nephSAP

Nephrology Self-Assessment Program

Volume 20  Number 2  January 2022

Electrolytes and Acid-Base Disorders

Guest Editor:
Julian L. Seifter, MD

Editorial Director:
Alice M. Sheridan, MD

Deputy Editor:
Martina M. McGrath, MBChB, FASN
nephSAP
EDITORIAL DIRECTOR, nephSAP
Alice M. Sheridan, MD
Brigham and Women’s Hospital
Boston, MA
DEPUTY EDITOR, nephSAP
Martina M. McGrath, MBChB, FASN
Brigham and Women’s Hospital
Boston, MA
GUEST EDITOR
Julian L. Seifter, MD
Brigham and Women’s Hospital
Boston, MA
SENIOR PROGRAM MANAGER FOR
SELF-ASSESSMENT
Suzanne P. Armstrong, MA
American Society of Nephrology
Washington, DC
PAST EDITORS
Jeffrey S. Berns, MD, FASN
Ronald J. Falk, MD, FASN
Stanley Goldfarb, MD, PhD
Gerald A. Hladik, MD, FASN
Raymond R. Townsend, MD
Jerry Yee, MD, FASN
FOUNDING EDITORS
Richard J. Glassock, MD
Editor-in-Chief Emeritus
Robert G. Narins, MD
Send Your Feedback nephsap@asn-online.org
Preface
Launched in 2002, the Nephrology Self-Assessment Program (nephSAP®) is one of the premier educational
activities of the American Society of Nephrology (ASN) Alliance for Kidney Health. nephSAP focuses on
self-assessment and education and provides Continuing Medical Education (CME) credits and Maintenance
of Certification (MOC) points for individuals certified by the American Board of Internal Medicine (ABIM).
Starting with Volume 19 (2020), nephSAP content is available electronically through the nephSAP website
(nephsap.org). Content for Volume 18 and earlier, and all archived nephSAP content, are available on the
main ASN website (asn-online.org/nephsap).
PROGRAM MISSION AND OBJECTIVES: nephSAP® provides a learning vehicle for physicians,
scientists, advanced practitioners, nurses, pharmacists, and other health professionals working and training in
the field of nephrology to renew and refresh their clinical knowledge, diagnostic, and therapeutic skills. This
enduring material provides learners challenging, clinically-oriented questions based on case vignettes, detailed
learning objectives, a series of articles that review recent publications, and an editorial on an important
and evolving topic. This combination of materials enables learners to rigorously assess their strengths and
weaknesses in the broad domain of nephrology.
EDUCATION: nephSAP® supports continuous improvement and lifelong learning by helping busy clinicians
and trainees at all levels stay current with the latest scientific and medical advances in kidney care. Each issue
of nephSAP is dedicated to a specific theme, i.e., to a specific area of clinical nephrology, hypertension,
dialysis, and transplantation, and consists of an editorial, topical articles, and self-assessment questions. All
clinically relevant and key elements of nephrology are reviewed and updated every two years. The authors of
each issue digest and interpret key studies published since the release of the previous issue and integrate this
new material with the body of existing information. Occasionally a special edition is produced to cover an
area not ordinarily addressed by core issues of nephSAP.
SELF-ASSESSMENT: An examination with thirty, single-best-answer questions follow the 60 to 100
pages of topical articles. This examination is available online with immediate feedback which includes answers
to all questions, brief discussions, and an updated bibliography.
CME and MOC: Those answering 75% correctly can claim up to 10 CME credits and MOC points per issue.
CONTRIBUTING AUTHORS
Robert Jay Alpern, MD Solomiia Savedchuk, MD
Yale University School of Medicine Duke University Medical Center
New Haven, CT Durham, NC
Tushar Chopra, MD, FASN Zhabiz Solhjou, MD
University of Virginia Health System Brigham and Women’s Hospital
Charlottesville , VA Boston, MA
Thomas D. DuBose, Jr., MD, FASN Andrew S. Terker, MD, PhD
Wake Forest School of Medicine Vanderbilt University Medical Center
Winston Salem, NC Nashville, TN
David H. Ellison, MD, FASN Naoto Tominaga, MD, PhD
Oregon Health & Science University Kawasaki Municipal Tama Hospital
Portland, OR Kawasaki Kanagawa
Japan
Namrata Krishnan, MD
Yale School of Medicine Joseph G. Verbalis, MD
New Haven, CT Georgetown University
Washington, DC
Ruediger W. Lehrich, MD
Duke University Medical Center
Durham, NC
Martina M. McGrath,
MBChB, FASN
Brigham and Women’s Hospital
Boston, MA
nephSAP® ©2022 by The American Society of Nephrology
nephSAP
Editorial
Teaching Renal Physiology at the Bedside ............................. 67
Julian L. Seifter
Case 1: Why Would a Healthy Subject in a Research Study, in
the Midst of a Water Diuresis, Suddenly Become Anuric?....... 67
Case 2: What Stimulates Release of Atrial Natriuretic Peptide
from the Heart? ......................................................................... 68
Case 3: Can the Urine Be Concentrated in the Absence of
Antidiuretic Hormone?............................................................. 69
Case 4: Can a Patient Have Diabetes Insipidus of Pregnancy
Manifesting Only in the Postpartum Period? .......................... 71
CASE 5: Can Lithium Cause Both Central and Nephrogenic
Diabetes Insipidus?................................................................... 72
References ................................................................................ 73
Articles
Pathophysiology, Evaluation, Outcomes, and Treatment of
Hyponatremia........................................................................... 74
Naoto Tominaga and Joseph G. Verbalis
Learning Objectives.................................................................. 74
Pathophysiology of Hyponatremia ......................................... 74
Definition and Prevalence of Hyponatremia ........................ 74
Sodium Concentration and Sodium Content: Two Related
but Different Concepts........................................................ 74
Total Plasma Osmolality and Effective Plasma Osmolality
(Tonicity)............................................................................ 74
Two Defense Systems Protecting against Body Water
Losses.................................................................................. 75
Arginine Vasopressin: Appropriate Secretion ....................... 75
Nonosmotic AVP Stimuli: Inappropriate Secretion.............. 76
+
Etiologies of Disorders of Serum [Na ] ................................ 76
Evaluation of Hyponatremia ................................................... 77
Check Plasma Osmolality (Posm) ......................................... 77
Isotonic Hyponatremia (280–295 mOsm/kg
H2O) ......................................................................... 77
Hypertonic Hyponatremia (>295 mOsm/kg
H2O) ......................................................................... 78
Volume 20 4 Number 2 4 January 2022
Hypotonic Hyponatremia (<280 mOsm/kg
H2O) ......................................................................... 78
Assess ECF Volume ............................................................ 78
Common Causes of Hyponatremia related to Nonosmotic
and/or Inappropriate AVP Release .......................................... 80
Syndrome of Inappropriate Antidiuretic Hormone Secretion
versus Syndrome of Inappropriate Antidiuresis .................... 80
Drug-Induced Hyponatremia ............................................. 80
Iatrogenic Hyponatremia .................................................... 81
Symptoms and Adverse Outcomes of Hyponatremia .............. 82
Acute Hyponatremia .......................................................... 82
Chronic Hyponatremia ...................................................... 82
Treatment of Hyponatremia .................................................... 82
Current Recommendations regarding Rate of Serum [Na+]
Correction .......................................................................... 82
Osmotic Demyelination Syndrome ..................................... 85
Overly Rapid Correction of Serum [Na+]: Risks and
Prevention .......................................................................... 85
Conventional, Specific, and Potential Future Treatment
Options for Hyponatremia .................................................. 86
Fluid Restriction ....................................................... 86
Furosemide with NaCl in Combination with Fluid
Restriction ................................................................. 87
Vasopressin Receptor Antagonists............................. 87
Urea ........................................................................... 87
Sodium-Glucose Cotransporter-2 Inhibitors in
Combination with Fluid Restriction ........................ 87
Conclusion ............................................................................... 87
References ................................................................................ 88
Pathophysiology, Evaluation, and Treatment of
Hypernatremia ......................................................................... 90
Solomiia Savedchuk and Ruediger W. Lehrich
Learning Objectives.................................................................. 90
Physiology of Osmoregulation, Thirst, and Urinary
Concentration .......................................................................... 90
Regulation of Thirst ............................................................ 90
nephSAP
Homeostatic and Anticipatory Thirst .................................. 90
Urinary Concentration ........................................................ 91
Incidence of and Risk Factors for Hypernatremia ................... 91
Hospital-Acquired Hypernatremia ...................................... 91
Intensive Care Unit Hypernatremia..................................... 91
Community-Acquired Hypernatremia................................. 92
Salt Intoxication .................................................................. 92
Athletic Activity as a Risk Factor for Hypernatremia ............ 92
Prognosis of Hypernatremia .................................................... 92
Permissive Hypernatremia ....................................................... 94
Diabetes Insipidus .................................................................... 94
Medication-Induced Diabetes Insipidus .............................. 94
Diagnosis of Diabetes Insipidus ........................................... 95
Treatment of Hypernatremia ................................................... 96
Donor and Recipient Hypernatremia in Solid Organ
Transplantation ........................................................................ 99
Heart................................................................................... 99
Liver.................................................................................... 99
Lung ................................................................................... 99
Kidney and Pancreas............................................................ 99
References ................................................................................. 99
Pathophysiology, Evaluation, and Treatment of
Hypokalemia .......................................................................... 102
Tushar Chopra and Thomas D. DuBose Jr
Learning Objectives................................................................ 102
Introduction ........................................................................... 102
Total Body Potassium Distribution ....................................... 102
Regulation of Potassium Homeostasis ................................... 102
Cell Shifts ......................................................................... 102
Renal Potassium Absorption and Secretion ........................ 103
Proximal Tubule ..................................................... 103
Thick Ascending Limb of Henle (TALH) ............... 103
Distal Convoluting Tubule (DCT) ......................... 103
Volume 20 4 Number 2 4 January 2022
Potassium Absorption in Distal Convoluted Tubule 2
(DCT2) and Collecting Duct (CD) by the H+,
K+-ATPases ....................................................................... 104
Role of Hypokalemia in Maintenance of Metabolic
Alkalosis.................................................................................. 104
Clinical Approach to the Hypokalemic Patient .................. 105
Causes of Hypokalemia ..................................................... 106
Low Dietary K+ Intake ........................................................... 106
Potassium Intake in CKD Patients .................................... 107
Redistribution of Potassium .............................................. 107
Extrarenal K+ Loss ............................................................ 109
Increased Renal K+ Excretion ................................................. 110
Increased Distal Sodium Delivery ...................................... 110
Hypokalemia and Nongap Metabolic Acidosis................... 110
The Urine Anion Gap and the Urine Osmolar Gap............ 111
Hypokalemia with Metabolic Alkalosis, Volume Depletion,
and Normal or Low BP—High Urine [Cl]: Bartter
Syndrome and Gitelman Syndrome ................................... 111
Assessment of Renal Potassium Excretion .......................... 113
Treatment of Hypokalemia ............................................... 113
Complications and Outcomes ................................................ 113
Acute Complications ......................................................... 113
Muscle Weakness..................................................... 113
Rhabdomyolysis ...................................................... 114
Cardiac Arrhythmia........................................................... 114
Long-Term Outcomes....................................................... 114
Hypokalemic Nephropathy (Kaliopenic
Nephropathy) .......................................................... 114
New-Onset Diabetes ................................................ 114
References .............................................................................. 114
Pathophysiology, Evaluation, and Treatment of
Hyperkalemia ......................................................................... 117
Andrew S. Terker and David H. Ellison
Learning Objectives................................................................ 117
Introduction ........................................................................... 117
nephSAP
Cardiovascular Outcomes and Mortality ............................... 117
Total Body Potassium Distribution ....................................... 117
Regulation of Potassium Homeostasis ................................... 117
Gastrointestinal Absorption............................................... 117
Renal Potassium Reabsorption and Secretion..................... 117
Proximal Tubule...................................................... 117
Thick Ascending Limb of Henle.............................. 118
Distal Convoluted Tubule....................................... 118
Connecting Tubule and Collecting Duct ................ 118
Integrated Renal Potassium Excretion: The Potassium
Switch ..................................................................................... 118
Diagnosis and Evaluation....................................................... 120
Causes and Risk Factors .................................................... 121
Prevention............................................................................... 122
Treatment ............................................................................... 122
Acute Hyperkalemia .......................................................... 122
Stabilize the Membrane ........................................... 123
Shift Potassium into Cells ....................................... 123
Remove Potassium from the Body .......................... 123
Gastrointestinal Potassium Removal ...................... 124
Chronic Hyperkalemia ..................................................... 124
References .............................................................................. 126
Metabolic Acidosis ................................................................. 130
Zhabiz Solhjou and Martina McGrath
Learning Objectives................................................................ 130
Introduction .......................................................................... 130
Lactic Acidosis ........................................................................ 130
Ketoacidosis............................................................................ 131
Diabetic Ketoacidosis ........................................................ 131
Euglycemic Ketoacidosis with Sodium-Glucose
Transporter-2 Inhibitors.................................................... 131
Continuous RRT and Ketoacidosis.................................... 132
Drug-Induced Metabolic Acidosis ..................................... 132
Sodium Thiosulfate ........................................................... 132
Metformin ........................................................................ 132
Volume 20 4 Number 2 4 January 2022
Chronic Metabolic Acidosis in CKD...................................... 135
Background ...................................................................... 135
Eubicarbonatemic Metabolic Acidosis and Urine Citrate ... 135
Mechanisms of Injury Associated with Chronic Metabolic
Acidosis in CKD ............................................................... 136
Treatment of Metabolic Acidosis in CKD.............................. 137
Veverimer ............................................................................... 140
Metabolic Acidosis and Kidney Transplant Outcomes.......... 141
References ............................................................................... 142
Metabolic Alkalosis ................................................................ 145
Namrata Krishnan and Robert Jay Alpern
Learning Objectives ............................................................... 145
Introduction .......................................................................... 145
Mechanisms That Prevent Metabolic Alkalosis ..................... 145
Buffering .......................................................................... 145
Respiratory Compensation ............................................... 145
Renal Excretion ................................................................. 145
Generation and Maintenance of Sustained Metabolic
Alkalosis ................................................................................. 146
Factors That Result in Maintenance of Metabolic
Alkalosis ........................................................................... 146
Volume Contraction ................................................ 146
Potassium Depletion ............................................... 147
Enhanced Distal Acidification Due to Imbalances
in Distal Nephron Na+Absorptive Capacity and
Distal Delivery of Na+ and Water............................ 147
Defects in Distal Bicarbonate Secretion.................. 147
Factors That Result in Generation of Metabolic Alkalosis... 147
External H+ Loss ..................................................... 148
Exogenous Alkali Gain ............................................ 148
Metabolic Alkalosis in the Absence of H+ Loss or
Alkali Gain (potassium depletion) .......................... 148
Clinical Conditions That Cause Metabolic Alkalosis ............ 148
Exogenous Alkali Gain ...................................................... 148
Decreased Effective Arterial Blood Volume........................ 148
Gastric HCl Loss (Gastric Alkalosis) ....................... 148
nephSAP Volume 20 4 Number 2 4 January 2022

Lower GI HCl Loss .................................................. 149 Kidney Replacement Therapy............................................ 155

Increased Distal Delivery of Sodium....................... 150 Acetazolamide ................................................................... 155
Diuretic Induced ..................................................... 150 Non-sodium Based Acid Solutions .................................... 155
Distal Delivery of Nonreabsorbable Anions ........... 150 Treatment of Specific Clinical Scenarios ............................ 156
Bartter Syndrome .................................................... 150 Diuretic-Induced Metabolic Alkalosis ................... 156
Gitelman Syndrome ................................................ 150 Genetic Disorders Resulting in Secondary
Mineralocorticoid Excess......................................... 156
Magnesium Depletion ............................................. 150
Syndromes of Primary Mineralocorticoid
Hypercalcemia ........................................................ 150
Excess ....................................................................... 156
Post–Hypercapneic Alkalosis .................................. 150
Posthypercapneic Metabolic Alkalosis.................... 156
Decreased Distal Bicarbonate Secretion ............................ 150
References ............................................................................... 157
Pendred Syndrome .................................................. 150
Self-Assessment Questions
Cystic Fibrosis ......................................................... 151
nephSAP Volume 20, Number 2, January 2022..................... 160
Increased Distal Transport Activity.................................... 151
High Renin, High Aldosterone ............................... 151 Planned Issues
Low Renin, High Aldosterone ................................. 151 Acute Kidney Injury and Critical Care Nephrology
Low Renin, Low Aldosterone ................................. 151 Guest Editor: Paul M. Palevsky, MD, FASN
March 2022
Increase in a Nonaldosterone Mineralocorticoid
Receptor Agonist ..................................................... 151 Chronic Kidney Disease
Activation of the Mineralocorticoid Receptor ........ 151 Guest Editor: Valerie A. Luyckx, MD, MS, PhD
April 2022
Activation of Transport Mechanisms Downstream
of the Receptor......................................................... 151 Transplantation
Unclear Mechanism: Postfasting alkalosis ......................... 151 Guest Editor: Sumit Mohan, MD, MPH, FASN
May 2022
Evaluation......................................................................... 151
Epidemiology and Outcomes ................................................ 153 Hypertension
Treatment ............................................................................... 153 Guest Editor: George L. Bakris, MD, FASN
June 2022
Indications for Intervention............................................... 153
Correct Causes of Generation and Maintenance................. 153
nephSAP Volume 2044Number
Volume19 Number00
244 October
January 2022
2020

The nephSAP editorial team and the KSAP editorial board extend their sincere appreciation to the following
reviewers. Their efforts and insights help improve the quality of these postgraduate education offerings.

nephSAP Review Panel

Mustafa Ahmad, MD, FASN Armando Coca, MD, MPH Susie L. Hu, MD, FASN
King Fahad Medical City Hospital Cl
ınico Universitario Warren Alpert Medical School of Brown University
SAUDI ARABIA SPAIN UNITED STATES
Jafar Al-Said, MD, FASN Scott D. Cohen, MD, MPH, FASN Ekambaram Ilamathi, MD, FASN
Bahrain Specialist Hospital George Washington University Northwell Health - Southside Hospital
UNITED STATES UNITED STATES UNITED STATES
Carmichael Angeles, MD, FASN Beatrice P. Concepcion, MD, FASN
Talha Hassan Imam, MD
Pharmaceutical Product Development, LLC Vanderbilt University Medical Center
Kaiser Permanente
UNITED STATES UNITED STATES
UNITED STATES
Kisra Anis, MD Gabriel Contreras, MD, MPH
University of Miami Health System Joshua Kaplan, MD, FASN
Jacobi Medical Center, Albert Einstein College of
UNITED STATES Rutgers New Jersey Medical School
Medicine
UNITED STATES
UNITED STATES Patrick Cunningham, MD, FASN
Naheed Ansari, MD, FASN University of Chicago Medical Center Amir Kazory, MD, FASN
Jacobi Medical Center, Albert Einstein College of UNITED STATES University of Florida
Medicine UNITED STATES
Kevin A. Curran, MD
UNITED STATES Kevin A. Curran, MD, PA Quresh T. Khairullah, MD, FASN
UNITED STATES St. Clair Nephrology
Nabeel Aslam, MD, FASN
Mayo Clinic Florida Rajiv K. Dhamija, MD UNITED STATES
UNITED STATES Rancho Los Amigos National Rehabilitation Center
Yong-Lim Kim, MD, PhD
UNITED STATES
Nisha Bansal, MD, FASN Kyungpook National University Hospital
Kidney Research Institute Alejandro Diez, MD, FASN SOUTH KOREA
UNITED STATES Ohio Sate University
UNITED STATES Nitin V. Kolhe, MD, FASN
Krishna M. Baradhi, MD, FASN Royal Derby Hospital
University of Oklahoma Health Sciences Center John J. Doran, MD, FASN UNITED KINGDOM
UNITED STATES Emory University School of Medicine
UNITED STATES Farrukh M. Koraishy, MD, PhD, FASN
Gopal Basu, MD, MBBS, FASN Stony Brook University New York
The Alfred Hospital Lynda A. Frassetto, MD, FASN
UNITED STATES
AUSTRALIA University of California San Francisco
UNITED STATES Eugene C. Kovalik, MD, FASN
Emmy Klip Bell, MD, MPH Duke University Medical Center
University of Alabama at Birmingham Tibor Fulop, MD, PhD, FASN
Medical University of South Carolina UNITED STATES
UNITED STATES
UNITED STATES Steven W. Kraft, MD
Mona B. Brake, MD, FASN
Duvuru Geetha, MD, FASN Western Nephrology
VA Medical Center
John Hopkins Bayview Medical Center UNITED STATES
UNITED STATES
UNITED STATES
Ruth C. Campbell, MD, FASN Vineeta Kumar, MD
Ilya Glezerman, MD University of Alabama at Birmingham
Medical University of South Carolina
Memorial Sloan Kettering Cancer Center UNITED STATES
UNITED STATES
UNITED STATES
Chia-Ter Chao, MD, PhD, FASN Norbert H. Lameire, MD, PhD
Carl S. Goldstein, MD, FASN
National Taiwan University Hospital University Hospital
Medical Diagnostic Associates, PA
TAIWAN BELGIUM
UNITED STATES
Joline L.T. Chen, MD, MS, FASN Steven M. Gorbatkin, MD, PhD, FASN Sheron Latcha, MD, FASN
University of California, Irvine Emory University School of Medicine Memorial Sloan Kettering Cancer Center
UNITED STATES UNITED STATES UNITED STATES
Karen I. Ching, MD, FASN Aditi Gupta, MD, FASN Vincent W.S. Lee, MBBS, PhD
Hawaii Permanente Medical Group University of Kansas Medical Center Westmead Hospital
UNITED STATES UNITED STATES AUSTRALIA
nephSAP Volume 2044Number
Volume19 Number00
244 October
January 2020
2022

Paolo Lentini, MD, PhD, FASN Phuong-Thu T. Pham, MD, FASN Stephen M. Sozio, MD, FASN
Ospedale San Bassiano,Bassano del Grappa (VI) UCLA Medical Center Johns Hopkins University School of Medicine
ITALY UNITED STATES UNITED STATES
Tingting Li, MD, MS, FASN Pairach Pintavorn, MD, FASN Ignatius Yun-Sang Tang, MD, PharmD, FASN
Washington University in St. Louis East Georgia Kidney Group University of Illinois Hospital and Health Sciences
UNITED STATES UNITED STATES System
Roberto Pisoni, MD UNITED STATES
Orfeas Liangos, MD, DrMed, FASN
Kuratorium f€ur Dialyse und Nierentransplantation Medical University of South Carolina Ahmad R. Tarakji, MD, FASN
GERMANY UNITED STATES King Saud University
Paul H. Pronovost, MD, FASN SAUDI ARABIA
Ajit Mahapatra, MD
Waterbury Hospital
The Permanente Medical Group Hung-Bin Tsai, MD, MS, PhD
UNITED STATES
UNITED STATES National Taiwan University Hospital
Mohammad A. Quasem, MD TAIWAN
A. Bilal Malik, MD United Health Services Hospitals-Binghamton
University of Washington Medical Center UNITED STATES Kausik Umanath, MD, MS, FASN
UNITED STATES Henry Ford Health System
Wajeh Y. Qunibi, MD UNITED STATES
Ernest I. Mandel, MD, MS, FASN University of Texas Health Science Center
Brigham and Women's Hospital UNITED STATES Puchimada M. Uthappa, MD, MBBS, FASN
UNITED STATES Columbia Asia Hospital, Mysore
Pawan K. Rao, MD, FASN
INDIA
Naveed N. Masani, MD, FASN Nephrology Hypertension Associates
Wintrop University Hospital UNITED STATES Anthony M. Valeri, MD
UNITED STATES Hernan Rincon-Choles, MD, MS, FASN Columbia University Medical Center
Cleveland Clinic UNITED STATES
Ellen T. McCarthy, MD
University of Kansas Medical Center UNITED STATES Allen W. Vander, MD, FASN
UNITED STATES Dario Roccatello, MD Kidney Center of South Louisiana
Ospedale San GIovanni Bosco UNITED STATES
Kirtida Mistry, MBChB, FASN
ITALY
US Food and Drug Administration Jon R. Von Visger, MD, PhD
UNITED STATES Ehab R. Saad, MA, MD, FASN Jacobs School of Medicine & Biomedical Sciences
Medical College of Wisconsin UNITED STATES
Lawrence S. Moffatt, MD UNITED STATES
Charlotte Medical Clinic South Park Nand K. Wadhwa, MD, FASN
UNITED STATES Mark C. Saddler, MBChB New York Health Center for Nephrology
Durango Nephrology Associates UNITED STATES
Thangamani Muthukumar, MD, FASN UNITED STATES
New York Presbyterian Hospital Weill Cornell Connie J. Wang, MD
Medical Center Mohammad N. Saqib, MD Hennepin County Medical Center
UNITED STATES Valley Kidney Specialists, PC UNITED STATES
UNITED STATES
Mohanram Narayanan, MD, FASN Maura A. Watson, DO, FASN, MPH
Hitesh H. Shah, MD, FASN
Baylor Scott & White Healthcare Walter Reed National Military Center
Zucker School of Medicine at Hofstra/Northwell
UNITED STATES UNITED STATES
UNITED STATES
Macaulay A. Onuigbo, MD, MS, MBA, FASN Michiko Shimada, MD, PhD, FASN Dawn F. Wolfgram, MD, FASN
University of Vermont Medical Center Hirosaki University Medical College of Wisconsin
UNITED STATES JAPAN UNITED STATES
Rosemary Ouseph, MD Shayan Shirazian, MD Brian Y. Young, MD
St. Louis University Winthrop University Hospital UC Davis Medical Center
UNITED STATES UNITED STATES UNITED STATES
Todd E. Pesavento, MD, FASN Arif Showkat, MD, MBBS, MPH, FASN Mario Javier Zarama, MD, FASN
Ohio State University Wexner Medical Center University of Tennessee Kidney Specialists of Minnesota
UNITED STATES UNITED STATES UNITED STATES
nephSAP Volume 20 4 Number 2 4 January 2022
Volume 19 4 Number 4 October 2020

Learning Objectives
1. To examine recent scientific advances in our understanding of the pathophysiology of disorders of fluid, electrolytes, and
acid-base balance.
2. To review how the understanding of pathophysiology can be applied to the care of patients.
3. To analyze how recent studies related to fluid, electrolyte, and acid-base disorders can be applied to clinical decision making.

Target Audience:
Physicians, scientists, advanced practitioners, nurses, pharmacists, and other health professionals working and training in the
field of nephrology.

Accreditation and AMA Credit Designation Statements

In support of improving patient care, the American Society of Nephrology is jointly accredited by the
Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for
Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide
continuing education for the healthcare team.

The American Society of Nephrology designates this internet activity (enduring material) for a maximum of 10.00 AMA PRA
TM
Category 1 Credits . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

ABIM MOC Statement

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to
earn up to 10.00 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) pro-
gram. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity
provider’s responsibility to submit participant completion information to Joint Accreditation for the purpose of granting ABIM
MOC credit.

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.

Original Release Date

January 2022

CME/MOC Termination Date

February 28, 2023

Examination Available Online

On or before January 30, 2022

Estimated Time for Completion

10 hours

Self-Assessment Examination
4 Answers with explanations are provided with a passing score after the first and/or second attempt.
4 This issue will be archived in March 1, 2023, and answers with explanations will be posted on the ASN website.
nephSAP Volume 20 4 Number 2 4 January 2022
Volume 19 4 Number 4 October 2020

Method of Participation
4 Read the entire issue that is supplemented by original articles in the reference lists.
4 Complete the online self-assessment examination.
4 Each participant is allowed two attempts to pass the examination (75% correct) for CME and MOC.
4 Upon completion, review your score and incorrect answers and print your certificate.

Activity Evaluation, CME, and MOC

1. Go to the ASN eLEARNING CENTER (education.asn-online.org)
2. Select MY ACTIVITIES from the left-hand navigation.
3. Select the corresponding issue.
4. Read all information on the Overview screen.
5. Follow the onscreen instructions to:
a. Complete the Exam (i.e., post test),
b. Complete the Evaluation,
c. Claim credit/MOC, and
d. Print a Certificate

Your complete ASN Transcript is available on the ASN eLEARNING CENTER:

4 Select TRANSCRIPT on the left-hand navigation.
4 View course status, credits claimed, or print a certificate for completed learning activities.

System Requirements
Compatible Browser and Software
The nephSAP website (nephsap.org) is formatted for cross-browser functionality and should display correctly in all currently
supported web browsers. Individual nephSAP articles are available as dynamic HTML or in Portable Document Format (PDF),
which requires Adobe Reader or comparable PDF viewing software.

Monitor Settings
The nephSAP website was designed to be viewed in a 1024  768 or higher resolution.
Medium or Combination of Media Used
The media used include content provided online as dynamic HTML or downloadable PDF, in addition to an online evaluation
and self-assessment examination.
Technical Support
If you have difficulty viewing any of the pages, please refer to the nephSAP technical support page for possible solutions. If you
continue having problems, contact ASN at nephsap@asn-online.org.
nephSAP Volume 20 4 Number 2 4 January 2022
Volume 19 4 Number 4 October 2020

ASN Disclosure Policy

It is the policy of American Society of Nephrology (ASN) that all individuals in a position to control the content of ASN's educational activities are expected to
disclose all their and their life spouse/partner's financial relationships with “ineligible companies” within the prior 24 months as well as other non-financial
interests. (“Ineligible companies” are those whose primary business is producing, marketing, selling, re-selling, or distributing health care products used by or on
patients.) Participants should note that the use of products outside U.S. Food and Drug Administration (FDA) approved labeling should be considered
experimental and are advised to consult current prescribing information for approval indications.
The intent of this policy is not to prevent expert faculty with relevant relationship(s) with commercial interest(s) from involvement in educational activities,
but rather to ensure that these activities promote quality and safety, are effective in improving medical practice, are based on valid content, and are inde-
pendent of control from commercial interests and free of commercial bias. In addition, all faculty were instructed to provide balanced, scientifically rigor-
ous, and evidence-based presentations.
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Disclosures have been reviewed and assessed by ASN. All relationships with ineligible companies have been identified and all relevant financial relationships
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EDITORS:
Alice M. Sheridan, MD—Employer(s): Brigham and Women's Hospital; No additional relevant financial relationship(s) with ineligible companies to disclose.
Martina M. McGrath, MBChB, FASN—Employer(s): Brigham and Women's Hospital; VA Boston Medical Center; No additional relevant financial
relationship(s) with ineligible companies to disclose.
EDITORIAL AUTHOR:
Julian L. Seifter, MD—No additional relevant financial relationship(s) with ineligible companies to disclose.

AUTHORS:
Robert Jay Alpern, MD—Employer(s): Yale University School of Medicine; Ownership Interest: Abbott, AbbVie, Tricida, Apple, Berkshire Hathaway,
IBM, Icahn Enterprises, Ford, Intel, Johnson and Johnson, Kraft Heinz, Merck, Pfizer, Verizon, Coca-Cola, UPS, Microsoft, Newell Brands, Organon,
Peoples United Financial, Texas Pacific Land Corp, First Trust Nasdaq Bank, T. Rowe Price Real Estate Investor; Advisory/Leadership Role: Director of
Abbott, AbbVie and Tricida. All are publicly traded for-profit; Other Interests/Relationships: Director of NewHYTES, a non-profit that uses tennis and
education to help underprivileged children in New Haven.
Tushar Chopra, MD, FASN—Employer(s): University of Virginia Health System; Patents/Royalties: UpToDate
Thomas D. DuBose, Jr., MD, FASN—Employer(s): Wake Forest School of Medicine; No additional relevant financial relationship(s) with ineligible
companies to disclose.
David H. Ellison, MD, FASN—Employer(s): Oregon Health & Science University, Portland VA Medical Center; Patents/Royalties: UpToDate
Namrata Krishnan, MD—Employer(s): Veterans Affairs Medical Center, West Haven, CT; Yale School of Medicine, New Haven, CT; Advisory/Leadership
Role: Leadership roles within my institution, no outside paid roles; Other Interests/Relationships: NKF education committee, KSAP question writing committee.
Ruediger W. Lehrich, MD—Employer(s): Duke University Medical Center; No additional relevant financial relationship(s) with ineligible companies to disclose.
Martina M. McGrath, MBChB, FASN—Employer(s): Brigham and Women's Hospital, VA Boston Medical Center; Other Interests/Relationships: Deputy
Editor, nephSAP; No additional relevant financial relationship(s) with ineligible companies to disclose.
Solomiia Savedchuk, MD—Employer(s): Duke University; No additional relevant financial relationship(s) with ineligible companies to disclose.
Zhabiz Solhjou, MD—Employer(s): Brigham and Women's Hospital; Patents/Royalties: Microneedle-Based Platform for Simultaneous Local Delivery of
Drugs and Institial Skin Fluid Sampling for Management of Immune Mediated Skin Diseases; Other Interests/Relationships: ASN member
Andrew S. Terker, MD, PhD—Employer(s): Vanderbilt University Medical Center; Consultancy: Andrew Terker consultancy fees by Ampio
Pharmaceuticals; Ownership Interest: Ampio Pharmaceuticals
Naoto Tominaga, MD, PhD—Employer(s): Kawasaki Municipal Tama Hospital; Research Funding: Bayer Yakuhin, Ltd.; Chugai Pharmaceutical Co.,
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Joseph G. Verbalis, MD—Employer(s): Georgetown University; Consultancy: Corcept, EUSA, Otsuka; Honoraria: Corcept, EUSA, Otsuka
ASN STAFF: Suzanne P. Armstrong, MA—Employer(s): American Society of Nephrology; No additional relevant financial relationship(s) with ineligible
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Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Editorial
Teaching Renal Physiology at the Bedside
Julian L. Seifter, MD
Brigham and Women's Hospital, Boston, Massachusetts
“He who studies medicine without books sails an uncharted sea,
but he who studies medicine without patients does not go to sea
at all.”
Sir William Osler
In the clinical environment, underlying renal pathophysiology is
often evident in a patient’s symptoms and findings. However, fur-
ther investigation is often required to identify the precise nature of
the disease. When researchers investigate a question, they design a
means to solve the problem through experimentation or the gather-
ing of data. A clinician, like a researcher, can ask fundamental
questions and develop tests that reveal answers to puzzling findings,
particularly the clinician who is undeterred by complexity and feels
free to explore different scenarios.
The cases that I will be discussing below feature unusual, para-
doxical, or seemingly insignificant findings that invite an experimental
bent of mind. In my experience, it is usually some “outlier” piece of
information that stimulates the sleuthing instinct and engages learners
in the process of solving the problem at hand. All of these cases
prompted open-ended questions: Why are we seeing this? Is there a
precedent for this? Have you seen this in another context? Can you
imagine what’s happening within the kidney? How would you design
a plan to address the questions that you would like answered?
Each case below is followed by a discussion that puts together
existing data or adds new data to enhance understanding of the
patient’s illness. The representation of data in tabular or graphic form
organizes information as it accumulates and changes over time and
illustrates the correlation between laboratory data and the clinical pro-
gress of the patient, including the effects of interventions. Visual rep-
resentation frequently reveals important interrelationships between
various pieces of data and directs the clinician toward further tests.
These salt-and-water encounters suggest that an experimental
approach, involving stepwise assessment, can inculcate a deeper
understanding of physiology and increase curiosity, creativity, and
scientific rigor in the clinical setting.
Case 1: Why Would a Healthy Subject in a
Research Study, in the Midst of a Water Diuresis,
Suddenly Become Anuric?
A healthy 25-year-old male volunteer entered a research study
involving an infusion of a synthetic natriuretic peptide. Before he
was given the drug, a water diuresis was initiated by infusing hypo-
tonic 5% dextrose in water and replacing urine volume with oral
water, millimeter for millimeter. After 3 hours, in the midst of a
brisk water diuresis, his intravenous (IV) catheter infiltrated and had
to be replaced. He did not void for the next 6 hours. When he
Copyright # 2022 by the American Society of Nephrology
67
voided 6 hours later, the urine osmolality had increased from ,50
to 1000 mOsm/kg (Figure 1).
When a healthy subject with a normal GFR is given a water
load of 15 ml/kg of body weight, 90% of that water load will be
excreted within 4 hours in a maximally dilute urine with high uri-
nary flow rate (i.e., water diuresis) (1). This occurs because the small
dilution of the plasma osmolality due to the water intake suppresses
the secretion of antidiuretic hormone (ADH), allowing the remain-
ing ADH to disappear quickly from the circulation given its very
short half-life of approximately 3 minutes. Thus, its antidiuretic
effect is reversed rapidly when physiologic stimuli such as hyperto-
nicity or hypovolemia are removed (2,3).
If the excreted water is replaced, as in this case, the water diure-
sis is maintained and ADH levels remain low. Decreased binding of
ADH to the basolateral V2 receptor on the principal cells of the col-
lecting duct, on the connecting tubule and the distal convoluted
tubule, and on the cortical thick ascending limb results in the net
endocytosis and intracellular localization of aquaporin-2 (1–3). The
signaling mechanism underlying aquaporin-2 endocytosis is less well
defined than that underlying its translocation to the apical mem-
brane, but likely involves protein kinase C—induced ubiquitination
of aquaporin (4).
In this subject, urinary flow rates of almost 1 L/h were
achieved. The administration of hypotonic fluids sufficient to cause
a water diuresis achieves the highest possible urinary flow rates—
much higher than that associated with isotonic fluids. Equal vol-
umes of saline expansion take longer to excrete and at lower urinary
flow rates. The different responses to water and saline were observed
by Homer Smith and others over 70 years ago and is a result of the
independent regulation of solute and water excretion (5). A liter of
saline might take a day to be eliminated because of the time required
to decrease the new sodium transporters in the membranes from the
steroid mineralocorticoid receptors under aldosterone regulation.
If the majority of the excreted volume is non–solute-containing
water, replacement of the output with an equal amount of water
sustains the diuresis. Though it may sound counterintuitive in the
testing of a diuretic (or in this case a natriuretic peptide), a water
diuresis is useful because it allows urine to be produced about every
30 minutes without necessitating a catheter in the bladder. In this
case the goal was to determine a time course of electrolyte excretion
rates. In a rare patient with hyponatremia, another reason to perform
a water load might be as a test of diluting capacity. Before a water
load is given to any patient, the serum [Na1] must be known. It is
important to predict a worst-case scenario of hyponatremia in case
all added water is retained instead of being eliminated in the urine.
This subject stopped making urine despite the hypotonic fluids
because of a nonosmotic stimulus to ADH secretion, which had
nephsap.org
68
Water load in normal volunteer
1200
D5W 400ml/hr
Urine osm in mOsm/kg, (red) 1000
Urine volume, ml (blue)
800
600
400
200
0
1 2
Figure 1. Water load in a normal volunteer. This figure shows the urine volume (blue bars) and urine osmolality (red bars) over time.
been osmotically suppressed. In this case the cause of ADH secretion
was the pain of an infiltrated IV catheter. Other physiologic stimuli
that cause ADH secretion include physical or emotional stress, rage,
nausea, and hypoxemia (6). Although many have heard of these
stimuli to ADH secretion, they are underappreciated in terms of
severity and duration. For the subject’s safety, the water intake was
immediately discontinued to prevent hyponatremia.
Case 2: What Stimulates Release of Atrial
Natriuretic Peptide from the Heart?
A 67-year-old woman with a history of tuberculosis was admitted
with massive peripheral edema, distended neck veins, and a pulsatile
liver. She had a calcified pericardium. She was admitted for pericar-
dial stripping.
An astute medical resident had read in the literature that
patients with heart failure with edema had very high atrial natri-
uretic peptide (ANP) levels. Some claimed the mechanism of
peptide release from granules of cardiac myocytes to be high intra-
chamber atrial pressures (Pa), whereas others suggested myocardial
stretch as the mechanism. Myocardial stretch is a distention of the
myocyctes due to an increasing gradient between Pa and intrapleural
pressure (Pip). The gradient, then, is (Pa2Pip) (7).
We expected that Pa would decrease during removal of the non-
distensible calcium barrier and, similarly, that the transmural pres-
sure gradient would also decrease. However, despite the fall in the
transmural pressure gradient, the removal of the calcium encasement
would allow the difference in pressures, still positive, to stretch the
heart muscle. If the initial cause of ANP release was due to increased
Pa, then ANP levels would decrease after stripping. But if the cause
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
lv replaced
3 4 5 6 7 8 9
Hour of test
of ANP release was transmural stretch, then ANP would increase
after stripping. In heart failure, not involving pericardial constric-
tion, both Pa and distending pressure are increased.
Figures 2 A–C show the effects of pericardial stripping on right
atrial pressure, ANP levels, and urine flow rates during and after the
surgery. Right atrial pressure fell from very high levels to significantly
lower, but still abnormally elevated, levels (Figure 2A). The ANP
level before surgery was moderately elevated (though not as high as
reported in heart failure) and increased two- to three-fold during sur-
gery. The increase of ANP in the course of the surgery is consistent
with the hypothesis that the hormone is released according to atrial
stretch and transmural pressure gradients (8) (Figure 2B).
Figure 2C shows the pattern of diuresis associated with
improvement in cardiac function after release of the calcified pericar-
dium. As mentioned in Case 1, the highest urinary flow rates occur
in a hypotonic diuresis that follows the suppression and rapid degra-
dation of ADH. However, given that ANP increased in our patient,
we should consider interactions between ANP on ADH effect. ANP
inhibits ADH release and decreases cortical collecting duct response
to ADH (9,10). It has been observed that normal volunteers, when
given isotonic saline while supine, excrete hypotonic urine with urine
chemistries that could be interpreted as showing diabetes insipidus
(DI) (10). The experiments that demonstrated the effect of volume
expansion on free water excretion were done years before the oppo-
site effect of hypovolemia to stimulate ADH release (11), although
the effect of hypovolemia on ADH gets much more attention.
We suggest that the high urinary flow rates seen in Figure 2C
represent a volume-expanded ANP-assisted diuresis, with ANP-
mediated suppression of ADH. By the end of the pericardiectomy
the urine flow rate was 35 ml/min—a rate even higher than that in
Case 1.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 69

A B
30 280

PCWP

Atrial Natriuretic Peptide PG / ML

240
25 RA MEAN After
Stripping
200
20 Before
Stripping
160
mmHg

15
120
10
80

5
40

0 0
0 2 4 6 8 10 12 14 16 18 -24 0 4 24 48
HOURS Hours

C
40

35

30
Urinary Flow ( ml/min )

25

20

15

10

0
0 2 4 6 8 10 12 14 16 18
Hours ( 0 = start of pericardiectomy )

Figure 2. Atrial natriuretic peptide after pericardiectomy (A) Right atrial (RA) mean pressure and pulmonary capillary wedge pressure (PCWP)
during and after pericardiectomy, which started at 0 hour and ended at the sixth hour. There was a near parallel decrease in pressures from 29
to 15 mm Hg. (B) Plasma atrial natriuretic peptide (ANP) levels increased and remained increased after pericardiectomy. Supine peripheral
blood samples were collected at 24 hours before surgery, just after induction of anesthesia (0 time), at 4 hours when a significant portion of the
heavily calcified pericardium had been removed, and at 24, 48, and 240 hours postoperatively. Supine ANP levels were obtained from a brachial
arterial line intraoperatively; otherwise, samples were from the right antecubital vein. Only the mean value is reported. Values for six normal
human subjects were 28.562.6 pg/ml. (C) Urine flow rates after pericardiectomy showed a dramatic postoperative increase to nearly 35 ml/min
despite decreases in central pressures and increase in ANP. The high flow state, however, appeared to be only short lived. Used with permission
from reference 8 (Wolozin MW, Ortola FV, Spodick DH, Seifter JL: Release of atrial natriuretic factor after pericardiectomy for chronic con-
strictive pericarditis. Am J Cardiol 62: 1323–1325, 1988).

In addition, ANP inhibits adrenal aldosterone production (9). Case 3: Can the Urine Be Concentrated in the
This effect was shown in the urine indices (not shown); the urine [Na] Absence of Antidiuretic Hormone?
was 48 meq/L and the urine [K] was 20 meq/L—a ratio of sodium to
An institutionalized 33-year-old woman with a history of trau-
potassium consistent with suppressed aldosterone. Most importantly,
matic brain injury was admitted to the intensive care unit in
those urine chemistries with a serum [Na] of 139 meq/L suggest that coma. Her admission [Na1] was 170 meq/L, and her urine
the postoperative urine was a mixed saline and water diuresis. In the 4 osmolality was 550 mOsm/kg. After 2 days of treatment, she was
liters excreted during the first 6 hours, approximately 50% was awake; her serum [Na1] was 156 meq/L and her urine osmolal-
osmole-free water clearance and 50% was isotonic saline diuresis. ity was ,150 mOsm/kg.
70
180
170
Serum (Na+), meq/L
160
150
140
130
120
1 2 3 4 5
days
600
500
Urine Osm. mOsm/Kg
400
300
200
100
0 The first step in solving this puzzle requires thinking through
1 2 3 4 5 the renal processes required to put out a maximally dilute urine.
days
Figure 3. Serum sodium and urine osmolality. The serum sodium
and urinary osmolal concentration were plotted versus days in the
hospital The graph shows profound hypernatremia with increased
urine osmolality initially, suggesting retained ability of the kidney to
concentrate the urine to protect from further water losses.
Graphing the serum sodium and urinary osmolal concentration
versus days in the hospital (Figure 3) yields an interesting pattern.
The initial observation is profound hypernatremia with increased
urine osmolality, suggesting retained ability of the kidney to concen-
trate the urine to protect from further water losses. An increased urine
osmolality could be due to increased ADH in either hypertonic
expansion or hypertonic depletion of the body water volume, as well
as in extracellular volume depletion regardless of osmolality. However,
on day 2, a clear diagnosis emerged. The serum sodium concentration
decreased, although it remained in a hypertonic range. However, the
urine concentration decreased to a significantly hypotonic level despite
the serum hypertonicity, which is characteristic of DI.
It would be logical to assume that the DI was of central origin
because of the patient’s history of traumatic brain injury, although
this was not tested. A trial on day 2 to see whether the urine could
concentrate after administration of vasopressin would have been
diagnostic. If the patient clearly, on day 2, had DI, the obvious
question is why on presentation she had the ability to concentrate
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
ARGININE VASOPRESSION (PERCENT REMAINING)
100
80 CONTROL
60
PATIENT
40
20
0
0 10 20 30
TIME (MIN)
Figure 4. Postpartum serum versus control serum. This figure shows
AVP levels in patient's postpartum serum and in control serum after
the in vitro addition of AVP. The patient's serum compared to con-
trol serum shows a decrease in level of AVP, suggesting the presence
of vasopressin in the patient's serum.
her urine in the absence of ADH. Is there a mechanism by which
the urine can be concentrated in the absence of ADH?
First, there must be ample isotonic filtration of plasma into the
renal tubules without excessive proximal reabsorption of that fluid.
This enables a high rate of delivery into the loop of Henle (i.e.,
the delivery phase). Second, the water-impermeable diluting seg-
ment, consisting of the thick ascending limb in the medulla and
parts of the cortical distal nephron, must be able to reabsorb
sodium in the absence of water, thus producing a dilute fluid. It
follows that the greater the delivery from the proximal tubule, the
more separation of salt from water will occur, and maximal
amounts of dilute tubular fluid will be available (i.e., the separa-
tion phase). In the absence of ADH, large quantities of
electrolyte-free water can be excreted as dilute urine (the regulation
phase).
However, in conditions of excessive extracellular volume deple-
tion, filtration decreases and proximal reabsorption increases, which
sharply limits fluid delivery to the diluting segments. The reabsorp-
tion of sodium in the thick ascending limb and corresponding water
reabsorption in the descending limb of Henle results in a very low
flow rate of tubular fluid to the ADH-sensitive portions of the neph-
ron in the cortex and medulla.
A key fact is that even in the absence of ADH, the collecting
duct is slightly permeable to water. This contrasts with the water-
impermeable thick ascending limb in the medulla and parts of the
cortical distal nephron. Even if only slightly permeable, when tubu-
lar flow is very low, the collecting duct reabsorbs enough water to
raise the osmolality of the tubular fluid (12). However, despite the
relatively high osmolality of tubular fluid in such cases, the absolute
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 71

A B
400
Urine Osmolality (mOsm/liter)

Urine Osmolality (mOsm/liter)

Urine Output (ml/hr)

300 300

Urine Output (ml/hr)

200 200

100 100

0 0
3-hr mean 1 2 3 3-hr mean 1 2 3

Hour Hour

Figure 5. (A) Nephrogenic diabetes insipidus response to indomethacin plus dDAVP. Lightly shaded bars indicate urine osmolality, and heavily
shaded bars indicate urine output. Arrows denote the time at which a single dose of subcutaneous desamino-D-arginine vasopressin (dDAVP)
was administered. (B) In the absence of indomethacin plus dDAVP. Lightly shaded bars indicate urine osmolality, and heavily shaded bars urine
output. Arrows denote the time at which a single dose of subcutaneous desamino-D-arginine vasopressin (dDAVP) was administered. Used with
permission from reference 17 (Stasior DS, Kikeri D, Duel B, Seifter JL: Nephrogenic diabetes insipidus responsive to indomethacin plus
dDAVP. N Engl J Med 324: 850–851, 1991).

amount of absorbed water is low, and not nearly enough to decrease
the serum sodium.
By comparison, under high flow rate conditions this ADH-
independent reabsorption would not be enough to concentrate the
tubular fluid, although more free water is absorbed in the collecting
duct during a water diuresis in the absence of ADH than when there
is low tubular delivery and non–ADH-dependent water reabsorption.
In this case it is notable that the osmolality of the urine was not
maximal at 550 mOsm/kg. This was likely because of her chronic DI.
Inasmuch as she had sufficient water loss to drive her extreme hyper-
natremia, there would also be enough non-ADH water reabsorption
to wash out the existing gradient between the interstitium and the
tubular lumen. With any persistently high urine flow rate, enough
water is generally reabsorbed to wash out the interstitial solute gradi-
ent so that the maximum interstitial fluid osmolality, and accordingly
the maximum urine osmolality, is lowered until the gradient can be
re-established. Maximal urine osmolality will be achieved only when
the polyuric process is corrected—whether by treating low volume
states or by administering ADH in central DI—and enough solutes
such as salt and urea are available to restore medullary hyperosmolal-
ity. This usually takes days of repletion of solutes.
Sixty years ago experiments were done to test the presence of
non–ADH-dependent urinary concentrating ability. In one experi-
ment, the bladder was ligated in dogs hypophysectomized to remove
ADH and produce DI (13). A pipette was placed into each hemi-
bladder so that functionally the two urinary systems consisted of a
kidney, ureter, and half-bladder. In these animals with DI, both
hemibladders excreted maximally dilute urine at baseline. One renal
artery was clamped to create renal artery constriction, which unilat-
erally decreased the GFR. This decreased the flow rate of tubular
fluid from the proximal nephron into the collecting duct. Compared
with the contralateral unclamped kidney, the kidney with the artery
constriction yielded concentrated urine. The contralateral control
urinary system continued to generate dilute urine consistent with
DI. This phenomenon is known as the Berliner–Davidson effect
(13). The Berliner–Davidson effect is demonstrated in multiple clin-
ical scenarios, including the following:

DI is more profound in patients who are given a high-salt diet
compared with a low-salt diet.

A loss of posterior pituitary function creates more water loss
than panhypopituitarism. In the latter case, hypocortisolemia
resulting from decreased adrenocorticotrophic hormone
(ACTH) causes hypotension and limits the excretion of large
volumes of hypotonic urine.

In patients with nephrogenic DI, urinary flow can be
decreased by a thiazide diuretic, which, by causing extracellu-
lar volume depletion, decreases the GFR, enhances proximal
reabsorption, and decreases distal delivery. This limits the
production of electrolyte-free water and controls the polyuria.
The following two cases also demonstrate the Berliner–Davidson
effect, among other physiologic findings.
Case 4: Can a Patient Have Diabetes Insipidus of
Pregnancy Manifesting Only in the
Postpartum Period?
A 28-year-old woman began to excrete high urine volumes, as much
as 1 L an hour, 1 to 2 days after the delivery of healthy twins. She had
no history of polyuria. She had experienced third-trimester preeclamp-
sia, with marked edema and hypertension, which resolved immediately
after delivery. On postpartum day 2, the result of physical examination
was notable only for trace edema. Laboratory evaluation revealed
serum [Na1] 143 meq/L. Serum osmolality was 296 mOsm/kg, urine
osmolality was 110 mOsm/kg, and UNa1 was 20 meq/L.
Polyuria regularly occurs in the postpartum period as a result of
the mobilization of the large volume of extracellular and intracellular
fluid accumulated during pregnancy. At termination of pregnancy,
hormonal balance changes. For example, natriuretic peptides
increase salt excretion, normal sensitivity to vasopressin returns, and
72
the water excretion corrects the normal hyponatremia of pregnancy.
However, this patient experienced a much greater loss of fluid than
would be expected. The edema decreased, suggesting a decrease in
extracellular fluid, but the rapid rise in serum sodium concentration
to 143 meq/L suggested excessive loss of hypotonic fluid. The high
urine flow rate at 1 L/h was investigated by evaluating the urine
chemistry. The urine osmolality was hypotonic at 110 mOsm/kg,
approximately one third of the serum osmolality. Thus, two thirds
of the urine output was solute-free water, whereas one third was
isosmotic. Multiplying the urine osmolar concentration by the vol-
ume of urine over time yields the solute excretion rate per time:
_ CH O 1 Cosm
V5 2
and
Cosm 5 ½Uosm 3 1L=hr=Posm:
Rearranging for free water clearance:
_ Cosm
CH2 O 5 V2
or
_
CH2 O 5 V½1– ðUosm =Posm Þ
where the total flow rate of urine, V, _ is compartmentalized into an
isosmotic clearance, Cosm, and a solute-free water clearance, CH2O.
In our patient, V_ was 1 L/h, and Cosm was (110/296). Cosm 
0.372 L/hr. CH2O 5 1.0-0.372 5 0.628 L/h.
The urine sodium concentration, 20 meq/L, multiplied by 1
L/h, indicates the loss in the urine of 1 L of isotonic salt solution every
seven hours, which, while indicating the presence of an osmotic diure-
sis, also indicates that the polyuria is excessive for the usual postpar-
tum natriuresis and suggests a large electrolyte-free component. The
excretion of water is inappropriately high for the serum sodium con-
centration of 143 meq/L, suggesting a water diuresis characteristic of
DI. In this patient, the differential diagnosis of DI includes pituitary
infarction (Sheehan syndrome) and, more likely, given the large pla-
cental mass of a twin pregnancy, DI of pregnancy due to the presence
of excessive placental vasopressinase (14).
However, one question relating to this diagnosis is this: Why is
this condition presenting for the first time post partum, when she
did not have gestational polyuria?
The enzyme vasopressinase (oxytocinase) is present in the placenta
early in gestation to prevent premature labor and is elevated in multi-
gestational pregnancies or with large placental mass. Vasopressinase
continues to be present for days to weeks after removal of the placenta
because of the slow clearance of the enzyme; therefore, ADH continues
to be suppressed, and DI not only becomes evident after delivery of
the placenta but continues for a period of time post partum (14). The
diagnosis is tested by administering an IV dose of arginine vasopressin
(AVP), the normal ADH peptide, and measuring the urine osmolality.
If vasopressinase is present, the administered AVP fails to concentrate
the urine. By contrast, the administration of desamino-D-arginine
vasopressin (dDAVP), which is a synthetic nondegraded analogue of
vasopressin, will concentrate the urine. Figure 4 shows an in vitro test
of the patient’s postpartum serum with AVP added to it, which, com-
pared with control serum, shows a decrease in level of AVP.
Another question relating to the diagnosis is this: If the patient
had DI of pregnancy with vasopressinase present, why didn’t she
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
have gestational polyuria when the enzyme level would be expected
to be even higher?
The answer lies in an interaction between salt and water reminis-
cent of the Berliner–Davidson effect discussed earlier. Pre-eclampsia
is a sodium-avid disorder characterized by edema. Therefore, in her
pre-eclamptic state she was reabsorbing excessive amounts of isotonic
fluid in the proximal tubule and the loop of Henle, limiting the deliv-
ery of hypotonic water to the collecting duct. Thus, even in the
absence of vasopressin, water excretion was limited, preventing the
manifestation of DI. However, once delivery occurred, the pre-
eclampsia resolved, and the postpartum saline diuresis followed. The
increased flow rate to the distal nephron markedly increased free
water excretion because AVP was absent.
CASE 5: Can Lithium Cause Both Central and
Nephrogenic Diabetes Insipidus?
A 44-year-old woman taking long-term lithium was admitted from
a nursing home with cholecystitis. She was noted to be polyuric,
with serum [Na1] of 150 meq/L. Assuming the patient had nephro-
genic DI, the surgical resident started the nonsteroidal anti-
inflammatory drug (NSAID) indomethacin, having read reports
that indomethacin decreased urine volume in the setting of DI (15).
When the patient remained polyuric, indicating that NSAIDs alone
did not correct the polyuria, a renal consultation was requested, and
a diagnostic test was done.
We administered a single dose of dDAVP to test whether the
urine could be concentrated. Notably, the patient was already dehy-
drated, with serum sodium of 150 meq/L; thus, water restriction
before dDAVP was not required. The results are shown in Figure 5A.
The dDAVP increased the urinary concentration and decreased urine
volume, suggesting central DI.
The test was repeated after the NSAID was stopped (Figure 5B).
The serum sodium concentration was again 150 meq/L, so that water
restriction was not required. After the NSAID was stopped, dDAVP
did not concentrate the urine or decrease urinary volume further.
The absence of an effect of dDAVP in the setting of dehydra-
tion and polyuria usually indicates nephrogenic DI (16). However,
in this case, the NSAID plus the supraphysiologic addition of ADH
(dDAVP) concentrated the urine, but ADH alone did not (17).
There are two possible explanations for this observation. The first
is that indomethacin potentiated the ADH effect in the collecting
duct by inhibiting prostaglandins (18). Prostaglandins such as PGE2
diminish the effect of ADH. The other possibility is that the NSAID
decreased renal plasma flow and therefore GFR. The decreased GFR
would increase proximal and loop of Henle reabsorption of Na1,
which would decrease flow to the medullary collecting duct.
This case is another example of the Berliner–Davidson effect.
Again we see that decreasing Na1 delivery limits the output of dilute
urine and allows for concentration of urine. Increasing Na1 delivery
improves water excretion and urinary dilution when ADH is absent
or nonfunctional. A vasopressin level from blood drawn before the
second dehydration test later came back showing high levels of ADH.
In conclusion, fluid and electrolyte balance in the body is an
integrated system. Examples of the interconnections are observable
in each of the cases presented. A common theme is how the regula-
tion of sodium balance by the renal tubules is connected to the
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
handling of water. These investigations illustrate critical thinking at
the bedside, illuminate connections between basic science and clini-
cal medicine, and refine diagnoses so as to improve patient care.
References
1. Demers L: Pituitary function. In: Tietz Textbook of Clinical Chemis-
try, 3rd Ed., edited by Burtis CA, Ashwood ER, Philadelphia, W.B.
Saunders, 1999, pp 1470–1499.
2. Cheung PW, Bouley R, Brown D: Targeting the trafficking of kidney
water channels for therapeutic benefit. Annu Rev Pharmacol Toxicol 60:
175–194, 2020 PubMed
3. Knepper MA, Inoue T: Regulation of aquaporin-2 water channel
trafficking by vasopressin. Curr Opin Cell Biol 9: 560–564, 1997 PubMed
4. Kamsteeg EJ, Hendriks G, Boone M, Konings IB, Oorschot V, van der
Sluijs P, et al: Short-chain ubiquitination mediates the regulated endocy-
tosis of the aquaporin-2 water channel. Proc Natl Acad Sci U S A 103:
18344–18349, 2006 PubMed
5. Smith HW: Salt and water volume receptors: an exercise in physiologic
apologetics. Am J Med 23: 623–652, 1957 PubMed
6. Kamoi K, Ishibashi M, Yamaji T: Interaction of osmotic and nonosmotic
stimuli in regulation of vasopressin secretion in hypoosmolar state of
man. Endocr J 44: 311–317, 1997 PubMed
7. Ruskoaho H, Lang RE, Toth M, Ganten D, Unger T: Release and regulation
of atrial natriuretic peptide (ANP). Eur Heart J 8: 99–109, 1987 PubMed
8. Wolozin MW, Ortola FV, Spodick DH, Seifter JL: Release of atrial
natriuretic factor after pericardiectomy for chronic constrictive pericardi-
tis. Am J Cardiol 62: 1323–1325, 1988 PubMed
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9. Inoue T, Nonoguchi H, Tomita K: Physiological effects of vasopressin
and atrial natriuretic peptide in the collecting duct. Cardiovasc Res 51:
470–480, 2001 PubMed
10. Strauss MB, Davis RK, Rosenbaum JD, Rossmeisl EC: Water diuresis
produced during recumbency by the intravenous infusion of isotonic
saline solution. J Clin Invest 30: 862–868, 1951 PubMed
11. Orloff J, Burg M: Kidney. Annu Rev Physiol 33: 83–130, 1971 PubMed
12. Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK, Knepper
MA: Vasopressin increases water permeability of kidney collecting duct
by inducing translocation of aquaporin-CD water channels to plasma
membrane. Proc Natl Acad Sci U S A 92: 1013–1017, 1995 PubMed
13. Berliner RW, Davidson DG: Production of hypertonic urine in the
absence of pituitary antidiuretic hormone. J Clin Invest 36: 1416–1427,
1957 PubMed
14. Marques P, Gunawardana K, Grossman A: Transient diabetes insipidus in
pregnancy. Endocrinol Diabetes Metab Case Rep 2015: 150078, 2015 PubMed
15. Allen HM, Jackson RL, Winchester MD, Deck LV, Allon M: Indometh-
acin in the treatment of lithium-induced nephrogenic diabetes insipidus.
Arch Intern Med 149: 1123–1126, 1989 PubMed
16. Erden A, Karag€oz H, Başak M, Karahan S, Cetinkaya A, Avci D, et al:
Lithium intoxication and nephrogenic diabetes insipidus: a case report
and review of literature. Int J Gen Med 6: 535–539, 2013 PubMed
17. Stasior DS, Kikeri D, Duel B, Seifter JL: Nephrogenic diabetes insipidus
responsive to indomethacin plus dDAVP. N Engl J Med 324: 850–851,
1991 PubMed
18. Berl T, Raz A, Wald H, Horowitz J, Czaczkes W: Prostaglandin synthe-
sis inhibition and the action of vasopressin: Studies in man and rat. Am J
Physiol 232: F529–F537, 1977 PubMed
74
Article
Pathophysiology, Evaluation, Outcomes, and Treatment of
Hyponatremia
Naoto Tominaga, MD, PhD
Division of Nephrology and Hypertension, Kawasaki Municipal Tama Hospital, Kawasaki, Kanagawa, Japan and
Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of
Medicine, Kawasaki, Kanagawa, Japan
Joseph G. Verbalis, MD
Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, DC
Learning Objectives
1. To determine the differential diagnosis of hyponatremic states
and the pathophysiology underlying each
2. To identify the causes of nonosmotic and inappropriate
arginine vasopressin secretion and how they relate to the
causation of hyponatremia
3. To appreciate the symptoms of hyponatremia and how they
differ according to the chronicity of the hyponatremia
4. To explain the treatment options for hyponatremia and how
they differ according to the neurologic symptoms of the
hyponatremia
5. To determine the risk factors for the osmotic demyelination
syndrome and the correction limits that should be observed in
the treatment for chronic hyponatremia
Pathophysiology of Hyponatremia
Definition and Prevalence of Hyponatremia
In most cases, hyponatremia is a disorder of water balance in the
body. Hyponatremia is defined as a serum sodium concentration
([Na1]) below the normal limits. Although most clinicians regard
hyponatremia as a serum [Na1] of ,135 mmol/L, minor variations
in definition ranging from [Na1] of ,136 mmol/L (1–3) to [Na1]
of ,135 mmol/L (4–7) exist in the medical literature.
Hyponatremia is the most common electrolyte abnormality in
hospitalized and critically ill patients, with a prevalence of 15% to
30% (8,9). Incidences of hyponatremia from 7% to 53% have been
reported in institutionalized geriatric patients, even with the use of
strict criteria to define hypo-osmolality (10,11). Up to 40% to 70%
of hyponatremia cases are iatrogenic/hospital-acquired, as reported
by some studies (12,13).
nephsap.org
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Sodium Concentration and Sodium Content: Two
Related but Different Concepts
In this review, Na1 represents exchangeable Na1 in the body.
Serum [Na1] and Na1 content are related but different concepts.
Na1 is the predominant cation in extracellular fluid (ECF) (Figure
1) and is the major component of plasma osmolality (Posm); differ-
ences in effective Posm cause movement of water between the intra-
cellular fluid (ICF) and ECF compartments. Thus, serum [Na1] is
tightly regulated to maintain water balance. Pathologic hyponatre-
mia or hypernatremia occurs when electrolyte-free water becomes
excessive or insufficient relative to the Na1 content in the ECF, and
it can occur regardless of the total body Na1 content. In other
words, hyponatremia can develop with any ECF volume status or
body Na1 content.
Total Plasma Osmolality and Effective Plasma
Osmolality (Tonicity)
As discussed, an abnormality in serum [Na1] is usually caused by an
imbalance in the amount of water in the ECF. How is the effective
Posm (tonicity), which regulates the amount of water, defined? Osmolal-
ity reflects the concentration of all solutes in a solution, but effective
osmolality reflects only solutes that cannot easily pass through cell
membranes. Movement of water between the ICF and ECF compart-
ments is caused by differences in effective Posm. In other words, effective
osmolality can most simply be understood as osmolality by solutes effec-
tive at moving water across body fluid compartments.
For example, K1 in the ICF and Na1 and glucose in ECF are all
substances that generate effective Posm. In contrast, urea is an osmotic
substance but can move freely between the ICF and ECF compart-
ments; therefore, it does not generate effective Posm. In the ECF, K1
concentration ([K1]) is negligible compared with [Na1]; thus, most
of the effective Posm generated can be considered to be due to the
effective osmoles of Na1 and corresponding anions
Posm and effective Posm are expressed by the following formulae:
Posm ðmOsm=kg H 2 OÞ 5 2 3 serum ½Na1  ðmmol=LÞ
1 glucose ðmg=dLÞ=18 1 BUN ðmg=dLÞ=2:8
Copyright © 2022 by the American Society of Nephrology
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 75

<Increased free water in the ECF compartment> Plasma

Posm AVP concentration
(mOsm/kg H2O) (pg/ml)
+
++
Na
Na
Na
Na+ +
+
Na
Na
Na
++
Na+ 296 9
Na

Na
Na
++
+ 294 8
+
Na
Na+ ++ +
Na
Na
Na
Na+ 7 Uosm
+ + +
++ Thirst 292
Na
Na
Na+ Na
Na
Na
Na+ (mOsm/kg H2O)
osmotic 6
++ +
Na
Na
Na
Na+ threshold 290
5 1000
ICF ECF
n free water in the ECF Shift of free water 288 4
from ECF to ICF 800
286 3
pserum [Na ]
+
intracellular edema 600
284 2
400
<Decreased free water in the ECF compartment>
282 1 300
++ + AVP 200
Na
Na
Na
Na+
osmotic 280 0 100
+ +
Na
Na
Na
Na
++
+
++ +
Na
Na
Na
Na
++
+
threshold 0
Na
Na
Na
Na+ 278 0 250 500 750 1000
++ +
Na
Na
Na
++ +
Na
Na
Na
++
Na+
+ Na
Na
Na
Na+ Urine volume (ml/h)
Na+
++ +
Na
Na
Na
++ + 276
Na
Na
Na
Na+ Na+

ICF ECF p free water in the ECF Shift of free water

from ICF to ECF
nserum [Na+] dehydration
Figure 1. Na1 is an effective osmole and serum [Na1] contribution
to effective Posm (tonicity). Na1 content and serum [Na1] are related
but different concepts. Na1 is the predominant cation in ECF and is
the major component of Posm. Differences in effective Posm cause
movement of water between the ICF and ECF compartments. Path-
ologic hyponatremia or hypernatremia occurs when electrolyte-free
water becomes excessive or insufficient relative to the Na1 content in
the ECF, and can occur regardless of the total body Na1 content.
Dotted lines indicate normal body fluid status in the ICF and ECF
compartments. Light blue boxes indicate ECF water. Circles indicate
Na1 molecules. Abbreviations: ECF, extracellular fluid; ICF, intra-
cellular fluid; Posm [Na1], ECF sodium concentration; Na1, sodium
ion.
Effective Posm ðmOsm=kg H 2 OÞ 5 2 3 serum ½Na1 
ðmmol=LÞ 1 glucose ðmg=dLÞ=18:
In the absence of hyperglycemia, effective Posm can be estimated
as two times the serum [Na1] 1 10 (which represents the osmolality
of other effective solutes in the ECF). From these formulae, it should
be clear that serum [Na1] is the major determinant of effective Posm.
Two Defense Systems Protecting against Body
Water Losses
When Posm increases above 285 mOsm/kg H2O, arginine vasopres-
sin (AVP) is secreted by the posterior pituitary gland (Figure 2) (14).
As a result, plasma AVP concentrations increase, and more free water
is reabsorbed from the renal collecting ducts, resulting in increased
urine osmolality (Uosm) and a net decrease in urine output. When
Posm exceeds approximately 295 mOsm/kg H2O, thirst is provoked,
leading to increased drinking. AVP secretion and thirst represent the
two major body defenses against water losses.
Special attention must be provided to older adults because they
demonstrate unique characteristics. Older adults are less likely to
feel thirsty and to have a narrower dynamic range of thirst than
Figure 2. Arginine vasopressin and renal responses to increased
plasma osmolality. When Posm increases above 285 mOsm/kg H2O,
AVP secretion from the posterior pituitary gland is stimulated. As a
result, plasma AVP concentrations increase, more free water is reab-
sorbed from the renal collecting ducts, and Uosm is increased, result-
ing in a net decrease in urine output. However, when Posm continues
to rise, it increases AVP secretion further and activates thirst when
Posm exceeds approximately 295 mOsm/kg H2O. Abbreviations:
AVP, arginine vasopressin; ml/h, milliliters per hour; mOsm/kg
H2O, milliosmoles per kilogram of water; pg/ml, picograms per milli-
liter; Posm, plasma osmolality; Uosm, urine osmolality. Reprinted with
permission from reference 14 (Robinson AG: Disorders of antidi-
uretic hormone secretion. Clin Endocrinol Metab 14: 55–88, 1985).
younger individuals (Figure 3) (15). This has been attributed to
cerebral cortex dysfunction, based on a study using positron emis-
sion tomography (16). Simply speaking, thirst in older adults is
quenched with relatively smaller amounts of water, which can be
insufficient to compensate for body water deficiency in some
circumstances.
Arginine Vasopressin: Appropriate Secretion
AVP is a 9-amino acid neuropeptide, which acts as a hormone
involved in water homeostasis as well as a neurotransmitter modulat-
ing nerve transmission. AVP is often referred to as antidiuretic hor-
mone (ADH). However, considering that there are three types of
AVP receptors—V1a, V1b, and V2 receptors—and that these recep-
tors exist in various organs (17), the more appropriate terminology
for the hormone is AVP. AVP is secreted when the effective Posm
increases or when the effective circulating plasma volume decreases.
Homeostasis of body fluids is maintained via these two major AVP
secretory stimuli (Table 1). In a dehydrated state, osmoreceptors in
the hypothalamus can detect an increase of just 1% to 2% in the
effective Posm, triggering AVP secretion from the posterior pituitary
gland. AVP acts on AVP V2 receptors in the renal collecting ducts
to decrease the excretion of free water in urine (Figure 4). As noted
76 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

14 volume rather than on Posm (18). This is an important physiologic

point because AVP secretion is enhanced when the ECF volume
12
65+ decreases even while Posm is not elevated. This represents the most
YOUNG common type of hypovolemic hyponatremia seen in clinical prac-
10
Control tice, especially in the older population. Because of this mechanism,
Thirst rating, cm

AVP secretion will persist until the ECF losses are corrected or
8
improved, resulting in no net improvement of hyponatremia. Con-
6
sequently, the secretion of AVP in response to situations where the
effective Posm is increased or the effective circulating plasma volume
4 is decreased represents "appropriate” AVP secretion.

2 Nonosmotic AVP Stimuli: Inappropriate Secretion

0
278 283 288 293
Posm, mosmol · kg H2O–1
Figure 3. Differences in thirst perception between young and elderly
individuals. Older adults are less likely to feel thirsty with a higher
set point of Posm of approximately 287 mOsm/kg H2O, and they
have a narrower dynamic range of thirst than young individuals.
Abbreviations: cm, centimeter; mosmol・kg H2O21, milliosmoles per
kilogram of water; mOsm/kg H2O, milliosmoles per kilogram of
water; Posm, plasma osmolality; 651, 65 years and older. Reprinted
with permission from reference 15 (Mack GW, Weseman CA, Lan-
ghans GW, Scherzer H, Gillen CM, Nadel ER. Body fluid balance
in dehydrated healthy older men: Thirst and renal osmoregulation. J
Appl Physiol 76: 1615–1623, 1985).
previously, with further increases in Posm, thirst is activated and
stimulates drinking behavior. The combination of these responses
leads to the retention of ingested free water and normalization of
the elevated Posm.
In cases of volume depletion, the decrease in the effective circu-
lating plasma volume triggers the activation of both the sympathetic
nervous system and the renin-angiotensin system to maintain the
plasma volume by reducing urine Na1 excretion. However, when
there is a large decrease in circulating plasma volume (loss of 5% to
10% of body fluid volume) that lowers blood pressure (BP), AVP is
secreted independently of Posm by activation of arterial barorecep-
tors, and the excretion of free water is suppressed, thus maintaining
ECF volume. When ECF volume is severely reduced, AVP secretion
is overwhelmingly dependent on the effective circulating plasma
In addition to the two physiologic regulatory systems described, there
298
are both physiologic and pathologic conditions in which nonosmotic
AVP secretion occurs. These include malignant tumors, lung diseases,
central nervous system diseases, drugs, and transient causes (nausea,
vomiting, pain, general anesthesia, prolonged strenuous exercise).
Hyponatremia has occasionally been observed in patients infected
with SARS-CoV-2 (COVID-19), which has spread worldwide in a
short time since December 2019. The potential causes of hyponatre-
mia with COVID-19 infection include pneumonitis, vomiting, diar-
rhea, inadequate oral intake, the administration of natriuretics, and
the syndrome of inappropriate antidiuresis (SIAD) (19).
Because these conditions usually are not related to physiologic
conditions that appropriately stimulate AVP secretion, i.e., hyperos-
molality or hypovolemia, they are often termed “inappropriate”
stimuli of AVP secretion. Interleukin-6 (IL-6) released by monocytes
and macrophages during inflammation may play an important role
in the pathogenesis of some cases of hyponatremia (20). IL-6 crosses
the blood–brain barrier and acts in the circumventricular organs,
such as the subfornical organ and the organum vasculosum, trigger-
ing nonosmotic AVP release from both the supraoptic and the para-
ventricular nuclei and inducing thirst (20).
In all cases of nonosmotic stimulation of AVP secretion, elimi-
nating the root cause of increased AVP secretion will allow excretion
of excess retained water and correct the hyponatremia; however, if
this is not possible, then direct treatment of the hyponatremia may
be necessary.
Etiologies of Disorders of Serum [Na1]
Plasma [Na1] is the main determinant of effective osmolality (tonic-
ity). Plasma [Na1] is nearly equal to the total number of cations in
the body (total Na1 content 1 total K1 content), which cannot

Table 1. Physiologic regulatory systems controlling AVP secretion

Osmoregulatory System Volume Regulatory System

Input Posm Effective circulating arterial volume

Sensors Hypothalamic osmoreceptive neurons Carotid sinus, atrial, and renal afferent arteriole baroreceptors
Effectors AVP, and thirst Sympathetic nervous system, renin-angiotensin-aldosterone
system, natriuretic peptide system, and AVP
Outputs Urine free water excretion, and fluid Urine Na1 and free water excretion
intake (drinking behavior)

AVP, arginine vasopressin; Posm, plasma osmolality.

Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
ISOTONIC VOLUME DEPLETION
ISOVOLEMIC OSMOTIC INCREASE
50
PLASMA AVP CONCENTRATION (pg/ml)
45 PAVP = 1.3e–0.17 VOL
40
35
30
25
PAVP = 2.5 OSM + 2.0
20
15
10
5
0
0 5 10
PERCENT CHANGE
Figure 4. Changes in plasma AVP concentrations in response to iso-
volemic increases in Posm and isotonic volume depletion. AVP is
secreted when the effective Posm (tonicity) increases or when the
effective circulating plasma volume decreases. In a dehydrated state,
osmoreceptors in the hypothalamus can detect increases of 1%–2%
in the effective Posm, triggering AVP secretion from the posterior
pituitary gland. In a severely volume-depleted state (loss of 5%–10%
of body fluid volume) that lowers BP, AVP is secreted independently
of Posm by activation of arterial baroreceptors, and the excretion of
free water is suppressed, thus maintaining ECF volume. When ECF
volume is severely reduced, AVP secretion is overwhelmingly depen-
dent on the effective circulating plasma volume rather than on Posm.
Abbreviations: AVP, arginine vasopressin; blood pressure, BP; ECF,
extracellular fluid; pg/ml, picograms per milliliter; DOSM, percent
change in plasma osmolality; PAVP, plasma arginine vasopressin con-
centration; Posm, plasma osmolality; DVOL, percent change in blood
volume. Reprinted with permission from reference 18 (Dunn FL,
Brennan TJ, Nelson AE, Robertson GL: The role of blood osmolal-
ity and volume in regulating vasopressin secretion in the rat. J Clin
Invest 52: 3212–3219, 1973).
normally be measured, divided by the total body water, as is demon-
strated by Edelman’s equation (21):
 
Plasma Na1 ðmmol=LÞ 5 1:11

3 total body Na1 e 1 K 1 e ÞðmmolÞ=total body water ðLÞg 2 25:6:
This can be simplified conceptually as follows:
Plasma ½Na1  ðmmol=LÞ


5 total body Na1 e 1 K 1 e ðmmolÞ=total body water ðLÞ:
In the above formula, Na1e and K1e represent exchangeable
ions, that is, ions not affixed to bone or tissue.
77
Serum [Na1] is affected both by the tonicity of fluid ([Na1] 1
1
[K ]) entering the body and by the tonicity of fluid (mainly urine)
([Na1] 1 [K1]) discharged from the body. Serum [Na1] is regu-
lated by the balance of cations, such as Na1, K1, and free water.
Conditions affecting each part of the Edelman equation are illus-
trated in Figure 5 (22).
Thus, whenever an abnormality in serum [Na1] is observed, it
is necessary to assess the tonicity of both the infusion solution and
the excreted urine. If urine ([Na1] 1 [K1]) is higher than infusion
([Na1] 1 [K1]), then serum [Na1] tends to decrease; conversely, if
urine ([Na1] 1 [K1]) is lower, serum [Na1] tends to increase.
Therefore, when evaluating abnormalities in serum [Na1], urine
tonicity mainly consisting of urine ([Na1] 1 [K1]) cannot be
ignored because, unlike the negligible plasma [K1], urine [K1] con-
tributes significantly as an effective osmole.
Evaluation of Hyponatremia
When evaluating patients with hyponatremia, one must first exclude
15 20
isotonic and hypertonic hyponatremia.
Check Plasma Osmolality (Posm)
Most patients with hyponatremia have a Posm of ,280 mOsm/kg
H2O, but exceptions are cases of isotonic and hypertonic hyponatre-
mia, so it is important to exclude these two conditions first because
they do not require specific treatment of the hyponatremia
Isotonic Hyponatremia (280–295 mOsm/kg H2O). It is possible
for true hyponatremia to exist with normal Posm.
Causes include hyperglycemia, administration of osmotic agents
(mannitol, sorbitol, glycine, glycerol), and radiographic contrast
agents (23–25). The serum contains additional osmoles that increase
effective osmolality (tonicity) and reduce the serum [Na1] by moving
water from the ICF to the ECF compartments. The most common
cause is hyperglycemia due to uncontrolled diabetes mellitus. The
resulting hyponatremia is called a translocational hyponatremia.
Despite true hyponatremia, albeit with a normal Posm, hyperglycemia-
induced hyponatremia is frequently erroneously included as one of
the forms of pseudohyponatremia.
Pseudohyponatremia occurs when serum [Na1] is seemingly
low by measurement, but is actually normal. This occurs when the
amount of water in the plasma decreases because of solid compo-
nents such as increased protein or triglycerides that occupy part of
the measured serum volume at the time of measurement. Conse-
quently, the concentration of Na1 per volume of serum is low, but
the concentration of Na1 in the serum water is really normal. Pseu-
dohyponatremia is therefore an artifact of measurement and does
not represent true hyponatremia. It is usually caused by hypertrigly-
ceridemia or paraproteinemia from multiple myeloma. Because
serum osmolality is normal, no shifts of water from the ICF to the
ECF compartments occur, and no direct treatment of the hypona-
tremia is necessary. If there is uncertainty about a diagnosis of pseu-
dohyponatremia (such as when low serum [Na1] is detected in a
patient with known myeloma and increased serum light chains, or a
patient is known to have hypertriglyceridemia), direct measurement
of Posm or a blood gas measurement should be performed because
neither is affected by dilution of the blood.
78 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

DECREASED
Hypovolemic hyponatremia DECREASED
• Poor Na+ intake Vast majority of hypovolemic
• Renal or extrarenal Na+ losses and hypervolemic
hyponatremia
NORMAL • Poor K+ intake
Euvolemic hyponatremia • Renal or extrarenal K+ losses
Nae+ Ke+
• In the SIAD, small renal Na+
losses occur NORMAL
Euvolemic hyponatremia
INCREASED
• In the SIAD, small renal K+
Hypervolemic hyponatremia losses occur
• Na+ retention

Nae+ + Ke+
serum [Na+] =
TBW

TBW

DECREASED NORMAL INCREASED

Hypovolemic hyponatremia Hypovolemic hyponatremia Euvolemic hyponatremia
• Impaired aquaresis • Impaired aquaresis • Impaired aquaresis
Water retention falls short of Water retention normalizes Water retention expands TBW
normalizing TBW TBW • Excessive water intake

Hypervolemic hyponatremia
• Impaired aquaresis
Water retention expands TBW

Figure 5. Factors influencing serum [Na1] based on the Edelman equation. Hyponatremia represents an excess of water relative to the Na1
and K1 stores in the body. Hypotonic hyponatremia can show decreased, normal, or increased Nae1; decreased or normal Ke1; and decreased,
normal, or increased TBW, which means hyponatremia can occur with any ECF volume status. Abbreviations: Ke1, exchangeable potassium
ion; Nae1, exchangeable sodium ion; SIAD, syndrome of inappropriate antidiuresis; [Na1] sodium concentration; TBW, total body water.
Reprinted with permission from reference 22 (Adrogu
e HJ, Madias NE: The challenge of hyponatremia. J Am Soc Nephrol 23: 1140–1148,
2012).

Hypertonic Hyponatremia (>295 mOsm/kg H2O). Glucose, man-
nitol, sorbitol, glycerol, and radiographic contrast media are effective
osmotic substances and can move water from the ICF to the ECF,
leading to a dilutional (i.e., translocational) hyponatremia. These are
the same osmotically active molecules that can cause isotonic hypona-
tremia, but when concentrations in the plasma exceed levels that can
be compensated for by shifts of water from the ICF, then hyperosmo-
lality occurs. Hyperglycemia decreases serum [Na1] by 1.6 mmol/L
for every 100 mg/dL increase in glucose above the normal 100 mg/dL
blood concentration. However, when the blood glucose concentration
is $400 mg/dL, serum [Na1] decreases by 2.4 mmol/L for every 100
mg/dL increase in glucose above normal. Thus, recalculation is
required to ascertain the actual serum [Na1] (23).
A blood glucose concentration should be checked in all hypo-
natremic patients to have an accurate assessment of serum [Na1]. If
the blood glucose concentration is normal, recent administration of
mannitol, sorbitol, glycerol, or radiographic contrast medium should
be considered.
in the urine when needed, and a maximum of 15 to 20 L of water
can be excreted daily in individuals with normal renal function and
maximum urinary dilution ability (e.g., Uosm 50 mOsm/kg H2O) if
solute intake is adequate (e.g., 600–900 mOsm/day).
Hyponatremia due to water intoxication can occur when very
large volumes (i.e., 15–20 L/day) of fluids are consumed. However,
insufficient solute intake can also lead to hypotonic hyponatremia.
Solutes responsible for driving renal free water excretion include
electrolytes, such as Na1 and K1, and urea (26). The excretion of
these solutes decreases when oral intake is reduced; therefore, if daily
solute intake is decreased, the ability of the kidney to excrete free
water is decreased as well. If solute intake is limited, the ingestion of
lesser amounts of water than 15 to 20 L/day can result in dilutional
hyponatremia because decreased renal free water excretion will cause
water retention.
Evaluation of hypotonic hyponatremia requires further investi-
gation to determine the cause (Figure 6) (27).

Hypotonic Hyponatremia (<280 mOsm/kg H2O). In patients Assess ECF Volume

with hypotonic hyponatremia, urine osmolality and electrolytes When there are obvious signs of increased ECF volume status (such
should be measured to rule out water intoxication or inadequate sol- as edema or ascites), then heart failure, cirrhosis, nephrotic syn-
ute intake. The kidney has a very high capacity to excrete free water drome, or renal failure should be excluded. Conversely, when
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 79

Hyponatremia
Serum [Na+] < 135 mmol per L

Symptomatic (e.g., confusion, ataxia, seizures, Asymptomatic or mild symptoms

obtundation, coma, respiratory depression) (e.g., headache, lethargy, dizziness)

Severe hyponatremia Determine Posm

Normal Low High

280 to 295 mOsm per kg H2O < 280 mOsm per kg H2O > 295 mOsm per kg H2O

Isotonic hyponatremia Hypotonic hyponatremia Hypertonic hyponatremia

(e.g., pseudohyponatremia)

Assess volume status Assess for hyperglycemia, check for

Assess for hyperproteinemia mannitol or sorbitol use or recent
or hyperlipidemia administration of radiocontrast media
Evaluate vital signs, orthostatics, jugular venous
pressure, skin turgor, mucous membranes, peripheral
edema, and blood urea nitrogen and uric acid concentrations

Hypovolemic (decreased total Euvolemic (increased total body water, Hypervolemic (increased total
body water and Na+ content) normal total body Na+ content) body water more than Na+ content)

Urine [Na+] usually > 20-30 mmol per L

Urine [Na+] Urine [Na+] Urine [Na+] Urine [Na+]

> 20-30 mmol per L < 20 mmol per L < 20 mmol per L > 20-30 mmol per L

Uosm Uosm Variable

Renal loss (e.g., Extrarenal loss > 100 mOsm per kg H2O < 100 mOsm per kg H2O Uosm Heart failure Renal failure
from diuretics or (e.g., from cirrhosis, nephrosis,
mineralocorticoid vomiting, diarrhea, hypoalbuminemia
deficiency) third spacing, or
Syndrome of Primary polydipsia,
bowel obstruction)
inappropriate anti- low solute intake Reset
diuretic hormone (beer potomania osmostat
secretion, hypo- syndrome)
thyroidism, adrenal
insufficiency,
stress, drug use

Figure 6. Algorithm for the evaluation of hyponatremia. The presence or absence of symptoms associated with hyponatremia should first be
assessed. Subsequently, Posm is measured to exclude both isotonic and hypertonic hyponatremia. If hypotonic hyponatremia is revealed, evaluate
the ECF volume status and proceed with the differential diagnosis of the hyponatremia. Abbreviations: ECF, extracellular fluid; kg H2O, kilo-
gram of water; L, liter; mOsm, milliosmoles; Posm, plasma osmolality; [Na1], sodium concentration; Na1, sodium ion; Uosm, urine osmolality.
Licensed under a Creative Commons License (CC BY NC ND). Reprinted with permission from reference 28 (Fenske W, St€ork S, Koschker
AC, Blechschmidt A, Lorenz D, Wortmann S, et al.: Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on
diuretics. J Clin Endocrinol Metab 93: 2991–2997, 2008).

obvious signs of decreased ECF volume status are present (such as
decreased BP or dry mucous membranes and skin), insufficient
intake (malnutrition), vomiting or diarrhea, loss of Na1 and K1
from the gastrointestinal tract or skin due to burns, loss from the
kidneys due to diuretics (natriuretics), and adrenal insufficiency
should be excluded. The syndrome of inappropriate antidiuretic
hormone (SIADH) secretion, mineralocorticoid-responsive hy-
ponatremia of the elderly, severe hypothyroidism, glucocorticoid
deficiency, hypopituitarism, and adrenal insufficiency should
be considered when there is no apparent increase or decrease in
ECF volume (i.e., the patient is euvolemic). Specific hormones
can be measured to confirm the diagnosis. Urine [Na1] of .20 to
30 mmol/L in the absence of external natriuretic administration is
suggestive of euvolemic hyponatremia. The cutoff value of urine
[Na1] .30 mmol/L is less useful when a patient is being given
exogenous natriuretics, but a diagnosis of SIADH can be made in
such patients if the fractional excretion of uric acid (FEUA) is $12%
(28).
80
Common Causes of Hyponatremia related to
Nonosmotic and/or Inappropriate AVP Release
In the sections below, we mainly focus on SIADH, drug-induced
hyponatremia, and iatrogenic hyponatremia, related to nonosmotic
and/or inappropriate AVP release.
Syndrome of Inappropriate Antidiuretic Hormone
Secretion versus Syndrome of Inappropriate Antidiuresis
SIADH was first reported by Schwartz et al. (29) in 1957 in a
patient with bronchogenic carcinoma as “A Syndrome of Renal
Sodium Loss and Hyponatremia Probably Resulting from Inappro-
priate Secretion of Antidiuretic Hormone.” Schwartz consulted with
F. C. Bartter, who was enrolled in the National Institutes of Health
(NIH) at the time, about a case of hyponatremia of unknown cause.
Coincidentally, Bartter had also observed a similar case. As a result
of this initial case report and collaboration, SIADH is also known as
the Schwartz-Bartter syndrome; the story of SIADH was the final
episode of “Milestones in Nephrology” in the Journal of the Ameri-
can Society of Nephrology (30). In SIADH, AVP secretion is not
suppressed despite hypotonicity and hyponatremia, and despite
euvolemic (normal ECF volume) status. Therefore, it is a disorder
that presents with hyponatremia caused by inappropriate antidiure-
sis. Potential causes are many and include central nervous system
diseases, lung diseases, ectopic AVP-producing tumors, and many
drugs. Although the exact epidemiology is unknown, hyponatremia
is present in 15% to 30% of all hospitalized patients (8,9,31,32),
suggesting that the number of patients with SIADH is potentially
quite large.
SIAD is a more general term for any conditions that present
with hypotonic hyponatremia due to body water retention caused
by insufficient free water excretion that is inappropriate for a low
Posm. This term is currently preferred over SIADH for several rea-
sons: (1) a substantial number of cases of SIADH have low AVP
concentrations, often below detection limits for AVP radioimmuno-
assay (see type D below), and (2) a genetic disease caused by an
AVP V2 receptor mutation that causes constitutive activation (gain-
of-function mutations) of the V2 receptor is indistinguishable from
SIADH by standard clinical criteria and has been termed nephro-
genic SIAD (33–35). This patient group does not basically respond
to the use of vasopressin receptor antagonists (vaptans) (35). There-
fore, as long as the same criteria are used for the diagnosis, SIADH
and SIAD are synonymous and can be used interchangeably. Four
types of abnormal AVP secretion have been described in patients
with SIAD (Figure 7) (4):
Type A: AVP fluctuates randomly independently of serum
[Na1].
Type B: There is a constant low amount of AVP that is
increased further in response to increased serum [Na1].
Type C: Osmoregulation is shifted to the left (reset osmostat).
Type D: AVP is actually undetectable or low, in low serum
[Na1].
Types A through C are found in approximately 30% of SIAD
cases and include most of the cases due to malignant tumors. Type
D is found in about 5% to 10% of SIAD cases, and the causes are
currently not understood (4).
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
12
Plasma AVP concentration (pg/ml)
Type C
8
Type A
4
Type B
Type D
0
120 130 140 150
Serum [Na+] (mmol/liter)
Figure 7. Types of arginine vasopressin (AVP) secretion in the syn-
drome of inappropriate antidiuresis. SIAD presents with hypotonic
hyponatremia due to body water retention caused by insufficient free
water excretion that is inappropriate for a plasma hypo-osmolality.
There are four types of SIAD. In type A, plasma AVP concentration
fluctuates randomly, independently of serum [Na1]. In type B, there
is a constant low amount of AVP that is increased further in response
to increased serum [Na1]. In type C, osmoregulation is shifted to
the left, meaning AVP is released despite of a lower set point of
plasma [Na1] for AVP secretion than in the normal state (reset
osmostat). In type D, AVP is actually undetectable or low, in low
serum [Na1]. Abbreviations: AVP, arginine vasopressin; mmol/l,
millimoles per liter; pg/ml, picograms per milliliter; SIAD, syn-
drome of inappropriate antidiuresis; [Na1], sodium concentration.
Reprinted with permission from reference 4 (Ellison DH, Berl T:
Clinical practice. The syndrome of inappropriate antidiuresis. N
Engl J Med 356: 2064–2072, 2007).
Drug-Induced Hyponatremia
Hyponatremia is the most frequently observed drug-induced water
and electrolyte abnormality. In some cases, hyponatremia is caused
by natriuretic agents such as thiazide diuretics, but the majority of
drug-induced hyponatremia is due to impaired urine dilutional abil-
ity by nonphysiologic (i.e., inappropriate) antidiuresis as a result of
stimulation of AVP secretion or enhancement of AVP effects in the
kidney. Specific examples include (1) increased AVP secretion from
the posterior pituitary, (2) enhanced AVP action in the renal
medulla, and (3) decreased AVP secretion threshold (reset
osmostat).
Hyponatremia caused by diuretics (natriuretics) such as thia-
zides is frequently associated with other acid–base imbalance and
electrolyte abnormalities. Diuretic-associated hyponatremia is espe-
cially common among outpatients. Among them, patients taking
thiazide are about 10 times more frequent than those taking loop
diuretics, and the hyponatremia usually develops within 2 weeks
after initiation of diuretic therapy (36). However, thiazide-induced
hyponatremia may take 17 to 19 days to develop after the initiation
of thiazide therapy (37). This is because thiazides act on the distal
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 81

Table 2. Pathophysiology and common drugs of drug-induced AVP-related hyponatremia

Increased AVP secretion from the posterior pituitary

Antidepressants: tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitor
Antipsychotics: phenothiazine, butyrophenone
Antiepileptic drugs: carbamazepine, sodium valproate
Antimalignant tumor drug, immunosuppressive drug: vinca alkaloid (vinca alkaloid, vinblastine), platinum preparation (cisplatin,
carboplatin), alkylating drugs (cyclophosphamide intravenous injection, melphalan, ifosfamide), others (methotrexate, interferon
a/g, pentostatin)
Narcotics: morphine
Psychoactive substances: 3,4-methylenedioxymethamphetamine “ecstasy”, amphetamine
Enhanced AVP action in the renal medulla
Antiepileptic drugs: carbamazepine, lamotrigine
Antidiabetic drugs: chlorpropamide, tolbutamide
Antimalignant tumor drug: alkylating drug (cyclophosphamide intravenous injection)
Nonsteroidal anti-inflammatory drugs
Decreased AVP secretion threshold (reset osmostat)
Antiepileptic drug: carbamazepine
Decreased urine dilutional ability in the renal dilutional segment and increased AVP production in the hypothalamus
Natriuretics: thiazide, indapamide, loop diuretics
Miscellaneous
Angiotensin-converting enzyme inhibitors, sulfamethoxazole-trimethoprim, immunoglobulin preparations, proton pump inhibitors,
amiodarone, theophylline, oral bowel preparation for colonoscopy

AVP, arginine vasopressin.

tubules of the renal cortex and do not interfere with the formation
of interstitial osmotic gradients. Risk factors for drug-induced hypo-
natremia include older age, female sex, low body weight, low-
sodium diet, and concomitant use of drugs that affect water balance.
Drugs that cause hyponatremia are listed in Table 2. They
include angiotensin-converting enzyme (ACE) inhibitors, narcotics
(amphetamine, 3,4-methylenedioxymethamphetamine, immunoglob-
ulin preparations, sulfamethoxazole-trimethoprim, proton pump
inhibitors, theophylline, and amiodarone (38).
Hyponatremia is a commonly reported adverse effect associ-
ated with immune checkpoint inhibitors (ICIs), which have
become widely used in cancer immunotherapy in recent years
(39,40). In a recent review of 2458 patients who received ICIs,
62% experienced hyponatremia (defined as serum [Na1] ,134
mmol/L) during the first year of treatment, and 6% had severe
hyponatremia (defined as serum [Na1] ,124 mmol/L) (40). The
mechanism underlying the ICI-induced hyponatremia varies.
Because hypopituitarism or adrenal insufficiency may occur with
ICIs, hyponatremia may be caused by cortisol deficiency in some
cases. Hypopituitarism due to ICIs has been reported in all anti-
cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), anti-
programmed cell death 1 (PD-1), and antiprogrammed death
ligand 1 (PD-L1) antibodies, but it is especially common with
the use of anti-CTLA-4 antibodies (41–43). Hyposecretion of
ACTH causes hypocortisolism, which leads to impaired free
water excretion resulting from the effects on both AVP secretion
and renal water retention (44). Primary adrenal insufficiency due
to ICIs has been reported in all treatments with anti-CTLA-4,
anti-PD-1, and anti-PD-L1 antibodies, but the frequency is
reported to be only 0.7% in patients with these drugs, which is
considered to be a rare side effect (41). In the observational study
cited above (40), only nine cases of severe hyponatremia were
believed due to endocrinopathies, all of which resulted from sec-
ondary adrenal insufficiency. SIADH and volume disturbances
were diagnosed in 35% and 20% of severe hyponatremia cases,
respectively. Risk factors for hyponatremia included use of
CTLA-4 inhibitor, use of diuretics, and non-white race.
Iatrogenic Hyponatremia
A decrease in serum [Na1] indicates a decrease in effective osmolality
(tonicity), with a few exceptions. Normally, when Posm decreases,
thirst is naturally suppressed, and AVP secretion is also suppressed so
as to produce a dilute urine, which assists in maintaining Posm within
normal ranges. Within this physiologic construct, in order to cause
hyponatremia, there must be (1) abnormal urine dilutional ability
and (2) abnormal water intake or administration (i.e., drinking more
than is needed to maintain normal Posm).
The administration of exogenous hypotonic solutions during
hospitalization is an important cause that doesn’t occur during
normal life. In addition, nonosmotic AVP secretion may be
increased as a result of various physical and mental stresses during
hospitalization, which can be an important factor in the onset of
hyponatremia. Many inpatients are exposed to pain, vomiting, stress,
and various drugs, all of which can cause nonosmotic AVP secretion.
When hypotonic fluids are administered as maintenance infusions,
or when parenteral or enteral feedings are given, the free water con-
tent may exceed renal excretion ability, resulting in hyponatremia.
All infusion and nutritional therapies should be selected with consid-
eration of body fluid status, and it is necessary to review, on a daily
basis, whether the infusion is appropriate for body fluid homeostasis.
82
Symptoms and Adverse Outcomes of Hyponatremia
Patients with acute hyponatremia, especially when complicated by
severe neurologic symptoms, face a threat to life because of cerebral
edema and brain herniation; therefore, aggressive therapeutic inter-
vention is necessary. Chronic hyponatremia is often considered to
be asymptomatic; consequently, it is frequently not treated effec-
tively. However, in recent years, it has been understood that even
mild chronic hyponatremia can lead to gait instability, falls, frac-
tures, decreased quality of life, and worsening overall prognosis.
Acute Hyponatremia
Acute hyponatremia causes cerebral edema, and patients present
with neurologic symptoms resulting from central nervous system
injury. Symptoms related to acute hyponatremia depend on its
severity and rate of progression and include headache, malaise, nau-
sea, vomiting, confusion, convulsions, impaired consciousness, and
coma (hyponatremic encephalopathy) (5,6). Generally, when the
serum [Na1] is $125 mmol/L, there are no severe symptoms
(sometimes headache, vomiting, or memory impairment as mild to
moderate symptoms). However, at 120 to 125 mmol/L, confusion
and loss of appetite appear, and when serum [Na1] drops to 115 to
120 mmol/L, restlessness or somnolence may be observed. Life-
threatening symptoms such as convulsions and coma can occur
when serum [Na1] is ,115 mmol/L. However, it is important to
note that not only the absolute value of serum [Na1], but also the
rate of decrease in serum [Na1] has a significant impact on the
onset of symptoms and outcomes of hyponatremia. For example, an
acute fall in serum [Na1] to ,125 mmol/L has caused fatal brain
edema (e.g., marathon). Mortality rates of 30% for serum [Na1] of
115 to 120 mmol/L and .50% for serum [Na1] of ,115 mmol/L
have been reported (45).
Chronic Hyponatremia
Chronic hyponatremia neither results in cerebral edema nor causes
neurologic symptoms because of the ability of the brain to regulate
its volume by excretion of electrolyte and organic solutes (46,47).
However, as noted above, cognitive dysfunction such as attention
deficits and neurologic symptoms, including gait instability, have
been observed in patients with chronic hyponatremia considered to
be asymptomatic, and the risk of falls and fractures is increased in
such patients. Renneboog et al. (48) reported that gait stability was
reduced and the odds ratio of falls was as high as 67 times in
patients with relatively mild chronic hyponatremia with an average
serum [Na1] of 126 mmol/L. Verbalis et al. (49) demonstrated that
hyponatremia is associated with significantly increased odds of osteo-
porosis using cross-sectional human data, and that hyponatremia
markedly reduced bone mass via increased bone resorption using a
rat model of SIAD. Notably, the group showed that sustained low
ECF [Na1] directly stimulated osteoclastogenesis and that
hyponatremia-induced oxidative stress is involved in the mechanism
(49). The Rotterdam study, a population-based cohort study includ-
ing 5208 individuals who had serum [Na1] assessed at baseline,
found that hyponatremia was associated with an increased risk of
nonvertebral fractures after adjustment for age, sex, and body mass
index (hazard ratio, 1.39). In the fully adjusted model, hyponatre-
mia was also associated with an increased risk of vertebral fractures
(odds ratio, 1.78) and with significantly higher cumulative mortality
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
4 Acute hyponatremia (<48 hours) is associated
with cerebral edema and neurologic symptoms
including headache, malaise, nausea, vomiting,
confusion, convulsions, impaired consciousness,
and coma (hyponatremic encephalopathy).
4 Chronic hyponatremia (48 hours) is associated
with cognitive impairment, gait instability, osteo-
porosis, falls, fractures, decreased ADL, and
increased mortality.
(hazard ratio, 1.21) (50). Decreased bone mineral density may be
one of the causes of an increased risk of fractures associated with
hyponatremia.
Additionally, patients who were admitted to the hospital with
moderate hyponatremia, defined as a serum [Na1] ,130 mmol/L,
were more than seven times more likely to die in the hospital than
were control patients (51). Thus, chronic hyponatremia is associated
with various complications, including cognitive impairment, gait
instability, osteoporosis, falls, fractures, decreased activities of daily
living (ADL), and increased mortality (52).
Treatment of Hyponatremia
Treatment goals differ according to the time course and symptoms
of hyponatremia. Currently, there are no evidence-based uniform
standardized guidelines for treatment of hyponatremia. Many pub-
lished guidelines are, in fact, based on expert opinion derived from
observational or clinical studies with small sample sizes. Further-
more, the Hyponatremia Registry revealed that 21.6% of hyponatre-
mic patients were untreated for hyponatremia, suggesting a lack of
insight or concern about this condition (53).
It is relevant to ask why hyponatremia goes untreated so fre-
quently. First, hyponatremia is a very heterogeneous condition,
and its various causes, symptoms, and difficulty in determining
the true ECF volume status together make it challenging to arrive
at a definitive diagnosis that leads to effective treatment. Second,
there is less confidence on the magnitude of the impact of treat-
ing hyponatremia on clinical outcomes. Third, there is fear that
overly rapid correction of hyponatremia will lead to increased
risk of the osmotic demyelination syndrome (ODS), which is
described later. Finally, there are limited treatment options for
hyponatremia that have sufficient evidence-based data to verify
their effectiveness and safety (54).
Current Recommendations Regarding Rate of Serum
[Na1] Correction
When hyponatremia occurs, both electrolytes and organic osmolytes
begin to move from the inside to the outside of the brain cells as a
protection mechanism to prevent cerebral edema. Studies in both
experimental animals and humans suggest that this process is usually
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
complete after 48 hours (6). Therapeutic recommendations differ
depending on the time course (acute/chronic) and symptoms (symp-
tomatic/asymptomatic), the urgency of treatment, the degree of
serum [Na1] to be corrected, and the upper limit of the correction.
It is extremely important that serum [Na1] must be increased rap-
idly in acute/symptomatic hyponatremia, whereas serum [Na1]
should not be increased rapidly in chronic/asymptomatic hyponatre-
mia for reasons discussed below.
Symptoms of hyponatremic encephalopathy (i.e., symptoms
associated with cerebral edema) are observed in acute hyponatremia
and need to be treated (5,6). Higher-risk groups for hyponatremic
encephalopathy include children, premenopausal women, postopera-
tive patients, patients with central nervous system disorders, patients
with lung disease, and hypoxemic patients (55). Recent reports have
suggested that increased intracranial pressure may stimulate nonos-
motic AVP release (56), indicating that an increase in intracranial
pressure itself might lead to further exacerbation of hyponatremia.
Immediate correction of serum [Na1] is needed in such cases to
avoid the life-threatening consequences of tentorial brain herniation
and irreversible brain damage. A small, quick increase in the serum
[Na1] (2–5 mmol/L) is effective in treating acute hyponatremia,
because reducing cerebral edema will substantially decrease intracere-
bral pressure (57). Studies have shown that increasing serum [Na1]
by 5 mmol/L reduces intracranial pressure by 50% (58).
Expert panel recommendations and consensus guideline were
published in the United States (5) and Europe (6), respectively.
According to the United States expert panel recommendations,
 For severe symptoms, 100 mL of 3% NaCl infused intrave-
nously over 10 min 3 3 as needed.
 For mild to moderate symptoms with a low risk of herniation,
3% NaCl infused at 0.5 to 2 mL/kg per hour.
The rate of correction should not be restricted in patients with
true acute hyponatremia (defined as a duration ,48 hours), nor is
the re-lowering of excessive corrections indicated; however, if there
is any uncertainty as to whether the hyponatremia is chronic versus
acute, then the upper limits for correction of chronic hyponatremia
should be followed (discussed below).
A recent prospective study from Ireland reported that
patients with symptomatic hyponatremia due to SIAD were cor-
rected more quickly when treated with 3% NaCl bolus infusions
than were those treated with conventional continuous intrave-
nous infusions of 3% NaCl. Most importantly, a more rapid
improvement in the Glasgow Coma Scale score was also observed
in patients treated with boluses of 3% NaCl. Also of note, four
deaths occurred in the continuous intravenous infusion group,
whereas no deaths occurred in the bolus infusion group (59). If
the death of these four patients was due to hyponatremia, it can
be inferred that more immediate correction of severely symptom-
atic hyponatremia is critically important.
In the SALSA randomized clinical trial, published recently
from the Republic of Korea, both continuous intravenous infusion
and bolus infusions of 3% NaCl were reported to be effective and
safe treatments for symptomatic hyponatremia. In contrast to the
study from Ireland, larger volumes were used for the 3% NaCl
boluses (150 mL versus 100 mL), which resulted in higher rates of
re-lowering of serum [Na1] to prevent overly rapid correction of
hyponatremia (60).
83
From the results of both the Republic of Korea and the Ireland
studies, and as recommended in the United States expert panel rec-
ommendations and the EU guideline, bolus infusion of 3% NaCl
for acute hyponatremia with severe symptoms is considered both
safe and more effective than continuous infusions (Table 3). How-
ever, the data from both studies favors treatment using the smaller-
volume boluses recommended by the United States expert panel. It
is interesting to note that the United States expert opinion panel
recommendations were based on practical experiences with treat-
ment of exercise-associated hyponatremia (EAH). EAH is a com-
mon cause of acute/symptomatic hyponatremia, sometimes with
poor outcomes resulting from cerebral edema and brain herniation.
EAH occurs when exertion results in serum [Na1] ,135 mmol/L,
and symptoms can present up to 24 hours after physical activity.
Upon screening, #5% to 30% of asymptomatic ultramarathon run-
ners experience hyponatremia by the end of the event. The usual
cause of EAH is overhydration with hypotonic fluids such as water
or sports drinks; however, nonosmotic and inappropriate AVP secre-
tion caused by pain, stress, exercise, nausea, and hypoglycemia can
predispose to EAH. Severe EAH should be rapidly treated with 100
mL bolus infusion of 3% NaCl over 10 min, which can be repeated
every 30 min, as necessary, for a total of no more than three doses,
which can be repeated every 10 minutes for a total of three boluses.
These doses increase serum [Na1] by 2 to 5 mmol/L and do not
increase the risk of ODS, because this is an acute hyponatremia
(Figure 8) (5).
The situation for patients with chronic/asymptomatic hypona-
tremia is different from that for patients with acute/symptomatic
hyponatremia. Patients with a more chronic hyponatremia (defined
as $48-hour duration) and mild or no neurologic symptoms are at
little immediate risk from complications arising from the hyponatre-
mia itself, but they can experience ODS after overly rapid correction
of serum [Na1]. There is no indication to rapidly correct the serum
[Na1] in these patients, and slower-acting therapies such as fluid
restriction or discontinuation of drugs that limit free water excretion
should be used with correction of serum [Na1] during a 48- to
72-hour period. Although these situations have reasonably clear
treatment indications, most patients have hyponatremia of unknown
duration and varying degrees of neurologic impairment. This group
presents the most challenging treatment decision because hyponatre-
mia is sufficiently long to allow some degree of brain volume
regulation but is not long enough to prevent cerebral edema and
neurologic symptoms. Most authors recommend prompt treatment
for such patients because of their symptoms, but with methods that
allow a controlled and limited correction of their hyponatremia.
Reasonable correction parameters consist of a rate of correction of
serum [Na1] that results in a total magnitude of correction that
does not exceed 10 to 12 mmol/L during the first 24 hours and 18
mmol/L throughout the first 48 hours of correction (5). However,
the correction goal should be set lower than the limit (i.e., 6–8
mmol/L) to reduce the chance of exceeding the upper limit. If the
correction upper limit is exceeded, consideration should be given to
the administration of hypotonic fluid (e.g., dextrose 5% in water
[D5W]) to bring the correction magnitude back to the upper limit
(Figure 8) (5).
However, the maximum correction rates should be even lower
(no more than 8 mmol/L in 24 hours) if risk factors for the develop-
ment of ODS are present, including alcoholism, liver disease,
84 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Table 3. United States recommendations and European Union guideline for the treatment of hyponatremia.

Subject United States Recommendations European Union Guideline

Acute/symptomatic hyponatremia
Severe symptoms Severe symptoms
Bolus 3% NaCl (100 mL over 10 min 3 3 Bolus 3% NaCl (150 mL over 20 min 3
as needed) 2–3 as needed)
Moderate symptoms Moderate symptoms
Continuous infusion 3% NaCl Bolus 3% NaCl (150 mL over 20 min
(0.5–2 mL/kg/h) once)
Chronic/mild symptomatic hyponatremia
SIAD Fluid restriction (first line) Fluid restriction (first line)
Demeclocycline, urea, or vaptans (second Urea or loop diuretics 1 oral NaCl
line) (second line)
Do not recommend or recommend
against vaptansa
Recommend against lithium or
demeclocycline
Hypovolemic hyponatremia Normal (Isotonic) saline Normal (Isotonic) saline or balanced
crystalloid solution
Hypervolemic hyponatremia Fluid restriction Fluid restriction
Vaptansb Recommend against vaptans
Correction rates Minimum Minimum
Dserum [Na1] 148 mmol/L/d None
Dserum [Na1] 146 mmol/L/d Limit
(high risk of ODS) Dserum [Na1] 110 mmol/L/d
Limits
Dserum [Na1] 11012 mmol/L/d
Dserum [Na1] 18 mmol/L/d
(high risk of ODS)
Management of overly rapid correction Baseline serum [Na1] 120 mmol/L Start once limit is exceeded
Probably unnecessary Consult an expert to discuss infusion
Baseline serum [Na1] <120 mmol/L containing electrolyte-free water
Start re-lowering with electrolyte-free (10 mL/kg BW) with or without 2 mg
water or desmopressin after correction desmopressin IV
exceeds Dserum [Na1] 168 mmol/L/d

Reprinted with permission from reference 3 (Hoorn EJ, Zietse R: Diagnosis and treatment of hyponatremia: Compilation of the guidelines. J Am Soc Nephrol 28: 1340-1349,
2017). BW, body weight; IV, intravenous; ODS, osmotic demyelination syndrome; SIAD, syndrome of inappropriate antidiuresis.
a
Do not recommend when serum [Na1] is <130 mmol/L; recommend against when serum [Na1] is <125 mmol/L.
b
In liver cirrhosis, restrict to patients where potential benefit outweighs risk of worsened liver function.

malnutrition, hypokalemia, and a very low serum [Na1] (#105
mmol/L) (5). In such cases, goals should be commensurately lower
(i.e., 4–6 mmol/L), and if the correction rate exceeds the upper lim-
its, water should be administered, with or without desmopressin, to
bring the correction magnitude back to the upper limit (Figure 8)
(5). Recent studies have verified that ODS is uncommon even in
patients corrected for .8 mmol/L per 24 hours (0.5% of patients
with a serum [Na1] #120 mmol/L), but this complication occurred
more frequently in patients with hypokalemia and chronic alcohol-
ism (e.g., beer potomania) (31).
It follows from these recommendations that serum [Na1]
must be carefully monitored at frequent intervals during the
active phases of treatment (every 2 to 4 hours for 3% NaCl
administration; every 6 to 8 hours for vasopressin antagonist
administration) to adjust therapy so that the correction stays
within the desired upper limits. It cannot be emphasized enough
that it is necessary to correct the serum [Na1] acutely only to a
safe range rather than to normal concentrations. As a practical
point, after an acute correction has reached 8 mmol/L, the need
for continued acute therapy should be carefully assessed, because
ongoing correction may result in an overly rapid correction by
the time the next serum [Na1] is available. In some situations,
patients may spontaneously correct their hyponatremia via water
diuresis (aquaresis). If the hyponatremia is acute (e.g.,
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
4 Acute hyponatremia (<48 hours) with severe symp-
toms should be treated with 100 mL of 3% NaCl
infused intravenously over 10 min 3 3 as needed.
Patients with mild to moderate symptoms may be
treated with 3% NaCl infused at 0.5 to 2 mL/kg per
hour with the goal of increase of 6 to 8 mmol/L. The
rate of correction of chronic hyponatremia (48
hours) should be targeted to correct 6 to 8 mmol/L,
and the correction rate should be no greater than 10
to 12 mmol/L for the first 24 hours.
4 The rate should be lower (4 to 6 mmol/L) for indi-
viduals with risk factors for ODS such as alcohol-
ism, liver disease, malnutrition, hypokalemia, and
starting serum [Na1] <105 mmol/L.
psychogenic polydipsia with water intoxication), such patients do
not appear to be at risk for ODS. However, if hyponatremia is
chronic (e.g., hypocortisolism, natriuretic therapy), intervention
should be considered to limit the magnitude of correction of
serum [Na1], such as the infusion of hypotonic fluids to match
urine output and/or the administration of desmopressin 1 to 2
mg intravenously every 8 hours, using the same therapeutic end-
points as for active corrections.
Osmotic Demyelination Syndrome
Central pontine myelinolysis was first reported in 1959 by Adams et al.
(61). Originally thought to be produced by malnutrition and alcohol-
ism, central pontine myelinolysis was later found to be also produced
by rapid increases in Posm and was called the ODS (62). Clinical find-
ings of ODS can appear 1 to 7 days after treatment of chronic hypo-
natremia. Neurologic findings typically show a biphasic pattern:
1. When serum [Na1] rises, the symptoms caused by hyponatre-
mia improve.
2. Following that, new and more severe symptoms of ODS
appear.
Paradoxically, the patient's condition worsens despite the
improvement of electrolyte abnormality. Thus, ODS is a clinical
syndrome consisting of biphasic findings after treatment for hypona-
tremia (63). Symptoms of the second phase of ODS include dysar-
thria, dysphagia, pseudobulbar palsy (pyramidal tract disorder),
initial flaccid limb palsy, and later transition to spastic limb palsy
(corticospinal tract disorder). However, if the site of injury extends
to the pontine tegmentum, it can cause pupillary abnormalities and
ocular motility disorders. In more severe cases, the patient becomes
completely paralyzed and unable to communicate, resulting in a
so-called locked in syndrome. The hypothesized pathophysiology is
shown in Figure 9 (64).
High-risk patients with ODS include serum [Na1] of #105 mmol/
L, hypokalemia, alcoholism, malnutrition, liver disease, older age, and use
85
20
18
Re-lowering Re-lowering Re-lowering
16 unnecessary optional recommended
Change in serum [Na+]
14
in first 24 h, mmol/L
12
10
8
6 Goal
Goal
4
2
0
Acute water
intoxication
Low to moderate
risk of ODS
High
risk of ODS
Figure 8. Goals and limits for correction of hyponatremia. The rate
of correction need not be restricted in patients with true acute hypo-
natremia, nor is re-lowering of excessive corrections indicated. Thera-
peutic re-lowering of serum [Na1] is suggested if the correction
exceeds therapeutic limits in patients with low to moderate risk of
ODS, and is recommended in patients with high risk of ODS. Green
lines indicate the treatment goals for the correction of hyponatremia
and Red lines and dashed lines indicate the recommended upper limits
to avoid the risk of ODS in patients presenting with serum [Na1]
,120 mmol/L who exceed the recommended upper limits of
correction in the first 24 hours. Abbreviations: h, hour; mmol/L,
millimoles per liter; [Na1], sodium concentration; ODS, osmotic
demyelination syndrome. Reprinted with permission from reference
5 (Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier
RW, Sterns RH, et al.: Diagnosis, evaluation, and treatment of hypo-
natremia: Expert panel recommendations. Am J Med 126[Suppl 1]:
S1–S42, 2013).
of thiazide diuretics (5). As can be seen from the Edelman equation, serum
[Na1] is affected by total body K1 in addition to Na1. Therefore, it
should be remembered that the rapid replacement of K1 in patients with
hypokalemia may also result in overly rapid correction of the serum
[Na1] (65).
Overly Rapid Correction of Serum [Na1]: Risks
and Prevention
There is a risk that serum [Na1] will be overly rapidly corrected
when the cause of increased AVP secretion improves. Inappropriate
AVP secretion results in insufficient excretion of free water into the
hypertonic urine, and serum [Na1] remains low. However, if AVP
secretion is decreased as the underlying condition improves, a large
amount of free water is excreted in the urine, and serum [Na1] may
rise rapidly. That is, overly rapid correction can result from an unex-
pected excretion of dilute urine (decrease in urine tonicity) with
resultant increased urine volume. When AVP secretion is decreased
to a level that allows excretion of maximally dilute urine (Uosm
,100 mOsm/kg H2O), serum [Na1] can rises at a rate exceeding
2 mmol/L per hour (63).
Consequently, when urine tonicity decreases and urine volume
increases, it is necessary to monitor urine volume and blood/urine
86 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Hyponatremic brain
Decrease in organic osmolyte content
Decrease in protein-folding abilities
Overly rapid correction of hyponatremia

Brain dehydration (Sodium “overshoot”)

Increase in Na+ content and ionic strength

Increase in brain protein aggregate

Increase in astrocyte unfolded protein response
Excessive activation of ER stress

Combined gliosis and astrocyte death Oligodendrocyte death

(apoptosis, necroptosis) Microglial activation
Disruption of astrocyte – oligodendroglial syncitium Brain inflammation and BBB damage

BBB damage
Demyelination

Figure 9. Potential pathophysiology of osmotic demyelination after overly rapid correction of chronic hyponatremia. The schema illustrates the
potential pathophysiology of osmotic demyelination based on current data. Overly rapid correction of chronic hyponatremia induces protein
aggregation in astrocytes, along with unfolded protein response (conformational disorder) and an exaggerated endoplasmic reticulum stress that
leads to astrocyte death. These responses occur in regions susceptible to demyelination before any histologic evidence of myelin damage. Astro-
cytes not only provide trophic support to oligodendrocytes but also are required for maintenance of normal myelin; therefore, astrocyte death is
linked to myelin disruption. Abbreviations: BBB, blood–brain barrier; ER, endoplasmic reticulum. Licensed under a Creative Commons License
(CC BY NC ND). https://creativecommons.org/licenses/by-nc-nd/4.0/ Reprinted with permission from reference 64 (Gankam Kengne F, Dec-
aux G: Hyponatremia and the brain. Kidney Int Rep 3: 24–35, 2017).

analysis more frequently to anticipate subsequent increases in serum
[Na1]. Intravenous desmopressin 2 mg should be considered to stop
free water excretion if the daily upper correction limit for serum [Na1]
is likely to be exceeded. An example is a patient with severe hyponatre-
mia due to volume depletion who may be at risk for overly rapid cor-
rection once volume is restored. In such patients, an acute increase in
output of diluted urine may signal the risk of overly rapid correction.
Another example is a patient regularly taking drugs that potentially pro-
mote AVP secretion from the posterior pituitary and/or enhance AVP
effect in the renal collecting ducts. In such patients, discontinuation of
those drugs can lead to an increase of free water excretion from the kid-
neys, resulting in overly rapid correction of hyponatremia.
In the event of overly rapid correction, 5% glucose solution
(D5W) should be administered and serum [Na1] should be
re-lowered quickly to the original target upper limits, but it may be
difficult to decrease the increased serum [Na1] if only D5W is
administered. In such a case, desmopressin administration should be
considered as per the United States expert opinion recommendations
(5). The protocol of pre-emptive administration of desmopressin
every 6 to 8 hours in combination with a slow infusion of 3% saline
titrated to achieve a 6-mmol/L per day increase in serum [Na1] advo-
cated by Sterns et al. (66) is useful in the treatment of patients with
potentially reversible causes of hyponatremia along with an unpredict-
able aquaresis. This strategy intentionally creates a state of iatrogenic
SIAD and permits a controlled increase in the serum [Na1] with a
low risk of inadvertent overly rapid correction of serum [Na1]; des-
mopressin can be discontinued once the serum [Na1] has been
increased to a safe concentration (generally to 128 mmol/L (66)).
Regarding the need for re-lowering according to risk factors for the
development of ODS, maximum correction limits are shown in the
2013 United States expert panel recommendations (Figure 8) (5).
In the clinical practice of treatment of symptomatic hyponatre-
mia, it is most important to first understand the risk factors for ODS,
then to anticipate the possibility of a rapid decrease of AVP secretion
in the treatment course, and finally to achieve increases in serum
[Na1] to the target range by frequently checking the serum [Na1]
and fine-tuning the treatment parameters as necessary.
Conventional, Specific, and Potential Future Treatment
Options for Hyponatremia
To date, there is surprisingly little scientific evidence to support the
usual clinical treatments for hyponatremia in daily clinical practice.
From this point of view, we describe the following therapies, includ-
ing a few recent randomized controlled trials.
Fluid Restriction. In general, fluid restriction has been the first-line
treatment for hyponatremia with mild to moderate reduced serum
[Na1], regardless of the underlying cause. However, fluid restriction
commonly has a delayed onset of effect, hinders treatment of
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
underlying disease(s) by other infusion therapies, and can impair the
patient’s quality of life because of increased thirst (6). Although fluid
restriction is still identified in published guidelines as the first-line
therapy for mild to moderate hyponatremia secondary to SIAD (6),
the treatment was ineffective in more than half of the cases in the
United States and European Hyponatremia Registry (67).
In 2020, Garrahy et al. (68) investigated the efficacy of fluid
restriction compared with that of no specific treatment in a prospective
randomized controlled trial (RCT). Forty-six patients with chronic
moderate hyponatremia due to SIAD were divided into two groups:
(1) 1.0 L/d fluid restriction or (2) no specific treatment; and plasma
[Na1] at days 4 and 30 were compared. On day 4, plasma [Na1]
increased by 3 mmol/L (IQR 2–4) after 3 days of fluid restriction,
compared with 1 mmol/L (IQR 0–3) no specific treatment
(P50.005). There was minimal additional rise in plasma [Na1] by
day 30; at day 30, median plasma [Na1] increased from baseline by 4
mmol/L (IQR 2–6) with fluid restriction, compared with 1 mmol/L
(IQR 0–1) with no specific treatment (P50.04). After 3 days, 17% of
patients with fluid restriction had a rise in plasma [Na1] of
$5 mmol/L, compared with 4% with no specific treatment (RR, 4.0;
95% CI, 0.66 to 25.69; P50.35). After 3 days, 61% of fluid restric-
tion corrected plasma [Na1] to $130 mmol/L, compared with 39%
of no specific treatment (RR, 1.56; 95% CI, 0.87 to 2.94; P50.24).
Although fluid restriction was “statistically” more effective than no spe-
cific treatment in the plasma [Na1] rise at some time points, there was
not a great difference with respect to absolute increases in serum
[Na1], supporting previous retrospective observational studies that
fluid restriction might not be adequate for the treatment of chronic
hyponatremia in the majority of cases of SIAD (68).
Furosemide with NaCl in Combination with Fluid Restriction.
In the EU hyponatremia guideline, the administration of loop diu-
retics with oral NaCl is recommended as a second-line therapy for
chronic SIAD (6). The use of loop diuretics with high NaCl intake
represents an extension of treatment of acute/symptomatic hyponatre-
mia using 3% NaCl administration (69) to long-term management of
chronic hyponatremia. Successful cases have been reported (70).
However, the effectiveness of this approach in chronic hypona-
tremia is limited by a scarcity of evidence to prove the efficacy of
this approach for long-term treatment. Krisanapan et al. (71)
recently reported an open-label RCT (the EFFUSE-FLUID trial) on
the efficacy of three conventional treatments for chronic moderate
and severe hyponatremia. Ninety-one patients with serum [Na1]
#130 mmol/L due to SIAD were divided into three groups: (1)
fluid restriction, (2) fluid restriction 1 loop diuretic, and (3) fluid
restriction 1 loop diuretic 1 NaCl supplement; changes in serum
[Na1] on days 4, 7, 14, and 28 were compared. On day 28, it was
5.7 6 4.7, 7.8 6 7.2, and 8.6 6 7.8 mmol/L among the three
groups, respectively, indicating that there was no significant differ-
ence in efficacy among the groups (71). These data therefore
question the usefulness of this approach for treatment of chronic
moderate and severe hyponatremia.
Vasopressin Receptor Antagonists. Vasopressin V2 receptor antag-
onists (“vaptans”) bind to AVP V2 receptors in the renal collecting
ducts, thereby blocking water reabsorption and promoting
electrolyte-free water excretion (aquaresis) (72). The only high-
quality evidence for the effective treatment of hyponatremia has
87
been the placebo-controlled RCT of the vasopressin receptor
antagonist tolvaptan. In a study in which tolvaptan was adminis-
tered to patients with hyponatremia for 30 days (SALT-1, SALT-2
study), serum [Na1] increased from 128.5 mmol/L by approxi-
mately 7 mmol/L after 30 days (73). Furthermore, the efficacy and
safety of tolvaptan were confirmed in the SALTWATER open-label
extension study, in which tolvaptan was administered safely for an
average of approximately 700 days (74).
Urea. Urea has been identified as an alternative oral treatment for
SIAD and other diseases that cause hyponatremia. The main mecha-
nism of action of urea is to trigger solute-induced osmotic diuresis (75).
Reports from retrospective uncontrolled studies suggest that
urea is effective in treating SIAD in patients with hyponatremia due
to subarachnoid hemorrhage and in patients undergoing critical care
(76). In addition, recent evidence from a short-term study of a small
cohort of patients with SIAD suggests that urea has an efficacy
equivalent to that of vaptans in correcting hyponatremia due to
chronic SIAD (70). A retrospective study compared 12 patients with
SIAD-related hyponatremia (plasma [Na1] ,130 mmol/L) who
received urea to 12 matched patients who did not receive urea
(6 received NaCl tablets; 3 received potassium chloride (KCl);
2 received loop diuretics; 1 received a vasopressin antagonist, and
1 received hypertonic saline). Urea-treated patients had a greater
increase in plasma [Na1] (2.5 vs 20.5 mmol/L) at 24 hours but no
change over full course of treatment or length of hospital stay (77).
These reports suggest that urea may be an acceptable alternative
therapy for the treatment of chronic hyponatremia, but RCTs will
be required to show adequate scientific justification for the efficacy
and safety of this treatment for hyponatremia due to SIAD.
Sodium-Glucose Cotransporter-2 Inhibitors in Combination
with Fluid Restriction. Sodium-glucose cotransporter-2 (SGLT2)
inhibitors are the newest class of oral antihyperglycemic agents that
have been approved for the treatment of diabetes mellitus. SGLT2
inhibitors promote osmotic diuresis by increasing urinary glucose
excretion, leading to increased free water excretion.
Refardt et al. (78) investigated the efficacy of an SGLT-2 inhibi-
tor in the treatment of hyponatremia. Eighty-eight inpatients with
SIAD-induced moderate/severe hyponatremia (,130 mmol/L), in
addition to fluid restriction (,1000 mL/day), were assigned to either
orally administered empagliflozin or placebo daily for 4 days. Patients
treated with empagliflozin showed a significantly higher delta median
plasma [Na1] than did patients receiving placebo (10 versus 7
mmol/L; P50.04, respectively). Additionally, the treatment was well
tolerated, and no hypoglycemic or hypotensive events occurred in
patients receiving empagliflozin. This finding suggests that SGLT-2
inhibitors may be a potential treatment option for hyponatremia
(78), but as for many other therapies, larger randomized clinical trials
to verify efficacy and safety of this approach are lacking.
Conclusion
For current treatment recommendations of hyponatremia, the sever-
ity of neurologic symptoms and the time course of the hyponatremia
are of importance in the appropriate selection of treatment strategies
regardless of the underlying cause. The recommendations for treat-
ment are intended to be generalizable, but most of them lack
88
rigorous evidence-based proof, i.e., double-blinded randomized
placebo-controlled studies. Most importantly, therapy of hyponatre-
mia must always be individualized to the patient being treated.
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90
Article
Pathophysiology, Evaluation, and Treatment
of Hypernatremia
Solomiia Savedchuk, MD, and Ruediger W. Lehrich, MD
Duke University Medical Center, Department of Medicine, Division of Nephrology, Durham, North Carolina
Learning Objectives
1. To discuss recent advances in the physiology that governs
osmoregulation and thirst
2. To describe the incidence, risk factors, and prognostic value of
hypernatremia
3. To review recent advances in the diagnostic approaches to and
treatment of hypernatremia and diabetes insipidus
Physiology of Osmoregulation, Thirst, and Urinary
Concentration
Hypernatremia is defined as a serum sodium concentration ([Na1])
.145 mmol/L. In clinical practice this occurs from a loss of
electrolyte-free water, a loss of hypotonic fluid, or a gain of hyper-
tonic fluid (1). Overall control of water balance is achieved by the
regulation of several behavioral and physiologic responses orches-
trated to maintain the volume and osmolarity of extracellular fluid
near an ideal set point. If such behavioral and physiologic responses
are impaired, hypernatremia develops. The two main physiologic
principles that govern water and sodium homeostasis are thirst and
urinary concentration.
Regulation of Thirst
Thirst is the major behavioral regulator of water intake. Similar to
any other behavioral response, it involves complex neuronal interac-
tion. Understanding of these interactions originated in the 1950s
with Bengt Anderson, who discovered that the infusion of hyper-
tonic saline solution into the anterior hypothalamus of goats stimu-
lated drinking and water retention (2). Subsequent studies identified
the anterior wall of the third ventricle as crucial in its role to pro-
voke thirst. The foremost brain structure responsible for sensing and
regulating internal water balance within this region is the lamina ter-
minalis, which contains three main nuclei: the subfornical organ
(SFO), the organum vasculosum of the lamina terminalis (OVLT),
and an integratory structure, the median preoptic nucleus (MnPO)
(3). The SFO and OVLT both lack the normal blood-brain barrier;
therefore, the populations of neurons within these nuclei have
unconstrained access to the circulation. By contrast, MnPO does
not sense input from the blood and only receives feedback from the
SFO and the OVLT. Recent studies have shown that osmoreception
is hierarchically organized, with MnPO neurons as the major output
neurons with integrated inputs from SFO and OVLT (3,4).
nephsap.org
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Activation of this network triggers a coordinated set of responses
that restores fluid balance. These responses include behavioral mech-
anisms that motivate drinking by activating the cingulate and insular
cortex, and physiologic mechanisms that activate neuroendocrine
activation leading to water and sodium retention by the kidneys.
Homeostatic and Anticipatory Thirst
Recent studies make a distinction between two types of thirst:
homeostatic thirst and anticipatory thirst (5). Homeostatic thirst is
stimulated in response to an established water deficit. Homeostatic
thirst is induced by the following three main mechanisms.
First, an increase in [Na1] is sensed by sodium-specific recep-
tors (Nax channels), which are expressed in the glial cells of the SFO
and the OVLT, initiating neural signals that are capable of activating
thirst-encoding neurons. Furthermore, the activation of Nax chan-
nels leads to an increase in the firing rate of inhibitory (g-aminobu-
tyric acid)-ergic neurons in the SFO, leading to the inhibition of salt
intake behavior. In addition to this central mechanism, afferent fibers
in the hepatic and mesenteric branches of the vagus nerve detect
changes in [Na1], relaying signals to the nucleus tractus solitarius,
which then projects into thirst-promoting regions. Additionally,
peripheral signals may be directly or indirectly relayed to the thala-
mus, from which thalamic neurons transmit sensory information to
anterior cingulate and insular cortex to promote thirst (5).
The second mechanism to induce homeostatic thirst involves a
change in blood osmolality, which is detected by SFO and OVLT
directly via osmoreceptors. Using stretch-sensitive properties,
changes in cell volume after intracellular dehydration in the setting
of increased plasma osmolality are detected. Stimulation leads to a
nonselective cation current, which induces cell depolarization and
subsequent activation of MnPO (6). As opposed to all other
neurons, SFO and OVLT neurons do not adapt to hypo- or hyper-
osmolality by losing or generating osmoles, and their change in vol-
ume is maintained as long as the osmotic stimulus persists (4).
Third, changes in effective blood volume are indirectly moni-
tored by pressure receptors. Low-pressure cardiopulmonary barore-
ceptors in the atria, pulmonary arteries, and vena cava detect blood
volume. High-pressure baroreceptors in the wall of the aortic arch
and carotid sinuses detect arterial pressure. In the setting of low
blood volume and/or blood pressure, these baroreceptors send inhib-
itory inputs from the periphery via afferent fibers of cranial nerves
IX and X to the nucleus tractus solitarius, activating the sympathetic
nervous system and activating thirst mechanisms. Reduced kidney
blood flow stimulates renin release from the juxtaglomerular appara-
tus, which converts angiotensinogen to angiotensin (Ang) I, which
is subsequently converted to Ang II by the angiotensin-converting
Copyright # 2022 by the American Society of Nephrology
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
enzyme. Ang II causes afferent arteriole and systemic vasoconstric-
tion and is a potent stimulation of SFO via Ang II receptor type 1
(5,7). By contrast, hypervolemia inhibits thirst through the humoral
mechanism of atrial natriuretic peptide, which is released when spe-
cialized cardiac myocytes are stretched. Atrial natriuretic peptide
stimulates natriuresis in the kidneys and is an important inhibitor of
thirst (5).
In contrast to thirst in response to an established water deficit,
anticipatory thirst occurs with an impending water deficit. Thirst in
response to food intake, or prandial thirst, is stimulated during eat-
ing to ensure that adequate water is available for food ingestion and
digestion and also to counteract the increase in plasma osmolality
due to absorption of osmolytes in food. Conversely, dehydration
potently suppresses food intake when water is unavailable (5). In the
context of anticipatory thirst, presomnial thirst helps prevent dehy-
dration during prolonged sleep. Activation of neurons in the supra-
chiasmatic nucleus, which is the center of circadian regulation, in
the hours immediately preceding sleep, projects to the OVLT,
which in turn activates thirst-regulating centers. This increase in pre-
somnial drinking prevents the development of small rises in plasma
osmolality that could otherwise occur during sleep (5).
Cessation of water intake once thirst results in drinking water
is just as important to prevent overhydration. In fact, the unpleas-
ant emotion associated with thirst rapidly declines in part because
of the activation of specific neurons in the MnPO, thus avoiding
overhydration (8). Furthermore, recent studies have discovered
anticipatory thirst satiety in thirsty mice once they begin drinking,
and demonstrated SFO neuron inhibition with the onset of drink-
ing before any changes in the composition of blood occurs. This
rapid feedback is triggered by the detection of water in the oral cav-
ity and enables the neurons of the SFO to closely monitor water
ingestion. Therefore, SFO neurons control water intake in real time
by comparing the level of physiologic need through the level of
blood osmolality and the amount of water ingested via checking
signals from the oropharynx. This model explains how drinking
can rapidly quench thirst (2,5).
Urinary Concentration
As thirst leads to ingestion of hypotonic or electrolyte-free water,
urinary concentration allows for the retention of free water. Arginine
vasopressin (AVP) mediates water retention in the kidney by render-
ing the collecting duct permeable to water. Water retention is then
driven by an osmotic gradient that favors water to flow from the
lumen to the interstitial space (1). Urinary concentration and AVP
action are described elsewhere in this issue of NephSAP.
Incidence of and Risk Factors for Hypernatremia
Clinically relevant hypernatremia is less common than hyponatre-
mia. It is a clinical problem affecting various populations but is
most often encountered in hospitalized patients and most frequently
affects critically ill hospitalized patients. But it also occurs in patients
who present to EDs as community-acquired hypernatremia. Of
those patients, the elderly are at a particular risk. Salt intoxication,
as well as hypernatremia which develops during high-intensity activ-
ity can be categorized as community-acquired hypernatremia.
91
Hospital-Acquired Hypernatremia
The development of hypernatremia in the hospital setting is more
common than community-acquired hypernatremia. A large retro-
spective study of 46,634 patients from Italy focusing on hospital-
acquired dysnatremias reported the incidence of hypernatremia to
be 4.3%. This study specifically excluded intensive care unit (ICU)
patients and patients with dysnatremias on admission (9).
A prospective cohort from Australia enrolled 180 hospitalized
general medicine patients who experienced moderate hypernatremia
defined as a serum [Na1] of 150 to 159 mmol/L. Approximately
10% of patients experienced progression to severe hypernatremia
(serum [Na1] .160 mmol/L). Risk factors for progression were
CKD stage, rising creatinine, and administration of intravenous
normal saline solution. The authors stress that patients with CKD
and AKI may have an increased risk of severe hospital-acquired
hypernatremia and that hospital-acquired hypernatremia is often
iatrogenic (10).
Intensive Care Unit Hypernatremia
Hypernatremia is particularly common in ICU patients. As in other
settings, impaired thirst or inability to drink water is the driving fac-
tor for hypernatremia. In the ICU setting, this is a result of sedation,
intubation, mechanical ventilation, or altered mental status. In
patients able to drink, restriction of oral water is frequently ordered
for patients with a high risk of aspiration or gastrointestinal issues,
such as gastrointestinal bleeding, obstruction, or ileus. Excessive
renal or other insensible fluid losses (skin losses with sweating in the
setting of fever, respiratory losses with mechanical ventilation) with-
out adequate free water replacement are also common contributors
to the increased risk of hypernatremia. Last, medication-induced
diuresis, osmotic catharsis with lactulose, iatrogenic hypernatremia
from hypertonic saline solution, mannitol, bicarbonate, or large
amounts of intravenous fluids are common in ICU patients. Unsur-
prisingly, the presence of hypernatremia on admission or develop-
ment of hypernatremia in the ICU setting is associated with higher
mortality and increased length of stay (11,12).
Early intravenous fluid resuscitation is a necessary tool to
improve hemodynamic stability in critically ill patients admitted to
the ICU. A retrospective study of 844 ICU patients receiving intra-
venous fluids compared the incidence of hypernatremia in patients
receiving 5% dextrose in water versus saline diluents, with the results
showing significantly higher rates of hypernatremia in the saline
diluents group (27.4% versus 14.6%, P,0.001) (13).
Once hemodynamic stability has been achieved after shock, a
positive fluid balance secondary to excess fluid accumulation is often
observed in critically ill patients in the ICU. Pharmacologic diuresis
is frequently used in this setting. In a recent single-center, non-
randomized study, volume overloaded patients were subjected to a
protocolized diuresis regimen and compared with a historical cohort.
A multidisciplinary team assessed the fluid balance every 8 hours.
The protocolized diuresis regimen was associated with a significant
decrease in net cumulative fluid balance at 72 hours after shock reso-
lution and reduced in-hospital mortality (0.16% versus 0.05%,
P50.008). However, it was also associated with a significant
increase in hypernatremia and hypokalemia (14).
Hypernatremia might also be associated with glucocorticoid
therapy in critically ill patients with refractory septic shock. A nested
92
case-control study in Japan investigated the relationship between
ICU-acquired hypernatremia and glucocorticoid therapy in critically
ill patients. ICU-acquired hypernatremia was associated with high-
dose glucocorticoid therapy in a duration- and response-specific
manner (15).
Hospitalized children usually receive isotonic solutions in accor-
dance with the guidelines of the American Academy of Pediatrics to
prevent hyponatremia (16). In critically ill children this approach is
less established. To study electrolyte disturbances including hyperna-
tremia in critically ill children, a randomized trial was conducted to
compare the effect of a “plasma-like” isotonic solution and moder-
ately hypotonic solutions. The “plasma-like” isotonic fluid contained
Na 140 mmol/L and K 5 mmol/L in 5% dextrose; the control fluid
contained Na 80 mmol/L and K 20 mmol/L in 5% dextrose.
Hypernatremia developed in only a small number of patients
(1.3%) in the group that received isotonic fluid (16).
Community-Acquired Hypernatremia
A large retrospective study of 10,558 patients presenting to the ED
in a single center in Japan between 2015 and 2017 demonstrated a
prevalence of community-acquired hypernatremia of 1.5% in elderly
patients (age .65) without CKD and #3.5% in elderly patients
with CKD (P,0.001). This was about twice as high as in the non-
elderly group (age ,65). The incidence of community-acquired
hypernatremia was 0.8% in nonelderly patients without CKD and
2.0% when CKD was present. The authors conclude that hyperna-
tremia in the elderly population is not uncommon and is more fre-
quent in elderly patients with underlying CKD (17). The concept
of hypernatremia as a function of aging is supported by recent
experimental studies showing that elderly, but otherwise healthy,
men experience reduced osmotic thirst compared with young men
(controls) after hypertonic saline solution infusion. Additionally,
when perceived thirst was assessed by a visual analogue scale, it was
significantly less expressed in older patients (18).
Dysnatremias are also associated with patients who present to
the ED with AKI. In a cross-sectional analysis of all patients who
presented to a single ED, the Acute Kidney Injury Network (AKIN)
classification was used to establish the presence and stage of acute
renal failure. Of a total of 65,489 ED presentations, 1692 patients
had either AKIN stage 1, 2, or 3. Even though dysnatremias were
quite common, with 24.5% of patients being affected, the majority
of patients had hyponatremia (23.6%), and only a small fraction
were found to be hypernatremic (1.4%) (19).
Seasonal variations in the incidence of hypernatremia are well
described, with hot weather being considered a classic risk factor for
hypernatremia. A recent retrospective study from Ireland conducted
during a 10-day heat wave in 2017 and 2018 showed the incidence
of hypernatremia to be 2.5 times higher in samples drawn during
the heat wave than in the control period (3.6% during heat wave
versus 1.4% in the control period) (20). By contrast, a retrospective
study conducted in Japanese ED patients showed a higher preva-
lence of hypernatremia in the elderly group during the winter
months (2.9% in winter versus 2.4% in summer, P50.004). This
correlation was not observed in the nonelderly control group. This
finding was attributed to potentially less significant care being given
to the patient's hydration status in winter months than during sum-
mer months (21).
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Salt Intoxication
An unusual cause of community-acquired hypernatremia is acciden-
tal or malicious salt poisoning, and several cases are being described
each year (22–25). Serum sodium concentrations as high as 238
mmol/L have been described in this setting (24), with causes ranging
from soy sauce or bay salt ingestion to eating disorders. It has to be
recognized that salt intoxication in contrast to other forms of hyper-
natremia is not due to the loss of water but rather to single or multi-
ple massive salt ingestions. The change in serum tonicity in chronic
hypernatremia allows for the formation of idiogenic osmoles coun-
terbalancing the osmotic gradient, which becomes particularly
impactful in brain cells. The lack of idiogenic osmoles in acute salt
ingestion has implications regarding therapy. Rapid lowering of the
serum sodium concentration with substantial free water administra-
tion and extracorporeal removal is paramount (22).
Athletic Activity as a Risk Factor for Hypernatremia
Altered hydration status is a potentially serious complication that
can develop during high-intensity exercise activities. Exercise-
associated hyponatremia due to overhydration and inappropriate
vasopressin secretion was first reported in the 1980s, and it is now a
well-recognized disorder. Hypernatremia is a more intuitive sequela
of high-intensity exercise activities and results from hypotonic fluid
losses. A recent observational study of 266 ultra-marathon runners
carefully delineated the incidence of exercise-associated hypo- and
hypernatremia. The runners were recruited in 2017 and 2018 before
running 50-mile races in the desert climates of Chile, Namibia, and
Mongolia. Weight change and serum sodium concentration upon
finishing the race were reviewed. Eleven runners (6.3%) experienced
exercise-associated hyponatremia EAH. and 30 runners (17.3%)
experienced hypernatremia. Predictably, hypernatremic runners were
more often volume depleted with a loss of weight during the mara-
thon. Also, unsurprisingly, hypernatremia occurred more often in
races during hot weather than in races in colder temperatures (odds
ratio [OR], 8.8; 95% CI, 2.9 to 39.5) (26).
Another study of 81 randomly selected runners of a 2017 Cali-
fornia half marathon showed no cases of hyponatremia at the end of
the marathon, but instead discovered six cases of asymptomatic
hypernatremia (7.4%). Whereas hyponatremia has been associated
with high fluid intake and with races performed in cool weather,
such as the Boston Marathon in spring, hypernatremia tends to hap-
pen in marathons that take place in warmer weather (27).
Prognosis of Hypernatremia
Serum sodium and mortality are often associated in a U-shaped rela-
tionship, with mortality rising with both hypo- and hypernatremia.
This was demonstrated again in an analysis of 1-year out-of-hospital
mortality in a cohort of 55,901 hospitalized patients. The nadir of
the U-shaped relationship was in the normal serum sodium range,
at 136 to 142 mmol/L (28). A similar relationship was also observed
in in-hospital mortality in patients with AKI (29).
Although the focus is often on hyponatremia, recent studies
suggest that hypernatremia might be a better predictor for
in-hospital mortality compared with the predictive value of hypona-
tremia. A recent single-center study involving 6400 hospitalized
patients investigated the association between admission serum
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 93

sodium and in-hospital mortality. Compared with normonatremia,
severe hypernatremia ([Na1] .155 mmol/L) had the odds ratio of
11.1 for in-hospital mortality (95% CI, 3.83 to 32.21; P,0.001),
whereas the odds ratio for in-hospital mortality in patients with
severe hyponatremia ([Na1] ,125 mmol/L) was 3.9 (95% CI, 1.73
to 8.93; P50.001) (30). In another recent study of 879 ED patients
presenting with sepsis, the prognostic value of [Na1] on the mortal-
ity rates was examined. Unsurprisingly, patients with dysnatremia
had significantly higher mortality rates. However, when dysnatremic
patients were further subdivided into hypo- and hypernatremic,
hypernatremia was associated with a significantly higher mortality
rates at 7 and 30 days than was hyponatremia. The hazard ratio
(HR) for death in the hypernatremia and hyponatremia groups was
3.5 (95% CI, 1.58 to 7.82; P50.002) and 2.14 (95% CI, 1.17 to
3.92, P50.014), respectively (31).
Although single serum sodium levels have been shown to be
associated with patient outcomes, directional changes in serum
[Na1] offer additional information regarding the outcomes in hospi-
talized patients. A carefully conducted recent single-center cohort
study investigated in-hospital [Na1] trajectories and their association
with in-hospital and 1-year mortality outcomes. A total of 43,000
patients were categorized into five groups: stable normonatremia,
corrected hyponatremia, uncorrected hyponatremia, borderline high
serum sodium, and fluctuating serum sodium. After adjustment for
admission serum sodium, significantly higher odds of in-hospital
mortality were noted in patients with uncorrected hyponatremia
(OR, 1.33; 95% CI, 1.06 to 1.67), corrected hyponatremia (OR,
1.5; 95% CI, 1.02 to 2.2), borderline high [Na1] (OR, 1.66; 95%
CI, 1.38 to 2.00), and fluctuating [Na1] (OR, 4.61; 95% CI, 3.61
to 5.88). This again underscored higher mortality rates in patients
with hypernatremia than in patients with hyponatremia. Of note,
patients with fluctuating [Na1] trajectory had the greatest 1-year
mortality (HR, 2.1; 95% CI, 1.89 to 2.33) compared with patients
with borderline high serum sodium (HR, 1.18; 95% CI, 1.11 to
1.26) (Figure 1). The authors note that not a single serum sodium
or a weighted sodium average, but rather the in-hospital serum
[Na1] trajectory, is the most useful parameter to predict in-hospital
as well as 1-year mortality (32).
Further characterizing the incidence and outcomes of hyperna-
tremia, a recent analysis of 19,072 unselected hospitalized patients
studied the crude relationship between hypernatremia, defined as a
serum [Na1] .142 mmol/L, and mortality. In this unusually low
sodium cutoff, community-acquired hypernatremia was diagnosed
in as many as 21% of hospitalized patients, whereas hospital-
acquired hypernatremia developed in 25.9% of hospitalized patients.
Both were associated with increased in-hospital mortality (OR,
1.67; 95% CI, 138 to 2.01) and (OR, 3.17; 95% CI, 2.45 to 4.09),
respectively. Also, both were associated with a greater likelihood of
discharge to a long- or a short-term care facility, as well as increased
length of hospital stay (33).
Unsurprisingly, the poor prognostic value of hypernatremia
holds true in several more specific care settings. In a retrospective
study, the outcomes in elderly patients with underlying CKD (age
.75 years, GFR ,60 ml/min per 1.73 m2) with hypo- and hyper-
natremia were compared with those in normonatremic elderly
patients with CKD. In this study, the results suggested that only

Figure 1. In-hospital serum sodium trajectories and mortality. A) Serum sodium in-hospital trajectories were generated by the use of group-
based trajectory modeling. A total of 43,000 patients were categorized to have corrected hyponatremia, stable normonatremia, uncorrected hypo-
natremia, borderline high serum sodium, and fluctuating serum sodium. B) One-year mortality was worst in patients with fluctuating serum
sodium and best in patients with stable normonatremia. Of patients with dysnatremia, those with high borderline serum sodium had the most
favorable 1-year mortality (32). Used with permission from reference 32 (Chewcharat A, Thongprayoon C, Cheungpasitporn W, Mao MA,
Thirunavukkarasu S, Kashani KB: Trajectories of serum sodium on in-hospital and 1-year survival among hospitalized patients. Clin J Am Soc
Nephrol 15: 600–607, 2020).
94
hypernatremia was associated with increased risk of death, differing
from previously shown data indicating a U-shaped curve relationship
between dysnatremias and mortality (34). In a retrospective cohort
in Japan of terminally ill cancer patients, hypernatremia emerged,
alongside leukocytosis and hypoalbuminemia, as a significant predic-
tor for poor prognosis (35). Expectedly, admission and discharge
[Na1] were also a poor prognostic marker for patients who were hos-
pitalized with congestive heart failure (36). Inpatient palliative care
consultation in patients with dementia can be an important segue to
engage in goals of care discussions with families. In a recent study,
hypernatremia on admission was recognized as an important predic-
tor for inpatient palliative care consultation alongside the presence of
pressure ulcers and being bedbound (37). Clearly, clinicians should
instinctively recognize the importance of hypernatremia in judging
overall prognosis.
Permissive Hypernatremia
Hypernatremia is associated with increased mortality in patients in
medical and surgical ICUs; however, in neurosurgical and neurologic
ICUs hypernatremia is often a component of the treatment of cere-
bral edema with intravenous mannitol or hypertonic saline solution
(38). Hyperosmolar solutes acutely increase the systemic serum
osmolality. When combined with blood-brain barrier impermeability
to mannitol and sodium, water extraction from brain tissue into the
intravascular compartment should occur as a result of the flow of
water following a concentration gradient. Currently, the Brain
Trauma Foundation Guidelines for the management of severe trau-
matic brain injury recommend using 3% saline solution rather than
mannitol as initial treatment for traumatic brain injury with elevated
intracranial pressure (ICP), mostly because of its predictable response
when targeting serum [Na1] between 150 and155 mmol/L (39).
Although interventions with hypertonic saline are clearly of
physiologic benefit for the treatment of intracranial hypertension,
the high mortality associated with ICU-acquired hypernatremia
challenges this concept. There are very few studies on the safety of
hypertonic saline solution in patients with elevated ICP after trau-
matic brain injury. A recent retrospective analysis investigated
in-hospital mortality, length of stay, and frequency of tracheostomy
and percutaneous endoscopic gastrostomy placements in hypernatre-
mic and normonatremic adults with a diagnosis of traumatic brain
injury who required mechanical ventilation, ICP monitoring, or cra-
niotomy. Hypernatremic patients had a higher mortality rate, longer
length of stay, higher rates of tracheostomy, and higher rates of
endoscopic gastrostomy placements, suggesting poor functional out-
comes in those who did survive. Because severe traumatic brain
injury is often associated with the development of central diabetes
insipidus (DI), its presence could be a confounding factor in the
assessment of the association of ICU-acquired hypernatremia and
outcomes in this patient population (40).
Another retrospective analysis that included 458 patients with
moderate to severe traumatic brain injury investigated the associa-
tion between hypernatremia and hyperchloremia and mortality rates.
Over the entire duration of an ICU stay, the time-weighted average
(TWA) of sodium and chloride was calculated. Unadjusted mortal-
ity rates were near linearly increasing for both the TWA of sodium
and chloride, and were the highest for serum [Na1] of .160
mmol/L and serum [Cl-] .125 mmol/L. When evaluated in
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
combination, TWA of chloride, but not sodium, remained indepen-
dently associated with in-hospital mortality (41).
Whether hypertonic saline infusions are an effective and safe
strategy to reduce ICP and improve outcomes still remains uncer-
tain; one effort to shed light on this question is currently being
investigated. A multicenter, randomized, controlled, open-label,
two-arm study is being conducted, which compares standard care
with continuous hyperosmolar therapy plus standard care in patients
who experienced traumatic brain injury 24 hours prior. The primary
outcome is the score on the Extended Glasgow Outcome Scale at
6 months. Safety data such as the degree of hypernatremia or hyper-
chloremia will be of utmost interest to nephrologists (42).
AKI in a patient with a traumatic brain injury requiring renal
replacement therapy represents a therapeutic challenge because of
the increased risk of cerebral edema with intermittent conventional
hemodialysis. Dialysis can potentially compromise the therapeutic
goal of hyperosmolality by acutely decreasing the serum osmolality
and by causing intradialytic hypotension. Therefore, in such a popu-
lation of patients, continuous renal replacement therapy (CRRT)
has emerged as the preferred modality. A recently published article
on therapeutic hypernatremia management during CRRT discusses
options of achieving hypernatremia in patients receiving CRRT.
Unfortunately, the sodium concentrations of commercially available
replacement fluids are lower than the desired hypernatremia levels
for patients with elevated ICP. Therefore, induction and mainte-
nance of hypernatremia can be accomplished by use of an adjustable
infusion of hypertonic saline solution during CRRT. In a recent
review the authors discuss strategies like using a separate pump to
deliver 3% saline solution during CRRT as a preferred option to
using the post–filter replacement fluid pump, among other alterna-
tives (43).
Diabetes Insipidus
Diabetes insipidus is characterized by hypotonic polyuria caused by
impaired synthesis (central DI) or action (nephrogenic DI) of the
antidiuretic hormone (ADH)/AVP (Figure 2).
Central DI is more common than nephrogenic DI. It is most
often an acquired disorder that is caused by disruption of the neuro-
hypophysis, whereas hereditary forms are less common and are
caused by mutation of the AVP gene. Nephrogenic DI is most com-
monly the result of an adverse effect of various drugs, or of electro-
lyte disorders such as hypercalcemia and hypokalemia. In much rarer
instances, nephrogenic DI is due to a mutation in the AVP-2 recep-
tor (hereditary nephrogenic DI). A third, rare form of DI, termed
gestational DI, can occur during pregnancy and results from the
enzymatic breakdown of endogenous AVP by increased placental
vasopressinase levels in pregnancy (44).
Medication-Induced Diabetes Insipidus
Lithium remains the most common cause of nephrogenic DI.
Whereas glomerular damage appears after years of lithium treat-
ment, tubular dysfunction can happen within weeks after lithium
initiation. Lithium inhibits adenylate cyclase, with a resultant
decrease in the formation of cAMP. By doing so, lithium impairs
the fusion of aquaporin storage vesicles with a luminal wall in the
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 95

Central diabetes
insipidus
Destruction of
p Pituitary
neurohypophyseal
AVP release
neurons or
mutations in AVP

Primary
polydipsia
Excessive
fluid intake

Renal Nephrogenic
resistance diabetes insipidus
to serum AVP Decreased response
to AVP or mutations
in AVPR2 or AQP2

n AVP degradation

Gestational
diabetes insipidus
Excessive activity
p Free water reabsorption
of placental
nSolute-free water diuresis
vasopressinase

Figure 2. Pathophysiology of diabetes insipidus (DI). There are three principle causes of DI. A decrease in arginine vasopressin (AVP) release or
central DI is caused by destruction of neurohypophyseal neurons or a mutation in the AVP gene. A decreased response to AVP or nephrogenic
DI is due to renal unresponsiveness to AVP. Increased AVP degradation or gestational DI is caused by excessive activity of the placental vaso-
pressinase. Of note, the excessive fluid intake in primary polydipsia similarly to central DI causes a decrease in AVP release (44). Reprinted with
permission from reference 44 (Christ-Crain M, Bichet DG, Fenske WK, Goldman MB, Rittig S, Verbalis JG, Verkman AS: Diabetes insipidus.
Nat Rev Dis Primers 5: 54, 2019).

collecting duct. It renders the collecting duct impermeable to water
and hence causes hypo-osmolar polyuria (44).
Up to 20% of patients treated with lithium may experience
nephrogenic DI, which can persist even after lithium has been
stopped. As long as the patient has access to water, hypernatremia is
not common. However, if an additional insult impairs the access to
water or a mitigating factor is present, hypernatremia occurs. A recent
retrospective study investigated cofounding factors leading to hyper-
natremia in patients previously treated with lithium. Concomitant
infections were identified as the dominant cause of hypernatremia,
accounting for 37% of all episodes. This was followed by intoxica-
tions other than lithium, which were identified as a confounding fac-
tor in 15% of patients in this cohort. In patients .65 years of age,
infections were identified in 51% of patients taking lithium who
experienced hypernatremia (45).
There are currently no known strategies to prevent lithium-
induced DI in patients who require it. In mice, however, statins
have been shown to increase the expression of membrane aquaporin
2 in the renal tubules. Cross-sectional studies showed that the use of
statins is associated with a lower risk of nephrogenic DI. Currently,
a randomized control trial of atorvastatin for lithium-induced neph-
rogenic DI is being conducted in Canada (46).
Two recently published articles raise concerns about
medication-associated occurrences of DI in the ICU setting. A retro-
spective study of 35 patients receiving sevoflurane showed a 20%
incidence of nephrogenic DI during the ICU stay. There is an asso-
ciation between the development of nephrogenic DI and the con-
centration of sevolfurane, as well as the duration of exposure. All
patients with nephrogenic DI were sedated for more than 72 hours
with mean end-tidal concentration of sevoflurane .1.0 vol % (47).
Another recent single-center case series from the UK reported the
development of central DI after discontinuation of vasopressin infu-
sion for treatment of shock, with the exact cause being unclear (48).
Diagnosis of Diabetes Insipidus
In routine clinical practice, the measurement of urine osmolarity
and urine volume aids in establishing the cause of hypernatremia.
Careful assessment of urinary output, daily weight, and accurate
balance reporting in hospitalized patients is often neglected. Addi-
tionally, assessment of extracellular fluid volume in clinical prac-
tice is challenging and can be misleading. Therefore, the need for
novel diagnostic markers for the differential diagnosis of hyperna-
tremia arises.
96
To briefly review the diagnosis of DI, the diagnostic criterion
standard in clinical practice is the indirect water deprivation test.
Patients are deprived of fluid intake while serum sodium and osmo-
lality, along with urine volume and urine osmolality, are carefully
monitored. This test is required to last for 17 hours or until the
serum sodium concentration exceeds 150 mmol/L. At that time,
exogenous AVP is administered, and its effect on urine osmolality is
measured. This test indirectly establishes the lack or effect of AVP.
Needless to say, this test is cumbersome in clinical practice. Unfor-
tunately, previous attempts to incorporate direct measurements of
AVP levels were largely unsuccessful because the assay had technical
limitations and never made its way into routine clinical practice.
Another biomarker with potential to aid in the diagnostic workup
of hypernatremia was found with the discovery of copeptin in the
mid-1970s. Copeptin is the C-terminal segment of the AVP precur-
sor peptide and mirrors the AVP concentration. It can be easily
measured and provides a reliable surrogate marker for AVP. How-
ever, it wasn’t until the last decade that its potential as a diagnostic
marker for DI was further investigated. Copeptin is released in
response to the same stimuli as AVP. The main osmotic stimulus is
an increase in serum osmolarity. Reduction in arterial blood volume
and pressure is the primary nonosmotic stimulus. A normal range of
plasma copeptin levels has been established in two large clinical trials
evaluating healthy volunteers under normal osmotic conditions
where plasma copeptin levels ranged from 1.0 to 13 pmol/L, with a
median concentration of 4.2 pmol/L. Previous studies have shown
that nephrogenic DI can be easily diagnosed by the use of a single
baseline copeptin level of .21.4 pmol/L without prior thirsting.
However, baseline copeptin values in the other entities (i.e., central
DI and primary polydipsia) largely overlapped (49).
A recent prospective multicenter observational study conducted
in Switzerland assessed the value of baseline copeptin in 92 patients
with [Na1] .155 mmol/L (50). Copeptin levels varied according
to underlying pathology, where the highest levels were seen in
patients with nephrogenic DI, and the lowest median levels occurred
in those with central DI. Median levels of copeptin differed signifi-
cantly in patients with central DI (3.39 pmol/L, IQR 1.99–3.9
pmol/L), salt overload (53.19 pmol/L, IQR 34.39–85.95 pmol/L),
dehydration-induced hypernatremia (54.95 pmol/L, IQR
35.01–71.70), and nephrogenic DI (77.75 pmol/L); (P50.001).
No difference in copeptin levels was seen between cases of
dehydration-induced hypernatremia and salt overload (P50.64).
Additionally, in this study low urea values were highly specific and
sensitive for diagnosis of central DI. This phenomenon is caused by
net absorption of the urea, which is dependent on the renal action
of ADH. In vitro experiments in rats show that the inner medullary
collecting tubule urea permeability rises in response to AVP; there-
fore, urea levels might reflect AVP action in the nephron and may
differentiate patient's DI from dehydrated states (50).
Inasmuch as baseline copeptin levels are unable to differentiate
between central DI and primary polydipsia, a recent prospective
multicenter study added a hypertonic saline infusion test to the algo-
rithm to more accurately differentiate between central DI and pri-
mary polydipsia. A total of 156 patients with hypotonic polydipsia
underwent the water deprivation test as well as the hypertonic saline
infusion test (measurement of copeptin after a hypertonic saline
infusion was done after the [Na1] reached at least 150 mmol/L).
The underlying cause of hypotonic polydipsia was established
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
independently of the copeptin measurements. Combining serum
copeptin levels with the hypertonic saline infusion test reliably dif-
ferentiated between central DI and primary polydipsia (Figure 3).
Of note, the hypertonic saline infusion test did not aid in differenti-
ating between complete and partial central DI (51).
Hypertonic saline stimulation of AVP release, however, is
poorly tolerated, with #70% of patients experiencing vertigo, head-
ache, or malaise. Another recent study tested the diagnostic value of
AVP-stimulated copeptin levels in the workup of DI. In a prospec-
tive diagnostic study, a development cohort was recruited to derive
the cutoffs for copeptin to discriminate between patients with cen-
tral DI and those with primary polydipsia, and later the diagnostic
performances of these cutoffs were validated in the validation
cohort. All patients had a baseline copeptin checked, and patients
whose levels were consistent with nephrogenic DI were excluded.
The median copeptin values for those with primary polydipsia dou-
bled after AVP stimulation, from 3.6 pmol/L (IQR 2.4–5.7 pmol/L)
at baseline to a maximum of 7.9 pmol/L (IQR 5.1–11.8 pmol/L)
at 120 minutes (P,0.0001). By contrast, in patients with DI,
copeptin increased only slightly after AVP stimulation (median 2.1
pmol/L (IQR 1.9–2.7 pmol/L) at baseline) to a maximum of 2.5
pmol/L (IQR 1.9–3.1 pmol/L) at 60 minutes (P50.0013). In the
subgroups of patients with complete and partial DI, only a small
change in copeptin concentrations was observed for those with
complete DI (from 1.9 pmol/L (IQR 1.6–2.4 pmol/L) to a maxi-
mum at 60 minutes of 2.2 pmol/L (IQR 1.6–28); P50.0032),
whereas for those with partial DI, copeptin concentrations
increased from 2.5 pmol/L (IQR 2.2–3.0 pmol/L) to a maximum
at 120 minutes of 3.3 pmol/L (2.9–3.9; P50.0035) (52).
Outlined above are the recent developments in the diagnosis of
patients with hypotonic polyuria, which may change the decades-
old algorithm currently used but have not entered routine clinical
practice yet.
4 A single copeptin level of >21.4 pmol/L without
prior thirsting identifies patients with nephrogenic
diabetes insipidus, but it does not distinguish
between central diabetes insipidus and primary
polydipsia.
4 A copeptin level obtained after hypertonic infusion
reliably differentiates central diabetes insipidus
from primary polydipsia.
4 An increase in AVP-stimulated copeptin levels may
identify patients with primary polydipsia.
Treatment of Hypernatremia
Chronic hypernatremia for clinical purposes is defined as increased
serum [Na] for a duration of .48 hours or unknown in the case
of community-acquired hypernatremia. Adaptation of brain cells
to chronic hypernatremia is characterized by an increase in intracel-
lular osmolality by accumulating organic osmoles. With the rapid
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 97

Stimulated Copeptin Levels in Response to the Hypertonic

Saline Infusion and Water-Deprivation Tests in Patients with
Hypotonic Polyuria.

W Fenske et al. N Engl J Med 2018;379:428-439.

Figure 3. Patients with hypotonic polyuria and copeptin levels after hypertonic saline infusion test or water deprivation test. (A) Copeptin levels
are significantly higher in patients with primary polydipsia after the hypertonic saline infusion than in patients with central diabetes insipidus.
This is not the case after the water deprivation test. (B) Neither the hypertonic saline infusion test nor the water deprivation test was able to dis-
tinguish between complete and partial diabetes insipidus. DI, diabetes insipidus (51). Reprinted with permission from reference 51 (Fenske W,
Refardt J, Chifu I, Schnyder I, Winzeler B, Drummond J, Ribeiro-Oliveira A Jr, Drescher T, Bilz S, Vogt DR, Malzahn U, Kroiss M, Henzen
CE, Fischli S, Tonjes A, Mueller B, Schopohl J, Flitsch J, Brabant G, Fassnacht M, Christ-Crain M: A copeptin-based approach in the diagnosis
of diabetes insipidus. N Engl J Med 379: 428–439, 2018).

correction of hypernatremia, the extrusion of these accumulated
organic osmoles is delayed, potentially leading to subsequent cere-
bral edema. Cerebral edema is particularly dangerous in young chil-
dren, whose brains fill the whole cranial vault, unlike those of
adults.
Guidelines recommend a correction of hypernatremia of no
more than 8–10 mmol/L per 24 hours. with a maximal rate of 0.5
mmol/L per hour in chronic hypernatremia. These recommendations
were derived from observations in the pediatric population of hyper-
natremic newborns. There, a sodium correction of 1.02260.1278
mmol/L per hour led to rehydration seizures in 9 newborns, compared
with 22 newborns with a sodium correction of 0.61860.083 mmol/L
per hour, who remained seizure free. There were no seizures in 27
newborns who received correction by ,0.5 mmol/L per hour. Based
on these retrospective studies, recommendations on hypernatremia
correction were made for both children and adults. In this context it is
important to note that the data governing the rate of correction for
hypernatremia are less robust than the data that are used to recom-
mend a rate of correction in patients with hyponatremia (53).
The cornerstone of treatment of hypernatremia is correction of
the free water deficit by administration of free water, orally or intra-
venously with 5% dextrose solution. The free water deficit can be
calculated by the following formula: Free water deficit5% of total
body water (as fraction of 1)3body weight (kg)3[(sodium concen-
tration/140)21], where % total body water is 60% for adult male,
50% for adult female, 50% for elderly male, and 45% for elderly
female. The change in serum sodium for each liter of administered
free water can be calculated by this formula: change in serum
sodium5[(infusate sodium)2(serum sodium)]/[total body water
(L)11].
98
Figure 4. Thirty-day survival in patients with hypernatremia depend-
ing on the rate of correction of the serum sodium concentration.
A) Patients with hypernatremia on admission. B) Hospital-acquired
hypernatremia. The 30-day survival between slow correction group
(,0.5 mmol/L per hour) and rapid correction group (.0.5 mmol/L
per hour) was similar (56). Used with permission from reference 56
(Chauhan K, Pattharanitima P, Patel N, Duffy A, Saha A, Chaudh-
ary K, Debnath N, Van Vleck T, Chan L, Nadkarni GN, Coca SG:
Rate of correction of hypernatremia and health outcomes in critically
ill Patients. Clin J Am Soc Nephrol 14: 656–663, 2019).
As recently reviewed, current recommendations for rate of cor-
rection of hypernatremia likely led to undertreatment of hypernatre-
mia in adults. For instance, in a retrospective analysis of a cohort of
hypernatremic patients that investigated treatment success, 24 hours
after initiation of hypernatremia treatment the sodium levels wors-
ened in 34% of patients and remained unchanged in 8% of patients.
After 3 days, hypernatremia normalized in only 32% of patients
(54). Additionally, there may be evidence that extremely slow rates
of correction of chronic hypernatremia are associated with higher
mortality in adults (55).
Addressing the rate of correction for patients with hypernatre-
mia, a recently published study challenged the classic hypernatremia
correction guidelines by comparing more rapid correction with slow
correction in 449 critically ill patients with severe hypernatremia.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Rapid correction was defined as a rise in the [Na1] of .0.5 mmol/
L per hour, or .12 mmol/L per day. Slow correction was defined as
a rise in [Na1] of ,0.5 mmol/L per hour and ,10 mmol/L per
day. The in-hospital mortality was similar between patients with
rapid versus slow correction. This was the case in patients who had
hypernatremia on admission and patients with hospital-acquired
hypernatremia (in-hospital 30-day mortality 25% versus 28%,
P50.8, in the admission hypernatremia group; 44% versus 40%,
P50.50, in the hospital-acquired hypernatremia group) (Figure 4).
Furthermore, there were no cases of cerebral edema in the 78
patients with serum sodium correction of .12 mmol/L/day. The
authors argue that fears of more rapid correction of hypernatremia
are probably overstated (56).
Severely burned ICU patients represent a unique subset of
hypernatremic patients, inasmuch as high ongoing free water losses
frequently occur in this patient population. Conventional treatments
with free water replacement and nutritional support are often subop-
timal in the correction of hypernatremia. A recent single-center ret-
rospective study investigated the implementation of continuous
venovenous hemofiltration (CVVH) if hypernatremia failed to cor-
rect after 24 hours of conventional therapy. A total of 13 patients
were enrolled. At the beginning of CVVH, the sodium concentra-
tion in the replacement fluid was 8 mmol/L lower than the serum
[Na1] and was reduced by 2 mmol/L every 4 hours subsequently.
With a serum reduction rate of 0.6 mmol/L per hour, all patients
experienced a successful correction of hypernatremia within 48
hours and showed no complications (57).
There are controversial opinions on the choice of anticoagula-
tion during CVVH in patients with severe hypernatremia and
bleeding risk. Infusion of regional citrate anticoagulation (RCA)
solution can theoretically result in significant sodium load (408
mmol/L for a 4% sodium citrate solution); therefore, hypernatre-
mia was considered one of the potential contraindications to
citrate anticoagulation. A recent retrospective study evaluated the
efficacy and safety of RCA versus no-anticoagulation CVVH in
acute severe hypernatremia patients with increased bleeding risk.
The mean rate of sodium reduction was 0.9560.39 mmol/L per
hour in the no-anticoagulation group and 0.9260.28 mmol/L per
hour in the RCA group, challenging the prior notion to avoid
4 A growing body of evidence suggests that prior
guidelines for managing hypernatremia were too
conservative and led to undertreatment of
hypernatremia.
4 Inadvertent rapid correction of hypernatremia is
much less likely than that of hyponatremia.
4 More rapid correction of hypernatremia in adults
appears to be less harmful than was previously
thought.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
RCA use in hypernatremia. The mortality rate was similar in both
groups (58).
Donor and Recipient Hypernatremia in Solid Organ
Transplantation
For several solid organ transplants, such as heart, liver, kidneys and
pancreas, donor hypernatremia has been found to be associated with
reduced graft survival. Cell lysis and graft damage, as well as post-
transplantation edema, of the hypernatremic graft in the recipient
with normal or low serum sodium levels have been proposed to be
responsible for some of the pathogenic effects of donor hypernatre-
mia (59).
While the detrimental effects of sodium dysregulation are well
known at a cellular level, its effect on patient-centered outcomes has
not been consistently demonstrated. Here, we review the most
recent studies on the association of hypernatremia with solid organ
transplantation outcomes.
Heart
Donor hypernatremia has been associated with primary graft failure
in heart transplant patients. A retrospective analysis of data from the
University of Vienna on outcomes of heart transplantation (rejected
by University of Vienna but accepted elsewhere) showed survival
rates of only 46% at 3 years (60). Similar results were reported in a
retrospective cohort of 200 heart transplant recipients. Donor hyper-
natremia was associated with higher incidence of primary graft fail-
ure. Patients who receive a heart transplant from a donor with a
[Na1] .159 mmol/L were significantly more likely to have pri-
mary graft failure (incidence of graft failure 63.3% versus 32.4%,
P,0.001) (61).
Liver
Before liver transplantation, recipients typically have hyponatremia
reflective of the severity of the liver cirrhosis. Pretransplantation
hyponatremia in a recipient is a poor prognostic factor. The liver
transplantation procedure itself requires a large amount of blood
products, fluid resuscitation, and albumin infusion, which, in com-
bination with potentially rapid intraoperative ceasing of endogenous
ADH, can lead to a rapid change in the [Na1]. The size of the
intraoperative delta [Na1] is associated with a prolonged hospitali-
zation and higher early mortality (62). Hypernatremic donors in
liver transplantation are considered expanded criteria donors. In a
recent retrospective analysis, the degree of donor hypernatremia per
se had little impact on short-term graft survival. However, the overall
survival rate of the grafts from hypernatremic donors rather
depended on exposure time from hypernatremia to reperfusion, cold
ischemia time, and MELD score (63).
Lung
In a recent Dutch study analyzing all consecutive lung transplanta-
tions from 1996 to 2016, donor hypernatremia was not associated
with primary graft dysfunction or long-term survival. Donors were
categorized as normonatremic (,145 mmol/L), moderately hyper-
natremic (146 to 154 mmol/L), and severely hypernatremic (.155
mmol/L). Short-term graft function defined as the duration of
mechanical ventilation, as well as 10-year mortality, was similar
99
among all donors. The authors speculate that critically ill patients
with respiratory diseases are less harmed by the otherwise detrimental
effect of hypernatremia in the ICU patient population, which was
previously reported. The authors surmise that hypernatremia in the
lung transplant donor (unlike than in other solid organ donors) pro-
duces a neutral effect on lung transplantation outcomes and argue
that donor hypernatremia should not exclude such donors (64).
Kidney and Pancreas
A recent revision of Eurotransplant data on which donor factors
were associated with nontransplantation of donor pancreas found
hypernatremia as one of the frequent causes of pancreas graft refusal.
However, a subsequently published study on the association of
donor sodium levels with postoperative morbidity and pancreas graft
loss in simultaneous pancreas-kidney transplantation failed to find a
difference between hyper- and normonatremic donors (59).
In kidney transplantation, out of 11 observational studies
included in a recent systemic review that analyzed the effect of
donor hypernatremia on renal graft function, five studies found an
association between donor hypernatremia and recipient graft func-
tion, whereas six did not. Of the five studies concluding an associa-
tion between donor sodium and graft dysfunction, most defined
hypernatremia as serum sodium .155 mmol/L. Among six studies
that did not find an association between donor sodium and graft
function, two studies included donor cohorts with serum sodium
levels between 145 and 150 mmol/L, three studies included donor
cohorts with serum sodium between 150 and 155 mmol/L, and one
pediatric study included donors with the most extreme mean serum
sodium of 163610 mmol/L. This systematic review raises the point
that evidence regarding the effect of donors’ sodium levels and trans-
plantation outcomes is inconclusive and that labeling organs from
hypernatremic donors as marginal may be unsubstantiated and lead
to the discard of a valuable and limited resource (65).
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102
Article
Pathophysiology, Evaluation, and Treatment of Hypokalemia
Tushar Chopra, MD, FASN
Division of Nephrology, University of Virginia School of Medicine, Charlottesville, Virginia
Thomas D. DuBose Jr., MD, FASN
Wake Forest School of Medicine, Section on General Internal Medicine, Winston-Salem, North Carolina and Division
of Nephrology, University of Virginia School of Medicine, Charlottesville, Virginia
Learning Objectives
1. To summarize the mechanisms underlying internal and
external potassium balance
2. To define the pathophysiology of hypokalemia
3. To examine the consequences of reduced potassium intake
and hypokalemia
Introduction
The defense of body potassium (K1), homeostasis requires coordi-
nation of external balance (dietary intake) with absorption and
excretion by the kidney and gastrointestinal tract, as well as internal
balance through the asymmetric distribution of K1 between the
intracellular space (intracellular fluid [ICF]) and the extracellular
space (extracellular fluid [ECF]).
This topic reviews the mechanisms underlying the maintenance
of internal and external potassium balance and the pathophysiology
of hypokalemia. We emphasize the causes and significant conse-
quences for lower values for plasma K1 concentration or [K1]p.
Total Body Potassium Distribution
Total body K1 (TBK) is approximately 55 mmol/kg body wt for a
70-kg person (or approximately 3675 mmol) and is distributed pri-
marily to the ICF compartment (98%). The ICF distribution is
largely in skeletal muscle (3000 mmol), red blood cells (200 mmol),
and the liver (200 mmol). The driving force for K1 to shift into
cells is the more negative intracellular voltage. Accordingly, a steady
state is maintained with a [K1] in skeletal muscle cells that is
approximately 35-fold higher than in the ECF. The [K1]p, the com-
ponent that represents the K1 distribution to the ECF compart-
ment, accounts for only 2% of TBK (1).
Regulation of Potassium Homeostasis
Internal and external potassium balance is maintained by a highly
regulated system involving three integrated components: (1) cellular
shifts; (2) absorption and excretion by the kidney; and (3) to a lesser
extent, transport in the gastrointestinal tract (1). Assuming a daily
dietary intake in the recommended range, approximately 95% of
nephsap.org
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
the daily K1 intake is excreted in the urine, whereas 5% is excreted
by the gastrointestinal tract to maintain the steady state.
The sensor that evokes the mechanisms that maintain extracellu-
lar potassium has not been completely clarified. A traditional view
that focuses on renal excretion is that an increase in extracellular
potassium concentration provoked by dietary intake directly and
indirectly (via aldosterone) stimulates excretion by the collecting
duct. However, an alternative hypothesis is that the activation of
enteric sensors located in the splanchnic bed increases potassium
secretion even in the absence of an increase in the extracellular potas-
sium (2). Several recent studies have suggested that enteric sensors
participate in the shift of K1 into skeletal muscle (3), as well as renal
secretory processes upon K1 entry into the gastrointestinal tract (2).
The sensitivity, magnitude, and physiologic significance of enteric
sensors in the regulation of TBK homeostasis have not been fully elu-
cidated. Moreover, it is possible that intracellular shifts in response to
enteric sensors may be elicited by hormones or neuropeptides that
are known to be derived from the gastrointestinal tract.
Cell Shifts
Transmembrane potential difference results from the unequal dis-
tribution of ions (particularly Na1 and K1) between intracellular
and extracellular compartments. Maintenance of the asymmetric
K1 concentration gradient across the cell membrane ([K1]in .
[K1]out) is essential to preserve the transmembrane potential dif-
ference and equal to approximately 90 mV. This potential differ-
ence is important for cellular function in all cells but particularly
for nerve cells, cardiac muscle, and skeletal muscle. Factors that
affect potassium distribution are shown in Table 1. Catecholamines
and insulin cause transient intracellular shifts of serum potassium to
help regulate the distribution of TBK and to protect against wide
swings in the [K1]p (4). After ingestion of a meal, insulin release
stimulates K1 uptake in skeletal muscle cells by the Na1, K1-
ATPase, which translocates from intracellular stores to the cell sur-
face. Translocation allows for a highly regulated short-lived effect.
The cellular uptake of potassium into cells is also promoted by
b-adrenergic stimulation, xanthines, and alkalemia. In contrast,
mineral acid acidemia, hypertonicity, a-adrenergic agonists, b2-
adrenergic antagonists, and glucagon increase K1 exit into the ECF.
During exercise, catecholamine release via b2-stimulation lessens the
increase in extracellular K1 concentration that would otherwise
result from the normal K1 release by contracting muscle. Pharmaco-
logic stimulation of b2-receptors with exogenous b2-agonists can
Copyright # 2022 by the American Society of Nephrology
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Table 1. Shifts of K1 between extracellular fluid and intracellular fluid
Drives K1 into Cells to Lower [K1]p
Insulin release or administration
b2-adrenergic agonists
a1-adrenergic antagonists
Stress-related epinephrine release
Drugs
Theophylline
Albuterol
Terbutaline
Xanthines
Anabolic state
Rapid advancement of lymphoma or leukemia
Treatment of pernicious anemia
Hypokalemic periodic paralysis
Acquired (thyrotoxicosis)
Familial (periodic hypokalemic paralysis)
Drug induced
Barium
Cesium salts
Thyroxine
Chloroquine
Alkalosis (minimal impact on [K1]p)
result in symptomatic hypokalemia in patients with asthma, heart
failure, and exposure to heroin contaminated with clenbuterol (5,6).
Tocolytic agents, such as ritodrine and terbutaline, in preterm labor
may be associated with severe hypokalemia by stimulating the cellu-
lar uptake of potassium (7).
In addition to factors that affect Na1, K1-ATPase, the distri-
bution of K1 across the cell membrane and the maintenance of the
transmembrane potential are also regulated by Na1/H1 exchanger
(NHE1) and the K1 channel. NHE1 increases Na1 entry into the
cell and thereby secondarily increases the activity of the Na1, K1-
ATPase. Aldosterone affects the transcellular distribution of K1 in
muscle cells by increasing the activity of the NHE1.
Renal Potassium Absorption and Secretion
The ability to conserve potassium is limited. As a result, even with
extreme dietary K1 restriction, although the urine [K1] declines sig-
nificantly, it is not rendered K1 free. This contrasts with the ability
of the kidney to diligently conserve Na1 during extreme dietary
Na1 restriction. In contrast, with higher dietary intake of K1, the
kidney exhibits extraordinary capacity to excrete excess K1 to main-
tain potassium balance.
Proximal Tubule. The majority of the filtered load of K1 is reab-
sorbed in the proximal tubule and the thick ascending limb of
Henle (TALH). ECF K1 is freely filtered by the glomerulus
and then avidly reabsorbed by the proximal tubule and TALH
so that only a small amount of the daily filtered load of K1 reaches
the distal nephron (Figure 1). Reabsorption in the proximal tubule
103
Drives K1 out of Cells to Increase [K1]p
Mineral acid acidosis (not organic endogenous acids)
Hypertonicity
Hyperglycemia
Sucrose
Mannitol
Drugs
a1-adrenergic agonists
b2-adrenergic antagonists
Glucagon
Digoxin overdose
Succinylcholine
Extreme exercise
Crush and tissue injury
Rhabdomyolysis
Hemolysis
Tumor lysis syndrome
is primarily accomplished through the paracellular pathway and is
proportionate to Na1 and water absorption in this segment.
Thick Ascending Limb of Henle (TALH). K1 reabsorption in the
TALH is mediated by the apical Na1, K1-2Cl2 cotransporter
(NKCC2) (Figure 2). The K1 secretory channel on the apical mem-
brane of the TALH recycles K1 at the apical membrane in series with
operation of NKCC2, generating a lumen-positive potential difference
“potassium leak,” which is an important driving force for the passive
reabsorption of K1, Ca12, and Mg12 through the paracellular path-
way. Because solute is reabsorbed avidly, but water is not, the ascend-
ing limb of the loop of Henle is characterized by a progressive decline
in the concentration of Na1, Cl2, and K1 (thus, the designation
“cortical diluting segment”). On arrival of tubule fluid at the distal
convoluted tubule 1 (DCT1), most (approximately 90%) of the fil-
tered load of K1 has already been absorbed so that only approximately
10% of the filtered load of K1 reaches the distal nephron (Figure 1).
Distal Convoluting Tubule (DCT). The DCT1 segment is charac-
terized by the emergence of the sodium-chloride cotransporter (NCC)
on the apical membrane, which is responsible for Na1 and Cl2
absorption as well as the delivery of solute to DCT2 and the collect-
ing duct (Figure 3). NCC is inhibited specifically by thiazide diuretics,
and its function is diminished in Gitelman syndrome through a loss-
of-function mutation of NCC. Gitelman syndrome is characterized
by severe hypokalemia, metabolic alkalosis, salt craving, hypomagnese-
mia, and hypocalciuria and is discussed at greater length below.
Changes in dietary potassium intake and the plasma [K1]
evoke changes in NCC-mediated NaCl transport in DCT1 and
104 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Secretion DCT2,
Reabsorption PCT CNT, CD

Filtered Load K+
10% Filtered Load
700 mEq/day
K+ to DCT1

Reabsorption
Reabsorption CD:
TALH
H+, K+-ATPase

Normal [K+] Hypokalemia

Excrete 10 –15% of Excrete <1% of
Filtered Load Filtered Load

Figure 1. Segmental potassium transport: 80%–90% of filtered load is reabsorbed in proximal convoluted tubule (PCT) and thick ascending
limb of Henle (TALH); approximately 10% of filtered load is delivered to distal convoluted tubule 1 (DCT1). Secretion is highly regulated to
control potassium excretion that occurs predominantly in aldosterone-responsive cells of distal convoluted tubule 2 (DCT2), connecting tubule
(CNT), and collecting duct (CD). H1, K1-ATPase secretes H1 and reabsorbs K1, and is upregulated by hypokalemia (see text).

subsequently, epithelial sodium channel (ENaC) activity in
aldosterone-responsive cells in late distal tubule (DCT2) and cortical
collecting duct, which adjust Na1 absorption and thereby, K1
secretion by renal outer medullary K1 (ROMK) and big potassium
(BK) channels channels (8).
Recent studies from the laboratory of Wang et al. (9) showed
that a specialized K1 conductance channel on the basolateral mem-
brane of DCT1 (Kir4.1) (Figure 3) acts as an intrarenal sensor of
[K1]p and forms a heterotetramer (Kir4.1/Kir5.1). The Kir4.1/Kir5.1
heterotetramer signals through WNK kinases (WNK4, SPAK, and
OSR1), forming “WNK bodies” that modify NCC activity. Accord-
ingly, Na1 absorption and K1 secretion in the more distal nephron
segments (DCT2, CNT, and CCD) are in response to changes in
Na1 delivery to the aldosterone-responsive principal cells. For exam-
ple, low-K1 intake activates Kir4.1 channel activity, which stimulates
the WNK-SPAK kinase pathway and increases NCC activity in
DCT1 cells. When there is a reduction in [K1]p, the WNK kinases
phosphorylate the downstream kinases SPAK and OSR1, which phos-
phorylate and activate NCC. The increase in NCC activity causes an
increase in Na1 and Cl2 reabsorption by DCT1 that decreases Na1
delivery downstream to aldosterone-sensitive cells. The reduction in
Na1 delivery to DCT2 and CD reduces Na1 absorption by ENaC,
which reduces transepithelial voltage and decreases the driving force
for K1 secretion by ROMK and BK potassium channels (10). This
series of events protects the [K1]p from further decline during hypo-
kalemia by reducing the secretion of K1 by principal cells.
This K1-sensing and signaling pathway is supported by con-
struction of a kidney-specific loss-of-function mutation of Kir4.1 in
mouse kidney that recapitulates the classical features of Gitelman
syndrome (e.g., hypokalemia and hypomagnesemia) (11). Apprecia-
tion of the sensor mechanism function of Kir4.1/Kir5.1 in the
kidney has significantly enhanced our understanding of the regula-
tory mechanism of overall K1 homeostasis by the kidney.
Potassium Absorption in Distal Convoluted Tubule 2
(DCT2) and Collecting Duct (CD) by the H1, K1-ATPases
Two isoforms of hydrogen-potassium ATPase a-subunits (H1, K1-
ATPases) are expressed in the apical membrane of a-intercalated cells of
the collecting duct, HKa1 (gastric) and HKa2 (colonic), and are
robustly upregulated by dietary K1 deficiency in experimental animal
models (Figure 4) (12). The upregulation of these ATPases represents
important physiologic adaptive responses, which occur in synchrony
with a decrease in the activity of the ROMK and BK potassium secre-
tory channels to maximally conserve K1 in hypokalemic states.
Pregnancy is an important example of physiologic adaptation
by the kidney to maximally conserve K1. It is widely recognized that
gestational K1 retention, typically occurring in late pregnancy, is essen-
tial for fetal development. West et al. (13) recently reported synergistic
decreases in the cellular expression of potassium secretory channels
ROMK and BKa in a rodent model of late pregnancy. These changes
were concomitant with increases in the mRNA expression of the colonic
subunit of the H1, K1-ATPase (HKa2). A decrease in expression of
the BK channel as well as a parallel increase in HKa2 was also observed
in the distal colon. The combination of changes in the kidney and colon
during pregnancy is consistent with avid potassium retention (13).
Role of Hypokalemia in Maintenance of
Metabolic Alkalosis
In hypokalemic, hypochloremic metabolic alkalosis, the upregula-
tion of HKa2 by hypokalemia contributes to the maintenance of
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
H+ Cl –
Na+ K+
2K+
3Na+
Na+ Cl –
2Cl –
K+ Na+
3HCO3–
Cl –
HCO3 –
K+
Figure 2. Potassium reabsorption in the thick ascending limb of Henle (TALH) is driven by the (1) transepithelial potential as a result of
operation of the apical Na1-K1-2Cl2 cotransporter (NKCC2) in parallel with the renal outer medullary K1 (ROMK) secretory channel (leak
pathway). Transport is passive through the paracellular pathway along with Mg12 and Ca12.
metabolic alkalosis because of continual secretion of H1 into the
tubule fluid. The secretion of H1 by HKa2, in response to the pre-
vailing hypokalemia, is maladaptive for the prevailing metabolic
alkalosis because it compromises the ability of the kidney to excrete
the excess bicarbonate load. Therefore, hypokalemia “maintains” the
alkalosis and must be corrected to repair the metabolic alkalosis.
Additionally, the hypokalemia increases the production and excre-
tion of ammonium to increase urinary net acid excretion that also
serves to maintain the metabolic alkalosis until the hypokalemia is
corrected (14,15). This topic is discussed in greater depth in the
topic on alkalosis in this issue of nephSAP.
Clinical Approach to the Hypokalemic Patient
The concentration of K1 in plasma is maintained in a narrow range
(3.6–4.5 mEq/L), although published normal ranges vary. Hypokale-
mia is defined as a [K1]p ,3.5 mEq/L, whereas a [K1]p of ,2.5
mEq/L should be considered severe, as values below this limit may
be associated with muscle weakness, paralysis, cardiac arrhythmia,
and rhabdomyolysis. Values between 2.5 and 3.0 indicate substantial
hypokalemia requiring diagnosis and treatment. Values for [K1]p are
0.5 mEq/L lower than serum values in the absence of hemolysis. The
105
higher value for [K1] in serum is because clot formation in collected
blood samples causes release of [K1] from platelets.
The reporting of “normal” values for plasma or serum [K1]
diverges somewhat according to the reporting laboratory, especially for
the upper and lower range values. Some reported high “normal values”
(e.g., 5–5.5 mEq/L) are too generous. This review endorses a normal
range for [K1]p equal to 3.6–4.9 mEq/L (or millimoles). Clinicians are
advised to become acquainted with the “normal” or reference range
values for [K1]p in their local clinical chemistry laboratory.
Because the ECF content of K1 is relatively small and is sensi-
tive to cell shifts, it follows that the plasma [K1] is not a reliable
index of TBK. For example, in hypokalemia, a plasma [K1] of
either 3 or 2 mmol/L is approximately equal to a TBK deficit of
200 or 500 mmol, respectively.
Hypokalemia is reported in approximately 3% of unselected
patients admitted to the hospital; however, 20% may develop
hypokalemia during admission as a consequence of infection or
prescribed medication, especially diuretics, or preexisting malnu-
trition, alcoholism or eating disorders, and fever. Although often
modest in severity, hypokalemia can be life threatening. Hypoka-
lemia represents a medical emergency when either cardiac
106 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Na+
NCC 2K+
Cl–
3Na+

K+
Kir4.1

Cl–

ClC-K2

DCT1

NCC inhibited by thiazides and inactive in

Gitelman syndrome

Figure 3. Distal convoluting tubule 1 (DCT1) is the site of Na1-Cl2 cotransport and regulation of sodium-chloride cotransporter (NCC) activ-
ity, and is crucial in the regulation of K1 secretion in downstream segments through delivery of Na1 and Cl2 distally to the aldosterone-
responsive distal tubule (ARDT) of the distal convoluting tubule 2 (DCT2), connecting tubule (CNT), and collecting duct (CD). The sensor
for feedback regulation of plasma [K1] is Kir4.1 on the basolateral membrane of the DCT1 cell. With hypokalemia, Kir4.1 forms tetrameric
Kir4.1/5.1 to phosphorylate WNK and SPAK/OSR1 kinases that then phosphorylate NCC and the Na1, K1-ATPase. Activation of NCC
increases Na1 and Cl2 cotransport by DCT1, therefore reducing the delivery of Na1 downstream and subsequently limiting K1 secretion by
the ARDT. The opposite series of events occurs with an increase in the [K1]p (see in this nephSAP issue: Terker, AS; Ellison, DH: Pathophysi-
ology, Evaluation and Treatment of Hyperkalemia. nephSAP V20N2, Article 4).

arrhythmia or muscle weakness is detected. Patients with moder-
ate or severe acute hypokalemia with symptoms such as muscle
weakness or cardiac arrhythmia require intravenous administra-
tion of KCl emergently.
Transient hypokalemia is usually due to cell shifts, whereas sus-
tained hypokalemia suggests inadequate dietary intake or excessive
K1 loss from the kidney or gastrointestinal tract. The clinical history
and physical examination with careful assessment of ECF volume
status, drug and dietary history, and determination of the acid-base
status will allow the etiology of the hypokalemia to be ascertained in
most cases (Flowchart 1).
Causes of Hypokalemia
Hypokalemia may be caused by low potassium intake, redistribu-
tion, extrarenal potassium loss, and renal potassium loss.
Low Dietary K1 Intake
Dietary potassium restriction is unusual as a solitary cause of chronic
hypokalemia, but it can occur with starvation and malnutrition or
chronic avoidance of potassium-rich foods as is common among
patients with CKD.
Potassium intake is generally low among adults in the United
States. Although the recommended daily dietary intake of potassium
for healthy adults is approximately 4700 mg, several studies have
revealed that ,2% of United States adults reach this goal (16). Food
insecurity is increasingly recognized as a cause of mild or borderline
hypokalemia because of poor access to a healthy diet that includes
daily intake of fruits and vegetables, and this is associated with poor
cardiovascular outcomes (17,18) and development of CKD (19–22).
As noted previously, human kidneys do not conserve potassium
effectively even in the face of a chronically low average daily intake.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
4 Dietary potassium intake evokes coordinated
mechanisms that maintain extracellular potas-
sium concentration within a narrow range. The
sensor(s) may include the extracellular potassium
concentration itself or enteric sensors.
4 Decreased potassium intake and [K1]p increase
activity of the thiazide-sensitive cotransporter
(NCC), which decreases potassium secretion by
ENaC. Decreases in ROMK and BKa and increases
in the H1, K1-ATPase likely conserve potassium
in late pregnancy.
Some have speculated that the inefficient conservation of potassium
results from the evolution of kidneys during the Paleolithic era
when the diet of our hunter-gatherer ancestors provided as much as
15,000 mg of potassium per day (21).
Low potassium intake of itself has been correlated with hyper-
tension, mortality, and cardiovascular risk, possibly because a higher
potassium intake tends to counteract the effects of a high sodium
intake on these outcomes (17,18,20). The studies are discussed
below in the section on complications and outcomes.
Potassium Intake in CKD Patients
As in the non-CKD population, hypokalemia in CKD patients usu-
ally indicates chronic nutritional deficiency (inadequate intake of
fruit and vegetables) or a complication of drug (e.g., diuretic) ther-
apy. Because hypokalemia also carries a higher risk for more rapid
progression of CKD, with or without diuretic use, recognition of
inadequate dietary intake is important (22).
There are no randomized clinical trials that have identified the
ideal daily intake of potassium or even the ideal plasma [K1] for
patients with CKD at any specific stage. Unfortunately, patients
with even early-stage CKD are often instructed, inappropriately, to
adhere to a “renal failure or kidney diet” and restrict dietary K1.
Such a broad generalization may be detrimental. For most hyperten-
sive patients with stage 1 or 2 CKD, we recommend a daily intake
of 4 g of K1 per day (or 102 mmol) and do not recommend dietary
potassium restriction until kidney disease is more advanced (stage
3b and greater). However, dietary K1 should be restricted in
patients with earlier-stage CKD who have a history of documented
hyperkalemia (e.g., hyporeninemic hypoaldosteronism). The mis-
match between nutritional requirements encoded into the human
genome during evolution and the current substandard average daily
intake of K1-rich foods is incriminated in various chronic diseases,
such as hypertension, cardiovascular disease, osteoporosis, and neph-
rolithiasis. An increase in dietary intake of K1 is associated with
reduced BP, decreased risk of stroke, improved bone health, and
reduced risk of nephrolithiasis (23).
Alcohol abuse is a common cause of hypokalemia, as well as
hypomagnesemia and hypophosphatemia. Although starvation is
clearly a feature of hypokalemia associated with alcohol abuse, alco-
hol per se can also adversely affect skeletal muscle membrane integ-
rity. Hypokalemia is of particular concern among individuals with
107
alcohol abuse given its association with QT prolongation and ven-
tricular arrhythmias (24). Such changes have been suggested to play
a role in the increased risk of sudden death reported in patients with
chronic alcohol abuse.
Redistribution of Potassium
As noted previously, the cellular uptake of potassium into cells is
promoted by insulin, B-adrenergic stimulation, xanthines, and alka-
lemia. Pathologic stimulation of b2-receptors can result in symp-
tomatic hypokalemia. A common example is the severe symptomatic
hypokalemia (including hypokalemic paralysis) that is observed with
the hyperadrenergic state that accompanies alcohol withdrawal syn-
dromes (25). Another example of hypokalemia from pathologic
b-adrenergic stimulation is with the drug clenbuterol, which is a
rapidly acting b2-adrenergic agonist with prolonged duration that is
approved in veterinary medicine. Hypokalemia has been reported in
association with clenbuterol used illicitly to increase muscle mass or
cut heroin (26).
Hypokalemic periodic paralyses include acquired (i.e., associated
with thyrotoxicosis) and inherited forms. The inherited disorders are
characterized by muscle weakness or paralysis due to the sudden move-
ment of K1 into cells and caused by channelopathies (of calcium or
sodium channel). All inherited forms are autosomal dominant with
incomplete penetrance. The most commonly observed mutation is in
the muscle calcium channel a-1 subunit gene (CACNA1S). The a-1
subunit is the pore for movement of calcium into the T tubule and
contains the dihydropyridine binding site. Mutations reduce the cal-
cium current. Reduced sarcolemma ATP-sensitive K1 channel activity
underlies the altered K1 fluxes through muscle cells and depolarization
of fibers (27). Less common mutations involve the gene encoding the
skeletal muscle sodium channel (SCN4A) and the K1 channel subunit
gene KCNE3 (R83H mutation), which cause the abnormal sodium
channel to create a gating pore in the voltage sensor, allowing cation
leakage in the resting state (28).
Patients with familial hypokalemic periodic paralysis are
most characteristically men age 20–40 who present with weak-
ness in the setting of conditions associated with release of cate-
cholamines or insulin, such as stress, high-carbohydrate meals,
and exercise. Patients with the familial form are typically younger
than those with acquired hypokalemic paralysis. Attacks often
occur during the rest period immediately following exertion and
may be preceded by muscle cramps and aches. Hypophosphate-
mia and hypomagnesemia may occur with acute attacks and
result from transcellular shifts into the intracellular compart-
ment. The carbonic anhydrase inhibitor, acetazolamide, reduces
the number of attacks in patients with familial hypokalemic
paralysis, possibly related to the induction of metabolic acidosis.
However, although generally effective, a small number of patients
given acetazolamide may demonstrate an exacerbation of symp-
toms (29). The variability of response to acetazolamide may be
dependent on the specific mutation. One hypothesis is that the
specific mutation (as an example, the R83H mutation in the K1
channel subunit gene KCNE3) decreases channel conductance,
and the decrease in conductance is made worse by low pH. This
hypothesis would explain why the paralytic attacks occur after
exercise (because skeletal muscle intracellular pH drops with
exertion) and why symptoms worsen after acetazolamide.
108 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Flowchart 1. Flowchart: Approach to diagnosis of hypokalemia.

Reprinted with permission from reference 15 (Hamm L, DuBose TD Jr: Disorders of acid-base balance. In: Brenner & Rector's The Kidney,
11th Ed., edited by Yu A, Chertow GM, Luyckx VA, Marsden PA, Skorecki K, and Taal MW, Philadelphia, Elsevier, 2020, pp 559–592).

The acquired form of hypokalemic periodic paralysis occurs in
association with thyrotoxicosis, with the highest incidence observed
among Asians and men (30). Patients present with a sudden onset of
generalized weakness, which can last hours to days and is accompanied
by signs and symptoms of thyrotoxicosis (low TSH, high T4 or T3,
tachycardia, fine tremor, weight loss, and heat intolerance). The age of
onset is older than with the familial form, typically after 20 years. The
potassium fluxes are provoked by increased release of catecholamines
or insulin and observed in settings such as stress, high-carbohydrate
meals, and rest after exercise. Hypophosphatemia and hypomagnese-
mia are common during acute attacks. The underlying mechanisms
may be that excess thyroid hormone during thyrotoxicosis increases
Na1, K1-ATPase activity, which drives K1 intracellularly.
The acute attacks are treated with intravenous KCl in
nondextrose-containing saline solutions and nonselective b-adrenergic
blockers. Dextrose will cause insulin release and worsen K1 shifts.
Patients may develop rebound hyperkalemia, which may be severe
and life threatening if KCl is given in excess or too rapidly. One
approach is to reduce or stop intravenous administration and switch
to oral KCl 20 mEq every 2 hours with a maximum dosage of 90
mEq in 24 hours while continuing to monitor the [K1]p. Propranolol
both inhibits the peripheral conversion of T4 to T3 and blocks cate-
cholamines, and it is continued until hypokalemia is corrected. Treat-
ment includes antithyroid drugs until definitive treatment (such as
radioactive iodide or thyroidectomy) is provided. Periodic paralysis
does not recur after the patient becomes euthyroid.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 109

Lumen Interstitial space

AE1
H+-ATPase Cl–
H+ HCO3–
2
1
H+ + HCO3–
H+ H+
4
3 CA II

CO2 + H2O KCC4

H+
5 Cl–
K+ K+
H+, K+-ATPase

Figure 4. Examples of cellular transport abnormalities causing nongap metabolic acidosis of classical dRTA (classical dRTA or type 1 renal tubu-
lar acidosis [RTA]). (1) Abnormality of the gene (SLC4A1) that encodes the Cl2/HCO32 exchanger expressed on the basolateral membrane may
be inherited as either an autosomal dominant or autosomal recessive defect. The latter is associated with early-onset sensorineural deafness, and
the severity of the metabolic acidosis is less than for defects of the H1-ATPase. (2) Abnormality of one of the genes (ATP6V0A4) that encodes
either the A1 subunit of the H1-ATPase, usually associated with deafness, or ATPV1B1 that encodes the B1 subunit. Either may be inherited
(autosomal dominant). Most adult patients with the diagnosis of dRTA have acquired dRTA. One example of acquired dRTA is caused by auto-
antibodies in Sj€ogren syndrome (dry eyes and dry mouth), manifest as (a) lymphocytic infiltration of the salivary gland and impairment of salivary
secretion and (b) NAG acidosis and hypokalemia with defective H1 secretion. The latter is because autoantibodies associated with Sj€ogren syn-
drome disrupt the insertion of the H1-ATPase into the apical membrane, causing a marked decrease in H1 secretion. The clinical features of
dRTA are reviewed in the text. (3) Carbonic anhydrase II deficiency is autosomal recessive abnormality of the CA2 gene that encodes the intracel-
lular enzyme present in the proximal and distal renal tubules and in other organs. It is associated with RTA, osteopetrosis, mental retardation,
recurrent bone fractures, growth failure, and recurrent nephrolithiasis. (4) Permeability defect or “gradient defect” (e.g., usually acquired by
administration of amphotericin B [antifungal agent]; may be inherited rarely). (5) Abnormality of H1, K1-ATPase.

Extrarenal K1 Loss polypeptide, which causes a watery diarrhea syndrome similar to

Extrarenal potassium loss may be cutaneous or gastrointestinal.
Cutaneous loss of K1 sufficient to cause hypokalemia may occur in
the setting of intense exercise in a hot humid environment (31)
when large volumes of sweat can be lost each day.
Gastrointestinal loss is a common cause of hypokalemia and is
observed with high-volume secretory diarrhea. Hypokalemia has also
been reported with the paraneoplastic syndrome of watery diarrhea,
hypokalemia, and achlorhydria in patients with neuroendocrine
tumor and is related to secretion of vasoactive intestinal polypep-
tide (32). Hypokalemia may also be observed with pancreatic
that of vasoactive intestinal polypeptideoma, and with excessive
secretion of K1 by a villous adenoma (33).
Ogilvie syndrome is characterized by diarrhea, hypokalemia due
to high excretion of K1 in stool, and a dilated colon and has been
reported in elderly patients after nongastrointestinal surgery. Mea-
surement of the rectosigmoid potential difference in a patient with
Ogilvie syndrome was reported as 213 mV (lumen negative) (34),
suggesting active K1 secretion along with active Na1 reabsorption
across the colonic mucosa. The pseudo-obstruction resolves slowly
after K1 replacement.
110
As in the kidney, K1 is both absorbed and secreted in the
colon. Colonic K1 absorption occurs via the colonic isoform of
H1, K1-ATPase (HKa2), which is upregulated by hypokalemia as
in the collecting duct (35). K1 secretion occurs via a luminal
calcium-activated BK potassium channel that is upregulated by high
dietary K1 intake (36,37).
Bowel cleansing solutions are occasionally associated with hypo-
kalemia, hyperphosphatemia, hypocalcemia, and hypernatremia,
particularly in older individuals or those with the presence of bowel
obstruction, poor gut motility, and kidney disease.
Increased Renal K1 Excretion
There are generally two causes of increased kidney potassium excre-
tion. These include increased activity of ENaC and increased
sodium delivery to the distal nephron.
Increased ENaC activity may be due to increased aldosterone
(hyperaldosteronism) or be aldosterone independent. Hyperaldosteron-
ism may be secondary to increased renin or primary with suppressed
renin concentration. Increased ENaC activity in the absence of increased
renin or aldosterone is associated with low-renin and low-aldosterone
concentrations. The conditions are often classified as high renin/high
aldosterone, low renin/high aldosterone, and low renin/low aldosterone
(Table 2 and Flowchart 1). All conditions are associated with volume
expansion, hypertension, and usually, hypokalemia and alkalosis.
High renin/high aldosteronism is caused by renal artery stenosis
and less commonly, renin-secreting tumor. Low renin/high aldoste-
ronism is due to adrenal adenoma, bilateral adrenal hyperplasia, and
glucocorticoid-remediable aldosteronism.
Low renin/low aldosterone causes include Cushing disease or
syndrome, 11b-hydroxylase deficiency, 17a-hydroxylase deficiency,
Liddle syndrome, and decreased activity of 11b-hydroxysteroid
dehydrogenase enzyme type II (either familial due to autosomal
recessive inheritance or acquired due to licorice/glycyrrhizin acid).
Increased Distal Sodium Delivery
Conditions that increase sodium delivery include diuretics, poorly
reabsorbed anions such as bicarbonate (vomiting or type 2 renal
Table 2. Hypokalemia due to increased epithelial sodium channel (ENaC) activity
Serum Renin and Aldosterone Levels
High renin/high aldosterone
Low renin/high aldosterone
Low renin/low aldosterone
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
tubular acidosis [RTA]), ketoanions (as in ketoacidosis), and penicil-
lin derivatives. These conditions are usually associated with normal
or low volume status and BP. Poorly reabsorbed anions increased
the electronegativity of the lumen, which increases the driving force
for potassium excretion into the lumen.
The evaluation of these disorders requires assessing the ratio of
the plasma aldosterone concentration to plasma renin activity. Imag-
ing of the renal arteries (doppler, CTA, or MRA), renal vein sam-
pling, and adrenals imaging may yield a diagnosis. In the setting of
low renin and aldosterone, genetic analysis is required to
differentiate.
Hypokalemia and Nongap Metabolic Acidosis
The defect in proximal RTA (type 2 RTA) impairs bicarbonate
reabsorption in the proximal tubule and is manifest as a reduction
in the threshold for bicarbonate reabsorption causing self-limited
bicarbonaturia, nongap metabolic acidosis, hypokalemia, and vol-
ume depletion. Secondarily, volume depletion activates the RAAS.
Increased aldosterone levels coupled with increased distal delivery of
Na1 and HCO32 cause renal K1 wasting; additionally, HCO32
behaves as a poorly reabsorbed anion in the distal nephron (15). In
the steady state when the filtered load of HCO32 declines to the
proximal tubule threshold level (15–17 mEq/L), this reduced
amount can be absorbed, and bicarbonaturia subsides; consequently,
renal K1 secretion also declines. Nevertheless, most patients with
proximal RTA require chronic K1 replacement. Unfortunately,
treatment of the metabolic acidosis with bicarbonate improves the
acidosis but exacerbates the degree of hypokalemia by enhancing K1
excretion because of higher distal Na1 and HCO32 delivery. There-
fore, a combination of potassium and base precursor may be
provided as potassium citrate (K1-Shohl solution or K1-citrate)
in proximal RTA.
Most patients with classical distal RTA present with a nongap
metabolic acidosis with hypokalemia (type 1 RTA). Distal RTA
may be the result of an inherited (autosomal recessive) defect in the
genes that encode acid-base transporters in the distal nephron. For
example, either of two subunits of the apical H1-ATPase transporter
(ATP6V0A4 or ATPV1B1) of a-intercalated cells may be defective
Causes
Renal artery stenosis
Hemangiopericytoma
Adrenal adenoma
Bilateral adrenal hyperplasia
Glucocorticoid remediable aldosteronism
11b-hydroxylase deficiency
17a-hydroxylase deficiency
Liddle syndrome
Apparent mineralocorticoid excess (familial due to
11b-hydroxysteroid dehydrogenase II deficiency)
Apparent mineralocorticoid
Excess (acquired) due to licorice/glycorrhyzic acid
Cushing disease
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
(Figure 4). Patients who present in adolescence, with an autosomal
dominant pattern of inheritance and often with accompanying sen-
sorineural hearing loss, typically have a defect in SLC4A1 (the gene
that encodes the basolateral HCO32/Cl2 exchanger [SLC26A7] in
the outer medullary collecting duct). In addition to nongap meta-
bolic acidosis, the phenotype includes volume depletion, growth
retardation, osteomalacia, nephrolithiasis, and secondary hyperaldos-
teronism with increased renal K1 excretion. The most common
acquired form of distal RTA is that associated with Sj€ogren syn-
drome. The autoantibodies generated in Sj€ogren syndrome interfere
with the normal trafficking of the H1-ATPase to the apical mem-
brane, thus preventing its activation. Kidney biopsies of Sj€ogren syn-
drome patients with classical dRTA that have been immunostained
specifically for the H1-ATPase antibody have revealed coalescence
of the H1-ATPase in intracellular compartments (38). A third
potential defect causing dRTA involves loss of function of the H1,
K1-ATPase that would impair K1 reabsorption in the collecting
duct to increase renal K1 excretion. Such an abnormality has been
proposed as an explanation for the combined presentation of severe
hypokalemia and nongap metabolic acidosis in an infant, but a
defect in the H1, K1-ATPase per se has not been unequivocally
demonstrated (39). Finally, dRTA can be acquired as a result of a
“gradient defect.” An example of this type of dRTA is that due to
nephrotoxicity caused by administration of amphotericin B. In
amphotericin B induced distal RTA, K1 wasting is the result of an
increase in permeability of the collecting duct a-intercalated cell
causing K1 to leak from the cell to the lumen increasing K1 secre-
tion, whereas the normally secreted H1 leaks back from the lumen
into the cell across the leaky apical membrane, consequently decreas-
ing net H1 secretion (15). The locations of the cellular transporter
abnormalities responsible for the various causes of classical dRTA
are reviewed in Figure 4. All varieties of untreated classical distal
RTA are associated with a decrease in urinary ammonium (NH41)
excretion. Type 4 RTA, probably the most commonly observed
form of RTA, is usually a result of hyporeninemic hypoaldosteron-
ism or obstructive nephropathy and the only type of RTA associated
with hyperkalemia.
Toluene inhalation, although uncommon, may cause severe
hypokalemia concurrent with a nongap metabolic acidosis. Symp-
toms are caused by the toluene metabolite, hippuric acid, and the
renal excretion of its sodium salt. Chronic exposure may lead to a
persistent dRTA (15). Toxicity from transdermal exposure was
recently described in a case report (40).
The Urine Anion Gap and the Urine Osmolar Gap
The urine anion gap (UAG) is a clinical method to estimate NH41
excretion and is commonly used in assessment of nongap metabolic
acidosis. The UAG is zero to slightly positive in healthy individuals
on a typical Western diet. The appropriate response by the normal
kidney to an increase in dietary protein that increases net acid
production is to significantly increase NH41 excretion. The UAG cal-
culated as the U[Cl2]–(U [Na1]1[K1]) is an arithmetic estimate of
urine [NH41], and by convention, a negative UAG indicates the
presence of [NH41] in the urine. For example, the normal kidney
responds to nongap metabolic acidosis of nonrenal origin (e.g., diar-
rhea) by significantly increasing urine [NH41]. Therefore, the UAG
is negative when ammonium is present in urine and with nonrenal
111
acidosis, should be 220 mEq/L or more. In contrast, failure to
increase NH41 excretion in the face of a nongap metabolic acidosis is
a sentinel feature of RTA and is implied by a positive UAG: U
[Na11K1].U [Cl2]. Unfortunately, calculation of the UAG failed
to consistently represent the measured urine [NH41] in the AASK
trial (41). The concentration of urine NH41 can be estimated from
the urine osmolar gap (UOG) and is equal to the UOG/2. The
UOG is the difference between the measured urine osmolality and
the calculated urine osmolality. Estimated urine [NH41] concentra-
tions exceeding 75 mEq/L or more are anticipated if renal tubular
function is intact and may be more accurate than the UAG. Never-
theless, the most accurate analysis is to request the clinical laboratory
to measure the urine [NH41]. Unfortunately, some clinical laborato-
ries resist performing urine [NH41] analysis, although urine [NH41]
can be measured accurately if the urine sample is diluted appropriately
(1:100) for analysis using a standard autoanalyzer ammonia assay
(42). We recommend measurement of urine ammonium concentra-
tion by clinical laboratories rather than reliance on imprecise surro-
gates, such as the UAG or the UOG, which when compared with
measured values, do not correlate reliably or reproducibly with actual
measured values for urine [NH41] (41,43).
In summary, patients with hypokalemic nongap metabolic aci-
dosis in combination with an alkaline urine pH as well as evidence
of an abnormally elevated level of renal potassium excretion and a
positive UAG should be suspected of having distal RTA (type 1
RTA). Under normal circumstances, ammonium salts are the major
solutes contributing to urine osmolality. Pitfalls include other
osmoles, such as Hippurate anions that increase the UOG by .150
mosmol/kg with nongap metabolic acidosis. If there is a suspicion of
toluene abuse, a UOG should be obtained. If the UOG is .150
mosmol/kg, the nonanion gap acidosis is due to the excretion of
other osmotically active substances (e.g., toluene intoxication with
Hippurate excretion).
Hypokalemia with Metabolic Alkalosis, Volume
Depletion, and Normal or Low BP—High Urine [Cl]:
Bartter Syndrome and Gitelman Syndrome
Bartter and Gitelman syndromes are hereditary disorders character-
ized by hypokalemic metabolic alkalosis.
Bartter syndrome is characterized by severe hypokalemia that may
be associated with rhabdomyolysis and flaccid paralysis (15,44,45).
Five types of defects in transporters of the TALH can account for the
phenotypes of Bartter syndrome. Bartter syndromes are caused by
recessive mutations of transport proteins in the TALH cell involved in
NaCl and K1 transport. The “type I defect” is of the SLC12A1 gene
that encodes NKCC2. The type II defect impairs the KCNJ1 gene
that encodes the potassium channel on the apical membrane, ROMK.
The type III defect impairs the CLCNKB gene that encodes the baso-
lateral ClC-Kb channel. The type IV defect involves the BSND gene
that encodes the intracellular accessory protein Bartten that binds ClC-
Ka and ClC-Kb. Alternatively, type IV-B is represented by a combined
defect in CLCNKA and CLCNKB genes that encode both the ClC-Ka
and ClC-Kb channel proteins. The decreased NaCl and fluid reab-
sorption in the thick limb is similar to effects of a loop diuretic.
Types I and II Bartter syndrome are severe and usually present
as polyhydramnios in pregnancy or as hypokalemia and weakness in
premature infants. Affected infants with types 1 and 2 may have
112 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

transient hyperkalemia due to loss of function of ROMK in the col-
lecting duct. However, hypokalemia occurs as infants mature as a
result of increased K1 secretion via maxi-K1 (or BK) channels in
the DCT and CD because of an increase in tubule fluid flow. This
model is supported by studies in an ROMK-deficient mouse model
of type II Bartter syndrome (46).
The most common phenotype, type III Bartter syndrome, is
less severe than types I and II and presents later in life. The disease
is due to a reduced activity of ClC-Kb (the basolateral Cl2 channel
in the TALH) but with a degree of preservation of ClC-Kb activity.
Some patients exhibit features of Gitelman syndrome (hypomagne-
semia and hypocalciuria). The specific transport defects for Bartter
syndrome (TALH) and Gitelman syndrome are compared and con-
trasted in Figure 5.
Gitelman syndrome is caused by a mutation of SLC12A3,
which encodes the thiazide-sensitive NCC in DCT1. Patients pre-
sent with hypokalemia, hypomagnesemia, hypocalciuria, and normal
BP with mild hypovolemia. A 2006 report demonstrated complete
absence of NCC immunostaining on renal biopsies of two individu-
als with Gitelman syndrome (15,47).
Most patients with Gitelman syndrome come to the
attention of nephrologists because of difficult hypokalemia with
severe muscle weakness. Gitelman syndrome has been asso-
ciated with severe complications, including hypokalemia- and
hypomagnesemia-related paralysis and prolongation of the QT
interval with malignant arrhythmias (48,49). Consensus guidance
was published by Kidney Disease Improving Global Outcomes
(KDIGO) in 2017 (50). The KDIGO group suggested that
Gitelman syndrome be suspected in the setting of chronic hypo-
kalemia with urinary K wasting, metabolic alkalosis, hypomagne-
semia, hypocalciuria, high plasma renin, fractional chloride excre-
tion .0.5%, low or normal BP, and a normal ultrasound.
Although patients typically respond well to emergent K1 replace-
ment, chronic management can be challenging. Patients are typi-
cally managed chronically with potassium and magnesium sup-
plementation, amiloride, and spironolactone. This regimen is
usually successful, especially initially, but may be overwhelmed
because patients with Gitelman syndrome commonly crave salt.
The increased salt and fluid intake enhances Na1 delivery to the
distal nephron and drives K1 secretion by the unaffected CCT
principal cells. Therefore, in patients with salt craving and exces-
sive dietary salt intake, reducing salt intake is needed because
continued delivery of a high-NaCl load to the distal nephron and
collecting duct aggravates K1 secretion. Accordingly, we agree
with the KDIGO recommendation that ad libitum salt intake
should be encouraged but only in patients with evidence of lower
salt intake and not in patients with an established high-salt intake
(50).

A B

H+
Na+ Cl–
Na+ 2K+
K+ NCC
Cl– 3Na+

Na+
2Cl– NKCC2 2K+
K+ 3Na+
I

K+ Cl–
Cl–
II III

TALH Cell DCT Cell

Bartters Gitelmans

Figure 5. Contrasting transporter abnormalities responsible for Bartter syndrome versus Gitelman syndrome. (A) Bartter syndrome types I, II,
and III are inherited in the autosomal recessive manner. Genes responsible are I. SLC12A1, II. KCNJ1, and III. CLCNKB. (B) Gitelman syn-
drome is an inherited (autosomal recessive) defect of one of the genes (SLCl2A3 or CLCNKB) that encodes the protein NCC, the apical Na1/
Cl2 cotransporter.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Assessment of Renal Potassium Excretion
Measurement of renal K1 excretion confirms whether potassium
loss is renal or extrarenal. Renal K1 excretion can be measured via a
24-hour urine collection, but it is often more convenient to measure
a spot urine K1/creatinine ratio. A spot urine K1/Cr ratio ,13
mEq/g (1.5 mEq/mmol) of creatinine suggests extrarenal loss of
potassium, whereas a urine K1/Cr ratio .13 mEq/g (1.5 mEq/
mmol) of creatinine suggests excessive K1 excretion by the kidney.
Because the urine K1/Cr ratio can be affected by the rate of creati-
nine excretion, a low body mass index or loss of muscle mass can
reduce the rate of creatinine excretion and falsely elevate the urine
K1/Cr ratio.
Use of the urine K1/Cr ratio was reported to differentiate
between 30 patients with hypokalemic periodic paralysis (redistribu-
tion hypokalemia) versus ten patients with nonhypokalemic periodic
paralysis due to renal K1 loss (11 versus 36 mEq/g creatinine or 1.3
versus 4.1 mEq/mmol creatinine, respectively) (51).
The transtubular K1 gradient (TTKG) was previously pro-
posed to evaluate renal K1 excretion. Unfortunately, the assump-
tions made in calculating the TTKG are not entirely correct. The
first assumption is that there is only water reabsorption (i.e., without
solute transport) in the medullary collecting duct. The reabsorption
of any solute, such as Na1 or urea, would lower urine osmolality,
resulting in an overestimate of the gradient for K1 secretion in the
upstream collecting duct. Second, for the TTKG to provide an
accurate estimate, conditions should be optimal for K1 secretion at
the time of measurement. Thus, the urine Na1 should be .25
mEq/L to ensure adequate Na1 delivery to the collecting duct.
Urine osmolality should be equal to plasma osmolality. A higher
urine osmolality suggests the presence of circulating vasopressin,
which stimulates K1 secretion in the collecting duct. If these condi-
tions are not met, the TTKG cannot be used reliably. Because of
these limitations and as clinicians obtain more experience with the
urine K1/Cr ratio, the use of the TTKG will probably be discarded.
Treatment of Hypokalemia
Potassium should be given either orally or intravenously as the KCl
salt. Potassium citrate should not be used unless the patient has met-
abolic acidosis (as in patients with proximal RTA). Potassium citrate
may increase K1 excretion because the citrate is converted to bicar-
bonate, which raises the plasma bicarbonate concentration and
increases excretion.
KCl should be given slowly (i.e., ,10 mmol/h in dilute saline
solution) to patients with extreme muscle weakness or cardiac
arrhythmias. To prevent rebound hyperkalemia, a conservative goal
is to increase the [K1]p to 3.4 mEq/L using intravenous KCl and
then, to use oral KCl. In a 2007 survey of 140 hospitalized patients
with hypokalemia, 16% developed therapy-induced hyperkalemia
(52). In the face of life-threatening complications, more aggressive
KCl administration may be required using central intravenous
access, frequent measurement of [K1]p, and continuous electrocar-
diographic monitoring.
As noted previously, treatment of the hypokalemia due to with
Bartter or Gitelman syndrome involves both potassium and magne-
sium replacement. Oral magnesium replacement, at least initially, is
preferable in asymptomatic patients. Oral magnesium therapy may
not be tolerated because of the development of frequent bowel
113
4 Increased potassium excretion by the kidney is
caused by increased activity of ENaC and
increased sodium delivery to the distal nephron.
4 Increased sodium delivery results from diuretics
(or inherited disorders, such as Bartter and Gitel-
man syndromes, or vomiting), poorly reabsorbed
anions, or type 2 RTAs.
4 Bartter and Gitelman syndromes are caused by muta-
tions of transporter proteins in the TALH loop and the
thiazide-sensitive NCC in DCT1. There is overlap in
clinical presentation, and the diagnosis should be
confirmed by genetic testing when possible.
movements and diarrhea that will increase potassium excretion by
the colon. Intravenous magnesium increases serum magnesium lev-
els, but the patient will lose 50% of the administered magnesium
into the urine.
Amiloride reduces renal Mg12 wasting in patients with Gitel-
man or Bartter syndrome. Amiloride should only be given as amilor-
ide (Midamor) and not with a thiazide in combination. The dose of
amiloride may be advanced slowly from 5 to 15–20 mg/d.
Angiotensin-converting enzyme inhibitors help reduce aldosterone
levels and are used as adjunctive therapy, but because of possible
hypotension, they should be used in very small doses. In Bartter syn-
drome, nonsteroidal anti-inflammatory drugs have been used to
ameliorate the effect of increased prostaglandin E2 in the loop of
Henle.
For chronic treatment of hypokalemia in classical distal RTA,
administration of alkali as K1 citrate is preferred to correct both the
nongap acidosis and the hypokalemia. After the hypokalemia is cor-
rected, either sodium citrate (modified Shohl solution) or sodium
bicarbonate tablets (650 mg per tablet) may be initiated. With cor-
rection of the acidosis, the hypokalemia often subsides, and K1
administration may be discontinued in adults. Correction of acidosis
is important for normal growth in children to inhibit progression of
CKD in both adults and children. Finally, with the increase in urine
citrate and decrease in urine [Ca12] excretion, the frequency of
nephrolithiasis declines dramatically.
Complications and Outcomes
Hypokalemia can cause a variety of clinical manifestations due to
alterations in the excitability of neuromuscular tissues (Table 3). In
addition, both hypokalemia and decreased dietary potassium intake
have been associated with adverse long-term outcomes. Both acute
complications and long-term outcomes are discussed below.
Acute Complications
Muscle Weakness. Muscle weakness is a common symptom of
hypokalemia and is caused by hyperpolarization of the cell mem-
brane (53).
114
Rhabdomyolysis. Severe hypokalemia may cause rhabdomyolysis
especially when associated with alcohol intoxication and alcohol-
associated malnutrition. A possible mechanism is that decreased
accumulation of K1 in the interstitial space limits blood flow to
skeletal muscle and increases muscle breakdown. Chronic alcohol
abuse is also associated with acquired compromise of the integrity of
skeletal cell muscle membrane and renders it susceptible to damage.
Cardiac Arrhythmia
Cardiac arrhythmias are seen in some patients with hypokalemia.
EKG changes include T-wave flattening, U waves, and ST-segment
depression. Hypokalemia causes direct electrophysiological effects
such as resting membrane hyperpolarization; reduced repolarization
reserve; inhibition of Na1, K1 ATPase; and suppression of K1 con-
ductance channels, which predispose the myocardium to early after
depolarizations (54).
Long-Term Outcomes
Hypokalemic Nephropathy (Kaliopenic Nephropathy). Chronic
hypokalemia causes a tubulointerstitial lesion characterized by
tubular atrophy and interstitial fibrosis, an interstitial macrophage
infiltrate and renal cysts (55). Affected patients have polyuria, pro-
teinuria, and often mildly decreased GFR. Kidney injury is caused
by ischemia, complement activation related to increased ammonia-
genesis, and effects of angiotensin II and endothelin.
New-Onset Diabetes. Hypokalemia likely underlies the association
between new-onset diabetes mellitus and use of thiazide diuretics. In
a systematic review including 50 trials that compared thiazides with
other drugs or placebo, hypokalemia was associated with the devel-
opment of hyperglycemia, such that there was an approximately
10-mg/dl increase in glucose for every 1-mEq/L decrease in K1 (56).
The prevention of hypokalemia with K1 supplements decreases
the risk of thiazide-induced glucose intolerance (57). More recently,
a randomized trial examined whether the addition or substitution of
amiloride to thiazide treatment would prevent the glucose intoler-
ance associated with thiazide diuretics (58). This trial included 145
patients assigned to amiloride, 146 assigned to hydrochlorthiazide,
and 150 assigned to combination therapy with amiloride and hydro-
chlorthiazide. At 12 and 24 weeks, 2-hour glucose and oral glucose
tolerance tests were significantly lower in the amiloride and the
amiloride/hydrochlorthiazide groups compared with the hydrochlor-
thiazide group.
Table 3. Consequences of severe hypokalemia
Consequence
Severe muscle weakness—serum K1 ,3.0 mEq/L
Acute rhabdomyolysis, myoglobinuria—serum K1 ,2.5 mEq/L
Cardiac arrhythmia
Respiratory muscle weakness, respiratory arrest
Ileus
Acquired diabetes insipidus
Kaliopenic nephropathy
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Table 4. Potential harmful effects of chronic hypokalemia
in CKD
Harmful Effect
Worsening of hypertension
Expansion of renal fibrosis and enhanced cyst formation
Acceleration of progression of CKD
Ventricular arrhythmias
In ESKD: Intradialytic hypotension
The mechanism of thiazide-induced hyperglycemia may be due
to decreased insulin release from the pancreatic b-cell because ATP-
sensitive K1 channels modulate insulin secretion (59).
True hypokalemia is associated with higher rates of all-cause
mortality and higher rates of major cardiovascular events and hospi-
talization. Several studies have documented a “U-shaped” relation-
ship between the serum [K1] and mortality in patients with CKD,
cardiovascular disease, or diabetes; that is, higher mortality is
observed similarly for both hypokalemia and hyperkalemia in the
lowest and highest ranges, respectively (60,61). In general urban
populations, mild chronic hypokalemia has been associated with a
higher incidence of hypertension, poorly controlled hypertension,
cardiovascular disease, progression of established kidney disease, and
nephrolithiasis (Table 4) (62,63).
Studies have been conflicting in CKD patients. A recent analy-
sis of data from the Korean Cohort Study of outcomes in 1821
patients with CKD demonstrated a higher risk of CKD progression
(defined as a 50% decrease in eGFR) among individuals with the
lowest quartile of urinary potassium to creatinine compared with
those in the highest quartile (64). These result are consistent with
some (65–67), although not all (68), previously published data. The
Chronic Renal Insufficiency Cohort study reported higher incidence
of ESKD in individuals with high potassium excretion (68). The
reason for conflicting results from these studies is not clear (20).
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Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Article
Pathophysiology, Evaluation, and Treatment of Hyperkalemia
Andrew S. Terker, MD, PhD,1 and David H. Ellison, MD, FASN2
1
Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee
2
Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland,
Oregon
Learning Objectives
1. To summarize the mechanisms underlying internal and
external potassium balance
2. To define the pathophysiology of hyperkalemia
3. To summarize current approaches to acute and chronic
hyperkalemia
Introduction
Potassium is the predominant cation inside of cells, and it plays
essential roles, especially in setting the resting potential of most cells
throughout the body. Potassium homeostasis requires coordination
of external balance, derived primarily via gastrointestinal absorption
and renal excretion, and internal balance, meaning the asymmetric
distribution of K1 between the intracellular space and the extracel-
lular space. This article briefly reviews aspects of normal internal
and external potassium balance and then discusses the pathophysiol-
ogy of hyperkalemia.
Cardiovascular Outcomes and Mortality
Population-based studies have consistently demonstrated a strong
correlation between dietary potassium intake and poor cardiovascu-
lar outcomes. In most analyses, the mortality risk related to plasma
potassium concentration is U shaped, with excess in both the hypo-
kalemic and hyperkalemic ranges (1). A 2018 meta-analysis of the
CKD Prognosis Consortium included patient-level data from 27
international cohorts (10 general population, 10 with CKD, 7 high
cardiovascular risk) (1). At 6.9 years, the lowest all-cause mortality
risk was associated with potassium 4 to 4.5 mEq/L. Compared with
potassium of 4.2 mEq/L, the associated hazard ratio was 1.22 (95%
CI, 1.15 to 1.29) for potassium 5.5 mEq/L and 1.49 (95% CI, 1.26
to 1.76) for potassium 3.0 mEq/L. There were similar U-shaped
associations for cardiovascular mortality and ESKD.
Total Body Potassium Distribution
Total body potassium abundance has been estimated to be about 55
mmol/kg, or between 3000 and 4000 mmol for a 70-kg person,
with approximately 98% of the cation found intracellularly. Most of
the intracellular potassium resides in skeletal muscle, given the abun-
dance of this tissue in the body, although significant amounts are
also in other tissues, including red blood cells and liver. Only
Copyright # 2022 by the American Society of Nephrology
117
approximately 2% of the total body potassium, or 70 mmol, exists
in the extracellular compartment, and precise control of the distribu-
tion between intracellular and extracellular compartments is impera-
tive to ensure proper cell function, particularly for electrically excit-
able cells such as cardiac and skeletal muscle and neurons. This
distribution is maintained by a system that ultimately requires activ-
ity of the Na1/K1 adenosine triphosphate (ATP)ase, which uses
energy to actively pump potassium into cells against its electrochem-
ical gradient. The tendency of potassium to lead out of cells, via
membrane channels, leads most cells to have a membrane voltage
oriented with the cell interior negative, relative to the cell exterior.
Disruption of this system can result in pathologic aberrations in
plasma potassium and secondarily affect cell membrane potential,
which increases the risk of life-threatening cardiac arrhythmias.
Regulation of Potassium Homeostasis
Daily dietary potassium intake generally ranges between 50 and 150
mmol, which is roughly equivalent to the entire extracellular pool.
Avoiding significant and sustained aberrations in both total and
plasma potassium levels requires a quick and efficient system to
maintain homeostasis. The potassium homeostatic mechanism
involves coordinated regulation between its major components,
including the gastrointestinal tract, which absorbs dietary potassium;
skeletal muscle, which harbors the majority of intracellular potas-
sium and is involved in intracellular/extracellular redistribution; and
the kidney, which is the predominant site of potassium excretion,
most of which derives from secretion along the aldosterone-sensitive
distal nephron (ASDN). Coordination of these components is
accomplished via hormonal control, including contributions from
aldosterone, insulin, adrenergic stimuli, and plasma potassium itself.
Gastrointestinal Absorption
Dietary potassium intake can vary widely across populations as well
as temporally in a given individual. In general, potassium consumed
in the diet is well absorbed.
Renal Potassium Reabsorption and Secretion
Proximal Tubule. Potassium is freely filtered by the glomerulus
and then reabsorbed along the proximal tubule (PT), where approxi-
mately 60%–65% of total reabsorption occurs. Reabsorption occurs
primarily via a paracellular pathway wherein potassium flux occurs
secondary to bulk water reabsorption.
nephsap.org
118
Thick Ascending Limb of Henle. Approximately 20%–25% of the
filtered potassium load is reabsorbed along the thick ascending limb
of Henle (TAL). The reabsorptive pathway along this segment
depends on apical activity of the sodium-potassium-2 chloride
cotransporter (NKCC2). The renal outer medullary potassium
channel (ROMK or Kir1.1) is expressed and active along the apical
plasma membrane of the TAL and permits a portion of the potas-
sium that traverses the NKCC2 to recycle across the apical mem-
brane; coupled with basolateral chloride efflux, via ClC chloride
channels, this generates a net-positive lumen potential. This positive
potential then drives paracellular potassium reabsorption along with
other cations, such as Ca21 and Mg21. When this mechanism fails,
as in Bartter syndrome or during furosemide administration,
patients present with hypokalemia caused by renal potassium losses.
Although potassium is reabsorbed along the TAL under most condi-
tions, recent experiments show that the transport direction may
reverse when animals consume a low-sodium/high-potassium diet,
in which case the TAL becomes a potassium-secreting segment (2).
Under these conditions, furosemide administration becomes potas-
sium sparing. Whether similar effects occur is humans has not
been studied.
Distal Convoluted Tubule. Studies have failed to consistently dem-
onstrate meaningful quantities of potassium reabsorption or secre-
tion along the distal convoluted tubule (DCT). The contribution of
this segment is, however, integral to maintaining potassium bal-
ance—a finding highlighted by dysregulated potassium homeostasis
in Mendelian tubulopathies affecting the DCT such as Gitelman
syndrome and familial hyperkalemic hypertension (also called pseu-
dohypoaldosteronism type 2 or Gordon syndrome). Substantial
work over the past decade has demonstrated that this segment’s role
in potassium reabsorption is a consequence of its ability to act as a
modulator of sodium flow to the more distal connecting segment
and collecting duct (CD), major sites of sodium-dependent potas-
sium secretion. Inasmuch as these more distal segments require
sodium reabsorption to generate a lumen-negative transepithelial
voltage to secrete potassium, the DCT can increase or decrease
potassium excretion by allowing more or less sodium to flow dis-
tally. The DCT accomplishes this by modulating apical sodium
reabsorption via the sodium-chloride cotransporter, which is regu-
lated by a molecular signaling pathway (WNK-SPAK) that is known
to be potassium sensitive and allows this system to sense and
respond to aberrations in plasma potassium levels (3,4). (See
“Integrated renal potassium excretion: The potassium switch” below
for additional details.)
Connecting Tubule and Collecting Duct. The connecting tubule
(CNT) and the CD are targets of aldosterone and act as the pre-
dominant sites for active potassium secretion in the body. After
reabsorption along the PT and TAL, approximately 10% of the fil-
tered potassium load reaches the CNT. Along the CNT and CD,
net potassium transport can range from nearly complete reabsorp-
tion of the remaining filtered load (approximately 10%) to net secre-
tion. Under normal conditions, potassium secretion predominates
and is responsible for the majority of potassium excreted in the
urine. This system relies on a net negative lumen potential created
by apical sodium reabsorption via the epithelial sodium channel
(ENaC) to drive electrogenic potassium secretion via apically
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
expressed ROMK and BK (Maxi K) channels. Extensive work has
clearly shown that this system is activated by aldosterone via miner-
alocorticoid receptor signaling (5,6), which is why this nephron
segment is often referred to as the aldosterone-sensitive distal neph-
ron (ASDN).
The secretory capacity of these segments is exceptional, with
animal models demonstrating minimal changes in plasma potassium
levels after the consumption of heavily potassium-loaded diets
(#5% wt/wt). It has become clear that under typical dietary condi-
tions, the CNT is the most active potassium secretory site, whereas
the CD typically becomes active primarily when aldosterone secre-
tion is stimulated by depletion of the extracellular fluid volume or
by hyperkalemia (7).
During states of potassium depletion, potassium can be reab-
sorbed along this segment; a-intercalated cells are the major cells
responsible for potassium reabsorption. They express the hydrogen-
potassium ATPase (H1-K1 ATPase), for which two isoforms exist:
HKa1 and HKa2. In models of experimental hypokalemia, H1-K1
ATPase abundance increases (8) to maximally conserve total body
potassium.
Integrated Renal Potassium Excretion: The
Potassium Switch
During the past several years, an increased understanding of renal
potassium handling has emerged, in large part driven by the molecu-
lar solutions to monogenic diseases of potassium retention and potas-
sium wasting. Gitelman syndrome, an autosomal recessive disease,
typically presents with profound hypokalemia (see the NephSAP
article on hypokalemia) and is caused by mutations in the gene
encoding NCC, expressed exclusively along the DCT (9). Yet, as
noted above, this segment of the nephron does not transport substan-
tial amounts of potassium, which suggests that the mechanisms of
potassium wasting are indirect.
The mirror image disease, familial hyperkalemic hypertension
(also known as pseudohypoaldosteronism type 2 or Gordon syn-
drome) is a monogenic disease characterized by hyperkalemia, which
can be severe (10). Yet, once again, we now know that the muta-
tions that cause the disease do so primarily by activating NCC,
again having effects primarily along the DCT, which does not trans-
port potassium.
The resolution to this apparent paradox is the potassium switch
(Figure 2), which links the DCT with the ASDN (primarily CNT
and CD) and aldosterone. Work has made clear that a dominant
factor modulating NCC is the plasma potassium concentration;
when plasma potassium concentration is high, NCC is “turned off”
(dephosphorylated). When the plasma potassium concentration is
low, NCC is “turned on” (4). Hyperkalemia therefore both stimu-
lates aldosterone secretion by the adrenal glands AND inhibits
NCC. This means that more sodium flows into a nephron segment
(the CNT/CD) that is primed to secrete potassium by aldosterone.
The converse situation is also relevant. When plasma potassium is
low, NCC is activated. This limits sodium delivery to the ASDN,
thereby limiting potassium secretion and therefore potassium excre-
tion. These monogenic diseases (Gitelman syndrome and familial
hyperkalemic hypertension) cause abnormalities in plasma potassium
concentration because they break this switch (11).
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120 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

The potassium switch discovery appears to resolve the

Figure 2. Potassium switch. The ‘potassium switch’ involves the
potassium-induced interaction between the distal convoluted tubule
(DCT) and the connecting tubule (CNT). When dietary K1 intake
is high (left panels), elevated plasma potassium stimulates aldosterone
secretion. As the NCC is turned off by high K1, sodium delivery to
the activated CNT is high and sodium exchange for potassium is
robust. In contrast, when dietary K1 intake is low, NCC is stimu-
lated directly, but aldosterone secretion is inhibited. Most sodium is
therefore reabsorbed electroneutrally along the DCT, preventing
potassium loss. Used with permission from reference 11 (Ellison
DH, Terker AS, Gamba G: Potassium and its discontents: new
insight, new treatments. J Am Soc Nephrol 27: 981–989, 2016).
The signaling pathway that underlies the potassium switch has
also been clarified by monogenic diseases. NCC is activated by phos-
phorylation along its amino terminal cytoplasmic domain (12). The
kinase that is primarily responsible is SPAK, which is expressed
broadly along the distal nephron (13). SPAK itself is activated
when it is phosphorylated. In this case, the kinase responsible is
primarily WNK4, produced by one of the genes that, when
mutated, leads to hyperkalemic hypertension (14). The WNK
kinases are sensitive to intracellular chloride concentration (15),
which turns out to be the link with plasma potassium. When
plasma potassium is high, it increases intracellular chloride con-
centration secondarily, which turns off WNK kinases (4,16).
Conversely, when the plasma potassium concentration is low,
that reduces intracellular chloride concentration, leaving WNKs
in a chloride-unbound state, which activates them.
“aldosterone paradox,” the observation that the same hormone,
aldosterone, can mediate primarily kaliuresis when induced by
hyperkalemia, and primarily sodium retention, when induced pri-
marily by angiotensin II (via extracellular volume depletion) (17).
We can now see that during hyperkalemia, aldosterone concentra-
tions are high, activating the epithelial sodium channel along the
CNT/CD, generating a lumen-negative voltage. Yet, NCC is turned
off, meaning that there is little salt reabsorption along the DCT. In
this situation, Na flows distally, leading to robust potassium secre-
tion, but sites of sodium reabsorption are mostly shifted from more
proximal (DCT) to more distal (CNT/CD); net sodium reabsorp-
tion is not stimulated.
By contrast, when extracellular fluid volume is low, angio-
tensin II is stimulated. In this case, NCC is activated by angio-
tensin II, while at the same time, aldosterone activates the CNT/
CD. In this case, sodium delivery to the CNT/CD is low, and
therefore, even though the segment is activated, transport there is
limited, limiting potassium secretion. In contrast, because
sodium reabsorption is stimulated all along the distal nephron,
net sodium retention occurs.
Diagnosis and Evaluation
Although flame photometry ushered in the era of electrolyte mea-
surement in the 1940s, nearly all laboratories now determine potas-
sium concentration using ion-sensitive electrodes. Three different
methods of collection are currently used to estimate the concentra-
tion of extracellular potassium in plasma, serum, or whole blood.
Each approach has strengths and limitations, and all three are used
clinically.
Serum is collected into tubes that often have red tops and
contain a clotting activator, like silica. The collected blood is
allowed to clot at rest, and then potassium is measured in the
clear serum component. When blood clots, a certain amount of
potassium is released from red cells; this is in vitro hemolysis
and should be distinguished from hemolysis related to phlebot-
omy or in vivo hemolysis, resulting from disease. Additionally,
some potassium is released from platelets and leukocytess.
These processes account for the fact that serum potassium con-
centrations typically exceed plasma or whole blood measure-
ments by 0.1–0.7 mM (18). Spectrophotometric measurement
of hemolysis is typically used to detect hemolysis when serum

Figure 1. Algorithm for treating moderate or severe hyperkalemia in adults. *IV 1 g calcium gluconate (10 ml of 10% solution [repeated up to
3 times, if necessary after 5 minutes], each containing 93 mg elemental calcium, 2.3 mmol) or calcium chloride (10 ml of 10% solution, 273
mg elemental calcium, 6.8 mmol). †IV regular insulin 5 units plus 25 g glucose (50 ml of 50%) is as effective as albuterol (salbutamol) 10 mg
nebulized; insulin and albuterol may have an additive effect. Beware of hypoglycemia. IV bicarbonate (1 amp of 50 ml of 8.4% solution, Na 50
mmol, HCO3 50 mmol) over 15 minutes. **Potassium binders: sodium polystyrene sulphonate 15–60 g orally/rectally (do not give with sorbi-
tol) or zirconium cyclosilicate 10 g 3/d (patiromer not advisable because onset of action is 7 hours). This guidance is suggestive because there are
limited data on onset of action with no head-to-head studies between potassium binders. ‡Hemodialysis is the modality of preference. Potassium
homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO)
Controversies Conference. Used with permission from reference 18 (Clase CM, Carrero JJ, Ellison DH, Grams ME, Hemmelgarn BR, Jardine
MJ, Kovesdy CP, Kline GA, Lindner G, Obrador GT, Palmer BF, Cheung M, Wheeler DC, Winkelmayer WC, Pecoits-Filho R; Conference
Participants: Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global
Outcomes (KDIGO) controversies conference. Kidney Int 97: 42–61). License (CC BY NC ND).
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
measurements are performed in laboratories, with a recom-
mended threshold of ,2%, but higher values are common,
especially when blood is obtained from intravenous catheters
(19).
The other approaches to determine the amount of potassium in
circulating blood use plasma and whole blood. Plasma is collected
into heparinized tubes and obtained by centrifugation; the potas-
sium concentration is obtained with an ion-sensitive electrode auto-
analyzer. By contrast, whole blood techniques measure potassium
immediately after the sample is obtained, without further processing;
these methods determine potassium concentrations that are essen-
tially those in plasma and are used commonly in emergency depart-
ments and intensive care units. Patients who have substantial leuko-
cytosis (.503109/L) (20) or thrombocytosis are at risk for
pseudohyperkalemia, when serum measurements are used.
In fact, determination of whole blood potassium is used
increasingly, owing to its speed and accessibility. It is often
argued that serum potassium is the criterion standard, inasmuch
as the American Society of Clinical Pathology has the most
clearly developed quality control metrics for its use. In many
recent trials, whole blood methods have been used routinely
(21). In many series, it has been noted that the value obtained
from whole blood point-of-care testing is often 0.3–0.5 mM
lower than that obtained from serum in the laboratory (22).
Overall, these data raise the possibility that whole blood potas-
sium is a more accurate measure of the relevant physiologic vari-
able than is serum (23).
In the acute setting, an important goal of treating hyperkalemia
is to prevent arrhythmias. Unfortunately, arrhythmias are not closely
correlated with serum or blood potassium concentrations. Several
well-described electrocardiographic (ECG) changes occur in the set-
ting of hyperkalemia, including tall “peaked” T waves, a prolonged
P-R interval, intraventricular blocks, widening of the QRS com-
plexes, eventually resulting in “sine wave” patterns, ventricular fibril-
lation, and asystole. Some work has suggested that ECG changes are
reliable and predictive of more serious arrhythmias (24), but the
associated findings have not included such early signs as peaked T
waves.
An interesting approach explored recently has used artificial
intelligence and deep learning algorithms to detect subtle ECG
changes that are associated with hyperkalemia. Such approaches
have been termed bloodless blood tests and have used ECG leads in
the dialysis unit (25,26). Recently, approaches using routine ECGs
have also been shown to correlate well with the results of serum
potassium measurements and to exceed the performance of experi-
enced cardiologists at detecting hyperkalemia (27,28). In one study
a deep learning model was trained to detect potassium .5.5 mEq/L
using .1.5 million ECGs from 449,380 patients and tested in a val-
idation cohort including 61,965 CKD patients (28). The area under
the receiver operating curve ranged from 0.853 to 0.883. Using a
high sensitivity operating point to maximize its utility as a screening
tool, the negative predictive value was .99%. This is as good as, or
better than, many other commonly used screening tools, including
mammography and colonoscopy for detecting breast cancer and
colorectal cancers, respectively.
Of course, the utility of such approaches currently is limited
because of the ease of measuring blood potassium concentrations
clinically and the lack of implemented software. On the other hand,
121
were these approaches able to predict serious arrhythmias more accu-
rately than humans examining ECG tracings, they could become
very useful in emergency settings.
Causes and Risk Factors
In approaching a patient with an elevated blood potassium concen-
tration, the first question is whether the measurement reflects a true
increase in circulating levels. Given that 95% of body potassium is
inside of cells, and that methods for measurement depend on blood
collection, it is not surprising that cell leakage can artificially elevate
potassium; this phenomenon is called pseudohyperkalemia. Hemo-
lysis during or after blood collection is the most common cause. A
falsely elevated potassium level may occur with fist clenching during
phlebotomy, mechanical trauma, tourniquet use .1 minute, and
during blood clotting, but, as noted, most laboratories include spec-
trophotometric analysis of hemolysis and have cutoffs of 1%–2%.
Additionally, patients with elevated leukocyte or platelet counts may
have release from those formed elements. In general, if formed ele-
ments are increased (as discussed above), or if there is suspicion of
hemolysis, the potassium should be assessed by use of the converse
technique (serum versus whole blood or plasma). If there is uncer-
tainty, treatment is often provided.
A second question to address is the duration of hyperkalemia.
Causes that involve shifting of potassium from inside of cells are
typically acute and do not involve a change in body potassium con-
tent. By contrast, chronic hyperkalemia, with or without a tempo-
rary increase, requires an impairment of potassium secretion along
the ASDN. Most common cases of hyperkalemia, at least in patients
who do not have ESKD, reflect a congruence of factors that impair
renal potassium secretion. Although high potassium intake may con-
tribute, its role may have been overemphasized in the past, and there
has been a reconsideration of dietary recommendations for patients
with CKD or other hyperkalemic risk factors (29). In view of the
cardioprotective effects of diets high in potassium, especially those
that emphasize fruits and vegetables, many authorities now advocate
that patients at risk for hyperkalemia focus on eating a healthy diet,
without undue focus on potassium restriction; this may help address
the low adherence to typical CKD diets observed in practice (30).
It is not surprising that the major risk factors for hyperkalemia
include kidney failure (acute or chronic), use of drugs that block the
renin/angiotensin/aldosterone system (RAAS), and acidosis. Other
common drug-induced causes are numerous, and they have been
reviewed (31). Patients with ESKD are at special risk. On the basis
of epidemiologic evidence, other frequently identified factors include
male sex, lower body mass index, malignancy, and diabetes (32).
Whereas these risk factors increase the prior probability of true
hyperkalemia, other important, but less common, bona fide causes
of hyperkalemia exist. These include hyperkalemic periodic paralysis,
an autosomal dominant disorder in which episodes of flaccid weak-
ness and intermittent myotonia can be precipitated by cold, exercise,
fasting, or the ingestion of small amounts of potassium. The most
common abnormality in hyperkalemic periodic paralysis is a point
mutation in the SCNA4 gene for the a subunit of the skeletal mus-
cle cell sodium channel (a channel that is molecularly distinct from
ENaC in the kidney) (33).
Hypoaldosteronism can result from Addison disease or be iso-
lated. Isolated hypoaldosteronism, often a part of hyporeninemic
122 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

hypoaldosteronism, was previously diagnosed commonly in patients

with chronic diabetes or interstitial nephritis; it is often viewed as
synonymous with type 4 renal tubular acidosis, but some cases of
hyperkalemic acidosis have distal resistance to aldosterone, rather
than aldosterone insufficiency, and have been termed hyperkalemic
distal RTA (34)
Pseudohypoaldosteronism type 1 is usually diagnosed early in
life and presents with severe salt wasting and hyperkalemia. It can
result from genetically defective ENaC channels and can be inher-
ited in an autosomal recessive manner or from mutations in the
mineralocorticoid receptor itself, and either be inherited in an auto-
somal dominant manner or be de novo (35). The recessive form is
sometimes referred to as systemic and presents with severe lifelong
salt losing. The form resulting from mutations in the mineralocorti- Figure 3. KDIGO-recommended classification of hyperkalemia.
coid receptor is sometimes called the renal form and is milder; many *indicates that hyperkalemia is defined as either .5.0 or .upper
times, salt supplementation becomes unnecessary by 1–3 years of limit of normal potassium for the laboratory. Potassium homeostasis
age. Interestingly, the salt wasting is likely secondary to both a defi- and management of dyskalemia in kidney diseases: conclusions from
ciency in ENaC and secondary inhibition of NCC resulting from a Kidney Disease. Used with permission from reference 18 (Clase
hyperkalemia. Animal models have indicated that the salt wasting CM, Carrero JJ, Ellison DH, Grams ME, Hemmelgarn BR, Jardine
can be mitigated by correcting the plasma potassium, thereby reacti- MJ, Kovesdy CP, Kline GA, Lindner G, Obrador GT, Palmer BF,
vating NCC (36), and this phenomenon has recently been reported Cheung M, Wheeler DC, Winkelmayer WC, Pecoits-Filho R; Con-
in humans (37). A third form of pseudohypoaldosteronism type 1 is ference Participants: Potassium homeostasis and management of dys-
acquired and is associated with urinary tract abnormalities and uri- kalemia in kidney diseases: Conclusions from a Kidney Disease:
nary infections (35). Improving Global Outcomes (KDIGO) controversies conference.
Pseudohypoaldosteronism type 2, which is now also referred to Kidney Int 97: 42–61). License (CC BY NC ND).
as familial hyperkalemic hypertension or Gordon syndrome, also
presents with hyperkalemia, but in this case is associated with nor-
now known to disrupt their binding to KLHL3, preventing their
mal BP (early in life) and hypertension later. It occurs most com-
degradation (41). Most mutations of Cullin 3 and KLHL3 are
monly as an autosomal dominant disease, but some cases, discussed
inherited in a dominant manner, but some KLHL3 mutations are
below, can also be recessive. The disease is caused by mutations in
recessive (Table 1).
genes encoding proteins that affect NCC. The first discovered were
mutations in WNK (with no lysine) kinase 1 and WNK4, and they
resulted in increased phosphorylation and activation of NCC (38). Prevention
Inhibition of potassium channels may also be involved, but the phe-
Expert guidelines suggest that plasma potassium should be moni-
notype is mimicked in mice that have activated NCC alone (39).
tored within several weeks of starting or increasing drugs that block
Mutations have more recently been identified in genes that
the RAAS (18).
modulate WNK activity, including Kelch-like 3 and Cullin 3 (40),
which are detected more commonly. These proteins are part of the
Cullin ring ligase complex, which leads to ubiquitylation of proteins, Treatment
targeting them for degradation via the proteasome. The mutations
The decision to treat hyperkalemia, and the urgency of such treat-
appear to disrupt the ability of the complex to bind to WNK kin-
ment, is not standardized. One approach to this decision is to cate-
ases, leading to their accumulation; the WNK kinase mutations are
gorize hyperkalemia according to a consensus-based algorithm that
incorporates both measured potassium and ECG changes and that
classifies hyperkalemia as mild, moderate, and severe (Figure 3). The
indications for controlling hyperkalemia in the long term are dis-
4 The sodium-chloride cotransporter (NCC) in the cussed below.
distal convoluted tubule modulates potassium
Acute Hyperkalemia
excretion by regulating the amount of sodium
A KDIGO controversies conference recently addressed the manage-
delivered to the connecting segment and ment of hyperkalemia (18). The initial management of acute hyper-
collecting duct. kalemia typically includes the use of insulin/glucose and b agonists
4 NCC is dephosphorylated (turned off) when the for potassium .6.5 mEq/L, with use of intravenous calcium if
EKG changes are present; the algorithm also recommends calcium
plasma potassium is high and phosphorylated
use if a repeat serum or blood potassium is above 6.5 mEq/L, even
(turned on) when the plasma potassium is low. in the absence of ECG changes. Bicarbonate may be considered if
acidosis is present. Intravenous loop diuretics and potassium binders
are also considered. Immediate short-term treatment of potentially
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Table 1. Causes of pseudohyoaldosteronism
Type Mode of Inheritance
Pseudohypoaldosteronism type IA Dominant
Pseudohypoaldosteronism type IB Recessive
Pseudohypoaldosteronis type IIA Dominant
Reprinted with permission from reference 34 (Batlle, D, Arruda, J: Hyperkalemic forms of renal tubular acidosis: clinical and pathophysiological aspects. Adv Chronic Kidney Dis
28: 321–333, 2018).
life-threatening hyperkalemia is based on experience and opinion;
although it is relatively standardized (42), wide variation in
approaches persists (43) (Figure 1).
Stabilize the Membrane. For urgent cases, calcium is usually
administered; calcium chloride contains three times the amount of
calcium as calcium gluconate, but the gluconate salt is sometimes,
although not always, preferred as it causes less local irritation. The
European Resuscitation Council recommends use of 10 ml 10% cal-
cium chloride over 2–5 minutes in hyperkalemic patients with ECG
changes (44); the KDIGO conference recommended calcium gluco-
nate, but this would require 30 ml of a 10% solution to obtain the
same amount of elemental calcium (18). The effects are short lived
(30-60 minutes) and doses can be repeated if ECG changes persist.
Hyperkalemia depolarizes the resting potential of myocytes, putting
it closer to the threshold potential, increasing the likelihood of aber-
rant action potentials. Calcium raises the threshold potential,
thereby restoring the difference between it and the resting potential;
calcium may have other effects on cardiomyocytes, as well.
Shift Potassium into Cells. Insulin shifts potassium into cells pri-
marily by stimulating the Na/K ATPase, is clearly effective in lower-
ing potassium concentrations, and forms the centerpiece of most
approaches to acute hyperkalemia; it is usually given with glucose to
avoid hypoglycemia, unless the baseline serum glucose exceeds 250
mg/dL. The insulin effect occurs quickly (10-20 minutes) and can
last four to six hours. The most recent guidelines from the UK
Renal Association are very clear and recommend that all patients
with moderate or severe hyperkalemia (potassium .6 mEq/L)
receive 10 units of insulin in 25 grams of glucose. When the base-
line serum glucose is less than 126 mg/dl, this should be followed
by 10% glucose at 50 ml/h for 5 hours, with a target glucose of
72-126 mg/dl) (https://renal.org/health-professionals/guidelines/
guidelines-commentaries).
Yet, even using this approach, hypoglycemia may occur. A
recent meta-analysis evaluated retrospective cohort studies of lower
dose strategies with low or moderate risk of bias (45). The standard
approach was considered to be 10 units of insulin and the alternative
approaches included 5 units, 0.1 units/kg, and ,10 units. Alterna-
tive dosing had lower pooled odds of hypoglycemia and severe hypo-
glycemia, without detected differences in potassium reduction.
b-Adrenergic agonists, primarily albuterol (also called salbuta-
mol), can also be used to shift potassium into cells. The drug lowers
plasma potassium by approximately the same amount as insulin,
and its use by nebulizer is generally preferred over intravenous
123
Gene Mutations Clinical Features
Mineralocorticoid receptor Milder
Epithelial sodium channel Severe phenotype
WNK 1, WNK4, KLHL3, Hypertension, short stature,
CUL 3 responsive to thiazides
administration (42). Its effects have been reported to be additive
with insulin, although studies have been small (46). A randomized
control trial comparing nebulized albuterol and insulin with glucose,
versus both treatments combined, is currently in progress (47).
Sodium bicarbonate has been used, but its effects are limited,
and it has generally fallen out of favor unless there is systemic meta-
bolic acidosis. The minimal effect of bicarbonate has been con-
firmed in several studies (48), although it should be noted that sus-
tained alkali treatment in CKD has several other benefits and may
enhance urinary potassium excretion in the long term.
Remove Potassium from the Body. Except when hyperkalemia is
the result of an internal shift, removal from the body is the definitive
approach. For individuals with kidney function, diuretic-induced
kaliuresis is often effective. Although it is often stated that there is
little experimental support for the use of diuretics to treat hyperkale-
mia in the short term, and there certainly are no large controlled
studies of loop diuretic efficacy in this situation, many smaller physi-
ologically based trials show preserved kaliuresis in situations of low
GFR, as long as urine volumes increase (49,50). Therefore, in the
absence of extracellular fluid volume depletion, loop diuretics should
be given; using natriuretic (often higher) doses is essential because
potassium clearance correlates with sodium clearance during loop
diuretic administration (51).
When there is doubt about the utility of diuresis, or if forced
diuresis fails, dialysis is often used. Hemodialysis is the most effective
approach to rapid potassium removal, with rates of removal inversely
proportional to dialysate potassium concentration (52). Each hemo-
dialysis session removes approximately 70–100 mmol of potassium
(53) The serum potassium concentration typically falls by 1 mmol/L
during the first hour of dialysis, when the gradient between the
serum and dialysate K1 is highest, then by 1 mmol/L over the next
2 hours. It reaches a steady state during the last hour of the
treatment.
Hemodialysis patients have a high risk of hyperkalemia, which
is associated with mortality and may be responsible for 3%–5% of
deaths (54). At the same time, there is also speculation that the sud-
den reduction in serum potassium that occurs during dialytic
removal may be just as important (55). The most common time for
hyperkalemic events in hemodialysis patients is immediately after
the 3-day weekend break (56). The long interdialytic break also cor-
relates with hospitalization (57) and mortality in hemodialysis
patients (58). In a large study of 52,734 hemodialysis patients
receiving three-times-weekly dialysis who underwent 533,889
repeated serum potassium measurements over a 2-year period, the
124
serum was .5.5 mEq/L in 20% of all measurements, particularly
after the long interdialytic interval (i.e., 24%, 16%, and 20% of
measurements conducted on Monday, Wednesday, and Friday,
respectively) (59).
In rigorous analyses, the investigators found that increasingly
higher serum potassium levels were associated with incrementally
higher short-term hospitalization risk. Serum potassium levels of
5.5–6.0 mEq/L obtained on Friday were potently associated with
higher hospitalization risk within 4 days of measurement (adjusted
odds ratio, 1.68; 95% CI, 1.22 to 2.30), whereas levels obtained on
Monday and Wednesday were linked with mild to no greater risk,
respectively. Notably, serum potassium levels .6.0 mEq/L were
associated with greater hospitalization costs across all days of mea-
surement. On the basis of data such as these, the UK Renal Associa-
tion Clinical Practice Guideline on Haemodialysis recommends an
optimal predialysis serum K1 in the range of 4.0–6.0 mmol/L.
Although dialysate potassium concentrations ,2 mM remove
more potassium than those $2 mM , low dialysate potassium con-
centrations (0 or 1 mM) associate with mortality, at least when used
in the long term—an association that is magnified in patients with
higher predialysis potassium concentrations (60). Whether this asso-
ciation reflects confounding by indication is not clear, but very low
dialysate potassium concentrations should typically be avoided, espe-
cially if ECG monitoring is not used.
Continuous renal replacement therapy (CRRT) is commonly
used to treat critically ill patients, many of whom have hyperkale-
mia. Inasmuch as blood flow is lower in CRRT than in hemodialy-
sis, potassium clearance is typically less, and therefore hemodialysis
is preferred as first-line treatment. Nevertheless, there are individuals
in whom hemodynamic considerations suggest the use of CRRT; in
such patients, blood flow and replacement fluid/dialysis flow rates
should be maximized initially; if persistent hyperkalemia is a prob-
lem, it may signal persistent tissue breakdown/ischemia (61).
Gastrointestinal Potassium Removal. Sodium polystyrene sulfo-
nate (SPS), still often used with sorbitol, has been a common treat-
ment for hyperkalemia, but its history is checkered. Even an initial
report found little effect on plasma potassium concentration beyond
that of sorbitol alone (62). Meaney et al. (63) found three clinical
studies of its use, which reported lowering of approximately 1 mM
within 1–3 days. Reports of serious gastrointestinal complications,
especially when SPS was administered with sorbitol, caused the U.S.
Food and Drug Administration (FDA) to recommend discontinua-
tion of its use with sorbitol, but even when it is used without, intes-
tinal necrosis may occur (64). SPS, however, is still administered
with sorbitol in many settings. The FDA also recommends that SPS
administration be separated temporally from that of other drugs
because it can alter drug absorption. Given that there are now safer
and clearly effective potassium-binding agents, many authorities rec-
ommend against using SPS (64); its price may be lower than the pri-
ces of the new agents, perhaps fostering continued use.
Two newer potassium-binding agents have been approved in
the past 10 years: patiromer in 2015 and sodium zirconium cyclosi-
licate in 2018. Each has been shown to be effective in lowering
plasma potassium, although neither has been compared directly
with SPS in terms of efficacy. The sites of action, benefits, and side
effects of each, as well as their physical chemistry, differ, although
both lead to increased potassium removal through the gut.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
In the setting of acute hyperkalemia, or during a transition
from the acute phase of treatment to more sustained approaches,
sodium zirconium cyclosilicate has the advantage of faster
action, with potassium lowering beginning as early as 1 hour (11)—
a result of its acting along both the small and the large intestines.
Yet, a recent although somewhat limited study found little advan-
tage to adding sodium zirconium cyclosilicate to standard treatment,
including insulin and glucose (65). The UK Renal Association
guidelines do provide sodium zirconium cyclosilicate (level 1B) and
patiromer (level 1C) recommendations for treating acute
hyperkalemia.
Chronic Hyperkalemia
There is no consensus regarding the optimal management of chronic
hyperkalemia, although a common approach was recently summa-
rized by KDIGO (18).
In the setting of chronic hyperkalemia, the focus has been on
withdrawing offending drugs, increasing urinary excretion, increas-
ing gastrointestinal removal, and possibly reducing intake (with the
caveats noted above). Whereas reducing the doses of, or discontinu-
ing, drugs that contribute to hyperkalemia has long been a core
component of treatment, drugs that interfere with the RAAS are
among the most effective in mitigating both cardiovascular and renal
disease. Given the development of demonstrably safe and effective
agents that can reduce plasma potassium, the possibility of combin-
ing RAAS inhibition with potassium-binding drugs is now being
evaluated and is widely used.
Among the traditional approaches to mitigating hyperkalemia
in patients taking RAAS blocking agents, and especially with CKD,
is to increase urine sodium and water excretion with loop diuretics.
Although lacking randomized controlled data, this approach is
almost surely effective, as noted above, and inasmuch as potassium
excretion can be normalized in patients with Addison disease, who
lack aldosterone, as long as salt and water consumption provides suf-
ficient distal flow. When such patients are hypertensive, as is often
the case with CKD, loop diuretics can treat both the hyperkalemia
and the hypertension.
Another traditional approach is to administer fludrocortisone.
This mineralocorticoid agonist directly stimulates potassium secre-
tion in the ASDN and can be quite effective. It also causes sodium
retention, however, and directly counteracts many of the beneficial
effects of RAAS blockers, making its use restricted to relatively rare
cases of chronic hyperkalemia with salt wasting.
The development of new potassium-binding drugs has raised
the prospect that preventive treatment with oral potassium-binding
drugs might permit RAAS blockade to be continued in situations
where it would otherwise require discontinuation. Unlike SPS,
which has limited efficacy, poor tolerability, and potential safety
issues, patiromer and sodium zirconium cyclosilicate are generally
safe and well tolerated. There are now multiple studies showing their
efficacy.
Patiromer was the first agent approved (Table 2) and is a pow-
der for oral suspension. It is a cation exchange polymer that is not
absorbed along the gastrointestinal tract, where it exchanges calcium
for potassium, especially the colon. In one initial open-label trial,
306 diabetic patients with CKD (eGFR 15–59 ml/min per 1.73
m2) and serum potassium of 5.1–5.9 mEq/L were randomized to
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 125

Table 2. Selected characteristics of K1 binding agents for hyperkalemia

Characteristic SPS Patiromer SZC

Approval date 1958 US, 2015; EU, 2017 US, 2018; EU, 2018
Mechanism of action K1 binding in exchange for K1 binding in exchange for K1 binding in exchange for
Na1 in GI tract (" fecal Ca21 in GI tract (" fecal H1 and Na1 in GI tract
excretion) excretion) (" fecal excretion)
Site of action Colon Colon Small and large intestines
Selectivity for K1 Nonselective; also binds Nonselective; also binds Highly selective; also binds
Ca21 and Mg21 Na1 and Mg21 NH41
Onset of action Variable; several hours 7h 1h
Na1 content 1500 mg per 15-mg dose None 400 mg per 5-g dose
Ca21 content None 1.6 g per 8.4-g dose None
Sorbitol content 20,000 mg per 15-g dose 4000 mg per 8.4-g dose No sorbitol content
Dosing 15 g 1–4 times (oral); 30–50 g 8.4 g QD (oral), titrate up to 10 g TID (oral) for initial
1–2 times (rectal) 16.8 g or 25.2 g QD correction of hyperkalemia
(for #48 h), then 5 g QOD
to 15 g QD for maintenance
Serious AEs Cases of fatal GI injury reported None reported None reported
Most common AEs GI disorders (constipation, GI disorders (abdominal GI disorders (constipation,
diarrhea, nausea, vomiting, discomfort, constipation, diarrhea, nausea, vomiting),
gastric irritation), diarrhea, nausea, flatulence), mild to moderate edema
hypomagnesemia, hypomagnesemia
hypokalemia, hypocalcemia,
systemic alkalosis

Reprinted with permission from Elsevier: Palmer BF, Carrero JJ, Clegg DJ, Colbert GB, Emmett M, Fishbane S, Hain DJ, Lerma E, Onuigbo M, Rastogi A, Roger SD, Spinowitz BS,
Weir MR. Clinical Management of Hyperkalemia. Mayo Clin Proc. 96(3): 744–762, 2021. Licensed under CC-BY-NC-ND.

different doses of patiromer and followed up for 1 year. All patients
were also treated with stable doses of an angiotensin-converting
enzyme inhibitor or an angiotensin II receptor blocker, or both,
often in combination with spironolactone. Serum potassium
decreased by 20.35 to 20.55 mEq/L at 4 weeks, with initial doses
of 4.2–12.6 g twice daily among those with mild hyperkalemia, and
from 20.87 to 20.97 mEq/L with initial doses of 8.4–12.6 g twice
daily among those with moderate hyperkalemia. Serum potassium
concentrations remained in the normal range at 1 year with contin-
ued patiromer therapy. Patiromer discontinuation resulted in an
increase in the serum potassium within 3 days. There were no
treatment-related serious adverse events in this trial, although consti-
pation (6.3% of patients) and hypomagnesemia (8.6% of patients)
was reported. Hypomagnesemia occurred more commonly with
higher doses of patiromer (66).
In another early study of 237 patients with CKD who were receiv-
ing RAAS inhibitors and who had serum potassium levels of 5.1 to
,6.5 mmol per liter, patiromer was given during a correction phase for
4 weeks followed by a randomized withdrawal phase. At week 4, 76%
of the patients had reached the target potassium level (,5.1 mM). Sub-
sequently, 107 patients were randomly assigned to patiromer (55
patients) or placebo (52 patients) for the randomized withdrawal phase.
The median increase in the potassium level from baseline was greater
with placebo than with patiromer (P,0.001); as in the other study,
mild to moderate constipation was the most common adverse event (in
11% of the patients), and hypomagnesemia occurred (in 3%) (66).
An interesting recent study tested the effects of patiromer on
serum and stool electrolytes in 27 anuric dialysis patients who had a
tendency toward hyperkalemia at baseline. During 12 weeks, treat-
ment with patiromer reduced serum potassium concentration (by
0.6 mM) and increased stool potassium excretion—effects that
reversed when the treatment was discontinued. Additionally, during
the treatment phase, serum calcium increased (from 8.9 to 9.1 mg/
dL) and serum magnesium decreased (from 2.6 to 2.4 mg/dL) com-
pared with pretreatment levels, and the changes in serum potassium
and magnesium were directly related (67).
Patiromer has been shown to reduce plasma potassium concen-
trations for longer periods of time, in a variety of settings, and has
permitted uptitration of RAAS-blocking drugs (68). The AMBER
study was a phase 2 multicenter, randomized, double-blind, pla-
cebo-controlled study that was designed to determine whether con-
comitant use of patiromer would permit greater use of spironolac-
tone for uncontrolled hypertension in participants with CKD (69).
Participants were randomly assigned (1:1) to receive either placebo
or patiromer (8.4 g once daily) in addition to open-label spironolac-
tone (starting at 25 mg once daily). The primary endpoint was the
between-group difference at week 12 in the proportion of patients
taking spironolactone. Two hundred ninety-five patients were ran-
domly assigned to spironolactone in addition to double-blind treat-
ment with either placebo (n5148) or patiromer (n5147). At week
12, 66% of patients in the placebo group and 86% of patients in
the patiromer group continued with spironolactone (statistically
126
significant). Adverse events were mostly mild or moderate in severity
and occurred in 79 (53%) of 148 patients in the placebo group and
82 (56%) of 147 patients in the patiromer group. In a prespecified
subgroup analysis of patients with heart failure, the treatment group
was able to receive more spironolactone than the placebo group
(70).
It appears that the approach of using potassium binders to per-
mit continued RAAS blockade is being used commonly in a variety
of healthcare settings. In one study, 288 veterans with hyperkalemia
who were treated with patiromer were studied after patiromer initia-
tion. All had heart failure, diabetes, or CKD, but not ESKD, and
had a median age of 70 years. Potassium concentration reductions
after patiromer initiation were, on average, 21.0 mM (P,0.001),
and RAAS inhibitor therapy was continued in .80%–90% of
patients (71).
A retrospective cohort study used data from a large dialysis pro-
vider and examined dialysis patients who had a medication order for
patiromer or SPS or who had laboratory evidence of hyperkalemia.
Patiromer initiators were 2.6 times more likely to have had multiple
prior episodes of hyperkalemia. Sixty percent of patients’ first
patiromer orders remained open after 180 days, with statistically sig-
nificant reductions in serum potassium, averaging approximately
20.5 mM.
In nearly all studies, the most common side effects of patiromer
use are gastrointestinal intolerance, such as constipation, and hypo-
magnesemia, as mentioned above. Because the drug exchanges cal-
cium for potassium, it does not deliver a sodium load, but it does
alter divalent mineral metabolism. In addition to hypomagnesemia,
some recent case reports have detected hypercalcemia in some
patients (72).
Sodium zirconium cyclosilicate was approved in 2018 (Table
2). It is an insoluble, nonabsorbed cation exchange crystal that
exchanges potassium for sodium. Zirconium silicates have been used
extensively in medical and dental applications because of their safety;
in the case of sodium zirconium cyclosilicate, the molecule is com-
plexed with sodium. Many studies include a correction phase, often
using higher doses, and then a maintenance phase at a lower, once-
daily dose. Most do not use a placebo group during the initial cor-
rection phase, because leaving patients uncorrected might put them
at risk. In one early study, treatment reduced serum potassium by
0.46 mM within 48 hours during the uncontrolled correction phase
(73). After correction, patients were randomized to zirconium or
placebo for 2 weeks, during which serum potassium concentration
was lower in the treatment groups than in the placebo group.
Later studies have supported this efficacy and demonstrated
more prolonged effects. In the HARMONIZE multisite randomized
controlled study, 267 patients were treated during an open-label cor-
rection phase, followed up, and then randomized to 5 g or 10 g
daily of sodium zirconium cyclosilicate in the controlled sustained
phase. During the first 48 hours, serum potassium declined by 1.28
mmol/L. During the maintenance phase (days 8–29), serum potas-
sium was 10% and 18% lower, with low and high sodium zirco-
nium cyclosilicate doses, than with placebo (P,0.001 for both).
More patients had normokalemia with sodium zirconium cyclosili-
cate 5 (58.6%) and 10 g (77.3%) versus placebo (24.0%), with the
greatest number of normokalemic days in the 10-g group (74).
One group of patients at substantial risk of hyperkalemia is
those with ESKD treated with dialysis. The DIALIZE study was a
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
double-blind, placebo-controlled multicenter study in which
patients with predialysis hyperkalemia were randomized to receive
placebo or sodium zirconium cyclosilicate on nondialysis days over
4 weeks. One hundred ninety-six patients were randomized to
sodium zirconium cyclosilicate or placebo. Significantly more
patients in the treatment group (41.2%) maintained serum potas-
sium concentrations below 5 mM than did patients treated with pla-
cebo (1.0%). Rescue therapy to reduce potassium was required in
fewer patients receiving zirconium cyclosilicate compared with pla-
cebo (2.1% versus 5.1% respectively). There were no differences in
adverse effects, and the weight gains in the two groups were similar
(75).
The sodium load delivered with sodium zirconium cyclosilicate
(Table 2) can be substantial and is believed to be the reason that sus-
tained use has been associated with edema in .10% of patients,
especially in those patients with eGFR ,30 ml/min (76). This con-
cern may be one factor leading many cardiologists to prefer
patiromer to sodium zirconium cyclosilicate during sustained use
(D.H. Ellison, unpublished observation). Otherwise, the drug is
usually well tolerated, with constipation being the most commonly
reported side effect.
One potential benefit of sodium zirconium cyclosilicate is that
is also removes hydrogen ions and can increase the serum bicarbon-
ate concentration (77). Acidosis complicating CKD is recognized
increasingly as having adverse consequences, and a modest improve-
ment in acid-base balance is likely to be beneficial (78). Roger et al.
(77) examined data from three placebo-controlled phase 3 trials of
sodium zirconium cyclosilicate. The results showed a significant
dose-dependent increase in mean serum bicarbonate of 0.3 to 1.5
mM within 48 h of treatment. These changes were maintained over
29 days. With highest sodium zirconium cyclosilicate maintenance
doses, the proportions with serum bicarbonate ,22 mM declined
from 39% at baseline to 4.9% at 29 days (P50.005).
4 Both hypo- and hyperkalemia are associated with
increased cardiovascular and overall mortality,
and with ESKD risk, although these associations
do not define cause.
4 Patiromer and sodium zirconium cyclosilicate are
effective and safe for the treatment of chronic
hyperkalemia and allow continued use or
up-titration of RAAS blocking agents
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Article
Metabolic Acidosis
Zhabiz Solhjou, MD
Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts
Martina M. McGrath, MBChB, FASN
Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts
Renal Division, Veterans Affairs Boston Healthcare System, Boston, Massachusetts
Learning Objectives
1. To detail the diagnosis and management of ketoacidosis in
specific clinical scenarios
2. To describe the risk factors for and management of drug-
induced nonanion gap and high–anion gap metabolic acidosis
3. To discuss the significance of metabolic acidosis in CKD and its
impact on CKD progression
4. To review recent clinical trials of alkali therapy for treatment of
metabolic acidosis in CKD
Introduction
Metabolic acidosis is associated with increased mortality and negative
clinical outcomes, emphasizing the importance of timely diagnosis
and treatment. Important causes of metabolic acidosis include net
accumulation of acid arising from excess intake (ingestion of acid-
producing food, medications, or toxins, including toxic alcohols),
increased production (ketoacidosis or lactic acidosis), decreased excre-
tion (renal tubular acidosis [RTA] types I and IV or CKD), or net
loss of bicarbonate ([HCO32]; gastrointestinal losses or RTA type
II) (1,2).
Low serum HCO32 is the hallmark of metabolic acidosis, but
analysis of arterial blood gas is required for accurate diagnosis of a
specific acid-base disturbance. Measurement of pH, pCO2, and cal-
culation of [HCO32] (using the Henderson–Hasselbach equation)
from the arterial blood gas can identify chronic respiratory alkalosis,
mixed metabolic and respiratory acidosis, or other acid-base
derangements that can also present with low [HCO32]. Full assess-
ment of an acid-base disturbance also requires consideration of the
adequacy of compensatory mechanisms to maintain normal pH and
calculation of the anion gap (AG).
In clinical practice, total serum CO2 (CO2) is measured in
venous blood and reported as a surrogate of [HCO32]. CO2 is cal-
culated as the sum of [HCO32] 1 dissolved CO2 (pCO2 3 0.031)
and typically runs 1–1.5 mEq/L higher than [HCO32]. In adults,
normal [HCO32] is between 23 and 29 mEq/L, but the reported
“normal” range can vary widely across clinical laboratories. Kraut
and Madias (3) reviewed the reporting of venous [HCO32] in 64
laboratories across multiple institutions. This study emphasized the
prominent variation between laboratories, where serum [HCO32]
nephsap.org
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
could be reported as “normal” when as low as 18 and as high as 34.
The authors argue that this wide variability can result in “hidden”
yet clinically important acid-base disorders and suggest that adhering
to a more narrow normal range of 23–29 could prevent missed diag-
noses of milder acid-base disorders (3).
Despite perturbations in [HCO32], the sum of circulating cati-
ons must always equal the sum of circulating anions, so that electro-
neutrality is maintained. The difference between these two sums
represents unmeasured circulating anions. The AG, calculated using
the equation Na1 (Cl2 1 HCO32), is a readily available tool to
assess acid-base disturbance. However, several points are worthy of
note when interpreting the AG. Depending upon the laboratory
methods used to measure electrolytes, the AG can vary widely
between laboratories. Albumin, with its negative charge, contributes
a large component of unmeasured anions, and variations in serum
albumin concentration can lead to changes in the AG such that for
every 1-g reduction in serum albumin concentration, the AG falls
by 2.5 mEq/L (4). Differences in serum albumin concentrations
may explain much of the interindividual variability observed in the
AG and should be considered when estimating a change from nor-
mal AG. Spuriously low AG is seen in several situations, including
severe hypoalbuminemia, monoclonal gammopathies (again related
to the charge properties of the circulating paraprotein), and severe
hypertriglyceridemia or hyperparaproteinemia (secondary to pseudo-
hyponatremia). Lithium is a cation and in high concentrations (.4
mEq/L), can lead to reduced AG. Bromide intoxication, such as in
pyridostigmine overdose, can lead to falsely elevated measurement of
serum chloride concentration, resulting in a low or extremely nega-
tive AG. These caveats aside, the AG is an important tool to differ-
entiate the underlying cause of metabolic acidosis.
High-AG metabolic acidosis results from accumulation of
organic acids, whereas renal or GI losses of HCO32 lead to normal
AG metabolic acidosis (1,2). Normal AG metabolic acidosis was
extensively reviewed in a prior NephSAP issue and is addressed in
another article within this issue. Here, we provide an update on the
latest studies on diagnosis, etiologies, and treatment of high-AG
metabolic acidosis and review drug-induced metabolic acidosis.
Lactic Acidosis
Lactic acid was identified as part of a glycolysis pathway in the
1940s, but in recent years, it is increasingly recognized as playing a
key role in a diverse range of cellular processes (5). The average adult
generates around 1500 mM lactic acid daily from muscle (25%),
Copyright # 2022 by the American Society of Nephrology
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
skin (25%), brain (25%), red blood cells (20%), and intestine
(10%). This circulates as lactate at physiologic pH and is cleared
through the Cori and Krebs cycles. Lactate is the main precursor for
more than half of renal gluconeogenesis, which typically contributes
approximately 10% of overall blood glucose. Physiologic studies sug-
gest that this percentage can rise significantly in settings of stress,
such as hypoglycemia, fasting, exercise, and high adrenaline states
(up to 40% of total body gluconeogenesis), using lactate as a key pre-
cursor (5). Lactate is also an important source of fuel for cardiomyo-
cytes, particularly during vigorous exercise (6). It appears to play a
role in angiogenesis and wound healing (5). In the immune system,
lactic acid acts as an energy source for multiple innate and adaptive
immune cells and can contribute to immune response modulation
by reducing the activation of proinflammatory macrophages and NK
cells and increasing production of anti-inflammatory cytokines (7,8)
Although lactic acid serves important physiologic functions, its
rise in critically ill patients is associated with increased mortality. Lactic
acidosis occurs when production exceeds degradation. Sepsis, local or
global tissue hypoxia, and hypoperfusion are the most important
causes of hyperlactatemia in hospitalized patients. A number of other
causes are also worthy of note. Elevated circulating epinephrine levels,
as seen in cardiogenic/hemorrhagic shock, extensive trauma, cocaine
ingestion, or severe asthma, lead to markedly increased anaerobic gly-
colysis. This is an efficient mechanism for rapid production of ATP
but also produces large amounts of lactate and resulting lactic acidosis.
Liver dysfunction in sepsis or fulminant acute liver failure can lead to
both increased lactate production and reduced clearance, and it is a
poor prognostic sign (9). Nonhypoxemic lactic acidosis primarily arises
due to exposure to drugs or toxins that impair mitochondrial oxidative
phosphorylation, including propofol, metformin, salicylates, nucleoside
reverse transcriptase inhibitors, cyanide, and toxic alcohol (9).
In high-AG metabolic acidosis, the ratio of changes in AG to
changes in serum bicarbonate (DAG/DHCO32) is used to detect
coexisting acid-base derangements. When high-AG metabolic acido-
sis is the sole acid-base disorder, an equivalent change in AG and
serum bicarbonate is observed. A DAG/DHCO32.1 suggests the
presence of an additional metabolic alkalosis, whereas DAG/
DHCO32,1 implies a coexisting normal AG metabolic acidosis.
Lactic acidosis is traditionally thought of as a cause of high-AG aci-
dosis where DAG/DHCO32 is close to one. In lactic acidosis, lactate
excretion falls due to decreased renal perfusion and function, and
lactate molecules accumulate as unmeasured anions in extracellular
fluid compartment, whereas the H1 buffering occurs intracellularly
and in bone. This differential distribution of lactate and buffered
H1 can lead to an increase in DAG/DHCO32 in lactic acidosis
(10). In animal models of lactic acid infusion, the ratio of DAG/
DHCO32 is 1.0 early in the course but increases to 1.6–1.8 after
several hours (4). Similarly, in humans, Rudkin et al. (10) studied
45 trauma patients with serum lactate of .2.1 mmol/L and showed
the presence of DAG/DHCO32 1.86 within the first hours of devel-
opment of hypovolemic shock, suggesting a similar effect.
Treatment of lactic acidosis is primarily aimed at reversal of the
underlying abnormality and prompt restoration of normal tissue perfu-
sion. There are no clinical trial data that show reductions in mortality
after treatment with intravenous bicarbonate and limited evidence of
benefit. In general, treatment with bicarbonate should be limited to
those patients with severe acidosis, unresponsive to resuscitative meth-
ods. There are several important risks for intravenous bicarbonate
131
treatment in lactic acidosis. First, when bicarbonate buffers excess H1,
carbon dioxide is generated and can move intracellularly more freely
than HCO32, thereby generating an intracellular acidosis. This effect
can be particularly marked in patients given large volumes of intrave-
nous bicarbonate or those with severe circulatory failure. Second, as
bicarbonate level acutely rises, levels of ionized calcium can drop sud-
denly, with negative effects on myocardial function. Measures to coun-
teract these negative effects include optimization of ventilation and
consideration of coadministration of intravenous calcium (11).
Ketoacidosis
Diabetic Ketoacidosis
Large volume resuscitation with intravenous normal saline delivers a
substantial chloride load, which can result in hyperchloremic acidosis,
renal vasoconstriction, and hypoperfusion, and has been associated
with increased risk of AKI in several studies over the last decade
(12,13). The SMART and SALT-ED trials, published in New
England Journal of Medicine in 2018, were pragmatic, open-labeled,
cluster-randomized trials of balanced crystalloids (Ringer lactate or
Plasma-Lyte A) versus normal saline in critically ill patients admitted
to an intensive care unit (SMART) and noncritically ill patients
admitted through the emergency department (SALT-ED) (14,15).
Over 29,000 patients were enrolled between the two studies, and in
both trials, treatment with balanced crystalloid was associated with a
significant reduction in the prespecified composite outcome compris-
ing death, new need for RRT, and persistent renal dysfunction at 30
days. No difference in mortality as a single end point was observed
(14,15). In SMART, the greatest benefit was observed in patients
with sepsis and higher predicted mortality. Limitations of these stud-
ies include open-label design and the lack of significant difference for
individual components of the composite end point. Based on the
number of events, the studies were not powered to detect a difference
for individual components. However, the trend for benefit was simi-
lar for each component of the composite end point, and it has been
estimated that among patients with sepsis, the number needed to
treat to prevent the composite end point was 20 (16).
Normal saline is generally considered the fluid of choice to treat
patients who present with diabetic ketoacidosis (DKA). A subgroup
analysis of patients enrolled in SMART and SALT-ED was recently
published, examining the effect of normal saline versus balanced
crystalloids in patients admitted with DKA. This secondary analysis
included 172 patients: 94 given balanced crystalloids and 78 given
saline. The primary outcome was time from emergency department
admission to resolution of DKA. When compared with those treated
with saline, patients treated with balanced crystalloids had earlier
resolution of DKA (13 versus 16.9 hours). They also had higher
bicarbonate levels, lower serum chloride, and earlier discontinuation
of intravenous insulin infusion (17). A number of other smaller
studies have shown similar results, suggesting that there may be ben-
efit to using balanced crystalloids as an alternative to normal saline
in the management of patients with DKA.
Euglycemic Ketoacidosis with Sodium-Glucose
Transporter-2 Inhibitors
For patients with CKD (eGFR .30 ml/min per 1.73 m2) and type
2 diabetes, sodium-glucose transporter-2 (SGLT2) inhibitors and
132
metformin are recommended as first-line oral hypoglycemic agents.
SGLT2 inhibitors have been shown to have beneficial effects on a
range of cardiovascular outcomes and significantly reduce the risk of
progression of CKD, development of ESKD, and death (18).
SGLT2 inhibitors improve glycemic control by reducing proximal
tubular reabsorption of glucose, thereby promoting glycosuria and
an osmotic diuresis. Urinary glucose loss reduces insulin secretion
and promotes glucagon release. This reduced insulin-to-glucagon
ratio promotes a switch to lipolysis and promotes hepatic ketoacid
production. Physiologic studies have demonstrated increases in levels
of ketoacids in SGLT2 inhibitor–treated patients with and without
underlying diabetes (19). However, the occurrence of ketoacidosis
in SGLT2 inhibitor–treated patients was rare in initial clinical trials.
Postmarketing surveillance suggests that ketosis occurs much more
commonly in clinical practice than initially recognized (20). The
majority (.70%) of such cases present with euglycemic ketoacidosis
(glucose ,250 mg/dl), thought to be driven by SGLT2
inhibitor–mediated ketogenesis (21,22).
Patients with euglycemic ketoacidosis frequently present with
vague symptoms, such as abdominal pain, nausea, and fatigue.
Although the AG is significantly elevated, diagnosis may be delayed
due to the absence of significant hyperglycemia. Recommended treat-
ment is similar to hyperglycemic DKA, although the degree of volume
depletion is significantly less due to the absence of hyperglycemia.
SGLT2 inhibitors are currently Food and Drug Administration
(FDA) approved only for use in type 2 diabetes, and their use is
associated with higher risk of ketoacidosis in patients with type 1
diabetes. Other risk factors for euglycemic ketoacidosis include
female gender, excessive reduction or discontinuation of insulin,
major surgery/trauma, intercurrent illnesses that limit the ability to
eat/drink, alcohol consumption, and low carbohydrate intake,
including ketogenic diets (20,23,24). Euglycemic ketoacidosis has
also been reported in patients taking SGLT2 inhibitors who develop
coronavirus disease 2019 (25). To reduce the risks of euglycemic
ketoacidosis, SGLT2 inhibitors should be used with caution in
patients with type 1 diabetes and discontinued in the setting of
intercurrent illness and 48–72 hours prior to planned major surgery.
Decreases in insulin dosage of .20% should be avoided, and
patients should be counseled to avoid excessive alcohol intake or
ketogenic diets (26). Euglycemic ketoacidosis appears to have a
higher mortality than classic DKA (20), and therefore, SGLT2
inhibitors should be permanently discontinued in affected patients.
Combination treatment with metformin and an SGLT2 inhibi-
tor was commonly used in cardiovascular outcome trials and has
been FDA approved. Both agents can cause metabolic acidosis
through differing mechanisms, but to date, there have been no
reports of increased risk of metabolic acidosis in patients treated
with both agents.
Continuous RRT and Ketoacidosis
A recent case series described a group of eight critically ill diabetic
patients who developed euglycemic ketoacidosis while on continuous
RRT (CRRT) (27). Three patients required insulin therapy prior to
admission; the others were on oral hypoglycemic agents (no SGLT2
inhibitors) or no treatment. After an initial improvement after start-
ing CRRT, patients developed a rising AG and falling serum
[HCO32]. All patients were dialyzed using a glucose-free CRRT
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
solution, and despite stable blood glucose levels, patients were found
to have elevated b-hydroxybutyrate levels. Mean time from initiation
of CRRT to recognition of ketoacidosis was 57 hours. In all cases, a
supplemental glucose infusion was initiated, which allowed an
increase in insulin administration, and ketosis resolved over an aver-
age of 14 hours. The authors hypothesized that in these cases, major
contributors to ketosis were the lack of caloric intake in critically ill
patients along with glucose loss in glucose-free CRRT, both of which
promote gluconeogenesis and ketosis. Furthermore, in diabetic
patients with underlying insulin deficiency, the resulting “well-
controlled” blood sugars led to a reduction in administered exoge-
nous insulin, increasing their risk of ketosis. A persistent high-AG
acidosis in intensive care unit patients treated with CRRT should
alert clinicians to search for possible coexisting ketosis.
Drug-Induced Metabolic Acidosis
A large number of drugs used in everyday clinical practice are associ-
ated with the development of metabolic acidosis via a variety of
mechanisms. An exhaustive review of all agents causing acidosis and
the associated pathophysiology are beyond the scope of this article.
However, the compounds and associated clinical features
highlighted in Tables 1 and 2 are of particular interest to contempo-
rary nephrology practice.
Sodium Thiosulfate
Sodium thiosulfate (STS) is commonly used in the treatment of cal-
ciphylaxis, despite a lack of strong evidence to support its use. The
mechanism of action of STS is unclear. STS is cleared equally by
the kidneys and liver, and thus, its clearance declines by half in
ESKD (28), where its use is frequently associated with increased AG
acidosis. STS-induced high-AG acidosis is thought to arise due to
accumulation of the metabolite hydrogen sulfide, which can inhibit
mitochondrial cytochrome complex IV and interfere with oxidative
phosphorylation and ATP generation, thereby resulting in lactic aci-
dosis (29).
In a retrospective study of 35 ESKD patients treated with STS,
33 (94%) had an increase in mean AG following initiation of STS
treatment. The average change in AG was 6.6 mmol/L on a dose of
25 g per hemodialysis session and 2.6 mmol/L after STS 12.5 g per
treatment. However, the change in AG varied widely, and an
increase in AG of 18 mmol/L was observed in several patients (30).
The degree of acidosis appears unpredictable, and although most
cases are mild, there have been reports of severe high-AG metabolic
acidosis presenting with weakness, arrhythmia, seizure, and altered
mental status associated with treatment with STS (31,32).
Metformin
Metformin is a first-line agent recommended for treatment of type 2
diabetes in patients with eGFR .30 ml/min per 1.73 m2, and its
use has been associated with reduced mortality in patients with
CKD (33). Generally safe and well tolerated, metformin reduces
blood glucose through several mechanisms but primarily through
inhibition of hepatic gluconeogenesis (34). Metformin inhibits the
mitochondrial respiratory chain components and mitochondrial
glycerophosphate dehydrogenase, inhibiting the conversion of glyc-
erol and lactate to glucose. These combined effects reduce
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 133

Table 1. Drug-induced high–anion gap metabolic acidosis: Mechanisms and clinical features (39)

Risk Factors and Clinical

Agent Drug Class Mechanism of Acidosis Type of Acidosis Features

Propofol Anesthetic agent Disrupts mitochondrial Lactic acidosis Increased risk with high dose and
function and impairs prolonged exposure
oxidative Propofol infusion syndrome:
phosphorylation Estimated incidence
approximately 1% of ICU
patients (77)
Associated with rhabdomyolysis,
hypertriglyceridemia, and AKI
Linezolid Antimicrobial Disrupts mitochondrial Lactic acidosis Increased risk with liver/renal
function and impairs dysfunction, higher doses,
oxidative prolonged exposure
phosphorylation Associated with myelosuppression
and liver toxicity (78)
Lamivudine abacavir Nucleoside/ Disrupts mitochondrial Lactic acidosis Used for treatment of HIV,
Zidovudine tenofovir NRTIs function and impairs Fanconi syndrome hepatitis B, and HIV pre-
Stavudine didanosine oxidative with non-AG exposure prophylaxis
phosphorylation metabolic acidosis Mild increase in lactate .20% of
seen with didanosine, treated patients, severe in
cidofovir, lamivudine, 1%–2% (79)
stavudine, tenofovir Increased risk with liver/renal
dysfunction, alcohol use,
obesity, pregnancy, and
combination therapy
Mortality up to 50% in severe
cases
High volume of distribution,
prolonged intracellular half-life.
NRTIs are less readily
dialyzable, but this may be
considered in severe cases (80)
Acetaminophen Analgesic Depletion of glutathione, High-AG metabolic Seen in chronic ingestion of
accumulation of acidosis acetaminophen, including at
pyroglutamic acid (5- Pyroglutamic acidosis therapeutic doses
oxoproline) Urinary 5-oxoproline elevated
Risk factors include malnutrition,
women, underlying liver/renal
dysfunction, sepsis, and alcohol
abuse
Concomitant use of antibiotics,
such as dicloxacillin/oxacillin,
may increase risk (81)
Treatment with n-acetylcysteine
may supplement cysteine, a
precursor of glutathione
Ethanol Alcohol Ketosis Poor carbohydrate intake, chronic
volume depletion, and insulin
(continued on next page)
134 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Table 1. Drug-induced high–anion gap metabolic acidosis: Mechanisms and clinical features (39) (cont.)

Risk Factors and Clinical

Agent Drug Class Mechanism of Acidosis Type of Acidosis Features

High-AG metabolic deficiency. Resolves when

acidosis treated with fluids and nutrition
Ketoacidosis
Methanol Toxic alcohols Generation of acid High-AG metabolic Certain laboratory instruments
Ethylene glycol metabolites (formic acid acidosis differentiate poorly between
and oxalate) High osmolar gap metabolites of ethylene glycol
and lactate and may give falsely
high lactate readings in ethylene
glycol ingestion (82)
Osmolal gap may not identify
small ingestions and may have
closed in those presenting late
Treatment with fomepizole
(alcohol dehydrogenase
inhibitor) and hemodialysis
Propylene glycol Carrier vehicle Lactic acidosis High-AG metabolic Used to administer intravenous
for Generation of acid acidosis lorazepam and diazepam
intravenous metabolites High osmolar gap Metabolized to lactic acid,
infusions pyruvate, and acetate
Increased risk in liver/renal
dysfunction and those at risk of
DKA
Valproate Antiepileptic Mitochrondrial High-AG metabolic Overdose or intoxication is
dysfunction acidosis associated with hepatoxicity,
hyperammonemia,
encephalopathy, and metabolic
acidosis
Emergent hemodialysis is
indicated for severe intoxication,
shock, and cerebral edema.
Valproate is effectively cleared
by dialysis (83)
Salicylates NSAID Disrupts mitochondrial High-AG metabolic Toxicity is also associated with
function and impairs acidosis respiratory alkalosis due to
oxidative stimulation of the medullary
phosphorylation respiratory center
Urinary alkalinization with
intravenous bicarbonate
increases renal clearance; oral
bicarbonate should be avoided
Hemodialysis is indicated for
severe intoxication, including
respiratory distress, altered
mental status, and levels
.90 mg/dl (84)

ICU, intensive care unit; NRTI, nucleotide reverse transcriptase inhibitor; AG, anion gap; DKA, diabetic ketoacidosis; NSAID, nonsteroidal anti-inflammatory drug.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
gluconeogenesis while also reducing degradation and increasing gen-
eration of lactate (35,36).
Metformin-associated lactic acidosis (MALA) is a rare but life-
threatening complication of treatment, with reported incidence of
,10/100,000 patient-years. A recently published retrospective,
nested case-control study using data from 2003 to 2013 in the Vet-
erans Affairs Healthcare system identified 2662 patients with type 2
diabetes, CKD, and a newly dispensed antihyperglycemic agent who
developed lactic acidosis (defined as lactate .5 mEq/L). A control
group of 26,000 patients was matched for demographic characteris-
tics, stage of CKD, and year of analysis. When comparing metfor-
min exposed with nonexposed, those treated with metformin had an
incidence of lactic acidosis of 2/1000 patient-years, with a rate dif-
ference of 0.04/1000 patient-years compared with nontreated refer-
ence group. A significant increase in risk of lactic acidosis was
observed with worsening renal function, where CKD stages 1 and 2
were at baseline risk, CKD stages 3a and 3b had a two- to three-fold
increase in risk, and CKD stages 4 and 5 had a five- to seven-fold
increase in risk of lactic acidosis (37). Among CKD stages 3a and
3b patients, although there was increased relative risk in metformin-
treated patients, the absolute risk remains small. The findings of this
study support the current recommendations that metformin is safe
in patients with eGFR.30 ml/min, but with progressive CKD,
alternative agents may be more suitable.
MALA most commonly occurs in the presence of other condi-
tions that promote accumulation of lactic acid. Important risk fac-
tors include AKI, volume depletion, hepatic impairment, congestive
heart failure, shock/tissue hypoperfusion, advanced age, and con-
comitant use of radiocontrast agents or other nephrotoxins (36).
Higher serum levels of metformin have been associated with poorer
outcomes, where level .5 mg/ml was associated with up to 30%
mortality compared with 11% in patients with levels ,5 mg/ml
(38). However, pH and lactate levels are not predictive of outcome
in MALA (39).
Metformin is a small, nonprotein-bound molecule and is effi-
ciently cleared by hemodialysis. Emergent RRT is indicated in cases
of severe MALA and should be initiated in cases where lactate level
is .20 mmol/L, pH#7.0, shock, decreased level of consciousness,
and failure of supportive measures (40). Additional indications may
include the presence of AKI, liver dysfunction, or other significant
comorbidities. Due to greater efficiency of clearance, hemodialysis is
preferred, but there are many case reports of successful treatment of
critically ill, unstable MALA patients with CRRTs. RRT should be
continued until lactate level is below 3 mmol/L and pH is .7.35.
Chronic Metabolic Acidosis in CKD
Background
With declining renal function, there is a reduction in renal ammo-
niagenesis and a reduced ability to generate bicarbonate in the proxi-
mal and distal tubules. The loss of ability to efficiently excrete
endogenous and exogenous H1 leads to accumulation of H1
beyond the buffering capacity of muscle and bone and eventually, to
the development of metabolic acidosis (41). Although multiple fac-
tors play a role, low GFR and decreased capacity for acid excretion
are the key factors in the development of metabolic acidosis in CKD
patients (42). Using a cutoff of [HCO32] #22mEq/L, 15% of all
135
CKD patients have metabolic acidosis, with increasing prevalence at
lower levels of renal function. In the Chronic Renal Insufficiency
Cohort study, the prevalence of acidosis was reported as 7% in stage
2, 13% in stage 3, and 37% in stage 4 CKD participants (42,43)
Untreated metabolic acidosis in the CKD population has been
associated with a range of adverse health consequences, including
loss of bone mineral density, muscle wasting, oxidative stress, and
negative cardiovascular outcomes (42). Multiple large cohort studies
have reported an association between the presence of metabolic aci-
dosis and greater mortality in patients with CKD, ESKD and renal
transplant recipients. These observations have led to the current rec-
ommendations, to treat all patients with a serum [HCO32]
,22mEq/L with alkali therapy (44).
Multiple factors have been identified to influence serum
[HCO32] level in patients with CKD, independent of GFR. Factors
associated with worsening metabolic acidosis in CKD include hyper-
kalemia, albuminuria, smoking, anemia, dietary protein intake, and
selected medications (43,45). The typical Western diet is particularly
acid generating and high in protein, and it can result in net acid
production of up to 1 mEq/kg per day (46). A large intake of animal
protein promotes acidosis, and several studies have shown that an
alternative diet of alkali-producing fruits and vegetables can prolong
the duration of eubicarbonatemia (47,48). Medications are also an
important factor in the development of metabolic acidosis; for
example, loop diuretics increase serum [HCO32], and others, such
as inhibitors of the renin-angiotensin system, promote acidosis (49).
Gardener et al. (50) studied the effect of medications with an acid
salt (i.e., hydrogen chloride) on serum bicarbonate levels in 74
United States veterans with diabetes and CKD stages 2–4 with eubi-
carbonatemia. In this cohort, 25% of prescribed medications con-
tained an acid salt, with metformin hydrochloride and gabapentin
hydrochloride having the highest acid load potential. Patients who
received the highest load of acid from medications had [HCO32]
1.7 mEq/L lower and AG 2.2 mEq/L higher than patients receiving
lower acid load (50).
Eubicarbonatemic Metabolic Acidosis and Urine Citrate
Experimental data indicate that patients with higher levels of GFR
or serum [HCO32] within the normal range also have evidence of
acid retention (known as eubicarbonatemic acidosis) and reinforce
the concept that low serum [HCO32] occurs later, when buffering
mechanisms have been overwhelmed. Eubicarbonatemic acidosis has
been associated with more rapid CKD progression in a number of
large cohort studies. In patients enrolled in African American Study
of Kidney Disease and Hypertension and the NephroTest cohort
(CKD stages 2–5), eubicarbonatemic patients in the lowest tertile of
baseline urine ammonium excretion had a higher odds of developing
hypobicarbonatemic metabolic acidosis within a year and greater
risk of progression to ESKD (41,46,51). Conversely, in United
States veterans with CKD and CKD patients from the Cleveland
Clinic Foundation, those with a high-normal serum [HCO32] had
lower risk of mortality or GFR decline than those with low-normal
serum [HCO32] (42). As a result, an alternative paradigm for the
management of metabolic acidosis in CKD has been proposed,
where earlier introduction of alkali therapy can be considered as a
measure to delay CKD progression (Figure 1).
136 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Measuring urine ammonium excretion is not feasible in stan-
dard clinical practice, and urine citrate has been suggested as an
alternative method to identify patients with H1 retention and eubi-
carbonatemia. With intracellular acidification of renal tubular epi-
thelium, there is increased proximal tubular reabsorption of citrate
as a mechanism to regenerate bicarbonate, resulting in hypocitraturia
(41). In a 2019 study, Goraya et al. (52) hypothesized that urine cit-
rate measurement could identify patients with acid (H1) retention,
including those without overt metabolic acidosis. They assigned 66
patients with albuminuric CKD stages 1 and 2 to a base-producing
diet for 30 days. At study end, they observed a reduction in H1
retention with an increase in urine citrate, suggesting that urine cit-
rate may reflect changes in H1 retention in nonacidotic patients
with CKD (52). In a subsequent study, the same group of investiga-
tors treated 120 patients with CKD stage 2 and total CO2 .24
mEq/L with oral NaCl, NaHCO3, or usual care and measured urine
citrate excretion at baseline and study end. Patients treated with oral
NaHCO3 had no significant change in H1 retention or urine citrate
excretion during the 10-year follow-up. In contrast, the NaCl and
usual care groups had significant increases in H1 retention and
reduction in urine citrate but with little change in plasma CO2 or
AG (both remained within the normal range). The authors suggest
that urine citrate may identify patients with subclinical H1 reten-
tion that is not apparent on routine laboratory measurement and
who may benefit from alkali therapy (47) (Figure 1). However,
despite these interesting findings, no studies have identified a rela-
tionship between urine citrate and renal outcomes to date, and this
remains an area of investigation.
Mechanisms of Injury Associated with Chronic Metabolic
Acidosis in CKD
In observational studies, both eubicarbonatemic and overt metabolic
acidosis have been associated with progression of CKD (49,53–55).
The kidney has multiple mechanisms to detect and respond to
changes in systemic acid-base status. In response to increased acid
load, ammoniagenesis increases, and H1 transporters are
upregulated along the course of the tubule to collecting duct, lead-
ing to an increase in urinary acid excretion within hours to days
(56). However, many of these compensatory mechanisms also upre-
gulate cellular pathways associated with fibrosis and endothelial cell
inflammation.
Reduction in interstitial and intracellular pH stimulates local
release of angiotensin II, aldosterone, and endothelin-1 (ET-1).
Angiotensin II increases proximal tubular acid excretion via upregu-
lation of NH3 and H1-ATPase and increases ammoniagenesis.
However, chronic elevation in intrarenal angiotensin II leads to
increased local aldosterone, elevated intraglomerular filtration pres-
sure, and activation of proinflammatory and profibrotic pathways
within the kidney, resulting in worsening proteinuria, fibrosis, and
tubular atrophy (56). ET-1 also increases tubular H1 secretion to
reduce acid retention, but sustained levels of ET-1 lead to foot pro-
cess effacement and similarly activate local profibrotic and proin-
flammatory pathways, exacerbating proteinuria and tubulointerstitial
injury (56,57). Increasing evidence suggests that that these compen-
satory mechanisms are upregulated early in CKD and may have det-
rimental effects on CKD progression. In a study of 120 patients
with macroalbuminuria and CKD stage 2, serum [HCO3] and acid-
base parameters were similar to patients with CKD stage 1. How-
ever, those with CKD stage 2 showed H1 retention, as assessed by
reduced net acid excretion following an acid load, and elevated
plasma and urine levels of aldosterone and ET-1 compared with
CKD stage 1. Plasma and urine aldosterone and ET-1 levels normal-
ized after 30 days of NaHCO3 treatment, suggesting alkali therapy
may be beneficial for such patients (58).
Increased ammoniagenesis is a central mechanism to excrete an
acid load. In CKD, ammoniagenesis is initially maintained despite a
reduced number of functional nephrons, due to increases in single-
nephron ammonia generation. However, ammonia activates the
alternative pathway of complement, leading to tubulointerstitial
inflammation and fibrosis (59). In studies of nephrectomized rats,
treatment with NaHCO3 reduced ammonia concentration, and
was associated with reductions in proteinuria, tubular injury and

A Current paradigm B Alternative paradigm C Alternative paradigm

Renal acid excretion (mEq/d)

No alkali therapy No alkali therapy

X X
Total CO2 (mEq/L)

Total CO2 (mEq/L)

Total CO2 (mEq/L)

X–1 X–1
85% of CKD No alkali therapy
Y
No alkali therapy
Treat subclinical
metabolic acidosis <Y
Treat subclinical
metabolic acidosis
22 22 22
21 21 21
15% of CKD 15% of CKD 15% of CKD
Treat metabolic acidosis Treat metabolic acidosis Treat metabolic acidosis

Figure 1. Urinary acid excretion may identify patients with CKD and normal total CO2 who have subclinical metabolic acidosis. (A) The cur-
rent metabolic acidosis treatment paradigm is to withhold alkali until serum total CO2 falls below 22 mEq/L, in which case only 15% of
patients with CKD receive alkali therapy. (B) An alternative paradigm assumes that patients with CKD and total CO2 below a threshold value
(represented as X) have either overt acidosis or subclinical metabolic acidosis and are potential candidates for alkali therapy. (C) Another possible
approach would be to treat patients with CKD with total CO2 of 22 mEq/L and those with subclinical metabolic acidosis defined by a normal
total CO2 and urinary acid excretion below a threshold value (represented as Y) (42).
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 137

Table 2. Drug-induced nonanion gap metabolic acidosis: Mechanisms and clinical features (39)

Mechanism of Risk Factors and Clinical

Agent Drug Class Acidosis Type of Acidosis Features

Topiramate Antiepileptic Inhibition of carbonic Non-AG metabolic Decreased urinary citrate levels
anhydrase acidosis Increased risk of calcium phosphate
calculi
Sevelamer Phosphate binder Release of chloride in Non-AG metabolic Increased risk in patients with CKD
hydrochloride GI tract leads to acidosis and limited renal HCO32
bicarbonate loss in regeneration
stool
Trimethoprim Antimicrobial Reduced H1 excretion Non-AG metabolic Blockade of Na1 channel on luminal
acidosis surface of principal cell reduces
lumen negative potential and limits
H1 and K1 excretion
Hyperkalemia and acidosis
Cyclosporin Calcineurin inhibitors Reduced H1 excretion Non-AG metabolic Blockade of Na1, K1-ATPase on
Tacrolimus acidosis principle cell, decreasing Na1
reabsorption, and K1 and H1
secretion
Acetazolamide Carbonic anhydrase Inhibition of carbonic Non-AG metabolic Bicarbonaturia
inhibitor anhydrase acidosis Increased risk in elderly, CKD, and
DM
Amiloride Potassium-sparing Reduced H1 excretion Non-AG metabolic Blockade of Na1 channel on luminal
Triameterene diuretics acidosis surface of principal cell reduces
lumen negative potential and limits
H1 and K1 excretion
Hyperkalemia and acidosis
ACEi Inhibitors of the renin- Reduced H1 excretion Non-AG metabolic Aldosterone and angiotensin II
ARB angiotensin- acidosis promote transport of H1 into
Renin inhibitors aldosterone system tubular lumen via H1-ATPase;
Aldosterone inhibited by renin-angiotensin-
antagonists aldosterone system blockade
Reduced Na1 reabsorption reduces
lumen negative potential and limits
H1 excretion via H1-ATPase
Hyperkalemia suppresses renal
ammoniagenesis and excretion of an
acid load

AG, anion gap; GI, gastrointestinal; DM, diabetes mellitus; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.

decreased deposition of C3 and C5–C9 complement components,
compared with controls, further demonstrating the intra-renal effects
of correction of acidosis (60).
Treatment of Metabolic Acidosis in CKD
Although the effects of metabolic acidosis on muscle, bone, and
CKD progression have been known for some time, until recently it
was unclear if treatment with alkali could reverse these effects and
delay CKD progression. Several recent trials have addressed this ques-
tion and demonstrated the benefits of treatment, as described below.
In 2010, Mahajan et al. (61) reported a randomized, controlled
clinical trial of bicarbonate supplementation in patients with hyper-
tensive nephropathy and mean eGFR of 75 ml/min. At 5 years
follow-up, patients treated with NaHCO3 had greater preservation of
eGFR and a slower trajectory of GFR decline than control groups
(61). More recently, the UBI study group randomized 740 patients
from Italy with CKD stages 3–5, metabolic acidosis (serum HCO32
.18 and ,24 mEq/L), and eGFR of 30612 ml/min per 1.73 m2
to either standard care or NaHCO3 treatment with a 3-year follow-
up period. Those treated with NaHCO3 had lower incidence of dou-
bling of serum creatinine (6.6% versus 17%) and significantly lower
rates of development of ESKD (6.9% versus 12.3%) and death
(3.1% versus 6.8%) (62) (Figure 2). No significant effect was
138 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Figure 2. Time to (A) creatinine doubling, (B) all-cause mortality, and (C) initiation of RRT, according to the Kaplan–Meyer methods (P value
refers to the unadjusted log-rank tests). Analyses are carried out as per intention to treat, and no data imputation on missing data is performed (62).
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 139

Figure 3. (A) The forest plot shows a slower decline in eGFR at the end of the study period with oral alkali supplementation or reduction of
dietary acid intake. I2 for the combined effect estimate: 39% (95% confidence interval [95% CI], 0% to 66%). df, degrees of freedom; IV,
inverse variance (64). (B) The forest plot shows the potentially reduced risk of ESKD with oral alkali supplementation or reduction of dietary
acid intake. I2 for the combined effect estimate: (95% CI, 0% to 73%). M-H, Mantel–Haenszel (64).
140
observed of NaHCO3 on BP, total body weight, or hospitalizations.
However, it is noteworthy that this study excluded patients with heart
failure NYHA III and IV and those with BP .150/90 mm Hg.
In the Bicarbonate Administration to Stabilize eGFR Pilot trial,
a multicenter, randomized trial, Raphael et al. (63) assessed the
safety and tolerability of two different NaHCO3 doses, 0.5 or 0.8
mEq/kg lean body wt per day, versus matched placebo over 28
weeks in 194 adults with eGFR of 20–44 or 45–59 ml/min per
1.73 m2 with urinary albumin-to-creatinine $50 mg/g and serum
[HCO3] 20–28 mEq/L. Both NaHCO3 doses were well tolerated
over the study period, with no significant difference in weight,
diuretic requirement, BP, or hospitalizations across the three groups
by week 28 of follow-up. Mean urinary ammonium excretion was
25% lower in the group that received the high dose of NaHCO3,
suggesting that this may be an appropriate dose for a future larger
study (63). In this study, no differences in GFR were observed.
However, a small but statistically significant increase in the urine
albumin-to-creatinine ratio was observed in the high-dose NaHCO3
group. This was an unexpected finding, not observed in the UBI
study or in a meta-analysis discussed below, and is of unclear signifi-
cance, but it necessitates future follow-up.
A 2019 systematic review and meta-analysis of treatment of
metabolic acidosis in CKD using either oral alkali or dietary inter-
vention included data from 14 clinical trials, comprising 1394 par-
ticipants (64). Four of the studies included patients treated for
eubicarbonatemic metabolic acidosis. Eight studies used oral alkali,
five studies had a dietary intervention, and one study used both. In
the pooled analysis, treatment of metabolic acidosis with oral alkali
supplementation or a reduction of dietary acid intake increased
serum bicarbonate levels and resulted in a slower decline in eGFR
and reduced risk of progression to ESKD (RR, 0.32; 95% confi-
dence interval [95% CI], 0.18 to 0.56) (Figure 3). However, in this
analysis, treatment with oral alkali was associated with increased
edema, necessitating increases in diuretics, worsening hypertension,
and the need to escalate antihypertensive therapy. The authors cau-
tion that these studies excluded patients with uncontrolled hyperten-
sion and decompensated heart failure, meaning that further research
is needed to establish how generalizable these findings are to a real-
world CKD population (64).
A more recent double-blinded, randomized, controlled trial
studied the effect of NaHCO3 therapy in elderly CKD stages 4 and
5 patients .60 years old (mean age 74 years) over 2 years and
reported no changes in physical function as assessed by the Short
Physical Performance Battery or secondary measures, such as of
quality of life and walk distance. However, there are several impor-
tant limitations to this study. There were challenges with recruit-
ment and a very high dropout rate. This was a cohort of advanced
CKD, with 22% of patients at CKD stage 5 at enrollment. Further-
more, the achieved difference in serum [HCO32] between the two
groups was ,1 mEq/L, suggesting either poor compliance or inade-
quate dosing for the level of GFR. Further studies will be required
to evaluate the effect of alkali therapy in older adults (65).
There also is considerable interest is investigating the effect of
alkali therapy on cardiovascular disease. In a pilot randomized, cross-
over study of 18 individuals with CKD (eGFR 15–44 ml/min) and
serum [HCO32] of 16–21 mEq/L, treatment of metabolic acidosis
with NaHCO3 was associated with improved vascular endothelial
function as evaluated by the increased brachial artery flow–mediated
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
dilation during the course of 14 weeks of observation (66). Prior
studies have reported that increases in brachial flow–mediated diam-
eter are associated with reduced risk of cardiovascular event, but this
study was not designed to examine such outcomes. Serum phos-
phate and FGF23 also increased in this small study, suggesting that
the effect of NaHCO3 on MBD parameters, vascular calcification,
and cardiovascular disease may warrant further investigation in
larger, longer-term studies.
There are a number of unanswered questions around alkali
therapy in CKD, including the most effective dose and the long-
term effect of treatment on renal and cardiovascular outcomes in
patients with CKD. There are some concerns around the safety of
NaHCO3 in CKD, although it has long been argued that chloride-
containing salts have a greater propensity to induce fluid retention
and edema than when sodium is given with bicarbonate (42). As
described above, alkali-producing fruits and vegetables have been
suggested as a potential therapy for treatment of metabolic acidosis,
and this intervention has been associated with increased urine citrate
excretion, reduced albuminuria, lower systolic BP, and weight loss,
along with many other cardiovascular benefits. However, evidence is
limited on the best practice of prescribing these fruits and vegetables,
and hyperkalemia remains a concern with this approach, particularly
in those with later stages of CKD. In future studies, investigation of
the coadministration of newer potassium binders may facilitate safe
consumption of alkali-producing fruits and vegetables in the CKD
population (67).
Veverimer
Veverimer (also known as TRC101) is an orally administered, non-
absorbed hydrochloric acid binder being evaluated as a novel therapy
for metabolic acidosis in CKD. Veverimer increases serum
[HCO32] by selectively binding and removing H1 and chloride
anions from the GI tract. It acts by sequestering HCl from the
stomach, similar to the physiologic effect of vomiting or nasogastric
suction, where acid removal stimulates increases in serum
[HCO32]. HCl-bound veverimer is then excreted unchanged in
feces (68). Veverimer is not an exchange resin; therefore, no sodium,
potassium, or calcium is added to the GI tract or systemically
absorbed.
The first human study of veverimer was a randomized,
double-blind, placebo-controlled, multicenter trial of 135 partici-
pants with mean baseline eGFR of 35 ml/min per 1.73 m2 and
mean baseline serum [HCO32] of 17.7 mEq/L, including patients
with hypertension (93%), diabetes (70%), and heart failure (21%)
(69). Patients were kept in a metabolic unit, fed a controlled diet,
and treated for 14 days with either placebo or one of four dosing
regimens of veverimer (1.5, 3, or 4.5 g twice daily or 6 g once
daily). After treatment, patients were followed for 7–14 days.
Treatment with veverimer was associated with a $1.3-mEq/L
increase in serum [HCO32] within 72 hours and a mean increase
of 3.2–3.9 mEq/L by study end. This effect cleared after 14 days
of termination of therapy.
The safety and efficacy of veverimer were further studied in a
phase III randomized, controlled, multicenter trial, where 217
patients with CKD, eGFR of 20–40 ml/min per 173 m2, and serum
[HCO32] of 12–20 mmol/L were randomly assigned to veverimer
(6 g/d) or placebo with unrestricted dietary protein intake, and they
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
were followed for 12 weeks (70). Veverimer treatment was associated
with significantly higher rates of increase in [HCO32] by 4 mEq/L or
more and higher rates of normalization of [HCO32]. Physical func-
tion was assessed using ten items from the Kidney Disease Quality of
Life Short Form-36 and the repeat chair stand test, and veverimer-
treated patients showed a significant increase in physical function
scores compared with controls. Adverse events were uncommon and
similar in both groups. In a follow-up extension study, 196 patients
continued on study assignment for a further 40 weeks. Those treated
with veverimer had stable [HCO32] out to week 52 and again,
showed significant improvements in measures of physical function as
compared with control. The investigators concluded that veverimer is
safe and effective for treatment of metabolic acidosis of CKD and
resulted in improvements in subjective and objective physical func-
tioning (71). As a counterion free hydrochloric acid binder, veverimer
may be especially useful in patients for whom sodium loading with
NaHCO3 may be of concern. However, further studies are required
to evaluate the effect of veverimer in such populations and on other
complications of metabolic acidosis, including bone density, CKD
progression, and cardiovascular outcomes.
Metabolic Acidosis and Kidney Transplant
Outcomes
The prevalence of metabolic acidosis in kidney transplant recipients
varies widely across studies, with reported rates of 11% to .50%.
However, the prevalence appears higher than nontransplant CKD,
at all levels of GFR. Several factors specific to transplantation may
play a role; a single kidney has more limited reserve to handle an
acid load, renal transplantation is commonly associated with immu-
nologically and nonimmunologically mediated tubular dysfunction,
and calcineurin inhibitors are associated with a dose-dependent
increased risk of metabolic acidosis secondary to tubular dysfunction
and type 4 renal tubular acidosis (72–74) (Table 2).
Several recent observational studies have reported an association
between metabolic acidosis in renal transplant recipients and
reduced patient and allograft survival (74,75). In a large, multicen-
ter, retrospective cohort study, Park et al. (74) analyzed data from
2318 renal transplant recipients who underwent renal transplanta-
tion between 1997 and 2012, with mean follow-up of 62 months.
Metabolic acidosis was defined as the presence of total CO2 ,22
mEq/L at 3 months post-transplant. Risk factors for metabolic aci-
dosis included GFR ,60 ml/min per 1.73 m2, deceased donor
transplantation, and treatment with tacrolimus (versus cyclosporin).
In adjusted Cox regression models, the presence of metabolic acido-
sis was associated with a significantly increased risk of graft loss (haz-
ard ratio [HR], 3.48; 95% CI, 2.47 to 4.90), mortality (HR, 3.16;
95% CI, 1.77 to 5.62), and death-censored graft failure (HR, 3.17;
95% CI, 2.12 to 4.73) (74). In a retrospective cohort of 468 trans-
plant recipients, 57 of whom had metabolic acidosis ([HCO32]
,22 mEq/L) at baseline, Gojowy et al. (75) also reported reduced
patient and allograft survival at 3-year follow-up. In this study, those
with metabolic acidosis had significantly lower GFR at baseline and
at 3 years, and the presence of acidosis was associated with relative
risk of death of 4.11 (95% CI, 1.58 to 10.67) at 3 years.
Djamali et al. (76) examined the association between meta-
bolic acidosis and cardiovascular events after renal transplantation.
141
In this observational study of 2128 renal transplant recipients,
38.8% had metabolic acidosis at 1 year post-transplant. Total
CO2 level ,20 mEq/L was associated with increased risk of car-
diovascular events (adjusted HR, 2.2; 95% CI, 1.29 to 3.10), and
this effect was driven mainly by the increased risk of ischemic car-
diovascular events. For every 1-mEq/L drop in total CO2 below
24 mEq/L, the risk of cardiovascular events rose by 17%. Similar
to other reports, acidosis was also independently associated with
all-cause mortality and with progressively higher risk with wors-
ening acidosis (76). Similar to in all CKD patients, treatment
with alkali therapy is recommended for renal transplant recipients
with [HCO32] ,22 mEq/L, but no studies have specifically
examined the effect of alkali therapy on outcomes in transplant
recipients. Given the prevalence of acidosis and high rates of com-
plications in this patient group, this is an area ripe for future
investigation.
4 Subgroup analysis of the SMART and SALT-ED tri-
als suggests that fluid resuscitation with balanced
crystalloid leads to earlier resolution of acidosis in
DKA when compared with saline therapy.
4 Euglycemic ketoacidosis is an important complica-
tion of treatment with SGLT2 inhibitors. Risk factors
include states of decreased oral intake, rapid reduc-
tions in insulin therapy, major surgery/trauma,
decreased carbohydrate intake, and ketogenic diets.
4 Eubicarbonatemic metabolic acidosis occurs
where total CO2 remains >22 mEq/L but there is
evidence of H1 retention. It has been associated
with increased rates of progression to ESKD.
Reductions in urine citrate may identify patients
with H1 retention and eubicarbonatemic meta-
bolic acidosis.
4 Untreated metabolic acidosis is associated with
increased intrarenal angiotensin II, aldosterone, and
endothelin-1 levels, which promote proinflammatory
and profibrotic pathways within the kidney.
4 Treatment of metabolic acidosis with NaHCO3 has
been associated with decreased rates of doubling
of serum creatinine, delayed progression to ESKD,
and decreased mortality.
4 Veverimer is an orally administered, nonabsorbed
hydrochloric acid binder. It increases serum
[HCO32] by selectively binding and removing H1
and chloride anions from the GI tract. Phase III stud-
ies have shown that it effectively increases [HCO32]
with improved physical functioning scores.
142
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Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Article
Metabolic Alkalosis
Namrata Krishnan, MD
Yale School of Medicine, New Haven, Connecticut, and
Veterans Affairs Medical Center, West Haven, Connecticut
Robert Jay Alpern, MD
Yale School of Medicine, New Haven, Connecticut
Learning Objectives
1. To state the normal homeostatic mechanisms that prevent
metabolic alkalosis
2. To describe the factors involved in the generation and
maintenance of metabolic alkalosis, including contraction of
effective arterial blood volume and the interactions of distal
delivery of Na1 and water with activated distal H1 secretory
mechanisms
3. To list the clinical examples that result in alkalosis by the
mechanisms defined above
4. To describe the approach to evaluation and treatment of
metabolic alkalosis in common clinical settings
Introduction
Metabolic alkalosis is a condition of great clinical importance that
occurs frequently in critically ill patients. It predicts and, in many
ways, contributes to poor clinical outcomes. It is common in hospi-
talized patients and correlates with increased morbidity, mostly as a
marker for severe underlying conditions but also as a cause of
adverse outcomes.
We begin this review with a discussion of the normal homeostatic
mechanisms that prevent metabolic alkalosis. We then discuss the
pathophysiologic processes that cause these mechanisms to fail, and
the evaluation and the treatment of established metabolic alkalosis.
Mechanisms That Prevent Metabolic Alkalosis
From a teleologic point of view, the more dangerous a clinical con-
dition is, the more powerful are the homeostatic mechanisms that
prevent it. Because alkalosis is dangerous, homeostatic mechanisms
ensure that the blood pH rarely rises above 7.6 and is typically
below 7.5. Increases in blood pH are generally limited in magnitude
because of a multitude of defense mechanisms that defend against it,
including (1) buffering mechanisms that moderate the acute effect
of net alkali addition on blood pH (2), respiratory compensation,
and (3) renal mechanisms that define the steady-state blood pH.
Copyright © 2022 by the American Society of Nephrology
145
Buffering
To define the buffer capacity of the extracellular fluid (ECF), Swan
et al. infused HCO32 into nephrectomized dogs and measured the
change in plasma bicarbonate concentration (HCO32) (1). As was
typical for such experiments, they framed it as an apparent volume
of distribution (Vd) for HCO32. Whereas such an approach is rela-
tively simple for nondecomposable solutes, the approach becomes
more complex for HCO32. Although the expected anatomic space
of bicarbonate is the extracellular space, the apparent Vd for infused
bicarbonate is closer to that of total body water. This is because
extracellular buffers (such as phosphate), intracellular buffers (such
as hemoglobin), and bone buffers (some which are extracellular and
some which involve changes in cellular membrane transport) all
defend blood pH and HCO32.
All buffers have a pHoptimum at which they are maximally effec-
tive. As a result, the apparent Vd for HCO32 varies with pH.
Because the body’s ability to prevent a change in HCO32 increases
as blood pH decreases, the apparent Vd for HCO32 increases at a
lower pH (2). Whereas Vd refers to buffering or the prevention of
acute changes in HCO32, the quantitatively most important buffer
system that defends blood pH is the HCO32/CO2 buffer system,
the buffer capacity of which is equal to 2.3 HCO32. Thus, whereas
the defense against changes in blood HCO32 is greatest at low pH
and HCO32, the defense against changes in blood pH is greatest at
more alkaline pH with a higher HCO32. This is a major reason
why one rarely sees blood pH above 7.5–7.6.
Respiratory Compensation
Acute buffering is followed by respiratory compensation (hypoventi-
lation), which returns blood pH toward normal. This is mediated
by changes in cerebrospinal fluid pH and generally takes a few hours
to evolve.
Renal Excretion
The major defense against metabolic alkalosis, which prevents it
from being sustained, is the efficient renal excretion of HCO32.
Owing to the kidney’s large capacity to excrete HCO32, individuals
can ingest large amounts of HCO32 without experiencing sustained
metabolic alkalosis. Acute infusions of #1500 mEq of NaHCO3
only transiently increase plasma HCO32 (3). Only if these renal
homeostatic mechanisms are disrupted will a patient maintain meta-
bolic alkalosis.
The mechanism by which the renal tubule regulates HCO3-
secretion is complex. Pitts and Lotspeich showed that if HCO32 is
nephsap.org
146 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

infused into dogs, all of the filtered HCO32 is reabsorbed until a

threshold (approximately 25 mmol/L), is reached at which bicarbo-
naturia occurs, and then HCO32 reabsorption approaches a tubular
maximum (Tm) (4). Normal plasma HCO3- will generally fall
around the threshold. The concept of a Tm for bicarbonate absorp-
tion is useful clinically but is not quite correct. In tubular microper-
fusion studies, proximal tubular HCO3- absorption increases linearly
up to a luminal HCO32 of 40 mEq/L, which is considerably higher
than the normal range of plasma HCO3- (25 mmol/L) (5). In the
absence of changes in luminal HCO32, increases in blood pH and
HCO32 inhibit proximal tubular HCO3- absorption (6). Thus, the
apparent Tm for HCO32 reabsorption actually represents inhibition
of tubular HCO3- absorption by peritubular alkalinity in the proxi-
mal tubule.
A similar phenomenon occurs in the distal nephron, where
increases in luminal HCO32 stimulate HCO32 absorption (7),
whereas alkalosis inhibits H1 secretion and more importantly stimu-
lates HCO32 secretion (8). HCO32 secretion is mediated by the
type B intercalated cell that uses a basolateral membrane H1
ATPase and the apical membrane Cl2/HCO32 exchanger pendrin,
encoded by SClc26a4 (Figure 1). The identification of genes encod-
ing pendrin and other intercalated cell proteins that contribute to
acid–base physiology was recently reviewed (9,10).

Generation and Maintenance of Sustained

Metabolic Alkalosis
There are two requirements for patients to have a sustained meta-
bolic alkalosis: the alkalosis must be generated and then maintained
(11). The generation of metabolic alkalosis refers to the addition of
alkali or, equivalently, the removal of acid from the body. Mainte-
nance of metabolic alkalosis refers to the failure of normal renal
homeostatic mechanisms to correct the alkalosis. Although both pro-
cesses are critical to a sustained metabolic alkalosis, one typically
approaches patients by first addressing the cause of maintenance and
then defining how the alkalosis was generated.
Factors That Result in Maintenance of
Metabolic Alkalosis
Factors resulting in the maintenance of metabolic alkalosis include
volume contraction, potassium depletion, imbalances in distal sodium
delivery and reabsorptive capacity, and defects in bicarbonate secretion.
Volume Contraction. The most important cause of maintained
metabolic alkalosis is a contracted effective arterial blood volume
(EABV) (12,13). When baroreceptors sense EABV contraction, the
kidney retains filtered NaCl to return EABV to normal. Other
mechanisms used to maintain EABV include increased thirst and
secretion of antidiuretic hormone, which maintains EABV at the
expense of hyponatremia. Increases in renal NaHCO3 retention lead
to defense of EABV at the expense of metabolic alkalosis.
Volume depletion increases the ability of the kidney to retain
an administered HCO32 load (14). Well-designed animal studies
have shown that the mechanisms by which a contracted EABV
increases renal HCO32 absorption include increased activity of the
proximal tubular luminal membrane Na/H antiporter (15); activa-
tion of the renin-angiotensin system, with angiotensin II-induced
Figure 1. Cells critical to H1 transport in the connecting tubule and
collecting duct. These segments contain three cells that are important
in the generation and maintenance of metabolic alkalosis in many
patients. The principal cell is responsible for electrogenic Na1
absorption via the epithelial sodium channel (ENaC), and electro-
genic K1 secretion via the renal outer medullary K1 channel
ROMK. Electrogenic H1 secretion is mediated mostly by the H1
ATPase in the type A intercalated cell with some contribution from
the H1 K1 ATPase. Last, the type B intercalated cell can secrete
HCO32, mediated by pendrin, a Cl2/HCO32 exchanger. The roles
these transporters play in the generation, maintenance, and correc-
tion of metabolic alkalosis are described in the text. Reprinted with
permission from reference 10 (Emmett M: Metabolic acidosis: a brief
pathophysiologic review. Clin J Am Soc Nephrol 15: 1848-1856,
2020).
increases in HCO32 absorption in the proximal and distal tubules
(16,17); and decreased distal Cl2 delivery, which limits Cl/HCO32
exchange in the distal lumen (9,18,19). Microperfusion studies that
compared volume-expanded and volume-depleted rats showed that
volume expansion also increases proximal tubular HCO32 perme-
ability, resulting in increased backleak when luminal HCO32 is
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
lowered, suggesting that the converse, i.e., volume contraction, may
allow greater net HCO3 reabsorption via decreased backleak (6).
Volume depletion decreases GFR in rodents, thereby lowering the
filtered load of HCO32, which could contribute to the maintenance
of metabolic alkalosis. However most studies suggest that volume
depletion-induced changes in GFR are minimal in human subjects
and cannot account for the maintenance of the alkalosis (12).
Another issue is the role of Cl- concentration and total ECF Cl-
in maintaining metabolic alkalosis. Metabolic alkalosis is always
hypochloremic. If the anion gap is relatively constant, an increase in
HCO32 in the presence of a normal Na1 level must be accompa-
nied by a decrease in Cl2. However low plasma Cl2 per se plays
little role in the maintenance of alkalosis associated with volume
contraction. In dogs, diuretic-induced metabolic alkalosis is cor-
rected by an infusion of NaCl and NaHCO3 in concentrations simi-
lar to those in the alkalotic plasma (20). In this setting, the infusion
did not directly alter the Cl2 or HCO32; yet, it did correct the
alkalosis, suggesting it is not Cl2 per se that is critical to the mainte-
nance of metabolic alkalosis but rather the ECF volume.
A separate issue that has been raised is whether it is volume per
se or total ECF Cl2. When NaCl is administered, both parameters
increase. Although it is difficult to separate volume from total ECF
Cl-, investigators have attempted to do so by using dialysis in rats to
remove Cl- in the absence of volume changes (isovolemic Cl- deple-
tion), and they found that metabolic alkalosis was maintained (21).
However, others have found that the generation of an “isovolemic”
hypochloremic metabolic alkalosis induces extracellular volume
depletion via shifts of fluid into cells (22). This issue remains unre-
solved because it is very difficult to separate total ECF Cl- from
ECF volume in a convincing manner. More importantly, it is not
clear how total ECF Cl- would be sensed. We therefore believe it is
more likely that the low EABV is the dominant determinant respon-
sible for maintenance of metabolic alkalosis.
Potassium Depletion. Metabolic alkalosis is almost always associ-
ated with hypokalemia, in part because alkalosis causes renal K1 loss
and in part because hypokalemia stimulates renal acidification. K1
depletion causes intracellular acidosis in renal tubules, which results
in many of the renal effects of acidosis, including increased ammo-
nia production, renal citrate absorption, and proximal tubular and
distal tubular acidification (23,24). However, hypokalemia sup-
presses aldosterone, which will suppress distal acidification (25).
Although hypokalemia may contribute to the maintenance of
alkalosis associated with volume contraction, it is not as important
as the volume contraction itself. In sustained hypokalemic metabolic
alkalosis associated with volume contraction, correction of volume
contraction without correcting hypokalemia leads to bicarbonaturia
and correction of the metabolic alkalosis (13). On the other hand,
in conditions in which aldosterone cannot be suppressed, the correc-
tion of hypokalemia is critical. K1 depletion significantly enhances
the alkalosis produced by exogenous mineralocorticoid administra-
tion (26). In addition, the magnitude of metabolic alkalosis in
patients with primary hyperaldosteronism correlates with the magni-
tude of the hypokalemia (27).
Enhanced Distal Acidification Due to Imbalances in Distal
Nephron Na1 Absorptive Capacity and Distal Delivery of Na1
and Water. Figure 1 shows the major cells relevant to H1/HCO32
transport in the connecting tubule and the cortical collecting duct
147
(CCD) (9). The principal cell absorbs Na1 via the epithelial Na1
channel, ENaC, which generates a lumen-negative voltage. This
drives K1 secretion mostly through the renal outer medullary K1
(ROMK) channel in the same cell, and H1 secretion mediated pre-
dominantly by the H1 ATPase in the type A intercalated cell.
Whereas mineralocorticoids can directly activate many of these
transporters, increased H1 transport seems dependent on increased
Na1 transport, which requires an activated ENaC and luminal Na1
and flow.
Because of this, distal nephron acid excretion is controlled by a
balance between the intrinsic capacity of the distal nephron to
absorb Na1, and distal delivery of Na1 and water (flow rate), both
which are affected by EABV. By contrast, distal H1 and K1 secre-
tion are generally not directly affected by EABV. Whereas a con-
tracted EABV results in increased mineralocorticoid levels, distal
H1 secretion is not altered because distal delivery of Na1 and water
is decreased. Thus, secondary hyperaldosteronism does not result in
hypokalemia or metabolic alkalosis (28–30). Similarly, an expanded
EABV results in increased distal delivery but suppressed mineralo-
corticoid, so that distal H1 and K1 secretion remains unchanged.
Increased distal H1 secretion occurs when both distal delivery of
Na1/water and distal nephron Na1 and H1 transporter activity
are increased. This occurs only when there is a primary change
in one of these determinants that is unrelated to alterations in
EABV. Because this mechanism can generate new alkali, its acti-
vation results in both the generation and the maintenance of
metabolic alkalosis.
The propensity for metabolic alkalosis is further enhanced if
the increased distal delivery of Na1 is accompanied by distal
delivery of a nonreabsorbable anion (31). The nonreabsorbable
anion prevents proximal Na1 and water reabsorption, which
increases distal delivery, and then, because the nonreabsorbable
anion cannot follow Na1 across the distal epithelium, Na1
absorption generates a more lumen-negative potential that drives
H1 secretion.
Defects in Distal Bicarbonate Secretion. Isolated defects in distal
HCO32 secretion can enhance the magnitude of metabolic alkalosis
and may be able to maintain metabolic alkalosis as a sole mechanism
(9,32). This is exemplified in patients with Pendred syndrome,
which is caused by a genetic mutation of the pendrin-encoding
gene, Slc26a4. Pendrin is an apical Cl/HCO32 exchanger on b
intercalated cells in the collecting duct and is discussed below.
Factors That Result in Generation of Metabolic Alkalosis
As noted previously, a sustained metabolic alkalosis requires both
maintenance by the kidney, and generation. The generation of met-
abolic alkalosis is caused by the loss of hydrogen ions (H1) or gain
of alkali. In the absence of H1 loss or alkali gain, potassium deple-
tion can also cause metabolic alkalosis by driving H1 to shift into
cells (33).
External H1 Loss. External H1 loss from the gastrointestinal (GI)
tract or the kidneys is the most important generator of metabolic
alkalosis. GI H1 loss is most commonly due to vomiting or nasogas-
tric suction. Less commonly, alkalosis may be generated by the loss
of acid fluids from the lower GI tract, as with villous adenomas or
congenital chloridorrhea.
148
Renal H1 loss is also an important cause of metabolic alkalosis
and occurs when renal acid excretion exceeds metabolic acid genera-
tion. This excess renal acid excretion is due to enhanced H1 secre-
tion in the distal nephron.
Although volume contraction contributes to the maintenance
of metabolic alkalosis, it does not generate alkalosis. As described
above, in the setting of volume contraction, aldosterone increases
the capacity of the distal nephron for Na1 absorption and H1
secretion, but metabolic alkalosis is not generated because distal
delivery of Na1 and water is low (28–30). Metabolic alkalosis is
generated when there is a primary increase in distal delivery of Na1
and water with natriuresis, leading to volume contraction and an
increase in aldosterone, or when there is a primary increase in the
transport activity of the distal nephron with increased Na1 absorp-
tion and volume expansion, which then leads to increased distal
delivery of Na1 and water.
Exogenous Alkali Gain. Exogenous alkali gain can occur with the
ingestion or intravenous infusion of HCO32 or other substances
that are metabolized to HCO32, such as citrate and other organic
anions. For the alkalosis to be maintained, there must be continued
addition of alkali, or one of the above maintenance mechanisms
must be activated.
Metabolic Alkalosis in the Absence of H1 Loss or Alkali Gain
(potassium depletion). Potassium depletion causes H1 to shift into
cells, resulting in the generation of metabolic alkalosis (33). In addi-
tion, ECF volume contraction can theoretically generate a metabolic
alkalosis by concentrating ECF HCO32 while PCO2 is maintained
unchanged. However, this alone does not lead to a clinically significant
metabolic alkalosis because of the extensive buffering that normally
occurs (34).
4 Major contributors to the maintenance of metabolic
alkalosis include volume contraction, conditions
that increase distal nephron Na1 and H1 transport
capacity along with increased distal delivery of
Na1 and water, and defects in bicarbonate secre-
tion. Potassium depletion contributes to the main-
tenance of alkalosis associated with primary aldo-
steronism, but to a much lesser degree in alkalosis
associated with volume contraction.
4 Alkalosis is generated via H1 loss from the gastro-
intestinal tract or kidney, exogenous alkali gain, and
potassium depletion resulting in H1 shift into cells.
Clinical Conditions That Cause Metabolic Alkalosis
Many diverse clinical entities result in metabolic alkalosis. (Table 1).
In each case the alkalosis must be generated and then maintained if
the alkalosis is to be sustained. Clinically it is often useful to con-
sider the causes based on the mechanisms that generate and main-
tain the alkalosis.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Exogenous Alkali Gain
Clinical examples of metabolic alkalosis due to exogenous alkali gain
include ingestion or infusion of bicarbonate, administration of cit-
rate with massive transfusions or plasmapheresis, or metabolism of
retained organic anions after treatment of lactic or keto acidosis with
alkali. In the absence of a stimulus for the kidney to maintain the
alkalosis, it will typically be transient (11,35).
Milk alkali syndrome occurs in patients who ingest large quan-
tities of calcium and alkali. Although this was seen in the past in
patients with peptic ulcer disease, more recently it has been noted in
patients being treated for osteoporosis. The metabolic alkalosis is
generated by alkali ingestion and is then maintained by volume con-
traction secondary to hypercalcemia-induced inhibition of thick
ascending limb NaCl absorption.
Decreased Effective Arterial Blood Volume
As noted previously, the most common causes of metabolic alkalosis
are associated with a decreased EABV, typically associated with
decreased ECF volume. The metabolic alkalosis is generated by H1
loss in the GI tract or the kidney and then is maintained by the kid-
ney. Causes include gastric HCl loss (gastric alkalosis), lower GI
HCl loss, and increased distal sodium delivery in the setting of acti-
vated distal nephron transport capacity.
Gastric HCl Loss (Gastric Alkalosis). In gastric alkalosis,
HCl is lost from the stomach by vomiting or nasogastric suction.
Gastric fluid contains approximately 100 mEq/L of HCl with
varying amounts of Na1 and K1. Removal of HCl from the
body generates a metabolic alkalosis, and removal of Na1 leads to
volume contraction, which causes the kidney to maintain the alka-
losis. However, the magnitude of the increase in plasma HCO32
far exceeds that which would be maintained by the level of vol-
ume contraction, resulting in bicarbonaturia. Bicarbonaturia is
associated with increased delivery of NaHCO3 to the distal neph-
ron, which in the presence of an increase in aldosterone (from vol-
ume contraction) enhances distal Na1 absorption with K1 and
H1 secretion (12). The net result is loss of NaHCO3 and
KHCO3 in the urine, volume depletion, and potassium depletion.
An important diagnostic clue is that while patients are volume
depleted they will continue to have a high urinary Na1 with a
low urinary Cl- and a urinary pH .7. This phase has been
referred to as the disequilibrium state.
Once the loss of gastric fluid ceases, bicarbonaturia slows and
then stops as the plasma HCO32 falls to a level that can be main-
tained by the degree of volume contraction and K1 depletion. At
this point, referred to as the equilibrium state, urinary Na1, Cl2,
and pH are low. Administration of NaCl and KCl corrects the fac-
tors maintaining the alkalosis, leading to bicarbonaturia and return
of plasma HCO32 to normal. As noted above, administration of
NaCl in the absence of correction of K1 deficiency corrects the alka-
losis, demonstrating that volume depletion is more critical to main-
tenance of the alkalosis than is K1 depletion (13). Of course, one
would never withhold KCl in this setting, given the sequelae of
severe K depletion.
Lower GI HCl Loss. Metabolic alkalosis can be seen with loss of
HCl from the lower GI tract in conditions such as congenital chlori-
dorrhea (congenital chloride diarrhea) or villous adenoma. The gen-
eration and maintenance of the metabolic alkalosis is similar to that
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 149

Table 1. Causes of metabolic alkalosis

Exogenous alkali gain Bicarbonate administration

Citrate in massive transfusions
Retained organic anions
Milk alkali syndrome
Maintained by decreased EABV GI acid loss
Gastric: vomiting, nasogastric suction
Lower GI: congenital chloride diarrhea, villous adenoma
Renal acid loss
Primary increase in distal delivery
Diuretics that function prior to the CCD
Edematous disorders treated with diuretics
Nonreabsorbable anions (penicillins, sulfate, nitrate)
Bartter syndrome
Gitelman syndrome
Mg21 deficiency
Hypercalcemia
Posthypercapneic metabolic alkalosis
Maintained by decreased bicarbonate secretion Cystic fibrosis
Pendred syndrome
Primary increase in activity of the distal nephron High renin/high aldosterone
transport Renovascular hypertension
Malignant hypertension
Scleroderma
Renal vasculitis
Renin-secreting tumor
Low renin/high aldosterone
Adrenal adenoma
Bilateral adrenal hyperplasia
Adrenal carcinoma
Glucocorticoid suppressible hyperaldosteronism
Low renin/low aldosterone
Increase in a non-aldosterone mineralocorticoid receptor agonist
Cushing syndrome
Glycyrrhizic acid
Apparent mineralocorticoid excess: mutation of 11-b-HSD-2
Adrenogenital syndromes
Defective 11-hydroxylation
Defective 17-hydroxylation
Activation of the mineralocorticoid receptor
Pregnancy-induced hypertension
Activation of transport mechanisms downstream of the receptor
Liddle syndrome
Unclear mechanism Postfasting alkalosis

11-b-HSD-2, 11-b-hydroxysteroid dehydrogenase; CCD, cortical collecting duct; GI, gastrointestinal.

seen with gastric alkalosis, with the exception that patients are con-
tinually in the disequilibrium state.
In contrast to gastric fluid, lower GI fluid is typically high in
HCO32, and increased losses as occur in patients with diarrhea
cause metabolic acidosis. Children with congenital chloride diarrhea
present with profuse watery diarrhea that is high in Cl- and a hypo-
kalemic metabolic alkalosis. This disease is due to an autosomal
recessive mutation in the Cl/HCO32 exchanger of the ileal and
colonic luminal membrane, encoded by SLC26A3 (36). In the lower
GI tract, NaCl absorption is mediated by Na/H and Cl/HCO32
exchangers working in parallel. Under normal circumstances, the
activity of the Cl/HCO32 exchanger exceeds that of the Na/H
exchanger, resulting in stool with a high HCO32. In these patients,
in the absence of Cl/HCO32 exchange, the unopposed Na/H
150
exchanger results in diarrheal fluid that is high in NH4Cl, with stool
Cl2 exceeding the sum of Na1 and K1.
Villous adenomas are occasionally associated with diarrhea and
metabolic alkalosis (37). The pathophysiology is similar to that
described above, with Na/H exchange functioning at a rate that
exceeds that of Cl/HCO32 exchange.
Increased Distal Delivery of Sodium. Increased distal sodium
delivery is caused by diuretics, the presence of nonreabsorbable
anions, Bartter and Gitelman syndromes, magnesium depletion, and
hypercalcemia.
Diuretic Induced. Renal acid loss is the most common cause of
metabolic alkalosis, and among these entities, diuretics are the most
common cause. Diuretics that cause hypokalemic metabolic alkalosis
inhibit NaCl absorption proximal to the CCD and enhance distal
delivery of Na1 and water to the H1/K1 secreting segments of the
distal nephron. Inhibition of Na1 absorption leads to a natriuresis
that results in volume contraction and high aldosterone levels. In
the presence of high aldosterone levels, high luminal Na1 and flow
rates in the CCD enhance H1 and K1 secretion. The net result is a
metabolic alkalosis generated in the CCD by enhanced H1 secre-
tion and maintained by the same mechanism, in addition to volume
contraction and hypokalemia stimulating proximal tubular HCO32
reabsorption.
In edematous disorders, decreased EABV is associated with
increased extracellular fluid volume. The low EABV in edematous
disorders such as congestive heart failure causes the kidney to main-
tain the alkalosis, but, as noted above, secondary hyperaldosteronism
does not generate a metabolic alkalosis because distal delivery of
Na1 and water is low. Thus, an untreated patient with congestive
heart failure is not expected to have metabolic alkalosis. However,
these patients are often treated with diuretics that increase distal
delivery of Na1 and water, which in the presence of high aldoste-
rone levels will generate hypokalemia and metabolic alkalosis.
Distal Delivery of Nonreabsorbable Anions. Filtration of Na1
with a nonreabsorbable anion causes the Na1 to be excreted in the
urine, resulting in volume depletion and increases in aldosterone. In
addition, the nonreabsorbable anion increases distal delivery by inhib-
iting proximal Na1 absorption. Sodium that is delivered to the distal
nephron with a nonreabsorbable anion generates a more lumen-
negative potential, resulting in enhanced H1 and K1 secretion, and
hypokalemic alkalosis (31,38). Examples of nonreabsorbable anions
include antibiotics such as carbenicillin, sulfate, and nitrate.
Bartter Syndrome. Patients with Bartter syndrome present with
hypokalemic metabolic alkalosis, normal to low blood pressure,
magnesium depletion, hypercalciuria, and increased plasma renin,
angiotensin, and aldosterone (39). The syndrome is due to a num-
ber of inactivating mutations in transporters that mediate thick
ascending limb NaCl absorption, including the apical membrane
Na-K-2Cl cotransporter, the ROMK K1 channel, the basolateral
membrane chloride channels ClC-Ka and ClC-Kb, and the chloride
channel subunit, Barttin (40). The syndrome can also be caused by
an activating mutation in the calcium sensing receptor (40). The
syndrome is similar to sustained ingestion of a loop diuretic with
metabolic alkalosis due to a primary increase in distal delivery of
Na1 and water.
Gitelman Syndrome. Gitelman syndrome is caused by inactivating
mutations in the distal convoluted tubule NaCl cotransporter (41).
Patients present with a syndrome similar to that seen with sustained
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
thiazide ingestion. The phenotype of Gitelman syndrome is more mild
than that of Bartter syndrome and has onset at an older age (42). By
contrast to Bartter syndrome, Gitelman syndrome presents with hypo-
calciuria rather than hypercalciuria (43).
Magnesium Depletion. Magnesium deficiency results in hypoka-
lemia and occasionally metabolic alkalosis that is prevented by spiro-
nolactone (44,45). The absence of hypertension suggests that the
hypokalemia and alkalosis may be due to a primary increase in dis-
tal delivery.
Hypercalcemia. Hypercalcemia inhibits thick ascending limb
NaCl absorption through calcium sensing receptor inhibition of the
apical K1 channel (46). The net effect is similar to that of furose-
mide. However, the incidence of metabolic alkalosis depends on the
cause of the hypercalcemia. Increases in parathyroid hormone
inhibit proximal tubule HCO32 absorption, which will ameliorate
or eliminate the metabolic alkalosis.
Post–Hypercapneic Alkalosis. Hypercapnea engenders a renal
compensation resulting in an increase in plasma HCO32 and ameliora-
tion of the acidemia. The retention of NaHCO3 expands EABV,
resulting in enhanced excretion of NaCl. Euvolemia in this setting is
maintained by high total ECF NaHCO3 and low total ECF NaCl.
Rapid correction of hypercapnea then leads to a primary metabolic
alkalosis resulting from the high plasma HCO32 with a normal
PCO2. The kidney then attempts to correct the alkalosis by excreting
HCO32, which is accompanied by excretion of Na1 and K1, the rela-
tive amounts of which are determined by the level of aldosterone. If
the patient has a low intake of NaCl, as is typical in this setting, bicar-
bonaturia will cease, resulting in a sustained metabolic alkalosis that is
maintained by volume contraction and hypokalemia. Only an increase
in total ECF NaCl can expand EABV and correct the metabolic alkalo-
sis. It should be noted that these patients frequently take diuretics that
can worsen the volume contraction and contribute to the generation
and maintenance of metabolic alkalosis. The metabolic alkalosis here is
clinically very important because it serves to suppress respiration.
Decreased Distal Bicarbonate Secretion
The causes of decreased bicarbonate secretion include Pendred syn-
drome and cystic fibrosis.
Pendred Syndrome. Bicarbonate secretion by the type B interca-
lated cell is mediated by apical membrane pendrin functioning in
series with a basolateral membrane H1ATPase (Figure 1). A few
patients with Pendred syndrome (mutation of Slc26a4, which enco-
des pendrin) have been reported to experience a more severe meta-
bolic alkalosis in response to alkalotic challenges, including thiazide
treatment in one patient and vomiting in another (9). It remains
unclear whether Pendred syndrome can serve as a sole mechanism
for maintenance of alkalosis (9).
Cystic Fibrosis. HCO32 secretion by the type B intercalated cell
requires CFTR, the protein responsible for cystic fibrosis (32). The
CFTR Cl- channel may be required to recycle Cl- to support pendrin.
Patients with cystic fibrosis have a predisposition to meta-
bolic alkalosis.
Increased Distal Transport Activity
Conditions characterized by a primary increase in the capacity of the
distal nephron to absorb Na1 and secrete H1 and K1 cause meta-
bolic alkalosis. These conditions are associated with secondary
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
hypertension and are distinguished by measurement of plasma renin
and aldosterone levels. These conditions are also discussed in the
section on Pathophysiology, Evaluation and Treatment of Hypoka-
lemia in this issue of nephSAP.
High Renin, High Aldosterone. Renovascular hypertension is an
important cause of high renin/high aldosterone but is only occasion-
ally associated with hypokalemic alkalosis (47). The true incidence is
difficult to ascertain because so many patients are taking diuretics.
Hypokalemic alkalosis with high renin/aldosterone can also be seen
in small vessel vascular disease, as occurs with malignant hyperten-
sion, scleroderma, or renal vasculitis (48). A rare cause of high renin/
high aldosterone is a renin-secreting tumor (49). The most common
cause of alkalosis with a high renin and high aldosterone is volume
contraction in patients taking diuretics, which is discussed above.
Low Renin, High Aldosterone. A low renin and high aldosterone
suggest primary adrenal disorders, which are the most common
causes of hypertension with hypokalemic alkalosis. The most com-
mon causes include adrenal adenoma and bilateral adrenal hyperpla-
sia (27,50,51). Adrenal carcinomas can occasionally secrete
compounds with mineralocorticoid activity (52).
Glucocorticoid-suppressible hyperaldosteronism is due to a
genetic crossover between two adjacent genes, CYP11B1, encoding
11-b-hydroxylase, and CYP11B2, encoding aldosterone synthase
(51,53). These enzymes control the synthesis of cortisol and aldoste-
rone, respectively. As a result, the 5’-flanking region of 11-b-hydrox-
ylase controls the transcription of aldosterone synthase, resulting in
regulation of aldosterone synthesis by ACTH, and the administra-
tion of dexamethasone decreases aldosterone secretion (52).
Low Renin, Low Aldosterone. This group of diseases can be
divided into three categories (35).
Increase in a Nonaldosterone Mineralocorticoid Receptor Ago-
nist. Approximately 30-40% of patients with Cushing syndrome
experience hypokalemic alkalosis, which is due to secretion of nonal-
dosterone mineralocorticoids as well as the mineralocorticoid activity
of cortisol (54,55). Hypokalemic alkalosis is most common when
Cushing syndrome is due to aberrant ACTH secretion (56).
Although mineralocorticoid receptors have a lower affinity for
glucocorticoids, cortisol circulates at levels that are two to three log
orders higher than aldosterone. The mechanism that prevents cortisol
from binding to and activating the mineralocorticoid receptor is
that target cells express the type 2 hydroxysteroid dehydrogenase
(11-b-HSD-2), which converts active cortisol to inactive cortisone.
Failure of this process allows cortisol to activate the mineralocorticoid
receptor. Most frequently, this occurs in Cushing syndrome when cor-
tisol levels are excessively high and exceed the activity of 11-b-HSD-2.
Glycyrrhizic acid, found in natural licorice or chewing tobacco, inhibits
11-b-HSD-2, allowing normal levels of cortisol to activate the receptor
(57). Last, the autosomal recessive genetic syndrome of apparent miner-
alocorticoid excess, due to inactivating mutations of 11-b-HSD-2, will
allow cortisol to activate the receptor (57–59).
Nonaldosterone mineralocorticoids can also be increased in the
adrenogenital syndromes. Defective 11-hydroxylation leads to defec-
tive cortisol synthesis, leading to high levels of desoxycortisol and
desoxycorticosterone, which have mineralocorticoid activity (60).
Defective 17-hydroxylation prevents synthesis of cortisol, androgens,
and estrogens, resulting in increases in the synthesis of desoxycorti-
costerone and aldosterone.
151
Activation of the Mineralocorticoid Receptor. A mutation in the
mineralocorticoid receptor has been described that causes constitu-
tive activation and allows it to be further activated by progesterone
and other steroids lacking 21-hydroxyl groups (61). In these
patients, pregnancy-induced hypertension develops, but hypokale-
mic metabolic alkalosis does not develop.
Activation of Transport Mechanisms Downstream of the Recep-
tor. Liddle syndrome is autosomal dominant and results from acti-
vating mutations in the subunits of the luminal membrane Na1
channel, ENaC (62–67). Liddle syndrome can be distinguished from
the above disorders in that it is not corrected by blockade of the min-
eralocorticoid receptor (62–64). However, Na1 channel inhibitors
correct the hypertension and the hypokalemic alkalosis (64).
Unclear Mechanism: Postfasting alkalosis
During starvation, patients experience ketoacidosis. After refeeding,
patients can experience a rebound metabolic alkalosis. In spite of
much research, it remains unclear how this alkalosis is generated or
maintained (35) Refeeding also can generate NaCl retention and
edema, suggesting that homeostatic mechanisms are perceiving a
low EABV, which could explain the maintenance of the alkalosis.
The alkalosis will gradually resolve on its own.
Evaluation
The symptoms of metabolic alkalosis often relate to the underlying
cause or to associated volume, potassium, or magnesium depletion.
In its severest form, symptoms manifest as cardiac and neuromuscu-
lar irritability (arrythmia, paresthesia, muscular spasm, confusion,
seizures) and are exacerbated by hypocalcemia. Hypoventilation due
to depressed respiratory drive, and symptoms of tissue hypoxemia
and cardiac and cerebral ischemia are other serious manifestations
(10,35,65,66). The cause is often apparent with a thorough history
and physical examination.
An elevated serum bicarbonate should be evaluated with a
blood gas determination to help differentiate primary metabolic
alkalosis versus primary respiratory acidosis with metabolic compen-
sation (Figure 2) (67,68). An arterial blood gas (ABG) is the crite-
rion gold standard for diagnosis. The currently well-established and
popular approach introduced by Schwartz and Relman (69) in the
1960s explores the physiologic relationship between pH, PaCO2,
and serum bicarbonate and allows accurate evaluation of acid–base
disorders in informed clinical settings. Standardized base excess
(SBE), or base excess of the ECF, is another method proposed to
evaluate acid–base disturbances. For a detailed discussion of SBE,
the authors refer the reader to an excellent review by Berend (70).
Briefly, the SBE is the amount of strong acid in mmol/L that needs
to be added to a liter of whole blood to return pH to 7.4 when
PCO2 is 40 mm Hg using an in vitro assay. By this definition, a
normal SBE is 0 6 2 mmol/L. An SBE .2 mmol/L suggests a base
excess that may be indicative of metabolic alkalosis (which could be
either primary or secondary [i.e., compensatory]). The standard
method advocated by Schwartz and Relman (69) is based on actual
empiric observations allowing us to predict expected compensatory
metabolic response to acute and chronic respiratory acidosis. The
concept of SBE is distinct from this standard approach, in that it
accounts for only the nonrespiratory (metabolic) component of
152 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Elevated serum bicarbonate, and low serum chloride

STEP 1 Check blood gas to confirm diagnosis of primary metabolic alkalosis

Assess Effective arterial blood volume (EABV)

STEP 2
(Physical exam; Orthostatic BP and pulse rate; BUN/Cr ratio; serum uric acid; urine electrolytes)

Contracted EABV Expanded EABV (Urine Cl >20meq/L)

Urine Cl >20meq/L Urine Cl <20meq/L Check PRA and PAC

High PRA High PAC Low PRA

x Active diuretic use x Gastric alkalosis; urine pH>7
High PAC Suppressed PRA Low PAC
x Bartter syndrome (NG suction/ vomiting)
x Gitelman x Posthypercapnic alkalosis
x Renal artery stenosis x PHA x Liddle
syndrome x CF and high sweat Cl losses
x Malignant hypertension x GRA x Cushing
x Hypercalcemia x Recent diuretic use
x Renin secreting tumors x CAH x Licorice /AME
x Magnesium x NRA (urine pH<6.5)
x Renal vasculitis x Androgenital
deficiency x Congenital chloride diarrhea
x Scleroderma syndromes**
x Villous adenoma
x Diuretic use*

Figure 2. Proposed algorithm for evaluation of metabolic alkalosis. AME, apparent mineralocorticoid excess; CAH, congenital adrenal hyperpla-
sia; CF, cystic fibrosis; GRA, glucocorticoid remediable or suppressible hyperaldosteronism; NG, nasogastric; NRA, nonreabsorbable anion;
PHA, primary hyperaldosteronism. *Diuretic use: ongoing use of diuretics with persistent volume overload can confuse the clinical picture as
hypervolemic patients tend to be hypertensive and diuretic use can cause an elevation in plasma aldosterone concentration and plasma renin
assay). **Androgenital syndromes such as defective 11-hydroxylation and 17-hydroxylation.

acid–base disturbances and does not factor in the role of respiration
in determining final plasma bicarbonate. The use of SBE, unless
modified as suggested by Berend (70), would lead to erroneous diag-
nosis of primary metabolic alkalosis when the rise in bicarbonate is
actually due to a compensatory renal response to this disorder (70).
If used in conjunction with the pH and PCO2, the SBE allows anal-
ysis of metabolic response to primary respiratory disorders that may
help identify mixed acid–base disturbances. It is not clear that this
method adds any value to that described by Schwartz and Relman
(69), however.
A venous blood gas (VBG) determination can be a more conve-
nient alternative to an ABG determination to evaluate acid–base
abnormalities and shows good correlation with regard to pH (0.03
to 0.05 pH units lower) and bicarbonate levels (71). Venous PCO2
is usually 3 to 8 mm Hg higher depending on sampling site (central
venous sample has a higher correlation than peripheral venous sam-
ple) (72) However, there has been concern regarding the accuracy of
a VBG in patients with circulatory shock. Schrauben et al. (73)
recently conducted a multicenter cross-sectional study in critically ill
patients with shock (N 5 23) and showed that a central VBG had
100% sensitivity for diagnosing metabolic acidosis, metabolic alkalo-
sis, and respiratory acidosis, and lower sensitivity (71%) for respira-
tory alkalosis. Analysis of ABG results versus VBG results in patients
receiving vasopressors (13/23 patients) yielded similar results. We
conclude from these data that a central VBG is an acceptable alter-
native to an ABG.
Once a diagnosis of primary metabolic alkalosis is made, further
evaluation requires consideration of factors responsible for its main-
tenance (Figure 2). Assessment of (EABV) is critical and includes
physical examination, especially postural changes in pulse and BP;
laboratory tests such as serum blood urea nitrogen (BUN), BUN/
creatinine ratio and serum uric acid, and urinary electrolytes (35). A
low urine Na and Cl suggests chloride depletion and low EABV. A
paradoxically high urine Na (with a low urine Cl) in a volume-
depleted patient may be related to bicarbonaturia (e.g., in vomiting)
or to the presence of another nonreabsorbable anion (e.g., antibiotic,
ketoacid). Urine pH may distinguish between the two; a urine pH
of $7 indicates significant bicarbonaturia, and a pH of #6.5 sug-
gests the presence of a nonreabsorbable anion. It’s noteworthy that
in metabolic alkalosis, the presence of bicarbonaturia points to the
generation of bicarbonate in excess of what the kidney is driven to
maintain. This suggests extrarenal generation of bicarbonate (vomit-
ing, Cl-secreting diarrhea, nasogastric suction). A high urine Na and
Cl in the setting of low EABV indicates active diuretic use, or disor-
ders such as Bartter syndrome or Gitelman syndrome.
An elevated urine Cl (and Na) in patients with preserved or
increased EABV suggests metabolic alkalosis that is caused by a pri-
mary increase in Na absorption via the ENaC in the setting of
maintained or high distal Na delivery. This ENaC activation may
be due to an intrinsic channel defect (Liddle syndrome) or to a pri-
mary mineralocorticoid excess state, as discussed in the pathophysi-
ology section. These disorders are characterized by hypertension and
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
accompanying hypokalemia and are causes of treatable hypertension.
Further evaluation requires measurement of plasma renin assay and
plasma aldosterone concentration (74). (Table 1, Figure 2). Urine K
in the face of hypokalemia can help in differentiating between renal
K wasting and nonrenal K wasting disorders; the former are typically
associated with primary metabolic alkalosis.
In the pediatric population, recurrent metabolic alkalosis should
raise suspicion for chloride-depleting causes such as Bartter syn-
drome, Gitelman syndrome, cystic fibrosis (urine Cl will be high),
or congenital chloride diarrhea and pyloric stenosis (urine Cl will be
low). Among adults who present with recurrent alkalosis and low
urine Cl), surreptitious vomiting should be considered
(10,70,75,76).
4 The evaluation of increased bicarbonate requires
a blood gas determination.
4 A central venous blood gas determination is an
acceptable alternative to an arterial blood gas
determination.
4 Once primary alkalosis is diagnosed, further eval-
uation should be directed at underlying factors
that allow maintenance of alkalosis, particularly a
careful assessment of volume status.
Epidemiology and Outcomes
Metabolic alkalosis (pure or combined with other acid–base disor-
ders) is frequently seen in heterogenous clinical settings in both
adult and pediatric populations. It is common in hospitalized and
critically ill patients and is associated with poor outcomes (77–84).
Alkalosis is likely a marker of severity of the underlying disorder
(82).
Clinical outcomes associated with alkalosis include prolonged
hospitalization, prolonged duration of mechanical ventilation, and
high mortality (79,81,83,84). Anderson et al. (83) found that the
mortality rate was 45% in patients with an arterial blood pH of
.7.5, and mortality increased to 80% at a pH .7.65. A large retro-
spective study that used the Multiparameter Intelligent Monitoring
in the Intensive care Unit II database and included 18,982 critically
ill patients found a high prevalence of metabolic alkalosis (29%),
defined in this study as a serum bicarbonate level .30 mEq/L (81).
There was a U-shaped relationship between serum bicarbonate levels
and mortality, with the lowest mortality seen between 25 and 30
mEq/L. In a recent retrospective cohort study of 627 critically ill
septic patients, metabolic alkalosis and late metabolic alkalosis (time
of onset .48 hours), regardless of severity, independently predicted
prolonged intensive care unit (ICU) length of stay (OR 5 6.461
[95% CI 4.421 to 9.443, P,0.001]) (79). However, this association
does not imply cause and effect. In addition, increased mortality
due to metabolic alkalosis (at 30 days and 12 months) was not seen
in this study.
153
Alkalemia has several deleterious multisystem effects, including
interference with dissociation of oxygen from hemoglobin at the
level of the peripheral tissues, vasoconstriction of vascular smooth
muscle tone, and respiratory depression via both central and periph-
eral chemoreceptors (35,65,66,80). These effects impair tissue oxy-
gen delivery and cause tissue hypoxia. Cardiac arrythmias due to
alkalosis-associated hypocalcemia and hypokalemia, alveolar hypo-
ventilation leading to hypercapnea and hypoxia, delirium, seizures,
vasoconstriction resulting in myocardial and cerebral ischemia, and
electrolyte abnormalities including hypomagnesemia, hypocalcemia,
and hypophosphatemia can result, although hypophosphatemia is
more common with respiratory alkalosis.
Oppersma et al. (85) recently examined the effects of compen-
sated metabolic alkalosis on the neural respiratory drive in 10 young
healthy subjects. Metabolic alkalosis was induced by oral ingestion
of 100 mL of 8.4% sodium bicarbonate solution, three times a day
for 10 doses, with a demonstrable increase in serum bicarbonate lev-
els (25.2 6 0.7 to 29.2 6 0.6 meq/L). The pH remained normal as
a result of respiratory compensation. The study demonstrated
decreased respiratory drive (indicated by diaphragmatic electrical
activity) and suppressed minute ventilation in healthy subjects that
persisted despite increasing inspiratory CO2 pressure, demonstrating
the hypoventilatory effects of metabolic alkalosis in the face of
hypercapneia even in healthy subjects.
Treatment
Indications for Intervention
Based on the available data, evidence for the causality of metabolic
alkalosis on mortality is weak; however, there appears to be a strong
association between metabolic alkalosis and poor patient outcomes
that should raise concern and encourage intervention when arterial
pH is $7.5, especially in critically ill patients.
Aggressive correction may be indicated in (1) patients with
chronic lung disease who have acute respiratory decompensation
and impending intubation or those with ventilator dependence due
to poor respiratory drive and (2) patients with myocardial ischemia
or cerebral hypoperfusion where alkalemia-induced tissue hypoxia is
a concern.
Correct Causes of Generation and Maintenance
Treatment of metabolic alkalosis must begin with correction of the
underlying precipitants, most importantly, factors involved in main-
tenance (i.e., interfering with renal bicarbonate excretion). Identify-
ing and removing the source of bicarbonate generation or acid loss
is helpful as well. (Table 2)
Optimization of effective arterial blood volume is central.
Sodium repletion (as normal saline) expands extracellular volume,
improves hypovolemia, downregulates the renin-angiotensin-aldoste-
rone system (RAASU), and repletes chloride. Hypokalemia should
be corrected. As noted previously hypokalemia contributes to main-
tenance of metabolic alkalosis, particularly in states when RAAS can-
not be suppressed (exogenous mineralocorticoid administration or
states of primary mineralocorticoid excess) and the magnitude of
metabolic alkalosis correlates with the severity of hypokalemia
(26,27). Potassium chloride (KCl) is the preferred salt because it
repletes both K and Cl in metabolic alkalosis.
154
Table 2. Summary of treatment of metabolic alkalosis
General measures to correct causes of generation and
maintenance
Aldosterone antagonists/RAAS blocking agents
Acetazolamide
Non-sodium based acid solutions (HCl/ammonium chloride/
arginine HCl)
Renal replacement therapy
CRRT, continuous renal replacement treatment; ENaC, epithelial sodium channel; HCl, hydrochloric acid; HD, hemodialysis; PPI, proton pump inhibitor; RAAS, renin-angiotensin-
aldosterone system. BS, Bartter Syndrome; GS, Gitelman syndrome.
Other measures may include treating primary mineralocorticoid
excess with RAAS antagonists, repleting magnesium, and discontinu-
ing diuretic therapy or nasogastric suctioning. In patients for whom
nasogastric suction cannot be stopped, H2 blockers or proton pump
inhibitors can help decrease acid loss and limit generation of alkalosis.
Kidney Replacement Therapy
Dialysis (intermittent or continuous renal replacement therapy
(CRRT)) with a low bicarbonate bath may be necessary to rapidly
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
Discontinue precipitants if possible
Discontinue nasogastric suctioning
(Trial H2 blockers/PPI if suctioning is necessary)
Treat vomiting
Treat chloride-rich diarrhea
Discontinue diuretics
Discontinue exogenous alkali (blood transfusions, milk-alkali
ingestion, citrate anticoagulation in CRRT)
Optimize volume status
Replete volume and electrolyte deficits (K, Mg) when indicated
Slow acting (3-7 days)
Particularly helpful in volume expanded patients with evidence
of mineralocorticoid excess or activated distal Na absorption
(ENaC blockers are used to treat Liddle syndrome because
aldosterone antagonists are not helpful)
Role in treatment of BS and GS
Improves outcomes in systolic heart failure
Caution with hyperkalemia, reduction in GFR
Effective within 18-24 hours
Diuretic-induced metabolic alkalosis in patients with heart
failure: increases natriuresis and bicarbonaturia
Posthypercapneic metabolic alkalosis: may help with ventilator
weaning
Caution with hypokalemia, hypophosphatemia, and worsening
hypercapnia
Role in severe alkalemia especially in patients with EABV
expansion
Relatively rapid correction (8-12 hours) with HCl
HCl infusions require central venous access
Monitor for hyperkalemia and metabolic acidosis
Role in refractory severe alkalemia and allows precise titration
Conventional HD: dialysate HCO32 cannot be lowered below
approximately 20-24 mEq/L; however, most patients with severe
alkalemia have a much higher serum HCO3, so conventional
HD is effective in treatment
CRRT is effective; however, the correction is slower than
conventional HD (approximately 12 hours versus 4 hours).
Citrate anticoagulation can worsen metabolic alkalosis especially
in patients with liver failure.
correct severe or refractory metabolic alkalosis, especially in patients
with advanced CKD or severe AKI (86). Dialysis allows precise con-
trol of serum bicarbonate. Conventional hemodialysis requires a mini-
mum dialysate bicarbonate of 20 to 24 mEq/L; however, most
patients with severe alkalemia have a serum bicarbonate level that is
much higher and therefore is corrected with conventional dialysis.
CRRT can be prescribed with bicarbonate-free replacement fluid and
can precisely and effectively treat metabolic alkalosis. However, cor-
rection with CRRT is slower than conventional hemodialysis (12
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
hours versus 4 hours) (80). Metabolic alkalosis can worsen if citrate
anticoagulation is used for CRRT because citrate is metabolized to
bicarbonate in vivo, so reducing bicarbonate in the replacement fluid
and monitoring pH is important (87).
Acetazolamide
Frequently, in clinical practice one might encounter patients with met-
abolic alkalosis where removal of precipitants is challenging. Examples
include patients with heart failure (HF) who require continued diuretic
therapy or patients with low EABV but elevated ECF volume (HF
and other edematous states) who cannot tolerate volume expansion
with normal saline. Treatment interventions that directly address the
alkalosis may be required in these patients (80).
Acetazolamide can be used to treat metabolic alkalosis, espe-
cially in the presence of volume overload, because it has weak
diuretic properties and facilitates bicarbonaturia. Owing to its ability
to decrease serum bicarbonate, acetazolamide can stimulate respira-
tory drive and counter the hypoventilatory effects of metabolic alka-
losis (88,89).
Acetazolamide inhibits the enzyme carbonic anhydrase (89). In
the proximal tubule, carbonic anhydrase is responsible for dehydra-
tion of luminal carbonic acid formed from the combination of fil-
tered HCO32 and secreted H1 into CO2 and H2O. It also catalyzes
the reaction between cellular H2O and CO2 to form cellular car-
bonic acid, which is the source of secreted H1. Inhibition of proxi-
mal tubular carbonic anhydrase with acetazolamide blocks renal
acidification and induces bicarbonaturia. The degree of bicarbonatu-
ria induced is proportionate to the degree of metabolic alkalosis. As
the HCO32 decreases, the clinical effectiveness of acetazolamide
declines in parallel (89). An important adverse effect of acetazol-
amide is hypercapneia (90). RBC carbonic anhydrase is required for
RBC uptake of CO2 from peripheral tissues as well as uptake of
RBC CO2 by the lung alveoli. Inhibition of CO2 uptake at these
sites can cause increases in arterial PCO2 and CO2 within peripheral
tissues. Acetazolamide can also increase kaliuresis as a result of
increased distal sodium bicarbonate delivery. Thus, patients using
acetazolamide should be monitored for a sudden drop in pH, devel-
opment of respiratory acidosis, hyperchloremic metabolic acidosis,
hypokalemia, hypophosphatemia, liver toxicity, and allergic reac-
tions (89,90). Acetazolamide is typically used in doses of 250 to 500
mg once or twice daily; however, dose adjustment is required with
declining estimated GFR because it is eliminated by the kidneys.
Non-sodium Based Acid Solutions
In severe and refractory metabolic alkalosis, acid solutions (such as
HCl, NH4Cl, and arginine HCl), which replete acid and chloride
but have no significant effect on EABV, can be used.
Infusion of acid-based solutions provides a source of acid and
reduces HCO32 in patients with severe refractory metabolic alkalo-
sis when other treatments are ineffective or contraindicated. HCl
infusion (0.1 or 0.2 N or 100 to 200 mmol Cl-/L concentration in
normal saline or dextrose 5% in water) has been used for this indica-
tion. Although its use in the treatment of severe metabolic alkalosis
was reported as early as the 1960s, no randomized controlled trials
(RCTs) have evaluated its use and safety. Guffey et al. (91) con-
ducted a single-center retrospective chart review of surgical ICU
patients at the University of Rochester who received at least 8 hours
155
of intravenous HCl for treatment of metabolic alkalosis (N 5 30).
They describe the use of intravenous HCl as a treatment of choice
for patients with diuretic-induced chloride depletion metabolic alka-
losis in whom a trial of acetazolamide had failed; 26/30 of the study
patients had diuretic-induced alkalosis, with a median pH of 7.5
(7.36 to 7.59) and total CO2 of 34 mmol/L (28–42) The average
HCl infusion rate was 10.5 6 3.7 mEq/h (4 to 16.6 mEq/h). The
average duration of the HCl infusion was 29.0 6 14.6 hours (9 to
68 hours). There was a significant decline in serum bicarbonate lev-
els from a median of 34 mM/L to 27 mM/L (P,0.001). No signifi-
cant adverse effects were reported, including hyperkalemia or severe
metabolic acidosis, attributed to the treatment. HCl is not commer-
cially available and must be prepared by the institutional pharmacy
from a concentrated, sterilized HCl solution using chemically safe
equipment and personal protection. CBC, electrolytes, blood gases,
and the infusion site must be closely monitored. There are rare
reported cases of chest wall necrosis and death with the use of HCl
resulting from malpositioned central catheters and tissue extravasa-
tion of HCl (92); therefore, it must be infused via a well-positioned
central venous catheter using its distal port. Concentrations .0.25
N are not recommended because of the risk of hemolysis. There are
reports of successfully administering HCl as a buffered lipophilic
amino acid solution via a peripheral vein (93) or adding it to total
parenteral nutrition bags to improve ease of administration and min-
imize local infusion reactions (94).
High cation gap-amino acid is a hyperchloremic formulation
that contains significantly less Na1 (Na1: 14 mEq/L versus Cl-:
94 mEq/L) and has been used to successfully treat refractory met-
abolic alkalosis in a hyponatremic patient without overcorrection
of low sodium (95). Dosing of acid solutions is based on formulas
using bicarbonate excess and total body water; however, these for-
mulas provide very rough estimates of the dose needed. Frequent
laboratory and blood gas assessments should drive treatment pro-
tocols (77).
Ammonium hydrochloride (NH4Cl) is buffered HCl. Its oral
use is relatively safe; however, intravenously it can cause ammonia
toxicity, especially in patients with liver disease. It can also raise urea
levels in patients with renal insufficiency (77). Arginine HCl is
approved for use in the United States as a pituitary stimulant for
release of human growth hormone. However, it has been studied,
off label, in the treatment of metabolic alkalosis, especially in the
pediatric population (77). Sierra et al. (96) recently conducted a
single-center retrospective observational study in 82 pediatric
patients (all hospitalized patients included, irrespective of severity of
illness or ventilator needs) over a 2-year period and found arginine
HCl (oral or intravenous) to be both effective and safe in the treat-
ment of metabolic alkalosis (83% of arginine administrations
resulted in normalization of abnormal bicarbonate levels) and hypo-
chloremia in this population. Severe hyperkalemia has been reported
with its use in the past (97), but none has been reported recently.
Treatment of Specific Clinical Scenarios
This section will provide guidance on evidence-based treatment of
metabolic alkalosis in certain common clinical scenarios.
Diuretic-Induced Metabolic Alkalosis. Diuretic-induced meta-
bolic alkalosis is a common clinical disorder most often seen in the
setting of HF. Alkalosis correlates with the severity of HF and the
156
use of combined loop and thiazide-like diuretics (80). It results from
diuretic-induced volume and Cl and K depletion along with the
underlying pathophysiology of HF (low EABV, RAAS activation,
and increased catecholamines and renal adrenergic tone) (78). In
patients with metabolic alkalosis and diuretic-resistant hypervolemia,
where diuretic de-escalation is not possible, several treatment strate-
gies can be attempted. Adding a K-sparing diuretic to a loop diuretic
can improve hypokalemia and metabolic alkalosis by antagonizing
the distal tubular effects of aldosterone, allowing renal bicarbonate
excretion (27).
Acetazolamide combined with loop and/or thiazide diuretics
has a role in the treatment of diuretic-resistant HF and metabolic
alkalosis. There is evidence that acetazolamide increases natriuresis
while allowing chloride reabsorption and renal bicarbonate excretion
in patients with HF. Wongboonsin et al. (98) performed a meta-
analysis of nine studies (three RCTs and six cohort studies, N 5
229 HF patients) and found that compared with placebo, acetazol-
amide significantly increased natriuresis (standardized mean differ-
ence of 0.67 (95% CI, 0.08 to 1.27). After acetazolamide treatment,
serum HCO32 levels dropped significantly (mean difference (MD)
of 26.42 mmol/L (95% CI, 210.05 to 22.79 mmol/L) with sig-
nificant but small decreases in serum pH (MD of 20.04 (95% CI,
20.06 to 20.02)) and PaCO2 (MD of 22.06 mm Hg (95% CI,
23.60 to 20.53 mm Hg)). This meta-analysis demonstrated the
safe use of acetazolamide to enhance natriuresis in HF with coinci-
dent improvement in metabolic alkalosis. This may be particularly
beneficial in HF with sleep apnea, inasmuch as there was demon-
strable improvement in sleep apnea indices in this study as well. The
Acetazolamide in Decompensated heart failure with Volume OveR-
load (ADVOR) trial is a multicenter randomized double-blind pla-
cebo-controlled study (actively recruiting) that evaluates the effect of
acetazolamide combined with loop diuretic therapy in patients with
decompensated HF. Although this trial does not evaluate improve-
ment in metabolic alkalosis as a primary outcome, the results will
inform us of the effectiveness of acetazolamide as a diuretic in HF
and its effect on important patient outcomes.
Genetic Disorders Resulting in Secondary Mineralocorticoid
Excess. Bartter and Gitelman syndromes typically present as
“diuretic-like disorders” with hypokalemic metabolic alkalosis with-
out hypertension, although hypertension may be seen in some adults
with Gitelman syndrome. The standard of care for Bartter and
Gitelman syndromes are RAAS antagonists, nonsteroidal anti-
inflammatory drugs (mediating prostaglandin inhibition), and elec-
trolyte and volume optimization.
Mazaheri et al. (99) evaluated the adjunctive use of acetazol-
amide as bicarbonate-lowering therapy in children with genetically
proven Bartter syndrome. In a multicenter open-labeled randomized
crossover trial (N 5 22; median age 24 months; range 6 to 42
months), patients were assigned to two groups, one receiving indo-
methacin, enalapril, and spironolactone and the second group
receiving the three drugs and acetazolamide (5 mg/kg per day) for 4
weeks. The groups were crossed over after a washout period of 2
days and treated for an additional 4 weeks. At 4 weeks, treatment
with acetazolamide resulted in a significant decrease in serum
HCO32 (22 versus 211 mmol/L, P50.01), fractional excretion of
K1, and serum aldosterone and renin levels as well as a significant
increase in serum K1 (10.2 versus 10.8 mmol/L, P50.03) and Cl-
(16 versus 19 mmol/L, P50.04), compared with the group that
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
received conventional therapy. This is the first study that has evalu-
ated the use of acetazolamide as adjunctive therapy for treatment of
electrolyte and acid–base derangements in Bartter syndrome. Mech-
anistically, acetazolamide when coadministered with indomethacin
and enalapril has been shown to result in a greater degree of inhibi-
tion of tubuloglomerular feedback and renin inhibition. Although
no significant adverse effects of acetazolamide were reported in that
study, no data are available on the long-term effectiveness and safety
of this therapy in Bartter syndrome.
Syndromes of Primary Mineralocorticoid Excess. Primary
mineralocorticoid excess syndromes manifest as hypertension, hypo-
kalemia, and metabolic alkalosis. The prevalence of primary hyperal-
dosteronism is much higher than previously thought, underscoring
the importance of widespread screening. Therapy is determined by
the specific cause, but in general K1 repletion, volume optimization,
and aldosterone receptor antagonists (spironolactone, eplerenone)
and/or ENaC blockers (amiloride, triamterene) have an important
role in the medical treatment of these disorders and their electrolyte
derangements (74). Given that Liddle syndrome is due to an activat-
ing mutation in ENaC, direct ENaC blockers (not aldosterone
receptor blockers) are required for treatment. Antagonism of the
aldosterone effect in the kidney decreases principal cell Na1 absorp-
tion via ENaC, decreases luminal electronegativity, and conse-
quently reduces distal H1 and K1 secretion. Spironolactone also
blocks the stimulatory effect of aldosterone directly on the H1
ATPase pump in type A intercalated cells (27).
Posthypercapneic Metabolic Alkalosis. Chronic hypercapnia
(as seen in patients with chronic lung disease) results in increased
renal acidification, chloruresis, and a compensatory increase in
plasma HCO32 (68). Following rapid restoration of a normal
PaCO2, as might occur in a mechanically ventilated patient with
chronic obstructive pulmonary disease (COPD), plasma HCO32
remains elevated, giving rise to post-hypercapneic metabolic alkalo-
sis. This state is exaggerated by volume and Cl- deficiency, which is
frequently exacerbated by concomitant use of diuretics. Reduced
renal function may make it more difficult to correct the alkalosis in
these patients. Post-hypercapneic alkalosis (and metabolic alkalosis
in general) is associated with ventilator dependence and prolonged
duration of ICU length of stay, presumably because of its suppres-
sive effect on central respiratory drive, mediated via central and
peripheral chemoreceptors (84,88). Acetazolamide has been used as
a “respiratory stimulant” in these settings because of its ability to
facilitate renal bicarbonate excretion and rapidly correct alkalemia,
especially when saline administration or cessation of diuretics is not
clinically appropriate. However, there has been concern over serious
adverse effects of acetazolamide, including worsening hypercapnia in
patients with severe chronic lung disease and induction of metabolic
acidosis (90).
In a multicenter RCT of 382 mechanically ventilated COPD
patients, Faisy et al. (100) showed that acetazolamide therapy
resulted in a decrease in serum HCO32 levels and a 16-hour
decrease in duration of mechanical ventilation in the study group
compared with placebo; however, the difference did not reach statis-
tical significance (95% CI, 236.5 to 4.0 h; P50.17), and the study
may have been underpowered.
A recently published systematic meta-analysis (6 RCTs, N 5
564 patients) by Tanios et al. (101) evaluated the effect of carbonic
anhydrase inhibitors (mostly acetazolamide) in patients with
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
respiratory failure (mostly COPD) and metabolic alkalosis. Car-
bonic anhydrase inhibitor therapy resulted in a clinically significant
decrease in the duration of mechanical ventilation (mean difference,
MD 27 h (95% CI, 250 to 24). There was also improvement in
blood gas parameters and metabolic alkalosis, with an increase in
PaO2 (MD 11.37 mm Hg, 95% CI, 4.18 to 18.56) and a decrease
in PaCO2 (MD 24.98 mm Hg, 95% CI, 29.66 to 20.3), serum
bicarbonate (MD 25.03 mEq/L, 95% CI 26.52 to 23.54), and
pH (MD 20.04, 95% CI 20.07 to 20.01). However, use of car-
bonic anhydrase inhibitors did not have any significant effect on
mortality (risk ratio (RR) 0.94, 95% CI 0.57 to 1.56) or total
duration of hospitalization (MD 0.42 days, 95% CI 24.82 to
5.66). Furthermore, there was a trend toward a higher risk of
adverse events in the carbonic anhydrase inhibitor group (RR
1.71, 95% CI 0.98 to 2.99), although the ill effects noted were
mild. This study demonstrates the effectiveness of carbonic anhy-
drase inhibitor therapy in improving blood gas parameters in
patients with respiratory failure and metabolic alkalosis, and it
suggests a benefit in decreasing the duration of mechanical ventila-
tion. Unfortunately, it failed to provide information on mortality
and overall duration of hospitalization.
In summary, acetazolamide may have a role as a respiratory
stimulant via its metabolic acidosis–inducing effect; however,
close monitoring is required for adverse effects, including
acetazolamide.
4 The treatment of metabolic alkalosis requires
removal/reversal of factors that allow its mainte-
nance, specifically correction of volume depletion
and hypochloremia.
4 Potassium and magnesium should be repleted if
needed.
4 Severe and refractory cases may require kidney
replacement therapy, or the use of acetazolamide
or acid solutions such as hydrochloric acid (HCl),
ammonium HCl, and arginine HCl.
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nephSAP Volume 20, Number 2, January 2022
Article 1: Pathophysiology, Evaluation, and
Treatment of Hyponatremia
1. A 25-year-old woman with no significant medical his-
tory participated in a full marathon for the first time.
After she completed the race in 5 hours, she experi-
enced seizures and was transferred to the emergency
department. According to her friend, she had been
drinking water frequently at the water stations during
the marathon.
Vital signs: Glasgow Coma Scale (GCS): E2V2M2 (Eye
response, opens eyes in response to pain; Verbal
response, makes sounds; Motor response, extension to
painful stimuli); BP 130/76 mm Hg (supine position),
pulse rate 70 beats/min, respiratory rate 18/min, SpO2
95% (room air), temperature 36.5
C, weight 63 kg (13 kg
more than usual)
Blood: total protein 7.3 g/dl, albumin 4.2 g/dl, BUN 12
mg/dl, creatinine 0.7 mg/dl, uric acid 3.0 mg/dl, Na 121
mmol/L, K 4.0 mmol/L, Cl 87 mmol/L, glucose 250
mg/dl, osmolality 260 mOsm/kg H2O
Urine: osmolality 450 mOsm/kg H2O
Which ONE of the following is the MOST likely cause
of this patient’s seizures?
A. Dehydration
B. Exercise-associated hyponatremia
C. Use of nonsteroidal anti-inflammatory drugs during
marathon training
D. Hyperglycemia
E. Volume depletion
2. A 21-year-old woman with no significant medical his-
tory participated in a rave party on a Saturday night.
Her friend recommended the use of ecstasy. The
patient was dancing and drinking several cocktails, and
she gradually became confused and drowsy. Unfortu-
nately, her friend thought that her drowsiness was due
to too much alcohol, and she was left unattended. Sub-
sequently, when she became unresponsive, she was
transported to the emergency department.
Vital signs: GCS: E1V1M1 (Eye response, does not open
eyes; Verbal response, makes no sounds; Motor
response, makes no movements); BP 100/60 mm Hg
(supine position), pulse rate 120 beats/min, respiratory
rate 12/min, SpO2 85% (room air), temperature 36.0
C,
weight 60 kg (13 kg more than usual)
Blood: total protein 7.5 g/dl, albumin 4.5 g/dl, BUN 25
mg/dl, creatinine 1.1 mg/dl, uric acid 3.0 mg/dl, Na
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120 mmol/L, K 4.5 mmol/L, Cl 85 mmol/L, glucose
100 mg/dl, osmolality 250 mOsm/kg
Urine: Na 120 mmol/L, K 30 mmol/L, osmolality 500
mOsm/kg H2O
Computed tomography of brain: cerebral edema
She received a diagnosis of cerebral edema caused by
acute hyponatremia resulting from ecstasy.
Which ONE of the following is the MOST appropri-
ate initial treatment for this patient?
A. Loop diuretic (furosemide) IV (20 mg)
B. 3% NaCl bolus IV (100 mL over 10 minutes up to
33)
C. 3% NaCl infusion (100 ml/h)
D. Tolvaptan (15 mg via nasogastric tube)
E. Urea (30 g via nasogastric tube)
3. A 47-year-old man who was a heavy drinker had
received a diagnosis of liver dysfunction for the past 5
years. He drank eight to 10 beers per day, and lived
alone, reportedly in poor circumstances. He visited the
clinic when his family noticed gait instability.
Vital signs: GCS: E4V5M6 (Eye response, opens eyes
spontaneously; Verbal response, oriented, converses
normally; Motor response, obeys commands); BP 120/
60 mm Hg (supine position), pulse rate 70 beats/min,
respiratory rate 14/min, SpO2 98% (room air), tempera-
ture 36.5
C, weight 59 kg (12 kg compared with a
month before), conjunctiva icteric
Blood: total protein 6.3 g/dl, albumin 3.0 g/dl, BUN 6
mg/dl, creatinine 0.5 mg/dl, uric acid 5.5 mg/dl, Na
120 mmol/L, K 2.8 mmol/L, Cl 70 mmol/L, glucose 80
mg/dl, osmolality 260 mOsm/kg H2O
Urine: Na 18 mmol/L, K 18 mmol/L, osmolality 100
mOsm/kg H2O
He received a diagnosis of chronic hyponatremia with
mild symptoms (gait instability) due to beer potomania,
and his serum [Na1] was corrected. After 24 hours, his
serum [Na1] increased to 132 mmol/L, his K was 3.1
mmol/L, and he had no other symptoms.
Which ONE of the following is the MOST appropri-
ate next step in management?
A. Continue current treatment until his serum [Na1]
reaches 135 mmol/L
B. Continue the current treatment until all symptoms
are eliminated
Copyright # 2022 by the American Society of Nephrology
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
C. Increase K1 replacement for his hypokalemia
D. Terminate the current treatment and observe the
patient carefully
E. Terminate the current treatment and re-lower the
serum [Na1] with 5% dextrose in water and
desmopressin
4. A 38-year-old woman with no significant medical his-
tory experienced severe nausea, vomiting, and diarrhea
for 2 days. She was referred to the emergency depart-
ment because of weakness and difficulty in food intake.
Vital signs: GCS: E4V5M6 (Eye response, opens eyes
spontaneously; Verbal response, oriented, converses
normally; Motor response, obeys commands); BP 90/50
mm Hg (supine position), pulse rate 120 beats/min,
respiratory rate 16/min, SpO2 99% (room air), tempera-
ture 37.8
C, body weight 55 kg (24 kg).
Blood: total protein 7.0 g/dl, albumin 3.8 g/dl, BUN 50
mg/dl, creatinine 1.2 mg/dl, uric acid 8.8 mg/dl, Na
128 mmol/L, K 3.5 mmol/L, Cl 90 mmol/L, glucose 80
mg/dl, osmolality 270 mOsm/kg H2O
Urine: Na 15 mmol/L, K 15 mmol/L, osmolality 450
mOsm/kg H2O
Volume depletion due to severe vomiting and diarrhea
was diagnosed; normal saline was administered to
restore her extracellular fluid volume. Subsequently,
her condition improved (BP 110/70 mm Hg [supine
position]), but serum [Na1] increased to 140 mmol/L
within a day.
Which ONE of the following is the MOST likely
cause of this patient’s serum [Na1] increase?
A. Extracellular fluid volume replacement by normal
saline infusion leading to increased free water
excretion (aquaresis)
B. Fluid restriction due to inability to consume fluids
orally
C. Increased water losses from sweating
D. Na1 repletion by normal saline infusion
E. Remission of nausea and vomiting, eliminating non-
osmotic arginine vasopressin secretion
5. An 88-year-old man with syndrome of inappropriate
antidiuretic hormone secretion caused by small-cell
lung cancer was being treated with fluid restriction and
urea, but his serum [Na1] did not improve sufficiently.
Moreover, his diet-related quality of life was reduced
by this treatment. Tolvaptan administration (15 mg/d)
led to an appropriate improvement in serum [Na1]
within the upper limit of correction. While initiating
tolvaptan, the doctor repeatedly instructed the patient
to drink water whenever he felt thirsty. At his initial
follow-up visit, the patient reported he was drinking
well, with good appetite and an improved diet-related
quality of life. However, 2 weeks later, he visited a
clinic because of lethargy.
161
Vital signs: GCS: E4V5M6 (Eye response, opens eyes
spontaneously; Verbal response, oriented, converses
normally; Motor response, obeys commands); BP 100/
60 mm Hg (supine position), pulse rate 65 beats/min,
respiratory rate 14/min, SpO2 95% (room air), tempera-
ture 36.2
C, weight 70 kg (22 kg)
Blood: total protein 6.3 g/dl, albumin 3.0 g/dl, BUN 40
mg/dl, creatinine 0.9 mg/dl, uric acid 5.0 mg/dl, Na
160 mmol/L, K 4.5 mmol/L, Cl 120 mmol/L, glucose
100 mg/dl, osmolality 350 mOsm/kg H2O
Urine: Na 15 mmol/L, K 30 mmol/L, osmolality 120
mOsm/kg H2O
Hypernatremia was diagnosed and 5% dextrose in
water was administered.
Which ONE of the following is the MOST likely
cause of this patient’s hypernatremia?
A. Aquaresis produced by tolvaptan
B. Decreased thirst in response to hypertonicity in the
elderly
C. Loss of appetite
D. Mistakenly continued fluid restriction
E. Partial improvement of syndrome of inappropriate
antidiuretic hormone secretion because of treatment
of small-cell lung cancer
Article 2: Pathophysiology, Evaluation, and
Treatment of Hypernatremia
6. A 59-year-old man with a medical history of type 2
diabetes mellitus, hypertension, coronary artery dis-
ease, and bipolar disorder taking lithium is admitted
to the intensive care unit with pneumonia and septic
shock. On examination, the patient is sedated, receiv-
ing mechanical ventilation, with an FiO2 40%, positive
end-expiratory pressure 8 cmH2O, BP 118/79 mm Hg,
heart rate 91 beats/min. The results of heart and lung
examination are unremarkable. There is no jugular
venous distension, or peripheral edema. For the past
24 hours, his urine output was 1300 ml.
Laboratory evaluation shows serum sodium 155
mmol/L, potassium 3.7 mmol/L, chloride 123 mmol/L,
total CO2 25 mmol/L, BUN 24 mg/dl, serum creatinine
1.3 mg/dl (baseline creatinine 1 mg/dl), blood glucose
170 mg/dl, and urine osmolarity 629 mOsm/kg.
Which ONE of the following answers is MOST likely
the correct cause of the patient’s hyponatremia?
A. Hypernatremia is iatrogenic and requires intrave-
nous or oral free water supplementation
B. Hypernatremia is secondary to lithium-induced
partial nephrogenic diabetes insipidus
C. Hypernatremia is secondary to osmotic diuresis
from hyperglycemia
162
D. Hypernatremia is secondary to lithium-induced
complete nephrogenic diabetes insipidus
7. An 86-year-old woman with a medical history of
hypertension, multi-infarct dementia, and atrial fibril-
lation presents from a nursing home with mental
status changes to the emergency department. On pre-
sentation, her BP is 106/58 mm Hg, heart rate is 90
beats/min (irregular), respiratory rate is 22/min, oxy-
gen saturation is 97% and weight is 60 kg. On exami-
nation she has dry mucous membranes, she is oriented
to name only, her lung and heart examination results
are unremarkable, and there is no leg edema.
Laboratory evaluation shows serum sodium 176
mmol/L, potassium 3.5 mmol/L, chloride 129 mmol/
L, bicarbonate 35 mmol/L, creatinine 1.5 mg/dl (base-
line creatinine 1.2 mg/dl), and urine osmolarity 655
mOsm/kg.
Which is the correct statement regarding the rate of
correction and amount of patient’s free water deficit?
A. Assuming minimal ongoing free water losses, the
infusion of 2 liters of free water would decrease
the serum sodium concentration to approximately
155 mmol/L
B. Assuming 45% total body water content in this
elderly woman, the free water deficit is 3.5 L
C. A change in the serum sodium concentration of 1
mmol/L/h is likely safe and should not cause neu-
rologic sequelae.
D. Assuming minimal ongoing free water losses, the
infusion of 4 liters of free water would decrease
the serum sodium concentration to approximately
154 mmol/L
8. A 44-year-old man with a medical history of pulmo-
nary sarcoidosis has his condition evaluated for
increased thirst and urination of 2 weeks duration. He
takes maintenance 10 mg of prednisone. He has no
other contributory medical history and does not take
other medications. On examination, BP is 125/74 mm
Hg, heart rate is 72 beats/min, and respiratory rate is
15/min. The lungs and heart examination results are
unremarkable.
Laboratory evaluation shows serum sodium 147
mmol/L, potassium 3.8 mmol/L, chloride 110 mmol/
L, BUN 16 mg/dl, creatinine 1.1 mg/dl, calcium 8.7
mg/dl, albumin 4 g/dl, urine sodium 20 mmol/L,
and urine osmolarity 115 mOsm/kg. The urine output
exceeds 6 liters per day.
What is the correct statement regarding the cause of
and diagnostic workup for hypotonic polyuria?
A. The indirect water deprivation test will accurately
differentiate between central diabetes insipidus
and primary polydipsia
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
B. Hypertonic saline infusion test and resultant
copeptin release will accurately differentiate
between central diabetes insipidus and primary
polydipsia
C. In the setting of sarcoidosis, nephrogenic diabetes
insipidus due to hypercalcemia is the most likely
cause of hypernatremia
D. Copeptin levels after a water deprivation test will
accurately differentiate between central diabetes
insipidus and primary polydipsia
9. A 40-year-old woman with a medical history of
schizophrenia presents to the emergency department
with tonic-clonic seizures. She is intubated on
arrival. On examination, BP is 179/88 mm Hg, and
heart rate 137 beats/min.
Laboratory evaluation shows serum sodium 183
mmol/L, serum osmolality 363 mOsm/kg, potas-
sium 3.6 mmol/L, chloride 128 mmol/L, blood glu-
cose 115 mg/dl, BUN 22 mg/dl, creatinine 1.0 mg/
dl. The patient’s family reports that she might have
ingested 500 ml of triple-strength Japanese seasoning
soy sauce 3 to 4 hours before seizure onset.
Which of the following statements regarding the
management of an acute salt intoxication is correct?
A. Goal serum sodium correction should not exceed
more than 10 mmol/L in 24 hours or 0.5 mmol/L
per hour to avoid the development of cerebral
edema
B. Cerebral edema is unlikely to occur in this setting
of acute hypernatremia, and rapid correction of
serum Na to baseline should be undertaken
C. Acute hypernatremia allows for the formation of
idiogenic osmoles counterbalancing the osmotic
gradient between extracellular and intracellular
compartments
D. Administration of free water at high rates is suffi-
cient to treat salt intoxication, and extracorporeal
removal can cause too rapid a decrease in the
serum sodium concentration
10. A 55-year-old man with a medical history of hyper-
tension, type 2 diabetes mellitus, hyperlipidemia,
and ESKD, receiving hemodialysis, is seen for a
nephrology consultation in the neurologic intensive
care unit, where he has been admitted for subarach-
noid hemorrhage. The patient is intubated, is using
minimal ventilatory settings, and does not require
any sedation. His GCS score is 7. An external ven-
tricular drain is placed, and the patient is given
hypertonic saline infusion. BP 135/75, heart rate 67
beats/min.
Laboratory evaluation shows sodium 147 mmol/L,
potassium 6.0 mmol/L, chloride 108 mmol/l, total
CO2 21 mmol/L, BUN 88 mg/dl, and creatinine
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
10.4 mg/dl. His last dialysis was performed 3 days
ago. The patient is full code, and the family would
like to pursue full medical and surgical manage-
ment at this point.
What is the optimal decision in regard to the renal
replacement therapy for this patient?
A. Perform intermittent hemodialysis with regular
blood and dialysate flows because the patient is
starting to experience electrolyte abnormalities,
and rising BUN might contribute to worsening
mental status
B. Begin continuous venovenous hemodiafiltration
with isotonic bicarbonate replacement fluid and
discontinue hypertonic saline infusion
C. Begin continuous venovenous hemodiafiltration
with standard sodium concentration dialysate and
replacement fluid; at the same time continue
hypertonic saline infusion to maintain permissive
hypernatremia
D. Hold off renal replacement therapy at this time
and manage the electrolyte abnormalities
medically
Article 3: Pathophysiology, Evaluation, and
Treatment of Hypokalemia
11. A 22-year old woman is referred for hypokalemia. The
patient’s history indicates progressive weakness over
the past 3 weeks and weight gain despite exercise and
following a healthy balanced diet. The patient does
not describe having diarrhea or vomiting, and she
does not have a history of using over-the-counter
(OTC) medications or herbal supplements. Her body
mass index (BMI) is 19 kg/m2, and BP is 120/80 mm
Hg. The results of physical examination are unremark-
able.
Laboratory evaluation shows plasma sodium 133
mEq/L, plasma potassium 2.7 mEq/L, plasma chlo-
ride 83 mEq/L, plasma bicarbonate 34 mEq/L, plasma
BUN 6 mg/dl, plasma creatinine 0.6 mg/dl, arterial
blood gases pH 7.46 and PCO2 44 mm Hg, urine elec-
trolytes (mEq/L) [Na1] 70, urine [K1] 35, urine [Cl2]
,15, urine pH 8.
What is the most likely cause of this patient’s
hypokalemia?
A. Early (“continuous”) vomiting
B. Magnesium deficiency
C. Long-term laxative use
D. Remote diuretic use
12. A 32-year-old man with a history of cystic fibrosis
presents to the emergency department with progres-
sive confusion and is unable to provide any medical
163
history. His family informs that over the past few
days, he had been painting a new roof in the heat of
summer. On medication review, it is learned that the
patient takes topiramate for migraine prophylaxis and
inhaled tobramycin for Pseudomonas aeruginosa coloni-
zation. History is limited because of altered mental
status.
On examination, BP is 90/60 mm Hg and pulse is 100
beats/min. Mucous membranes are dry, and poor
skin turgor is noted. Additional laboratory studies
show plasma sodium 135 mEq/L, plasma potassium
2.2 mEq/L, plasma chloride 86 mEq/L, plasma bicar-
bonate 40 mEq/L, plasma BUN 56 mg/dl, plasma cre-
atinine 2.3 mg/dl, plasma uric acid 12.2 mg/dl,
plasma creatine kinase 676 U/L.
What is the most likely pathophysiologic explana-
tion for this patient's severe hypokalemia?
A. Inhibition of carbonic anhydrase in the proximal
tubule
B. Activation of calcium-sensing receptor in the distal
tubule
C. Metabolic alkalosis–induced transcellular shift of
potassium out of the cells
D. Loss of potassium in the sweat glands from perspi-
ration with extracellular fluid volume depletion
and secondary hyperaldosteronism
E. Urinary loss of bicarbonate by the intercalated
cells
13. A 36-year-old man is referred to nephrology clinic for
evaluation of hypokalemia. The patient described pro-
gressive fatigue and leg cramps over the past year
since initiating intermittent fasting and adhering to a
vegetarian diet. He takes magnesium supplements for
the leg cramps but denies using other OTC medica-
tions, herbal supplements, or illicit drugs. The patient
is sexually active and is taking pre-exposure prophy-
laxis, emtricitabine, and tenofovir to prevent HIV. He
is afebrile, BP is 120/80 mm Hg, pulse is 80 beats/
min, and respiratory rate is 16/min. The results of
physical examination are unremarkable.
Laboratory data: Plasma sodium 138 mEq/L, potas-
sium 3.4 mEq/L, chloride 114 mEq/L, bicarbonate 15
mEq/L, BUN 28 mg/dl, creatinine 0.6 mg/dl, glucose
92 mg/dl, uric acid 2.3 mg/dl, serum phosphorus 1.9
mg/dl. Urine studies: pH 6, 11 protein, 21 glucose,
no erythrocytes or leukocytes.
The patient was admitted, and an intravenous hypo-
tonic saline solution (0.45% NaCl) containing 75 mEq
sodium bicarbonate was initiated at a rate of 1
mEq/kg per h. Spot urine and simultaneous plasma
electrolytes were obtained to measure fractional excre-
tion of HCO32.
164
What would you predict as the expected trend and
values for pertinent laboratory data shown in the
next series of choices?
A. Plasma K1 #, Plasma HCO32 ", Urine pH ", Frac-
tional excretion of [HCO32] 2%
B. Plasma K1 ", Plasma HCO32 ", Urine pH $, Frac-
tional excretion of [HCO32] 15%
C. Plasma K1", Plasma HCO32 #, Urine pH #, Frac-
tional excretion of [HCO32] 2%
D. Plasma K1 #, Plasma HCO32 ", Urine pH ", Frac-
tional excretion of [HCO32] 15%
14. A 22-year-old woman is seen in a nephrology clinic
for electrolyte abnormalities. The patient described
having excessive muscle cramps after ballet lessons
and indicates that she has been vigorously training for
an upcoming dance competition. She denies current
use of OTC medications, herbal supplements, or diu-
retics, and she specifically denies vomiting or diar-
rhea. There is a history of “idiopathic edema” for
which she received hydrochlorothiazide 12.5 mg/d,
but she categorically denies current use. Her sister has
a history of Hashimoto thyroiditis, and her mother
had a history of stroke. Her BP in the clinic is 110/60
mm Hg, and her BMI is 19 kg/m2. The results of phys-
ical examination are unremarkable.
Blood chemistry: Plasma sodium 138 mEq/L, potas-
sium 2.7 mEq/L, chloride 95 mEq/L, bicarbonate 32
mEq/L, creatinine 0.6 mg/dl, magnesium 1.3 mg/dl,
aldosterone 20 ng/dl (high). Spot urine studies: K1/
Cr ratio 32 mEq/g, Ca12/Cr ratio 0.4 mg/g (high),
fractional excretion of Mg12 3% (high).
What is the most likely cause of hypokalemia?
A. Abuse of laxatives
B. Surreptitious diuretic use
C. Herbal medicine containing glycyrrhizic acid
D. Remote vomiting
E. OTC thyroid supplementation
15. A 27-year-old man presents to a nephrology clinic for
consultation. The patient was seen in the emergency
department of a local hospital with profound muscle
weakness, and a [K1] of 2.3 mEq/L was reported. The
patient’s condition improved, and the discharge
plasma [K1] was 4.1 mEq/L. This same sequence of
events occurred 3 weeks later, and he is referred by
the emergency department physician for evaluation
of the recurrent hypokalemia. He has been describing
increased salt-craving and frequent muscle cramps.
His medical history is significant for depression
treated with selective serotonin reuptake inhibitor
antidepressants. He denies the use of any OTC medi-
cations or herbal supplements. He has been taking
magnesium oxide 400 mg four times a day and
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
potassium chloride 20 mEq two times a day for sev-
eral years. The patient is afebrile, with BP 100/70 mm
Hg, pulse 78 beats/min, and respiratory rate 16/min.
He appears euvolemic on examination. No sensory
deficits are noted, and muscle strength in the upper
and lower extremities is 2/4. Electrocardiogram
reveals “U” waves in limb leads II and V1.
The plasma electrolytes at the time of this visit: Plasma
sodium 139 mEq/L, potassium 2.7 mEq/L, chloride 95
mEq/L, bicarbonate 29 mEq/L, creatinine 0.7 mg/dl,
magnesium 1.1 mEq/L.
The patient is admitted to the hospital for diagnostic
studies and treatment of hypokalemia. Spot urine stud-
ies obtained after stabilization are as follows: K1/Cr
ratio 25 mEq/g, Ca12/Cr ratio 0.04 mg/g, fractional
excretion of Mg12 5% (high).
What is the most likely cause of hypokalemia and
hypomagnesemia?
A. Mutation in CLDN16 gene encoding claudin-16
B. Mutation in SLC12A3 gene encoding NCC in the
distal tubule
C. Mutation in KCNJ1 gene encoding ROMK in col-
lecting duct
D. Mutation in SLC12A1 gene encoding for NKCC2 in
thick ascending limb of Henle
Article 4: Pathophysiology, Evaluation, and
Treatment of Hyperkalemia
16. You are following up a 71-year-old man for CKD. He
has long-standing diabetes and hypertension. His
eGFR is 32 mL/min per 1.73, and his microalbumin-
to-creatinine ratio is 1.7 grams. His serum potassium
is 5.8 mEq/L and takes lisinopril 10 mg daily.
Which of the following is the best approach to the
management of his hyperkalemia?
A. Leave his regimen unchanged as recent studies
have shown that low potassium confers higher car-
diovascular risk and mortality than does high
potassium
B. Avoid potassium-binding agents as they all have
gastrointestinal side effects and are risky for long-
term use
C. Initiate patiromer to allow continued treatment
with renin-angiotensin system inhibitors.
D. Add fludrocortisone to reduce potassium in this
patient
17. A 16-year-old boy is referred for evaluation of hyper-
kalemia detected during emergency department
evaluation of muscle weakness. He notes frequent epi-
sodes of muscle weakness since childhood, associated
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
with physical exertion or exposure to cold. Episodes
of weakness have worsened as he has gotten older
and are associated with muscular pain after episodes.
During the most recent episode his potassium was 6.5
mEq/L and was associated with electrocardiographic
changes, with normal chloride, sodium, and bicarbon-
ate. His condition was subsequently evaluated by his
pediatrician, who noted normal potassium of 4.5
mEq/L and normal renin and aldosterone concentra-
tions. The patient notes that his late father used to
describe the exact same problem, as do his uncle and
cousin. In addition, his younger sister is starting to
have the same symptoms.
What is the most likely underlying cause of
hyperkalemia?
A. A loss of function mutation of the gene encoding
the epithelial sodium channel
B. A mutation of WNK (with no lysine) kinase result-
ing in increased expression of the sodium-chloride
(NCCT) cotransporter and inhibition of potassium
channels in principal cells
C. A mutation in the SCNA4 gene for the alpha subu-
nit of the skeletal muscle cell sodium channel
D. A mutation in genes encoding proteins that modu-
late WNK activity, including Kelch-like 3 and
Cullin 3
18. You are invited to speak at a symposium sponsored
by the Federal Emergency Management Agency
(FEMA) on emergency preparedness in urban centers.
A FEMA council member has heard that hyperkalemia
is a major cause of death of victims with crush injury
sustained as a result of being buried under rubble in
earthquakes. She asks you how to best determine
hyperkalemia, particularly when there are multiple
victims and time to treat is limited.
What is your response?
A. Measuring potassium in serum is faster than mea-
suring potassium in whole blood
B. A deep learning algorithm using an electrocardio-
gram is able to exclude hyperkalemia with accept-
able accuracy
C. Serum potassium is usually lower than plasma
potassium
D. Measuring potassium in whole blood is not as
accurate as measuring potassium in serum or
plasma
19. A 79-year-old woman with ESKD routinely presents
on Tuesday mornings with predialysis potassium 6.8
mEq/L. She undergoes dialysis three times weekly for
4 hours via a fistula. Her Kt/V is 1.7.
165
Which of the following is most likely to be an evi-
dence-based approach to her hyperkalemia?
A. Sodium zirconium cyclosilicate should not be cho-
sen as it is effective in reducing potassium in non-
dialysis CKD patients but not in dialysis patients
B. Sodium zirconium cyclosilicate should be chosen
for this patient rather than patiromer as it is less
likely to cause edema
C. Sodium zirconium cyclosilicate also removes
hydrogen ions and may increase serum
bicarbonate
D. Sodium zirconium cyclosilicate works quickly and
has been shown to provide added benefit to insu-
lin and glucose in the treatment of acute severe
hyperkalemia
Article 5: Metabolic Acidosis
20. A 74-year-old man with type II diabetes mellitus
and heart failure with reduced ejection fraction
presents to the emergency department with a
1-week history of fatigue, vomiting, headache, and
abdominal pain. He is found to have AKI, with
creatinine increased to 2.3 mg/dl from baseline
1.2 mg/dl. Other laboratory results show Na1
134mEq/L, K1 4.0mEq/L, Cl2 98mEq/L, HCO32
15mmol/L, BUN 68mmol/L, glucose 196mmol/L.
Lactate is 1.5 mEq/L. On examination, he is in
hemodynamically stable condition, with a mildly
tender abdomen, but the results of physical exami-
nation are otherwise unremarkable. For his diabe-
tes, he takes insulin and another oral antidiabetic
medication that he cannot recall the name of.
He reports that his blood sugars have been very
well controlled, such that his insulin was recently
reduced by 50%.
In considering this case, which of the following
statements is most accurate?
A. Metformin is the most likely culprit agent for aci-
dosis in this case
B. The recent reduction in insulin dosing may be the
precipitant for this clinical presentation
C. The patient’s near-normal blood glucose excludes
ketoacidosis as a cause of this presentation
D. This patient should be given an intravenous infu-
sion of isotonic bicarbonate
21. The internal medicine residency director asks you to
lead a teaching session for medicine residents on
drugs and the kidney. She references a patient recently
admitted with zidovudine-induced metabolic acidosis
and asks that you include an overview of drug-
induced acidosis.
166
With regard to drug-induced metabolic acidosis,
which of the following is correct?
A. Topiramate is associated with urine crystals and
with crystalline stone formation
B. Valproate is highly protein bound and is not ame-
nable to removal with hemodialysis
C. Concomitant use of antibiotics has been associated
with increased risk of pyroglutamic acidosis from
acetaminophen use
D. Linezolid causes a non-anion gap by blocking car-
bonic anhydrase
22. A 37-year-old male patient with CKD stage IV comes
for clinic follow-up. At last review, [HCO3] had
decreased to 19 mEq/L, and NaHCO3 650 mg twice
daily was initiated. Today, he reports abdominal
bloating and some nausea after taking the medica-
tions. His BP is well controlled at 122/68 mm Hg, and
on examination he has trace lower limb edema. He
has read that NaHCO3 may promote fluid retention
and is reluctant to continue taking it. He asks for an
explanation why it is necessary.
Which of the following is correct with regard to
treatment of metabolic acidosis in CKD?
A. A meta-analysis of treatment with NaHCO3 for met-
abolic acidosis did not show any increase in require-
ment for antihypertensive or diuretic agents
B. Increased ammoniagenesis resulting from acidosis
leads to increases in endothelin-1 (ET-1) levels
C. In renal transplant recipients, metabolic acidosis
has been associated with increased risk of graft
failure, but not cardiovascular events
D. Alkali therapy has been shown to reduce urine
ET-1 and aldosterone levels
23. A 54-year-old woman with CKD stage III, eGFR 45
mL/min, secondary to IgA nephropathy comes to
clinic for review. She also has type II diabetes mellitus,
obesity with BMI 35 kg/m2, and hypertension. Her
laboratory results show BUN 24 mmol/L, creatinine
1.8 mg/dl, Na 135 mEq/L, K 4.3 mEq/L, Cl 102 mEq/
L, HCO3 23 mEq/L. Urine microalbumin/creatinine
ratio is 200 mg/g. BP is 122/74 mm Hg while she
takes valsartan 160 mg daily, and for her diabetes, she
takes dapagliflozin and insulin and has an HbA1c of
6.8%. She is endeavoring to make lifestyle changes
and lose weight to improve her overall health but asks
if you have other suggestions that may reduce the risk
of CKD progression.
With regard to acidosis in early-stage CKD, which of
the following is correct?
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022
A. Switching to a diet of alkali-producing fruits and
vegetables may delay progression to hypobicarbo-
natemic acidosis
B. In observational studies, up to 40% of patients
with CKD stage III have metabolic acidosis
C. Decreases in urine citrate suggest H1 retention in
patients with CKD and have been shown to trend
closely with changes in serum [HCO32]
D. Inhibitors of the renin angiotensin system have
been shown to be protective against the develop-
ment of acidosis
24. A 66-year-old woman with a history of hypertension,
CKD stage IV, and dyslipidemia is seen at renal clinic.
On review of her laboratory results, total CO2 has
decreased to 20 mEq/L. You advise her to increase her
intake of alkali-generating fruits and vegetables, but she
is reluctant to make dietary changes. As an alternative,
you suggest that she start oral bicarbonate therapy.
Regarding the benefits of alkali therapy in CKD,
which of the following is correct?
A. In patients with CKD stage III to stage V, treat-
ment of metabolic acidosis has been associated
with reduction in progression to ESKD
B. Bicarbonate therapy has not been associated with
improvements in mortality in randomized con-
trolled trials (RCTs)
C. Patients with uncontrolled hypertension and
advanced heart failure have been enrolled in RCTs
investigating the use of NaHCO3 in CKD
D. In an RCT, treatment with veverimer was associ-
ated with improved [HCO32] but no significant
improvement in physical function scores
Article 6: Metabolic Alkalosis
25. A 22-year-old woman presents to her primary care
physician with weakness and fatigue that has been
worsening for the past few months. Her medical his-
tory is significant for mild depression. She does not
smoke cigarettes daily but drinks alcohol on week-
ends. She is currently not sexually active. She denies
recreational drug use. Medications include a daily
multivitamin. Family history includes hypertension
and diabetes in her mother and father.
Physical examination: weight 52 kg, pulse 84 beats/
min, BP 110/70 mm Hg, temperature 37
C. Dentition
is normal, no pallor, no icterus. Lungs are clear bilater-
ally. Heart reveals normal S1 and S2, 2/6 ejection sys-
tolic murmur at the left sternal border. Abdomen soft,
bowel sounds present. Extremities have no edema,
strong peripheral pulses. Neurologic examination
reveals no focal problems.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 167

Initial laboratory results He is given bumetanide 2 mg intravenously, three times

a day, with improvement in his initial laboratory results:
Study Result Reference Range
Study Day 1 Day 4 Reference Range
Leukocyte count 6000/ml 4000–11,000
Hemoglobin 12.9 g/dl 12–16 Leukocyte count 6000/ml 8000/ml 4000–11,000
Platelets 189,000/ml 150,000–450,000 Hemoglobin 10.9 g/dl 11.8g/dl 12–16
Serum Platelets 189,000/ml 200,000/ml 150,000–450,000
Sodium 142 mEq/L 136–145 Serum
Potassium 2.9 mEq/L 3.5–5.0 Sodium 142 mEq/L 144 mEq/L 136–145
Chloride 98 mEq/L 98–106 Potassium 3.9 mEq/L 3.1 mEq/L 3.5–5.0
Total CO2 38 mEq/L 23–30 Chloride 108 mEq/L 92 mEq/L 98–106
BUN 8 mg/dl 8–20 Total CO2 28 mEq/L 40 mEq/L 23–30
Creatinine 0.6 mg/dl 0.5–1.1 BUN 20 mg/dl 8 mg/dl 8–20
Random glucose 98 mg/dl Creatinine 1.4 mg/dl 0.6 mg/dl 0.5–1.1
Magnesium 1.8 mg/dl 1.5 mg/dl 1.7–2.2
Urine toxicology screen results are negative. Electro- B-natriuretic 800 pg/ml 450 pg/ml ,100
cardiogram reveals sinus rhythm. Urine electrolytes: peptide
spot urine K1 50 mEq/L, Cl2 8 mEq/L, Na1 52 mEq/
L. Plasma renin activity is elevated. plasma aldoste-
What is the next best step in the management of this
rone concentration is elevated.
patient’s metabolic alkalosis?
On the basis of these findings, of the following, A. Intravenous normal saline
what is the most likely cause of the patient’s hypo- B. Discontinue bumetanide
kalemic metabolic alkalosis? C. Intravenous 0.3 N hydrochloric acid
D. Oral spironolactone
A. Glucocorticoid-remediable hyperaldosteronism
B. Surreptitious vomiting
27. A 75-year-old man is admitted to the intensive care
C. Gitelman syndrome
unit and intubated for acute respiratory failure caused
D. Diuretic abuse
by exacerbation of severe chronic obstructive pulmo-
26. A 75-year-old man is admitted to the cardiac intensive nary disease with altered mental status. He is known
care unit for exacerbation of acute congestive heart to be a chronic CO2 retainer according to previous
failure. His medical history is significant for ischemic blood gas evaluations. You are consulted on day 3 for
cardiomyopathy with an ejection fraction of 45%, evaluation of acid-base derangements.
insulin-dependent diabetes mellitus, hypertension, His medical history is notable for well-controlled
chronic gastritis, and depression. He has a 10-pack- hypertension with a single medication, gastritis, and
year smoking history but quit 10 years ago. He drinks osteoarthritis. Review of his medications includes aspi-
occasionally and has no history of recreational rin, lisinopril, pantoprazole, ipratropium bromide, and
drug use. Home medications include amlodipine 10 albuterol sulfate nebulizer, intravenous methylpred-
mg daily, bumetanide 1 mg twice daily, lisinopril 20 nisolone, intravenous piperacillin-tazobactam, intrave-
mg daily, omeprazole 20 mg daily, metoprolol 25 mg nous propofol, and furosemide.
twice daily, and a multivitamin.
Weight 73 kg, BP 150/54 mm Hg, heart rate 102 beats/
Physical examination results: weight 102 kg, pulse 84 min, temperature 38
C. He is sedated. O2 saturation on
beats/min, BP 124/70 mm Hg, and temperature 40% FiO2 is 96%. Jugular venous distention is absent.
37
C. Dentition is normal, no pallor, no icterus. Jugu- Heart examination reveals tachycardia and a loud S4.
lar venous distension is noted 8 cm above sternal Lungs have decreased breath sounds bilaterally. Abdo-
angle. Lungs have coarse breath sounds and rales men is soft with active bowel sounds. Extremities have
bilaterally. Heart reveals normal S1 and S2, S3 is pre- trace edema and 11 peripheral pulses.
sent, 2/6 ejection systolic murmur is audible at the
left sternal border. Abdomen soft, bowel sounds pre- Arterial blood gases on admission: pH 7.1, PaCO2 92
sent. Extremities have 21 pitting edema, 11 periph- mm Hg, PaO2 72 mm Hg on 6 L/min oxygen via nasal
eral pulses. Neurologic examination reveal no focal cannula; 48 hours later (while still intubated): pH 7.48,
problems. PaCO2 42 mm Hg, PO2 84 mm Hg on 40% FiO2.
168 Nephrology Self-Assessment Program - Vol 20, No 2, January 2022

Laboratory results Peripheral pulses are noted to be weak, extremities are

cold, and skin is mottled. Neurologic examination is
Reference noteworthy for a depressed mental status.
Study Day 1 Day 3 Range
Initial laboratory values
Leukocyte count 12,000/ml 8000/ml 4000–11,000
Hemoglobin 10.9 g/dl 11.8 g/dl 12–16 Study Result Reference Range
Platelets 189,000/ml 200,000/ml 150,000–450,000
Serum Leukocyte count 12,000/ml 4000–11,000
Sodium 142 mEq/L 144 mEq/L 136–145 Hemoglobin 13.3 g/dl 12–16
Potassium 3.8 mEq/L 3.9 mEq/L 3.5–5.0 Platelets 120,000/ml 150,000–450,000
Chloride 102 mEq/L 92 mEq/L 98–106 Serum
Total CO2 34 mEq/L 33 mEq/L 23–30 Sodium 138 mEq/L 136–145
BUN 20 mg/dl 30 mg/dl 8–20 Potassium 4.0 mEq/L 3.5–5.0
Creatinine 1.1 mg/dl 1.2 mg/dl 0.5–1.1 Chloride 103 mEq/L 98–106
Magnesium 1.8 mg/dl 1.5 mg/dl 1.7–2.2 Total CO2 6 mEq/L 23–30
B-natriuretic 300 pg/ml 250 pg/ml ,100 BUN 45 mg/dl 8–20
peptide Creatinine 2.0 mg/dl 0.5–1.1
Random glucose 98 mg/dl
Urinalysis: pH 5.2, specific gravity 1.015, negative for Workup reveals arterial blood gases with PO2 90 mm
protein, blood, glucose. Chest X-ray: hyperinflated lung Hg, pH 7.06, PCO2 18 mm Hg, [HCO32] 5 mEq/L,
fields, mild pulmonary venous congestion. and serum lactate 20 mEq/L. The patient is given
broad-spectrum antibiotics and because of the low pH
What is the most likely cause of this patient’s elevated [HCO32] is administered (5% dextrose in half normal
blood pH on the second blood gas determination? saline with 75 mEq/L NaHCO3).
A. Acute respiratory alkalosis
Over the next 2 days, the patient’s hemodynamics sta-
B. Posthypercapneic metabolic alkalosis
bilize, and arterial blood gases show PO2 92 mm Hg,
C. Intravenous methylprednisolone-induced alkalosis
pH 7.47, PCO2 48 mm Hg, [HCO32] 34 mEq/L. Urine
D. Nasogastric suctioning
pH is 8.
28. A 65-year-old man presents with the sudden onset of
On the basis of the patient’s course, which of the fol-
severe weakness and fever developing over the previ-
lowing is true regarding the patient’s metabolic
ous 24 hours. The patient had been followed up by his
alkalosis?
primary care physician before admission, and earlier
laboratory values and BP have all been normal. Rele- A. It is due to Gitelman syndrome that was not
vant medical history is that the patient has had diffi- apparent on admission
culty urinating, with urinary retention and nocturia. B. It is due to primary hyperaldosteronism that was
Previous workup has revealed benign prostatic hyper- not apparent on admission
trophy. C. It was generated by metabolism of retained lactate
to bicarbonate and is now maintained by volume
Early on the day of admission the patient awoke feel- contraction
ing weak and warm and experienced burning on uri- D. It was generated by metabolism of retained lactate
nation. His temperature was elevated, and he came to to bicarbonate and should spontaneously correct
the emergency department. Physical examination
shows a patient who is pale and confused. Weight 55 29. A 45-year-old woman presents with new onset of
kg, pulse 120 beats/min, BP 70/50 mm Hg, tempera- hypertension but is otherwise healthy. Physical exami-
ture 40
C. Lungs are clear bilaterally. Heart reveals nation results are is noteworthy for a BP of 160/105
normal S1 and S2, abdomen is soft with some supra- mm Hg and are otherwise normal, with no evidence
pubic tenderness and right flank pain tenderness. of volume depletion or edema.
Nephrology Self-Assessment Program - Vol 20, No 2, January 2022 169

Laboratory values are noteworthy for a BP of 155/110 mm Hg and are

otherwise normal, with no evidence of volume deple-
Study Result Reference Range tion or edema.
Laboratory values
Leukocyte count 5000/ml 4000–11,000
Hemoglobin 13.9 g/dl 12–16 Study Result Reference Range
Platelets 230,000/ml 150,000–450,000
Serum Leukocyte count 5500/ml 4000–11,000
Sodium 145 mEq/L 136–145 Hemoglobin 14.2 g/dl 12–16
Potassium 2.5 mEq/L 3.5–5.0 Platelets 200,000/ml 150,000–450,000
Chloride 97 mEq/L 98–106 Serum
Total CO2 34 mEq/L 23–30 Sodium 145 mEq/L 136–145
BUN 8 mg/dl 8–20 Potassium 2.3 mEq/L 3.5–5.0
Creatinine 0.6 mg/dl 0.5–1.1 Chloride 96 mEq/L 98–106
Random glucose 98 mg/dl Total CO2 35 mEq/L 23–30
BUN 8 mg/dl 8–20
Creatinine 0.6 mg/dl 0.5–1.1
A random plasma renin is low, and a plasma aldoste- Random glucose 98 mg/dl
rone is high.

On the basis of these findings, what is the most Random plasma renin and aldosterone are low. Corti-
likely diagnosis? sol levels are normal.
A. Gitelman syndrome
B. Renovascular hypertension
C. Primary hyperaldosteronism On the basis of these findings, what is the most
D. Liddle disease likely diagnosis?
A. Surreptitious diuretic abuse
30. A 35-year old man presents with new onset of hyper- B. Syndrome of apparent mineralocorticoid excess
tension but is otherwise healthy. History was noncon- due to glycyrrhizic acid
tributory with the exception of extensive use of C. Primary hyperaldosteronism
chewing tobacco. The results of physical examination D. Villous adenoma