDING EDITORS
Richard J. Glassock, MD
Editor-in-Chief Emeritus
Robert G. Narins, MD
 Volume 13, Number 2, March 2014

Editorial 84 Primary Aldosteronism

57 Management of Resistant Hypertension: Do Not Give 84 Genetic Mutations in Aldosterone-Producing

Up on Medication Adenomas with Relevant Clinical and
Eric Judd, MD, David A. Calhoun, MD Mechanistic Implications
85 Updates Relevant to the Diagnosis of Primary
Syllabus Aldosteronism

64 NephSAP, Volume 13, Number 2, March 86 Drug Treatment of Aldosterone Excess in Primary
2014—Hypertension Aldosteronism
Raymond R. Townsend, MD, Aldo J. Peixoto, MD, FASN
87 Pheochromocytoma
64 Update on Epidemiology of BP
90 Preeclampsia
64 Resistant Hypertension
90 Angiogenic Profile and the Diagnosis, Treatment, and
67 ABPM in CKD Prognosis of Preeclampsia
67 Circadian Pattern 91 Preeclampsia and Future Risk of Cardiovascular
67 CVD Outcomes Disease

68 ESRD Outcome 91 Mechanisms of Hypertension

91 Salt Sensitivity
68 Mild Hypertension
92 Novel Kelch-Like 3 and Cullin 3 Mutations Identified
69 Sodium Intake
in Familial Hyperkalemic Hypertension Invoke
69 Arterial Stiffness and Central BP a Novel Mechanism to Explain Sodium Retention
and Hyperkalemia
70 Between-Arm BP Differences
93 Novel Findings Regarding the Long-Term Regulation
70 Bad Air = Bad Blood
of Sodium Excretion Have Implications for the
73 Secondary Hypertension: CKD, Renal Cysts, and Assessment of Sodium Balance in Hypertension
Proteinuria Research and Clinical Practice
73 Kidney Disease as a Cause of Hypertension 94 ENaC Mediates Endothelial Cell Stiffness
73 Association of Simple Renal Cysts with 95 Gut Microbiota and Hypertension
Hypertension
96 Novel Potential Treatment Targets
74 Proteinuria as a Driver of Hypertension
96 Plasminogen Activator Inhibitor-1 Antagonism
74 Renovascular Disease Improves Endothelial Function and Periaortic
74 Noninvasive Identification of the Clinical Fibrosis
Significance of Renal Artery Stenosis 97 ACE2 Activation Improves Endothelial Function
75 RAS Blockade in Renal Artery Stenosis 101 Updates on Treatment
76 Renal Revascularization Update 101 Angiotensin-Converting Enzyme, Angiotensin
Receptor Blocker, and Direct Renin Inhibitor
80 Future Directions in Renovascular Disease–Insights
Interactions
from Experimental Models
102 Body Mass Index
82 Obesity
103 Renal Denervation for (Resistant) Hypertension
82 Obstructive Sleep Apnea
104 Renal Denervation Procedure
83 Relevance of Treatment of OSA to Improve BP
Control and Cardiovascular Outcomes 105 Renal Denervation Studies
 Volume 13, Number 2, March 2014

107 CTD versus HCTZ: The Debate Continues Richard J. Glassock, MD and Patrick H. Nachman, MD
July 2014
107 Nondrug, Nondiet Treatments for Hypertension
Renal Bone Disease, Disorders of Divalent Ions and
107 Orthostatic Hypotension Nephrolithiasis
Kevin J. Martin, MBBCh and Stanley Goldfarb, MD
108 Sodium Glucose Transporter-2
September 2014
109 Update on BP Management in Stroke
End-Stage Renal Disease and Dialysis
109 Ischemic Stroke John Middleton, MD and Ruedigar Lehrich, MD
111 Hemorrhagic Stroke November 2014

112 Clinical Practice Guidelines for Treating Fluid, Electrolyte, and Acid-Base Disturbances
Hypertension in CKD and Diabetes Mellitus Asghar Rastegar, MD and Manoocher Soleimani, MD
112 KDIGO Clinical Practice Guideline for Management March 2015
of Blood Pressure in CKD
Acute Kidney Injury
Patrick T. Murray, MD and Charuhas V. Thakar, MD
CME Self-Assessment Questions May 2015
122 NephSAP, Volume 13, Number 2, March 2014— Chronic Kidney Disease and Progression
Hypertension Linda F. Fried, MD and Michael J. Choi, MD
132 Erratum September 2015

Transplantation
Upcoming Issues John P. Vella, MD and Alexander Wiseman, MD
Glomerular, Vascular, and Tubulointerstitial Diseases November 2015
 Volume 13, Number 2, March 2014

The Editorial Board of NephSAP extends its sincere appreciation to the following reviewers. Their efforts and insights have helped to improve
the quality of this postgraduate education offering.
NephSAP Review Panel
Alok Agrawal, MD, FASN Christopher A. Dyer, MD Nitin V. Kolhe, MD, FASN
Wright State University University of Texas Health Science Royal Derby Hospital
Dayton, OH Center at San Antonio Derby, Derbyshire, UK
San Antonio, TX
Mustafa Ahmad, MD, FASN Rahul Koushik, MD
King Fahad Medical City Mahmoud El-Khatib, MD University of Texas
Riyadh, Saudia Arabia University of Cincinnati Health Science Center
Cincinnati, OH San Antonio, TX
Kamal E. Ahmed, MD, FASN
Yuma Nephrology Lynda A. Frassetto, MD, FASN
University of California at Lalathaksha Murthy Kumbar, MBBS
Yuma, AZ
San Francisco Henry Ford Hospital
Sadiq Ahmed, MD
San Francisco, CA Detroit, MI
University of Kentucky
Lexington, KY Claude Mabry Galphin, MD Nicolae Leca, MD
Nephrology Associates University of Washington
Nasimul Ahsan, MD, FASN Chattanooga, TN Seattle, WA
North Florida/South Georgia
VA Health System Mohammad Reza Ganji, MD Paolo Lentini, MD, PhD
Gainesville, FL Tehran University San Bassiano Hospital
Tehran, Iran Bassano del Grappa, Italy
Jafar Al-Said, MD, FASN
Duvuru Geetha, MD, FASN
Bahrain Specialist Hospital Edgar V. Lerma, MD, FASN
Johns Hopkins University
Manama, Bahrain University of Illinois at Chicago
Baltimore, MD
College of Medicine
Naheed Ansari, MD, FASN Carl S. Goldstein, MD, FASN Chicago, IL
Jacobi Medical Center/Albert Einstein Robert Wood Johnson
College of Medicine Medical School Orfeas Liangos, MD, FASN
Bronx, NY New Brunswick, NJ Klinikum Coburg
Steven M. Gorbatkin, MD, PhD Coburg, Bayern, Germany
Gopal Basu, MD
Christian Medical College Emory University, Meyer Lifschitz, MD
Vellore, Tamil Nadu, India Atlanta, GA Shaare Zedek Medical Center
Mona B. Brake, MD, FASN Ashik Hayat, MD, FASN Jerusalem, Israel
Robert J. Dole VA Medical Center Taranaki Base Hospital
Newplymouth, Taranaki, NZ Jolanta Malyszko, MD, PhD
Wichita, KS
Medical University
Ruth C. Campbell, MD Ekambaram Ilamathi, MD, FASN Bialystok, Poland
Medical University of South Carolina State University of New York
Charleston, SC Stony Brook, NY Christopher Mariat, MD, PhD
University Jean Monnet
Talha Hassan Imam, MD
Chokchai Chareandee, MD, FASN Saint-Etienne, France
Kaiser Permanente
University of Minnesota Fontana, CA
Minneapolis, MN Naveed Masani, MD
Pradeep V. Kadambi, MD Winthrop University Hospital
Dalila B. Corry, MD, FASN University of Texas Medical Branch Mineola, NY
UCLA School of Medicine Galveston, TX
Northridge, CA Hanna W. Mawad, MD, FASN
Sharon L. Karp, MD University of Kentucky
Bulent Cuhaci, MD, FASN Indiana University Lexington, KY
American Hastanesi Indianapolis, IN
Istanbul, Turkey Kevin McConnell, MD
Amir Kazory, MD, FASN Jefferson Nephrology, Ltd
Kevin A. Curran, MD University of Florida Charlottesville, VA
Fresenius Medical Care & US Renal Gainesville, FL
Care Dialysis Facilities Apurv Khanna, MD Pascal Meier, MD, FASN
Canton, TX SUNY Upstate Medical University Centre Hospitalier du Valais Romand
Syracuse, NY Sion, Switzerland
Rajiv Dhamija, MD
Rancho Los Amigos National Istvan Kiss, MD, PhD Ashraf Mikhail, MBBCh
Rehabilitation Center Semmelweis University Morriston Hospital
Downey, CA Budapest, Hungary Swansea, Wales, UK
Tanuja Mishra, MD
Kaiser Permanente
Mid-Atlantic Region
Ellicott City, MD
Lawrence S. Moffatt, Jr., MD
Carolinas Medical Center
Charlotte, NC
Sumit Mohan, MD
Columbia University College of
Physicians and Surgeons
New York, NY
Shahriar Moossavi, MD, PhD, FASN
Wake Forest School of Medicine
Winston-Salem, NC
Koosha Mortazavi, MD
Vista Del Mar Medical Group
Oxnard, CA
Tariq Mubin, MD
Kern Nephrology Medical Group
Bakersfield, CA
Narayana S. Murali, MD
Marshfield Clinic
Marshfield, WI
Thangamani Muthukumar, MD
Cornell University
New York, NY
Mohanram Narayanan, MD, FASN
Scott and White Healthcare
Temple, TX
Macaulay A. Onuigbo, MD, FASN
Mayo Clinic
Rochester, MN
Kevin P. O'Reilly, MD
Ohio State University
Columbus, OH
Carlos E. Palant, MD
Washington DC VA Medical Center
Washington, DC
Malvinder Parmar, MB, MS, FASN
Northern Ontario School of Medicine
Timmins, ON, Canada
Pairach Pintavorn, MD, FASN
East Georgia Kidney and Hypertension
Augusta, GA
James M. Pritsiolas, MD, FASN
Hypertension and Renal Group
Livingston, NJ
Paul H. Pronovost, MD, FASN
Yale University School of Medicine
Waterbury, CT
Mohammad A. Quasem, MD
Universal Health Services Hospitals
Binghamton, NY
Wajeh Y. Qunibi, MD
University of Texas
Health Science Center
San Antonio, TX
Pawan K. Rao, MD, FASN
St. Joseph Hospital
Syracuse, NY
Bharathi V. Reddy, MD
University of Chicago
Medical Center
Chicago, IL
Joel C. Reynolds, MD, FASN
San Antonio Military Medical Center
Fort Sam Houston, TX
Brian S. Rifkin, MD
Hattiesburg Clinic
Hattiesburg, MS
Helbert Rondon-Berrios, MD, FASN
University of Pittsburgh
School of Medicine
Pittsburgh, PA
Bijan Roshan, MD, FASN
Kidney Associates of Colorado
Denver, CO
Mario F. Rubin, MD, FASN
University of Arizona
Tucson, AZ
Ehab R. Saad, MD, FASN
Medical College of Wisconsin
Milwaukee, WI
Bharat Sachdeva, MBBS
Louisiana State University
Health Sciences Center
Shreveport, LA
Mark C. Saddler, MBChB
Durango Nephrology Associates
Durango, CO
Mohammad G. Saklayen, MBBS
Wright State University
Boonshoft School of Medicine
Dayton, OH
Muwaffaq Salameh, MBBS
St. Martha Regional Hospital
Antigonish, NS, Canada
Mohammad N. Saqib, MD
Lehigh Valley Hospital
Orefield, PA
Henry L. Schairer, Jr., MD, FASN
Lehigh Valley Health Network
Allentown, PA
Gaurang M. Shah, MD, FASN
Long Beach VA Healthcare System
Long Beach, CA
Nita K. Shah, MD
St. Barnabas Health Center
Livingston, NJ
Arif Showkat, MD, FASN
University of Tennessee
Memphis, TN
Sandeep S. Soman, MD
Henry Ford Hospital
Detroit, MI
Manish M. Sood, MD, FASN
University of Manitoba
Winnipeg, MB, Canada
Susan P. Steigerwalt, MD
St. John Providence Hospital
Detroit, MI
Ignatius Yun-Sang Tang, MD
University of Illinois Hospital and
Health Sciences System
Chicago, IL
Ahmad R. Tarakji, MD, FASN
College of Medicine, King Saud University
Riyadh, Saudi Arabia
Hung-Bin Tsai, MD
National Taiwan University
Hospital
Taipei, Taiwan
Anthony M. Valeri, MD
Columbia University
New York, NY
Allen W. Vander, MD, FASN
Kidney Center of South
Louisiana
Thibodaux, LA
Juan Carlos Q. Velez, MD
Medical University of South
Carolina
Charleston, SC
Anitha Vijayan, MD, FASN
Washington University
in St. Louis
St. Louis, MO
Shefali Vyas, MD
St. Barnabas Health Center
Livingston, NJ
Nand K. Wadhwa, MD
Stony Brook University
Stony Brook, NY
Sameer Yaseen, MD
Nephrology PC
Des Moines, IA
Mario Javier Zarama, MD
Kidney Specialists of
Minnesota, PA
Saint Paul, MN
 Volume 13, Number 2, March 2014

Program Mission and Objectives

The Nephrology Self-Assessment Program (NephSAP) provides a learning vehicle for clinical nephrologists to renew and
refresh 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 an
important and evolving topic. This combination of materials enables clinicians to rigorously assess their strengths and
weaknesses in the broad domain of nephrology.

Accreditation Statement
The American Society of Nephrology (ASN) is accredited by the Accreditation Council for Continuing Medical Education to
provide continuing medical education for physicians.

AMA Credit Designation Statement

The ASN designates this enduring material for a maximum of 8.0 AMA PRA Category 1 Credits™. Physicians should claim
only the credit commensurate with the extent of their participation in the activity.

Original Release Date

March 2014

CME Credit Termination Date

February 29, 2016

Examination Available Online

On or before Wednesday, March 12, 2014

Estimated Time for Completion

8 hours

Audio Files Available

No audio files for this issue.

Answers with Explanations

•Provided with a passing score after the first and/or after the second attempt
•March 2016: posted on the ASN website when the issue is archived.

Target Audience
• Nephrology certification and recertification candidates
• Practicing nephrologists
• Internists
• Other

Method of Participation
•Read the syllabus that is supplemented by original articles in the reference lists.
•Complete the online self-assessment examination.
•Each participant is allowed two attempts to pass the examination (.75% correct) for CME credit.
•Upon completion, review your score and incorrect answers and print your certificate.
•Answers and explanations are provided with a passing score or after the second attempt.
 Volume 13, Number 2, March 2014

Activity Evaluation and CME Credit Instructions

• Go to www.asn-online.org/cme, and enter your ASN login on the right.
• Click the ASN CME Center.
• Locate the activity name and click the corresponding ENTER ACTIVITY button.
• Read all front matter information.
• On the left-hand side, click and complete the Demographics & General Evaluations.
• Complete and pass the examination for CME credit.
• Upon completion, click Claim Credits, check the Attestation Statement box, and enter your CME credits.
• If you need a certificate, Print Your Certificate on the left.

For your complete ASN transcript, click the ASN CME Center banner, and click View/Print Transcript on the left.

Instructions to obtain American Board of Internal Medicine (ABIM) Maintenance of Certification

(MOC) Points
Each 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
• Enroll for MOC via the ABIM website (www.abim.org).
• 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 to
complete the ABIM MOC enrollment process.

System Requirements
Compatible Browser and Software
The ASN website (asn-online.org) has been formatted for cross-browser functionality, and should display correctly in all
modern web browsers. To view the interactive version of NephSAP, your browser must have Adobe Flash Player installed or
have HTML5 capabilities. NephSAP is also available in Portable Document Format (PDF), which requires Adobe Reader or
comparable PDF viewing software.

Monitor Settings
The ASN website was designed to be viewed in a 1024 · 768 or higher resolution.

Medium or Combination of Media Used

The media used include an electronic syllabus and online evaluation and examination.

Technical Support
If you have difficulty viewing any of the pages, please refer to the ASN technical support page for possible solutions. If you
continue having problems, contact ASN at email@asn-online.org.
 Volume 13, Number 2, March 2014

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

EDITORIAL BOARD
Michael J. Choi, MD—Current Employer: Johns Hopkins University School of Medicine; Consultancy: GlaxoSmithKline; Research Funding:
Sanofi (unpaid co-investigator); Editorial Board: CJASN, Clinical Nephrology, National Kidney Foundation, KDOQI Education Committee
Vice Chair
Linda F. Fried, MD, FASN—Current Employer: VA Pittsburgh Healthcare System; Research Funding: Reata (site investigator); Merck (drug
donation to Veterans Affairs for study); Scientific Advisor/Membership: National Kidney Foundation, Steering Committee Kidney Early
Evaluation Program (KEEP)
Richard J. Glassock, MD—Consultancy: Bristol-Myers Squibb, Novartis, Genentech, Eli Lilly, Sanofi-Genzyme, QuestCor, Astellas,
ChemoCentrix, Bio-Marin, Aspreva (Vifor), NIH, UpToDate, American Journal of Nephrology; Ownership Interest: La Jolla Pharm, Reata;
Honoraria: Eli Lilly, Bristol-Myers Squibb, QuestCor, Chemocentryx, Genentech, Novartis, Astellas, Aspreva (Vifor); Scientific Advisor/
Membership: Los Angeles Bio Medical Institute, University Kidney Research Organization, JASN, American Journal of Nephrology, UpToDate
Stanley Goldfarb, MD, FASN—Current Employer: University of Pennsylvania School of Medicine; Consultancy: GE Healthcare, Fresenius
Healthcare, Genentech, Marval Bioscience; Honoraria: GE Healthcare, Fresenius Healthcare, Genentech; Scientific Advisor/Membership:
Clinical Nephrology (Editorial Board), Genentech
Gerald A. Hladik, MD—Current Employer: University of North Carolina at Chapel Hill; Scientific Advisor/Membership: Education Director for
Maintenance of Certification, American Society of Nephrology
Ruediger W. Lehrich, MD—Current Employer: Duke University Medical Center
Kevin J. Martin, MBBCh, FASN—Current Employer: Saint Louis University School of Medicine; Consultancy: KAI Pharmaceuticals, Cytochroma,
Abbvie, Diasorin, Keryx; Honoraria: Cytochroma, Diasorin, Keryx, Amgen, Abbvie; Scientific Advisor/Membership: Cytochroma, Clinical
Nephrology (Editorial Board), Abbvie, Keryx, Diasorin
John Paul Middleton, MD—Current Employer: Duke University; Consultancy: Astra Zeneca, Bristol-Myers Squibb; Research Funding: Eli Lilly,
Otsuka, Questcor, Keryx, Bristol-Myers Squibb; Scientific Advisor/Membership: Editorial Board Journal of Human Hypertension
Patrick T. Murray, MD, FASN—Current Employer: University College of Dublin School of Medicine and Medical Science; Consultancy: Abbott,
Argutus, FAST Diagnostics, Mitsubishi Pharmaceuticals, Sanofi, AM-Pharma, GlaxoSmithKline; Ownership: Merck; Research Funding:
Abbott, Alere, Argutus, FAST Diagnostic Health Research Board (Ireland), Dublin Centre for Clinical Research, Innovative Medicines Initiative/
SAFE-T Consortium; Honoraria: Abbott, Alere, Argutus, FAST Diagnostic, Mitsubishi, A Menarini, Sanofi; Scientific Advisor/Membership:
CJASN, Irish Medicines Board, Abbott, Alere, Argutus, FAST Diagnostics, AM-Pharma
Patrick Nachman, MD, FASN—Current Employer: University of North Carolina; Consultancy: GlaxoSmithKline; Research Funding: Alexion
(past)
Aldo J. Peixoto, MD, FASN—Current Employer: Yale University School of Medicine; Consultancy: St. Jude Medical; Honoraria: American Society
of Hypertension, Society of Critical Care Medicine, International Society of Nephrology, St. Jude Medical; Associate Editor: Pressure
Monitoring; Editorial Board: CJASN, American Journal of Nephrology, Brazilian Journal of Nephrology, Faculty of 1000 Prime; Society
Committees: American Society of Hypertension (CME Committee); Board of Directors: Eastern Chapter of the American Society of
Hypertension
Asghar Rastegar, MD—Current Employer: Yale University
Manoocher Soleimani, MD—Current Employer: University of Cincinnati Department of Medicine
Charuhas V. Thakar, MD—Current Employer: University of Cincinnati/Department of Veterans Affairs; Consultancy: Cytopherx; Research
Funding: Hospira, Pfizer (OhioPACE), Reata; Honoraria: National Kidney Foundation, University of Toronto
Raymond R. Townsend, MD—Current Employer: University of Pennsylvania School of Medicine; Consultancy: Novartis, GlaxoSmithKline, Merck,
Endo; Honoraria: American Society of Hypertension; Patents/Inventions: UpToDate, Jones & Bartlett (books); Scientific Advisor/Membership:
Medtronic
John P. Vella, MD, FASN—Current Employer: Maine Nephrology Associates, PA; Research Funding: Pfizer, Bristol-Myers Squibb; Scientific
Advisor/Membership: UpToDate
Alexander C. Wiseman, MD—Current Employer: University of Colorado at Denver and Health Sciences Center; Consultancy: MKSAP, Novartis,
Bristol-Myers Squibb, Tolera, Veloxis, Astella; Ownership Interest: Toler; Research Funding: Novartis, Quark, Pfizer, Bristol-Myers Squibb;
Honoraria: American Society of Transplantation, Novartis; Scientific Advisor/Membership: American Journal of Transplantation, Tolera
Jerry Yee, MD, FASN—Current Employer: Henry Ford Hospital; Consultancy: Amgen, Vasc-Alert, Alexion; Ownership: Alexion ZS Pharma;
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
 Volume 13, Number 2, March 2014

EDITORIAL AUTHORS:
David A. Calhoun, MD—Current Employer: University of Alabama; Consultancy: Bayer, Daichii-Sankyo; Research funding: Medtronic, Novartis;
Scientific Advisor/Membership: Journal of Human Hypertension, Hypertension, Journal of the American Society of Hypertension
Eric Judd, MD—Current Employer: University of Alabama

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

Commercial Support
There is no commercial support for this issue.

Editorial
Management of Resistant Hypertension: Do Not Give Up on Medication
Eric Judd, MD, and David A. Calhoun, MD
Vascular Biology and Hypertension Program, University of Alabama, Birmingham, Alabama
The emergence of favorable therapeutic outcomes
from device-based treatments and antihypertensive ther-
apy has fueled increased interest in resistant hyperten-
sion over the past 5 years. More recently, the focus of
intervention has shifted away from hypertension aware-
ness to awareness of BP control. Recent epidemiology
studies have more accurately defined the prevalence of
groups of individuals with difficult-to-control hyperten-
sion. In addition, and perhaps more importantly, these
studies have begun to identify specific reasons for
inadequate BP control. Are patients taking their antihy-
pertensive medication as prescribed? Are physician
prescribing practices optimized? How should we define
BP control: control of home, office, or nocturnal BP?
Who should be screened for secondary causes, and who
should be referred for device-based therapy evaluations?
This editorial explores these questions and delineates an
approach for the management of resistant hypertension
on the basis of currently available evidence.
Definitions
Individuals with resistant hypertension are high-
risk patients who likely benefit from specialized care,
including evaluation and treatment of secondary causes
of hypertension. The American Heart Association (AHA)
defines resistant hypertension as BP that remains above
goal in spite of optimal doses of three antihypertensive
agents of different classes, one, ideally, being a diuretic (1).
Notably, hypertension that is controlled with use of four or
more medications is also defined as resistant (Figure 1).
The AHA definition of resistant hypertension
does not distinguish between true resistant and pseudo-
resistant hypertension. Individuals with elevated office
BP measurements as a result of white-coat hyperten-
sion, improper BP measurement, or medication non-
adherence do not have true resistant hypertension but,
instead, have pseudo-resistant hypertension (1,2). The
term apparent resistant hypertension has been widely
57
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
used in epidemiologic studies and refers to patients
with an office BP.140/90 mmHg while taking three or
more antihypertensive medications (3). True resistant
hypertension can be distinguished from apparent re-
sistance by excluding pseudo-resistance with 24-hour
ambulatory BP monitoring, verifying proper office BP
measurement, and confirming medication adherence
(Figure 1). This distinction is clinically relevant be-
cause truly resistant individuals have an increased risk
of cardiovascular events, including stroke, myocardial
infarction, and ESRD (4,5).
Epidemiology
Observational studies published between 2003
and 2008 suggested that resistant hypertension com-
prised 12.8%–16.5% of the population treated for
hypertension in the United States (6–8). A portion of
this group achieved BP control while taking four or
more antihypertensive medications, yielding a 9.2%–
11.7% prevalence of uncontrolled apparent resistant
hypertension among individuals in the United States
with hypertension. After accounting for the estimated
50% of patients with pseudo-resistance, the prevalence
of true uncontrolled, resistant hypertension falls to ap-
proximately 5% of the treated hypertensive population.
Pseudo-resistance is largely due to white-coat
hypertension, in which BP is uncontrolled when mea-
sured in the office, yet controlled when measured by
24-hour ambulatory monitoring (e.g., mean 24-hour
BP,130/80 mmHg or mean daytime BP,135/85 mmHg).
Ambulatory BP monitoring is not performed on a large
scale in the United States, and the best estimate of the
prevalence of white-coat hypertension within the ap-
parent resistant population comes from an analysis of
.68,000 hypertensive patients in the Spanish Ambu-
latory BP Registry (9). The study by de la Sierra et al.
confirmed a 14.8% prevalence of resistant hypertension
and identified white-coat hypertension in 35.7% of the
58
Figure 1. Venn diagram of apparent and true resistant hy-
pertension. Area of subpopulations drawn to scale with 30%
of the patient population with hypertension, 50% of the
known hypertensives controlled, and 12%–15% of the known
hypertensives resistant. Among patients with resistant hyper-
tension, approximately 33% are controlled on more than three
medications and 50% of the remaining two thirds of patients
have true resistant hypertension.
uncontrolled, resistant population (9). More than one third
of the uncontrolled, resistant population was also found to
have white-coat hypertension in a Brazilian study (5).
Which BP Measurement Should Be Targeted?
Ambulatory BP monitoring has demonstrated
that BP is controlled for a subset of individuals with
resistant hypertension who are not controlled during
office measurements. Which measurement should be
targeted for management of resistant patients: office,
home, or ambulatory BP readings?
In both general and resistant hypertensive pop-
ulations, cardiovascular risk appears to be best pre-
dicted by 24-hour ambulatory BP measurements that
include nocturnal readings (5,10,11). Home BP mea-
surements correlate more closely with ambulatory BP
monitoring than office BP measurements, and are more
predictive of adverse cardiovascular outcomes (12–15).
Recent evidence supports the use of multiple home
BP measurements in the management of hypertension,
particularly in those with resistant hypertension in
which pseudo-resistance is common. With the avail-
ability and reliability of upper arm oscillatory BP de-
vices, consistently recorded home BP measurements
(after education on proper BP technique) are likely to
provide more reliable assessment of BP control and
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
cardiovascular risk than a limited number of office BP
measurements. Because ambulatory blood pressure
monitoring is costly and not widely available, we favor
targeting home BP measurements when there is dis-
cordance between home and office BP measurements.
Adherence
Suboptimal adherence to antihypertensive medi-
cations and/or suboptimal medical regimens also con-
tribute to pseudo-resistance and inadequate BP control.
Nonadherence rates have been reported as high as 53%
in the uncontrolled, resistant population undergoing
evaluation for renal denervation (16). However, larger
epidemiologic studies have shown much lower rates
of nonadherence among individuals with apparent
resistant hypertension, ranging from 7.0% to 12.4%
(8,17,18). In a large sample of United States adults
participating in the Reasons for Geographic and Racial
Differences in Stroke study, 2654 individuals (15.7%
of all hypertensive participants) met the diagnostic
criteria of apparent resistant hypertension. Among this
subgroup, low medication adherence, defined by answering
yes to two or more questions from the four-item Morisky
Medication Adherence Scale, was present in 8.1%.
Adherence is similar when assessed by pharmacy
refill rates. In the Kaiser Permanente Health System, 12.4%
of the 3472 patients with apparent resistant hypertension in
Colorado and Northern California showed low adherence
between 2002 and 2006 (18). In the Southern California
Kaiser Permanente Health System, poor adherence was
present in only 7% of patients diagnosed with resistant
hypertension between 2006 and 2007 (8). Selection bias
is unavoidable when measuring adherence rates. For
example, individuals who agree to participate in studies
or individuals with health insurance are likely to have
greater adherence rates. Selection bias in these studies,
consequently, underestimates nonadherence; true medi-
cation nonadherence in the resistant hypertensive pop-
ulation is therefore likely to be at least 10%. Overall, the
majority of patients with resistant hypertension reliably
take their antihypertensive medications and nonadherence
infrequently contributes to inadequate BP control in the re-
sistant population. Nonetheless, the importance of an af-
fordable and convenient medication regimen should not
be overlooked in the management of resistant hypertension.
Optimizing Treatment Regimens
There remains significant room for improvement
in the prescription of optimal medication regimens in
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
patients with resistant hypertension. Between 2007 and
2010, only 49.6% of the 44,684 patients with apparent,
resistant hypertension in the Outpatient Quality Im-
provement Network were prescribed optimal therapy
(19). Here optimal therapy was generously defined as
a diuretic and two or more other BP medications at
$50% of the maximum recommended hypertension
dose. The use of a mineralocorticoid receptor antagonist
(MRA) as a fourth-line medication and full medication
dosing was not required. Notably, ,9% of the individ-
uals with apparent resistance were prescribed an MRA.
Using data from the 2003–2008 National Health and
Nutrition Examination Survey, Persell found that only
3% of individuals with apparent, resistant hypertension
were receiving an MRA (6). Altogether, the limited
data support a decreasing, yet persistent, gap between
management recommendations for resistant hyperten-
sion and implementation. Intensification of medication
regimens to optimal doses and medication class may be
the most efficient means to achieve BP control in
individuals with resistant hypertension.
Evaluation of Resistant Hypertension
Treatment of specific pathophysiologic processes
is rarely considered in the initial treatment of hyper-
tension. Current guidelines recommend use of an
angiotensin converting enzyme inhibitor/angiotensin
receptor blocker, dihydropyridine calcium channel
blocker, or thiazide-like diuretic (20,21). Patients who
remain uncontrolled despite taking three optimally dosed
medications, ideally from these three classes, are classi-
fied as having resistant hypertension, and a more com-
prehensive search for an underlying secondary cause is
indicated.
The initial evaluation of resistant hypertension
includes screening for drugs or conditions that inter-
fere with BP control (1,22). Medications such as meth-
ylphenidate, estrogen-containing oral contraceptives, or
calcineurin inhibitors may contribute to inadequate
control of hypertension. Similarly, obstructive sleep
apnea (OSA), which is present in up to 96% of men
with resistant hypertension (23), contributes to worsened
BP control, yet alone does not cause resistant hyper-
tension. Treatment of OSA with continuous positive
airway pressure results in only modest reductions in BP
(i.e., approximately 2 mmHg in 24-hour mean sys-
tolic BP) (24). Identification of OSA, therefore, should
not delay efforts to ascertain a treatable cause of
hypertension.
59
Aldosterone excess is sufficiently common in re-
sistant hypertension to warrant systematic screening.
More than 20% of individuals with resistant hyper-
tension display abnormal sodium transport in the distal
nephron, principally mediated by excessive aldosterone
secretion (25,26). The diagnosis of primary aldosteron-
ism offers the option for surgical cure or targeted medical
therapy (e.g., spironolactone or eplerenone). Measure-
ment of the plasma aldosterone/renin ratio is an ef-
fective screening method for primary aldosteronism.
MRAs such as spironolactone, which raise plasma al-
dosterone levels, should be held for at least 6 weeks
before measurement of the ratio. b-Blockers, angioten-
sin converting enzyme inhibitors/angiotensin receptor
blockers, and direct renin inhibitors (e.g., aliskiren) tend
to lower serum aldosterone levels, and can be continued
during aldosterone testing. A ratio that is .20 in in-
dividuals receiving these medications is strong evi-
dence for primary aldosteronism, whereas a ratio ,20
does not exclude the diagnosis. In the setting of sup-
pressed plasma renin activity (PRA) (e.g., ,1 ng/ml
per hour), plasma aldosterone levels are expected to be
normal or low, especially if serum potassium levels
are ,3.5 mEq/L. In patients with suppressed renin
levels, higher than expected plasma aldosterone levels
(.15 ng/dl) should be verified by measuring 24-hour
urinary aldosterone excretion during oral sodium load-
ing after correction of hypokalemia, if present. Sodium
excretion should be measured simultaneously, and an
excretion of close to 200 mEq/d confirms adequate
sodium loading. Acquired mutations can be identified in
a minority of patients with primary aldosteronism (27,28).
Targeted screening is indicated for the more un-
common causes of secondary hypertension. Screening
for pheochromocytoma can be limited to individuals
with paroxysmal hypertension or hypertension accom-
panied by the triad of headache, sweating, and tachy-
cardia, with the exception of patients with a known
adrenal mass, or a family history of von Hippel–Lindau
syndrome or multiple endocrine neoplasia type 2. Al-
though Cushing’s syndrome is also rare, testing for this
condition should be considered when there is synchro-
nous onset of hypertension, obesity, and glucose intol-
erance, particularly in individuals with striae, proximal
myopathy, or supraclavicular fat pads. Note that 24-hour
urine cortisol levels can be easily added to the urine
sample collected for aldosterone levels. A suppressed
PRA, with an inappropriately low aldosterone level
for the serum potassium level, is consistent not only
60
with salt sensitivity but also with very rare sec-
ondary causes of resistant hypertension, including
Liddle’s syndrome or familial hyperkalemic hyperten-
sion (also called pseudohypoaldosteronism type 2 or
Gordon’s syndrome) (29,30). Currently, however, ge-
netic testing for Liddle’s syndrome or familial hyper-
kalemic hypertension is reserved for hypertensive
patients with suppressed renin and aldosterone when
there is a high index of clinical suspicion, such as
those who show a significant fall in BP to amiloride or
chlorthalidone, respectively. More detailed recommen-
dations for the evaluation of secondary causes or
hypertension are summarized in the AHA statement of
resistant hypertension (1).
Treatment of Resistant Hypertension
Individuals with resistant hypertension are more
likely to be salt sensitive, particularly when CKD or
African genetic heritage is present. Salt-sensitive hyper-
tension is characterized by low PRA and likely re-
presents dysregulation of aldosterone or the epithelial
sodium channel. Efforts to identify a broad genetic
cause, however, have thus far been unsuccessful (31).
Institution of a low-sodium diet can have dramatic
effects on BP reduction in salt-sensitive individuals.
In a controlled cross-over trial, mean 24-hour BP
decreased by an average of 20.1/9.8 mmHg after
reducing dietary sodium intake from 250 mmol/d to 50
mmol/d in individuals with resistant hypertension
(32). In the United States, where the typical diet
often includes .160 mmol/d of sodium, imple-
mentation of dietary sodium restriction can be chal-
lenging. Therefore, appropriate diuretic therapy is
often a crucial component to BP control in resistant
hypertension.
Hypokalemic metabolic alkalosis, primarily from
increases in aldosterone, is also common among indi-
viduals with resistant hypertension. Even in the absence
of primary aldosteronism, clinicians should consider
the addition of an MRA to counter chlorthalidone-
mediated kaliuresis and hypokalemia. The combination
of an MRA and a thiazide-like diuretic is appropriate
from a physiologic standpoint, especially in resistant
hypertension in which baseline aldosterone levels are
often high. Aldosterone infusion or oral fludrocortisone
are known to increase sodium chloride cotransporter
expression in rats (33). Furthermore, spironolactone and
chlorthalidone have been shown to be effective when
used in combination (34).
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
In addition to offsetting hypokalemia, MRAs
can dramatically reduce BP in patients with resistant
hypertension. In a follow-up analysis of the Anglo-
Scandinavian Cardiac Outcomes Trial, 1411 participants
received spironolactone at a median dose of 25 mg in
addition to a mean of 2.9 other antihypertensive med-
ications. With a median treatment duration of 1.3 years, BP
fell by 21.9/9.5 mmHg with the addition of spironolactone
(35). Interestingly, spironolactone lowered BP regardless
of serum aldosterone levels (36) and although it is often
contraindicated in advanced CKD, spironolactone
lowers BP in hemodialysis patients (37). The wide-
spread efficacy of MRAs at doses that are associated
with minimal side effects lead some to argue that
addition of an MRA is a vital component of therapy in
resistant hypertension.
Renal Denervation
Early studies indicate that catheter-based renal
denervation is an effective treatment for resistant hy-
pertension, with a mean reduction of 228.9 mmHg
(95% confidence interval, 237.2 to 220.6 mmHg) in
office systolic BP in clinical trials with a control group
(38). Currently, there is not a method to identify those
patients who will attain the greatest benefit from renal
denervation. The role of the renal nerves in the path-
ophysiology of hypertension has yet to be fully elucidated,
and clinical trials have enrolled a restricted population
with resistant hypertension and have largely excluded
individuals with moderate-to-severe kidney disease.
Animal studies have established three different
mechanisms by which renal sympathetic nervous sys-
tem activity influences renal physiology according to
varying levels: (1) low levels increase renin release
from the juxtaglomerular granular cells, (2) medium
levels promote sodium retention throughout the entire
nephron, and (3) high levels result in renal vasocon-
striction, reducing renal blood flow and glomerular
filtration (39). The association between natriuresis and
surgical renal denervation is well established in animal
models. Surgical renal denervation interferes with so-
dium reabsorption in rat models of sodium retention, in
rats fed a low-sodium diet, and in dogs in which obesity
was induced by a high-fat, sodium-controlled diet (40–
43). As a result of these studies and others, increased na-
triuresis is a leading hypothesis for the BP-lowering
effects of renal denervation.
If catheter-based renal denervation promotes na-
triuresis in obese and salt-retentive patients, then a
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
dramatic reduction in BP would be expected after renal
denervation for the majority of individuals with resistant
hypertension. Whether renal denervation is superior to
the established natriuretic agents (e.g., spironolactone
and chlorthalidone) remains unclear. To the authors’
knowledge, no clinical trial investigating renal denervation
has required the use of an MRA before randomization. As
results from ongoing and anticipated clinical trials are
published, it will be interesting to determine whether or not
patients who are truly refractory to medical therapy (i.e.,
uncontrolled while receiving maximum antihypertensive
treatment, including an MRA) respond to denervation.
These refractory patients as well as patients who cannot
tolerate MRAs, such as individuals with CKD stages 4 and
5, likely stand to gain the most from renal denervation.
Who should be referred for catheter-based renal
denervation evaluation? At this time, it is recom-
mended that individuals with apparent resistant hyper-
tension (defined as an office BP.140/90 mmHg while
receiving three or more antihypertensive agents, one
ideally a diuretic) undergo an expert-directed evalua-
tion of their hypertension before any consideration of
renal denervation (1,44). This evaluation includes iden-
tifying conditions or drugs that interfere with BP con-
trol, exclusion of pseudo-resistance, and clinically
appropriate screening for secondary causes of hyper-
tension. Because of its high prevalence in resistant
hypertension and potential for surgical cure, primary
aldosteronism should not be overlooked. In addition,
patients will likely benefit from an optimized medical
regimen, which includes use of chlorthalidone and an
MRA, if tolerated, before undergoing renal denerva-
tion. Catheter-based renal denervation can then be
considered in patients with resistant hypertension only
after completion of this thorough evaluation in pa-
tients with relatively well preserved kidney function
(e.g., eGFR.45 ml/min per 1.73 m2) with appropriate
anatomy and no prior revascularization. The future
role of catheter-based renal denervation as a therapy
for hypertension remains under extensive investiga-
tion and its indication will likely be more fully defined
as more is understood about its mechanism of action,
long-term effects, and overall safety.
Future Directions
Although the role of device-based interventions
in hypertension has not been fully elucidated, the con-
tinued need for effective medical therapy in the treat-
ment of hypertension remains essential. In addition to
61
more widespread use of MRAs in resistant hyperten-
sion, advancements in pharmacogenomics hopefully
will allow for greater individualization of drug therapy,
thereby maximizing benefit. The current trends of im-
proving BP control are likely to continue despite rising
rates of obesity, diabetes, and CKD, all of which are
strongly associated with risk of developing resistant
hypertension.
Acknowledgments
E.J. is supported by a grant from the National Institutes of
Health (T32-HL007457).
Disclosures
Research support has been provided by Medtronic to D.A.C.
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of spironolactone on blood pressure in subjects with resistant hyper-
tension. Hypertension 49: 839–845, 2007 PubMed
36. Nishizaka MK, Zaman MA, Calhoun DA: Efficacy of low-dose
spironolactone in subjects with resistant hypertension. Am J Hypertens
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37. Gross E, Rothstein M, Dombek S, Juknis HI: Effect of spironolactone
on blood pressure and the renin-angiotensin-aldosterone system in
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39. DiBona GF, Esler M: Translational medicine: The antihypertensive
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298: R245–R253, 2010 PubMed
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
40. Roman RJ, Cowley AW Jr: Characterization of a new model for the
study of pressure-natriuresis in the rat. Am J Physiol 248: F190–F198,
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Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Syllabus
NephSAP, Volume 13, Number 2, March 2014—Hypertension
Raymond R. Townsend, MD,* and Aldo J. Peixoto, MD, FASN
*
Division of Nephrology and Hypertension, Department of Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania; †Department of Medicine, Section of Nephrology, Yale University
School of Medicine, New Haven, Connecticut; and ‡Medical Service, Veterans Affairs Connecticut
Healthcare System, West Haven, Connecticut
Learning Objectives
1. To describe the criteria for the diagnosis of
high BP and treatment goals and measurement
standards for hypertension as a cardiovascular
and renal risk factor, particularly in CKD
2. To review trial outcome data related to treat-
ment of hypertension and the selection of anti-
hypertensive therapy
3. To list the basic science contributions to the
pathogenesis and potential management of
hypertension
4. To discuss current strategies for evaluation
and management of secondary hypertension
and how these strategies interact with CKD
Update on Epidemiology of BP
Hypertension sits atop the list of factors consid-
ered important in the global burden of disease. A
recent article in the New England Journal of Medicine
emphasizes this, pointing out that elevated BP rose
from the fourth position on this list in 1990, to the first
position as of 2010 (1). Other work from the World Health
Organization notes that hypertension is a major factor in
premature death and disability, irrespective of the socio-
economic status of the population studied (2). Continued
efforts to measure and manage BP, by any means possible,
remain a worldwide public health priority.
Recent information regarding the awareness,
treatment, and control of hypertension indicates some
good news. A review of the 1988–2008 National
Health and Nutrition Examination Survey (NHANES)
data, covering data from nearly 43,000 people, makes
64
†‡
the following points (3): more people are aware of the
diagnosis (69% in 1988 versus 81% in 2008); more people
with hypertension are treated (54% in 1988 versus 70% in
2008); and more people with hypertension, when treated,
are at BP targets (51% in 1988 versus 69% in 2008).
Resistant Hypertension
Following up on this same cohort, Egan et al.
drilled down further into the NHANES data, using the
same time period (1988–2008), to evaluate how many
people with hypertension have treatment or drug
resistance (4). Figure 1 presents several important
points. These data are valuable not only from a public
health perspective, but also because they provide
some insight (balanced by Kaiser Permanente data
reviewed in the next segment of this section) into the
prevalence of drug-resistant hypertension, which has
risen to worldwide recognition, given the increas-
ing use of denervation procedures (reviewed in the
section on updates on treatment). The proportion of
hypertensive patients with a BP of .140/.90 mmHg
in NHANES III decreased from 73% in 1988 to
52.5% in the 2005–2008 segment (to note, this in-
cludes all patients, receiving treatment or not). Trans-
lating this into public health terms, .30 million
hypertensive persons remain above goal BP (140/90
mmHg). Curiously, these uncontrolled patients are
primarily men, with infrequent health care contact,
lean body mass index (BMI), virtually no CKD, and a
Framingham 10 Coronary Heart Disease risk of ,10%.
As interest in resistance to drug treatment in
hypertension intensifies, it is increasingly important to
use accepted terminology. The red box comments
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Figure 1. The percentages of hypertensive patients who
reported taking 0, 1, 2, and $3 antihypertensive (BP) medi-
cations. Groups included all (A), all uncontrolled (B), treated
uncontrolled (C), and treated controlled patients (D) in the
different NHANES trials. Symbols over a trio of columns
indicate significant changes in the percentage of patients
reportedly taking a given number of antihypertensive medi-
cations across the three NHANES time periods. *P,0.01;
†P,0.001. Reprinted with permission from Egan BM, Zhao
Y, Axon RN, Brzezinski WA, Ferdinand KC: Uncontrolled
and apparent treatment resistant hypertension in the United
States, 1988 to 2008. Circulation 124: 1046–1058, 2011.
65
provide some current definitions applied to the relation-
ship between BP and treatment intensity. In particular,
there is growing scrutiny of truly refractory hypertensive
patients, because these individuals are the enrollment
focus of many device-based hypertension intervention
trials (5). The truly refractory hypertensive patients
appear to take their medications (adherence) and dem-
onstrate elevated out-of-office BP measurements (i.e.,
sustained hypertension).
Drug-resistant hypertension: a BP above
goal (usually .140/.90 mmHg) while tak-
ing at least three antihypertensive drug
classes at optimal doses, ideally with one
class being a diuretic, or taking four or
more classes of antihypertensive drugs,
irrespective of BP level (6,7). Refractory
hypertension: a BP above goal (usually
.140/.90 mmHg) while taking at least three
antihypertensive drug classes at optimal
doses, ideally with one class being a diuretic.
Apparent treatment-resistant hypertension:
uncontrolled BP on at least three classes of
antihypertensive drugs in a setting in which
dose, adherence, and BP measurement arti-
facts cannot be assessed or controlled for
statistically.
To illustrate the magnitude of identifying truly
refractory patients, two recent studies are of value.
Acelajado et al. (8) defined refractory hypertension as
“BP that remained uncontrolled after $3 visits to
a hypertension clinic within a minimum 6-month follow-
up period.” In the clinic where this study was conducted,
the typical evaluation of a patient referred for drug-
resistant hypertension included a 24-hour urine collec-
tion for sodium and potassium, in addition to attention
to a balanced pharmacologic regimen that typically
included the diuretic chlorthalidone and, often, the
addition of a mineralocorticoid antagonist, such as
spironolactone. Of 304 patients referred for drug-
resistant hypertension, 29 (or nearly 10%) remained
above the target BP after an average of 11 months and
six office visits. These data support the recommenda-
tion to refer a patient to a hypertension specialist or
a hypertension program when the patient fails usual
efforts to control his or her BP.
66
In addition to attention to salt intake and optimal
diuretic therapy, the assessment of adherence to med-
ication is a challenge in a typical clinical setting. To
this end, Jung et al. measured drug concentrations in
patients taking four or more antihypertensive drugs at
their hypertension center with treatment resistance of
clinic BP (.140/.90 mmHg) that was confirmed by
ambulatory BP monitoring (ABPM) (.130/80 mmHg)
(9). After adjustment of medications and various other
evaluations, there were 76 of the initial 367 patients
available for follow-up (21%) who remained treatment
resistant taking at least four medications (Figure 2).
Drug adherence was tested in this group using liquid
chromatography–mass spectroscopy analysis. Of 76
patients, 36 individuals (almost half) were adherent to
all of their drugs. Among the other 40 patients, 12
(30%) had no detectable antihypertensive drug levels
for any of their prescribed agents and the other 28 had
varying degrees of drug adherence. One point, not
discussed by the authors, is that this study was pub-
lished at a time when catheter-based renal denervation
was available in Germany. One wonders whether or not
some of the motivation for nonadherence in this pop-
ulation was a desire to be considered a renal denerva-
tion candidate.
Figure 2. Referral and reasons for inclusion or exclusion.
Reprinted with permission from Jung O, Gechter JL, Wunder
C, Paulke A, Bartel C, Geiger H, Toennes SW: Resistant
hypertension? Assessment of adherence by toxicological
urine analysis. J Hypertens 31: 766–774, 2013.
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Using the Spanish ABPM registry, de la Sierra
et al. evaluated the characteristics of patients with
treatment-resistant hypertension (n¼14,461) compared
with those with controlled 24-hour BP (n¼13,436).
These data were culled from .99,000 ABPM readings.
de la Sierra et al. observed that patients with treatment
resistance were older, took an average of 3.6 medica-
tions for BP, had a higher BMI, and had twice the
prevalence of diabetes and more target organ damage
(e.g., higher albuminuria, lower eGFR, more left
ventricular hypertrophy, and more prior cardiovascular
disease [CVD]) (10). Those patients with controlled BP
were taking an average of 1.8 medications. An impor-
tant observation in this cohort study and also noted in
the limited data available in renal denervation trials is
shown in Figure 3. For unclear reasons, those with
treatment-resistant hypertension often have a “white
coat” effect in their office BP readings. Approximately
40% of those patients with an uncontrolled office BP
had 24-hour ABPM,130/,80 mmHg, which was
Figure 3. Differences between office and ambulatory BPs
(white coat phenomenon) in patients with resistant hyper-
tension and those controlled with three or fewer antihyper-
tensive drugs. Reprinted with permission from de la Sierra A,
Banegas JR, Oliveras A, Gorostidi M, Segura J, de la Cruz
JJ, Armario P, Ruilope LM: Clinical differences between
resistant hypertensives and patients treated and controlled
with three or less drugs. J Hypertens 30: 1211–1216, 2012.
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
considered controlled by the investigators. The inves-
tigators also observed that masked hypertension (de-
fined as an office BP,140/,90 mmHg with 24-hour
ABPM.130/.80 mmHg) was present in 31% of those
individuals with what appeared to be controlled BP on
the basis of in-clinic assessment. Notice that 31% is
much greater than the at-large prevalence of 17% in the
general population. In their study, the difference in
office systolic BP (SBP) between those with controlled
BP by ABPM and those with uncontrolled BP by
ABPM was 31 mmHg. The difference in SBP by
ABPM was 11 mmHg. These data underscore the value
of ABPM in assessing true resistant hypertension. How-
ever, it is important to note that an 11-mmHg decrease
obtained from an ABPM-based measurement carries
more epidemiologic “weight” than an office-based mea-
sure because it incorporates many more readings and
includes the night-time profile, increasing the accuracy of
the estimate of a person’s true BP while assessing the
valuable nocturnal component (11,12).
The Kaiser Permanente Health Maintenance
Organization is one of the most comprehensive health
systems tracking BP levels and therapy. In a recent
review of subscribers in Northern California and Col-
orado, Kaiser tracked the progress of 250,000 people
with a new diagnosis of hypertension to determine how
many would remain uncontrolled (i.e., treatment re-
sistant) in a system that carefully tracks both BP levels,
as well as pharmacy utilization of prescribed drugs.
The majority of their patients achieved BP control.
After at least 1 year of follow-up, 1.9% (n¼2900) pa-
tients remained above target BP despite a three-drug
regimen, suggesting that in a high surveillance system,
such as Kaiser Permanente, drug-resistant hyperten-
sion is less common than in general populations in the
United States.
ABPM in CKD
Circadian Pattern
In healthy patients, BP during the sleep period is
usually 10%–20% lower than during the daytime. In
several situations, including CKD, this circadian
pattern is lost, and, in CKD in particular, there is an
increase in the sleep period values, a pattern in which
a patient is sometimes referred to as a riser. This was
well evaluated in a large Spanish study of hy-
pertensive patients classified by CKD stages (13).
Altogether, there were 3227 individuals with CKD
67
Figure 4. Prevalence of the different dipping patterns of
hypertensive patients with CKD in relation to state of disease
severity. Reprinted with permission from Mojón A, Ayala
DE, Piñeiro L, Otero A, Crespo JJ, Moyá A, Bóveda J, de Lis
JP, Fernández JR, Hermida RC; Hygia Project Investigators:
Comparison of ambulatory blood pressure parameters of
hypertensive patients with and without chronic kidney dis-
ease. Chronobiol Int 30: 145–158, 2013.
(defined by eGFR and albuminuria status). As shown
in Figure 4, with increasing CKD stage, the proportion
of patients with a riser pattern increased progressively,
and the proportion of patients with a normal decline in
nocturnal BP (referred to as dippers) decreased pro-
gressively. The mechanisms underlying this ten-
dency to increases in BP during sleep remain largely
unknown.
CVD Outcomes
Using the large International Database on Am-
bulatory Blood Pressure for Cardiovascular Outcomes,
Boggia et al. asked the question of whether or not CKD
influences the predictive value of 24-hour BP levels for
predicting CV outcomes (14). Using 24-hour ABPM
data derived from 11 populations, this group observed
cardiovascular events in 5322 individuals (43%
women) whose average age at the time of ABPM was
52 years during a follow-up period of slightly more
than 9 years. During this period, there were 513
deaths and 555 outcomes, including cardiac disease
and strokes. eGFR alone was an important predictor
of events, but it was of low predictive value. ABPM
was better at predicting outcomes, and the combina-
tion of ABPM and eGFR improved the performance
of either alone in an additive, not multiplicative,
fashion. Most of the participants in this study had
an eGFR.60 ml/min per 1.73 m2 (mean 79.4616.7).
Approximately 10% of participants were aged be-
tween 45 and 60 years and 1% were aged,45 years.
68
Thus, this study’s findings cannot be generalized to
patients with stage 3 or greater CKD.
ABPM remains a useful tool in under-
standing the pathogenesis of vascular
complications in CKD. In particular, higher
BP during sleep contributes to the overall
24-hour pattern and contributes substan-
tially to the heart disease and stroke bur-
den in CKD.
ESRD Outcome
Results from the National Kidney Foundation
Kidney Early Evaluation Program (KEEP) are a valu-
able data source for CKD research. The program now
has nearly 3 years of follow-up data for those
individuals that were successfully screened. KEEP
consists of volunteer-based screenings in public places
to perform BP and fingerstick glucose measurements,
obtain blood for serum creatinine (and sometimes
other data) measurements, and sometimes perform
a spot urine albumin check using a urine dipstick.
Family members of participants with CKD are often
screened at sessions; therefore, KEEP is an enriched
population. Peralta et al. evaluated which of the
standard brachial BP components was the strongest
predictor for progression to ESRD among 16,129
KEEP participants with 2.87 years of follow-up (15).
In this report, there were 320 ESRD events in
a heterogeneous population that was one quarter
African descent, 43% of whom had diabetes. In this
study, SBP accounted for most of the risk of pro-
gression to ESRD and levels$140 mmHg appeared
to be the threshold at which such risk was evident, as
shown in Figure 5A. The authors also noted that one
third of participants had a SBP$150 mmHg or a di-
astolic BP (DBP)$90 mmHg.
Mild Hypertension
Two opposing reports on BP appeared in fall
2012. The first report was a Cochrane meta-analysis by
Diao et al. that examined the evidence supporting the
drug treatment of mild hypertension (16). Mild hyper-
tension was a term used in previous BP definitions that
represented DBPs of 90–104 mmHg, per the 1980 Joint
National Committee report (17). The Diao analysis
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
consisted of four placebo-controlled randomized clin-
ical trials of at least 1 year duration involving 8912
individuals with an entry DBP of 90–99 mmHg or
a SBP of 140–159 mmHg. The results indicated that
death, coronary heart disease, stroke, and total cardio-
vascular events were not significantly reduced by active
drug compared with placebo treatment. To note, the
population studied was free of baseline CVD. In
addition, although the authors used four trials in this
meta-analysis, the entry criteria required them to
partition subsets from the total study population. The
most extreme example here is the use of the Systolic
Hypertension in the Elderly Program (SHEP) trial (18).
The main SHEP trial enrolled 4736 persons and was
predicated on a SBP$160 mmHg. In the Diao meta-
analysis, 7 of 4736 participants were used for the
Cochrane review. There are several other things to
consider, not the least of which is that the literature
search strategy was winnowed from 7700 candidate
articles to 4 studies and just parts of the 4 studies in 3 of
them. Three more points to consider are as follows: (1)
treatment of one stage of hypertension (e.g., stage 1
hypertension) reduces the likelihood of progression to
a higher stage when comparing active treatment with
placebo; (2) in the Diao meta-analysis, the reduction of
stroke on active therapy was 49%, although the
confidence interval was 1.08 (lower limit equaled
a 76% stroke reduction); and (3) the numbers available
to perform the comparisons of placebo versus active
therapy varied, depending on the endpoint. Overall,
although 8912 individuals formed the basis for the
analysis, that number was not always available for
comparison, thereby reducing the power to achieve
statistical significance. Balancing skepticism, it does
make one wonder in this evidence-based era how
strong our data are regarding many of the treatments
we render. The Diao meta-analysis is a study worthy of
further consideration and debate.
Although we do not usually cite nonpeer-reviewed
sources for these NephSAP updates on hypertension,
a story appeared in USA Today on September 4, 2012,
literally in parallel with the Diao analyses, which sets up
the contrast. The article, titled “Millions Do Not Have
Their Blood Pressure Controlled,” began with an in-
terview with Thomas Frieden, director of the US Centers
for Disease Control and Prevention (19). A summary of
the article’s essential points are as follows: 36 million
people have uncontrolled high BP; about 26 million with
uncontrolled high BP have seen a doctor at least twice in
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 69

Figure 5. Rates of ESRD per 1000 person-years. Rates according to systolic BP (A), diastolic BP (B), and pulse pressure (PP)
levels (C). Reprinted with permission from Peralta CA, Norris KC, Li S, Chang TI, Tamura MK, Jolly SE, Bakris G,
McCullough PA, Shlipak M; KEEP Investigators: Blood pressure components and end-stage renal disease in persons with
chronic kidney disease: The Kidney Early Evaluation Program (KEEP). Arch Intern Med 172: 41–47, 2012.

the past year; nearly 22 million know they have high BP,
but do not have it under control; 16 million take
medicine, but still do not have their BP under control;
and 14 million are unaware that they have high BP.
The author also interviewed several experts in the
field of high BP, and the article concluded with
a segment on the Dietary Approaches to Stop Hyper-
tension (DASH) diet and a reminder that “. . . it’s
critical to take the medications as prescribed. . .” (19).
Our own take on the issue of treating mild hypertension
with drug therapy is similar to commentary by Tom
Giles on the subject (20), in which he made the analogy
to colonoscopy or mammography. If you found a sus-
picious lesion on either of those screening tools, would
you not pursue it?
Sodium Intake
The last time we reviewed the issues with salt use
in the last NephSAP on hypertension in March 2012,
the controversy over sodium was heating up. Since
then, things have become even more interesting. The
average American consumes about 3400 mg of sodium
per day, the majority of which (approximately 85%) is
already in the food we eat, which leaves approximately
15% of our daily sodium intake to dietary discretion.
The American Heart Association has now recommen-
ded a reduction to 1500 mg of sodium per day in
patients at high risk, including those with hypertension,
diabetes, African descent, and CKD (21). This is based
on findings from studies like DASH (22). However,
there is some dissension about adopting such a stringent
recommendation that is so challenging to achieve for the
above-discussed reasons (i.e., the amount of sodium that
is typically under the control of dietary discretion). The
Institute of Medicine in particular has voiced concerns
about widespread adoption of such a difficult bar in
sodium intake, particularly because there is a paucity of
hard cardiovascular outcomes to support the efforts
needed to achieve this intake level (23).
Arterial Stiffness and Central BP
Aortic stiffness is reflected clinically by the
velocity of pulse wave travel in the circuit between
the carotid and femoral arteries. A meta-analysis by
Vlachopopoulos et al. concluded that pulse wave
velocity (PWV) was an independent predictor of death
and cardiovascular outcomes (24). Using data from the
Framingham study, Kaess et al. have added more
insight into the pathogenetic mechanisms related to
PWV and outcomes (25).
Using the Offspring of the Framingham cohort,
recruited from 1971 to 1975, these investigators evalu-
ated 1759 people aged about 60 years who were fol-
lowed for a period of approximately 7 years. In 1048
participants without hypertension at baseline, 338 (32%)
developed a BP.140/90 mmHg during the time of ob-
servation. Arterial stiffness, reflected in carotid to femoral
PWV, significantly predicted future hypertension (odds
70 Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

ratio, 1.3; 95% confidence interval, 1.0 to 1.6; P¼0.04). ipants. In everyone else, the carotid pulse pressure was
Interestingly, the opposite was not true. In other estimated from the brachial pressure taking into ac-
words, entry SBP did not predict PWV changes in count age, sex, height, and blood glucose. Also note
PWV during follow-up. This cohort study helps to that the scale on the x axis in Figure 6 is depicted for
inform the question of which comes first: arterial stiff- each 1 SD of B/C ratio (not the actual B/C ratio itself).
ness or increased BP? The data imply that the answer
is arterial stiffness. Between-Arm BP Differences
Arterial stiffness is recognized by the European
It is generally known that BP differs between
Society of Hypertension as a risk marker for cardiovas-
arms, even in healthy people. In hypertensive patients,
cular disease in the recent reappraisal of the European
it is not uncommon to see a 4- to 5-mmHg difference.
Society of Hypertension guidelines in which the fol-
When between-arm values of systolic pressure are
lowing was stated: “In both hypertensive patients and
different by .10 mmHg, a vascular assessment should
the general population, the presence of electrocardio-
be considered (28). When the values are different by
graphic and echocardiographic left ventricular hypertro-
.15 mmHg, it is a predictor of prevalent vascular
phy, a carotid plaque or thickening, an increased arterial
disease and death (28). An interesting study by Kallem
stiffness, a reduced eGFR (assessed by the Modification
et al. placed two different brands of ambulatory BP
of Diet in Renal Disease formula), or microalbuminuria
monitors on the arms of untreated normotensive par-
or proteinuria substantially increases the total cardiovas-
ticipants (29). They were worn for an 8-hour period
cular risk, usually moving hypertensive patients into the
while the monitors recorded BPs from each arm. The
high absolute risk range” (7).
authors observed that, although the mean arterial
Central pressure measurements have not been as
pressure was not different between arms, the SBP
widely accepted as arterial stiffness indices for cardio-
recorded by a standard oscillometric device was 3
vascular risk detection because much of the central
mmHg different, favoring the dominant (usually the
pressure (systolic or pulse pressure) is predicted by the
right) arm, when that same device was used to measure
corresponding brachial value (7). Despite this, a large
each of the participant’s arms. However, the ambulatory
study from France continues to show the potential
BP monitors recorded a 7- to 10-mmHg SBP difference,
usefulness of central pressure measures.
which took into account the different SBPs in the arms.
Regnault et al. collected prospective data on
This raises concern when large databases of ABPM
125,151 participants (52,714 women) who were en-
combine readings from different monitors. It is also an
rolled at approximately 40 years of age and followed
issue, as pointed out by Giles and Egan, with important
for about 12 years in Paris (26). The outcome was age-
implications for research and clinical care (30). For
related cardiovascular death. The authors used an
research, not uncommonly small differences in SBPs
algorithm to predict carotid artery pulse pressure based
become clinically significant when large numbers of
on brachial values adjusted for age, sex, height, and
patients are involved, and the noise introduced into the
blood glucose concentration (27). Once the carotid
BP measurements may be intensified when there is an
pulse pressure was known, the authors divided the
inconsistent approach to which arm is used in BP
brachial pulse pressure by the carotid pulse pressure to
measurement. For clinical care, treatment decisions are
derive a brachial to carotid (B/C) pulse pressure ratio as
increasingly scrutinized with respect to whether the
shown in Figure 6. During the study, 3028 men and 969
patient is at a goal. In general, it is recommended that
women died. The essence of this study is that during the
the higher BP of the two arms, at baseline evaluation, is
period of observation, the B/C ratio (representing pulse
used for all subsequent BP. The BP in the other arm
pressure amplification) was more strongly predictive of
should be measured at least once in the course of follow-
cardiovascular death in the women than men, and more
up because of issues raised previously (28).
so in women aged.54 years.
In interpreting this study, it is important to note
Bad Air ¼ Bad Blood
a few things. First, the actual carotid pulse pressure
was only measured (and by noninvasive means) in 834 Geomedicine is growing in popularity, whereby
individuals (from whom the algorithm was derived) the relationship between where a person lives and
and validated in a separate population of 285 partic- a health consequence, such as BP or diabetes, is
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 71

Figure 6. Forest plot. Adjusted risk of all-cause (A) and cardiovascular mortality (B) according to sex and age (♢, men; ♦,
women). Hazard ratio (95% confidence interval) associated with the increase of 1 SD in brachial pulse pressure (PP), carotid PP,
and/or the decrease of 1 SD in B/C PP ratio. Adjustments were made for height, weight, risk factors (smoking, physical activity,
cholesterol, and diabetes mellitus), and heart rate. Reprinted with permission from Regnault V, Thomas F, Safar ME, Osborne-
Pellegrin M, Khalil RA, Pannier B, Lacolley P: Sex difference in cardiovascular risk: Role of pulse pressure amplification. J Am
Coll Cardiol 59: 1771–1777, 2012.

pursued based on a city or, even more specifically, Los Angeles (31). This was conducted as part of the
a zip code. Coogan and associates recently evaluated Black Women Health Study, in which 59,000 women
the relationship between air pollution and incident of African descent were enrolled. An interesting les-
hypertension in women of African descent living in son in study recruitment from this endeavor was the
72
researchers’ use of the subscriber list from a popular
black woman’s magazine, Essence, to recruit volun-
teers. There were 531 incident cases of hypertension
during a 10-year follow-up and there were 183 incident
cases of diabetes. For this study, the investigators
measured exposures as data obtained at 23 state and
local district monitoring stations that assayed the level
of fine particulate matter with a diameter of ,2.5 mm
and nitrogen oxides reflective of automobile air pollu-
tion. There was an independent effect of air pollutants
on development of hypertension and diabetes when
these exposures were entered into predictive models
that also included age, BMI, education, income, num-
ber of people in the household, cigarette use, alcohol
consumption, physical activity level, and neighborhood
socioeconomic status. The importance of this study is
that it provides further linkage of environmental ex-
posures to chronic morbidities, such as diabetes and
high BP. Thus, public health efforts directly aimed at an
individual (e.g., diet and exercise) may not provide as
much benefit in urban areas if environmental exposures
(particularly the nitrogen oxides) from traffic-related air
pollution are not also considered. The increase in
hypertension incidence when adjusted for the above
factors is approximately 15%; however, from a public
health perspective, this represents an area ripe for
further investigation and potential intervention.
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Secondary Hypertension: CKD, Renal Cysts, and
Proteinuria
Kidney Disease as a Cause of Hypertension
CKD is a well known, common cause of hy-
pertension. Data from population-based studies indicate
that .95% of individuals with an eGFR,30 ml/min per
1.73 m2 have hypertension (1), which is typically
ascribed to the limited ability of the diseased kidneys
to handle sodium excretion in addition to the activation
of a variety of vasoconstrictive and sodium retentive
mechanisms. In contrast with patients with advanced
CKD, patients with structural kidney disease and pre-
served kidney function may develop hypertension due to
novel mechanisms that have recently been described (2).
Association of Simple Renal Cysts with
Hypertension
Previous evidence suggested an association be-
tween simple renal cysts and hypertension in cross-
sectional population studies, but these studies were
limited by sample size and insufficient adjustment for
relevant covariates that may have mediated this
73
association. Two recent studies have addressed these
limitations to a reasonable extent. Hong et al. studied
29,666 patients undergoing an extensive baseline health
evaluation, 5674 of whom (19%) had at least one renal
cyst on a screening computed tomography (CT) scan
and/or ultrasound (3). Oddly, hypertension was defined
as an average office BP.130/85 mmHg. Using this
definition, hypertension was present in 33.4% of the
entire cohort and was more common in patients with
renal cysts after adjustments for age, sex, body mass
index (BMI), and several biochemical markers associ-
ated with hypertension, such as glucose, eGFR, and uric
acid. The presence of any cysts was associated with
a 28% increased risk of hypertension (odds ratio [OR],
1.28 (1.20–1.36); P,0.001). The strength of this as-
sociation was attenuated among the 64% of patients
with only one cyst (OR, 1.08 (1.01–1.17); P¼0.04), and
strengthened among the 36% of participants with more
than one cyst (OR, 1.31 (1.19–1.44); P,0.001). Cyst
size also seemed to matter. Patients with cysts,1.4 cm
in diameter did not have excess rates of hypertension
(OR, 1.06 (1.98–1.16); P¼0.15), whereas those with
larger cysts did, especially those with cysts .4 cm in
diameter (OR, 1.29 (1.06–1.56); P,0.01) (3).
Another study of 14,995 individuals screened
with abdominal ultrasonography identified 1694 patients
with renal cysts (11.3%) (4). The overall prevalence of
hypertension, defined as office BP$140/90 mmHg, was
12.5%, and the risk of hypertension was increased among
patients with renal cysts after adjustments for age, sex,
body size, renal function, diabetes, smoking, exercise,
and lipid levels (OR, 1.54; 95% confidence interval [95%
CI], 1.32 to 1.8). Similar to the previous study, risk
increased with cyst number and size. Because it has long
been postulated that cysts compress adjacent renal
parenchyma and provoke focal ischemia and consequent
renin secretion, the authors further explored the relation-
ship between cysts and BP as a function of renin levels in
a subset of 197 controls and 394 patients with cysts.
Individual analyses according to cyst number and size
demonstrated a stepwise increase in plasma renin levels
as a function of increased cyst number (two or more) and
size (.2 cm in diameter). After adjustment for plasma
renin levels, the association between renal cysts and
hypertension was significant only among patients with
two or more cysts (OR, 2.26; P,0.001) compared with
those with one or none (4).
These two studies were performed in Asian pop-
ulations, and the generalizability to other populations may
74
be limited. However, they raise awareness of the possible
role of simple renal cysts in mediating hypertension risk,
at least in patients with large and/or numerous cysts that
may result in parenchymal compression and activation of
the renin-angiotensin system (RAS). Anecdotal observa-
tions have shown that cyst decompression can resolve
hypertension in patients with large cysts (2), although
these are likely unusual, extreme cases. More relevant
are the potential treatment implications regarding the use
RAS blockers. It will be interesting to see whether
patients with large or multiple simple cysts benefit from
RAS blockade in a way that is similar to those with
polycystic kidney disease, in whom this intervention is
an effective means of BP control and possibly of halting
disease progression (results of the HALT Progression of
Polycystic Kidney Disease study addressing this hy-
pothesis will be available in late 2014; ClinicalTrials.gov
identifier NCT00283686).
Proteinuria as a Driver of Hypertension
Although we typically see hypertension as a com-
plication of nephritic syndrome or in nephrotic patients
after renal function is lost, we often overlook the fact
that as many as 45% of young adults with minimal
change disease and preserved renal function are hyper-
tensive (5). This observation raises the possibility that
the presence of high levels of proteinuria may have
a hypertensive effect. A series of recent experiments and
clinical studies elucidated some of these mechanisms
and linked plasminogen activation in the urine to
increased activity of the epithelial sodium channel
(ENaC) (6). Plasminogen that is abnormally leaked into
the urinary space in the nephrotic syndrome is activated
to plasmin by tubular urokinase–like plasminogen
activator. Plasmin directly stimulates the ENaC in the
distal nephron through proteolytic cleavage of the ENaC
extracellular a- and g-subunits. Consistent with en-
hanced ENaC activity, the increased sodium conduc-
tance is inhibited by amiloride. Although the initial
reports of this mechanism were made in nephrotic
animals and children with nephrotic syndrome, recent
studies have extended these observations to patients with
lower levels of proteinuria, such as those with pre-
eclampsia (7) and diabetic nephropathy [unpublished
observations described in a review article (6)]. Impor-
tantly, a detailed case series of nephrotic children
before and after treatment with steroids or other
immunosuppressive agents demonstrated that once
nephrosis enters remission, the urine of these children
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
no longer contains plasminogen/plasmin and loses its
in vitro ENaC stimulatory effect (8). Unfortunately,
the investigators did not report BP data.
These interesting studies have potential thera-
peutic implications. It is possible that amiloride (or
triamterene) is a good choice to manage edema and salt
sensitivity, including hypertension, in patients with
proteinuria. Indeed, a nonrandomized series of 13
nephrotic children given furosemide or amiloride alone
or the two drugs in combination showed that amiloride
and furosemide had similar natriuretic effects when
given alone; when given in combination, the natriuretic
effect was doubled, leading to complete control of
nephrotic edema (9). It will be important to test this
hypothesis using more rigorous methods in patients
with a wide range of proteinuria levels. As it pertains to
hypertension in patients with proteinuria, the role of
amiloride has not been formally tested. However, a recent
randomized crossover clinical trial of 31 patients with
essential hypertension showed that amiloride (10–20
mg/d) produces statistically similar BP reductions com-
pared with hydrochlorothiazide (25–50 mg/d) over a
4-week period (11/3 mmHg versus 7/2 mmHg; P¼0.23
versus P¼0.82) (10), although the differences were
numerically large and a larger study will be required
to settle the value of amiloride in such patients. These
results were similar to those of a previous study by the
same group demonstrating that high-dose amiloride
(40 mg/d) was equivalent to bendroflumethiazide or
spironolactone in essential hypertension (11). Over-
all, we believe that these findings deserve further at-
tention and formal testing of efficacy, not only in the
management of nephrotic edema, but also in the treat-
ment of salt-sensitive hypertension.
Renovascular Disease
Noninvasive Identification of the Clinical
Significance of Renal Artery Stenosis
In the previous issue of NephSAP on hyperten-
sion, we reviewed the importance of the development
of accurate noninvasive methods to assess the hemo-
dynamic significance of renal artery stenosis and the
need for tests that can accurately predict the clinical
response to renal artery revascularization (12). Al-
though it remains uncertain whether the use of blood
oxygen level–dependent magnetic resonance imaging
(BOLD-MRI) can predict outcomes after renal revas-
cularization, Saad et al. presented results of renal artery
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
stenting on renal volume, perfusion, and function as
well as on markers of tubular injury and inflammation
(13). The investigators performed detailed studies of 17
patients with renal artery stenosis and 32 controls with
essential hypertension. Patients with renal artery ste-
nosis had higher systolic BP (145 versus 137 mmHg;
P¼0.04) and lower GFR (66 versus 88 ml/min;
P¼0.01) than essential hypertensives. Compared with
kidneys of patients with essential hypertension, stenotic
kidneys had lower total and cortical volume, lower
cortical and medullary perfusion per tissue mass, and
lower single kidney GFR. All stenotic kidneys demon-
strated evidence of significant tissue hypoxia based on
BOLD-MRI measurements. Table 1 presents functional
data at baseline and 3 months after renal artery stenting
in the 17 patients with renal artery stenosis. These data
indicate that despite significant improvement in renal
perfusion and hypoxia (although not to normal levels),
there was no significant improvement in single kidney
GFR during follow-up. Total GFR also did not im-
prove because GFR in the contralateral kidney de-
creased to a degree similar that GFR in the stenotic
kidney increased, thus resulting in no net change.
Finally, the authors addressed the effect of revascu-
larization on markers of tubular damage (neutrophil
gelatinase-associated lipocalin [NGAL]) and inflamma-
tion (TNF-a and monocyte chemoattractant protein-1)
measured during renal vein sampling. Consistent with
previous experimental observations and clinical data,
patients with renal artery stenosis had significantly
higher levels of all three of these markers compared
with hypertensive controls. After renal artery stent-
ing, there were no significant changes in any of the
markers compared with baseline.
Once ischemia is severe enough to trigger
inflammation and tissue injury, revascular-
ization may restore perfusion, resolve hyp-
oxia, and allow recovery of kidney volume,
but it does not appear to improve markers
of inflammation and injury. Defining the
best means to identify ongoing inflamma-
tion and damage and pinpointing the time
when these changes become irreversible
will be one of the most important chal-
lenges in the future of renovascular disease
management.
75
RAS Blockade in Renal Artery Stenosis
Current guidelines propose that medical man-
agement of patients with peripheral arterial disease,
including renal artery stenosis, should consist of control
of atherosclerotic risk factors, smoking cessation, and
use of antiplatelet therapy, statins, and RAS blockers
with either angiotensin-converting enzyme (ACE) in-
hibitors or angiotensin receptor blockers (ARBs) (14).
The recommendation for use of RAS blockers is based
on retrospective observational data indicating improve-
ments in mortality and lower risk of kidney disease
progression. Chrysochou et al. performed a large pro-
spective observational study to test the value and safety
of RAS blockers in patients with renal artery stenosis
(15). Of the 621 patients enrolled, 74% were considered
to be “intolerant” of RAS blockers at inception. How-
ever, they prospectively attempted to introduce a RAS
blocker to 378 patients, 92% of whom tolerated it well,
even in the presence of bilateral renal artery stenosis.
After a follow-up of up to 10.6 years (median 3.1 years),
exposure to any RAS blocker was associated with a 39%
reduction in risk of death (hazard ratio [HR], 0.61; 95%
CI, 0.4 to 0.91; P¼0.02) after adjustment for a pro-
pensity score that included multiple relevant risk
factors (15). The point estimates for risk of renal and
cardiovascular endpoints were not statistically signif-
icant. It is important to note that a few patients can
lose significant kidney function after the introduction
of RAS blockers in the setting of severe bilateral
stenosis or stenosis to a single functioning kidney. In
this study, 16 patients fitting this category were
revascularized and tolerated the reintroduction of
a RAS blocker without problems thereafter (15).
New experimental evidence also lends support to
the use of RAS blockade in renal artery stenosis. Using
a model of porcine coil–induced renal artery stenosis,
Zhang et al. evaluated the effects of the ARB valsartan
on renal structure and function distal to the stenosis
(16). Six weeks after coiling of the renal arteries,
animals with angiographically proven stenosis (average
cross-sectional occlusion of 78%) were randomized to
valsartan, triple therapy with reserpine, hydralazine,
and hydrochlorothiazide, or no treatment for another
4 weeks. BP increased in all groups, but was higher in
the untreated group (mean arterial pressure 173 mmHg)
than in the treated groups (134 mmHg for the valsartan-
treated group versus 131 mmHg for the triple therapy-
treated group). Despite similar BP levels among all
76 Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

Table 1. Measurements of individual kidney volume, blood flow, glomerular filtration, and tissue hypoxia before and
3 months after renal artery stenting
Stenotic Kidney (n¼17) Contralateral Kidney (n¼10)
Baseline 3 mo Baseline 3 mo
Total kidney volume (ml) 124645 138649a 175652 162660
Cortical 79637 87636 109644b 111647
Medullary 45617 51617 66624b 51618
Total renal blood flow (ml/min) 2386119 2976174a 3986162b 3726221
Cortical 1896102 2436149 3256153b 3146195
Medullary 49625 54631 74637b 58640
Single kidney GFR (ml/min) 28616 33619 48622b 41621
Fractional hypoxia (% R2*.30/s)
Before furosemide 19.2 11.5a 14.3 9.3
After furosemide 12.5 5.2a 5.6 3.5
Data are presented as means6SD or percentages. Kidney volume and renal blood flow were measured by computed tomography. GFR was measured by iothalamate
clearance. Fractional hypoxia was measured by blood oxygen level–dependent magnetic resonance imaging (% R2.30/s). Reprinted (with modification) with permission from
Saad A, Herrmann SM, Crane J, Glockner JF, McKusick MA, Misra S, Eirin A, Ebrahimi B, Lerman LO, Textor SC: Stent revascularization restores cortical blood flow and reverses
tissue hypoxia in atherosclerotic renal artery stenosis but fails to reverse inflammatory pathways or glomerular filtration rate. Circ Cardiovasc Interv 6: 428–435, 2013.
a
P,0.05 compared with baseline.
b
P,0.05 compared with stenotic kidneys.

groups, only the valsartan-treated group experienced
a reduction in proteinuria and tubular injury (based on
NGAL levels), although this reduction was of small
magnitude. More important was the observation that
the GFR of animals with a stenotic kidney, already
lower than that of control animals, did not fall fur-
ther upon exposure to valsartan. Finally, the investiga-
tors demonstrated that compared with triple therapy,
valsartan resulted in similar improvements in renal hyp-
oxia (by BOLD-MRI), preservation of microcirculatory
integrity, especially in the outer cortex (Figure 7), and
stimulation of proangiogenic factors (16). These ob-
servations indicate that it may be not only safe but also
beneficial to expose a significantly stenotic kidney to
a RAS blocker, with a safety profile that is similar to
that of conventional antihypertensive therapy. These
agents may also be safely used to exert their beneficial
effects on other territories such as the contralateral kid-
ney, heart, and systemic vasculature.
Renal Revascularization Update
Renal revascularization procedures continue to
be performed, although Medicare trends indicated
substantial decreases during the early portion of the
first decade of this century (12), likely due to the
publication of studies casting doubt on the value of
indiscriminate use of renal artery stenting. Liang et al.
explored two databases, the Nationwide Inpatient Sample
and the State Inpatient and Ambulatory Databases, to
obtain representative information on inpatient procedures
throughout the United States and ambulatory procedures
in selected states between 1988 and 2009 (17). The large
majority of procedures were for atherosclerotic renovas-
cular disease, and .90% of patients were managed with
renal artery angioplasty and stenting. The peak of utiliza-
tion of revascularization procedures was in 2006 (13.7
cases per 100,000 adults), but this was followed by a steady
decline, resulting in a rate of only 6.7 cases per 100,000
adults by 2009. Complication rates were low and inpatient
data showed much lower rates of hospital mortality,
hospital complications, and length of stay for those treated
operatively compared with percutaneous interventions.
Perhaps most interesting in this report was the delineation
of the role of different specialties in performing percuta-
neous renal revascularization. Interventional cardiologists
have steadily retained approximately 70% of the market,
vascular surgeons have increased their market share to
approximately 20%, and interventional radiologists have
experienced a steady decline in their share (now ,10%). It
will be interesting to see the behavior of procedure
utilization after 2009, when the first large randomized
trials of renal artery stenting were published, and partic-
ularly from now onward, in the aftermath of the results of
the Cardiovascular Outcomes of Renal Atherosclerotic
Lesions (CORAL) trial (see below).
The main results of the CORAL trial were re-
cently published (18) and warrant a detailed discussion.
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 77

Figure 7. Microvascular changes (by micro-CT) in renal artery stenosis (RAS) in the pig. (A) Normal animals. (B) Untreated
animals with renal artery stenosis with marked rarefaction of small vessels. (C and D) Improved microvasculature with valsartan
(C) or triple therapy (TT) with reserpine, hydralazine, and hydrochlorothiazide. (E and F) Quantitative effects of therapy
according to vessel size and location, indicating a better effect of valsartan in both small- and medium-sized vessels of the outer
cortex. *P,0.05 versus normal; $P,0.05 versus RAS. Reprinted with permission from Zhang X, Eirin A, Li ZL, Crane JA,
Krier JD, Ebrahimi B, Pawar AS, Zhu XY, Tang H, Jordan KL, Lerman A, Textor SC, Lerman LO: Angiotensin receptor
blockade has protective effects on the poststenotic porcine kidney. Kidney Int 84: 767–775, 2013.

The trial enrolled 947 patients with uncontrolled hyper-
tension and atherosclerotic renal artery stenosis. Upon
initiation of the trial, systolic hypertension (systolic
BP.155 mmHg while using at least two antihyperten-
sive drugs) was an absolute requirement; however, later
in the trial, its presence was no longer required for pa-
tients with eGFR,60 ml/min per 1.73 m2. Initially, only
angiographically diagnosed renal artery stenosis was
acceptable for inclusion ($60% and ,80% with a $20
mmHg systolic pressure gradient using a #4 F diam-
eter device, or $80% and ,100% by angiography
with no gradient requirement); later in the trial, pa-
tients could be enrolled based on noninvasive methods,
such as duplex ultrasonography (peak systolic velocity
.300 cm/s) or magnetic resonance or CT angiography.
Relevant exclusion criteria included fibromuscular
dysplasia, underlying CKD due to a cause other than
ischemic nephropathy, and patients with baseline se-
rum creatinine.4 mg/dl.
After confirmation of the presence of renal artery
stenosis, participants were randomized to renal artery
stenting and best medical therapy or best medical therapy
alone (18). Best medical therapy consisted of an ARB
(candesartan, with or without hydrochlorothiazide or
amlodipine), aspirin, and atorvastatin. A bare metal
stent was used for the intervention group and distal
embolic protection devices were used at the discretion
of the interventionalist. The primary endpoint was
a composite cardiovascular and renal end point that
included cardiovascular or renal death, myocardial
infarction, hospitalization for congestive heart failure,
stroke, progressive CKD, and need for RRT. Baseline
characteristics of the two groups were similar and are
presented in Table 2. A total of 25 patients (5.3%)
randomized to stenting did not undergo the interven-
tion; conversely, 19 of the patients (4%) assigned to
medical therapy crossed-over to receive stenting during
the course of the trial.
After a median follow-up of 3.6 years, both
groups experienced an increase in the number of
antihypertensive agents required to achieve the BP
targets (,140/90 mmHg in most, ,130/80 mmHg in
patients with diabetes or CKD). The average systolic
BP was 2.3 mmHg lower in the stent group throughout
the trial (P¼0.03). As detailed in Table 3, there was no
difference in the incidence of the primary composite
endpoint (35.1% in the stent group versus 35.8% in the
medical group) (HR, 0.94; 95% CI, 0.76 to 1.17;
P¼0.58), any of its individual components, or any of
the secondary endpoints. Likewise, analyses of many
prespecified subgroups did not reveal any significant
signals of differential effect (18).
In addition to the negative results of the CORAL
trial, negative evidence related to interventions in con-
trolled clinical trials continues to accumulate. A ran-
domized clinical trial of 84 patients with atherosclerotic
78 Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

Table 2. Baseline characteristics of patients enrolled in the CORAL trial

Stenting Plus Medical Therapy Medical Therapy Only
Characteristic (n¼459) (n¼472)
Age (yr) 69.369.4 69.069.0
Men 51.0 48.9
Racea
Black 7.0 7.0
Other 93.0 93.0
Body mass index (kg/m2) 28.265.3 28.765.7
Systolic BP (mmHg) 149.9623.2 150.4623.0
BP at target level (%)b 29.2 25.3
eGFR (ml/min per 1.73 m2)c 58.0623.4 57.4621.7
Stage$3 CKD 49.6 50.4
Method of identification of stenosis
Angiography 68.4 68.6
Duplex ultrasonography 25.5 24.2
Computed tomographic angiography 4.4 5.3
Magnetic resonance angiography 1.7 1.9
Medical history and risk factors
Diabetes 32.4 34.3
Prior myocardial infarction 26.5 30.2
History of heart failure 12.0 15.1
Smoking in past year 12.0 32.2
Hyperlipidemia 89.4 90.0
Angiographic findingsd
% Stenosis, as assessed by core laboratory 67.3611.4 66.9611.9
% Stenosis, as assessed by investigator 72.5614.6 74.3613.1
Global ischemiae 20.0 16.2
Bilateral diseasef 22.0 18.1
Data are presented as means6SD or percentages. There were no significant differences between the groups in any of the characteristics listed here (P.0.05). Reprinted (with
modification) with permission from Cooper CJ, Murphy PT, Cutlip DE, Jamerson K, Henrich W, Reid D, Cohen DJ, Matsumoto AH, Steffes M, Jaff MR, Prince MR, Lewis EF, Tuttle
KR, Shapiro JI, Rundback JH, Massaro JM, D’Agostino RB Sr, Dworkin LD; the CORAL Investigators: Stenting and medical therapy for atherosclerotic renal-artery stenosis
[published online ahead of print November 18, 2013]. N Engl J Med doi:10.1056/NEJMoa1310753.
a
Race was self-reported. “Other” included white (91.5% in the stent group and 90.9% in the medical therapy–only group), as well as American Indian or Alaska Native, Asian,
and Native Hawaiian or other Pacific Islander.
b
The target level of BP was ,140/90 mmHg for patients without coexisting conditions and ,130/80 mmHg for patients with diabetes or CKD.
c
The eGFR was calculated using the modified Modification of Diet in Renal Disease formula.
d
Angiographic data are shown for patients who underwent invasive angiography.
e
Global ischemia was defined as stenosis of $60% of the diameter of all arteries supplying both kidneys or stenosis of $60% of the diameter of all arteries supplying a single
functioning kidney.
f
Bilateral disease was defined as stenosis of $60% of the diameter of at least one artery supplying each kidney.

renal artery stenosis failed to demonstrate any effect of
renal artery stenting on left ventricular mass, BP, or
renal function compared with optimal medical therapy
over a 12-month period (19). A meta-analysis of five
randomized clinical trials enrolling 1159 patients com-
pared the effect of percutaneous renal artery revascular-
ization (with or without stenting) versus medical therapy
on the future occurrence of nonfatal myocardial in-
farction (NFMI) (20). A total of 56 NFMIs occurred
during follow-up, and renal revascularization did not
affect the risk of NFMI (risk ratio, 0.86; 95% CI, 0.51 to
1.43; P¼0.55). These results remained unchanged re-
gardless of whether or not a stent was implanted and were
independent of follow-up renal function or length of
follow-up (20). Overall, we believe that the cumulative
evidence is now conclusive: in patients with stable ath-
erosclerotic renal artery stenosis, hypertension, and CKD,
renal artery stenting does not confer any renal or car-
diovascular benefit.
Certain patient groups, such as those with heart
failure or those with acute pulmonary edema, have
not been enrolled in any of the large clinical trials
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 79

Table 3. Clinical endpoints in the CORAL trial

Hazard Ratio
Stenting Plus Medical Medical Therapy (95% Confidence
End Point Therapy (n¼459) Only (n¼472) Interval) P Value
Primary end point: death from 161 (35.1) 169 (35.8) 0.94 (0.76 to 1.17) 0.58
cardiovascular or renal causes,
stroke, myocardial infarction,
hospitalization for congestive
heart failure, progressive renal
insufficiency, or permanent
renal-replacement therapya
Components of primary end pointb
Death from cardiovascular or 20 (4.4) 20 (4.2)
renal causes
Stroke 12 (2.6) 16 (3.4)
Myocardial infarction 30 (6.5) 27 (5.7)
Hospitalization for congestive heart 27 (5.9) 26 (5.5)
failure
Progressive renal insufficiency 68 (14.8) 77 (16.3)
Permanent RRT 4 (0.9) 3 (0. 6)
Secondary clinical end pointsc
Death from any cause 63 (13.7) 76 (16.1) 0.80 (0.58 to 1.12) 0.20
Death from cardiovascular causes 41 (8.9) 45 (9.5) 0.89 (0.58 to 1.36) 0.60
Death from renal causes 2 (0.4) 1 (0.2) 1.89 (0.17 to 20.85) 0.60
Stroke 16 (3.5) 23 (4.9) 0.68 (0.36 to 1.28) 0.23
Myocardial infarction 40 (8.7) 37 (7.8) 1.09 (0.70 to 1.71) 0.70
Hospitalization for congestive heart 39 (8.5) 39 (8.3) 1.00 (0.64 to 1.56) 0.99
failure
Progressive renal insufficiency 77 (16.8) 89 (18.9) 0.86 (0.64 to 1.17) 0.34
Permanent RRT 16 (3.5) 8 (1.7) 1.98 (0.85 to 4.62) 0.11
Hazard ratios were calculated using multivariable proportional-hazards regression. P values were calculated using the log-rank statistic. Reprinted (with modification) with
permission from Cooper CJ, Murphy PT, Cutlip DE, Jamerson K, Henrich W, Reid D, Cohen DJ, Matsumoto AH, Steffes M, Jaff MR, Prince MR, Lewis EF, Tuttle KR, Shapiro JI,
Rundback JH, Massaro JM, D’Agostino RB Sr, Dworkin LD; the CORAL Investigators: Stenting and medical therapy for atherosclerotic renal-artery stenosis [published online
ahead of print November 18, 2013]. N Engl J Med doi:10.1056/NEJMoa1310753.
a
Only the first event per participant is included in the composite.
b
Components of the composite are included only if it was the first event contributing to the primary end point.
c
The first event for each component of the primary composite end point is included as a secondary end point.

performed to date. A recent systematic review ana-
lyzed the outcomes of renal artery stenting in patients
with renal artery stenosis presenting either with acute
pulmonary edema (n¼79 patients) or with congestive
heart failure (CHF) and progressive kidney dysfunction
(n¼94 patients) (21). The analysis of acute pulmonary
edema indicated a substantial shift in the frequency of
recurrent pulmonary edema during follow-up of up to
52 months. Of the 67 patients with reported outcomes,
54 did not have any recurrence during follow-up, and
those who did were typically affected by restenosis of
the treated renal artery or had a new primary cardiac
event. The analysis of CHF showed a consistent im-
provement in functional heart failure class and fewer
hospitalizations for heart failure, but no significant
effect on renal function during follow-up. Interpretation
of these uncontrolled data is problematic; the quality of
the evidence is certainly low, but the clinical results are
consistent, especially in patients with acute (“flash”)
pulmonary edema without another apparent cause. In
these patients, it is highly unlikely that better evidence
will soon be available, and revascularization is often
performed empirically in such patients. The case of
CHF and kidney dysfunction is more complex, because
many different factors are operative. Demonstration of
a direct relationship between renal artery intervention
and improvement in outcomes in CHF will require
more rigorous methodologic approaches that include
80
uniform screening for renal artery stenosis, optimized
medical therapy for heart failure, and the randomized
assignment to revascularization.
In summary, there is no evidence of benefit from
intervening on RAS in patients with stable renal
function and BP. However, when renal artery stenosis
is diagnosed in patients presenting with rapid loss of
renal function (particularly if a result of RAS blockade
or achievement of BP control) or with unexplained acute
heart failure, our opinion is that renal artery stenting still
has value in clinical practice. These were patients typ-
ically excluded from the available trials, and common
sense along with anecdotal experience will continue to
drive clinical decisions in such patients.
Future Directions in Renovascular Disease—Insights
from Experimental Models
The development of a model of atherosclerotic
renal artery stenosis in the pig, wherein stenotic lesions
develop over several weeks in response to coil-induced
endothelial injury, has allowed the study of renal artery
stenosis and ischemic renal disease in a way that may
be directly applicable to human disease. Furthermore,
these large animals can also undergo percutaneous
revascularization and stenting, thus also allowing the
evaluation of treatment interventions. This model has
shown that blood flow restriction and induction of
renal ischemia in the setting of arterial stenosis promotes
chronic renal injury by way of progressive inflammation,
tissue fibrosis, and microvascular rarefaction (22). It has
also shown that angioplasty and stenting of these lesions
results in restoration of perfusion and improved BP,
but does not normalize the GFR of the stenotic kid-
ney. Moreover, revascularization does not restore tissue
integrity either, as demonstrated by persistent interstitial
fibrosis at the time of kidney analysis (4 weeks after
revascularization), persistently high levels of markers of
oxidative stress and inflammation, and unrestored mi-
crovascular rarefaction (23). These findings emphasize
the potential value of cointerventions that may modulate
the environment at the time of revascularization to one
that is less proinflammatory or profibrotic. Two such
strategies, using stem cells or drugs altering mitochon-
drial function, were explored in recent studies. Because
mesenchymal stem cells (MSCs) have proangiogenic
and anti-inflammatory properties, Ebrahimi et al. tested
the value of MSCs as adjunct therapy in pigs undergoing
renal artery stenting 6 weeks after the induction of
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
stenosis by renal artery coiling and consumption of an
atherogenic, high-cholesterol diet (24). Compared with
stenting alone, the infusion of MSCs into the renal
artery at the time of stenting resulted in greater ex-
pression of angiogenic markers (vascular endothelial
growth factor [VEGF] and fetal liver kinase-1), which
was associated with increased microvascular density
and decreased expression of proinflammatory (mono-
cyte chemoattractant protein-1, TNF-a) and profi-
brotic (CD1631 cells, matrix metalloproteinase-2)
factors, which was associated with decreased tubu-
lointerstitial injury. Figure 8 shows selected examples
of these observations.
One of the less frequently explored factors
related to renal injury at the time of revascularization
is reperfusion injury, which is associated with upregu-
lation of injury pathways with long-lasting effects.
Using the same swine model, Eirin et al. evaluated the
role of mitochondria-targeted peptide-131 (Bendavia),
a mitochondrial permeability transition pore (mPTP)
inhibitor, in decreasing progressive renal injury due to
atherosclerotic renal artery stenosis after stenting (25).
During reperfusion, the generation of reactive oxygen
species and/or ATP depletion can lead to opening of the
mPTP, leading to mitochondrial dysfunction that results
in cell apoptosis and increased proinflammatory signal-
ing (25). Mitochondria-targeted peptide-131 (mtp-131) is
a tetrapeptide that inhibits mPTP opening; its use in
models of myocardial and renal ischemia-reperfusion has
resulted in attenuated reperfusion injury. In this study, it
was administered as an intravenous infusion starting
30 minutes before stenting and continued for another
3.5 hours; this treatment resulted in increased markers of
mitochondrial biogenesis. Compared with the control
group (stenting alone), mtp-131 did not attenuate the
acute inflammatory response. However, mtp-131 treated
animals showed improved GFR in the stenotic kidney (68
versus 50 ml/min; P,0.01), significantly decreased renal
tubular cell apoptosis, increased neovascularization, de-
creased renal inflammation, and lower tubulointerstitial
and glomerular fibrosis scores. The same investigators
have now reported that mtp-131 administration at the time
of renal revascularization also improves myocardial in-
flammation, fibrosis, and microvascular architecture (26).
These distant effects are obviously independent of local
reperfusion injury and create a link between reduction of
the inflammatory response in the kidney and improve-
ments in structure and function at distant target organs
affected by renovascular hypertension. Interestingly,
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Figure 8. Effects of renal angioplasty and stenting with or
without mesenchymal stem cell infusion on microvascular
density (by vWf staining) and capillary count (direct in-
spection of fixed tissue), histological tubular injury score, tissue
expression of monocyte chemotactic protein-1, and overall
tissue fibrosis (percent area positive for trichrome). Normal
refers to control animals. ARAS, atherosclerotic renal artery
stenosis; MCP-1, monocyte chemotactic protein-1; MSC,
mesenchymal stem cell; PTRA, renal angioplasty and stenting.
Reprinted (with modification) with permission from Ebrahimi
B, Eirin A, Li Z, Zhu XY, Zhang X, Lerman A, Textor SC,
Lerman LO: Mesenchymal stem cells improve medullary in-
flammation and fibrosis after revascularization of swine athero-
sclerotic renal artery stenosis. PLoS ONE 8: e67474, 2013.
cyclosporine is a potent mPTP inhibitor with demonstra-
ble protective effects in myocardial ischemia (27). This
drug, which is familiar to most nephrologists and has
a well established track record, would be an interesting
drug to test for use during renal revascularization,
especially because short-term use is unlikely to have
significant long-term adverse renal toxicity.
Recent human studies have explored the timing
of generation of inflammatory signals in renovascular
disease in an attempt to explain the negative findings
of revascularization studies on renal function. Kotliar
et al. studied the profile of peripheral blood mono-
nuclear cells of hypertensive patients without any
evidence of renal artery stenosis and patients with
incidental renal artery atherosclerosis with ,50%
luminal occlusion (i.e., “early” disease) (28). None of
the patients had known atherosclerosis anywhere else
and all had documented absence of coronary or carotid
disease via angiography. Patients with heart failure,
albuminuria, or eGFR,60 ml/min per 1.73 m2 were
also excluded. Flow cytometry demonstrated an excess
of cell subtypes expressing specific markers (CD3,
81
CD4, CD83, CD86), suggesting increased expression
of proinflammatory lymphocytes and dendritic cells.
An increased CD41/CD81 ratio (8.361.4 versus
3.460.9; P,0.001) coupled with a lower CD251/
CD41 ratio (0.0960.02 versus 0.2960.09; P,0.001)
in patients with stenosis indicated a profile that was
proinflammatory and less immune tolerant. The inves-
tigators also examined renal atherosclerotic plaques of
deceased hypertensive patients in whom isolated renal
atherosclerosis was identified at autopsy. The plaques
exhibited a similar proinflammatory profile, suggesting
that the peripheral blood mononuclear cell profile
observed in live patients was, perhaps, driven by the
microenvironment of renal atherosclerotic plaques (28).
This evidence suggests inflammatory overactivity before
any tissue injury occurs; however, with time, the in-
flammatory environment is also extended to the post-
stenotic kidney. This finding was recently confirmed by
the evaluation of transjugular renal biopsy tissue of
kidneys distal to unilateral renal artery stenosis.70%
(29). In this study, the investigators compared the
interstitial inflammatory scores of poststenotic kid-
neys with those of normal kidneys (donor nephrecto-
mies) and of kidneys removed from patients with total
renal artery occlusion and resistant hypertension. Not
surprisingly, the authors observed progressive sever-
ity of inflammatory and fibrotic changes in stenotic
kidneys compared with those with complete occlu-
sion, including a 2-fold greater expression of profi-
brotic CD681 macrophages in atrophic kidneys with
occluded arteries.
The proinflammatory and profibrotic
changes in renal artery stenosis begin
early, are driven by an immune response
that is centered in the microenvironment
of the atherosclerotic plaque and the
ischemic kidney, and progress with the
severity of ischemia. Because this inflam-
matory response is not quelled by revas-
cularization alone, it is plausible that its
modification, either with targeted immu-
nomodulatory therapies or short-term con-
ventional immunosuppression, may be an
essential cointervention. This hypothesis
will require formal testing in human dis-
ease.
82
Obesity
In the previous NephSAP on hypertension, we
focused on the pathogenesis of obesity-related hyper-
tension (12). In the past 2 years, two important
randomized clinical trials were published addressing
the metabolic and BP effects of bariatric surgery in
obese patients with diabetes (30,31). In a multicenter
trial, Ikramuddin et al. randomized 120 obese patients
with diabetes with a BMI between 30 and 30.9 kg/m2
to either medical therapy (i.e., lifestyle changes;
n¼60) or gastric bypass (n¼60). At baseline, the
mean BMI was 34.6 kg/m2, 59% of patients had
a BMI,35 kg/m2, and the average BP was 132/79
mmHg in the lifestyle group (73% taking antihyper-
tensive medications) and 127/78 mmHg in the surgical
group (68% taking medications). After 12 months of
follow-up, the average weight loss was 16 kg greater
in the surgical group and was associated with 9/6
mmHg greater reduction in BP than in the lifestyle
group. The BP reduction achieved its maximum by 6
months and remained stable through the 12 months of
follow-up (30). Schauer et al. enrolled 150 obese
patients with diabetes (BMI 27–43 kg/m2) in a single-
center randomized trial comparing medical therapy
(i.e., lifestyle changes, n¼50) with two different bar-
iatric procedures (i.e., gastric bypass or sleeve gas-
trectomy, n¼50 each). At baseline, the mean BMI
was 36 kg/m2 (34% with BMI,35 kg/m2), and 64%
of patients had a history of hypertension. After 12
months, the average weight loss was 5.468 kg in the
medical therapy group, 29.468.9 kg in the gastric
bypass group, and 25.168.5 kg in the sleeve gastrec-
tomy group (all intergroup comparisons were highly
significant), with similar BP levels in all groups, but
with much higher antihypertensive drug use in the
medical therapy group (77%) than in the other two
groups (33% and 27%, respectively) (31). These
randomized trial data confirm the value of surgical
weight reduction in producing BP control in hyper-
tensive patients with diabetes, as suggested by pre-
vious observational and nonrandomized studies.
Furthermore, the fact that a substantial number of
patients had mild to moderate obesity (BMI,35
kg/m2) underscores the importance of weight reduc-
tion in the treatment of hypertension and raises
awareness of the potential value of bariatric surgery
in the management of hypertension, even in patients
without morbid obesity.
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) occurs in 30% of
patients with hypertension and up to 70%–90% of
patients with resistant hypertension (32). As discussed
in the previous NephSAP on hypertension (12), the
association between OSA and hypertension is depen-
dent on the severity of the OSA and is confounded by
the presence of obesity. A recent analysis of the
National Health and Evaluation Survey confirmed that
the relationship between OSA and hypertension is not
significant in individuals with BMI,25 kg/m2 (ad-
justed OR, 0.91; 95% CI, 0.54 to 1.53; P¼0.71) (33).
Because of the frequent presence of OSA in
clinical practice, nephrologists should be familiar with
the screening for OSA, especially in overweight and
obese patients, and in all patients with resistant hy-
pertension. In a recent article in the Journal of the
American Medical Association’s Rational Clinical
Examination series, Myers et al. performed a systematic
review that included 42 studies to identify clinical
features that are associated with a high likelihood of
OSA (34). Their analysis indicates that multiple signs
and symptoms are associated with the presence of
OSA, but that the likelihood ratios associated with
each individual sign or symptom are typically low (,2)
with the exception of witnessed nocturnal choking or
gasping. The presence of snoring does not confer a high
likelihood of OSA, but its absence makes the diagnosis
of OSA unlikely. The presence of daytime sleepiness
and a history of frequent car accidents are also more
common in OSA. Other elements deserve mention.
Men have a much greater prevalence of OSA, espe-
cially if they are aged.50 years and are overweight or
obese. Clinical signs such as a high Mallampati class
(i.e., a “crowded” oropharynx) or large neck circum-
ference (.50 cm) also have only limited positive
predictive value. Unfortunately, composites of findings
have not been adequately tested, and scores on some of
the published questionnaires (e.g., STOP-Bang, Berlin)
do not perform well to predict high likelihood of OSA,
but are effective in decreasing its likelihood when
scores are low. So what should we do as clinicians?
We should always consider OSA in hypertensive pa-
tients, should inquire about snoring, gasping/choking,
daytime somnolence, and car crashes in all patients, and
should perform a focused examination of the upper
airway and neck. Further details are available in the
article by Myers et al. (34). If many features suggesting
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
risk (and definitely if gasping/choking) are present, the
patient should be referred for polysomnography. On the
other hand, if the patient does not snore and does not
have multiple other symptoms, formal evaluation may
be avoided.
Relevance of Treatment of OSA to Improve BP
Control and Cardiovascular Outcomes
The mainstay of treatment of clinically significant
OSA is the use of noninvasive continuous positive
airway pressure (CPAP) ventilation. An updated meta-
analysis of 28 randomized clinical trials (n¼1948
patients) comparing CPAP with either sham CPAP or
best medical therapy showed an average greater re-
duction of 2.6/2 mmHg in diurnal BP in patients
receiving the CPAP intervention (35). The reduction
in nocturnal BP based on 10 studies was 4.1/1.9
mmHg. Although the effect is statistically significant,
this effect is numerically small, but appears to be more
relevant among patients who are younger (age,40
years), have higher sleepiness scores (Epworth Sleep-
iness Scale score.10), more severe OSA (apnea/
hypopnea index.30), greater CPAP adherence (.4
hours per night), and higher baseline diastolic BP.
However, even among these subgroups, the magnitude
of the effect is still small. A randomized clinical trial
comparing CPAP with medical therapy in 35 patients
with true resistant hypertension (daytime ambulatory
BP.135/85 mmHg) was recently published (36). Pa-
tients remained on the same drug therapy throughout
the 6-month duration of the trial. The average awake
ambulatory BP decreased in those patients randomized
to CPAP (26.5/24.5 mmHg), whereas it increased in
individuals given medical therapy alone (13.1/12.1
mmHg; P,0.05). These results show a significant ef-
fect of CPAP in patients with resistant hypertension;
however, only 16% of CPAP-treated patients and 6% of
control patients reached normal ambulatory BP values.
Therefore, although it is effective, the use of CPAP is
certainly far from curative in these patients.
The first long-term randomized clinical trial
exploring the effect of CPAP on BP and cardiovascular
disease in OSA was recently published (37). In this
large, multicenter Spanish trial, 723 nonsleepy OSA
patients (Epworth Sleepiness Scale score#10) were
randomized to CPAP or no intervention and followed
for a median of 4 years. Because withholding CPAP
therapy in patients with symptomatic OSA would be
unethical, this study chose to study the long-term
83
cardiovascular benefits in nonsleepy patients. At base-
line, all patients had moderate to severe OSA (apnea/
hypopnea index.20). None had a history of cardio-
vascular disease, and 52% had a diagnosis of hyperten-
sion, although only 24% were receiving antihypertensive
drugs. The primary endpoint of the study was a com-
posite of new hypertension (BP.140/90 mmHg) or new
cardiovascular event (nonfatal myocardial infarction,
nonfatal stroke, transient ischemic attack, hospitalization
for unstable angina or arrhythmia, heart failure, or
cardiovascular death). When the main components of
the composite endpoint were analyzed separately, there
were no significant effects of CPAP on either hyperten-
sion or cardiovascular events. A secondary analysis
according to severity of OSA based on apnea/hypopnea
index or total time with oxygen saturation ,90% showed
no significant interaction between OSA severity and
outcomes according to assigned treatment. However,
a subgroup analysis based on average time of adherence
to CPAP (.4 hours per night or ,4 hours per night)
showed a significant effect on the primary endpoint:
patients who wore CPAP >4 hours per night had
a significant reduction on the occurrence of the primary
endpoint whereas those with adhrence ,4 hours per
night were no different from controls.
Taken together with the observations that the
effect of CPAP on BP is more prominent in patients
with more symptomatic OSA (35), these results cor-
roborate the limited value of CPAP in asymptomatic
patients. However, we believe there is value in trying
CPAP therapy in patients with OSA who have difficult-
to-treat hypertension and are willing to adhere to CPAP
treatment, especially given its minimal risks and
potential value based on the subgroup analysis accord-
ing to adherence to therapy.
New therapies for hypertension may have value
in hypertensive OSA patients. Because sympathetic
overactivity is a key element in the pathogenesis of
hypertension and cardiovascular complications in OSA,
control of the sympathetic nervous system is an im-
portant component of the treatment of these patients.
Accordingly, b-blockers are among the most effective
antihypertensive agents in OSA (38). Moreover, renal
sympathetic denervation for the treatment of resistant
hypertension (see detailed discussion elsewhere in this
syllabus) may be particularly successful in OSA. A small
case series of 10 patients with OSA treated with renal
sympathetic denervation showed a sustained effect on
office BP in all patients (average BP change¼234/213
84
mmHg), but no significant effect on ambulatory BP
(average 24-hour systolic BP change¼28 mmHg) (39).
Some patients had improved glycemic control and
decreased severity of OSA during follow-up. Larger,
controlled studies (with active control groups that in-
clude effective antiadrenergic therapy) in OSA will be
necessary to confirm or dispel the value of renal de-
nervation in this population.
Primary Aldosteronism
Primary aldosteronism is among the most com-
mon causes of secondary hypertension. Most clinicians
screen for it by performing random measurement of
plasma aldosterone and renin activity. In patients with an
elevated aldosterone/renin ratio (ARR) and elevated
plasma aldosterone, a diagnosis of primary aldosteronism
is confirmed through documentation of nonsuppressible
aldosterone excess by one of several methods, most com-
monly a 24-hour urine collection for aldosterone under
conditions of high sodium intake. An updated meta-
analysis provided estimates on the prevalence of primary
aldosteronism in primary care and referral settings (40).
Among approximately 3300 primary care patients, the
prevalence of a high ARR was 16%, whereas the
prevalence of primary aldosteronism was 4.3%. In
patients referred to a subspecialist practice (approximately
9600), these numbers were 19.6% and 9.5%, respectively.
Therefore, although the prevalence of high ARR is not
much different between the two settings, the investigation
to confirm the presence of primary aldosteronism is twice
as yielding in specialty centers than in primary care. There
is no obvious explanation as to why this is the case; it is
possible that more false positive ARRs occur in primary
care due to less standardized testing procedures. Figure 9
provides a visual estimate of the variability of these results
across studies.
Genetic Mutations in Aldosterone-Producing
Adenomas with Relevant Clinical and Mechanistic
Implications
In the previous NephSAP on hypertension, we
provided a detailed review of the identification of
somatic mutations in the gene coding for the potassium
channel KCNJ5 in aldosterone-producing adenomas
(12). These mutations, present in about one third of
adenomas, produce loss of potassium selectivity of the
channel, allowing sodium influx and chronic depolar-
ization of the cell, which leads to calcium influx and
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Figure 9. Prevalence of elevated ARRs and primary aldo-
steronism in primary care and referred patients obtained from
individual studies included in a previous meta-analysis (gray
dots) and in an updated (red dots) meta-analysis. Reprinted
with permission from Hannemann A, Wallaschofski H:
Prevalence of primary aldosteronism in patient’s cohorts and
in population-based studies—a review of the current literature.
Horm Metab Res 44: 157–162, 2012.
consequent activation of aldosterone synthase and cell
proliferation. These changes help explain the develop-
ment of both disorderly cell growth (adenoma forma-
tion) and excessive secretion of aldosterone. The initial
studies were performed in a small group of patients, but
these observations have now been extended to larger
cohorts, including the European Network for the Study
of Adrenal Tumors, which reported the identification of
somatic KCNJ5 mutations in 380 aldosterone-producing
adenomas (41). These studies also explored the occur-
rence of germ line mutations in the peripheral blood of
344 patients with adenomas and 174 patients with
presumed bilateral adrenal hyperplasia, but were unable
to identify any such mutations. In addition, they could
not identify somatic mutations in the adrenal tissue
adjacent to tumors with the mutation. These observa-
tions indicate that mutations are acquired and restricted
to aldosteronomas.
The same group that originally reported the
KCNJ5 mutations has further developed the topic by
identifying somatic mutations in the gene encoding the
voltage-gated calcium channel CACNA1D in the tis-
sue of 5 of 41 aldosteronomas that had tested negative
for the more common KCNJ5 mutations (42). These
mutations lead to increased calcium influx and a similar
phenotype of cell proliferation and aldosterone syn-
thase activation as observed with KCNJ5 mutations.
There may be clinical implications to the identifi-
cation of these mutations. In a recent study of 28 patients
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
undergoing adrenalectomy, the 10 patients with KCNJ5
mutations achieved greater BP control after adrenal-
ectomy than the 18 patients without these mutations,
although the reported follow-up was limited to 6–8
months (43). These preliminary observations warrant
corroboration.
Updates Relevant to the Diagnosis of Primary
Aldosteronism
The ARR is the cornerstone of screening for
primary aldosteronism, and the Endocrine Society has
published detailed guidelines on its interpretation (44).
A recent development was the description of a signif-
icant effect on the ARR by two selective serotonin
reuptake inhibitors (SSRIs): sertraline and escitalo-
pram (45). Six weeks of treatment with these drugs
among depressed men resulted in substantial changes
in renin concentration and activity (increased mark-
edly) and aldosterone concentration (increased only
slightly), the net effect of which was a reduction of the
ARR. Several mechanisms were postulated for this
effect but none were formally tested. In case these
observations extend to other SSRIs, these results have
important practical implications to the screening of
primary aldosteronism, because SSRIs are the most
commonly used antidepressant agents.
In the previous NephSAP on hypertension, we
discussed the central value of adrenal venous sampling
(AVS) for subtype differentiation in primary aldoste-
ronism (12). The first report from the Adrenal Vein
Sampling International Study (AVIS) has been re-
leased, and it provides a summary of the AVS practices
in 20 countries on 4 continents (46). The AVIS database
contains data on 2604 AVS procedures, with an average
number of 130 per center over the 6-year collection
period. The database reports a 2.5-fold increase in use of
AVS between 2005 and 2010, with an average of 77% of
patients referred for primary aldosteronism being system-
atically subjected to the procedure, although the inter-
center variability was high (19%–100%). This data set
will be enormously informative about the prevalence of
different subtypes of primary aldosteronism and the
optimal means of interpretation of results, because
there still is wide variability in cutoff ratios to define
lateralization and suppression across centers (46).
Of interest to the nephrology readership, Burshteyn
et al. presented their experience with AVS in 25
patients with CKD (average eGFR, 37611 ml/min
per 1.73 m2; range, 12–54) (47). The procedure was
85
successful in distinguishing between subtypes of pri-
mary aldosteronism in 24 patients. The 25th patient
underwent a second AVS, which was then successful.
After an average contrast infusion of 25 ml (maximum
50 ml), two patients developed mild AKI (Acute
Kidney Injury Network stage 1) and both recovered
to baseline eGFR levels. These results indicate, for the
first time, that the procedure can be performed safely
and effectively in patients with CKD.
The two most common subtypes of primary
aldosteronism are bilateral adrenal hyperplasia and
aldosterone-producing adenoma (APA). A somewhat
unexpected result of the more frequent use of AVS has
been the increasingly more common identification of
unilateral adrenal hyperplasia (UAH). UAH presents
clinically in a way that is similar to APA, but no APA
is identified on histologic cuts of the removed adrenal
gland. Instead, either micronodular or diffuse adreno-
cortical hyperplasia is observed (48–50). In three
recent reports, one prospective (49) and two retrospec-
tive (48,50), UAH (micronodular or diffuse) accounted
for 46 of 140 patients who had lateralized on AVS and
underwent adrenalectomy. This number is unexpect-
edly high, and it is possible that some of the patients
classified as having “micronodular unilateral hy-
perplasia” actually had only a single functioning
micronodule. Only detailed immunohistochemistry
to localize aldosterone synthase activity would be able
to resolve this discrepancy by delineating more pre-
cisely the areas of functional activity, but this technique
was not performed in either report. Nevertheless, this
improved ability to identify patients who lateralize on
AVS and do not have adenomas is clinically relevant.
In the past, adrenal imaging (CT or magnetic resonance
imaging [MRI]) was the typical next step after bio-
chemical confirmation of aldosterone excess. However,
we now know that the overall agreement between
CT/MRI imaging and AVS is approximately 60%
(51). In a systematic review of the literature, AVS
demonstrated lateralization in 19% of patients in which
a CT/MRI scan was either negative or showed non-
adenomatous changes (51). In these cases, patients
would typically not be considered for further evaluation
and potentially curative adrenalectomy. These new re-
ports remind us that patients who would be good
candidates for adrenalectomy should be referred for
AVS in case a lateralizing lesion is identified. This
strategy includes especially patients who are young
and nonobese, and have limited hypertensive target
86
organ injury and a short duration of hypertension, and
hypokalemia. In the case of UAH, the clinical response
to adrenalectomy appears quite similar to that of pa-
tients with APA (48–50,52). Despite this plea, we are
cognizant of the beneficial effect of mineralocorticoid
receptor antagonists (MRAs) in patients with primary
aldosteronism, whether related to APA (or UAH) or
bilateral adrenal hyperplasia. Therefore, as discussed
below, the more important element of therapy is to fo-
cus on elimination of aldosterone excess, using patient
preferences to decide between medical or surgical ap-
proaches (when appropriate).
Drug Treatment of Aldosterone Excess in Primary
Aldosteronism
Patients with primary aldosteronism have in-
creased hypertensive target organ damage compared
with matched patients with essential hypertension.
Previous evidence suggested that elimination of aldo-
sterone excess by adrenalectomy or use of an MRA
eliminated this excess risk (53,54). Larger studies with
longer follow-up have furthered our understanding of
this physiology. A German registry of primary aldoste-
ronism compared mortality rates of 300 patients with
primary aldosteronism with 600 hypertensive patients
and 600 normotensive controls (55). All patients with
aldosteronism were treated either with adrenalectomy (if
lateralizing lesion on imaging or AVS) or with an
MRA, although only approximately 60% of medically
treated patients received spironolactone or eplerenone
(56). After a maximum of 16 years of follow-up, the
total mortality did not differ among the three groups.
However, patients with primary aldosteronism had
greater numbers of cardiovascular deaths (50% of
deaths) than the hypertensive and normotensive controls
(38% and 34%, respectively; P,0.05). Unadjusted
analyses suggested that those patients treated with
adrenalectomy did better than those treated with an
MRA. However, this association did not hold on
multivariable analyses, likely reflecting the fact that
patients with adenomas are often younger and more
often female, thus having lower cardiovascular risk.
Rossi et al. prospectively evaluated 180 patients with
primary aldosteronism treated with adrenalectomy
(n¼110) or an MRA (n¼70) according to the results
of AVS (57). Compared with controls with essential
hypertension, patients with aldosteronism had similar
degrees of BP reduction, control of serum potassium,
and reduction of left ventricular mass over a median
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
follow-up of 3 years. However, when left ventricular
mass was adjusted for the level of BP reduction and left
ventricular workload, both adrenalectomized and med-
ically treated patients with aldosteronism had a signifi-
cant over-representation of left ventricular hypertrophy
(50% and 51%, respectively) compared with essential
hypertensives (27%; P,0.001). Moreover, the preva-
lence of this “inappropriate” left ventricular hypertrophy
increased significantly from baseline to last follow-up in
all groups, but most prominently in those with aldoste-
ronism (Table 4). There were no differences between
surgically and medically treated patients. In summary,
these results indicate that primary aldosteronism is not
a benign disorder and that, even though appropriate
removal of aldosterone excess improves overall risk
(53,54), long-term outcomes may not be as favorable as
those of otherwise matched patients with essential
hypertension (55, 57).
In the previous NephSAP on hypertension, we
reviewed a randomized clinical trial showing that
spironolactone is superior to eplerenone in controlling
BP in patients with primary aldosteronism (58). In an ob-
servational analysis of the German Conn Registry, the BP
levels of 83 patients treated with either spironolactone
(n¼65) or eplerenone (n¼18) were statistically similar
(24-hour average BP, 139/82 versus 142/88 mmHg),
although the spironolactone group required fewer anti-
hypertensive drugs to achieve this level of control (2.2
versus 3.6; P,0.01), had higher serum potassium levels
(4.2 versus 4; P,0.05), and had a trend toward less
microalbuminuria (38615 versus 74628; P¼NS, value
not reported) (56). It is our impression that although
spironolactone is associated with increased rates of sex-
ual side effects and gynecomastia, it provides better re-
sults than eplerenone and should be used as the first
choice in this population.
Finally, the possible value of direct inhibition of al-
dosterone production by blockade of aldosterone syn-
thase activity was tested in a recent trial (59). Amar et al.
performed a sequential, nonrandomized crossover trial
comparing the metabolic and BP effects of eplerenone
and an aldosterone synthase blocker, LCI699, in 14
patients with primary aldosteronism (59). The protocol
called for 4 weeks of LCI699 (0.5 mg twice daily force-
titrated to 1 mg twice daily after 2 weeks) followed by
a 1-week washout period that was followed by 4 weeks
of eplerenone treatment (50 mg twice daily, force-
titrated to 100 mg twice daily after 2 weeks). Consis-
tent with its mechanism of action, LCI699 decreased
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 87

Table 4. Prevalence of LVH in patients with primary aldosteronism and matched controls with essential hypertension
Surgically Treated Medically Treated
PA (n¼110) PA (n¼110) PH (n¼143)
Variable Follow- P Value Follow- P Value Follow- P Value
(%) Baseline Up (2-Tail) Baseline Up (2-Tail) Baseline Up (2-Tail)
LVH 61.3 45.5 0.03 48.6 35.7 NS 52.8 42.7 0.09
Inappropriate 31.8 49.5 0.01 20.0 50.8 0.0002 16.2 27.0 0.03
LVH
At baseline, the prevalence of LVH did not differ significantly across groups, whereas that of inappropriate LVH was higher in surgically treated PA than in PH (P¼0.004); at the
last available follow-up, the prevalence of LVH did not differ significantly across groups, whereas that of inappropriate LVH was significantly higher in both surgically and
medically treated PA than in PH (P,0.001). Inappropriate LVH refers to the presence of high left ventricular mass adjusted for BP levels, sex, body mass, and left ventricular
workload. LVH, left ventricular hypertrophy; PA, primary aldosteronism; PH, primary hypertension. Reprinted (with modification) with permission from Rossi GP, Cesari M,
Cuspidi C, Maiolino G, Cicala MV, Bisogni V, Mantero F, Pessina AC: Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of
primary aldosteronism. Hypertension 62: 62–69, 2013.

aldosterone production by 70%–80%, whereas eplerenone
resulted in an increase in aldosterone levels. Eplerenone,
on the other hand, was more effective than LCI699 in
reducing 24-hour ambulatory BP (29.4/25.2 versus
24.1/22.1 mmHg; P¼0.02 and P¼0.06) and raising
potassium levels (4.3 versus 3.9 mEq/L; P¼0.01).
Although these results may indicate that aldosterone
synthase inhibition is a less effective antihypertensive
approach than mineralocorticoid receptor antagonism,
it does not exclude the possible long-term value of
the agent because the relative merits of aldosterone
blockade versus decreased aldosterone synthesis have
yet to be determined.
In considering the “big picture” of how to approach
the diagnosis and management of primary aldosteronism,
John Funder, a leader in the field of aldosteronism,
described his concerns about excessive testing and high
costs related to diagnosis and subtype differentiation in
primary aldosteronism (60). He argued that there may be
two strategies worth pursuing: to inform patients with
a high ARR that they have a likelihood of having primary
aldosteronism in the 30%–50% range and treating them
with a MRA; or, more drastically, to not screen anyone,
but simply add a low dose of an MRA to the initial
management of all hypertensive patients (60). Although
we think the latter suggestion may be unsubstantiated, the
former certainly could be used to allow targeted therapy
without incurring the high costs of multiple biochemical
and imaging tests, AVS, and surgery.
Pheochromocytoma
Pheochromocytomas (PHEOs) and paragangliomas
(PGLs) are catecholamine-secreting tumors that typi-
cally present with florid signs and symptoms of cate-
cholamine excess, such as hypertension (often with
paroxysmal spurts) and spells of headaches, palpita-
tions, diaphoresis, and at times pale flushing and or-
thostatic intolerance. A recent review explored the less
frequent “subclinical” PHEO/PGL (61). The rate of
occurrence of subclinical PHEO/PGL is unknown, but
is likely to increase with more widespread use of highly
sensitive imaging modalities that identify small tumors,
as tumor size is directly proportional to the quantity of
secreted catecholamine. The authors list some relevant
factors to consider when entertaining the diagnosis of
PHEO/PGL in an asymptomatic patient. In the evalu-
ation of an asymptomatic adrenal mass, the presence of
extensive tumor necrosis is often associated with few
symptoms, or in some cases, a single paroxysm followed
by absence of symptoms. Tumors with a predominantly
noradrenergic secretory pattern, including those associ-
ated with von Hippel–Lindau mutations, can present
primarily with asymptomatic hypertension, which can be
mild due to downregulation of a-adrenoceptors. On the
other hand, tumors that preferentially secrete epinephrine
(including those associated with multiple endocrine
neoplasia type 2 and neurofibromatosis 1 gene muta-
tions) may present with symptomatic paroxysms fol-
lowed by prolonged periods of quiescence. Tumors
associated with mutations in the succinate dehydroge-
nase B and D subunits (SDHB and SDHD, respectively)
can be devoid of secretory activity. These mutations
are often associated with PGL of the head and neck or
extra-adrenal abdominal masses such as in the para-
aortic area and the organ of Zuckerkandl. Their pre-
sentation may be marked not by stereotypical symptoms
of catecholamine excess, but by symptoms caused by
88
these space-occupying masses. Neuroendocrine tumors
can cosecrete other peptides with actions opposite to
catecholamines (e.g., vasodilators such as calcitonin
gene-related peptide and adrenomedullin), thus possibly
mitigating the intensity of symptoms produced by
catecholamine excess.
Much of the recent progress in the evaluation of
PHEO/PGL results from the use of genetic screening
for germ line mutations associated with hereditary
PHEO/PGL syndromes. In addition, recent studies
point to the occurrence of somatic mutations affecting
sporadic tumors in as many as 14% of patients, and
this number appears to be growing (62). The North
American Neuroendocrine Tumor Society Consensus
Guidelines mention that, contrary to previous esti-
mates, approximately 24%–27% of adults with PHEO
or PGL have a known genetic mutation, a prevalence
that can be as high as 40% in children (63). In these
guidelines, it was stressed that clinical features should
guide genetic testing. As noted in Table 5, the key
elements guiding the choice of genetic tests should
include younger age, the presence or absence of syn-
dromic features (i.e., the coexistence of other tumors
suggesting familial syndromes that include PHEO/PGL),
the location of the tumor(s), and the profile of catechol-
amine secretion (62,63). Exceptions are common and
combinations can occur such as tumors secreting both
epinephrine and NE (neurofibromatosis 1, multiple
endocrine neoplasia type 2, and MYC-associated
factor X mutations). In addition, many but not all
familial tumors are present in younger patients (,30
years) (63). In summary, genetic mutations are more
common than previously realized and selected features
of the presentation should guide the screening process.
Once discovered, genetic syndromes require close
surveillance of the index patient, as well as screening
of family members, as most of these syndromes have
autosomal dominant transmission (with the exception of
the hypoxia-inducible factor-2a mutation, which is
somatic rather than germ line).
Guidelines are also available to guide the
imaging of PHEO/PGL (63,64). After documentation
of increased catecholamine metabolites, the initial
screening in patients without a family history or other
syndromic features (see above) can be performed with
abdominal CT or MRI, which are very sensitive
procedures (63). In patients with suspected genetic
diseases, imaging should encompass the region from
neck to pelvis to rule out extra-abdominal disease.
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Previously, MRI was preferred because of fear of
triggering catecholamine release from the tumor upon
exposure to iodinated contrast. A study of 22 patients
with PHEO/PGL undergoing contrast CT without any
periprocedural a- or b-blockade demonstrated that
patients tolerated the procedure without problems
(specifically, without any change of catecholamine
levels) (65). Therefore, CT and MRI seem equally
safe and effective for the initial identification of the
tumor. If the tumor is adrenal and ,5 cm in diameter, the
likelihood of metastatic disease is close to nil, so no
further imaging is needed and the patient can be referred
for adrenalectomy after adequate perioperative prepara-
tion with the sequential addition of a- and b-blockers,
often supplemented by metyrosine.
In cases of adrenal tumors .5 cm in diameter,
extra-adrenal tumors, bilateral or multifocal tumors, or
normal initial abdominal imaging, functional imaging
is indicated because both CT and MRI have limited
specificity in PHEO/PGL due to the frequent identifi-
cation of adrenal incidentalomas (63). Functional imaging
techniques are used both for diagnosis (i.e., identification
of the primary site when there is biochemical evidence of
catecholamine excess) and for assessment of the extent of
disease in the case of multifocal disease, as is often seen
in syndromic PHEO/PGL or in malignant cases with
metastatic disease. This assessment is essential to guide
management decisions between the hypertension special-
ist and the endocrine surgeon.
The North American Neuroendocrine Tumor So-
ciety and the European Association of Nuclear Medicine
issued guidelines (64) on functional assessment in 2012.
The North American guidelines are practical and provide
general guidance, whereas the European guidelines
provide extensive detail about study characteristics
and interpretation. The salient points of these guide-
lines relevant to the hypertension specialist are sum-
marized as follows. First, functional imaging should
be performed in all patients with PHEO/PGL except
those with adrenal PHEO,5 cm in diameter. Second,
123I-labeled metaiodobenzylguanidine (MIBG), the most
widely available radiotracer, has high sensitivity (83%–
100%) and specificity (95%–100%) in sporadic PHEO.
However, it is flawed by large reductions in sensitivity
in familial PHEO/PGL, particularly for multifocal tumors
and PGL of the head and neck. Third, 18F-fluoroDOPA
(FDOPA) positron emission tomography (PET)/CT has
greater sensitivity (approximately 100%) for head and
neck PGL, but underperforms in the evaluation of the
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 89

Table 5. Clinical features that guide the choice of genetic testing in pheochromocytoma/paraganglioma cases
Feature Description
Syndromic clustering
VHL Retinal and CNS hemangioblastomas, renal cell carcinoma, pancreatic,
endolymphatic sac, epididymal tumors
NF1 Neurofibromas, café-au-lait spots
RET MEN2a: medullary thyroid carcinoma, hyperparathyroidism, cutaneous
lichen amyloid
MEN2b: medullary thyroid carcinoma, multiple neuromas, marfanoid habitus
HIF-2a Multiple duodenal somatostatinomas, polycythemia
Location
Extra-adrenal Head and neck PGL: SDHB, SDHC, SDHD, AF2
Retroperitoneal: SDHB
Multiple tumors Bilateral adrenal (PHEO): VHL, RET, MAX
Multiple PGLs: SDHB, SDHD, AF2, HIF-2a
Metastatic (malignant) PHEO/PGL: especially SDHB, also SDHD, NF1, VHL
Biochemical profile
Epinephrine (and metanephrine) RET, NF1
NE (and normetanephrine) VHL, HIF-2a
Dopamine SDHB
Methoxytyramine SDHB, SDHD
Nonsecreting SDHB, SDHC, SDHD
VHL, von Hippel–Lindau; CNS, central nervous system; NF, neurofibromatosis; RET, “rearranged during transfection” proto-oncogene; MEN, multiple endocrine neoplasia; HIF,
hypoxia-inducible factor; SDH, succinate dehydrogenase (subunits A, B, C, D); SDHAF2, enzyme responsible for flavination of SDHA; MAX, MYC-associated factor X. Reprinted
(with modification) with permission from Vicha A, Musil Z, Pacak K: Genetics of pheochromocytoma and paraganglioma syndromes: New advances and future treatment
options. Curr Opin Endocrinol Diabetes Obes 20: 186–191, 2013; and Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor
Society (NANETS): The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: Pheochromocytoma,
paraganglioma, and medullary thyroid cancer. Pancreas 39: 775–783, 2010.

retroperitoneum. It should not be used in the evaluation
of patients with suspected or documented SDHB mu-
tations because its sensitivity is substantially lower in
these patients. It is not yet easily available for use in the
United States. Fourth, 18F-fluoro-2-deoxy-D-glucose
(FDG) PET, the most commonly used PET tracer, is
the most sensitive technique in patients with metastatic
PHEO/PGL, particularly in patients with SDHB dis-
ease. However, it lacks specificity and has low positive
predictive value, particularly in patients with sporadic
PHEO. Fifth, a systematic review published after the
release of the guidelines concluded that MIBG is
consistently inferior to PET techniques in the evaluation
of PHEO/PGL in familial and metastatic disease (66). In
summary, sporadic cases can be evaluated with any of
the aforementioned techniques. The European guidelines
favored MIBG as the initial functional imaging modality
in these patients. For patients with head and neck
disease, FDOPA PET is initial test of choice, whereas
FDG PET can be used when FDOPA is not available.
For those with retroperitoneal disease, FDOPA is a good
choice except in patients with SDHB disease, in which
case a combination of MIBG and FDG PET should be
utilized. Patients with known metastatic disease should
be evaluated with FDG PET.
A recent systematic review evaluated the long-
term prognosis of benign PHEO after surgical re-
section, with the goal of providing general guidelines
for clinical care (67). The authors evaluated 10 studies
that included 1486 patients treated between 1950 and
2009. Of these patients with PHEO, 14% were inherited
and 5.5% were initially labeled as malignant based on
histopathology. Of the remaining patients, 11% pre-
sented with malignant tumors at follow-up and 6%
presented with new tumors that occurred after .10
years of follow-up. Given these rates, the authors pro-
posed that patients with PHEO/PGL be followed for the
rest of their lives. The proposed frequency and modality
of follow-up varies according to clinical features of the
tumors. Patients with adrenal PHEO,5 cm in diameter
and no suspected hereditary syndrome should have
biochemical screening at 1 year, and then every other
year thereafter. Patients with hereditary syndromes,
PHEO.5 cm in diameter, or multifocal PGL should
90
undergo biochemical evaluation after 6 months, and then
yearly thereafter. These patients, as well as those with
biochemically silent disease, should also be screened
with periodic imaging (as described above).
Preeclampsia
Angiogenic Profile and the Diagnosis, Treatment,
and Prognosis of Preeclampsia
The most active area of clinical investigation in
the field of preeclampsia is the identification of its
predictors, which includes approaches such as the mea-
surement of proangiogenic and antiangiogenic factors,
screening of the urine for podocyturia (68), and screen-
ing of the urine proteome for potential novel biomarkers
(69). Of these, the most substantial progress is related to
the role of the imbalance of angiogenic factors in the
pathogenesis of preeclampsia. Although the sequence of
events remains uncertain, there is reasonable circum-
stantial evidence that a primary abnormality in placen-
tation leads to placental ischemia, which causes an
imbalance between proangiogenic and antiangiogenic
factors culminating in an antiangiogenic response.
The key mediators of this process include soluble fms-
like tyrosine kinase-1 (sFLT-1), a soluble form of
VEGF receptor-1, and soluble endoglin (sEng), a glyco-
protein that is part of the TGF-b receptor complex. Both
are increased in preeclampsia and act as antiangiogenic
factors by scavenging VEGF and TGF-b, respectively,
and thereby impeding their signaling. Both VEGF and
TGF-b are important to maintain adequate endothelial
function and their relative deficiency results in maternal
endothelial dysfunction (70). In addition, other proan-
giogenic factors, such as placental growth factor (PlGF)
and adiponectin, are decreased, whereas other antiangio-
genic factors, such as endostatin, are increased in
preeclampsia (70). These mechanistic insights may
portend new possibilities for early diagnosis and treat-
ment. Several studies have shown that the ratio of
antiangiogenic to proangiogenic factors becomes abnor-
mally high weeks before the development of clinical
preeclampsia and is therefore of diagnostic relevance.
Although there is presently no established use of these
biomarkers in the routine care of pregnant women, a few
recent developments deserve mention.
As an initial counterpoint, Craici et al. recently
demonstrated that, among 15 women who developed
preeclampsia (from a cohort of 315 pregnant women),
the presence of podocyturia in the second trimester
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
performed better than sFLT-1 or sEng levels to predict
the likelihood of developing preeclampsia during
follow-up (68).
Two recent studies evaluated the ability of dif-
ferent angiogenic factors to predict adverse pregnancy
outcomes in women presenting with suspected pre-
eclampsia (71,72). These studies were performed by
the same group and the authors defined adverse out-
comes as the occurrence of preeclampsia compli-
cated by the new development of at least one of the
following: abnormal liver function tests, thrombocyto-
penia, disseminated intravascular coagulation, placen-
tal abruption, cerebral hemorrhage, pulmonary edema,
AKI, progression to eclampsia, maternal death, or need
to proceed to delivery due to high BP. In the first study,
616 women were evaluated with the sFLT-1/PlGF ratio
(71). As expected, the authors observed much higher
ratios in women with preeclampsia than in those who
were normotensive or who had chronic or gestational
hypertension without superimposed preeclampsia. Com-
pared with women without adverse outcomes (n¼348),
those with adverse events (n¼268) had 2- to 3-fold
higher log-transformed sFLT-1/PlGF ratios. Moreover,
there was a strong negative correlation (r¼20.71;
P,0.001) between the sFLT-1/PlGF ratio and the time
from presentation to delivery. The authors also observed
a dose-dependent relationship between tertiles of the
sFLT-1/PlGF ratio and risk of development of an
adverse outcome, an observation that was independent
of BP, proteinuria, and uric acid levels (71). In the
second study, the investigators demonstrated that sEng
levels performed similarly to sFLT-1 or the sFLT-1/
PlGF ratio in predicting outcomes (72). Overall, these
were the first reports linking evaluation of these bio-
markers not only to diagnosis but also to prognosis in
suspected or diagnosed preeclampsia.
Chronic hypertension is a risk factor for super-
imposed preeclampsia. In order to estimate the rele-
vance of angiogenic factors to identify women at risk
of superimposed preeclampsia, Perni et al. followed
109 women with chronic hypertension with serial
angiogenic profiles during pregnancy (weeks 12, 20,
28, and 36 of pregnancy and 6 weeks postpartum)
(73). The 32 women who developed superimposed
preeclampsia had significantly elevated levels of sFLT-1
and sEng and decreased levels of PlGF starting between
20 and 28 weeks of pregnancy. These levels returned to
normal values, well below the baseline (12 weeks),
when measured postpartum (73). Despite the small
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
sample size and high variability of the values, which
confound the development of specific recommenda-
tions and thresholds for test interpretation, these results
suggest that the measurement of angiogenic factors
anticipates the development of superimposed pre-
eclampsia in women with chronic hypertension, par-
ticularly in patients with baseline proteinuria.
In a proof-of-concept study, Thadhani et al.
sought to define whether hemoadsorption of sFLT-1
with a dextran sulfate cellulose apheresis membrane
could be used as a treatment tool to improve outcomes
in women with preterm preeclampsia (,32 weeks) by
allowing the delivery to be safely delayed (74). After
determining that sFLT-1 was effectively removed by
the membrane ex vivo (reduction ratios of approxi-
mately 80%–85%), the investigators applied the pro-
cedure to five women with severe preeclampsia,
including two with the hemolysis, elevated liver func-
tion tests, and low platelets syndrome (HELLP syn-
drome). They observed a reduction in circulating sFLT-1
levels by approximately 20% after the procedure, with
recovery to baseline levels after about 24 hours. All
women underwent premature delivery after 1–7 days.
After this initial experience, the investigators offered
multiple procedures to three additional women, with an
average sFLT-1 reduction of 25%–35% per treatment.
These women received 2–4 treatments, each resulting
in transient improvements in proteinuria and stabiliza-
tion of BP, thus allowing delivery to be safely pro-
longed by 15–23 days. In a field in which there are no
other options to prolong pregnancy to improve fetal
outcomes, this study not only presented a possible
therapeutic option, but also served as proof of concept
that sFLT-1 is a major pathogenetic factor in the
clinical syndrome of preeclampsia.
Preeclampsia and Future Risk of Cardiovascular
Disease
The risk factors associated with preeclampsia are
similar to those associated with cardiovascular disease.
Previous studies had suggested an increased risk of
hypertension, cardiovascular events, and death among
women with a history of preeclampsia. A recent meta-
analysis has summarized the available data to quantify
the risk of adverse cardio-renal outcomes after pre-
eclampsia (75). The analysis included 48 studies that
enrolled women with a history of documented or self-
reported preeclampsia or eclampsia in order to evaluate
cardiovascular outcomes, including the development
91
of chronic hypertension, cardiovascular disease, and
cerebrovascular disease. At the time of enrollment,
women were aged 25–60 years, and the average follow-
up for individual studies varied between 0.6 and 37
years. Table 6 summarizes the findings of the meta-
analysis. It is clear that women with a history of
preeclampsia have an increased risk of cardiovascular
complications, although the absolute risk is small. A
previous meta-analysis also reported a graded cardiac
risk according to the severity of the presentation: mild,
risk ratio (RR) of 2 (95% CI, 1.83 to 2.19); moderate,
RR of 2.99 (95% CI, 2.51 to 3.58); and severe, RR
of 5.36 (95% CI, 3.96 to 7.27) (P,0.001) (76). The
mechanisms underlying this relationship remain un-
clear. It is possible that the association relates to risk
factors common to both preeclampsia and cardiovas-
cular disease such as obesity, glucose intolerance,
high BP, and kidney disease. However, it is also
possible that the diffuse endothelial injury that occurs
during preeclampsia creates an environment of per-
sistently increased risk.
From a clinical standpoint, we believe that women
with a history of preeclampsia should undergo screening
for and active management of modifiable risk factors
such as hypertension, glucose intolerance, hyperlipidemia,
and smoking.
Recent studies have also explored the relation-
ship between a history of preeclampsia and future
kidney disease, including the development of micro-
albuminuria (RR, 4.3) (77), CKD (RR, 9.4) (78), and
ESRD (RR, 4.7–12.4) (78,79). Again, the absolute risk
of these outcomes is small, with the exception of
microalbuminuria, which was observed in 30% of
participants from six cohort studies (77). In addition,
because of the confounding inherent in the measure-
ment of proteinuria, it is possible that many of these
patients already had a primary renal disease at the time
of presentation, making the analysis of causality even
more complicated (80).
Mechanisms of Hypertension
Salt Sensitivity
Calcineurin inhibitors (CNIs) induce a salt-
sensitive form of hypertension that is responsive to
thiazide diuretics. CNIs (tacrolimus, cyclosporine) are
effective immunosuppressive agents whose use is com-
plicated by hypertension in more than half of patients,
an effect that is more prominent with cyclosporine but is
92
also significant with tacrolimus (81). The pathogenesis
of CNI-induced hypertension is multifactorial and
includes vascular, renal, and neural mechanisms that
lead to vasoconstriction and sodium retention. The
primary importance of sodium retention was highlighted
recently in a study that explored a novel paradigm.
Hoorn et al. produced tacrolimus-induced hyperten-
sion in mice and observed an overall phenotype that
was similar to familial hyperkalemic hypertension
(also known as pseudohypoaldosteronism type II or
Gordon’s syndrome), including hypertension, renal
sodium and potassium retention, renal tubular acidosis,
hypomagnesemia, and in some animals, hypercalciuria
(82). Serum aldosterone was modestly elevated in the
treated animals. As expected, the severity of the BP
elevation in treated animals was directly related to
the fall in renal sodium excretion and was exacer-
bated with a high-sodium diet. Hypertension was
accompanied by increased renal expression of the
phosphorylated (active) form of the thiazide-sensitive
NaCl cotransporter (NCC) (Figure 10A), along with
increases in the expression of kinases that mediate
activation of NCC, such as with-no-lysine kinase 3
(WNK3) and STE20/SPS1-related proline/alanine-
rich kinase. More importantly, when the investiga-
tors tested the effect of tacrolimus in mice lacking
NCC, the hypertensive phenotype could not be re-
produced, implicating the effects on NCC as the
primary mechanism of tacrolimus-induced hyper-
tension. This hypothesis was further corroborated
by a large BP-lowering effect of hydrochlorothiazide
in the tacrolimus-treated wild-type animals (Figure
10B) (82). Furthermore, Hoorn et al. analyzed renal
allograft biopsy tissue of renal transplant patients
treated with CNIs and demonstrated significantly
greater tissue expression of NCC (total and phos-
phorylated) than in azathioprine-treated patients
(never exposed to a CNI) and in kidneys from healthy
donors at the time of donation. Finally, admini-
stration of bendroflumethiazide to CNI-treated pa-
tients with the hyperkalemic hypertensive phenotype
produced a significantly greater increase in the frac-
tional excretion of chloride than in controls (82).
Taken together, this evidence points to the importance
of NCC activation in the generation of this common
phenotype in CNI-treated patients, and brings to the
surface the value of using thiazide diuretics to manage
these patients, a strategy that has not been routinely
used.
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Novel Kelch-Like 3 and Cullin 3 Mutations
Identified in Familial Hyperkalemic Hypertension
Invoke a Novel Mechanism to Explain Sodium
Retention and Hyperkalemia
The syndrome of familial hyperkalemic hyper-
tension discussed in the previous section (also referred
to as pseudohypoaldosteronism type II or Gordon’s
syndrome) consists of the triad of hypertension, hyper-
kalemia, and metabolic acidosis. Over the past decade,
the genetic basis of some patients with familial hyper-
kalemic hypertension (FHH) was identified as a gain-
of-function mutation in the with-no-lysine kinase 4
(WNK4) gene, a kinase that regulates the function of
NCC, ENaC, and the renal outer medullary potassium
channel (ROMK); other mutations were localized to the
gene for WNK1, a kinase that regulates WNK4. Using
whole-exome sequencing, a new approach to the id-
entification of genetic disorders in which only the
exome is coded, Boyden et al. studied 52 FHH kindreds
with 122 affected individuals. All of these participants
were hyperkalemic (with normal renal function), 71%
were hypertensive, and 82% had metabolic acidosis
(83). WNK4 and WNK1 mutations were identified in
seven kindreds (13%). In 41 kindreds (79%), the
authors identified mutations in Kelch-like 3 (KLHL3)
(24 kindreds, with 16 dominant and 8 recessive) and
Cullin 3 (CUL3) (17 kindreds, 8 of them de novo).
KLHL3 encodes Kelch-like 3, a protein that facilitates
ubiquitination, a process that allows protein recycling
through the ubiquitin-proteasome system. CUL3 is
a ubiquitin ligase that interacts with KLHL3 to facilitate
its function. Therefore, mutations in KLHL3 or CUL3
can result in impaired ubiquitination of proteins bound
to KLHL3. Using mouse kidney, Boyden et al. dem-
onstrated the expression of CUL3 in all nephron seg-
ments and KLHL3 in the distal convoluted tubule and
collecting duct. The authors speculated that these
mutations resulted in impaired removal of NCC from
the apical membrane, a process known to be mediated
by ubiquitination. However, the explanations for the
hyperkalemia and acidosis are not obvious from this
model, because these mutations should result in in-
creased ROMK activity, which should cause hypoka-
lemia. Further studies will be necessary to help explain
the full phenotype conferred by these mutations.
From a clinical perspective, KLHL3 and CUL3
mutations explain the previously observed large var-
iability in phenotype severity in FHH. As shown in
Table 7, different mutations are associated with variable
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 93

Table 6. Meta-analysis of the risk of hypertension and vascular disease in women with a history of preeclampsia/
eclampsia compared with women with uncomplicated pregnancies
History of PE/E No PE/E
Studies (n) Patients (n) Event Rate (%) Patients (n) Event Rate (%) OR (95% CI)
Hypertension 32 4257/44,574 10 17,267/782,011 2.2 3.13 (2.51 to 3.89)
Cardiovascular 15 1379/99,782 1.4 13,817/1,910,874 0.7 2.28 (1.87, 2.78)
disease
Cerebrovascular 7 790/62,235 1.3 9305/1,364,253 0.7 1.77 (1.43, 2.21)
disease
PE/E, preeclampsia/eclampsia. Reprinted (with modification) with permission from Brown MC, Best KE, Pearce MS, Waugh J, Robson SC, Bell R: Cardiovascular disease risk in
women with pre-eclampsia: Systematic review and meta-analysis. Eur J Epidemiol 28: 1–19, 2013.

severity of the phenotype, the worst with CUL3 and
the least severe with WNK1 mutations (83). The fre-
quency of KLHL3 mutations among hypertensives in
the general population is very low (84). When Louis-
Dit-Picard et al. explored the prevalence of these
mutations in 1232 Caucasian patients with essential
hypertension, only 1 patient (with a serum potassium
of 5.1 mEq/L) had a mutation in the KLHL3 gene. In
summary, although these new findings have little im-
plication on the care of hypertensive patients, they
outline a new set of molecular mechanisms to explain
abnormalities in sodium, potassium, and acid handling
in the distal nephron.
tion is not perfectly coupled to water disposition (i.e.,
sodium can be stored nonosmotically in soft tissues,
especially the skin), and that factors regulating sodium
balance are subject to yet unexplained periodic varia-
tions, as reviewed in detail by Titze et al. (85). In an
interesting report, Rakova et al. evaluated sodium
balance in healthy cosmonauts undergoing prolonged
training (105 or 205 days) in a facility simulating life
in space, but with normal gravity (86). By carefully
monitoring water and electrolyte intake and excretion

Novel Findings Regarding the Long-Term

Regulation of Sodium Excretion Have
Implications for the Assessment of Sodium
Balance in Hypertension Research and Clinical
Practice
In the previous issue of NephSAP on hyperten-
sion, we reviewed the topic of nonosmotic sodium
storage in the skin and the mechanisms involved in its
regulation (12). Work in the field has evolved since
then, with some developments that are relevant to
clinical practice. Until recently, our appreciation of
sodium handling has been that an acute sodium load
results in extracellular fluid volume expansion, where-
upon sodium is promptly excreted through a pressure- Figure 10. (A) Tacrolimus-induced renal tissue expression
induced natriuresis mechanism over a period of 3 to 4 of phosphorylated sodium chloride cotransporter (pNCC).
days, consequently restoring the original steady state. (B) Effect of HCTZ versus vehicle (Veh) on systolic BP in
tacrolimus (Tac)-treated mice. Reprinted with permission
In cases of acute sodium restriction (or volume loss),
from Hoorn EJ, Walsh SB, McCormick JA, Fürstenberg A,
the opposite occurs. However, several lines of evidence Yang CL, Roeschel T, Paliege A, Howie AJ, Conley J,
indicate that the physiology is more complicated than Bachmann S, Unwin RJ, Ellison DH: The calcineurin
initially appreciated, because there are mismatches inhibitor tacrolimus activates the renal sodium chloride
between expected and observed weight gain after stand- cotransporter to cause hypertension. Nat Med 17: 1304–
ardized sodium loads, indicating that sodium disposi- 1309, 2011.
94
Table 7. Phenotypes of familial hyperkalemic hypertension based on different genotypes
Mutant Gene Kindreds (n) Affecteds (n) Dx/Ref Age
CUL3 17 21 966
KLHL3 recessive 8 14 26614
KLHL3 dominant 16 40 24618
WNK4 5 15 28618
WNK1 2 23 36620
P value 0.0002
For explanations of different mutations, see text. Dx/Ref Age, age at diagnosis or referral; %htn, percent of patients with a diagnosis of hypertension before age 18 years.
Reprinted (with modification) with permission from Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G,
Lebel M, Gordon RD, Semmekrot BA, Poujol A, Välimäki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, Porter CC, Anand SK,
Whiteford ML, Davis ID, Dewar SB, Bettinelli A, Fadrowski JJ, Belsha CW, Hunley TE, Nelson RD, Trachtman H, Cole TR, Pinsk M, Bockenhauer D, Shenoy M, Vaidyanathan P,
Foreman JW, Rasoulpour M, Thameem F, Al-Shahrouri HZ, Radhakrishnan J, Gharavi AG, Goilav B, Lifton RP: Mutations in Kelch-like 3 and Cullin 3 cause hypertension and
electrolyte abnormalities. Nature 482: 98–102, 2012.
as well as other factors regulating sodium balance, such
as levels of aldosterone and cortisol/cortisone, the au-
thors observed a large variability in sodium excretion
on a day-to-day basis. In the long term, about 95%
(range, 70%–103%) of ingested sodium was ultimately
recovered, but the patterns of sodium excretion during
prolonged periods of stable sodium intake were ex-
tremely variable and independent of BP and sodium
intake. Instead, urine sodium excretion varied as a
function of circaseptan fluctuations (6–9 days in this
case) in levels of aldosterone and cortisol/cortisone (the
cortisol/cortisone excretion rate was used as a marker of
11b-hydroxysteroid dehydrogenase type II activity).
Moreover, total body sodium stores had even longer
infradian variations (on the order of weeks, as shown
in Figure 11), the mechanisms of which remain un-
clear. These observations have clinical implications
for the use of urine sodium excretion as a marker for
sodium intake. As these data indicate, there are wide
day-to-day variations that cannot be captured in a sin-
gle collection.
In order to better translate these findings into cli-
nical research and practice, better methods for mapping
the distribution of sodium in the body are essential.
New imaging protocols to detect tissue sodium have
been recently published using magnetic resonance
technology (87,88). In these studies, 23Na-MRI was
used to visualize (and quantify) sodium content in the
calves of patients using a 23Na coil at 9.7 Tesla in rats
and at 3 Tesla in humans, while simultaneously using
1H-MRI to identify water content (Figure 12). To ex-
plore the clinical applicability of these measurements,
Kopp et al. studied 57 hypertensive patients and 56
normotensive controls (88). Tissue sodium increased
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
K1 (mm) HCO32 (mm)
(nl 3.5–5.0) (nl 22–28) % htn#age 18
7.560.9 15.562.0 94
6.860.5 17.661.5 14
6.260.6 17.262.5 17
6.460.7 20.862.3 10
5.860.8 22.464.6 13
,0.001 ,0.001 ,0.001
with age in all participants, was higher in hypertensive
patients than controls, and was highest among patients
with treatment-resistant hypertension. Moreover, the
authors noticed differences based on clinical interventions;
for example, tissue sodium content decreased by ap-
proximately 30% in five patients with primary aldoste-
ronism after adrenalectomy (n¼4) or treatment with
spironolactone (n¼1) (87). Likewise, patients with re-
sistant hypertension treated with spironolactone had
sodium content levels similar to those of normotensive
controls, indicating that tissue sodium excess is mod-
ifiable (88). These exciting developments have poten-
tial implications not only for the physiology and
treatment of hypertension and salt sensitivity, but also
for the study of disorders of extracellular volume
expansion (heart failure, cirrhosis, kidney disease) and
dysnatremia (89).
ENaC Mediates Endothelial Cell Stiffness
ENaC is expressed in several nonepithelial tis-
sues, such as the vascular endothelium. A recent study
has contributed to our understanding of ENaC expres-
sed in vascular endothelium as a mediator of endothe-
lial cell stiffness, a process that is thought to be
important in the pathogenesis of endothelial dysfunc-
tion, hypertension, and vascular disease (90). Jeggle
et al. used atomic force microscopy to measure
nanoindentations on endothelial cells under different
conditions of ENaC expression. They observed that
conditions with increased expression of ENaC (aldo-
sterone stimulation, cellular transfection of aENaC
mouse model of Liddle’s syndrome) were associated
with increased endothelial cell stiffness. Conversely,
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 95

Figure 11. Long-term (205 days) total body sodium levels in six participants under strict metabolic control. The large day-to-day
variations can be noted as well as the long infradian (weeks) shifts in sodium balance. TBNa, total body sodium. Reprinted with
permission from Rakova N, Jüttner K, Dahlmann A, Schröder A, Linz P, Kopp C, Rauh M, Goller U, Beck L, Agureev A,
Vassilieva G, Lenkova L, Johannes B, Wabel P, Moissl U, Vienken J, Gerzer R, Eckardt KU, Müller DN, Kirsch K, Morukov B,
Luft FC, Titze J: Long-term space flight simulation reveals infradian rhythmicity in human Na(1) balance. Cell Metab 17: 125–
131, 2013.

conditions associated with decreased ENaC expres-
sion (aENaC knockdown, spironolactone) or inhibi-
tion of ENaC with amiloride resulted in significant
reductions in endothelial stiffness, and the combination
of spironolactone and amiloride resulted in further
reductions (90). Endothelial cell stiffness impedes the
necessary endothelial cell cortical (subsurface) de-
formation that is necessary for nitric oxide release.
Therefore, it is possible that endothelial ENaC is an
important player in the vascular responses to salt and
aldosterone (91). These observations have potential
treatment implications, because one could envision
the development of amiloride analogs that preferen-
tially target the vascular endothelial ENaC, possibly
resulting in improved endothelial function (lower BP,
less atherosclerosis) without secondary effects on
potassium handling (91).
Gut Microbiota and Hypertension
There has been increasing interest in the relation-
ship between the gut microbiota and human disease. It
is now apparent that the resident microbiota of the
gastrointestinal tract has important effects on the de-
velopment of immune responses (local and systemic),
regulation of body weight and nutrient utilization,
modulation of responses to different drugs, and per-
missive or protective roles in a variety of infectious,
inflammatory, and autoimmune disorders, both in the
intestinal tract and in distant organs (92). Very little
has been published in the realms of kidney disease
and hypertension. However, extremely interesting obser-
vations have been published linking the gut microbiota,
short chain fatty acid (SCFA) production by gut bacteria,
and olfactory receptors expressed in the kidney that may
have an important role in BP regulation (93,94).
Olfactory receptors are chemoreceptors that are
distributed throughout the body. At diverse sites, ol-
factory receptors “smell their odorants” but nonetheless
signal in the same way, always involving the olfactory
G protein, which then activates the olfactory isoform of
adenylyl cyclase (AC3). In the kidney, olfactory G
protein and AC3 colocalize to the macula densa and the
distal convoluted tubule. In addition, AC3 knockout
96
Figure 12. 23Na magnetic resonance imaging (23Na-MRI) of
tissue sodium. (A) Representative 23Na-MR image of the
lower leg of a young normotensive man and an older
hypertensive man. Tubes with solutions containing 10, 20,
30, and 40 mmol/L of NaCl are arranged below the
extremity, thereby allowing calibration of tissue sodium.
Tissue sodium content is increased in the older patient
compared with the younger patient. (B) Tissue water in the
same young man and the older man detected with conven-
tional 1H-MRI. No difference in muscle water content is
visible to the naked eye. Reprinted with permission from
Kopp C, Linz P, Wachsmuth L, Dahlmann A, Horbach T,
Schöfl C, Renz W, Santoro D, Niendorf T, Müller DN,
Neininger M, Cavallaro A, Eckardt KU, Schmieder RE, Luft
FC, Uder M, Titze J: (23)Na magnetic resonance imaging of
tissue sodium. Hypertension 59: 167–172, 2012.
mice have a phenotype suggestive of a macula densa
lesion that includes low plasma renin (approximately
50% lower than littermates) and reduced GFR (approx-
imately 40%) despite intact glomerular and tubular
structure and function (94). These results indicate that
olfactory signaling has relevance to the physiology of
renin secretion and regulation of GFR.
At least six olfactory receptors have been iden-
tified in kidney tissue. In follow-up studies, Pluznick
et al. deorphanized one of these receptors (i.e., identi-
fied the odorant that it senses), Olfr78, which senses
SCFAs, particularly acetic and propionic acids (93). In
a series of experiments, they determined that Olfr78 is
located in smooth muscle cells associated with large
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
arteries in the kidney and elsewhere in the body. Because
SCFAs have dose-dependent vasodilatory and hypoten-
sive actions, the investigators explored the BP effects of
the interaction between SCFAs and Olfr78 using the
Olfr78 knockout mouse model. When infused with
propionic acid, both wild-type and knockout animals
had large decreases in BP but the reactive renin release
from the macula densa was 3-fold higher in wild-type
animals, thus establishing Olfr78 as required for the
adaptive response to propionic acid–induced hypoten-
sion. Furthermore, when animals underwent gut decon-
tamination with antibiotics, only the knockout animals
had an increase in BP (20/18 mmHg; P,0.01) compared
with baseline, thus indicating that the gut flora may
regulate BP (presumably through SCFAs) in a way that
is modulated by Olfr78 (93). The clinical relevance of
these findings to hypertension remains unclear, espe-
cially because the wild-type mice did not have a hyper-
tensive response to bowel decontamination. However,
one could speculate that genetic variations in Olfr78
expression may have relevance to adaptation to low BP,
as is often necessary during acute illness, particularly in
patients with shock and altered gut flora.
Novel Potential Treatment Targets
Plasminogen Activator Inhibitor-1 Antagonism
Improves Endothelial Function and Periaortic
Fibrosis
Plasminogen activator inhibitor-1 (PAI-1) is the
primary regulator of plasminogen activation in the
circulation. In the vasculature, PAI-1 is profibrotic and
impairs cell migration and extracellular matrix degra-
dation. When PAI-1 levels are measured in the serum of
patients, high levels are linked to adverse vascular
outcomes and arterial stiffness in several populations
(95). In addition, PAI-1–deficient mice experience an
abrogation of the hypertensive and atherosclerotic phe-
notype associated with inhibition of nitric oxide syn-
thase. In view of these findings, PAI-1 was considered
a suitable target in hypertension and vascular disease,
and several PAI-1 antagonists have been developed (96).
Boe et al. administered the oral PAI-1 antagonist
TM5441 for 8 weeks to wild-type mice receiving the
nitric oxide synthase inhibitor N-v-nitro-L-arginine
methyl ester (L-NAME), a model that is associated
with hypertension and vascular senescence (96). As
shown in Figure 13, cotreatment with TM5441 pro-
duced a moderate antihypertensive effect (although not
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
fully abolishing the effect of L-NAME), and completely
abrogated the effects of L-NAME on myocardial and
periaortic fibrosis. Furthermore, TM5441 fully pre-
vented L-NAME–induced telomere shortening mea-
sured in liver and aorta. In separate experiments using
angiotensin II in lieu of L-NAME, the investigators
obtained similar overall results (96). These results in-
dicate that PAI-1 antagonism can lower BP and improve
vascular injury and senescence. It remains unclear
whether TM5441 can rescue injury that has already
occurred, as the published experiments were restricted to
simultaneous administration of L-NAME and TM5441.
Addressing this question will be essential to understand
the translational value of this treatment strategy.
ACE2 Activation Improves Endothelial Function
The RAS is thought to have two separate axes.
The first and most widely recognized includes the
ACE, angiotensin II (AngII), and the AngII type 1
receptor, a system that causes vasoconstriction, in-
flammation, proliferation, and fibrosis. The second axis
includes ACE2, angiotensin 1–7, and the Mas receptor,
with actions that are opposite those of the ACE/AngII
axis. Given the potentially salutary effects of ACE2 and
angiotensin 1–7 on vascular function, BP, and organ
damage, there has been growing interest in stimulation
Figure 13. The effect of L-NAME and TM5441 on hyper-
tension. SBP was measured throughout the course of the
study every 2 weeks using a tail cuff device. WT, wild type.
All P values ,0.01 (*,#,$). Reprinted with permission from
Boe AE, Eren M, Murphy SB, Kamide CE, Ichimura A,
Terry D, McAnally D, Smith LH, Miyata T, Vaughan DE:
The PAI-1 antagonist TM5441 attenuates L-NAME-induced
hypertension and vascular senescence. Circulation 128:
2318–2324, 2013.
97
of the ACE2/angiotensin 1–7 axis as a target for the
management of hypertension and cardiovascular dis-
ease. Fraga-Silva et al. studied the effect of an ACE2
activator, xanthenone, on ex vivo endothelial function
in vessels excised from spontaneously hypertensive rats
and streptozotocin-induced diabetic rats (97). Xanthenone
administration for 4 weeks resulted in approximately 30%
improvement in endothelium-dependent vasodilation, an
effect that was mediated through the Mas receptor and
decreased reactive oxygen species. The investigators did
not report BP, but a previous publication demonstrated
large acute BP reductions in spontaneously hypertensive
rats and Wistar-Kyoto rats (mean arterial pressure de-
creases of 71 and 21 mmHg, respectively) and more
modest 28-day reductions in spontaneously hypertensive
rats (17 mmHg) but not in the normotensive Wistar-
Kyoto rats (98). In addition, xanthenone administra-
tion resulted in significant reductions in myocardial,
perivascular, and renal interstitial fibrosis scores in
spontaneously hypertensive rats (99). These results
underscore the potential value of targeting ACE2
in the treatment of hypertension and hypertension-
related organ damage.
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Updates on Treatment
Angiotensin-Converting Enzyme, Angiotensin
Receptor Blocker, and Direct Renin Inhibitor
Interactions
Aliskiren, the first orally active direct renin in-
hibitor, was approved for hypertension in the United
States in 2007. Nearly a year later, the Aliskiren in the
Evaluation of Proteinuria in Diabetes (AVOID) trial
was published (1). The AVOID trial enrolled 599
patients with type 2 diabetes and an albumin/creatinine
ratio (ACR) of .300 mg/g (or 200 mg/g for those taking
drugs blocking the renin-angiotensin-aldosterone sys-
tem [RAAS]). During a 3-month open-label period,
anti–RAAS-blocking drugs (except b-blockers) were
discontinued and treatment with losartan (100 mg/d)
was initiated, with a goal BP,130/80 mmHg. The pa-
tients were randomly assigned to either aliskiren (150
mg once daily for 3 months, titrated to 300 mg once
daily for another 3 months) or placebo (for all 6 months).
The primary outcome was the change in urine albumin
excretion at 6 months. The trial achieved its endpoint:
the urine ACR decreased by 20% in the active arm, by
$50% in approximately one quarter of patients re-
ceiving aliskiren plus losartan, and by $50% in 12.5%
of individuals taking placebo plus losartan. BP was 2/1
mmHg lower in the aliskiren group and was not likely
a major contributor to the endpoint. Adverse events were
similar between the groups, with the only difference
being a slightly higher likelihood of a potassium val-
ue$6.0 mEq/L in the aliskiren group (14 patients, 4.7%)
compared with the placebo arm (5 patients, 1.7%;
P¼0.06). The decline in eGFR was slightly less in the
aliskiren group (2.4 ml/min per 1.73 m2) compared with
the placebo group (3.8 ml/min per 1.73 m2). Despite the
trial’s short duration and small numbers, there were no
safety issues apart from a modest tendency toward more
hyperkalemia.
Encouraged by the results from the AVOID trial,
the Aliskiren in Type 2 Diabetes Using Cardio-Renal
Endpoints (ALTITUDE) study was organized in 853
centers in 36 countries (2). Although the Ongoing
Telmisartan Alone and in Combination with Ramipril
Global Endpoint Trial (ONTARGET) (3) and the
Valsartan in Acute Myocardial Infarction trials (4) had
not supported the concept of dual RAAS blockade, two
hypotheses were proposed to explain the lack of
benefit in these trials. The first hypothesis proposed
that failure to show benefit resulted from aldosterone
101
escape (5). The second hypothesis was based on an
analysis of renin activation in the Heart Outcomes
Prevention Evaluation study, in which a poorer out-
come was observed in those participants who dem-
onstrated compensatory renin activation (6). It was
thought that direct renin inhibition could overcome at
least one of these hypothetical scenarios (compensa-
tory renin activation). The demonstrated increased re-
duction in proteinuria in AVOID without a worrisome
signal for adverse events, coupled with an absence of
evidence regarding dual therapy on hard renal out-
comes in diabetic kidney disease provided the impetus
for the ALTITUDE trial. The study was a randomized,
double-blind, placebo-controlled, parallel-group, two-
arm study undertaken in two phases. In the 12-week
first phase, all eligible participants were titrated to either
an optimal dose of an angiotensin-converting enzyme
inhibitor (ACEI) or an angiotensin receptor blocker but
not both, and use of mineralocorticoid receptor antago-
nists was not permitted. Eligibility for the second phase
(randomization) required the following: ACR.200 mg/g
from two of three first morning voids, or eGFR of 30–59
ml/min per 1.73 m2 (by Modification of Diet in Renal
Disease formula) with microalbuminuria from two of
three first morning voids, or history of cardiovascular
disease, and optimal therapy with an ACEI or an an-
giotensin receptor blocker (but not both)
Participants who completed phase I qualifying
for phase II were then randomized in the double-blind
portion of the trial and began either 150 mg/d of aliskiren
or a matching placebo. Four weeks later, aliskiren was
titrated up to 300 mg/d or matching placebo. The pro-
tocol allowed downtitration of the aliskiren/matching
placebo for severe adverse events.
Trial duration was anticipated at 48 months or
accrual of 1620 primary outcome events. The primary
objective of the ALTITUDE study was time to first event
of a composite endpoint that included the following:
cardiovascular death, resuscitated sudden cardiac death,
nonfatal heart attack, nonfatal stroke, hospitalization for
heart failure, ESRD (defined as initiation of maintenance
dialysis, kidney transplantation, or serum creatinine.6.0
mg/dl [530 mmol/L]) or renal death (death attributed to
kidney failure), loss of kidney function (defined by the
need for RRT with no dialysis or transplantation avail-
able), or doubling of baseline serum creatinine with
persistence for .1 month.
The ALTITUDE study randomized 8561 partic-
ipants of a planned 8600 (7). After median follow-up
102
of 32.9 months and the second interim safety analysis
in December 2011, the trial was prematurely terminated
by the Data Safety Monitoring Board. The primary
endpoint occurred in 783 participants (18.3%) in the
aliskiren group and 732 participants (17.1%) in the
placebo group. Similar results emerged in the analysis
of secondary renal endpoints. The aliskiren group dem-
onstrated 1–2 mmHg lower systolic BP (SBP) and
greater reduction in proteinuria. The systolic BP actually
rose from randomization values of 137 mmHg in both
groups to the 139–142 mmHg range, consistently higher
throughout the study in the placebo group. Table 8
details the outcomes. Note that five of seven components
of primary composite outcomes showed a trend for
increased adverse outcomes in the aliskiren-treated
group. Principal aliskiren group findings included a
25% greater stroke rate and more frequent occurrence
of hyperkalemia. It was speculated that this adverse
result was a chance finding or the consequence of
deranged diabetic and cerebrovascular autoregulation.
However, prior studies in hypertension in general, and in
the Action to Control Cardiovascular Risk in Diabetes
(ACCORD) trial in particular, demonstrated that lower
BP is associated with reduced stroke outcomes (8).
The ALTITUDE trial contributes further data to
the growing list of studies that document a greater
reduction in proteinuria in one particular group that
failed to translate into a cardiovascular (or renal)
benefit. As noted by Krakoff in a recent commentary,
the combination of renin-angiotensin blockade by mul-
tiple agents represents yet another example of medical
“hormesis”—the phenomenon or condition of a sub-
stance or other agent having a beneficial physiologic
effect at low levels of exposure despite being toxic or
otherwise harmful at higher levels (9).
Body Mass Index
In a prior NephSAP on hypertension (10), we
reviewed the Avoiding Cardiovascular Events through
Combination Therapy in Patients Living with Systolic
Hypertension (ACCOMPLISH) trial, which revealed
a cardiovascular benefit in patients treated with a com-
bination ACEI (benazepril) plus a dihydropyridine
calcium channel blocker (CCB) (amlodipine) ther-
apy compared with a combination ACEI (benazepril)
and diuretic (hydrochlorothiazide [HCTZ]) (11). The
ACCOMPLISH trial comprised a high-risk hyperten-
sive population, as prespecified by entry criteria that
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
required the presence of cardiovascular and/or kidney
disease for enrollment (12). Clinical trials in high-risk
hypertensive patients have often shown a paradoxically
higher event rate in leaner individuals (13–15), and the
ACCOMPLISH investigators examined whether body
mass index (BMI) was a significant contributor to
outcomes in their study.
Briefly, the primary outcome of the ACCOM-
PLISH trial was the time to first event of cardiovas-
cular death, nonfatal heart attack, or nonfatal stroke. A
total of 11,482 patients participated in the trial: 14%
had a normal BMI (,25 kg/m2), whereas 36% were
overweight (BMI, 25–29.9 kg/m2) and 50% were obese
(BMI$30 kg/m2). Figure 14 depicts the event rates for
these three groups, in which the participants taking
either therapy were combined to form one of three BMI
groups (16).
As noted in Figure 14, the overall trend was
significant; within the three BMI groups, the normal
BMI differed significantly only from the obese BMI
group. Forest plots confirmed that the trend in individual
outcome components (cardiovascular death alone, non-
fatal heart attack alone, nonfatal stroke alone) also
favored the progressively higher BMI groups, pro-
viding internal consistency of the findings. However,
the story does not end there. Figure 15 illustrates the
finding of greatest interest in the ACCOMPLISH trial
(16). Here, there was a clear difference by BMI cate-
gories only when patients were treated with ACEI
(benazepril) plus diuretic (HCTZ) therapy. There was
substantial blunting in those patients randomized to
ACEI (benazepril) plus CCB (amlodipine) therapy, to
the point of complete insignificance of the trend seen in
the other therapy group.
In the ACCOMPLISH trial, therapy that
combined an ACEI with a diuretic showed
more benefit for the primary outcome in
those with progressively higher BMI, whereas
therapy that combined an ACEI with a
CCB had little effect of BMI category on
outcomes.
The reasons for the difference in outcome by
therapeutic assignment and BMI category is not readily
evident in the ACCOMPLISH trial data. There is good
reason to suspect a component of the therapy influenced
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 103

Table 8. Prespecified primary and secondary composite outcomes and deaths in the ALTITUDE trial
Hazard Ratio
Aliskiren Placebo (95% Confidence
Outcome (n¼4274) (n¼4287) Interval) P Valuea
Primary composite outcome 783 (18.3) 732 (17.1) 1.08 (0.98 to 1.20)
Death from cardiovascular causes 246 (5.8) 215 (5.0) 1.16 (0.96 to 1.39) 0.12
Cardiac arrest with resuscitation 19 (0.4) 8 (0.2) 2.40 (1.05 to 5.48) 0.04
Myocardial infarction (fatal or nonfatal) 147 (3.4) 142 (3.3) 1.04 (0.83 to 1.31) 0.72
Stroke (fatal or nonfatal) 147 (3.4) 122 (2.8) 1.22 (0.96 to 1.55) 0.11
Unplanned hospitalization for heart failure 205 (4.8) 219 (5.1) 0.95 (0.78 to 1.14) 0.56
ESRD, death attributable to kidney failure, 121 (2.8) 113 (2.6) 1.08 (0.84 to 1.40) 0.56
or loss of kidney functionb
Doubling of baseline serum creatinine 210 (4.9) 217 (5.1) 0.97 (0.80 to 1.17) 0.75
Cardiovascular composite outcome 590 (13.8) 539 (12.6) 1.11 (0.99 to 1.25) 0.09
Renal composite outcome 257 (6.0) 251 (5.9) 1.03 (0.87 to 1.23) 0.74
Death from any cause 376 (8.8) 358 (8.4) 1.06 (0.92 to 1.23) 0.42
A patient may have had multiple cardiovascular and renal events of different types. All composite outcomes reflect only the first occurrence of any of the components.
Reprinted (with modification) with permission from Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS,
Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA; ALTITUDE Investigators: Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 367: 2204–2213,
2012.
a
P values have not been adjusted for multiple comparisons.
b
Loss of kidney function was defined by the need for RRT with no dialysis or transplantation available or initiated.

the results. For example, the placebo group in the Systolic
Hypertension in the Elderly Program (SHEP) trial
showed no association of BMI with outcomes, whereas
the active treatment group based on chlorthalidone
(CTD) therapy showed a similar relationship of BMI to
outcomes as observed in the ACCOMPLISH trial (15).
It may be that the pathogenesis of hypertension in
obesity is simply different than in lean individuals,
with a greater degree of volume dependence (thus
progressively favoring the diuretic benefit) as BMI
category increases (17). Leaner individuals may have
more prominent renin activity and sympathetic nervous
system activity in their hypertension (18), which could
worsen with diuretic therapy, although we might ex-
pect this to be offset by the benazepril. There are two
important practical points that can be learned from the
ACCOMPLISH data. The first is that the choice of
hydrochlorothiazide rather than CTD, a criticism of the
ACCOMPLISH study design (19), does not appear to
be as important given the similar findings to the SHEP
trial, which did use CTD. The second point relates to
the management of lean high-risk hypertensive pa-
tients. The ACCOMPLISH data would argue for pre-
ferential addition of a CCB over a diuretic to an ACEI.
In an obese high-risk hypertensive patient, the choice
of whether to add a diuretic versus a CCB to an ACEI
is less important.
Renal Denervation for (Resistant) Hypertension
The successful reduction of drug-resistant hyper-
tension by device-based therapies has refocused atten-
tion on what has traditionally been an unrewarding
pursuit (i.e., that of managing patients with high
systolic BPs who are already taking four or more
antihypertensive agents). In updating the management
of hypertension using device-based therapies, it may
help to review the current semantics as noted below.
Drug-resistant hypertension: this term refers to
a repeated BP of .140/.90 mmHg in the office/clinic
while taking three or more antihypertensive drugs in
optimal doses, with at least one drug being a diuretic or
any office/clinic BP, irrespective of actual values, in
a patient taking four or more antihypertensive drugs
(20). Drug refractory hypertension: this term refers to
persistent drug-resistant hypertension after evaluation
by a hypertension specialist and/or at a hypertension
center (20,21). Apparent treatment-resistant hyperten-
sion: the National Health and Nutrition Examination
Survey data record the number of antihypertensive
medications a participant takes but not the medication
dose, adherence or a check for BP measurement
artifacts, which represent significant factors in defining
inadequately treated and treatment-resistant hyperten-
sion. Thus, the term apparent treatment-resistant
104
Figure 14. Event rates for primary endpoint according to
body mass index category for all patients. Reprinted with
permission from Weber MA, Jamerson K, Bakris GL, Weir
MR, Zappe D, Zhang Y, Dahlof B, Velazquez EJ, Pitt B:
Effects of body size and hypertension treatments on cardio-
vascular event rates: Subanalysis of the ACCOMPLISH
randomised controlled trial. Lancet 381: 537–545, 2013.
hypertension is used to recognize these limitations in
defining drug resistance in this cohort (22). Severe
drug-resistant hypertension: this entity is similar to the
definition for drug-resistant hypertension except that
the systolic BP must be $160 mmHg. This definition is
used in the Symplicity HTN-1, Symplicity HTN-2 , and
Symplicity HTN-3 (22–24) trials (which will form the
basis for the new device application to the US Food and
Drug Administration anticipated in 2014) (25).
The use of renal denervation technologies is
rapidly expanding because at least one catheter is
approved for use in .80 countries worldwide for
resistant hypertension. The role of the renal nerves in
the pathogenesis of hypertension is shown in Figure 16
(26), which shows the efferent sympathetic nerves from
the brain as well as the afferent signals returning to the
brain. Interruption of the afferent signals, outgoing
from the renal arteries, is thought to confer the BP
reduction in renal denervation procedures.
Renal Denervation Procedure
At this time, the procedure is typically done with
a radiofrequency ablation (RFA) catheter via a femoral
approach and is completed in approximately 1 hour. Pro-
tocol studies usually require a kidney artery length of at
least 2 cm before its bifurcation and a 4 mm diameter
vessel, on each side, that supplies most or all of the kidney
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Figure 15. Comparison of primary endpoint event rates
between treatment arms, according to body mass index
category. Reprinted with permission from Weber MA,
Jamerson K, Bakris GL, Weir MR, Zappe D, Zhang Y,
Dahlof B, Velazquez EJ, Pitt B: Effects of body size and
hypertension treatments on cardiovascular event rates: Sub-
analysis of the ACCOMPLISH randomised controlled trial.
Lancet 381: 537–545, 2013.
(i.e., accessory vessels are not treated and patients with
a substantial kidney volume perfused by an accessory
vessel are excluded from protocol studies). The procedure
may be uncomfortable, and conscious sedation is often
utilized. The catheter is passed into the kidney artery and
RFA energy is applied for approximately 2 minutes. This
heats the surrounding tissue to 50°C–70°C depending on
the catheter. To achieve circumferential ablation, the RFA
catheter is sequentially rotated and withdrawn in small
increments 4–6 times (23). At this time, participants in
renal denervation studies are usually kept overnight for
observation because of an occasional substantial re-
duction in BP, not unlike the remarkable reductions in
BP that were seen in the early period after the in-
troduction of captopril into the market (27). Procedure
time will become shorter as catheter technology im-
proves to where a single RFA energy application via
multiple coils will replace the rotate-and-withdraw
methodology, and this modification is already under
development (28).
The use of a radial artery approach, in which
smaller bore introducers and better local homeostasis
are feasible, may facilitate outpatient use. In general,
the procedural complications associated with renal
denervation are mostly limited to the femoral puncture
site (groin hematomas) and the occasional large BP
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 105

Figure 16. Efferent and afferent renal sympathetic nerves. HR, heart rate; RBF, renal blood flow. Reprinted with permission
from Mahfoud F, Lüscher TF, Andersson B, Baumgartner I, Cifkova R, Dimario C, Doevendans P, Fagard R, Fajadet J,
Komajda M, Lefèvre T, Lotan C, Sievert H, Volpe M, Widimsky P, Wijns W, Williams B, Windecker S, Witkowski A, Zeller T,
Böhm M; European Society of Cardiology: Expert consensus document from the European Society of Cardiology on catheter-
based renal denervation. Eur Heart J 34: 2149–2157, 2013.

reduction, as discussed in a recent systematic review of
denervation studies (29).
Renal Denervation Studies
Table 9 summarizes the worldwide published
experience (as of June 30, 2013) regarding selected
features of renal denervation. Although it is not entirely
comprehensive, Table 9 delineates the magnitude of BP
change and use of denervation procedures in situations
other than drug-resistant hypertension. In general, it
appears that 85%–90% of patients with severe drug-
resistant hypertension experience at least a 10-mmHg
decrease in office-based BP 6 months after denervation.
In the CKD population cited in Table 9, the in-
vestigators also performed 24-hour ambulatory BP
monitoring (ABPM) (30). ABPM demonstrated smaller
changes in SBP (decrease of 5 mmHg) but did show
a 10-mmHg reduction in nocturnal BP, lowering the
average decline in sleep BPs from 4% to 11% (10%–
20% is considered normal). It is important to note that
only 8 of the 15 participants had a second 24-hour
ABPM at the 6-month time point. There was a statisti-
cally insignificant increase in hemoglobin at 6 months,
increasing from 11.8 g/dl to 12.5 g/dl (P¼0.08) and
a statistically insignificant decline in urinary protein
excretion from 1.41 g/24 h to 0.82 g/24 h (P¼0.24). By
contrast, a study of moderate hypertensive patients
(office SBP 140–159 mmHg while taking at least three
drugs) revealed a similar reduction in 24-hour ABPM
SBPs (214 mmHg) as observed with office levels (31).
It is curious that we assume that both sides (i.e.,
both kidney arteries) need to be treated to produce the
anticipated results from renal denervation. There is
a paucity of experience with unilateral renal denervation;
however, we did find a case report on this from Germany
(32). Himmel et al. treated an 83-year-old woman taking
seven antihypertensive drugs who fulfilled criteria similar
to those in Table 10 (see below) and whose automated
home SBP was 173622 mmHg when taken three times
daily over 1 week. She had uneventful left kidney artery
denervation. However, her right-sided anatomy was
complicated and renal denervation was not attempted
on that side. At 3 months after the procedure, her SBP
had decreased to 148615 mmHg. This 25-mmHg SBP
decline is similar to values shown in Table 10.
A consensus document regarding renal denerva-
tion was recently issued after endorsement by the
European Society of Cardiology and the European
Association of Percutaneous Cardiovascular Interven-
tions (26). This document provides the prerequisites
for candidacy for this procedure, and these prerequi-
sites essentially formed the basis of the inclusion
criteria of the US Symplicity HTN-3 trial (22). Just
prior to the publication of this edition of NephSAP,
a press release indicated that the Symplicity HTN-3
trial failed to meet its primary efficacy endpoint. The
106 Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

Table 9. Overview of renal denervation studies at baseline and 6-month follow-up

Sham Starting Starting
First Treatment (% SBP6SD SBP6SD
Study Author Year (% Men) Men) (Treatment) (Sham) DSBP (mmHg) Comments
Symplicity Kruma 2009 45 (58) 5 (80) 17769 177620 222610/141 (NS) Average number
HTN-1 of medications:
5 in each group
Symplicity Eslerb 2010 52 (65) 54 (50) 178618 178616 232623/21621 Average number of
HTN-2 medications: 5 in
each group; no
change in kidney
function in either
group
Symplicity Eganc 2013d Fully enrolled about
HTN-3 550 patients, 2/3
treated with RDN
at randomization,
1/3 sham procedure
CKD Heringe 2012 15 (60) — 174622 — 232 Average eGFR was
31 ml/min per
1.73 m2 with no
significant change
after intervention
Moderate Ottf 2013 54 (70) — 15166 — 213 (NS) Average of 5.1
resistant medications
HTN
EnligHTN-1 Worthleyg 2013 46 (67) — 1766 (NS) — 2266 (NS) Average of 4.1
medications
SBP, systolic BP; HTN, hypertension; Sham, sham treatment or no catheter treatment.
a
Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M: Catheter-based renal sympathetic
denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet 373: 1275–1281, 2009.
b
Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M; Symplicity HTN-2 Investigators: Renal sympathetic denervation in patients with treatment-resistant
hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial. Lancet 376: 1903–1909, 2010.
c
Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC: Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation 124:
1046–1058, 2011.
d
Enrollment completed.
e
Hering D, Mahfoud F, Walton AS, Krum H, Lambert GW, Lambert EA, Sobotka PA, Böhm M, Cremers B, Esler MD, Schlaich MP: Renal denervation in moderate to severe CKD.
J Am Soc Nephrol 23: 1250–1257, 2012.
f
Ott C, Mahfoud F, Schmid A, Ditting T, Sobotka PA, Veelken R, Spies A, Ukena C, Laufs U, Uder M, Böhm M, Schmieder RE: Renal denervation in moderate treatment-resistant
hypertension. J Am Coll Cardiol 62: 1880–1886, 2013.
g
Worthley SG, Tsioufis CP, Worthley MI, Sinhal A, Chew DP, Meredith IT, Malaiapan Y, Papademetriou V: Safety and efficacy of a multi-electrode renal sympathetic denervation
system in resistant hypertension: The EnligHTN I trial. Eur Heart J 34: 2132–2140, 2013.

study did meet the primary safety endpoint, however,
and the Data Safety Monitoring Board indicated that
there were no safety concerns in the study (33).
In the future, questions to be addressed regarding
renal denervation are at least 2-fold. The first is whether
the procedure promotes renal artery atherogenesis, for
which there is little evidence aside from a few occur-
rences that might be expected given the older age and
drug resistance in this population (34). Second, one must
wonder about the ability of the kidneys to tolerate future
insults to kidney function (volume depletion, infection,
trauma, drug exposures, etc.) in the denervated state.
There are other neural systems in the kidney aside from
sympathetic nerves such as calcitonin gene-related pep-
tides that, in experimental situations, limit the effects
of insults such as hypertension on kidney histology and
function (35). These systems are also likely to be de-
pleted or downregulated by renal denervation. This
concern highlights the need for registry data as the
number of people who have undergone renal dener-
vation increases. At least one company, Medtronic
(Minneapolis, MN), has an existing renal denervation
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Table 10. Criteria patients should comply with before
renal denervation is considered
Criterion
Office-based systolic BP$160 mmHg ($150 mmHg
diabetes type 2)
$3 antihypertensive drugs in adequate dosage and
combination (including diuretic)
Lifestyle modification
Exclusion of secondary hypertension
Exclusion of pseudo-resistance using ABPM (average BP
.130 mmHg or mean daytime BP.135 mmHg)
Preserved renal function (GFR$45 ml/min per 1.73 m2)
Eligible renal arteries: no polar or accessory arteries, no renal
artery stenosis, no prior revascularization
Reprinted (with modification) with permission from Mahfoud F, Lüscher TF,
Andersson B, Baumgartner I, Cifkova R, Dimario C, Doevendans P, Fagard R, Fajadet
J, Komajda M, Lefèvre T, Lotan C, Sievert H, Volpe M, Widimsky P, Wijns W, Williams
B, Windecker S, Witkowski A, Zeller T, Böhm M; European Society of Cardiology:
Expert consensus document from the European Society of Cardiology on catheter-
based renal denervation. Eur Heart J 34: 2149–2157, 2013.
registry, and it is likely that other manufacturers will
join this effort.
Furthermore, renal denervation has been used in
settings outside of severe drug-resistant hypertension,
adding to our knowledge of the far-reaching consequen-
ces of the renal nerves. Finally, renal denervation serves
as a tool for treating symptoms and findings in disorders
such as atrial fibrillation, left ventricular hypertrophy,
sleep apnea, heart failure, and insulin resistance (36).
CTD versus HCTZ: The Debate Continues
CTD maintains its position as a useful diuretic
in hypertensive patients owing to the resurging in-
terest in CTD as an antihypertensive agent (37), the
switch to CTD from HCTZ when patients are eval-
uated at hypertension centers (21), and concern ex-
pressed by clinical trialists that dosages of HCTZ
of #12.5 mg/d have no evidence to support benefit.
In the 1980s, it was more common to see significant
hypokalemia with 50 or 100 mg of CTD compared
with 50 or 100 mg of HCTZ. With the recognition of
the longer duration of action and higher potency of
CTD, use of lower doses of CTD (e.g., 25 mg/d) has
resulted in a reduction in the adverse effects noted 3
decades ago. Moreover, there is continued interest in
whether there is a true advantage to using CTD over
HCTZ in hypertension. To that end, Roush et al.
conducted a meta-analysis of hypertension trials in
which one arm was either CTD or HCTZ, identifying
107
nine trials studying .78,000 people (38). The Forest
plot in Figure 17 shows the bottom line of this meta-
analysis, favoring use of CTD.
The authors of this meta-analysis make several
additional points. There is a greater likelihood that
CTD with its longer action will control office BP
better. Furthermore, when the office-based BP re-
duction achieved in a trial using HCTZ is compared
with the same office-based BP achieved in a trial using
CTD, the cardiovascular event rate for CTD is 19%
less than in the HCTZ arm. Such findings indicate that
either the out-of-office BP is better with CTD, a finding
confirmed in a study by Ernst previously reviewed in
NephSAP (39), or there is a beneficial pleomorphic (i.e.,
a non–BP-related) effect with CTD treatment.
Nondrug, Nondiet Treatments for Hypertension
The American Heart Association sponsored a sci-
entific statement whose charge was to evaluate the role
of nondrug, nondiet treatments in high BP (40). This was
broken down into three areas: behavioral therapies, such
as meditation and biofeedback, device or procedure
usage such as acupuncture, and exercise regimens. Table
11 summarizes these findings. The most effective non-
drug, nondietary therapy was dynamic, aerobic exercise,
defined as effort performed against an opposing force
accompanied by purposeful movement of joints and large
muscle groups (e.g., using Nautilus-type exercise ma-
chines at a gym). Although these exercises are often
undertaken to improve strength, they also reduce BP. In
addition, dynamic resistance exercises and device-guided
breathing (Resp-e-rate) were also effective but less so.
Orthostatic Hypotension
One of the more difficult clinical challenges is the
management of patients with orthostatic hypotension.
The presence of orthostasis confers a substantial risk of
hypotensive complications such as falls and fractures,
makes piloting a vehicle unsafe, and adds a great deal
of stress to just performing activities of daily living in
patients who have this disorder. The American Society
of Hypertension published a recent position paper
regarding this clinical conundrum, authored by experts
with a reputation for the evaluation and management
of orthostasis (41). The position paper makes a number
of useful suggestions for nondrug as well as drug
therapy. In particular, nondrug maneuvers to raise BP
include the following: increase fluid and salt intake,
108 Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

Figure 17. The Forest plot shows the bottom line of this meta-analysis. RR, relative risk. Reprinted with permission from
Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, Pergola PE, Szychowski JM; SPS3 Study Group:
Blood-pressure targets in patients with recent lacunar stroke: The SPS3 randomised trial. Lancet 382: 507–515, 2013. OSBP,
Office Systolic Blood Pressure; CTDN, Chlorthalidone; MRFIT, Multiple Risk Factor Intervention Trail.

avoid getting up quickly or standing motionless, use an Sodium Glucose Transporter-2

abdominal binder or compressive waist-high stock-
ings, raise head of the bed by 6–9 inches during night-
time, avoid prolonged standing and exposure to hot
environment (hot showers), cross legs while standing
(cocktail party posture), drink 16 ounces of tap water
(drink as a bolus), and maintain an exercise program
(swimming, recumbent bicycle, rowing).
The article also contains recommendations for
combination therapy, including dosages for fludrocorti-
sone, midodrine, and pseudoephedrine. A useful algo-
rithm for the evaluation and management of orthostasis
is shown in Figure 18.
Other features within the article include a section
on managing orthostasis in the hospitalized patient
and referral to the American Autonomic Society web-
site (www.americanautonomicsociety.org), along with
recommendations regarding appropriate referral. Some
final points include a reminder to evaluate BP and heart
rate at 1 and 3 minutes after standing, the recognition
that symptomatic BP changes occur more frequently in
the morning, and the realization that the goal of therapy
is a functioning patient, not a specific BP number.
Sodium glucose transporter-2 (SGLT-2), one of
six known glucose transporters, is a low-affinity, high-
capacity transporter expressed by the S1 and S2 segments
of the proximal renal tubule, where 90% of glucose
reabsorption occurs (42). In April 2013, the first drug
to block SGLT-2 for the management of diabetes was
approved in the United States (canagliflozin; Janssen
Pharmaceuticals, Titusville, NJ). There are other agents
in development within this class that emulate the dis-
order known as renal glucosuria, which is considered
a benign clinical entity when it occurs in isolation (i.e.,
not a component of more widespread proximal tubule
dysfunction as in Fanconi’s syndrome).
Dapagliflozin was studied at a dose of 10 mg/d
and compared with both placebo and HCTZ 25 mg/d
in 75 individuals with type 2 diabetes (43). This study
evaluated blood volume, renin activity, kidney function,
and 24-hour ABPM. The main findings were as follows:
(1) there was a 3.3-mmHg reduction in 24-hour ambu-
latory SBP compared with 6.6 mmHg with HCTZ and
0.9 mmHg with placebo at 12 weeks; (2) dapagliflozin
reduced weight progressively over time (presumably
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 109

Table 11. Class of recommendation and level of Update on BP Management in Stroke

evidence for BP lowering
Hypertension is a known risk factor for stroke
Alternative Level of Class of and stroke recurrence (45,46). In this section, two recent
Treatments Evidence Recommendation trials that address BP management in the presence of
Behavioral therapies stroke are reviewed.
Transcendental B IIB
meditation Ischemic Stroke
Other meditation C III (no benefit)
One pattern of stroke associated with high BP is
techniques
Biofeedback B IIB the development of subcortical brain lacunar infarc-
approaches tion, accounting for approximately one of four ische-
Yoga C III (no benefit) mic strokes (47). In the recent Secondary Prevention of
Other relaxation B III (no benefit) Small Subcortical Strokes (SPS3) trial, the study
techniques investigators tested two interventions using two target
Noninvasive procedures BP levels and two antiplatelet therapeutic regimens
or devices (which are not yet reported at this time). The study was
Acupuncture B III (no benefit)
predicated on the question of whether there is a benefit
Device-guided breathing B IIA
Exercise-based regimens to lowering SBP to ,130 mmHg after lacunar stroke.
Dynamic aerobic A I The study enrolled 3020 participants with a magnetic
exercise resonance imaging–confirmed lacunar infarct within 6
Dynamic resistance B IIA months of study enrollment and at least 2 weeks after
exercise the stroke event. Participants were randomized to either
Isometric handgrip C IIB a 130–149 mmHg SBP goal or a ,130 mmHg SBP goal.
exercise Treatment to the goal SBP was open label. If participants
Reprinted (with modification) with permission from Brook RD, Appel LJ, Rubenfire
M, Ogedegbe G, Bisognano JD, Elliott WJ, Fuchs FD, Hughes JW, Lackland DT,
were randomized to the higher BP range and their SBP
Staffileno BA, Townsend RR, Rajagopalan S; American Heart Association Pro- fell to ,130 mmHg, antihypertensive medications were
fessional Education Committee of the Council for High Blood Pressure Research,
Council on Cardiovascular and Stroke Nursing, Council on Epidemiology and
reduced or stopped. Participants were followed at 3-
Prevention, and Council on Nutrition, Physical Activity: Beyond medications and month intervals. If SBPs were not within target range,
diet: Alternative approaches to lowering blood pressure: A scientific statement
from the American Heart Association. Hypertension 61: 1360–1383, 2013.
antihypertensive therapy was adjusted and participants
were reevaluated in 1 month. Choice of antihypertensive
therapy was at the discretion of the study investigators at
through caloric losses in the urine); (3) dapagliflozin and each site. The primary outcome of the SPS3 trial was the
HCTZ both increased renin activity and aldosterone rate of recurrent stroke of any kind.
concentration, HCTZ more so than dapagliflozin, sug- At randomization, the SBP was 142 mmHg in the
gesting a diuretic-like effect as a potential mechanism more intense SBP group and 144 mmHg in the 130–149
for SGLT2 inhibitor-associated BP reduction; and (4) mmHg SBP group. The mean age was 63 years. At 1 year,
dapagliflozin treatment showed a decline in iohexol there was an 11-mmHg SBP difference (127 mmHg in the
GFR of 11%, whereas HCTZ had a 3% reduction. more intense group, and 138 mmHg in the other group).
Similar results have been seen with canagliflozin During a mean of 3.7 years of follow-up, the
(44). These results are intriguing for the possibility endpoint occurred in 125 of the 1501 (event rate¼2.25%
of doing three useful things to manage cardiovascular per patient-year) participants randomized to the lower
risk: (1) reducing glucose levels, (2) reducing weight, SBP goal compared with 152 events in the 1519 (2.77%
and (3) reducing BP. Thus far, hypoglycemia and per patient-year) participants randomized to the 130–149
symptomatic hypotension are infrequent occurren- mmHg goal. There was a 19% reduction in the hazard for
ces. The most common bothersome side effect of stroke (P¼0.08), which was less than the 25% reduction
SGLT2 inhibition is genitourinary infection (approx- planned for by the study organizers. Among stroke
imately 5% to date, with women more affected than subtypes, a statistically significant reduction was observed
men) as might be anticipated from urinary glucose only in intracerebral hemorrhage in the more intense SBP
enrichment. goal group. Table 12 shows event occurrence rates.
110 Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

Figure 18. Approach to the evaluation and treatment of orthostatic hypotension. SBP, systolic BP; DBP, diastolic BP; HTN,
hypertension; CHF, congestive heart failure; PRN, as needed. Reprinted with permission from Shibao C, Lipsitz LA, Biaggioni
I; American Society of Hypertension Writing Group: Evaluation and treatment of orthostatic hypotension. J Am Soc Hypertens
7: 317–324, 2013.

The SPS3 trial prespecified two subgroup analyses.
In the first, the benefit of the lower SBP goal in the
population who manifested hypertension before the index
stroke (n¼2706), and in which the results were similar to
the main study, was evaluated. In the second analysis, the
investigators determined outcomes in participants who
survived and did not withdraw from the study for at least
6 months after randomization, irrespective of whether an
event had occurred in the first 6 months. Once again, this
had little effect on outcomes in the SPS3 trial. Adverse
events were similar in the two BP goal arms, but
orthostasis with syncope was about twice as common in
the more intense BP goal group (11 versus 5 events).
Notably, the SPS3 trial was initially planned for
the enrollment of 2500 participants, but as with the
case of other recent large randomized trials such as
ACCORD (8), the event rate was lower than expected.
Consequently, the oversight committee increased the
enrollment to 3000 participants.
The SPS3 trial does suggest a benefit from a lower
SBP (,130 mmHg), but the benefit did not achieve the
magnitude anticipated by the investigators. Moreover,
benefit requires increased use of antihypertensive medi-
cations: 2.4 antihypertensive agents per patient in the
lower BP arm compared with 1.8 drugs per patient in the
130–149 mmHg group. In the future, the ongoing
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 111

Table 12. Event occurrence rates

Higher-Target Lower-Target
Group (n¼1519) Group (n¼1501)
Hazard Ratio
Rate (% per Rate (% per (95% Confidence
Event Patients (n) patient-year) Patients (n) patient-year) Interval) P Value
Stroke
All stroke 152 2.77 125 2.25 0.81 (0.64 to 1.03) 0.08
Ischemic stroke or 131 2.4 112 2.0 0.84 (0.66 to 1.09) 0.19
unknown
Intracranial
hemorrhage
All 21a 0.38 13b 0.23 0.61 (0.31 to 1.22) 0.16
Intracerebral 16 0.29 6 0.11 0.37 (0.15 to 0.95) 0.03
Subdural or 5 0.091 6 0.11 1.18 (0.36 to 3.88) 0.78
epidural
Other 2 0.036 4 0.072 1.97 (0.36 to 10.74) 0.43
Disabling or fatal 49 0.89 40 0.72 0.81 (0.53 to 1.23) 0.32
strokec
Myocardial 40 0.70 36 0.62 0.88 (0.56 to 1.39) 0.59
infarction
Major vascular 188 3.46 160 2.91 0.84 (0.68 to 1.04) 0.10
eventa
Deaths
All 101 1.74 106 1.80 1.03 (0.79 to 1.35) 0.82
Vascular death 41 0.70 36 0.61 0.86 (0.55 to 1.35) 0.52
Nonvascular 35 0.60 40 0.68 1.12 (0.71 to 1.76) 0.62
Uncertain 25 0.43 30 0.51 1.18 (0.69 to 2.00) 0.55
Reprinted (with modification) with permission from Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, Pergola PE, Szychowski JM; SPS3 Study Group:
Blood-pressure targets in patients with recent lacunar stroke: The SPS3 randomised trial. Lancet 382: 507–515, 2013.
a
One classified as both intracerebral and other, and one as both intracerebral and subdural or epidural.
b
One classified as intracerebral and subdural or epidural, and two as both intracerebral and other.
c
Disabling strokes classified as a modified Rankin score $3 after 3–6 months.

Systolic Blood Pressure Intervention Trial might confirm
this SPS3 finding, or, by way of meta-analytic combina-
tion, demonstrate the desired statistical significance re-
quired in the evidence-based treatment era.
Hemorrhagic Stroke
Uncertainty remains regarding whether, and to
what degree, to intervene on BP elevations in the
presence of an acute stroke, particularly intracerebral
hemorrhage (ICH). ICH is principally at issue because
most cases of severe hypertension occur in this setting
(48). A few years ago, as reviewed in a prior NephSAP,
the pilot study for the Intensive Blood Pressure Reduc-
tion in Acute Cerebral Hemorrhage Trial (INTERACT 1)
was published and advocated cautious optimism regard-
ing the safety of acute BP lowering in this scenario, as
well as the possible benefit of lowering BP on hematoma
growth. The INTERACT 1 study was short term and laid
the foundation for the larger INTERACT 2 trial whose
results were published in June 2013 (49).
In the INTERACT 2 study, there were 2974
participants with a SBP of 150–220 mmHg and a di-
agnosis of ICH confirmed by CT or MRI randomized to
either intense BP control or guideline-recommended
treatment. In participants randomized to aggressive BP
control, the goal was reduction of SBP to ,140 mmHg
within 1 hour of randomization, with maintenance to that
level for the ensuing 7 days or until the time of discharge.
In participants randomized to the guideline-recommended
treatment group, antihypertensive therapy was adminis-
tered for SBPs.180 mmHg. The primary outcomes in the
INTERACT 2 study were death and severe disability, as
determined by a modified Rankin score (0, no disability;
5, severe disability; and 6, death). In the intensively
treated group, 90% received an intravenous agent to
achieve BP goal, and the most popular intravenous agents
112
used were the a-adrenergic antagonist urapidil (32%),
followed by the CCBs nicardipine or nimodipine
(16%). Choice of antihypertensive agents was at the
discretion of the investigators and did not follow a
prespecified protocol. In the intensive treatment group,
52% experienced an outcome compared with 55.6% in
the guideline-recommended group (P¼0.06). In apply-
ing a prespecified ordinal analysis to the modified
Rankin score, which has more power to show a signif-
icant benefit than the primary analysis, the Rankin
score was 13% higher in the intensive treatment group
(P¼0.04). Serious adverse events occurred at a similar
rate in both groups.
The INTERACT 2 study shows a trend toward
better outcomes in the intensive treatment group when
intense BP-lowering therapy is initiated early in the
course of ICH and applied aggressively to a SBP,140
mmHg within the first hour. Approximately two thirds of
the enrollees were Chinese, a population with a notori-
ously higher ICH risk, thus limiting generalizability of
the trial. It should be noted that 84% of the bleeds were
at deep locations and were relatively small (,11 ml).
Nonetheless, there were not significant safety issues with
more intensive BP lowering in this group.
The next anticipated study is the North American
Antihypertensive Treatment of Acute Cerebral Hemor-
rhage II (ATACH II) trial (47). The ATACH II trial plans
to assign acute ICH patients to a SBP of ,140 mmHg or
,180 mmHg, and specifies the use of nicardipine as the
antihypertensive agent. Results are expected in 2016.
Overall, the concern that more intensive BP low-
ering in acute stroke may worsen outcomes by com-
promising the penumbral zone appears unfounded. The
less than anticipated event rates observed in recent
clinical trials, although a nuisance to investigators, are
welcome news in that they likely reflects overall
improved cardiovascular risk management.
Clinical Practice Guidelines for Treating Hypertension
in CKD and Diabetes Mellitus
A number of clinical practice guidelines have been
published over the past 2 years. In December 2012,
Kidney Disease: Improving Global Outcomes (KDIGO)
published a supplement to Kidney International on clin-
ical practice guidelines for the treatment of hypertension
in CKD (50). Shortly thereafter, the KDIGO CKD Work
Group published the 2012 Clinical Practice Guideline
for the Evaluation and Management of Chronic Kidney
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Disease, with only subtle differences in treatment guide-
lines (51). In 2013, the American Diabetes Association
also published new clinical practice guidelines for the
management of hypertension in patients with diabetes
mellitus (52). At the time of this writing, hypertension
treatment guidelines were updated in Europe by the
European Society of Hypertension at its annual meeting
in Milan, Italy, in June 2013 (53). Shortly before the
publication of this edition of NephSAP, several major
organizations published varying clinical practice guide-
lines regarding hypertension management, including the
American Heart Association in conjunction with the
American College of Cardiology and the Centers for
Disease Control and Prevention, the American Society
of Hypertension and the International Society of Hyper-
tension, and the Eighth Joint National Committee (Joint
National Committee 8) (54–56).
The publication of guidelines for hypertension
began in 1977 (57) as an extension of the National
Heart, Lung, and Blood Institute’s (NHLBI) High Blood
Pressure Education Program. The original Joint National
Committee report comprised seven text pages and a single
reference. Over the years, the report grew to include
staging/classification schemes, incorporated the word
prevention in the title, and expanded to include extensive
discussions of complicating comorbidities (e.g., diabetes
or CKD) as well as detailed approaches to drug and
nondrug treatment. Joint National Committee 7, pub-
lished in 2003, comprised 38 text pages and 386 re-
ferences. The most recent Joint National Committee
diverged from this path of growth in two ways. First,
the panel agreed from the start to strive to present re-
commendations for BP evaluation and management
based on evidence whenever possible. Second, the panel
also decided that the primary audience for the recom-
mendations in this report would be primary care pro-
viders, not hypertension specialists. Finally, the NHLBI,
which had originated the hypertension guidelines process
in the mid-1970s, has determined that it no longer holds
responsibility for guideline development (58). Guidelines
regarding the BP targets and the use of ACEIs or
ARBs with regard to CKD, diabetes, or albuminuria
status (when indicated) are summarized in Table 13.
KDIGO Clinical Practice Guideline for Management
of Blood Pressure in CKD
Historically, two things led to the formation of
KDIGO. The first was the successful and effective
Table 13. Summary of Clinical Practice Guidelines: Hypertension Goals and Use of ACEI or ARB with Regard to CKD, Diabetes, or Albuminuria Status
(When Indicated)
2013 American
Society of
Hypertension
2013 AHA/ and the
2013 American ACC/CDC International
2012 KDIGO HTN 2013 KDIGO CKD Diabetes Science Society of 2014 Eighth Joint
Guideline Recommendationa Recommendationb Associationc Advisoryd Hypertensione National Committee f

Hypertension Target BP#140/90 Target BP#140/90 People with No BP treatment Target BP In the general
goals mmHg if mmHg if diabetes and goal explicitly for patients population aged$60 yr,
albuminuria,30 albuminuria,30 hypertension indicated. aged,80 yr treat to a goal SBP,150
mg/d (1B) mg/d (1B) should be Guideline is ,140/90 mmHg and goal DBP ,90
treated offers an mmHg, mmHg (grade A)
to a SBP goal algorithm for although
of ,140 hypertension some experts
mmHg (B) treatment, with still
recommendations recommend
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

to start treatment ,130/80

when the BP is mmHg if
.140/90 mmHg albuminuria
is present in
patients with
CKD
Target BP#130/80 Target BP#130/80 Lower SBP goals, Target BP Corollary
mmHg if mmHg if such as ,130 for patients recommendation:
albuminuria$30 albuminuria$30 mmHg, may be aged $80 yr In the general
mg/d ($30 mg/d (2D) appropriate for is ,150/90 population aged$60 yr,
mg/d ¼ 2D; certain mmHg unless if pharmacologic treatment
$300 mg/d ¼ 2C) individuals, these patients for high BP results in
such as have CKD or lower achieved SBP
younger patients, diabetes (e.g., ,140 mmHg)
if it can be mellitus, when and treatment is not
achieved ,140/90 can associated with adverse
without undue be considered effects on health or
treatment quality of life, treatment
burden (C) does not need to be
adjusted (grade E)
(continued)
113
 114
Table 13. continued
2013 American
Society of
Hypertension
2013 AHA/ and the
2013 American ACC/CDC International
2012 KDIGO HTN 2013 KDIGO CKD Diabetes Science Society of 2014 Eighth Joint
Guideline Recommendationa Recommendationb Associationc Advisoryd Hypertensione National Committee f

Hypertension See above See above Patients with See above See above In the general population
goals (continued) diabetes should aged,60 yr, initiate
be treated to pharmacologic treatment
a DBP ,80 to lower BP at DBP$90
mmHg (B) mmHg and treat to a goal
DBP,90 mmHg (for ages
30–59 yr, grade A; for
ages 18–29 years, grade E)
In the general population
aged,60 yr, initiate
pharmacologic
treatment to lower BP
at SBP$140 mmHg
and treat to a goal
SBP,140 mmHg
(expert opinion –
grade E)
In the population
aged$18 yr with CKD,
treat to goal SBP,140
mmHg and goal
DBP,90 mmHg
(grade E)
In the population
aged$18 yr
with diabetes, treat
to a goal SBP,140
mmHg and goal
DBP,90 mmHg
(grade E)
(continued)
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Table 13. continued
2013 American
Society of
Hypertension
2013 AHA/ and the
2013 American ACC/CDC International
2012 KDIGO HTN 2013 KDIGO CKD Diabetes Science Society of 2014 Eighth Joint
Guideline Recommendationa Recommendationb Associationc Advisoryd Hypertensione National Committee f

Use of ACEI Diabetes: use Diabetes: use Pharmacologic Use ACEI or First drug In the population
or ARB with ACEI or ARB ACEI or ARB if therapy for ARB in selection aged$18 yr with
regard to CKD, if albuminuria$30 albuminuria$30 patients with kidney when CKD, initial (or
diabetes, or mg/d (2D) mg/d (2D) diabetes and disease HTN is add-on)
albuminuria hypertension associated antihypertensive
status (when should be with with other treatment should
indicated) a regimen that conditions include an ACEI
includes either (see guideline or ARB to improve
an ACEI or for second kidney outcomes;
ARB and third this applies to
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

drug all CKD patients

selection): with hypertension
HTN and regardless of
diabetes— race or diabetes
ARB or status (grade B)
ACEI (in
black patients,
it is acceptable
to start with
CCB or
thiazide)
(continued)
115
 116
Table 13. continued
2013 American
Society of
Hypertension
2013 AHA/ and the
2013 American ACC/CDC International
2012 KDIGO HTN 2013 KDIGO CKD Diabetes Science Society of 2014 Eighth Joint
Guideline Recommendationa Recommendationb Associationc Advisoryd Hypertensione National Committee f

Use of ACEI Nondiabetes: Diabetes and In the treatment Use ACEI or HTN and See above
or ARB with use ACEI nondiabetes: use of the ARB, CKD—
regard to CKD, or ARB if ACEI or ARB if nonpregnant thiazide, ARB or ACE
diabetes, or albuminuria$30 albuminuria$300 patient with b-blocker, inhibitor (in
albuminuria mg/d in mg/d (1B) modestly and/or CCB black patients,
status (when nondiabetic elevated in diabetes good evidence
indicated) (continued) adults in whom (30–299 mellitus for renal
treatment with mg/d) (C) or protective
BP-lowering higher levels effects of
drugs is $300 mg/d) ACEIs)
indicated (2D) of urinary
albumin
excretion (A),
either ACEIs
or ARBs are
recommended
Guideline types are as follows: 1, “we recommend”; 2, “we suggest”; B, moderate quality of evidence; C, low quality of evidence; D, very low quality of evidence; A, clear evidence from well conducted, generalizable randomized
controlled trials that are adequately powered; B, supportive evidence from well conducted cohort studies; C, supportive evidence from poorly controlled or uncontrolled studies; grade A, strong recommendation (there is high
certainty based on evidence that the net benefit is substantial); grade B, moderate recommendation (there is moderate certainty based on evidence that the net benefit is moderate to substantial or there is high certainty that the net
benefit is moderate); grade E, expert opinion (there is insufficient evidence or evidence is unclear or conflicting, but this is what the committee recommends; net benefit is unclear; balance of benefits and harms cannot be
determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, but the committee thought it was important to provide clinical guidance and make a recommendation; further research is
recommended in this area). RAAS, renin-angiotensin-aldosterone system; KDIGO, Kidney Disease Improving Global Outcomes; AHA, American Heart Association; ACC, American College of Cardiology; CDC, US Centers for Disease
Control and Prevention; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HTN, hypertension; CCB, calcium channel blocker.
a
Data are from KDIGO Panel: KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int Suppl 2: 343–387, 2012.
b
Data are from Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group: KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 3: 1–150, 2013.
c
Data are from American Diabetes Association: Standards of medical care in diabetes—2013. Diabetes Care 36(Suppl 1): S11–S66.
d
Data are from Go AS, Bauman M, King SM, Fonarow GC, Lawrence W, Williams KA, Sanchez E: An effective approach to high blood pressure control – a science advisory from the American Heart Association, the American
College of Cardiology, and the Centers for Disease Control and Prevention [published online ahead of print November 15, 2013]. Hypertension doi:10.1161/HYP.0000000000000003.
e
Data are from Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, Flack JM, Carter BL, Materson BJ, Ram CV, Cohen DL, Cadet JC, Jean-Charles RR, Taler S, Kountz D, Townsend R, Chalmers J, Ramirez AJ,
Bakris GL, Wang J, Schutte AE, Bisognano JD, Touyz RM, Sica D, Harrap SB: Clinical practice guidelines for the management of hypertension in the community: A statement by the American Society of Hypertension and the
International Society of Hypertension. J Clin Hypertens 32: 3–15, 2014.
f
Data are from James PA, 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, 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 Eighth Joint National Committee (JNC 8) [published online ahead of print December 18,
2013]. JAMA doi:10.1001/jama.2013.284427.
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Nephrology Self-Assessment Program - Vol 13, No 2, March 2014 117

Table 14. Summary of KDIGO recommendations for management of BP in CKD

Target Population Goal BP Evidence Level Commentary
Nondiabetic CKD with normal to #140/90 mmHg 1B Evidence based
mild albuminuria
Recommend ,140/90 mmHg
Nondiabetic CKD with moderate to #130/80 mmHg 2D moderate, 2C Reasonable to select a
severe albuminuria severe goal of ,140/90 mmHg,
especially for moderate
albuminuria
Diabetic CKD with normal to mild #140/90 mmHg 1B Evidence based
albuminuria
Recommend ,140/90 mmHg
Diabetic CKD with moderate to #130/80 mmHg 2D Reasonable to select a
severe albuminuria goal of ,140/90 mmHg
Kidney transplant recipients #130/80 mmHg 2D Reasonable to select a goal of
,140/90 mmHg
Children with CKD #90th percentile for age, sex, height 2D No evidence to support either
#50th percentile for age, sex, recommendation
height with any proteinuria
Elderly with CKD Individualize Not available Reasonable to consider a
higher goal, especially for
age.80 yr
Reprinted (with modification) with permission from Taler SJ, Agarwal R, Bakris GL, Flynn JT, Nilsson PM, Rahman M, Sanders PW, Textor SC, Weir MR, Townsend RR: KDOQI
US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis 62: 201–213, 2013.

publication of dialysis guidelines in 1993 (59), a process Quality Initiative (KDOQI) whose first four guidelines
espoused by the National Kidney Foundation (NKF) covering peritoneal dialysis and hemodialysis adequacy,
under the rubric of the Kidney Dialysis Outcomes vascular access management and anemia followed 4

Figure 19. Number of randomized controlled trials published in nephrology and 12 other specialties of internal medicine from
1966 to 2010. Reprinted with permission from Palmer SC, Sciancalepore M, Strippoli GF: Trial quality in nephrology: How are
we measuring up? Am J Kidney Dis 58: 335–337, 2011.
118
years later, as chronicled by Eknoyan and Agodoa (60).
The recognition that evidence-based guidelines were
a good way to reduce inefficiency and enhance efficacy
spurred the process. The second factor leading to the
genesis of KDIGO was the recognition that CKD is
a global issue. Subsequently, international cooperation
was solicited in the assemblage and dissemination of
CKD clinical practice guidelines (61).
The KDIGO clinical practice guidelines regarding
the management of hypertension in CKD are divided into
seven content areas (see the red box), four appendix
sections regarding methods, and a summary (62). Fre-
quently, the NKF KDOQI group writes an editorial
response summarizing the KDIGO clinical practice
guidelines, providing advice and recommendations
regarding their implementation. The table in the KDOQI
response to the KDIGO clinical practice guideline is
reproduced here as Table 14, and provides a sum-
mary of the clinical practice guidelines with editorial
comments (63).
The KDIGO clinical practice guidelines
covered hypertension in the following: (1)
lifestyle and drugs for managing hyper-
tension in CKD not dialyzed (ND), (2) hy-
pertension treatment in CKD ND and not
diabetic, (3) hypertension treatment in CKD
ND with diabetes, (4) hypertension treat-
ment in kidney transplant recipients, (5)
hypertension treatment in children with CKD
ND, (6) hypertension treatment in elderly
patients with CKD ND, and (7) future direc-
tions and controversies.
Several observations can be made from the NKF
editorial to the KDIGO clinical practice guidelines.
The first is the absence of any highest quality level “A”
evidence upon which to base the KDIGO recommen-
dations. The second is the issue of target BP. KDIGO
continued to recommend 130/80 mmHg in many
scenarios based on 2D evidence, in which the 2 means
that the wording of the recommendations is “we
suggest” (1 would mean “we recommend”) and the D
means that the quality of the evidence is “very low.”
Perhaps the largest gap in the evidence is the BP
recommendation for children with CKD and elderly
individuals with CKD. It remains sobering how thin the
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
evidence is for managing hypertension in CKD. This is
not surprising, considering the poor funding responses
for clinical trials in nephrology (64). Figure 19 illus-
trates this point well (64).
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chlorthalidone: putting the ACCOMPLISH study into perspective.
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How are we measuring up? Am J Kidney Dis 58: 335–337, 2011 PubMed
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

Nephrology Self-Assessment Program

Examination Questions
Original Release Date
March 2014
CME Credit Termination Date
February 29, 2016
Examination Available Online
On or before Wednesday, March 12, 2014
Estimated Time for Completion
8 hours
Audio Files Available
No audio files for this issue.
Answers with Explanations
• Provided with a passing score after the first and/or after the second attempt
• March 2016: posted on the ASN website when the issue is archived.
Target Audience
• Nephrology certification and recertification candidates
• Practicing nephrologists
• Internists
• Other
Method of Participation
• Read the syllabus that is supplemented by original articles in the reference lists.
• Complete the online self-assessment examination.
• Each participant is allowed two attempts to pass the examination (.75% correct) for CME credit.
• Upon completion, review your score and incorrect answers and print your certificate.
• Answers and explanations are provided with a passing score or after the second attempt.
Activity Evaluation and CME Credit Instructions
• Go to www.asn-online.org/cme, and enter your ASN login on the right.
• Click the ASN CME Center.
• Locate the activity name and click the corresponding ENTER ACTIVITY button.
• Read all front matter information.
• On the left-hand side, click and complete the Demographics & General Evaluations.
• Complete and pass the examination for CME credit.
• Upon completion, click Claim Credits, check the Attestation Statement box, and enter your CME credits.
• If you need a certificate, Print Your Certificate on the left.
For your complete ASN transcript, click the ASN CME Center banner, and click View/Print Transcript on the left.

Instructions to obtain American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) Points
Each 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
• Enroll for MOC via the ABIM website (www.abim.org).
• 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 to
complete the ABIM MOC enrollment process.

122
 Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
NephSAP, Volume 13, Number 2, March 2014—Hypertension
1. A 49-year-old man with diabetes is seen in con-
sultation for BP management. He has been taking
an angiotensin-converting enzyme inhibitor (ACEI)
for about 5 years and his daytime home BP mea-
surements average 130–134/80 mmHg. He re-
cently had an echocardiogram for evaluation of
a soft murmur heard by his primary care doctor and
was surprised to find that he had left ventricular
hypertrophy with preserved systolic function, nor-
mal wall motion, a normal aortic valve, and modest
mitral insufficiency with normal right-sided pres-
sures. A 24-hour ambulatory BP monitor was ordered
and the hourly averaged data are graphed in Figure 1.
Which ONE of the following is MOST likely
present in this patient?
A. A troponin I level .3 times the upper limit
of normal
B. A low serum aldosterone concentration
C. A serum creatinine value representing an
eGFR of ,60 ml/min per 1.73 m2
D. Q waves in limb leads II, III, and aVF
E. An albumin/creatinine ratio of ,30 mg/g
2. A 41-year-old man with a history of hypertension
who recently relocated to your area is admitted for
management of acute onset of breathlessness and
severe hypertension. He indicates that he was
taking an ACEI/diuretic combination tablet. In the
emergency department, his BP measurements are
repeatedly in the 180–190/105–125 mmHg range.
There are rales at both lung bases and an S4 gallop
is audible. No abdominal or flank bruits are heard.
There is no peripheral edema. His serum creati-
nine level is 1.5 mg/dl (no baseline value avail-
able), and his urinalysis is significant for protein
(11). Microscopic examination of the urinary
sediment shows several fine granular casts.
Which ONE of the following BEST describes
this patient?
A. Drug-resistant hypertension
B. Refractory hypertension
123
C. Recalcitrant hypertension
D. Adrenergic hypertension
E. Secondary hypertension
3. A 62-year-old executive had a physical exami-
nation that included vascular assessments at his
workplace. He brings a sheaf of reports to his
visit for you to review. He shows you a page,
entitled “vascular stiffness,” as assessed by carotid-
femoral pulse wave velocity (PWV). His value was
12.4 m/s. The normal for his age is said to be
10.060.6 m/s. He has a BP of 134/70 mmHg at
this visit.
Which ONE of the following is MOST
accurate?
A. Treating him with antihypertensive drugs
now will preempt target organ damage
from hypertension
B. His chances of developing hypertensive
BP in the next 7 years are increased
C. The values obtained for PWV in his case
are reassuring and need no further therapy
D. The values obtained of PWV in his case
suggest that he should be screened for
renovascular disease
4. A 56-year-old woman with type 2 diabetes is
sent to you for a second opinion about her
hypertension control. Home BP readings have
confirmed persistent systolic hypertension in the
range of 145–155 mmHg. She is taking the
maximal dose of valsartan and 50 mg of chlor-
thalidone daily, along with a generic sulfonyl-
urea. Her BP is 144/80 mmHg taken three times
seated. Her heart rate is 78 beats per minute. The
patient’s body mass index (BMI) is 32 kg/m2 and
there is trace pedal edema. The remainder of
the physical examination is normal. Her serum
electrolytes are normal, and her serum creatinine
level is 1.1 mg/dl, yielding an eGFR of 51 ml/min
per 1.73 m2 (using the Modification of Diet in
Renal Disease formula). Her urine shows an
124
Figure 1. 24-hour ABPM graph for the patient in Question 1.
albumin/creatinine ratio of 1580 mg/g, consistent
with her proteinuria (21) shown on dipstick
testing. The patient’s hemoglobin A1C is 7.2%.
Which ONE of the following is the MOST
appropriate next step in her management?
A. Add enalapril
B. Check 24-hour urine for sodium
C. Conduct a renal artery Doppler study
D. Substitute lisinopril for valsartan
E. Request 24-hour ambulatory BP monitoring
5. You see a 39-year-old woman for a first visit
after a worksite screening examination uncov-
ered high BP. She is asymptomatic. Her primary
care doctor, who confirmed elevated BP, won-
ders whether or not she might have a secondary
form of hypertension and refers her for evalua-
tion. She is taking no medications, and there
is no family history of hypertension. Her BP is
155/96 mmHg in the right arm (average of three
readings) and 150/95 mmHg in the left arm using
the same device. Cardiac and pulmonary exami-
nations are normal. There are no flank or ab-
dominal bruits. Pulses are 21 and symmetric and
there is no radial-femoral delay. The rest of the
examination is unremarkable. Her serum creati-
nine level is normal at 0.6 mg/dl. The patient’s
complete blood count, serum electrolytes, fasting
lipid profile, fasting glucose, urinalysis, and
electrocardiogram are normal.
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
Regarding the interarm difference in BP,
which ONE of the following is the MOST
appropriate management for this patient?
A. A magnetic resonance angiogram of the
chest to examine for Takayasu arteritis
B. An arterial Doppler examination of the
arms
C. A renal Doppler ultrasound for kidney size
and blood flow restriction
D. No further diagnostic testing
E. Two-dimensional and Doppler echocardi-
ography
6. A 48-year-old woman of black descent is seen
for hypertension. She has a BMI of 24.8 kg/m2
and is a nonsmoker. She exercises regularly,
consumes a vegetarian diet, is cautious with her
salt intake, and has an occasional glass of wine at
social occasions. Her parents are both alive,
living in a rural setting, and, although they both
have high BP, hypertension was not present until
they both were aged$60 years. The patient’s BP
measurements are 144/90 mmHg in her dominant
arm, an average of three readings.
Which ONE of the following would help
MOST in understanding contributors to her
hypertension?
A. A plasma angiotensin concentration
B. Serum calcium concentration
C. Assessment of history of increased expo-
sure to air pollutants
D. Echocardiography
E. Funduscopic examination
7. A new patient makes an appointment to see you
because her brother is on dialysis. She is of
African descent, aged 35 years, and is not
diabetic. She has a BMI of 26 kg/m2, a negative
urine result for blood and albumin by dipstick
testing, and an unremarkable physical examina-
tion. Her seated BPs (average of three values) in
her dominant arm are 135/83 mmHg, with
a regular heart rate of 77 beats per minute. These
values are mildly higher than those she records
weekly at home after 5–10 minutes of quiet
sitting, which range from 125 to 130 mmHg
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
for systolic BP (SBP), with an occasional value
above or below that range during the last 6 months.
You discuss her concerns about her developing
ESRD. Her serum creatinine level is 0.7 mg/dl,
stable from the value obtained 1 year ago. The
urine albumin/creatinine ratio is 15 mg/g.
Which ONE of the following is the MOST
appropriate next step in management?
A. Initiation of ACEI therapy with a goal of
130 mmHg SBP
B. Initiation of diuretic therapy with a goal of
130 mmHg SBP
C. Kidney ultrasound
D. 24-hour ambulatory BP monitoring
E. Periodic in-office and home BP measurements
8. A 48-year-old man with no significant past med-
ical history is referred for evaluation of renal
cysts found incidentally on a computed tomog-
raphy (CT) scan obtained 1 month earlier during
an evaluation for acute diverticulitis. Other than
this recent illness, he is asymptomatic. He has no
family history of kidney disease. He does not
take any medications. The patient’s BMI is 25.4
kg/m2 and his heart rate is 68 beats per minute.
His BPs average 148/92 mmHg on multiple mea-
surements. The remainder of the examination is
unremarkable. His serum creatinine is 0.8 mg/dl
and his potassium is 4.1 mmol/L. The CT scan
shows normal-sized kidneys with two simple
renal cysts on each kidney, with the largest
measuring 3.8 cm. The patient informs you
that his BP had been noted to be elevated on
several occasions and inquires about the re-
lationship between his renal cysts and his
hypertension.
Which ONE of the following statements BEST
addresses his question?
10. Which ONE of the following statements is
A. He has autosomal dominant polycystic
kidney disease, a known cause of second-
ary hypertension
B. The presence of multiple simple cysts is
associated with an increased risk of hy-
pertension
C. He has medullary cystic kidney disease,
a known cause of secondary hypertension
125
D. He likely has a multifocal, cystic renin-
producing tumor
E. There is no known relationship between
the two conditions
9. A 19-year-old woman is referred for evaluation
of nephrotic syndrome. Over the past 8 weeks,
she has developed progressive edema and a
10-kg weight gain, without other symptoms. Her
BP is 150/94 mmHg and there is leg edema (31).
The patient’s serum creatinine is 0.8 mg/dl,
potassium is 3.9 mg/dl, and albumin is 2.2 g/dl.
Urine sediment shows scattered oval fat bodies
and hyalofatty casts. A 24-hour urine collection
reveals proteinuria of 6 g. The kidney biopsy
shows minimal change glomerulopathy. Predni-
sone (60 mg/d), furosemide (40 mg/d), ramipril
(10 mg/d), calcium carbonate, and omeprazole are
initiated. Over the next 3 weeks, the patient
continues to have persistent edema, despite in-
creasing furosemide to 80 mg three times daily
and adding optimally dosed chlorthalidone. On
physical examination, the patient’s BP is 148/92
mmHg. There is persistent leg edema (31).
Laboratory studies show the following: sodium,
138 mmol/L; potassium, 3.5 mmol/L; chloride,
101 mmol/L; total CO2, 32 mmol/L; BUN, 26
mg/dl; and serum creatinine, 0.9 mg/dl. Her urine
protein/creatinine ratio is 5600 mg/g.
Of the options listed below, which ONE of the
following is the MOST appropriate manage-
ment for this patient?
A. Add cyclosporine
B. Add cyclophosphamide
C. Add amiloride
D. Add amlodipine
E. Add losartan
CORRECT regarding the functional findings
you would expect to see 3 months after
stenting of a hemodynamically significant re-
nal artery stenosis?
A. Partially restored renal blood flow and
reduced tissue hypoxia, but unchanged
markers of tubular injury measured in the
renal vein
126
B. Fully restored renal blood flow, but
unchanged tissue hypoxia and markers
of tubular injury measured in the renal
vein
C. Unchanged renal blood flow, but improved
tissue hypoxia and markers of tubular
injury measured in the renal vein
D. Unchanged renal blood flow, tissue hyp-
oxia, and markers of tubular injury mea-
sured in the renal vein
E. No such assessments are possible in
humans
11. A 74-year-old woman with hypertension, hyper-
lipidemia, and tobacco abuse is referred to you
for the evaluation and management of recently
identified unilateral renal artery stenosis during
a cardiac catheterization for chest pain. The
angiogram showed no significant coronary dis-
ease, but identified a 70% ostial right renal artery
stenosis. The patient feels well overall and quit
smoking 3 weeks ago. Her medications include
amlodipine, metoprolol, atorvastatin, and aspi-
rin. On examination, her BP is 126/72 mmHg
and her heart rate is 60 beats per minute. Other
than trace ankle edema, she has no other positive
findings. Laboratory studies show the following:
creatinine, 1.0 mg/dl (stable); potassium, 4.3
mmol/L; LDL cholesterol, 74 mg/dl; and HDL
cholesterol, 56 mg/dl.
Which ONE of the following is the MOST
appropriate next step in her management?
A. Substitute rosuvastatin for atorvastatin
B. Substitute clopidogrel for aspirin
C. Substitute lisinopril for metoprolol
D. Add fish oil
E. Do not change therapy at this time
12. A 60-year-old man with hypertension and coro-
nary disease is referred to you for a second
opinion regarding the management of unilateral
renal artery stenosis. Other than episodic angina
that promptly responds to nitrates, he is asymptom-
atic. The patient’s medications include lisinopril,
amlodipine, metoprolol, atorvastatin, aspirin,
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
isosorbide mononitrate, and as needed, nitroglyc-
erin. His BP is 158/92 mmHg and his heart rate is
64 beats per minute. He has a loud S4 and bilateral
ankle edema (11). The patient’s serum creatinine
is 1.2 mg/dl (stable). He brings a CT angiogram
demonstrating a 90% right renal artery stenosis.
Another local physician has recommended renal
artery stenting in order to improve the patient’s
cardiovascular and renal outcomes.
Which ONE of the following is your BEST
recommendation to the patient based on
available evidence?
A. You agree with the other physician’s
recommendations
B. You recommend renal artery stenting to
improve his cardiovascular outcomes, but
explain to him that there will be no
expected renal benefits
C. You recommend renal artery stenting to
improve his renal outcomes, but explain to
him that there will be no expected cardio-
vascular benefits
D. You agree with revascularization, but
recommend that it be done by a vascular
surgeon using an operative open approach
E. You disagree with the recommendations
and suggest the addition of a thiazide di-
uretic for better BP control
13. A 49-year-old man with obesity, diabetes, and
hyperlipidemia is referred for evaluation and
management of resistant hypertension. Other
than diffuse arthralgias, he feels relatively well.
Medications include atorvastatin, lisinopril,
chlorthalidone, amlodipine, carvedilol, spirono-
lactone, metformin, and glargine insulin. Home
BP readings are 150–160/95–105 mmHg. Other
than severe obesity (BMI of 41.5 kg/m2) and an
S4 gallop, the remainder of the physical exam-
ination is normal. All chemistries are normal ex-
cept for glycosylated hemoglobin, which is 9.1%. A
thorough evaluation for secondary causes of
hypertension is negative. You are contemplating
whether or not to refer the patient for bariatric
surgery, and a discussion regarding the indica-
tions and potential benefits of this intervention
ensues.
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
On the basis of available clinical trials, which
ONE of the following statements is CORRECT
regarding the expected results of bariatric
surgery?
A. BP control will improve, leading to lower
medication needs, and, in some cases, full
discontinuation
B. The 12-month risk of congestive heart
failure will decrease
C. Glucose control will not improve
D. His BMI is still too low for him to have any
benefit from the operation; it should be de-
ferred until his weight has further increased
E. Weight loss will occur, but there will be no
other tangible benefits
14. A 79-year-old man with obesity, diabetes, atrial
fibrillation, and coronary artery disease is re-
ferred to you for resistant hypertension. His only
complaint is stable exertional dyspnea. His wife
notes that he snores, but he denies daytime
hypersomnolence or fatigue. Medications in-
clude chlorthalidone, lisinopril, metoprolol,
and amlodipine. A physical examination shows
a BP of 152/64 mmHg and a heart rate of 58
beats per minute. There is central obesity and the
uvula cannot be visualized without instrumentation.
There is trace ankle edema. A polysomnogram
reveals moderate obstructive sleep apnea with an
apnea/hypopnea index of 23 per hour. Treatment
with noninvasive continuous positive airway
pressure ventilation is recommended.
Assuming that the patient is adherent to the
treatment, which ONE of the following state-
ments BEST describes the expected effects of
continuous positive airway pressure on his
hypertension?
A. It will produce a large (approximately 20/10
mmHg) BP reduction during sleep, but only
a small reduction (,5/3 mmHg) during
wakefulness
B. It will produce a large (approximately 20/10
mmHg) BP reduction both during sleep and
wakefulness
C. It will produce a small reduction (,5/3
mmHg) during sleep and a moderate
127
reduction (approximately 10/5 mmHg)
during wakefulness
D. It will produce a small (,5 mmHg) BP
reduction during both sleep and wakefulness
15. An otherwise healthy 42-year-old woman is
referred for management of recently diagnosed
primary aldosteronism. She presented to her
internist 4 weeks earlier with fatigue and was
found to have hypertension and hypokalemia.
Laboratory studies showed serum potassium of
2.9 mmol/L, serum aldosterone of 31 ng/dl, and
plasma renin activity of 0.18 ng/ml per hour. A
24-hour urine collection during oral sodium
loading showed increased aldosterone excretion
at 21 mg/d (normal range, ,12 mg/d). Her med-
ications include amlodipine and potassium chlo-
ride. An adrenal CT scan was normal. She is now
asymptomatic. Her BP is 140/88 mmHg and her
serum potassium has increased to 3.8 mmol/L on
potassium supplementation.
Which ONE of the following is the MOST
appropriate next step in this patient’s
management?
A. Perform adrenal venous sampling (AVS)
B. Check a diuretic screen
C. Add amiloride
D. Do not initiate additional management
E. Order genetic testing for KCNJ5 mutations
16. A 53-year-old man without previous medical
problems presents with hypertension and border-
line hypokalemia. He denies diarrhea or vomit-
ing and is taking no medications. Biochemical
evaluation shows elevated serum aldosterone
and suppressed plasma renin activity. After oral
sodium loading, the 24-hour urinary aldosterone
excretion increased, confirming the diagnosis of
primary aldosteronism. You recommend AVS
after tetracosactide (a1-24 corticotropin) stimu-
lation, with results as indicated in Table 1. An
adrenal CT scan shows a 9-mm microadenoma
of the right adrenal gland and a normal left
adrenal gland.
Which ONE of the following represents the
MOST likely diagnosis?
128
Table 1. Results of adrenal venous sampling
Lateralization
Index (Left A/C
Ratio:Right
A/C Ratio A/C Ratio)
Right adrenal vein 0.8 13.1
Left adrenal vein 10.5
Inferior vena cava 1.3
A/C, aldosterone/cortisol.
A. Aldosterone-producing adenoma of the
right adrenal gland
B. Unilateral hyperplasia or microadenoma of
the right adrenal gland
C. Right adrenal incidentaloma plus unilat-
eral hyperplasia of the left adrenal gland
D. Right adrenal incidentaloma plus bilateral
adrenal hyperplasia
E. Inconclusive findings
17. A 69-year-old man with resistant hypertension,
sleep apnea, and cerebrovascular disease is re-
ferred to you for evaluation and management of
his hypertension. As part of his evaluation, you
screen for and diagnose primary aldosteronism
on the basis of biochemical parameters. You
obtain an adrenal CT scan, which shows bilateral
micronodularity of the adrenal glands but no
defined adenoma. The patient is not interested in
surgical interventions; thus, a presumptive di-
agnosis of bilateral adrenal hyperplasia is made
and AVS is not performed. His BP is 152/74
mmHg while receiving chlorthalidone, losartan,
amlodipine, and carvedilol. The patient’s serum
potassium is 3.5 mmol/L.
Which ONE of the following is the MOST
appropriate treatment for this patient?
A. Add amiloride
B. Add eplerenone
C. Add aliskiren
D. Add dexamethasone
E. Add spironolactone
18. A 60-year-old woman is evaluated for complaints
of episodic headache, palpitations, and diaphoresis
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
for the past several months. She has no sig-
nificant medical history. Her family history is
negative for any endocrine, renal, or retinal
tumors. On examination, the patient’s BP is
156/98 mmHg supine, decreasing to 128/82
mmHg upon standing. Her plasma normeta-
nephrine is elevated at 6.3 nmol/L (reference
range, ,0.9) and her plasma metanephrine is
increased at 5.95 nmol/L (reference range, ,0.5).
Abdominal magnetic resonance imaging (MRI)
reveals an 11.5-cm right adrenal mass with ap-
pearance consistent with a pheochromocytoma.
She is started on phenoxybenzamine and is re-
ferred for recommendations regarding perioper-
ative management.
Which ONE of the following additional di-
agnostic studies is indicated for this patient?
A. A CT or MRI scan from the base of the
skull through the pelvis
B. 123I-labeled
metaiodobenzylguanidine or
6-[18F]-fluorodopamine positron emission
tomography scan
C. 111Indium-diethylenetriamine pentaacetic
acid octreotide scintigraphy
D. Genotype the patient for succinate dehy-
drogenase gene mutations
E. No further diagnostic testing is indicated
19. A 42-year-old man presented with severe hyper-
tension, progressive dyspnea on exertion, and
paroxysms of palpitations and diaphoresis. After
extensive biochemical testing and imaging, he
was found to have a 4-cm right adrenal pheochro-
mocytoma that was successfully excised 4 weeks
ago. He is now asymptomatic. His BP is normal
and he is referred to you for recommendations for
future follow-up. He has no family history of
pheochromocytoma or any other tumors.
Which ONE of the following is the MOST
appropriate management for this patient?
A. Yearly plasma metanephrines; no further
imaging
B. Yearly plasma metanephrines and ab-
dominal MRI scan
C. Yearly metaiodobenzylguanidine scan; no
further biochemical testing
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
D. Yearly abdominal MRI scan; no further
biochemical testing
E. Yearly clinical evaluation; biochemical
testing or imaging only if symptoms
recur
20. Which ONE of the following statements is
CORRECT about the clinical value of angiogenic
factor profiling or modification in pregnancy?
A. Patients with low soluble fms-like tyrosine
kinase-1 (sFLT1) levels and suspected
preeclampsia are at increased risk of pre-
mature delivery
B. High sFLT1 levels are associated with
increased risk of ESRD
C. High sFLT1 levels are associated with
chronic hypertension and remain high after
delivery
D. sFLT1 dextran sulfate apheresis results in
decreased proteinuria and BP stabilization
E. sFLT1 infusion improves BP, but has no
effect on proteinuria
23. A 51-year-old woman with stage 1 hypertension
21. Which ONE of the following statements is
CORRECT about long-term risk of vascular
and renal complications in women who had
preeclampsia?
A. The risk of chronic hypertension is ap-
proximately 30%, 10-fold higher than
controls
B. The risk of myocardial infarction is ap-
proximately 10%, 12-fold higher than
controls
C. The risk of stroke is approximately 1%,
2-fold higher than controls
D. The risk of ESRD is approximately 10%,
15-fold higher than controls
E. There is no increase in risk of cardiovas-
cular or renal complications
22. A 39-year-old kidney transplant recipient is
evaluated for hypertension and hyperkalemia. He
has ESRD due to IgA nephropathy and under-
went living-related donor kidney transplantation
10 months earlier. He feels well. He denies a pre-
vious history of hyperkalemia, except during his
129
time on hemodialysis. Medications include pred-
nisone, tacrolimus, mycophenolic acid, amlodi-
pine, terazosin, atovaquone, omeprazole, and
calcium carbonate. The patient’s BP is 158/94
mmHg. His serum creatinine is 1.2 mg/dl, po-
tassium is 5.8 mmol/L, and total CO2 is 16 mmol/L.
His 24-hour urinary calcium excretion is
360 mg/d.
Which ONE of the following statements is
MOST applicable to the pathogenesis of his
hypertension?
A. He has a mutation in the WNK4 gene
B. He received a kidney from a patient with
a kelch-like 3 gene mutation
C. He has tacrolimus-induced activation of
the renal sodium-chloride cotransporter
D. He has an activating mutation of the
epithelial sodium channel
E. He has acquired 11-b-hydroxysteroid de-
hydrogenase deficiency
and chronic hepatitis C infection is seeking your
advice on managing her BP. The serum alanine
aminotransferase level is persistently elevated at
approximately twice the upper limit of normal.
There was minimal fibrosis on a liver biopsy
performed 3 years ago. Office BPs are approxi-
mately 144/94 mmHg, and home BP values
(averaging 136–140/90 mmHg) confirm the
presence of hypertension. She has been treated
in the past with a variety of different medication
classes and, after 1–4 months, stops taking them
because of fear that they will affect her liver
enzymes. In two instances, a modest increase in
alanine aminotransferase was documented. She
has a family history of hypertension. She follows
a 2 g sodium-restricted diet, walks 1–2 miles
daily, and works with a trainer on resistance
exercises at the local gym. She frowns when you
ask about alcohol and indicates “Of course not!”
Her BMI is 23.8 kg/m2. There is nothing on the
examination to suggest a secondary cause for her
BP increase. Her electrocardiogram results are
normal. Serum electrolytes, BUN, serum creati-
nine, and blood glucose are within their normal
ranges.
130
Which ONE of the following would you
recommend as MOST likely to benefit her
BP?
A. Gingko biloba extract
B. Chinese green tea
C. St. John’s wort
D. Device-guided breathing
E. Leg muscle tensing
24. A 65-year-old man is referred to you. The
patient takes five BP medications, including
chlorthalidone, eplerenone, ramipril, amlodipine,
and metoprolol. He has had hypertension for
.15 years. His control has “always been diffi-
cult” to maintain and he has been treated with
“everything,” including minoxidil, in the past.
He had a lacunar stroke about a year ago from
which he fully recovered. He has never smoked.
His BP measurements in your office are 168–170
mmHg systolic, with a heart rate of 56 beats
per minute. The patient’s BMI is 26.8 kg/m2. The
fundi show grade 2 hypertensive changes with
arteriovenous nicking. He has an S4 gallop and
a shift in the point of maximum impulse by
approximately 2 cm to the left. There is a soft
midline abdominal systolic bruit. The pedal pulses
are present. The remainder of the physical ex-
amination is unremarkable.
Which ONE of the following would you
recommend next?
A. Doxazosin therapy
B. Renal arteriography
C. 24-hour urine metanephrines
D. Polysomnography
25. A 62-year-old man with stage 4 CKD of un-
known etiology and hypertension is seen in
follow-up. He feels well and has no history of
headaches, palpitations, diaphoresis, or flushing.
He has had hypertension for .20 years, which
was very difficult to manage until he had a renal
denervation procedure in Germany about 2 months
ago. His company transferred him to the United
States about a month after this. He goes back and
forth to Germany about twice a month, but is in
the United States the majority of the time. He has
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
never smoked. His medication doses have been
stable and include chlorthalidone (25 mg/d),
metoprolol (100 mg twice daily), amlodipine
(10 mg/d), and ramipril (20 mg/d). His BP is
136/72 mmHg, and his heart rate is 62 beats
per minute. The remainder of the physical ex-
amination is unremarkable. Laboratory studies
show the following: sodium, 138 mEq/L; potas-
sium, 4.9 mEq/L; chloride, 106 mEq/L; total
CO2, 22 mEq/L; BUN, 38 mg/dl; creatinine, 2.4
mg/dl; and eGFR, 28 ml/min per 1.73 m2. His
hemoglobin has increased from recent levels
that have averaged 10–11 g/dl to 12.4 g/dl. The
increase is confirmed on repeat measurement.
A kidney ultrasound shows 9-cm kidneys with
moderate cortical thinning bilaterally. His urine
albumin/creatinine ratio is 102 mg/g.
Which ONE of the following is the MOST
likely explanation for the increase in this
patient’s hemoglobin level?
A. Low oxygen concentration on the trans-
atlantic flights
B. Excessive chlorthalidone dose
C. ACEI side effect
D. A renal denervation procedure
E. Pheochromocytoma
26. A 36-year-old woman with orthostatic hypotension
on midodrine (10 mg three times daily as needed) is
seen for a regularly scheduled appointment. She is
managing reasonably well, but noticed two episodes
of near syncope last week. Her BP measurements in
the office today are 108/84 mmHg sitting and 94/78
mmHg standing with no heart rate changes noted.
She asks if there is anything else that she can do,
besides lying down, when she feels dizzy.
Which ONE of the following is the MOST
reasonable recommendation?
A. Drink a bolus of 16 ounces of water
B. Try coughing or grunting
C. Take an extra midodrine tablet
D. Stand motionless
E. Take a hot shower
27. A 71-year-old man recently discharged from the
hospital after a “mini-stroke” is seen in follow-up.
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014
He brings records, among which is an MRI scan
of the brain showing several subcortical lacunar
infarctions. During the hospital stay, his SBP
ranged from 150 to 180 mmHg. Today his speech
is slightly slurred and he shows less dexterity in
one hand compared with the other, consistent with
his deficits at the time of discharge. The patient’s
medications include amlodipine (10 mg/d) and
aspirin (81 mg/d). His BP today is 158/76
mmHg, with a regular heart rate of 74 beats
per minute. Aside from the modest neurolog-
ic findings noted above, the examination is
unremarkable.
Which ONE of the following would be the
MOST appropriate next step?
A. Add an additional antihypertensive drug
from a different class
B. Add warfarin
C. Discontinue the aspirin
D. Do not change current management
28. You see a 57-year-old woman in follow-up for
continued adjustment of her BP medication. She
has stable coronary artery disease and quit
smoking at the time of discovery of her coronary
disease 4 years ago. You started an ACEI two
visits ago. During the last visit, you titrated the
dose to about three fourths of the manufacturer-
recommended maximum. The patient’s BMI is
23.2 kg/m2. Her BP today is 151/86 mmHg
(average of two readings).
Which of the following is the MOST appro-
priate next step in treating this patient’s
hypertension?
A. Titrate the ACEI to maximal dose
B. Add hydrochlorothiazide
C. Add amlodipine
D. Discontinue the ACEI and initiate chlor-
thalidone
E. Add hydralazine twice a day
131
29. You are asked to evaluate a 44-year-old engineer
of African descent for hypertension. Your eval-
uation does not indicate a likelihood of second-
ary forms of hypertension, and his BP in the last
three visits over 2 months’ time averaged 151/98
mmHg, with a regular heart rate of 70 beats
per minute. These results are confirmed by
multiple home readings. His BMI is 28 kg/m2
and he does not get much exercise. He is cautious
with salt intake and does not drink alcoholic bev-
erages. You provide advice about lifestyle modifi-
cations and suggest that, while he works on those, it
would be reasonable to initiate drug treatment with
a diuretic. He wants to be treated with the drug with
the “best” evidence for good outcomes.
Which ONE of the following diuretics would
you recommend to him?
A. Hydrochlorothiazide
B. Bendroflumethiazide
C. Metolazone
D. Torsemide
E. Chlorthalidone
30. A 54-year-old woman with type 2 diabetes and
hypertension comes in for a routine follow-up
visit. Since her last interval visit 6 months ago, she
has lost 3.5 kg, her BP is about 4 mmHg systolic
lower, and her home blood glucose levels are
better compared with her prior office values. She
feels well. Her antihypertensive medications are
unchanged, consisting of an angiotensin receptor
blocker and a calcium channel blocker.
Which ONE of the following BEST explains
these improvements in her overall profile?
A. Interval treatment with pioglitazone
B. Interval initiation of insulin therapy
C. Smoking cessation
D. Walking 1 mile three times a week
E. Interval initiation of a sodium-glucose
cotransporter 2 inhibitor
Nephrology Self-Assessment Program - Vol 13, No 2, March 2014

Erratum
NephSAP Erratum for the Transplantation Issue published in November 2013

In the “Proteinuria after Kidney Transplantation”

section of the Syllabus, page 342, in the above issue of
NephSAP, the reprint citation of Figure 6 omitted
a citation of the original article in which it appeared.
Figure 6 was incorrectly referenced as being reprinted
with permission from Shamseddin MK, Knoll GA:
Posttransplant Proteinuria: An Approach to Diagnosis
and Management. Clin J Am Soc Nephrol 6: 1786–
1793, 2011.
Figure 6 was originally published as Figure 1 in
Amer H, Cosio FG: Significance and Management of
Proteinuria in Kidney Transplant Recipients. J Am Soc
Nephrol 20: 2490–2492, 2009.
The Figure 6 legend in the NephSAP Transplan- Figure 6. The relationship between proteinuria after kidney
tation Issue published in November 2013 should have transplantation and graft loss. Reprinted with permission
from Amer H, Cosio FG: Significance and Management of
appeared as follows:
Proteinuria in Kidney Transplant Recipients. J Am Soc
Nephrol 20: 2490–2492, 2009, and Shamseddin MK, Knoll
GA: Posttransplant Proteinuria: An Approach to Diagnosis
and Management. Clin J Am Soc Nephrol 6: 1786–1793,
2011.

The editors regret any inconvenience this may

have caused.

132