Volume 9 • Number 4 • July 2010

NephSAP
®

Nephrology Self-Assessment Program

Clinical Pharmacology for

the Nephrologist
Guest Co-Editors:
Suzanne K. Swan, MD,
Ali Olyaei, PharmD, and
Domenic A. Sica, MD
■ Editor-in-Chief: Stanley Goldfarb, MD
■ Deputy Editor: Jeffrey S. Berns, MD
NephSAP
®

EDITOR-IN-CHIEF
Stanley Goldfarb, MD
University of Pennsylvania Medical School
Preface
Philadelphia, PA NephSAP® is one of the three major publications of the American Society of Nephrology
(ASN). Its primary goals are self-assessment, education, and the provision of Continuing
DEPUTY EDITOR Medical Education (CME) credits and Maintenance of Certification (MOC) credits for
Jeffrey S. Berns, MD individuals certified by the American Board of Internal Medicine. Members of the ASN
University of Pennsylvania Medical School
Philadelphia, PA
automatically receive NephSAP with their monthly issue of The Journal of the American
Society of Nephrology (JASN).
MANAGING EDITOR
EDUCATION: Medical and Nephrologic information continually accrues at a rapid pace.
Gisela Deuter, BSN, MSA
Washington, DC Bombarded from all sides with demands on their time, busy practitioners, academicians,
and trainees at all levels are increasingly challenged to review and understand all this new
ASSOCIATE EDITORS material.
Rajiv Agarwal, MD Each bimonthly issue of NephSAP is dedicated to a specific theme, i.e., to a specific
Indiana University School of Medicine area of clinical nephrology, hypertension, dialysis, and transplantation, and consists of an
Indianapolis, IN
Editorial, a Syllabus, a Commentary on the Syllabus, and self-assessment questions. Over
David J. Cohen, MD
Columbia University the course of 24 months, all clinically relevant and key elements of nephrology will be
New York, NY reviewed and updated. The authors of each issue digest, assimilate, and interpret key
Michael Emmett, MD publications from the previous issues of other years and integrate this new material with the
Baylor University body of existing information.
Dallas, TX
Steven Fishbane, MD SELF-ASSESSMENT: Twenty-five single-best-answer questions will follow the 50 to 75 pages
Stony Brook School of Medicine of Syllabus text. The examination is available online with immediate feedback. Those answer-
Minneola, NY ing ⬎75% correctly will receive CME credit, and receive the answers to all the questions along
Richard J. Glassock, MD with brief discussions and an updated bibliography. To help answer the questions, readers may
Professor Emeritus, The David Geffen School
of Medicine at the University of California
go to the ASN web site, where relevant material from UpToDate in nephrology will be posted.
Los Angeles, CA Thus, members will find a new area reviewed every 2 months, and they will be able to test their
Kevin J. Martin, MBBCh understanding with our quiz. This format will help readers stay abreast of developing areas of
St. Louis University School of Medicine clinical nephrology, hypertension, dialysis, and transplantation, and the review and update will
St. Louis, MO support those taking certification and recertification examinations.
Rajnish Mehrotra, MD
Harbor UCLA Research and Education Institute CONTINUING MEDICAL EDUCATION: Most state and local medical agencies as well as
Torrance, CA hospitals are demanding documentation of requisite CME credits for licensure and for staff
Patrick T. Murray, MD appointments. A maximum of 36 credits annually can be obtained by successfully completing
University College Dublin the NephSAP examination. In addition, individuals certified by the American Board of Internal
Dublin, Ireland
Medicine may obtain credits towards Maintenance of Certification (MOC) by successfully
Patrick H. Nachman, MD
University of North Carolina completing the self-assessment portion of NephSAP.
Chapel Hill, NC
BOARD CERTIFICATION AND INSERVICE EXAMINATION PREPARATION: Each issue
Paul M. Palevsky, MD
University of Pittsburgh School of Medicine
will also contain 5 questions and answers examining core topics in the particular discipline
Pittsburgh, PA reviewed in the Syllabus. These questions are designed to provide trainees with challenging
Richard H. Sterns, MD questions to test their knowledge of key areas of nephrology.
University of Rochester School of Medicine
and Dentistry ⬁ This paper meets the requirements of ANSI/NISO Z39.48-1921 (Permanence of Paper),
Rochester, NY effective with July 2002, Vol. 1, No. 1.
Stephen C. Textor, MD
Mayo Clinic
Rochester, MN GUEST CO-EDITORS Suzanne K. Swan, MD
Raymond R. Townsend, MD Ali Olyaei, PharmD Hennepin County Medical Center
University of Pennsylvania Medical School Oregon Health and Science University Minneapolis, MN
Philadelphia, PA Portland, OR
FOUNDING EDITORS
John P. Vella, MD Domenic A. Sica, MD
Maine Medical Center Richard J. Glassock, MD, MACP
Virginia Commonwealth University Editor-in-Chief Emeritus
Portland, ME Richmond, VA
Robert G. Narins, MD, MACP

NephSAP®
©2010 by The American Society of Nephrology
NephSAP
®
Volume 9, Number 4, July 2010

Clinical Pharmacology for the Nephrologist

Editorial 213
Pharmacology and Kidney Disease: Lessons Learned from the
Gadolinium–Nephrogenic Systemic Fibrosis Story
—Mark A. Perazella, MD

Syllabus 220
Clinical Pharmacology for the Nephrologist—Suzanne K. Swan, MD,
Ali Olyaei, PharmD, and Domenic A. Sica, MD
Altered Pharmacokinetic Principles . . . . . . . . . . . . . . . . . . .220
Stepwise Approach to Dosimetry . . . . . . . . . . . . . . . . . . . . .222
Step 1: History and Physical Examination . . . . . . . . . . . .222
Step 2: Assess Renal Function . . . . . . . . . . . . . . . . . . . . .223
Step 3: Determine Loading Dose . . . . . . . . . . . . . . . . . . .224
Step 4: Determine Maintenance Dose . . . . . . . . . . . . . . .224
Step 5: Drug-Level Monitoring . . . . . . . . . . . . . . . . . . . .224
Drug Clearance in Dialysis . . . . . . . . . . . . . . . . . . . . . . . .225
Antimicrobial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .227
Antibacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . .227
Antifungal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .228
Amphotericin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .228
Azoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .229
Echinocandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .230
Antiviral Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .230
Hepatitis B and C Antiviral Agents. . . . . . . . . . . . . . . .230
Anti-Influenzal Agents . . . . . . . . . . . . . . . . . . . . . . . . . .230
NephSAP
®
Volume 9, Number 4, July 2010

Antiretroviral Agents . . . . . . . . . . . . . . . . . . . . . . . . . . .230

Psychiatric Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . .233
Antidepressant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . .233
Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .235
Anticonvulsant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .236
Older Anticonvulsant Drugs . . . . . . . . . . . . . . . . . . . . . . .236
Newer ACDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .237
“Traditional” Medications, Food Contaminants, and
Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .238
Use of Extracorporeal Measures to Remove Drugs and
Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .238
Immunosuppressive Therapies . . . . . . . . . . . . . . . . . . . . . . .240
Induction Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .240
Basiliximab and Daclizumab . . . . . . . . . . . . . . . . . . . . .240
Antithymocyte Globulin Equine/Rabbit. . . . . . . . . . . . .241
Muronomab-CD3 (OKT-3). . . . . . . . . . . . . . . . . . . . . . .241
Alemtuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
Maintenance Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
Calcineurin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . .242
Tacrolimus (FK-506) . . . . . . . . . . . . . . . . . . . . . . . . .245
Generic Formulations of CNIs . . . . . . . . . . . . . . . . . .246
Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .246
MPA Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .247
TOR Inhibitors: Sirolimus and Everolimus . . . . . . . . . .248
Common Drug–Drug Interactions . . . . . . . . . . . . . . . . . . .248
Pharmacokinetic Drug Interactions . . . . . . . . . . . . . . . . . .249
Cardiovascular Medications . . . . . . . . . . . . . . . . . . . . . . . . .252
Antihypertensive Agents . . . . . . . . . . . . . . . . . . . . . . . . . .252
Peripheral ␣ Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . .252
NephSAP
®
Volume 9, Number 4, July 2010

Central ␣ Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . .253

␤ Blockers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .253
Calcium Channel Blockers . . . . . . . . . . . . . . . . . . . . . . .253
Angiotensin-Converting Enzyme Inhibitors. . . . . . . . . .254
Angiotensin Receptor Blockers . . . . . . . . . . . . . . . . . . .255
Direct Renin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . .255
Antianginal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .256
Cholesterol-Lowering Agents . . . . . . . . . . . . . . . . . . . . . .256
Triglyceride-Lowering Agents . . . . . . . . . . . . . . . . . . . . .257
Antiarrhythmic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . .258
Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .259
Thiazide-Type Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . .259
Loop Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .260
Potassium-Sparing Diuretics . . . . . . . . . . . . . . . . . . . . . . .260
Mannitol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .261
Gastrointestinal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . .261
Antidiabetic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .262
Analgesic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .264
Acetaminophen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .264
Opioid Analgesic Agents . . . . . . . . . . . . . . . . . . . . . . . . .264

CME Self-Assessment Questions . . . . . . . . . . . . . . . . . . . . . 266

Questions Linked to UpToDate in Green

Upcoming Issues
Renal Bone Disease, Disorders of Divalent Ions, and
Nephrolithiasis—
Kevin Martin, MBBCh, and Stanley Goldfarb, MD . . . .September 2010
NephSAP
®
Volume 9, Number 4, July 2010

End-Stage Renal Disease and Dialysis—

Rajiv Agarwal, MD, and Rajnish Mehrotra, MD . . . . . .November 2010

Geriatric Nephrology—
Dimitrios G. Oreopoulos, MD, PhD, Vanita Jassal, MD, Ann M. O’Hare, MD,
Mitchell H. Rosner, MD, Mark A. Swidler, MD, Jocelyn Wiggins, BM, BCh,
Mark E. Williams, MD, and Richard J. Glassock, MD . . . . .January 2011

Fluid, Electrolyte, and Acid-Base Disturbances—

Richard H. Sterns, MD, and Michael Emmett, MD . . . . . . .March 2011

Acute Kidney Injury and Critical Care Nephrology—

Patrick T. Murray, MD, and Kathleen D. Liu, MD . . . . . . . . .May 2011
NephSAP
®
Volume 9, Number 4, July 2010

The Editorial Board of NephSAP extends its sincere appreciation to the following reviewers. Their efforts and insights have helped to
improve the quality of this postgraduate education offering.
NephSAP Review Panel
Nihal Y. Abosaif, MBBCh Rajiv Dhamija, MD Pranay Kathuria, MD, FASN
St. James University Hospital Walk in Medical Care University of Oklahoma College of Medicine
Leeds, United Kingdom Artesia, CA Tulsa, OK
Georgi Abraham, MBBS Susan R. DiGiovanni, MD Quresh T. Khairullah, MD, FASN
Sri Ramachandra University Virginia Commonwealth University St. Clair Specialty Physicians
Medical Center Richmond, VA Detroit, MI
Chennai, India
Francis Dumler, MD Apurv Khanna, MD
Pablo H. Abrego, MD, FASN William Beaumont Hospital SUNY Upstate Medical University
Marshfield Clinic Royal Oak, MI Syracuse, NY
Wausau, WI
Mahmoud T. El-Khatib, MD, PhD, FASN Ramesh Khanna, MD
Anil K. Agarwal, MD, FASN University of Cincinnati Medical Center University of Missouri at Columbia
Ohio State University Medical Center Cincinnati, OH School of Medicine
Columbus, OH Columbia, MO
Lynda A. Frassetto, MD, FASN
Mustafa Ahmad, MD University of California at San Francisco Edgar V. Lerma, MD, FASN
King Fahad Medical City San Francisco, CA University of Illinois at Chicago
Riyadh, Saudi Arabia College of Medicine
Duvuru Geetha, MD
Chicago, IL
Jafar Al-Said, MD, FASN Johns Hopkins University
Bahrain Specialist Hospital Baltimore, MD Meyer D. Lifschitz, MD
Manama, Bahrain Shaare Zedek Medical Center
Carl S. Goldstein, MD
Jerusalem, Israel
Dante Amato-Martinez, MD, PhD Robert Wood Johnson Medical School
Universidad Nacional Autónoma de México New Brunswick, NJ Philippe S. Madhoun, MD
Tlalnepantla, Mexico Chu Charleroi
Nabil G. Guirguis, MD
Charleroi, Belgium
Anis U. Ansari, MD Kidney Dialysis and Transplant Group
Medical Associates Bridgeport, WV Jolanta Malyszko, MD, PhD, FASN
Clinton, IA Medical University
Pawan K. Gupta, MD
Bialystok, Poland
Akhtar Ashfaq, MD, FASN Altoona Regional Health System
North Shore University Hospital Altoona, PA Naveed N. Masani, MD
Great Neck, NY Winthrop University Hospital
Carsten Hafer, MD
Mineola, NY
Azra Bihorac, MD, FASN University of Hannover
University of Florida Hannover, Germany Hanna W. Mawad, MD, FASN
Gainesville, FL University of Kentucky Medical Center
Richard N. Hellman, MD
Lexington, KY
Mona B. Brake, MD Indiana University School of Medicine
Robert J. Dole VA Medical Center Indianapolis, IN Pascal Meier, MD, FASN
Wichita, KS Centre Hospitalier Universitaire Vaudois
Ekambaram M. Ilamathi, MD, FASN
Lausanne, Switzerland
Mauro Braun, MD Suffolk Nephrology Consultants
Cleveland Clinic Florida Stony Brook, NY Beckie Michael, DO, FASN
Weston, FL Marlton Nephrology and Hypertension
Viswanathan S. Iyer, MD, FASN
Marlton, NJ
Chokchai Chareandee, MD, FASN AKD-HTN LLC
Regions Hospital Harrisburg, PA Shahriar Moossavi, MD, PhD
Saint Paul, MN Wake Forest University Baptist
Bernard G. Jaar, MD
Medical Center
W. James Chon, MD, FASN Johns Hopkins Medical Institutions and
Winston-Salem, NC
University of Chicago Medical Center Nephrology Center of Maryland
Chicago, IL Baltimore, MD Scott R. Mullaney, MD
University of California at San Diego
Devasmita Choudhury, MD Avanelle V. Jack, MD
San Diego, CA
University of Texas Southwestern Louisiana State University Health
Medical School Sciences Center Quaid J. Nadri, MD, FASN
Dallas, TX New Orleans, LA King Faisal Specialist Hospital and
Research Center
Bulent Cuhaci, MD, FASN Sharon L. Karp, MD
Riiyadh, Saudi Arabia
Drexel University College of Medicine Indiana University School of Medicine
Philadelphia, PA Indianapolis, IN
Suzanne M. Norby, MD, FASN Karthik M. Ranganna, MD Robert J. Shay, MD, FASN
Mayo Clinic Drexel University College of Medicine East Georgia Kidney and
Rochester, MN Philadelphia, PA Hypertension Group
Augusta, GA
Michal Nowicki, MD Pawan K. Rao, MD, FASN
Medical University of Łódź St. Joseph’s Hospital Health Center Rolf A.K. Stahl, MD
Łódź, Poland Syracuse, NY University of Hamburg
Hamburg, Germany
Macaulay A. Onuigbo, MD, FASN Joel C. Reynolds, MD, FASN
Mayo Clinic Brooke Army Medical Center Harold M. Szerlip, MD, FASN
Eau Claire, WI San Antonio, TX Medical College of Georgia
Augusta, GA
Than N. Oo, MD Robert M.A. Richardson, MD
Nephrology Center University of Toronto Bekir Tanriover, MD
Kalamazoo, MI Toronto, ON, Canada Dialysis Nephrology Associates
Dallas, TX
Kevin P. O’Reilly, MD Bijan Roshan, MD
Columbus Nephrology, Inc. Joslin Diabetes Center Tushar J. Vachharajani, MD, FASN
Columbus, OH Harvard Medical School Wake Forest University
Boston, MA School of Medicine
Malvinder S. Parmar, MB, MS, FASN
Winston-Salem, NC
Northern Ontario School of Medicine Abinash C. Roy, MD
Timmins, ON, Canada University of Utah School of Medicine Allen W. Vander, MD, FASN
Saint George, UT Kidney Center of South Louisiana
Pairach Pintavorn, MD, FASN
Thibodaux, LA
East Georgia Kidney and Hypertension Mario F Rubin, MD
Augusta, GA Massachusetts General Hospital Luigi Vernaglione, MD
Boston, MA M. Giannuzzi Hospital
Paul H. Pronovost, MD, FASN
Manduria, Italy
Yale University School of Medicine Ehab R. Saad, MD, FASN
Waterbury, CA Medical College of Wisconsin Shefali Vyas, MD
Milwaukee, WI Saint Barnabas Medical Center
Mohammad A. Quasem, MD, FASN
Livingston, NJ
State University of New York Mohammad G. Saklayen, MD
Binghamton, NY Wright State University Medical School Alexander Woywodt, MD, FASN
Dayton, OH Lancashire Teaching Hospitals NHS
Wajeh Y. Qunibi, MD
Foundation Trust
University of Texas Health Sciences Center Ramesh Saxena, MD, PhD
Preston, United Kingdom
San Antonio, TX University of Texas Southwestern
Medical Center
Venkat Ramanathan, MD, FASN
Dallas, TX
Baylor College of Medicine
Houston, TX Gaurang M. Shah, MD
Long Beach VA Healthcare System
Long Beach, CA
NephSAP
®
Volume 9, Number 4, July 2010

Program Mission and Objectives

The mission of the Nephrology Self-Assessment Program (NephSAP) is to regularly provide a vehicle that will be useful for clinical
nephrologists who seek to renew and refresh their clinical knowledge and diagnostic and therapeutic skills. This Journal consists of a
series of challenging, clinically oriented questions based on case vignettes, a detailed Syllabus that reviews recent publications,
and an Editorial on an important and evolving topic. Taken together, these parts should assist individual clinicians under-
taking a rigorous self-assessment of their strengths and weaknesses in the broad domain of nephrology.

Accreditation and Credit Designation

The American Society of Nephrology is accredited by the Accreditation Council for Continuing Medical Education to provide con-
tinuing medical education for physicians.
The ASN designates this educational activity for a maximum of 8.0 AMA PRA Category 1 Credits™. Physicians should only claim
credit commensurate with the extent of their participation in the activity.

Continuing Medical Education (CME) Information

CME Credit: 8.0 AMA PRA Category 1 Credits™
Date of Original Release: July 2010
Examination Available Online: on or before Friday, July 9, 2010
Audio Files Available: No audio files will be available for this issue.
CME Credit Eligible Through: June 30, 2011
Answers: Correct answers with explanations will be posted on the ASN website in July 2011 when the issue is archived.
UpToDate Links Active: July and August 2010
Core Nephrology question links active: There are no core questions for this issue.
Target Audience: Nephrology Board and recertification candidates, practicing nephrologists, and internists.
Method of Participation:
● Read the syllabus that is supplemented by original articles in the reference lists, and complete the online self-assessment
examination.
● Examinations are available online only after the first week of the publication month. There is no fee. Each participant is
allowed two attempts to pass the examination (⬎75% correct).
● Your score and a list of question/s (by number) answered incorrectly can be printed immediately.
● Your CME certificate can be printed immediately after passing the examination.
● Answers and explanations are provided ONLY with a passing score on the first or second attempt.
● Your ASN transcript will be updated in 6 to 8 weeks after passing the examination.
Instructions to access the Online CME Center to take the examination and complete the evaluation:
● Login at ASN’s website: www.asn-online.org
● Click the “CME” tab at the top of the homepage
● In the left-hand column click “Online CME Center”
● Scroll down; in the center of the page click the computer screen image to “Visit the Online CME Center”
● Once you’re in the Center, click the “NephSAP” banner in the center of the page
● Select a topic and click on “Enter Activity” to the right
● Read through the instructions, and then click on “Continue” at the bottom of the page
● Click on “Examination Questions/Evaluations” to begin
● Your score and a list of question numbers answered incorrectly can be printed immediately
● Follow the prompts to retake the examination if you failed, or print your certificate and the correct answers if you passed
● You can save and finish the exam to complete at another time
● You can retake the exam at any time; each participant is allowed two attempts
NephSAP
®
Volume 9, Number 4, July 2010

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

(MOC) Points:
Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria:
● Be certified by ABIM in internal medicine and/or nephrology and must be enrolled in the ABIM–MOC program
via the ABIM website (www.abim.org).
● Pass the self-assessment examination within the timeframe specified in this issue of NephSAP.
● Designate the issue for MOC points by clicking on the MOC link on the CME certificate page after passing the examination.
You will be leaving the ASN-CECity site and transferring the information directly to the ABIM in real-time.
● Provide your ABIM Certificate ID number and your date of birth.
● You will receive a confirmation message from the ABIM indicating the receipt of your information.
MOC points will be applied to only those ABIM candidates who have enrolled in the program. It is your responsibility to complete
the ABIM MOC enrollment process.

Instructions to access the ASN website, NephSAP, and the UpToDate link
Compatible Browser: The ASN website (asn-online.org) has been formatted for cross-browser functionality, and should
display correctly in all modern web browsers. We recommend that you use Internet Explorer.
Monitor Settings: The ASN website was designed to be viewed in a 1024 ⫻ 768 or higher resolution.
Technical Support: If you are having difficulty viewing any of the pages, please refer to the ASN technical support page
for possible solutions. If you continue having problems, contact Hal Nesbitt at hnesbitt@asn-online.org.
UpToDate provides an additional source of information that should help you answer up to 5 selected NephSAP
questions from each issue. The link is free and will remain active for the first 60 days after publication for each
issue.
● On the ASN home page, double click on the NephSAP link (NephSAP cover) on the bottom side of the page.
● On the NephSAP page, click on the UpToDate button on the left hand side to access the current links.
NephSAP
®
Volume 9, Number 4, July 2010

Disclosure Information
The ASN is responsible for identifying and resolving all conflicts of interest prior to presenting any educational activity to learners to ensure
that ASN CME activities promote quality and safety, are effective in improving medical practice, are based on valid contents, and are inde-
pendent of the control from commercial interests and free of commercial bias. All faculty are instructed to provide balanced, scientifically
rigorous and evidence-based presentations. In accordance with the disclosure policies of the Accreditation Council for Continuing Medical
Education (ACCME) as well as guidelines of the Food and Drug Administration (FDA), individuals who are in a position to control the con-
tent of an educational activity are required to disclose relationships with a commercial interest if (a) the relation is financial and occurred
within the past 12 months; and (b) the individual had the opportunity to affect the content of continuing medical education with regard to that
commercial interest. For this purpose, ASN consider the relationships of the person involved in the CME activity to include financial relation-
ships of a spouse or partner. Peer reviewers are asked to abstain from reviewing topics if they have a conflict of interest. Disclosure informa-
tion is made available to learners prior to the start of any ASN educational activity.
Agarwal, Rajiv—Research funding: Abbott; Consultant/scientific advisor: Rockwell Medical, Watson Pharma; Honoraria: Abbott, Astra-
Zeneca, Merck
Berns, Jeffrey S.—Consultant: Amgen; Research funding: NxStage; Advisory board: Affymax, NAAC
Cohen, David J.—Research funding: Life Cycle Pharma, Novartis, Roche, Wyeth; Honoraria: Bristol-Myers-Squibb, Novartis, Roche
Emmett, Michael—Honoraria: ABIM, Albert Einstein Medical Center, American Renal Associates, Best Doctors, Braintree Labs,
Brown University, Fresenius, Partners-Boston, Renal Ventures, Shire, Temple Medical, TIPS; Editorial board membership:
American Journal of Cardiology, Baylor Proceedings
Fishbane, Steven—Consultant: Abbott, Affymax, AMAG, Genzyme, Watson; Research funding: Affymax, Biogen Idec, Genentech,
Takeda; Honoraria: Abbott, Affymax, AMAG, Takeda, Watson; Expert testimony: Roche; Advisory board: Affymax, Genzyme,
Takeda, Watson
Fuchs, Elissa (Medical Editor)—none
Glassock, Richard J.—Consultant: Bio-Marin, Bristol Myers Squibb, FibroGen, Genentech, Gilead, Lighthouse Learning, Novartis,
Quest Diagnostics/Nichols Institute, Science Partners, QuestCor, Vifor (Aspreva) Pharmaceutical, Wyeth; Ownership interests:
LaJolla Pharmaceutical, Reata Inc.; Honoraria: Various medical schools—Columbia University, University of South Florida, USC,
Cedars Sinai Medical Center, Lupus Foundation of America; Membership board of directors/scientific advisor: Los Angeles
Biomedical Institute, University Kidney Research Associates, Vifor (Aspreva) Pharmaceutical, Wyeth; Editorial board: UpToDate;
Royalties: Lippincott, Williams and Wilkins, Oxford University Press
Goldfarb, Stanley—Consultant: Lupitold, Omeros; Ownership interests: Polymedix; Honoraria: GE Healthcare, Fresenius; Expert
testimony: Bayer; Editorial board: Journal of Clinical Investigation
Martin, Kevin J.—Research funding/honoraria: Abbott; Advisory board: Abbott, Cytochroma
Mehrotra, Rajnish—Research funding: Amgen, Baxter, Shire; Consultant: Novartis; Honoraria: AMAG, Baxter Healthcare, Shire
Murray, Patrick T.—Employment: spouse, Merck, Sharpe, & Dohme (Europe); Consultant/honoraria/research funding/
scientific advisor: Abbott Laboratories (USA), Argutus Medical (UK), FAST Diagnostics (USA); NxStage Medical (USA).
Nachman, Patrick H.—Honoraria: QuestCor; Multicenter clinical trial participation: Otsuka
Palevsky, Paul M.—Consultant: Nephrion; Advisory board/membership: Member, Board of Directors, Renal Physicians Association;
President ESRD Network 4
Sterns, Richard H.—Consultant: Astellas, Otsuka; Honoraria: Astellas, Otsuka; UpToDate; Scientific advisor: UpToDate
Textor, Stephen C.—Editorial board membership: Journal of the American Society of Nephrology, Clinical Journal of the American
Society of Nephrology
Townsend, Raymond T.—Consultant: Daiichi-Sankyo, GlaxoSmithKline, Merck, Nicox, Novartis, Roche; Research funding: Novartis;
Honoraria: American Society of Hypertension, National Kidney Foundation
Vella, John P.—none
Guest Co-Editors:
Swan, Suzanne K.—none
Olyaei, Ali—Consultant: Drug Safety and Research Institute; Research funding/honoraria: Astella, Novartis, Roche
Sica, Domenic A.—Consultant: Bayer, Novartis, Takeda; Research funding: CVRx, GlaxoSmithKline, Novartis, Takeda; Honoraria:
Boehringer Ingelheim, Daiichi Sankyo, Forest, Ligand, Merck, Novartis, Sanofi/Bristol-Myers Squibb, Takeda; Scientific advisor/
member editorial board: Section editor-Journal of Clinical Hypertension and Cardiology Reviews, Merit Review committee for
Veteran’s Administration, NIH study section, Sun Tech
Editorial:
Perazella, Mark A.—Membership: ABIM Nephrology Subspecialty Board

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Editorial
Pharmacology and Kidney Disease: Lessons Learned from the
Gadolinium–Nephrogenic Systemic Fibrosis Story
Mark A. Perazella, MD
Section of Nephrology, Department of Medicine, Yale University School of Medicine,
New Haven, Connecticut
Very infrequently does a new disease suddenly
appear in a group of patients who have been closely
observed for the past 30 to 40 years. Nonetheless, this
occurred in patients with chronic kidney disease
(CKD) and ESRD when nephrogenic systemic fibrosis
(NSF) caught the nephrology community by surprise
with its initial identification in 1997 and its subsequent
formal description as a unique entity in 2001 (1).
During the subsequent several years, the cause of NSF
eluded diagnosis, but it was clear that it occurred only
in patients with kidney disease. In 2006, a break-
through occurred as the causative agent: Gadolinium-
based contrast agents (GBCAs) were identified and
subsequently verified in numerous studies (2).
As with any newly recognized disease or com-
plication in medicine, an adverse drug effect must be
suspected, and, in general, it is reasonable to assume
that “it is a drug until proven otherwise.” In this case,
a drug in the guise of a magnetic resonance contrast–
enhancing imaging agent was the culprit. As we look
back and ponder this new disease called NSF, the
question that lingers for all of us is whether toxicity
was a predictable complication of the GBCAs. When
faced with such a question, we must return to basics
and examine whether the drug chemistry and/or its
pharmacokinetics in patients with kidney disease sug-
gest potential for toxicity.
Gadolinium Chemistry
A quick look at the chemistry of gadolinium and
the lanthanides is a worthwhile starting point. Gado-
linium has paramagnetic properties that disturb relax-
ation of water protons and by shortening relaxation
times increases signal intensity, making it an excellent
contrast agent. Like all lanthanides, it exists in the ⫹3
213
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
oxidation state in aqueous solutions and has an ionic
radius nearly equal to divalent calcium (Ca2⫹). Be-
cause of this characteristic, free ionic gadolinium
(Gd3⫹) competes with Ca2⫹ in biologic systems (3).
Because Gd3⫹ has a higher binding affinity than Ca2⫹,
it readily reduces neuromuscular transmission by ob-
structing Ca2⫹ channels in muscle and nerve tissue
cells and alters enzyme kinetics (3). In addition, the
lanthanides enhance the polymerization rate of colla-
gen and mediate fibrillogenesis by direct binding to
the collagen helix (4). These effects suggest potential
for toxicity.
For safe use of the contrast-enhancing benefits of
Gd3⫹ with magnetic resonance imaging (MRI), the
metal must be sequestered by an organic ligand (3).
Chelation of Gd3⫹ to a nontoxic ligand allows forma-
tion of a stable complex and renders the metal bio-
chemically inert (3). A few important points about
Gd3⫹–ligand complex stability are reviewed to permit
an understanding of GBCA differences in causing
NSF. In general, there are two major categories of
ligand, linear and macrocyclic, which are based on
biochemical structure. Charge (ionic versus nonionic)
allows further subclassification of the GBCAs.
The “tightness” with which a ligand binds Gd3⫹, or
“complex stability,” is determined primarily by the
amine characteristics of the ligand. Linear ligands have
amines with amide-containing side chains, whereas mac-
rocyclic ligands have acetate side chains, which are more
basic and form more stable and presumably safer com-
plexes (3). For measurement of complex stability, a
number of yardsticks are used, including the ther-
modynamic stability constant, conditional stability
constant, and dissociation kinetics. In a test tube,
the thermodynamic and conditional stability con-
214 Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

stants are reflective of ligand affinity to Gd3⫹;
however, in biologic media such as human blood, in
contrast to the in vitro system, additional competi-
tors for ligand binding are present (3). These in-
clude zinc, copper, and iron, which are capable of
forming very stable complexes with the organic
ligand. Also, Gd3⫹ has high affinity for endogenous
anions such as phosphate, carbonate, and citrate,
which compete with the ligand.
In this situation, the rate of complex dissociation
or kinetic stability is more reflective of actual stability
of the GBCA in the bloodstream. The more kinetically
inert the complex, the less likely it will dissociate and
participate in “transmetallation.” Transmetallation
(Figure 1) entails Gd3⫹ dissociation from its ligand,
whereby the ligand binds an endogenous metal such as
zinc, copper, or iron and Gd3⫹ binds an endogenous
substance such as phosphate, citrate, or carbonate (5).
This process is more likely to occur the longer the
GBCA resides in the bloodstream, which as is dis-
cussed later is very relevant to patients with underly-
ing kidney disease. Thus, the safest GBCA is one that
dissociates the slowest— essentially one that is kinet-
ically inert.
On the basis of this information, we can make
predictions about the various GBCAs as it relates to
complex kinetic stability and risk for transmetallation.
Despite data that reflect reasonably good thermody-
namic and conditional stability constants with linear
GBCAs, they are not as kinetically stable as macro-
cyclic agents and will dissociate more readily in a
biological system. In fact, animal studies and obser-
vations in humans who were exposed to GBCA sup-
port these data.
Rats that were exposed to GBCAs had tissue
3⫹
Gd concentrations that were highest with linear-
based agents and were approximately 30-fold lower
with two macrocyclic agents (6). Long-term retention
of linear GBCAs was noted within skin, whereas three
different macrocyclic GBCAs had unmeasurable con-
centrations (7). Partially nephrectomized rats that were
exposed to various linear-based GBCAs developed
significant Gd3⫹ concentrations in various tissues as
compared with saline and chelate-only controls (8).
Finally, 5/6-nephrectomized rats had skin concentra-
tions at day 168 that were highest with linear GBCAs,
which were approximately 500 times higher than mac-
rocyclic GBCAs (9).
In humans, Gd3⫹ is noted within tissues after
GBCA exposure. Bone concentrations were higher
with linear- versus macrocyclic-based agents. For ex-
ample, after 0.1-mmol/kg dosing with GBCA in
healthy individuals, Gd3⫹ bone concentrations were
nearly four times higher with a linear agent as com-
pared with macrocyclic agents (10). Furthermore, pa-
tients with NSF had Gd3⫹ tissue concentrations that
are 35 to 150 times higher than those in normal control
subjects who were exposed to linear agent gadodia-
mide (11,12).
Gadolinium-Based Contrast Pharmacology
The toxicity of most drugs relates primarily to
two factors: (1) innate drug toxicity and (2) overall
host exposure. We know that Gd3⫹ has toxic potential.
The exposure issue is addressed by examining the
pharmacokinetics of these agents. Area under the
curve as a measure of exposure is primarily driven by
dosage, distribution half-life (T ⁄ ), and elimination
12

Gd3+
Fe3+
Gd3+ Gd3+
Ca2+
C Gd3+
2+ 3+
Zn Gd
Gd3+ Fe3+
F
Cu2+ 3+
Gd (CH3)NHCO CONH(CH3)
(CH3)NHCO CONH(CH3) N N N
N N N HOOC COOH
HOOC COOH Ca2+
C

(CH3)NHCO CONH(CH3)
N N N
HOOC COOH
Figure 1. Transmetallation of injected GBCA. A linear GBCA binds Gd3⫹ less tightly than other ligands (macrocyclic),
allowing endogenous cations such as copper (Cu2⫹), iron (Fe3⫹), zinc (Zn2⫹), and Ca2⫹ to compete with Gd3⫹ for ligand
binding. This allows free Gd3⫹ to be released into the bloodstream, where it may bind other anions such as phosphate.
Abbreviations: GBCA, gadolinium-based contrast agent. Reprinted from reference 5, with permission.
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
T ⁄ . Injected GBCAs are rapidly distributed into the
12
extracellular space and quickly equilibrate between the
plasma and interstitial compartments (Figure 2), con-
sistent with a two-compartment model (13). They do
not undergo biotransformation, are not protein bound,
and have a small volume of distribution (Vd; approx-
imately 0.26 L/kg). Although the bulk of available
GBCAs are extracellular fluid (ECF) agents, some are
ECF agents that also enter liver cells, whereas others
are albumin bound and limited to the plasma compart-
ment (Vd approximately 0.15 L/kg) (14).
The ECF GBCAs are eliminated unchanged by
the kidneys via glomerular filtration without any tu-
bular secretion (Figure 2). Renal clearance approxi-
mates creatinine clearance in normal individuals. They
possess a terminal T ⁄ of approximately 1.3 to 1.6
12
hours, and ⬎95% of an injected dose is eliminated
within 24 hours (13). Hence, kidney function is im-
portant in determining overall terminal T ⁄ and drug
12
exposure. Certain GBCAs have a component of he-
patic clearance; 2 to 4% for gadobenate and 50% for
gadoxetate (14). These agents are associated with a
terminal T ⁄ in normal individuals of 1.5 to 2.0 hours
12
and 1.0 hour, respectively. In contrast, terminal T ⁄ for12
the plasma-limited agent gadofosveset is 18.5 hours as
GBCA
GBCA GBCA
Intravascular Interstitial
space space
Extra-cellular space
GBCA
GBCA
Figure 2. Pharmacokinetics of injected GBCA. GBCA is
distributed within the extracellular space (two-compartment
model) and is excreted primarily by the kidneys for all
agents. A few agents are excreted in variable amounts by the
liver.
215
a result of albumin binding and absence of hepatic
clearance (14).
The Vd for ECF GBCAs is unchanged in patients
with kidney disease; however, renal clearances are
much lower in stages 3 and 4 CKD than in normal
individuals. As a result, the terminal T ⁄ is prolonged
12
in patients with stage 3 (4 to 8 hours) and stage 4 (18
to 34 hours) CKD (13,14), increasing total agent
excretion time from 24 hours to ⱖ1 week. Agents with
a component of liver clearance have a terminal T ⁄ of
12
6.1 and 9.5 hours with stages 3 and 4 CKD, respec-
tively (14). Gadoxetate has a terminal T ⁄ of 12 hours
12
in patients with ESRD. It is also not well appreciated
that CKD is associated with reduced hepatic drug
metabolism, potentially limiting hepatic clearance of
GBCAs that also use this excretion pathway. For
gadofosveset, stages 3 and 4 CKD, respectively, are
associated with two- and threefold increases in termi-
nal T ⁄ above that seen in normal individuals (14).
12
Pharmacokinetic data of GBCAs predict that
they can be removed relatively efficiently by hemodi-
alysis. On average, the T ⁄ of GBCAs in nondialysis
12
patients with ESRD is 34.3 hours but decreases sig-
nificantly to 2.6 hours with hemodialysis (13). GBCA
serum elimination using hemodialysis is approxi-
mately 74% with one treatment, 92% with two treat-
ments, and 99% after three treatments (13). In con-
trast, low-dosage peritoneal dialysis (8 to 10 L/d) is
ineffective in GBCA removal, with T ⁄ of approxi-
12
mately 53 hours (13). In general, 6 to 8 hours of
hemodialysis using high-flux membranes would pre-
dictably remove a significant amount of GBCA.
GBCA Imaging in Kidney Disease
On the basis of the chemistry and pharmacology
of the available GBCAs, perhaps we should have been
more vigilant about the potential for adverse effects in
patients with kidney disease; however, we were reas-
sured by data from GBCA-exposed normal individuals
that supported safety. Food and Drug Administration
approval for the five US GBCAs between 1988 and
2004 was based on an excellent safety profile from
combined premarketing studies on ⬎3000 patients.
The most common adverse effect was a mild allergic
reaction that resulted in rash, sweating, itching, hives,
and facial swelling. Only rarely was the reaction
severe with potential for fatality. No other notable
acute or chronic adverse effects were recognized. In
fact, millions of GBCA doses have been used safely in
216
patients with normal kidney function—again very re-
assuring.
Studies were also undertaken of patients with
various levels of CKD. Unfortunately, few patients
who either had advanced CKD or dialysis were in-
cluded. Most studies were small and had short-term
follow-up. The only adverse effect, which was not
universally noted in all studies, seemed to be modest
risk for nephrotoxicity, especially with higher GBCA
dosages in high-risk patients (15). The perceived
safety of these agents led to increased use of GBCA
MRI in the early to mid-1990s. In particular, renal and
peripheral vessels, the central nervous system, and the
liver were widely imaged in patients with acute kidney
injury (AKI), CKD, and dialysis-dependent ESRD.
Furthermore, contrast volumes two to three times the
approved dosage (0.1 mmol/kg) were commonly used
for angiography. The initial recognition of NSF as a
new and unusual fibrosing disorder in patients with
CKD in 1997 possesses an eerie temporal association
with the sudden spike in GBCA exposure in this
group. That Gd3⫹ has collagen fibrillogenesis proper-
ties (4) makes this observation more relevant.
NSF and Kidney Disease: Who Is Most at Risk?
Because NSF is a devastating and essentially
untreatable disease, it is our responsibility as physi-
cians to reduce its occurrence. We must also remem-
ber that our very strong emotional reaction to avoid all
GBCA exposure in patients with kidney disease has
potential untoward consequences. Our patients often
have disorders that require accurate imaging to allow
rapid diagnosis and intervention. Missing lesions such
as liver cancer or serious brain pathology with subop-
timal imaging choices will likely lead to adverse
outcomes. Also, exposing such patients to iodinated
radiocontrast studies in lieu of GBCA has several
possible complications. These include an increased
number of potentially life-threatening allergic reac-
tions, significant radiation exposure, and nephrotoxic-
ity. The last complication is of particular concern
because there are data to support that AKI after radio-
contrast may be associated with increased morbidity
and mortality, whereas loss of residual renal function
in dialysis patients has untoward consequences. Thus,
it is incumbent on the nephrology community to iden-
tify patients who are at highest risk and address their
imaging needs in a rational, evidence-based manner.
In addition to certain formulations of GBCA (linear),
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
the literature suggests that a threshold level of kidney
function must be crossed for NSF to develop after
GBCA exposure. Dialysis-dependent ESRD, stage 5
CKD, and AKI maintain the highest risk for NSF.
Nearly 80% are dialysis-dependent patients with
ESRD. When one considers the much larger number
of patients with stage 4 CKD relative to those with
stage 5 and ESRD, risk in this group is minimal
because only a very small number of patients with
stage 4 CKD have developed NSF. Notably, no cases
in stages 1 through 3 CKD have been confirmed in the
published literature. In fact, several studies of patients
who had stages 1 through 4 CKD and were exposed to
GBCAs did not note NSF as a complication (16 –18).
In the Halt Progression of Polycystic Kidney Disease
(HALT-PKD) study and Consortium of Radiologic
Imaging Study of PKD (CRISP), patients with auto-
somal polycystic kidney disease and stages 1 through
3 CKD in underwent 1111 GBCA exposures with no
occurrence of NSF (17). A total of 592 patients who
had stages 3 through 4 CKD and were exposed to
GBCA also did not develop NSF (16). Eighty-eight
patients who had stages 1 through 4 CKD and under-
went 94 GBCA exposures, including 38 patients with
stage 4 CKD, did not develop NSF (18). Finally, none
of 2053 patients (stage 3, 44.7%; stage 4, 23.9%; stage
5, 5.7%) who were exposed to 2278 GBCA MRIs
(various formulations) developed NSF during an av-
erage follow-up period of nearly 29 months (19). It
thus seems that advanced kidney disease with very low
GFR levels portends the highest risk, whereas stage 4
CKD seems to be very low risk and stages 1 through
3 have negligible risk.
One is left to wonder why NSF occurs so infre-
quently compared with other complications that affect
patients with kidney disease. The explanation almost
certainly lies with the fact that other patient-related
factors must coexist for NSF to develop, the proverbial
“perfect storm.” Advanced kidney disease and GBCA
exposure are necessary but not sufficient in and of
themselves. A number of putative co-factors have
been previously reviewed (Table 1) and include vari-
ous systemic and metabolic disorders and certain ther-
apies (20). Linear-based GBCAs themselves induce
inflammation, perhaps contributing further to patient
risk (20). Inflammatory states may facilitate profi-
brotic cytokine and chemokine synthesis, which would
attract profibrotic cells to tissues that contain Gd3⫹
and increase collagen formation.
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010 217

Table 1. Putative co-factors for NSF result of increased Gd3⫹ tissue exposure in patients
Proinflammatory states with CKD.
infection
connective tissue diseases
major surgery How Should We Image High-Risk Patients with
Hypercoagulable states CKD?
Vascular injury Because patients with CKD have numerous
Liver failure comorbidities that necessitate imaging tests, we
hepatorenal syndrome must make rational choices that are guided by pub-
liver transplantation lished data. The natural tendency is to avoid GBCA
Metabolic abnormalities
use in all patients with any form of kidney disease,
hyperphosphatemia
hypercalcemia but this approach has consequences, as described
metabolic acidosis previously. On the basis of what we currently know,
iron overload the following statements on patient risk for NSF can
Therapeutic agents be made:
high-dosage ESA
intravenous iron Y Patients with stages 1 through 3 CKD do not seem to
ESA, erythropoiesis-stimulating agent. maintain risk for NSF after GBCA exposure.
Y Patients with stage 4 CKD maintain modest risk, per-
haps increased when other factors (e.g., inflammation,
The vast majority of clinical observations pub-
metabolic abnormalities) are present.
lished on NSF after GBCA exposure support a rela- Y Patients with stage 5 CKD and AKI are at high risk,
tionship to dosage, whether single high-dosage or with dialysis-dependent patients with ESRD at highest
higher cumulative dosage. Furthermore, at one center, risk.
a protocol change that switched use from gadodiamide
to gadobenate, an agent that allows excellent imaging In my view, imaging options for patients who
with use of lower dosages (0.2 versus 0.1 mmol/kg), are defined as being at high risk for NSF should be
was associated with a reduction in NSF incidence from approached logically. First, use a non-GBCA–
2.6 to 0.0% (21). These data support high-dosage requiring technology that is safe and suitably di-
administration as a risk factor for NSF, likely as a agnostic (Table 2). When imaging with a GBCA

Table 2. Non– gadolinium-based contrast agent–requiring imaging technologies

Ultrasonography
grayscale ultrasonography provides information about organ size and echogenicity
color, power, and spectral Doppler ultrasonography may be useful for renal artery stenosis and other vascular disease;
this modality is highly operator dependent with only a few centers with expertise
contrast with microbubbles views liver lesions very well but is not FDA approved or available in the United States and
has a black box warning for patients with “cardiovascular instability”
CT scan
non–radiocontrast-enhanced is an option for some forms of imaging
radiocontrast-enhanced CT scan is an option for many (but not all) imaging needs
risk of radiation exposure, contrast allergy, and nephrotoxicity (AKI and loss of residual renal function)
MRA
contrast enhancement with ultrasmall superparamagnetic iron oxide (ferumoxytol) offers excellent imaging of various
organs such as brain and vasculature (aorta, carotid, peripheral arteries)
non-enhanced MRA techniques can image renal vessels and other vasculature very well without contrast
time of flight
arterial spin labeling
perfusion contrast angiography
steady-state free precession
nonenhanced MRI technique (diffusion-weighted) can image liver pathology very well
CT, computed tomography; FDA, Food and Drug Administration; MRA, magnetic resonance angiography.
218
is required, the following approach should be
considered:
Y Use only macrocyclic GBCAs; agents with hepatic
clearance should be studied further to document safety.
Y Use the lowest dosage of GBCA required to provide
quality images.
Y Avoid intravenous iron and high-dosage erythropoie-
sis-stimulating agents before and after the anticipated
exposure.
Y Optimize calcium, phosphate, and acid-base balance
before the anticipated exposure.
Y Consider arranging hemodialysis to follow GBCA ex-
posure for patients who are currently on this modality.
The recommendation of hemodialysis after GBCA
exposure is based primarily on pharmacokinetic data and
the hypothetical benefit of removing this agent from the
bloodstream, thereby decreasing tissue exposure. Retro-
spective studies reveal conflicting results showing no
preventive benefit of hemodialysis (22) or a possible
reduction in NSF occurrence (23) when performed on the
day of exposure. This may relate to differences in the
actual timing of dialysis after exposure (sooner versus
later). In reality, this issue has not been rigorously stud-
ied, and, in my opinion, the ability to perform hemodi-
alysis after exposure in and of itself does not justify
GBCA administration to a high-risk patient. Rather, this
modality should be considered for use, ideally within 2 to
3 hours of exposure and on consecutive days, in patients
who are already undergoing short- or long-term mainte-
nance hemodialysis.
Conclusions
The imaging needs of patients with kidney
disease are significant, but as we have learned with
iodinated radiocontrast, toxicity is an important ad-
verse effect of GBCAs. Although nephrotoxicity is
minor with these agents, systemic toxicity can be
substantial, as seen with the devastating illness
NSF. Focusing on GBCA agents as “drugs” reveals
that, on the basis of the combination of the known
toxicity of free Gd3⫹ (Ca2⫹ channel blockade, en-
hanced fibrillogenesis), the behavior of these agents
in biologic systems (various chelate stability prop-
erties), and their altered pharmacokinetics in pa-
tients with reduced GFR (increased T ⁄ ), one can
1 2
predict that some of these agents are potentially
hazardous. NSF has taught us that we must bear in
mind all of these issues when we use any drug or
imaging agent in patients with kidney disease, be-
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
cause what is safe in patients with normal kidney
function may not be in this group.
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genic systemic fibrosis: The perfect storm. Curr Opin Nephrol
Hypertens 18: 519 –525, 2009
21. Martin DR, Krishnamoorthy SK, Kalb B, Salman KN, Sharma P,
Carew JD, Martin PA, Chapman AB, Ray GL, Larsen CP, Pearson
TC: Decreased incidence of NSF in patients on dialysis after chang-
219
ing gadolinium contrast-enhanced MRI protocols. J Magn Reson
Imaging 31: 440 – 446, 2010
22. Broome DR, Girguis MS, Baron PW, Cotrell AC, Kjellin I, Kirk GA:
Gadodiamide-associated nephrogenic systemic fibrosis: Why radiol-
ogists should be concerned. AJR Am J Roentgenol 188: 586 –592,
2007
23. Prince MR, Zhang H, Morris M, MacGregor JL, Grossman ME,
Silberweig J, DeLapaz RL, Lee HJ, Magro CM, Valeri AM: Inci-
dence of nephrogenic systemic fibrosis at two large medical centers.
Radiology 248: 807– 816, 2008
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Syllabus
Clinical Pharmacology for the Nephrologist
Suzanne K. Swan, MD,* Ali Olyaei, PharmD,† and Domenic A. Sica, MD‡
*Division of Nephrology, Hennepin County Medical Center and University of Minnesota,
Minneapolis, Minnesota; †Division of Nephrology and Hypertension, Oregon State University,
College of Pharmacy/Oregon Health & Sciences University, Portland, Oregon; and ‡Division
of Nephrology, Virginia Commonwealth University, Richmond, Virginia
Learning Objectives:
1. To understand basic pharmacokinetic principles
that must be considered when prescribing medica-
tions for patients with decreased kidney function
2. To understand the effect that dialysis techniques
have on drug elimination
3. To understand various drug dosing strategies that
may be used for patients who undergo dialysis
therapy
4. To understand common drug-induced adverse
events that are encountered in patients with chronic
kidney disease and renal transplant recipients
5. To recognize and understand various drug– drug
interactions that may be encountered in renal
transplant recipients
The metabolism and elimination of a majority of
pharmacologic agents depend on normal renal func-
tion. In addition, many compounds have pharmacolog-
ically active metabolites that undergo renal excretion.
Somewhat surprising, Zhang et al. (1) recently re-
ported a study in which a large percentage of newly
approved drugs that do not undergo renal elimination
from the body nonetheless warranted dosage reduction
in patients with renal impairment. As such, dosage
adjustments may be required in patients with renal
insufficiency, both acute and chronic, across a wide
spectrum of disease states and drug categories. Famil-
iarity with basic pharmacologic principles is necessary
when approaching dosimetry in renal impairment set-
tings, because patients with kidney disease exist
within a narrow therapeutic window in which drug
accumulation (overdose) as well as subtherapeutic
dosing must be avoided. Complicating dosing regi-
mens further is that the urinary tract is the major “exit
220
route” from the body for myriad pharmacologic agents
and toxins, making the kidney especially vulnerable to
injury from such agents, as shown in Figure 1 (2).
Thus, understanding mechanisms of nephrotoxicity,
whether kidney specific, patient specific, or drug/toxin
specific, as well as interventions that either minimize
or exacerbate such nephrotoxic injury is critical for the
prescribing nephrologist. This section reviews basic
pharmacokinetic principles that are altered by renal
impairment, and a step-wise approach to dosage ad-
justment is presented. Specific drug-dosing recom-
mendations for a given pharmaceutical agent are not
presented here but can be found in tabular form in a
variety of reference sources listed in Table 1 as well as
package inserts. The most current and comprehensive
review of pharmacologic principles can be found in
the November 2009 issue of Clinical Pharmacology &
Therapeutics.
In general, dosage reduction is indicated in
patients with CKD when >30% of a drug or
an active metabolite appears unchanged
in the urine.
Altered Pharmacokinetic Principles
In general, dosage reduction is indicated in pa-
tients with chronic kidney disease (CKD) when ⱖ30%
of a drug or an active metabolite appears unchanged in
the urine. Metabolites of drugs are particularly prob-
lematic because information is rarely available regard-
ing their presence and whether they are pharmacolog-
ically active. Unanticipated responses to drugs should
raise suspicions that metabolites may be accumulating
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Figure 1. Kidney-specific factors that enhance nephrotoxic
risk. First, high renal blood flow (RBF) increases drug
delivery to the kidney. High metabolic rates of cells increase
risk for nephrotoxicity with certain drugs. Renal biotrans-
formation of drugs to toxic metabolites and reactive oxygen
species (ROS) overwhelms local antioxidants. Increased
concentration of drugs in the medulla and interstitium
causes nephrotoxicity. Finally, apical uptake of certain
drugs (aminoglycosides, sucrose) and basolateral transport
of drugs through the organic anion transporter (OAT; teno-
fovir) and organic cation transporter (OCT; cisplatin) trans-
porters increases renal toxicity. Reprinted from reference 2,
with permission.
or toxic, particularly with newly approved compounds,
for which little clinical experience exists.
Bioavailability and drug absorption, volume of
distribution, protein binding, metabolism or biotrans-
formation, and renal excretion are key pharmacoki-
netic parameters that are altered by decreased kidney
function. Bioavailability refers to the fraction (%) of
a given dose that reaches the systemic circulation and
is primarily determined by the rate and route of ad-
ministration of the drug. In general, bioavailability is
considered to be 100% after intravenous administration,
because all of the dose reaches the systemic circulation.
Table 1. Reference sources for dosing adjustments in patients with CKD
Drug Prescribing in Renal Failure: Dosing Guidelines for
Adults, 5th Ed.
MICROMEDEX Healthcare Series
Up to Date, Inc.
Lexi-Comp, Inc.
EPOCRATES
National Kidney Disease Education Program
FDA MedWatch
The Medical Letter on Drugs and Therapeutics
221
Oral, intramuscular, inhaled, or subcutaneous routes, in
contrast, often result in smaller percentages of a given
dose reaching target tissues. Furosemide, for example,
demonstrates 100% bioavailability when given intrave-
nously but is only on average 50% bioavailable (range
10 to 90%) when given orally. This explains the
common practice of doubling the dose of furosemide
when converting a patient from intravenous to oral
dosing regimens. Drug absorption dictates bioavail-
ability and may be altered in patients with renal
disease. For example, absorption may be reduced by
gastroparesis-induced nausea and vomiting secondary
to diabetic neuropathy or aging. Concomitant admin-
istration of medications such as phosphate-binding
agents (all classes) can form insoluble complexes with
various drugs such as quinolone antibiotics, reducing
their absorption and slowing gut motility (3). Gastric
acid–lowering agents such as proton pump inhibitors
and histamine2 blockers as well as phosphate-binding
agents can increase stomach pH, which may impair
drug absorption as well (e.g., atazanavir, antidepres-
sants, oral iron).
The volume of distribution (Vd) of a drug does
not refer to a specific anatomic “compartment” but
rather all of the compartments in which a given com-
pound may be found: Plasma, water, fat, red blood
cells, intracellular versus extracellular binding sites,
and tissue binding. In general, plasma concentrations of
a drug tend to correlate inversely with its Vd. Hydrophilic
drugs, for example, will demonstrate a lower Vd in
volume-contracted states with a corresponding rise in
plasma concentrations, whereas edema and ascites tend
to increase Vd values and lower measured drug levels.
Clinically, Vd can be used to calculate the dosage re-
quired to achieve a desired drug level systemically by
multiplying the desired concentration (mg/L) by the Vd
(L/kg). For example, a dose of 2.5 mg/kg of the
aminoglycoside tobramycin would be administered to
http://www.acponline.org (PDA version available)
http://www.utdol.com/online/index.do
http://www.lexi.com/individuals/physicians
http://www.epocrates.com
http://www.nkdep.nih.gov
http://www.fda.gov/medwatch
222
achieve a peak concentration of 10 mg/L given the Vd
of 0.25 L/kg of tobramycin. The Vd for many drugs
can be found in tabular form in pharmaceutical refer-
ences or package inserts but generally reflects values
that are obtained from healthy individuals, not patients
with CKD, who often display significant alterations in
Vd, as in the case of digoxin. Uremic waste products
are thought to displace digoxin from cellular binding
sites, thereby reducing the Vd of digoxin and increas-
ing plasma concentrations.
Protein binding can affect the Vd of a drug and
the methods by which the concentrations of the drug
are measured. Compounds circulate in both protein-
bound and unbound forms, although it is only the
unbound, or “free,” fraction that is biologically active.
Most drug assays, however, represent the “total”
amount of drug present (both bound and unbound).
Renal impairment tends to decrease protein binding of
drugs because accumulated organic waste products
displace these compounds from their binding proteins.
This, in turn, results in a larger proportion of the drug
circulating in its unbound (free) or active form but also
makes more drug available for hepatic metabolism/
elimination. As such, following free levels rather than
total concentrations of a given drug may be prudent,
because the latter may be unpredictable given the
reduced bound fraction (see the Older Anticonvulsant
Drugs section).
Biotransformation or metabolism of a drug
refers to its biochemical conversion from one chemical
form to another, usually mediated by hepatic enzy-
matic pathways such as oxidation, reduction, acetyla-
tion, glucuronidation, or hydrolysis. Pharmacologi-
cally active metabolites of inactive prodrugs or
metabolites with toxic effects that depend on renal
excretion to be eliminated from the body may be
formed. For example, many angiotensin-converting
enzyme inhibitors are inactive prodrugs that are con-
verted by the liver to active metabolites (e.g., lisinopril
3 lisinoprilat), which undergo renal elimination.
Thus, the half-life of lisinoprilat is markedly pro-
longed in acute renal failure settings and may delay
“recovery” of glomerular filtration given its site of
action. The narcotic meperidine undergoes hepatic
metabolism to normeperidine, which has no narcotic
activity but lowers the seizure threshold and relies on
the kidney for elimination from the body. As such,
meperidine should not be used in patients with CKD
given its ability to induce seizure activity (4).
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
There is mounting evidence that renal im-
pairment also affects hepatic drug metabo-
lism and disposition with a greater impact
on nonrenal clearance and bioavailability
than was previously recognized.
There is mounting evidence that renal impair-
ment also affects hepatic drug metabolism and dispo-
sition with a greater impact on nonrenal clearance and
bioavailability than was previously recognized. Ani-
mal data have shown a significant downregulation of
hepatic cytochrome P450 metabolism in CKD, and
additional evidence suggested the presence of a circu-
lating inhibitor of hepatic metabolic pathways that
could conceivably be removed by dialysis (5). How
this will ultimately affect drug dosing in patients with
CKD remains to be seen, but more compounds that do
not undergo renal elimination from the body will
likely warrant dosage adjustment when renal impair-
ment is present, as recently reported (1).
Stepwise Approach to Dosimetry
The following stepwise approach provides a
framework for dosage adjustment in patients with
renal impairment (Figure 2). It must be emphasized
that this approach simply represents a starting point
from which dosimetry must be closely monitored and
modified on a patient-by-patient basis.
Step 1: History and Physical Examination
A history and physical examination represent the
first step in determining the need for dosage adjust-
ments in any patient. Renal impairment should be
defined as acute or chronic and the cause ascertained
when possible to determine reversibility. A history of
drug intolerance, allergy, or nephrotoxicity is key. The
medication list, both prescribed and nonprescribed,
should be reviewed for both potential nephrotoxins
and drug– drug interactions. The dosage of many drugs
depends on a patient’s weight or size but may present
a clinical quandary regarding which weight to use:
Ideal body weight (IBW) versus actual body weight or
an intermediate value. IBW can be calculated using
the patient’s height. For women, IBW is 45.5 kg plus
2.3 kg for every 2.5 cm over 152.0 cm. For men, IBW
is 50.0 kg plus 2.3 kg for every 2.5 cm over 152.0 cm
(6). Body mass index (weight in kg/height in m2) has
been used increasingly as a measure of obesity but is
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
7
8 CG-derived Ccr ⫽ [(140 ⫺ age) ⫻ (wt in kg)]/
Figure 2. Stepwise approach to dosimetry.
generally not used to calculate drug dosage. Of note,
drug dosages are generally established in people of
moderate size (i.e., BMI 18 to 30), not morbidly obese
individuals, so Food and Drug Administration–ap-
proved drug dosages may be grossly inadequate in this
population. Alternatively, some medications, particu-
larly chemotherapy agents, are based on body surface
area, which can be calculated by various equations,
including the Dubois method (http://www.halls.md/
body-surface-area/refs.htm), which is discussed else-
where in this issue of NephSAP. Volume status is
important to assess, because extreme conditions can
significantly alter both the Vd and drug concentrations.
For example, severe “third-spacing” with 10 or 20 L of
ascites can increase the Vd of a drug and thereby lower
serum concentrations, whereas extensive burns can
have the opposite effect (i.e., marked decrease in Vd
with subsequent elevation in drug levels).
Step 2: Assess Renal Function
Drug elimination by the kidney correlates with
GFR; therefore, it is logical to use GFR to gauge
adjustments in drug dosage. Because serum creatinine
223
(Scr) and blood urea nitrogen values are crude markers
of kidney function at best, attempts to define better
measures of GFR have long been pursued. Histori-
cally, it is important to remember that dosage recom-
mendations for many drugs were generated at a time
when only the Cockcroft-Gault (CG) equation (7) was
being used to estimate creatinine clearance (Ccr).
[72 ⫻ Scr] ⫻ 0.85 (if female)
More recently, the Modification of Diet in Renal
Disease (MDRD) study equation (further modified as
the isotope dilution mass spectroscopy–traceable four-
variable equation) (8) has been derived in an effort to
estimate GFR more accurately because Ccr represents
an overestimation:
MDRD-GFR ⫽ 175 ⫻ Scr⫺1.154⫻ age⫺0.203⫻
1.2 (if black) ⫻ 0.74 (if female)
MDRD-derived GFR values, however, have not
been applied to pharmacokinetic studies from which
dosing recommendations often arise. Numerous pub-
lications debating whether the CG or MDRD equation
should be used to estimate kidney function for the
purpose of dosage adjustment have appeared, yet no
conclusions have been reached (9 –11). In fact, the
Food and Drug Administration has not finalized its
most recent draft guidance on the conduct of pharma-
cokinetic trials of patients with renal impairment given
the lack of consensus in the literature. A review of this
literature is beyond the scope of this issue of Neph-
SAP, but, in general, the MDRD equation underesti-
mates GFR, particularly at advanced stages of renal
impairment (i.e., ⬍30 ml/min) and in normal individ-
uals, whereas the CG equation overestimates it. All of
this is further complicated by newer assays to measure
creatinine (isotope dilution mass spectroscopy–trace-
able method versus older methods), which in turn
affect any mathematical formula in which the values
are used. Moving forward, MDRD-derived GFR val-
ues should be tested against CG-derived values in
pharmacokinetic Phase I studies involving new com-
pounds to provide greater clarification. Of note, in
patients with acute renal failure (particularly oliguric
or anuric), the prescribing physician should assume a
GFR of ⬍10 ml/min for the purposes of drug dosage
adjustment. Alternatives to measure kidney function
involving “plasma disappearance” techniques such as
iohexol- or iothalamate-derived methods exist but may
not be clinically feasible for many prescribers (12).
224
Step 3: Determine Loading Dose
A loading dose of a drug is given to achieve
steady-state conditions more rapidly, because it gen-
erally requires three to four half-lives of a given drug
to achieve steady-state concentrations. Attaining steady-
state levels could be significantly prolonged in renal
impairment as a result of prolongation of the half-life
of a drug. In general, the standard loading dose that is
given to patients with normal renal function should be
given to patients with renal impairment to reach ther-
apeutic drug levels rapidly. A loading dose can be
calculated (discussed already with tobramycin exam-
ple) by the following formula (Cp is the desired
plasma concentration):
Loading dose ⫽ Vd (L/kg) ⫻ Cp (mg/L) ⫻ IBW (kg)
Digoxin dosing represents one exception to this
rule. The Vd for digoxin is reduced by 50 to 75% in
severe kidney impairment that is great enough in mag-
nitude to warrant a corresponding reduction in loading
dose. Thus, given the direct proportionality between
loading dose and Vd, one could easily calculate a
“modified” loading dose by the following:
Modified loading dose ⫽ [patient’s Vd/normal
Vd] ⫻ standard loading dose
One area of controversy involves whether to use
actual body weight versus IBW or something midway
between these two values when calculating loading
doses. Vancomycin dosing, for example, is one that
should be based on actual body weight, not IBW, as
recently reviewed (13,14).
Step 4: Determine Maintenance Dose
The maintenance dose is the dosing regimen that
maintains steady-state concentrations and can be
achieved by one of three methods: Varying dose
method, varying interval method, or a combination of
the two. In the varying dose approach, a drug is
administered at the same interval used in patients with
normal renal function, but the actual dose is reduced in
proportion to the patient’s degree of renal impairment
as follows (assume normal Ccr of 100 ml/min):
Modified maintenance dose ⫽ [patient’s Ccr/
normal Ccr] ⫻ standard maintenance dose
Conversely, the dosing interval can be length-
ened (modified dosing interval) while keeping the
actual dose the same as the standard dose:
Modified dosing interval ⫽ [normal Ccr/pa-
tient’s Ccr] ⫻ standard dosing interval
Or one can combine these two approaches and
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
give a modified dose at a modified interval. Thus, one
of the following dosing regimens would be possible
for a patient with a 50% reduction in kidney function
when administering a drug with a standard dose of 300
mg every 6 hours daily:
Y 150 mg every 6 hours (varying dose)
Y 300 mg every 12 hours (varying interval)
Y 200 mg every 8 hours (combination)
Which method is used depends on the underlying
disease state being treated and the therapeutic window
of the drug. For example, the varying dose method
might be preferable when using a drug with a narrow
therapeutic concentration range (anticonvulsant or anti-
arrhythmic agents) in which more constant levels are
desired and subtherapeutic periods are avoided. Con-
versely, the varying interval method may be preferred
when dosing aminoglycoside antibiotics, which have a
long postantibiotic effect whereby long periods of low
drug levels are not problematic and bacterial killing
depends on high peak concentrations (15) (more detailed
discussion can be found in infectious disease textbooks).
Step 5: Drug-Level Monitoring
Varying the dosage or dosing interval for a given
therapeutic agent may not be sufficient to avoid tox-
icity and guarantee therapeutic efficacy in patients
with renal failure. Monitoring drug levels can greatly
enhance patient care, particularly in the setting of renal
impairment. Interpreting drug concentrations requires
knowledge of the exact dosage given, the route of
administration, whether the Vd or protein binding of
the drug is altered, the elapsed time from the last dose,
and the elimination half-life of the drug. Drug levels
may be monitored after an appropriate loading dose or
three to four maintenance doses have been given to
ensure that steady-state concentrations have been
reached. As a rough rule of thumb, peak drug levels
reflect the highest drug concentration achieved after an
initial distribution phase and tend to correlate with
efficacy. Trough levels are generally obtained imme-
diately before the next dose to determine the lowest
concentration in the blood, thus reflecting systemic
clearance, and generally reflect toxicity/accumulation.
Drug monitoring must include ongoing clinical assess-
ment of the patient because toxicity can occur even
when levels are within the “therapeutic” range or
undetectable. For example, digoxin toxicity can occur
in the setting of therapeutic levels when hypokalemia
or metabolic alkalosis is present. It is important to
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
remember that pharmacokinetic half-life (i.e., disap-
pearance from blood) does not necessarily equal “ef-
fect” half-life, as is the case with clopidogrel, a platelet
aggregation inhibitor. Clopidogrel has an elimination
half-life that is measured in hours, whereas its effect
half-life (inhibition of platelet aggregation) extends to
days and even weeks. The assumption that platelet
function has been restored because drug can no longer
be measured in the blood could prove lethal for a
patient who undergoes a surgical procedure if, in fact,
the antiplatelet effect is still present. Similarly, for
some drugs such as aminoglycoside antibiotics, drug-
level monitoring has not prevented toxicity because of
the poor correlation between serum levels and uptake
into tissues such as the proximal tubular epithelial cell
(nonoliguric acute renal failure) and inner ear (vestib-
ular ototoxicity). Last, the pharmacodynamic effects
of a drug may be amplified in patients with CKD or
ESRD as a result of increased sensitivity at the target
organ (e.g., excessive sedation and respiratory sup-
pression with narcotics).
Drug Clearance in Dialysis
The following information regarding dialytic
clearance of drugs is detailed in the recent issue of
Clinical Pharmacology & Therapeutics (referred to in
the introduction).
Patients who undergo dialysis therapy, both in-
termittent and continuous, require special attention
with regard to scheduling drug administration (prefer-
Table 2. Factors that affect drug dialyzability
Drug
size (molecular weight)
% protein bound
volume of distribution
water solubility (% of dose appearing “unchanged” in
urine)
Membrane
size (surface area)
permeability (pore size)
composition (polysulfone, cellulose-based, etc.)
drug-membrane–binding characteristics (if any)
Dialysis method
dialysis (drug removal by diffusion)
hemofiltration (drug removal by convection)
duration of procedure
blood and dialysate flow rate
ultrafiltration rate
replacement solution location (pre- or postfilter)
225
Figure 3. Compounds may traverse numerous compart-
ments in the body before elimination.
ably after dialysis) and/or supplemental dosing if an
agent is substantially cleared by dialysis (⬎30 to 40%
increased extracorporeal clearance). The dialyzability
of a drug, often unknown, can be approximated by
considering three factors: The drug, the dialysis mem-
brane, and dialysis method used (Table 2). First, phar-
macologic characteristics of a drug—size, water solu-
bility, protein binding, Vd, charge, and renal versus
nonrenal clearance— determine the extent to which it
may be removed. Thus, small (⬍500 Da), water-
soluble (appear unchanged in urine), unbound drugs
with small distribution volumes would likely be re-
moved from the body by dialysis. An example of this
is aminoglycoside antibiotics. Conversely, drugs that
exhibit a large Vd (often highly protein or tissue
bound) are not readily dialyzed, because only a small
portion of the total amount of drug in the body circu-
lates in the vascular space with a much larger portion
“out of reach” of dialytic removal. One can remove all
of the drug in the vascular space with a dialysis
treatment, but it is rapidly replenished with the large
amount of drug found in various tissue compartments,
as illustrated in Figure 3. Cyclosporine, digoxin, and
tricyclic antidepressants are examples of drugs that
exhibit such pharmacologic qualities.
Second, a dialysis membrane with a larger sur-
face area and greater permeability (larger pore size)
would be expected to remove more drug, larger com-
pounds (up to 40,000 Da in some cases), and some
protein-bound agents. Such membranes are referred to
as high-flux dialysis membranes and include polysul-
fone, polyacrylonitrile, and cellulose triacetate. This is
pertinent because vancomycin, for example, is signif-
icantly removed by such dialysis membranes in con-
trast to older, low-flux membranes (cellulose). As
such, vancomycin dosing in patients who undergo high-
flux dialysis has become more complicated, mandating
226
higher dosages, more frequent dosing, and more drug-
level monitoring. A review by Pallotta and Manley (14)
in addition to many previous reports detailed the phar-
macokinetic issues involved in vancomycin dosing for
patients who undergo dialytic therapy (16,17).
Last, assuming that a particular drug can be
removed by dialysis, the methods used during dialysis,
such as blood flow rate, dialysate flow rate, ultrafil-
tration rate, and duration of treatment, directly corre-
late with the amount of drug removed. With the advent
of short-daily and nocturnal hemodialysis, dosing reg-
imens may require further adjustment given the overall
increased clearance achieved by these methods (18).
In the case of continuous renal replacement therapy
(CRRT), combining hemofiltration with dialysis will
remove pharmaceutical agents by convection (hemofil-
tration) and diffusion (dialysis), resulting in dosing strat-
egies that fall somewhere between those that are used in
outpatient intermittent hemodialysis settings (GFR ⬍10
ml/min) and those that are used in mild impairment (GFR
50 to 80 ml/min). Convection removes unbound drug in
the serum, and this amount can be calculated as follows:
Amount removed ⫽ serum concentration ⫻ unbound
fraction ⫻ ultrafiltration rate ⫻ treatment duration
The amount of drug removed by diffusion during
concurrent dialysis can be added to this amount to
determine dosage regimens during CRRT. The loca-
tion of replacement solutions (pre- versus postfilter) in
the system can also affect drug clearance. Prefilter
replacement fluids may result in higher ultrafiltration
rates and higher midsize solute clearance, whereas
postfilter replacement fluid can increase filtration frac-
tion. A recent review by Susla (19) discussed the
impact of CRRT on drug removal.
A paucity of information exists regarding
altered pharmacology in the critical care
setting, where acute kidney failure, he-
patic insufficiency, altered volume sta-
tus, hypoalbuminemia, multiple drug in-
teractions, and the use of various dialysis
techniques further complicate drug-dos-
ing regimens.
Pea et al. (20) published an exhaustive review of
antimicrobial therapy for patients who undergo CRRT
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
and the pharmacologic principles that apply. Nonethe-
less, a paucity of information exists regarding altered
pharmacology in the critical care setting, where acute
kidney failure, hepatic insufficiency, altered volume
status, hypoalbuminemia, multiple drug interactions,
and the use of various dialysis techniques further
complicate drug-dosing regimens. This realization fur-
ther emphasizes the need to individualize each pa-
tient’s therapy by continuous clinical assessment
whereby “more” antimicrobial therapy rather than
“less” may be prudent given the danger of ineffective
therapy in the intensive care unit setting (21,22).
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305–311, 2009
2. Perazella MA: Renal vulnerability to drug toxicity. Clin J Am Soc
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iohexol as a measure of glomerular filtration rate. J Am Soc Nephrol
6: 257–263, 1995
13. Pai MP, Bearden DT: Antimicrobial dosing considerations in obese
adult patients. Pharmacotherapy 27: 1081–1091, 2007
14. Pallotta KE, Manley HJ: Vancomycin use in patients requiring
hemodialysis: A literature review. Semin Dial 21: 63–70, 2008
15. Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW,
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Quintiliani R: Experience with a once-daily aminoglycoside program
administered to 2,184 adult patients. Antimicrob Agents Chemother
39: 650 – 655, 1995
16. Rybak MJ: The pharmacokinetic and pharmacodynamic properties of
vancomycin. Clin Infect Dis 42: S35–S39, 2006
17. Pai AB, Pai MP: Vancomycin dosing in high flux hemodialysis: A
limited-sampling algorithm. Am J Health Syst Pharm 61: 1812–1816,
2004
18. Decker BS, Mueller BA, Sowinski KM: Drug dosing considerations
in alternative hemodialysis. Adv Chronic Kidney Dis 14: e17– e26,
2007
19. Susla GM: The impact of continuous renal replacement therapy on
drug therapy. Clin Pharmacol Ther 86: 562–565, 2009
20. Pea F, Viale P, Pavan F, Furlanut M: Pharmacokinetic considerations
for antimicrobial therapy in patients receiving renal replacement
therapy. Clin Pharmacokinet 46: 997–1038, 2007
21. Bouman CS: Antimicrobial dosing strategies in critically ill patients
with acute kidney injury and high-dose continuous veno-venous
hemofiltration. Curr Opin Crit Care 14: 654 – 659, 2008
22. Schetz M: Drug dosing in continuous renal replacement therapy:
General rules. Curr Opin Crit Care 13: 645– 651, 2007
Antimicrobial Agents
Antibacterial Agents
Much of what follows in this brief overview
comes from multiple references in older literature;
pharmacologic properties of specific agents can be
reviewed by the reader on a case-by-case basis. Im-
portant concepts that are needed by the prescribing
physician to design a “pharmacologic approach to
patients with kidney impairment” follow.
Many antibacterial agents appear in the
urine unchanged (water soluble), are small
molecules (<500 Da), and are not highly
protein bound, thereby necessitating dos-
age reduction in patients with CKD as well
as supplementation after dialysis.
Many antibacterial agents appear in the urine
unchanged (water soluble), are small molecules (⬍500
Da), and are not highly protein bound, thereby neces-
sitating dosage reduction in patients with chronic kid-
ney disease (CKD) as well as supplementation after
dialysis. ␤-Lactam agents, such as penicillins, cepha-
losporins, carbapenems, and monobactams, are exam-
ples of such compounds. Combining certain penicil-
lins with ␤-lactamase inhibitors such as sulbactam,
tazobactam, and clavulanate may minimize develop-
ment of antibiotic resistance and extend their spectrum
of activity. Different pharmacokinetic properties be-
227
tween a ␤-lactam antibiotic and its lactamase inhibitor
may affect their use in renal failure settings. In the
case of ampicillin/sulbactam, both components are
eliminated by the kidney and have similar half-lives
and volumes of distribution across all levels of renal
function and during dialysis. This allows for an equiv-
alent dosage reduction (or dosing interval extension)
for each component, thereby maintaining lactamase
inhibition during dosing intervals. The same is true for
piperacillin/tazobactam. In contrast, ticarcillin/clavu-
lanate may have greater pharmacokinetic disparity
between the two components such that clavulanate
levels may be insufficient to protect ticarcillin from
lactamase-producing organisms when the dosing inter-
val is extended in patients with ESRD (1). In general,
excess levels of penicillins may be associated with
central nervous system toxicity, including seizures,
coma, and myoclonus. Similarly, the carbapenem imi-
penem can lower the seizure threshold with accumu-
lation when dose reduction is not performed for pa-
tients with renal impairment (2).
Doxycycline is one tetracycline that does not
seem to have an antianabolic effect previously re-
ported for older agents in this category and thus is safe
to use in patients with CKD. Nitrofurantoin, com-
monly prescribed for chronic bacterial suppression
therapy in urologic disorders, should not be used in
CKD to avoid peripheral neuropathy attributed to toxic
metabolite accumulation (3).
Aminoglycoside antibiotics (gentamicin, tobra-
mycin, netilmicin, amikacin, and streptomycin) are
less commonly used because of nephrotoxicity and
ototoxicity but are nonetheless effective bactericidal
agents and relatively inexpensive. The kidney freely
filters aminoglycosides and then resorbs filtered drug
by megalin-mediated endocytosis in the proximal tu-
bule. High intracellular concentrations lead to lysoso-
mal, Golgi apparatus, and endoplasmic reticulum dis-
ruption in these tubular epithelial cells. Resulting cell
death of proximal tubular epithelia leads to nonoligu-
ric renal failure. Vestibular and cochlear abnormalities
are linked to injury of hair cells within the inner ear
bathed by aminoglycoside-containing endolymph.
Once-daily dosing has been shown to minimize neph-
rotoxicity (especially when GFR is ⬍60 ml/min) and
takes advantage of high peak levels delivering maxi-
mal bactericidal effect, which continues during longer
dosing intervals as a result of the postantibiotic effect
displayed by these agents (4). Because nephrotoxicity
228
correlates with frequency of dosing and high trough
levels, once-daily or once-every-other-day dosing for
patients with CKD is desirable. It is important to
remember that implanted aminoglycoside “reservoirs,”
which are used in orthopedic procedures, can also
lead to acute toxicity (5).
Allergic interstitial nephritis has classically been
associated with exposure to penicillins, cephalospo-
rins, and sulfa-containing agents. Fluoroquinolone an-
tibiotics such as ciprofloxacin, levofloxacin, and oth-
ers should be added to this list given numerous case
reports of quinolone-induced allergic interstitial ne-
phritis (6). Vancomycin dosing is discussed in the
previous Stepwise Approach to Dosimetry and Drug
Clearance in Dialysis sections.
Recently, Zietse et al. (7) reviewed fluid, elec-
trolyte, and acid-base disorders that are associated
with antibiotic therapy. Their work is a welcome
addition to the renal pharmacology literature with its
emphasis on various receptors, transporters, channels,
and/or pores that are found in renal tubular epithelial
cell membranes and can be affected by various anti-
microbials. Thus, renal tubular function can be af-
fected by antimicrobials often without a concurrent
rise in serum creatinine or decline in GFR. These
so-called “tubulopathies” that are associated with var-
ious antimicrobials include sodium wasting, potassium
wasting, renal tubular acidosis, and Fanconi syndrome
as well as nephrogenic diabetes insipidus. Table 3 lists
Table 3. Tubulopathy syndromes induced by antimicrobials (7)
Syndrome
Aminoglycosides and tetracyclines
proximal RTA or Fanconi syndrome
Bartter-like syndrome
Amphotericin B compounds
distal RTA (H⫹ “backleak”)
hypokalemia
polyuria/hypernatremia
Trimethoprim
distal RTA
blockade of ENaC
Penicillins
hypokalemia
hyperkalemia
Linezolid and tetracyclines
lactic acidosis
ENaC, epithelial sodium channels; RTA, renal tubular acidosis.
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
some of these clinical abnormalities that are schemat-
ically illustrated in the review.
Antifungal Agents
Antifungal agents include the azoles (flucon-
azole, itraconazole, voriconazole, and posaconazole),
the echinocandins (caspofungin, micafungin, and anidu-
lafungin), and the amphotericin family of polyenes
(amphotericin B, amphotericin B-liposome, amphoter-
icin B–lipid complex, and amphotericin B– cholesteryl
sulfate complex). An extensive review of antifungal
agents in the treatment of invasive fungal infections
has appeared recently (8). Table 4 is not an exhaustive
list of all antifungal agents and does not include Food
and Drug Administration–approved dosage guidelines
but simply highlights clinical issues that pertain to
patients with CKD. Detailed information can be found
online from the Infectious Diseases Society of Amer-
ica (http://www.idsociety.org) as well as previously
mentioned references (Table 1).
Amphotericin B
All antifungal agents disrupt the fungal cell
membrane by either binding to ergosterol in the lipid
bilayer (amphotericin-based agents) or inhibiting its
synthesis. This leads to an inability to maintain cell
membrane integrity and subsequent leakage of cell
contents. Unfortunately, much of the toxicity that is
associated with amphotericin therapy is linked to this
mechanism of action, because these compounds can
Description
Normal anion gap metabolic acidosis; hypokalemia; uric acid, glucose,
amino acid, phospho-wasting
Metabolic alkalosis with K⫹, Ca⫹, Mg⫹, Na⫹ wasting
Normal anion gap metabolic acidosis
K⫹ wasting; distal RTA
Nephrogenic diabetes insipidus
Normal anion gap metabolic acidosis
Hyperkalemia
High urine K⫹, low urine Cl⫺
High K⫹ content in setting of poor kaliuresis
High anion gap metabolic acidosis
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010 229

Table 4. Antifungal agents

Agent Dosage Reduction Adverse Effects
Echinocandins
caspofungin No
micafungin No
anidulafungin No
Amphotericin B
amphotericin B lipid complex No Lipid formulations less nephrotoxic
than amphotericin B, but tubular
cell injury still present and
decreased GFR; RTA; NDI; K⫹
and Mg2⫹ wasting. Infusion
reaction specific for lipid
preparations
amphotericin B liposomal No
amphotericin B No
cholesterylsulfate
Azoles
fluconazole Yes (Ccr ⬍50 ml/min); supplement after HD Alopecia
posaconazole No
itraconazole (cyclodextrin) Avoid intravenous form if Ccr ⬍30 ml/min; Hyperaldosteronism
no change if oral
voriconazole (cyclodextrin) Avoid intravenous form if Ccr ⬍50 ml/min; CNS (cyclodextrin versus drug),
no change if oral visual hallucinations, agitation,
myoclonus; photopsia (?
cyclodextrin); colored light,
flashing light; increased
creatinine
CNS, central nervous system; NDI, nephrogenic diabetes insipidus; RTA, renal tubular acidosis.

bind to cholesterol moieties in human cell membranes
as well. Renal tubular epithelial cell function is thus
impaired, leading to potassium and magnesium wast-
ing, distal renal tubular acidosis from H⫹ backleak,
and concentrating defects with nephrogenic diabetes
insipidus (see Table 3). These tubular defects can
persist long after antifungal therapy is discontinued.
Amphotericin is also thought to cause vasoconstric-
tion, reducing renal blood flow and contributing to
azotemia. This can be ameliorated with volume expan-
sion using intravenous sodium chloride before dosing.
In addition to nephrotoxicity, infusion-related adverse
reactions include fever, chills, nausea, vomiting, hy-
potension, and tachypnea. The amphotericin class of
antifungal agents has expanded in the past 10 to 15
years with the advent of lipid-based formulations in-
cluding liposomal amphotericin B, lipid complex, and
amphotericin B cholesteryl sulfate in an attempt to
minimize toxicity. Although the incidence and sever-
ity of nephrotoxicity and infusion reactions may be
reduced by lipid formulations, both persist and at
significant cost (9). A unique infusion reaction has
been observed with liposomal amphotericin B and
consists of chest pain, dyspnea, hypoxia, abdominal
pain, and urticaria. Amphotericin is highly protein
bound, has a large Vd, and undergoes little renal
elimination from the body. Dialysis therapies have
little effect on drug removal in any formulation.
Azoles
Azoles inhibit synthesis of ergosterol, an essen-
tial part of the fungal cell membrane. The “tri”-azoles
include fluconazole, itraconazole, voriconazole, and
posaconazole. They have largely supplanted the older
imidazole ketoconazole because of greater safety, ef-
ficacy, and improved pharmacokinetics. Of note, the
solubilizing agent used with voriconazole and itracon-
azole, cyclodextrin, is eliminated by the kidney, accu-
mulates when GFR is ⬍50 ml/min leading to toxicity,
and therefore is not recommended for patients with
significant renal impairment. Toxicity can take one of
two primary forms: Photopsia (flashing lights, colored
light) and central nervous system neurotoxicity, in-
230
cluding visual and auditory hallucinations, myoclonus,
and agitation (10). Elevation of serum creatinine and
photophobia/sun-induced skin reactions have also
been reported with voriconazole. Intravenous itracon-
azole is no longer available in the United States;
although cyclodextrin is found in the oral itraconazole
formulation, it does not accumulate in renal impair-
ment.
Echinocandins
A new class of antifungal agents, echinocandins,
inhibits synthesis of ␤-D-glucan, a component of the
fungal cell wall. Toxicity is much less with these
compounds because of the absence of glucan synthesis
enzymes in mammalian cells. Caspofungin, micafun-
gin, and anidulafungin are effective against Candida
species, including those that are resistant to the azoles
as well as Aspergillus. They can be given once daily,
intravenously, and do not require dosage adjustment in
renal failure (8).
Antiviral Agents
A limited number of antiviral therapies for hep-
atitis B, hepatitis C, and influenza are discussed in this
section because of a higher prevalence of such viral
infections in patients with ESRD. Dosage adjustment
of antiretroviral agents and their renal syndromes are
discussed primarily in tabular form. Other antiviral
compounds are discussed in the Immunosuppressive
Therapies section.
Hepatitis B and C Antiviral Agents
IFN alfa-2a and -2b as well as their pegylated
formulations can be used for both hepatitis B and C
infections. Pegylation refers to the attachment of a
polyethylene glycol side chain to the IFN molecule
that reduces the rate of renal elimination, thereby
allowing for once-weekly dosing. Guidelines issued
by the American Association for the Study of Liver
Diseases for the diagnosis, management, and treatment
of hepatitis C was updated in 2009 and can be ac-
cessed through the American Association for the
Study of Liver Diseases web site at http://www.aasld.
org/practiceguidelines. Currently, the treatment of
choice for chronic hepatitis C infection is a combina-
tion of pegylated IFN alfa plus ribavirin, both of which
undergo renal elimination (11). In patients with creat-
inine clearance (Ccr) ⬍50 ml/min, ribavirin and the
combination of ribavirin plus IFN alfa agents should
be avoided. Ribavirin has a long list of adverse effects,
but hemolytic anemia, red cell aplasia, and thrombotic
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
thrombocytopenic purpura are particularly problem-
atic for patients with CKD, who are often anemic at
baseline. Pegylated IFN alfa-2a and -2b can be used
alone for patients who have CKD with Ccr values ⬍50
ml/min but require close monitoring. For hepatitis B
infection, lamivudine, telbivudine, and entecavir can
also be used but require dosage reduction in patients
with Ccr ⬍50 ml/min (Table 5). Lamivudine (12) does
not seem to be removed by hemodialysis, whereas
entecavir (13) and telbivudine (14) should be admin-
istered after dialysis (Table 5).
Current opinion on hepatitis B vaccination for
patients with ESRD varies given the reduced response
of such patients to vaccination, which may result from
uremia-induced alterations in T lymphocyte and anti-
gen-presenting cell behavior (15). Further discussion
of hepatitis B vaccination regimens is beyond the
scope of this issue of NephSAP.
Anti-Influenzal Agents
Antiviral drugs are an important adjunct to influ-
enzal vaccinations for treatment and prophylaxis of
both pandemic and seasonal influenza. Table 6 is not
an exhaustive list of anti-influenzal agents but pro-
vides some guidance with regard to dosing for patients
with CKD. Amantadine, oseltamivir, and peramivir
undergo renal elimination and warrant dosage reduc-
tion in patients with Ccr ⬍50 ml/min (16).
Antiretroviral Agents
The introduction of highly active antiretroviral
therapy in the mid-1990s dramatically altered the
course of HIV infections, with marked improvement
in survival rates. As such, tens of millions of people
worldwide now live with HIV infection chronically,
and this number will continue to grow. Although viral
suppression contributes to improved morbidity and
mortality rates, long-term exposure to antiretroviral
Table 5. Hepatitis B and C antiviral agents
Agent Dosage Reduction Indicated
Hepatitis C
pegylated IFN alfa-2a and Ccr ⬍50 ml/min and ESRD
-2b
ribavirin (⫾ pegylated Avoid in Ccr ⬍50 ml/min
IFN)
Hepatitis B
pegylated IFN alfa-2a and Ccr ⬍50 ml/min and ESRD
-2b
lamivudine Ccr ⬍50 ml/min and ESRD
entecavir Ccr ⬍50 ml/min and ESRD
telbivudine Ccr ⬍50 ml/min and ESRD
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Table 6. Anti-influenzal agents
Agent Treatment
Oseltamivir Reduce dosage for Ccr ⬍30 ml/min (every day from
twice daily)
Peramivir Dosage reduction
Amantadine Reduce dosage for Ccr ⬍50 ml/min (every day from
twice daily)
Zanamivir No change
agents poses nephrotoxic injury, and certain agents
must be dosage-adjusted in the setting of CKD. It is
beyond the scope of this syllabus to provide a detailed
discussion of antiretroviral therapy, but two recent
reviews by Kalayjian (17) (drug-dosing recommenda-
tions) and Jao and Wyatt (18) (nephrotoxicity) were
published in January 2010 in Advances in Chronic
Kidney Disease, and the tabular information presented
in Tables 7 and 8 has been reprinted with permission
from these references.
In general, dosage reductions for kidney im-
pairment are not necessary for the following anti-
retroviral drug categories/agents: Integrase inhibi-
tors (raltegravir), fusion inhibitors (enfuvirtide),
CCR5 antagonists (maraviroc), protease inhibitors
(atazanivir, darunavir, fosamprenavir, indinavir,
lopinavir, nelfinavir, ritonavir, saquinavir, and ti-
pranavir), and nonnucleoside reverse transcriptase in-
hibitors (delavirdine, efavirenz, etravirine, and nevi-
rapine). In the case of nucleoside and nucleotide
reverse transcriptase inhibitors (including zidovudine,
lamivudine, emtricitabine, stavudine, didanosine, and
tenofovir), however, dosage adjustment is warranted
for patients with CKD. Specifically, nucleotide reverse
transcriptase inhibitors undergo glomerular filtration
and tubular secretion by proximal tubular epithelial
cells. Similar to aminoglycoside nephrotoxicity, high
intracellular concentrations of these agents can occur
in the proximal tubular epithelia, resulting in Fanconi
syndrome and other tubulopathies. Although protease
inhibitors do not require dosage adjustment, crystallu-
ria is common and can lead to urolithiasis. More
detailed dosing information with respect to both he-
patic and renal impairment can be found at http://
www.aidsinfo.nih.gov/ContentFiles/AdultandAdoles-
centGL.pdf (19).
References
1. Hardin TC, Butler SC, Ross S, Wakeford JH, Jorgensen JH: Com-
parison of ampicillin-sulbactam and ticarcillin-clavulinic acid in
231
Prophylaxis
Reduce for Ccr ⬍30 ml/min (every other day from
every day)
Dosage reduction
Dosage reduce for Ccr ⬍50 ml/min (every day
from twice daily)
No change
patients with chronic renal failure: Effects of differential pharmaco-
kinetics on serum bactericidal activity. Pharmacotherapy 14: 147–
152, 1994
2. Seto AH, Song JC, Guest SS: Ertapenem-associated seizures in a
peritoneal dialysis patient. Ann Pharmacother 39: 352–356, 2005
3. White WT, Harrison L, Dumas S 2nd: Nitrofurantoin unmasking
peripheral neuropathy in a type 2 diabetic patient. Arch Intern Med
144: 821, 1984
4. Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW,
Quintiliani R: Experience with a once-daily aminoglycoside program
administered to 2,184 adult patients. Antimicrob Agents Chemother
39: 650 – 655, 1995
5. Wu IM, Marin EP, Kashgarian M, Brewster UC: A case of an acute
kidney injury secondary to an implanted aminoglycoside. Kidney Int
75: 1109 –1112, 2009
6. Lomaestro BM: Fluoroquinolone-induced renal failure. Drug Saf 22:
479 – 485, 2000
7. Zietse R, Zoutendijk R, Hoorn EJ: Fluid, electrolyte and acid-base
disorders associated with antibiotic therapy. Nat Rev Nephrol 5:
193–202, 2009
8. Segal BH: Aspergillosis. N Engl J Med 360: 1870 –1884, 2009
9. Caillot D, Reny G, Solary E, Casasnovas O, Chavanet P, Bonnotte B,
Perello L, Dumas M, Entezam F, Guy H: A controlled trial of
tolerance of amphotericin B infused in dextrose or in intralipid in
patients with hematologic malignancies. J Antimicrob Chemother 33:
603– 613, 1994
10. Pea F, Viale P: Hallucinations during voriconazole therapy: Who is at
higher risk and could benefit from therapeutic drug monitoring? Ther
Drug Monit 31: 135–136, 2009
11. Ghany MG, Strader DB, Thomas DL, Seeff LB: Diagnosis, manage-
ment, and treatment of hepatitis C: An update. Hepatology 49:
1335–1374, 2009
12. Johnson MA, Verpooten GA, Daniel MJ, Plumb R, Moss J, Van
Caesbroeck D, De Broe ME: Single dose pharmacokinetics of lami-
vudine in subjects with impaired renal function and the effect of
haemodialysis. Br J Clin Pharmacol 46: 21–27, 1998
13. Lok AS, McMahon BJ: Chronic hepatitis B. Hepatology 45: 507–
539, 2007
14. Zhou XJ, Myers M, Chao G, Dubuc G, Brown N: Clinical pharma-
cokinetics of telbivudine a potent antiviral for hepatitis B, in subjects
with impaired hepatic or renal function. J Hepatol 40: S134, 2004
15. Litjens NH, Huisman M, van den Dorpel M, Betjes MG: Impaired
immune responses and antigen-specific memory CD4⫹ T cells in
hemodialysis patients. J Am Soc Nephrol 19: 1483–1490, 2008
16. Khazeni N, Bravata DM, Holty JE, Uyeki TM, Stave CD, Gould MK:
Systematic review: Safety and efficacy of extended-duration antiviral
chemoprophylaxis against pandemic and seasonal influenza. Ann
Intern Med 151: 464 – 473, 2009
17. Kalayjian RC: The treatment of HIV-associated nephropathy. Adv
Chronic Kidney Dis 17: 59 –71, 2010
18. Jao J, Wyatt CM: Antiretroviral medications: Adverse effects on
the kidney. Adv Chronic Kidney Dis 17: 72– 82, 2010
232 Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Table 7. Antiretroviral dosing guidelines with renal insufficiency

Antiretroviral Agent Daily Dosage CrCl (ml/min) Dosage
Abacavir (Ziagen) 300 mg twice daily No dosage adjustment
necessary
Didanosine (Videx EC) ⬎60 kg: 400 mg/d 30 to 59 200 mg
10 to 29 125 mg
CAPD or HD 125 mg
⬍60 kg: 250 mg/d 30 to 59 125 mg
10 to 29 125 mg
⬍10 Not recommended
CAPD or HD Not recommended
Didanosine oral ⬎60 kg: 200 mg twice daily 30 to 59 200 mg
solution (Videx) or 400 mg/d
10 to 29 150 mg
⬍10 100 mg
CAPD or HD 100 mg
⬍60 kg: 250 mg twice daily 30 to 59 150 mg
or 125 mg/d
10 to 29 100 mg
⬍10 75 mg
CAPD or HD 75 mg
Emtricidabine (Emtriva) 200-mg oral capsule daily 30 to 49 200 mg every 48 hours
15 to 29 200 mg every 72 hours
⬍15 200 mg every 96 hours
CAPD or HDa 200 mg every 96 hours
240 mg (24 ml) oral 30 to 49 120 mg every 24 hours
solution daily
15 to 29 80 mg every 24 hours
⬍15 60 mg every 24 hours
CAPD or HDa 60 mg every 24 hours
Lamivudine (Epivir) 300 mg/d or 150 mg twice 30 to 49 150 mg every 24 hours
daily
15 to 29 150 mg ⫻1 then 100 mg every 24 hours
5 to 14 150 mg ⫻1 then 50 mg every 24 hours
⬍5 50 mg ⫻1 then 25 mg every 24 hours
CAPD or HDa 50 mg ⫻1 then 25 mg every 24 hours
Stavudine (Zerit) ⬎60 kg: 40 mg twice daily 26 to 50 20 mg every 12 hours
10 to 25 20 mg every 24 hours
CAPD or HDa 20 mg every 24 hours
⬍60 kg: 30 mg twice daily 26 to 50 15 mg every 12 hours
10 to 25 15 mg every 24 hours
CAPD or HDa 15 mg every 24 hours
b
Tenofovir (Viread) 300 mg/d 30 to 49 300 mg every 48 hours
10 to 29 300 mg twice weekly
ESRD 300 mg weekly
CAPD or HDa 300 mg weekly
Zidovudine (Retrovir) 300 mg twice daily ⬍15 300 mg every 24 hours
CAPD or HDa 300 mg every 24 hours
Combination
medications
abacavir ⫹ 1 tablet daily Not recommended for
lamivudine CrCl ⬍50
(Epzicom)
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010 233

Table 7. Continued
Antiretroviral Agent Daily Dosage CrCl (ml/min) Dosage
tenofovir ⫹ 1 tablet daily 30 to 49 1 tablet every 48 hours
emtricitabine
(Truvada)b
⬍30 Not recommended
efavirenz ⫹ 1 tablet daily Not recommended for
tenovovir ⫹ CrCl ⬍50
emtricidabine
(Atripla)b
zidovudine ⫹ 1 tablet twice daily Not recommended for
lamivudine CrCl ⬍50
(Combivir)
zidovudine ⫹ 1 tablet daily Not recommended for
lamivudine ⫹ CrCl ⬍50
abacavir (Trizivir)
Dosage adjustments for renal insufficiency are not necessary for nonnucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, etravirine, and nevirapine),
protease inhibitors (atazanivir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saqinavir, and tipranavir), CCR5 antagonists (maraviroc), fusion
inhibitors (enfuvirtide), or integrase inhibitors (raltegravir). CAPD, chronic ambulatory peritoneal dialysis; CrCl, creatinine clearance; eGFR, estimated GFR; HD,
hemodialysis.
a
Dose after HD.
b
Some experts recommend against prescribing for eGFR ⬍60 ml/min per 1.73 m2.
Reprinted from Advances in Chronic Kidney Disease, Vol 17, Kalayjian, RC, The treatment of HIV-associated nephropathy, pages 59 –71 (reference 17), Copyright 2010,
with permission from Elsevier.

19. Panel on Antiretroviral Guidelines for Adults and Adolescents:
Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents, Washington, DC, Department of Health
and Human Services, Dcember 1, 2009. Available at: http://www.aidsinfo.
nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March
1, 2010
Psychiatric Medications
Antidepressant Drugs
Depressive illness is prevalent, affecting up to
one third of patients with chronic kidney disease
(CKD) by some estimates (1,2). That few clinical data
exist on antidepressant therapy in CKD underscores
the observation that depression is underdiagnosed and
undertreated in this population (3). One might assume
that currently available antidepressant medications
that are prescribed in the general population would be
efficacious in patients with CKD, yet such assump-
tions must be tempered by the realization that adverse
drug effects are more frequent in this patient popula-
tion and efficacy less frequent as a result of altered
pharmacokinetic and pharmacodynamic properties, re-
spectively.
A limited review of so-called second-generation
antidepressants, including selective serotonin reuptake
inhibitors (SSRIs), serotonin norepinephrine reuptake
inhibitors, norepinephrine dopamine reuptake inhibi-
tors, and noradrenergic/serotonergic agonists, is pre-
sented in Table 9 (4). The SSRIs inhibit serotonin
reuptake, leading to increased serotonin levels in the
intersynaptic region. Of all antidepressants prescribed
to patients with CKD, these agents have the most
clinical data available in the literature and with the
exception of paroxetine require no dosage adjustment
in renal impairment. They are generally well tolerated
but can display common adverse effects, including
sedation, headache, sexual dysfunction, insomnia,
nausea, and dry mouth. SSRIs display two unexpected
adverse effects that frequently are managed by neph-
rologists: Hyponatremia as a result of the syndrome of
inappropriate antidiuretic hormone secretion (5) and
increased upper gastrointestinal (GI) tract bleeding in
patients who take concomitant nonsteroidal anti-in-
flammatory drugs (NSAIDs) (6). The increased risk
for GI bleeding that is associated with SSRIs is
thought to be related to intraplatelet serotonin defi-
ciency as a result of reduced reuptake, resulting in
inadequate serotonin release, which diminishes plate-
let aggregation (6). In the general population, the
relative risk for GI tract bleeding associated with
concomitant SSRI/NSAID use (12.2 to 15.6) seems to
be synergistic in that it exceeds the additive value of
234 Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Table 8. Major nephrotoxicities of medications used in HIV

Medication Reported Nephrotoxicity
NRTIs
zidovudine (AZT) None
lamivudine (3TC) Fanconi
emtricitabine (FTC) None
stavudine (d4T) None
abacavir (ABC) Fanconi, NDI
didanosine (ddI) Fanconi, NDI
tenofovir (TDF) ARF, Fanconi, NDI, hypophosphatemic osteomalacia
NNRTIs
nevirapine Acute kidney injury in the setting of DRESS
efavirenz Minimal change disease, urolithiasis, ARF
etravirine None
Protease inhibitors
nelfinavir Urolithiasis
amprenavir Urolithiasis
saquinavir Urolithiasis
lopinavir/ritonavir Urolithiasis
indinavir Urolithiasis, interstitial nephritis, ARF, papillary necrosis, NDI
atazanavir Urolithiasis, AIN
Entry inhibitors
enfuvirtide MPGN
maraviroc, vicriviroc None
integrase inhibitors
raltegravir None
elvitegravir None
AIN, acute interstitial nephritis; ARF, acute renal failure; DRESS, drug rash with eosinophilia and systemic symptoms; MPGN, membranoproliferative glomerulonephritis;
NDI, nephrogenic diabetes insipidus.
Reprinted from Advances in Chronic Kidney Disease, Vol 17, Jao J, Wyatt CM, Antiretroviral medications: adverse effects on the kidney, pages 72– 82 (reference 18,
Copyright 2010, with permission from Elsevier.

relative risk of each drug (2.6 to 3.6 for SSRIs, 3.7 to
4.5 for NSAIDS) (6). Use of any antidepressant that
increases serotonin levels requires close monitoring
for signs/symptoms of serotonin syndrome, including
agitation, autonomic instability, confusion, diarrhea,
dizziness, diaphoresis, hyperreflexia, hyperthermia,
tremor, and unsteady gait, which may be seen after
initiation of therapy or an increase in dosage (7).
Conversely, given the high rate of medication non-
compliance seen in the ESRD population, symptoms
such as nausea, insomnia, imbalance, hyperarousal,
and malaise can be seen when serotonergic agents are
discontinued abruptly (“discontinuation syndrome”)
(8). Last, nearly all antidepressants are metabolized by
the cytochrome P450 system, leading to numerous
drug– drug interactions (see references in Table 1).
Older agents for treatment of depression, such as
tricyclic antidepressants (including amitriptyline, de-
sipramine, doxepin, imipramine, and nortriptyline) are
not discussed and should generally be avoided in
patients with ESRD because of an increased risk for
conduction abnormalities, arrhythmias, hyperthermia,
and anticholinergic adverse effects. Anticholinergic
adverse effects are important for nephrologists to be
aware of, because urinary retention is one of the most
common and may lead to worsening kidney function
acutely.
Antipsychotic medications with the exception of
lithium are not presented in detail because such agents
should be prescribed by psychiatrists and pharmacists
who are working jointly as the primary treatment team
and are beyond the scope of this issue of NephSAP;
however, one life-threatening adverse effect associ-
ated with antipsychotic, or “neuroleptic,” agents
should be mentioned. Neuroleptic malignant syn-
drome is characterized by rigidity, bradyreflexia, hy-
perthermia, autonomic instability, and mental status
changes and is seen with dopamine antagonism (9).
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Table 9. Antidepressant agents (4)
Agent Adverse Eventsa
SSRI
citalopram Increased
escitalopram Increased
fluoxetine Increased
paroxetine Increased
sertraline Increased
Serotonin-norepinephrine reuptake inhibitor
duloxetine SIADH, hypertension
venlafaxine Hypertension (dosage related)
Norepinephrine dopamine reuptake inhibitor
bupropion Seizures
Other
mitazapine Edema
SIADH, syndrome of inappropriate antidiuretic hormone secretion.
a
Urinary retention is a common adverse event with all agents.
Reprinted from Nephrology Nursing Journal, 2008, Volume 35, Number 3, pp 257–263 (reference 4). Reprinted with permission of the publisher, the American
Nephrology Nurses’ Association (ANNA), East Holly Avenue, Box 56, Pitman, NJ 08071-0056; 856-256-2320; FAX 856-589-7463; E-mail: nephrologynursing@ajj.com; Web
site: www.annanurse.org.
Lithium
Used widely since the 1940s as an effective
treatment for bipolar and major depressive disorders,
lithium therapy may also be beneficial in delaying
progression of amyotrophic lateral sclerosis and effec-
tive in Alzheimer’s disease, thus widening its thera-
peutic spectrum (10,11). A recent review of lithium
nephrotoxicity by Grunfeld and Rossier (12) discussed
the tubulointerstitial injury that is caused by lithium
and the consequent nephrogenic diabetes insipidus that
results from downregulation of aquaporin 2 water
channel expression. After undergoing glomerular fil-
tration and significant proximal tubular resorption (up
to 80%), only a small amount of filtered lithium enters
the distal nephron and undergoes further resorption via
the epithelial sodium channel on the apical membrane
of the collecting duct principal cell. Nonetheless, toxic
intracellular lithium levels may arise and are associ-
ated with inhibition of glycogen synthase kinase 3
␤-signaling pathways, which may be involved in the
maintenance of primary cilia (13). It is interesting that
the tubular microcystic transformation that is accom-
panied by interstitial fibrosis and FSGS-type lesions in
lithium-treated patients may mirror the same micro-
cystic changes that are seen in inherited cystic kidney
diseases (e.g., autosomal dominant polycystic kidney
disease), in which primary cilia abnormalities have
recently been implicated (14). Amiloride blocks the
235
Dosage Reduction for Ccr
<30 ml/min ⴙ ESRD
bleeding, SIADH None
bleeding, SIADH None
bleeding, SIADH None
bleeding, SIADH Yes
bleeding, SIADH None
Avoid
Yes
Yes
Yes
epithelial sodium channel from allowing lithium to
enter the principal cell and has demonstrated reversal
of polyuria and isosthenuria (15). Whether long-term
amiloride therapy, started early in a patient’s lithium
regimen, can prevent the chronic tubulointerstitial in-
jury that is incurred by lithium exposure remains to be
seen. Nephrologists are often asked to see lithium-
treated patients in consultation for a variety of signs
and symptoms that are associated with nephrogenic
diabetes insipidus, including polyuria and hypernatre-
mia; acute renal failure with concomitant angiotensin-
converting enzyme inhibitor use (16) and azotemia as
a result of chronic impairment of renal function. Im-
portant drug interactions that can lead to an abrupt rise
in serum lithium levels and acute lithium intoxication
include concomitant use of diuretics (particularly thia-
zides) (17), NSAIDs (18), and angiotensin-converting
enzyme inhibitors/angiotensin receptor blockers (19).
In addition, management of lithium-induced renal tu-
bular acidosis, hypercalcemia, hypothyroidism, and
intoxication that requires acute dialysis therapy man-
dates consultation with a nephrologist. Signs and
symptoms of lithium intoxication (both chronic and
acute) as well as the indications for dialysis interven-
tions can be found in dialysis and critical care hand-
books and are not discussed here. Numerous review
articles that discuss lithium and the kidney are avail-
able (20).
236
References
1. Tossani E, Cassano P, Fava M: Depression and renal disease. Semin
Dial 18: 73– 81, 2005
2. Hedayati SS, Minhajuddin AT, Toto RD, Morris DW, Rush AJ:
Prevalence of major depressive episode in CKD. Am J Kidney Dis 54:
424 – 432, 2009
3. Kimmel PL, Peterson RA: Depression in patients with end-stage
renal disease treated with dialysis: Has the time to treat arrived? Clin
J Am Soc Nephrol 1: 349 –352, 2006
4. Raymond CB, Wazny LD, Honcharik PL: Pharmacotherapeutic op-
tions for the treatment of depression in patients with chronic kidney
disease. Nephrol Nurs J 35: 257–263, 2008
5. Jacob S, Spinler SA: Hyponatremia associated with selective seroto-
nin-reuptake inhibitors in older adults. Ann Pharmacother 40: 1618 –
1622, 2006
6. Mort JR, Aparasu RR, Baer RK: Interaction between selective sero-
tonin reuptake inhibitors and nonsteroidal antiinflammatory drugs:
Review of the literature. Pharmacotherapy 26: 1307–1313, 2006
7. Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 352:
1112–1120, 2005
8. van Geffen EC, Hugtenburg JG, Heerdink ER, van Hulten RP,
Egberts AC: Discontinuation symptoms in users of selective seroto-
nin reuptake inhibitors in clinical practice: Tapering versus abrupt
discontinuation. Eur J Clin Pharmacol 61: 303–307, 2005
9. Adnet P, Lestavel P, Krivosic-Horber R: Neuroleptic malignant
syndrome. Br J Anaesth 85: 129 –135, 2000
10. Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca
ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano
G, Isidoro C, Murri L, Ruggieri S, Paparelli A: Lithium delays
progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci
U S A 105: 2052–2057, 2008
11. Martinez A, Perez DI: GSK-3 inhibitors: A ray of hope for the
treatment of Alzheimer’s disease? J Alzheimers Dis 15: 181–191,
2008
12. Grunfeld JP, Rossier BC: Lithium nephrotoxicity revisited. Nat Rev
Nephrol 5: 270 –276, 2009
13. Thoma CR, Frew IJ, Krek W: The VHL tumor suppressor: Riding
tandem with GSK3beta in primary cilium maintenance. Cell Cycle 6:
1809 –1813, 2007
14. Gunay-Aygun M: Liver and kidney disease in ciliopathies. Am J Med
Genet 151C: 296 –306, 2009
15. Batlle DC, von Riotte AB, Gaviria M, Grupp M: Amelioration of
polyuria by amiloride in patients receiving long-term lithium therapy.
N Engl J Med 312: 408 – 414, 1985
16. Lehmann K, Ritz E: Angiotensin-converting enzyme inhibitors may
cause renal dysfunction in patients on long-term lithium treatment.
Am J Kidney Dis 25: 82– 87, 1995
17. Jefferson JW, Kalin NH: Serum lithium levels and long-term diuretic
use. JAMA 241: 1134 –1136, 1979
Table 10. Newer anticonvulsant drugs
Drug Dosage Reduction for Ccr <50 ml/min
Gabapentin Yes (CNS toxicity)
Felbamate Yes
Lamotrigine No
Levetiracetam Yes
Oxcarbazepine Avoid (hyponatremia)
Pregabalin Yes
Topiramate Yes (renal calculi; RTA)
Zonisamide Yes (renal calculi; RTA)
CNS, central nervous system; HD, hemodialysis; RTA, renal tubular acidosis.
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
18. Reimann IW, Frolich JC: Effects of diclofenac on lithium kinetics.
Clin Pharmacol Ther 30: 348 –352, 1981
19. Vipond AJ, Bakewell S, Telford R, Nicholls AJ: Lithium toxicity.
Anesthesia 51: 1156 –1158, 1996
20. Gitlin M: Lithium and the kidney: An updated review. Drug Saf 20:
231–243, 1999
Anticonvulsant Drugs
Older Anticonvulsant Drugs
Despite their categorical name, anticonvulsant
drugs (ACDs) are used to treat an array of conditions
other than seizure disorders, including pain associated
with peripheral neuropathy (gabapentin and pregaba-
lin) and dementia-associated agitation (valproic acid).
The use of such agents for patients with chronic
kidney disease (CKD) was reviewed by Israni et al.
(1), who broadly categorizes them into two groups:
Those that were available before the 1990s (“older”)
and those that were developed more recently
(“newer”). Newer anticonvulsants were developed to
display more desirable pharmacokinetic properties
such as rapid and complete absorption from the gas-
trointestinal tract (100% bioavailability), linear kinet-
ics (predictable drug concentrations at a given dos-
age), fewer drug– drug interactions, and less reliance
on hepatic metabolism. As such, many of the newer
compounds rely on renal excretion for elimination
from the body and thus warrant dosage reduction in
the setting of renal impairment, as shown in Table 10.
Of the older ACDs, phenytoin highlights the
complex nature of altered pharmacologic properties
found in the setting of CKD. Phenytoin is highly
protein bound (⬎90%), with only the unbound, or
“free,” fraction (⬍10%) demonstrating pharmacologic
activity. In the uremic milieu of advanced kidney
disease, however, waste products displace phenytoin
from its binding protein, resulting in a greater free
Supplement Dose after HD
Yes
Avoid
Unknown
Yes
Avoid
Yes
Avoid (renal calculi)
Avoid (renal calculi)
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
fraction. As such, one might be tempted to decrease
the dosage of phenytoin for patients with advanced
CKD, but this would be incorrect. That more of the
drug is unbound means that more is available to
undergo hepatic metabolism, increasing clearance of
the drug (2). As a result, the dosage of phenytoin is
generally not altered for dialysis patients, but it is
imperative to monitor free phenytoin levels (therapeu-
tic range 1 to 2 mg/L), not “total” phenytoin levels
(typically 10 to 20 mg/L), in this patient population.
Because phenytoin is metabolized by hepatic P450
enzymes, concurrent use of medications that either
induce or inhibit this enzyme system may lead to
subtherapeutic or toxic phenytoin levels, respectively,
and should trigger increased drug monitoring of free
phenytoin levels. Fosphenytoin, a phenytoin prodrug
administered intravenously, can further complicate
care because its metabolite can cross-react with phe-
nytoin assays, leading to falsely elevated levels (3).
Hyponatremia is a frequent complication of car-
bamazepine therapy, although it is poorly understood
mechanistically (4). It may be caused by increased
vasopressin release or a more robust vasopressin re-
ceptor effect at the level of the collecting duct or
resetting of the hypothalamic osmoreceptors. Valproic
acid, like phenytoin and carbamazepine, is highly
protein bound and metabolized by the liver and under-
goes little renal elimination. All three agents have
been associated with interstitial nephritis. Fanconi
syndrome and hyponatremia have also been linked to
valproic acid use, and, rarely, hepatic failure has been
reported (5). Phenobarbital has been linked to mega-
loblastic anemia and osteomalacia, which may be
difficult to interpret given the accompanying bone
disease and anemia seen with CKD. Some dosage
reduction of phenobarbital may be in order with ad-
vanced CKD, because roughly 25% of a given dose
undergoes renal elimination (6). Ethosuximide is note-
worthy because of its potential for causing drug-
induced systemic lupus erythematosus, including lu-
pus nephritis (7).
Newer ACDs
Gabapentin is used for seizure disorders, spastic-
ity, and peripheral neuropathy pain. Like most of the
newer ACDs, it is not significantly protein-bound nor
metabolized by the liver and is eliminated from the
body by glomerular filtration. As such, drug accumu-
lation will occur in patients with reduced renal func-
237
tion, particularly those with severe impairment, unless
dosage reduction occurs (8). Gabapentin toxicity is
characterized by CNS symptoms including nystagmus,
ataxia, tremor, somnolence, and even coma in extreme
cases; use of hemodialysis to remove excess drug can
reverse these symptoms (9). Pregabalin is used for
seizure disorders, fibromyalgia, diabetic peripheral
neuropathy, and postherpetic neuralgia. Like gabapen-
tin, pregabalin is minimally protein-bound and elimi-
nated by the kidney with over 90% appearing un-
changed in the urine thus necessitating dose reduction
in CKD (10). Hemodialysis significantly reduces pre-
gabalin levels. Levetiracetam like gabapentin and pre-
gabalin is not highly protein-bound and not hepatically
metabolized. It undergoes glomerular filtration and
thus its dose must be reduced in severe CKD patients
(11). It is also significantly removed by dialysis and
thus should be administered following dialytic therapy
(11). Topiramate (12) and zonisamide (13) both inhibit
carbonic anhydrase and thus are associated with renal
tubular acidosis, metabolic acidosis, and renal stone
formation. Topiramate like other new ACDs is more
dependent on the kidney for elimination and dosage
reduction is warranted when GFR is below 30 ml/min;
it may also require supplemental dosing after dialysis
(12). Conversely, zonisamide demonstrates pharmaco-
logic parameters more in line with older ACDs in that
it is metabolized by the liver and moderately protein-
bound with only a third of a dose appearing in the
urine unchanged and dosage reduction not generally
indicated (13). Oxcarbazepine is structurally related to
carbamazepine and is associated with an even higher
incidence of hyponatremia (14). Unlike carbamaz-
epine, the parent compound and active metabolite
undergo renal elimination mandating dose reduction in
the setting of renal impairment (15). Felbamate dis-
plays a narrow therapeutic window with aplastic ane-
mia and hepatic failure complicating its use (16). Up
to 50% appears unchanged in the urine such that dose
reduction in advanced CKD is suggested (17). Both
oxcarbazepine and felbamate affect the cytochrome
P450 enzyme system, however, thus complicating
concomitant use with older ACDs and other hepati-
cally metabolized compounds. Lamotrigine like older
ACDs is metabolized in the liver to an inactive me-
tabolite and not significantly removed by dialysis (18).
Nonetheless, therapeutic concentrations vary widely
between patients, adverse effects do not appear to be
concentration-dependent and thus hard to predict, and
238
pharmacokinetic parameters may be altered with se-
vere kidney impairment (18). Similar to older ACDs,
interstitial nephritis has also been reported with lam-
otrigine (Table 10).
“Traditional” Medications, Food Contaminants,
and Others
The term “traditional” medicine encompasses a
wide array of products that are alternatively referred to
as “herbal,” “natural,” “supplemental,” “nutritional,”
“organic,” “alternative,” “complementary,” and other
labels. Use of such agents is growing worldwide
(exceeding 80% in some populations) and as a result
of nephrotoxic potential accounts for as much as one
third of acute kidney injury where usage is common.
Most of these compounds are produced outside con-
ventional regulatory pathways and as such are prone to
contamination with additional toxins (e.g., L-trypto-
phan contaminant resulting in eosinophilia-myalgia
syndrome) (19).
Renal syndromes that result from exposure to
such agents reflect the area of the kidney damaged,
including glomerular injury (nephrotic syndrome
and thrombotic microangiopathy), tubular injury
(electrolyte wasting, renal tubular acidosis, concen-
trating/diluting defects, and acute tubular necrosis),
hemodynamic disruption (acute renal failure), and
parenchymal injury (crystal nephropathy, nephroli-
thiasis, and obstruction). Nephrologists must be
aware of patient access to such products and include
exposure to these potential toxins in their differen-
tial diagnoses. Luyckx and Naicker (20) reviewed
the renal pathology of many traditional medicines
that are associated with kidney injury, and more
extensive lists can be found in standard references
(Table 1). A variety of nephrotoxic compounds are
discussed briefly.
Aristolochic acid (AA) ingestion can lead to AA
nephropathy (previously termed Chinese herb nephrop-
athy or simply herbal nephropathy), which is character-
ized by tubulointerstitial fibrosis, chronic renal failure
leading to ESRD, and urothelial cancer. The Aristolo-
chia species was mistakenly used in Chinese slimming
agents instead of the less toxic Stephania species
because they share a common herbal name, Fang Ji
(20). Animal models suggested a potential role for
hepatic P450 enzymes in the detoxification process of
AA (21).
Red yeast rice, long used for Chinese medicinal
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
purposes and cooking, is increasingly popular in cap-
sular form as a “natural” cholesterol-reducing agent.
As with other “statins,” however, myopathy and rhab-
domyolysis have occurred in patients who take red
yeast rice, and a mycotoxin, citrinin, found in these
products may cause acute renal failure (22).
A recent case report of lead-induced nephropathy
as a result of ingestion of Ayurvedic herbal remedies
from India by a patient in Toronto, Canada, under-
scores the “global” aspect of nephrotoxic injury asso-
ciated with unregulated products (23). Another exam-
ple of nephrotoxic injury in an era of globalization
involves melamine, which first appeared in tainted
animal feed and then in contaminated milk-based in-
fant formula, both manufactured in China but distrib-
uted worldwide. Melamine nephrotoxicity seems to
stem from precipitation of melamine-cyanuric acid
crystals in the distal tubule and renal papillae with
chronic inflammation, tubular necrosis, and stone for-
mation resulting, although much of what is know
comes from animal data (24). Melamine nephropathy
can be added to the long list of crystal-induced/lithogenic
renal diseases that are associated with both prescription
and nonprescription medications, including herbal/tradi-
tional compounds, as listed in Table 11.
Use of Extracorporeal Measures to Remove
Drugs and Chemicals
It is beyond the scope of this issue of NephSAP
to present an exhaustive discussion or comprehensive
list of all compounds that are removed by extracorpo-
real methods, but broad categories include pharmaceu-
Table 11. Agents associated with crystal nephropathy
Melamine-cyanuric acid
Silica-containing “supplements” (27)
Star fruit, Ma Huang, rhubarb, Djenkol beans, cranberry
juice
Pseudoephedrine (28)
Vitamin C
Aspirin
Acycolovir
Methotrexate
Indinavir
Foscarnet
Sulfonamide
Triamterene
Ciprofloxacin
Ampicillin
Cephalexin
Adapted from references 26 –28.
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Table 12. Properties of compounds that are removed by extracorporeal clearance methods
HD HP
Small molecule (⬍500 Da) Adsorbed by AC
Small Vd (⬍1L/kg) Small Vd
Minimally protein bound Minimally protein bound
Low endogenous clearance Low endogenous clearance
Water soluble – –
AC, activated charcoal; HD, hemodialysis; HF, hemofiltration; HP, hemoperfusion.
tical agents as well as inorganic metals, solvents,
alcohols, herbicides, insecticides, and plant or animal
venom. Extracorporeal methods to enhance elimina-
tion of substances from the body have included dial-
ysis, hemoperfusion, and hemofiltration. It may be
helpful to know basic principles that pertain to each of
these methods so that effective removal of toxic sub-
stances can be achieved rapidly and cost-effectively.
Table 12 outlines differences among these techniques.
Hemoperfusion involves passage of blood through an
extracorporeal column that contains activated charcoal
to which certain compounds may adsorb. Previously
used for theophylline, procainamide, or carbamaz-
epine overdose, hemoperfusion has largely been re-
placed by high-flux/high-efficiency dialysis and/or he-
mofiltration. Information regarding drug or toxin
removal can be readily obtained from poison control
centers, toxicology departments, and online resources
as well as textbooks such as Medical Toxicology (25).
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239
HF
Small/midsize (up to 40,000 Da)
Small Vd
Higher % protein bound
Low endogenous clearance
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Ed., edited by Dart RC, Philadelphia, Lippincott Williams & Wilkins,
2004, pp 269 –280
26. Perazella MA: Crystal-induced acute renal failure. Am J Med 106:
459 – 465, 1999
27. Flythe JE, Rueda JF, Riscoe MK, Watnick S: Silicate nephrolithiasis
after ingestion of supplements containing silica dioxide. Am J Kidney
Dis 54: 127–130, 2009
240
28. Smith CL, Gemar SK, Lewis MJ: Pseudoephedrine urolithiasis asso-
ciated with acute renal failure. Neprhol Dial Transplant 19: 263–264,
2004
Immunosuppressive Therapies
Induction Therapy
Polyclonal antibodies were the first class of bi-
ological agents used for the induction or treatment of
acute cellular rejection. The discovery of hybridoma in
1975 provided a new direction to manufacture several
different mAbs for diagnostic and therapeutic pur-
poses (1). OKT-3 was the first monoclonal biological
agent for the treatment of acute rejection. OKT-3
targets the CD3 complex expressed on mature T cell
receptors (1,2). Biological agents that were found to be
effective in the treatment of acute rejection were then
used for induction therapy in the early posttransplan-
tation period (3,4). These agents provide a high and
rapid level of immunosuppression in the vital early
posttransplantation period, when the risk for acute
rejection is highest. Although induction therapy is not
indicated for most patients, it is proved to decrease
acute rejection early after transplantation and improve
long-term allograft survival rate in immunologically
high-risk kidney transplant recipients. Patients who
benefit most from induction therapy include those with
preformed antibodies (panel-reactive antibodies ⬎20%),
previous organ transplants, delayed graft function,
HLA mismatches, multiorgan transplantation, and pro-
longed cold ischemic time and patients with expanded-
criteria donors (5). More important, the use of biolog-
ical agents early after transplantation allow for a delay
in the use of calcineurin inhibitors (CNIs) to avoid
associated nephrotoxicity (6). Induction therapy with
biological agents with T cell– depleting properties (an-
tilymphocyte antibodies, OKT-3, the antithymocyte
antibodies, and alemtuzumab) may also treat early
subclinical acute rejection or clinical acute rejection
during delayed graft function, a time when renal func-
tion cannot be assessed correctly via computation of
urine output and elevation of serum creatinine or other
urinary biomarkers (7–9). Cytokine release syndrome
is a common complication of T cell– depleting agents
after the first two doses and requires high-dosage
methylprednisolone (1 mg/kg), diphenhydramine, and
acetaminophen 30 to 60 minutes before infusion and
every 4 to 6 hours as needed (2,3).
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Basiliximab and Daclizumab
In the past two decades, a greater understanding
of the immunobiological processes that are involved in
allograft rejection have led to significant discoveries in
the field of clinical transplantation and production of
humanized and chimeric antibodies. Compared with
traditionally engineered mAbs or polyclonal antibod-
ies, these newer biological agents have not been asso-
ciated with cytokine release reactions and have been
associated with a very limited increased risk for op-
portunistic infections (8,10).
During acute cellular rejection, T cells are stim-
ulated. Activation of T cells and other cytokines re-
sults in activation of IL-2 receptor (IL-2R) ␣ chain
(CD25), which is located on the surface of antigen-
active T cells. IL-2 is an important cytokine that
activates cytotoxic T cells and increases helper T cell
proliferation, magnifying the allograft rejection cas-
cade. In addition, IL-2 may affect the proliferation of
natural killer cells, macrophages and monocytes, B
cells, epidermal dendritic cells, and lymphocyte-acti-
vated killer cells. Inhibition of IL-2 may ultimately
decrease inflammatory responses and allograft rejec-
tion (11,12).
Basiliximab and daclizumab are engineered
IgG1 mAbs that bind to the ␣ chain of the IL-2R
(CD25), which is expressed on the surface of activated
lymphocytes (6 – 8). The IL-2R is made of three high-
affinity subunits: The ␣ subunit (TAC antigen or
CD25), the ␤ subunit (CD122), and the ␥ subunit
(CD132). For transduction of an inflammatory signal
or activate T cells, ␣ subunit and ␤ subunit binding is
necessary. Daclizumab and basiliximab exert their ef-
fects by binding to the ␣ subunit of the IL-2R, thereby
acting as a competitive inhibitor of IL-2 (13–15).
Daclizumab is a humanized antibody in which
portions of the variable region that are not associated
with the binding site are replaced by human amino
acid sequences to decrease immunogenicity; therefore,
⬎90% of the antibody is human IgG, and only hyper-
variable regions are mouse antibody sequences. In
contrast, basiliximab is a chimeric antibody in which
the murine constant region of the Ig is replaced by
human amino acid sequences. Basiliximab is con-
structed by combining mouse variable regions with the
constant region of human IgG1 (13–15).
The efficacy and safety of both daclizumab and
basiliximab have been proved in a number of clinical
studies. Compared with placebo, at 12 months, a
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
significant reduction in acute rejection was reported in
the daclizumab-treated group (43 versus 28%; P ⬍
0.001); however, there was no statistical difference in
patient and allograft survival at 3 years (16,17).
Basiliximab and daclizumab are well tolerated.
In addition, administration of these agents has not
been associated with significant clinical toxicity or
cytokine release syndrome (fever, chills, headache,
and pulmonary edema), which is commonly observed
with T cell– depleting muromonab-CD3 therapy. Ad-
verse effects that are observed among basiliximab- and
daclizumab-treated patients are similar to those of
placebo-treated patients. No drug interactions have
been reported with the use of basiliximab and dacli-
zumab. The dosage of basiliximab is 20 mg intrave-
nously and should be given before the transplant
followed by a second 20-mg dose on day 4 after
transplantation.
The Food and Drug Administration–approved
dosages of daclizumab are 1 mg/kg within 24 hours of
transplant surgery and then 1 mg/kg administered
every 2 weeks after surgery for a total of five doses;
however, most transplant protocols dictate a two doses
with a preoperative dose and another dose at the time
of discharge (18). No dosage adjustment is necessary
in renal impairment, but no data are available for
dosage adjustments in hepatic dysfunction. Safety is
one of the most evident benefits of induction therapy
with IL-2R antibodies compared with other induction
agents. In 2010, Roche Pharmaceuticals and Diagnos-
tics will discontinue commercialized daclizumab for
organ transplant patients.
Antithymocyte Globulin Equine/Rabbit
Polyclonal antibodies such as equine and rabbit
antithymocyte globulin react with a number of T cell
surface receptors, including CD2, CD3, CD4, CD8,
CD11a, CD25, CD40, and CD54. Polyclonal antibod-
ies exert their pharmacodynamic properties in three
different ways. Initially, by binding to cell surface
markers, antithymocyte globulin may promote cell
lysis through complement-mediated process. Second,
antithymocyte globulin promotes T cell depletion
through opsonization by the reticuloendothelial sys-
tem. Finally, antithymocyte globulin provides immu-
nosuppression through vital T cell surface molecule
(CD2, CD3) inversion and modulation. Although
modulated cells are circulating, in general, these cells
are inactive and dysfunctional. Because of greater
potency and ease of administration, rabbit antithymo-
241
cyte globulin is the preferential agent over equine
antithymocyte globulin (19).
After T cell lysis, there is a significant release of
cytokines. Release of cytokines after the first two
doses is attributed to infusion-related reactions such as
fever and chills (70%); headache (40%); serum sick-
ness and back pain (40%); nausea, diarrhea, and diz-
ziness (30%); and myelosuppression (leukopenia and
thrombocytopenia; 45%) (20). The common dosing
strategy of thymoglobulin for the treatment of acute
rejection is 1 to 1.5 mg/kg per d for 7 to 10 days with
T cell monitoring. When used for induction therapy,
the dosage is 1.5 mg/kg for two to four doses. Equine
antithymocyte globulin is administered at 10 to 15
mg/kg per d intravenously for 10 to 14 days for
treatment of acute rejection and up to 7 days for
induction therapy. The first dose usually begins during
the preoperative period or shortly after transplantation.
For both equine antithymocyte globulin and rabbit
antithymocyte globulin, the first two doses should be
given over 6 hours after administration of methylpred-
nisolone intravenously, and acetaminophen and di-
phenhydramine should be given 30 to 60 minutes
before the dose and as needed every 6 hours for fever,
chills, and other infusion-related reactions. Compared
with Atgam, which must be administered through a
central line, rabbit antithymocyte globulin can be
given through a peripheral line with addition of hep-
arin and hydrocortisone to 500 ml of normal saline
solution (21).
Muronomab-CD3 (OKT-3)
Since introduction of rabbit antithymocyte glob-
ulin, the use of OKT-3 has been limited only to
patients with acute cellular rejection that is resistant to
other agents. CD3 is expressed on activated T cells,
and OKT-3 is a murine mAb that targets the CD3
receptor. Webster et al. (22) reviewed 21 studies (49
reports, 1387 patients) of the use of T cell– depleting
agents for the treatment of steroid-resistant rejection.
There was no benefit of muromonab-CD3 over either
equine or rabbit antithymocyte globulin with regard to
treatment of rejection, preventing subsequent rejec-
tion, or preventing graft loss or death. OKT-3 induces
T cell depletion through antibody-dependent cell cy-
totoxicity (ADCC), cell coating, and antigenic modu-
lation. Most likely, the ADCC and cell coating are
more important initially, whereas modulation is more
important later. OKT-3 binds to the CD3 receptor
epitope of the T cell receptor portion of the T lym-
242
phocyte cell membrane. Coating this target molecule
prevents activation of T lymphocytes and facilitates
lymphocyte removal from circulation via opsonization
through ADCC (23,24).
This agent is dosed at 2 to 5 mg/d for the
treatment of acute rejection or induction and usually is
given for a total of 10 to 14 days. When used alone,
OKT-3 may induce a rapid and strong human anti-
mouse antibody, which limits its use as an immuno-
suppressive agent.
The major adverse effects of OKT-3 are flu-like
symptoms; fever, chills, nausea, vomiting, diarrhea,
and headache are most often observed after the first
two doses. These reactions are related to release of
cytokines from activated T lymphocytes and mono-
cytes. Fatal pulmonary edema has been observed
among patients with fluid overload or in patients with
uncompensated heart failure. Capillary leak syndrome
results from cytokine release and is thought to be a
contributory factor to the development of pulmonary
edema. Before use of OKT-3, the weight of the patient
should be within ⱕ3% of minimum dry weight, and a
chest x-ray should be obtained within 24 hours to rule
out any evidence of pulmonary edema. OKT-3 has
also been associated with cytokine-induced nephrop-
athy. Because of these adverse drug reactions and
safer T cell– depleting agents, the role of OKT-3 is
limited to the treatment of severe acute rejection
(23,24).
Alemtuzumab
Preliminary results from a number of single-
center studies suggested that alemtuzumab could be an
important agent for prevention of allograft rejection.
Alemtuzumab is a recombinant DNA-derived mAb
that binds to CD52 and causes profound lymphopenia.
Alemtuzumab is not approved in transplantation and is
used primarily for the treatment of B cell lymphocytic
leukemia. CD52 is located on the cell surface of B and
T lymphocytes, many macrophages, natural killer
cells, and a subpopulation of granulocytes. Alemtu-
zumab affects B and T cells through complement-
mediated or antibody-dependent cell lysis. When used
for induction therapy, after a single dose of 30 mg,
alemtuzumab produces extensive and prolonged im-
munosuppression (25). A study of the use of a single
30-mg dose preoperatively showed a low acute rejec-
tion rate with a lower risk for infections in high-risk
recipients (21).
The reported adverse reaction and long-term com-
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
plications after alemtuzumab induction have varied with
the dosage that was used. Anemia, neutropenia, throm-
bocytopenia, headache, infusion-related reactions, and
infections are common after administration of alemtu-
zumab. Premedication with acetaminophen and oral an-
tihistamines is advisable to reduce the incidence of infu-
sion-related reactions (26 –28).
Maintenance Therapy
The objectives of maintenance immunosuppres-
sion are to prevent acute and chronic allograft rejec-
tion. Maintenance immunosuppression should mini-
mize the risk for rejection while improving the quality
of life and reduce the rate of allograft loss or death. To
balance the risk for rejection and infection/malig-
nancy, drugs must be selected with vigilance and
dosage should be titrated according to plasma drug
concentration or the risk for adverse drug reactions. In
addition, optimized patient and graft survival can be
acquired through avoidance or discontinuation of
drugs with the highest risk for toxicities; however,
sudden discontinuation of immunosuppression may
increase the risk for late rejection, which is a proven
poor prognosis and increases the risk for chronic
allograft nephropathy.
The most commonly used maintenance immuno-
suppressants include a double or triple protocol that
consists of the following classes of drugs: CNIs (cy-
closporine [CsA] and tacrolimus), antiproliferatives
(azathioprine and the mycophenolic acid [MPA] de-
rivatives), target of rapamycin (TOR) inhibitors
(sirolimus and everolimus), and corticosteroids (meth-
ylprednisolone and prednisone derivatives). Comorbid
medical conditions as well as potential drug interac-
tions that may affect long-term graft survival or in-
crease the risk for adverse drug reactions should be
considered. For example, although it is not contrain-
dicated, for patients who have a history of gout and are
taking allopurinol, the use of azathioprine should be
avoided or the dosage adjusted to 0.5 mg/kg per d.
Calcineurin Inhibitors
Both CsA and tacrolimus belong to a class of
immunosuppressants called CNIs (29). CsA and ta-
crolimus bind to their specific immunophilins and
inhibit dephosphorylation of N-FAT molecules. The
introduction of CNIs was associated with a significant
improvement in both patient and allograft survival at 1
year. CsA is a cyclic undecapeptide, which was dis-
covered from fungus isolated from Norwegian soil
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
(Tolypocladium inflatum) (29). In 1972, CsA was
initially used in preclinical and clinical transplantation
(30). CsA effects the activation and proliferation of T
lymphocytes through inhibition of IL-2 transcription.
The oral absorption of CsA is slow, erratic, and in-
complete, ranging from 10 to 70% with a mean bio-
availability of approximately 30%. Peak blood con-
centrations are usually achieved 2 to 6 hours after
administration of the standard formulation. The plasma
concentration at 2 hours has much better correlation to
the area under the curve (AUC) and clinical benefit of
CsA when compared with 12-hour trough levels (31).
Most centers, however, still use 12-hour trough levels
for CsA monitoring. Even though 2-hour levels corre-
late with AUC much better than trough levels, 2-hour
plasma concentration monitoring is not practical for
centers with many transplant patients (32). The ab-
sorption of CsA is subject to significant inter- and
intrapatient variability and can be affected by the
presence of food, fat content in the food, gastrointes-
tinal motility, and diarrhea (33). For improvement of
the pharmacokinetic properties of CsA and decrease
inter- and intrapatient variability, a microemulsion
formulation of CsA (Neoral) was developed in the
early 1990s. Despite better pharmacokinetic proper-
ties, microemulsion CsA has not resulted in better
patient or graft survival. The pharmacokinetics of CsA
follows a zero-order kinetic model and is subject to a
significant enterohepatic redistribution (recycling)
(34). CsA is widely distributed throughout the body
and is highly tissue bound. The volume of distribution
ranges from an average of 3.5 to 13.0 L/kg. CsA is
extensively metabolized through the cytochrome P450
IIIA4 isoenzyme system (35). The clearance of CsA is
higher in children compared with adults, and only 1%
of the drug is excreted unchanged through the urine.
Dialysis or renal dysfunction does not affect the phar-
macokinetics of CsA; therefore, CsA can be given
before or after any type of renal replacement therapy.
Nephrotoxicity and hypertension are commonly re-
ported with CsA (36,37). These adverse reactions are
concentration dependent. CsA nephrotoxicity has been
observed in 20 to 30% of kidney, heart, and liver
transplant recipients (36,37). This nephrotoxicity is
particularly important when CsA is used in patients
with marginal kidney function or in patients with
delayed graft function (38). Hypertension, fluid reten-
tion, hyperkalemia, hyperchloremia, and metabolic ac-
idosis are also frequently observed in CsA-treated
243
patients. Other functional manifestations of CsA neph-
rotoxicity are hypomagnesemia, hyperuricemia, and
hypocalcemia, which are independent of changes in
serum creatinine. Acute dosage-dependent nephrotox-
icity associated with CsA is usually reversible within
1 week with appropriate dosage reduction (31,39).
The most serious dosage-independent and irrevers-
ible toxicity of CsA is a progressive chronic nephropa-
thy. Therapeutic drug monitoring has a very limited
correlation with chronic histopathologic changes (31,38).
Some patients may develop ESRD and require renal
replacement therapy. Kidney biopsy in patients with CsA
nephrotoxicity suggests afferent arteriolopathy and a
striped pattern of tubulointerstitial atrophy and fibro-
sis. Finally, hemolytic uremic syndrome and acute
thrombotic thrombocytopenic purpura are significant
but rare adverse effects of CsA therapy.
Although the exact mechanism of CsA-in-
duced hypertension has not been elucidated, hyper-
tension is a common problem after transplantation,
even in patients with stable renal function. Although
hypertension is dosage and concentration depen-
dent, it can be observed in patients with therapeutic
or subtherapeutic plasma concentrations. Plasma
renin activity is usually normal or only mildly
elevated in CsA-treated patients with hypertension,
suggesting that hypertension in these patients is
mostly volume dependent (2,40).
Other major adverse effects of CsA are listed in
Table 13. Most of these adverse reactions can largely
be managed by careful therapeutic drug monitoring.
The most common oral adult dosage of CsA
ranges from 3 to 5 mg/kg per d in two divided doses
in transplant patients, whereas 1 to 3 mg/kg per d is
common for most autoimmune diseases. When con-
verting a patient from oral to intravenous administra-
tion, the dosage should be reduced to approximately
one third of the oral dose and not exceed more than 2
mg/kg per d. A number of CsA assays (HPLC, thera-
peutic drug monitoring, polyclonal, and monoclonal)
with different specificity for parent compounds or
inactive metabolites exist, creating an associated range
of therapeutic whole-blood concentrations. The type
of assay, renal function, comorbid conditions, and
time since transplantation all may affect desirable
plasma concentrations after transplantation. The ther-
apeutic range for more specific assays of CsA is
between 150 and 250 ng/dl (33,41).
244 Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Table 13. CsA and tacrolimus drug– drug interactions

Drug Mechanism Effects Severity Comments
ACEIs Renal dysfunction in RAS 1 serum creatinine 3 Physiologic elevation of
creatinine; anemia;
class effects
Acyclovir Inter-renal crystallization Stone formation 4 Avoid dehydration;
infuse over 1 hour
Amiodarone 2 clearance Nephrotoxicity 3 Very slow onset and
offset
Amlodipine 2 clearance 1 CNI level 4 Nifedipine is preferred
dihydropiradine
Amphotericin B Synergistic nephrotoxicity Nephrotoxicity 3 Require hydration and
electrolyte monitoring
Carbamazepine 1 clearance 2 CNI level 3 Slow onset (up to 7
days)
Chloroquine 2 clearance 1 CNI level 3
Cholestyramine 1 clearance 2 CNI level 4 Separate doses by 3
hours
Ciprofloxacin Possible 2 CSA effects Pharmacodynamic 4 May increase risk for
on IL-2 antagonism rejection
Clarithromycin 2 clearance 1 CNI level 2 Azithromycin is the
preferred agent
Clotrimazole troches 2 clearance of TAC Increase TAC level 3 Monitor TAC level
closely; no effect on
CsA
Colchicine Synergistic toxicity Increase neurotoxicity 3 Gastrointestinal
dysfunction and
neuromyopathy
Co-trimoxazole Inhibit creatinine Increase serum creatinine 4 Preferred agent for
secretion pneumocystis
pneumonia
Digoxin CSA may 2 clearance of Increase digoxin level 3 Monitor digoxin level
digoxin closely
Diltiazem 2 clearance 1 CNI level 3 Can be used to raise
CNI level when
needed
Erythromycin 2 clearance 1 CNI level 2 Azithromycin is the
preferred agent
Fluconazole 2 clearance 1 CNI level 3 Increase liver function
tests also
Fluvoxamine 2 clearance 1 CNI level 2
Fosphenytoin 1 clearance 2 CNI level 3 Monitor levels carefully
HMG-CoA reductase 2 clearance of statins Myopathy; 3 Less effect with TAC;
inhibitors (statins) (greater effect with rhabdomyolysis pravastatin is
CSA) preferred because it
has the least
interaction
Itraconazole 2 clearance 1 CNI level 3 Monitor levels
carefully; decrease
dosage 50 to 85%
Ketoconazole 2 clearance 1 CNI level 3 Monitor levels
carefully; decrease
dosage 25 to 75%
Methylprednisolone 2 clearance 1 CNI level 3 Only at high dosages
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Table 13. CsA and tacrolimus drug– drug interactions
Drug Mechanism
Metoclopramide 2 gastric emptying time
NSAIDs/COX-2 Synergistic nephrotoxicity
inhibitors
Phenobarbital 1 CNI clearance
Phenytoin 1 CNI clearance
Rifabutin 1 CNI clearance
Rifampin 1 CNI clearance
Verapamil 2 CNI clearance
1, Avoid combination; 2, usually avoid (use only no other alternative agents available); 3, monitor closely; 4, no action needed (the risk for adverse drug reaction is
small). ACEI, angiotensin-converting enzyme inhibitor; NSAID, nonsteroidal anti-inflammatory drug; RAS, renin-angiotensin system; TAC, tacrolimus.
Tacrolimus (FK-506)
Tacrolimus (Prograf, FK-506) is another CNI
produced from Streptomyces tsukubaensis, a fungal
organism found in Japanese soil (42,43). Tacrolimus
can be administered orally or by continuous intrave-
nous infusion and is approximately 20 to 25% bio-
available when given orally, although this ranges from
5 to 30%. The usual initial oral dosage for tacrolimus
ranges from 0.1 to 0.2 mg/kg per d in two divided
doses. When converting a patient from oral to intra-
venous administration, the dosage should be reduced
to approximately 15 to 20% of the total daily oral
dosage. Tacrolimus is highly bound to albumin, ␣-1
acid glycoprotein, and erythrocytes. Changes in
plasma protein binding can alter the pharmacokinetic
properties of tacrolimus. The usual therapeutic plasma
concentration of tacrolimus is 5 to 15 ng/ml (44). The
concentration of tacrolimus is significantly higher in
whole blood compared with plasma concentration.
Thus, whole blood should be used for therapeutic drug
monitoring of tacrolimus. Like CsA, tacrolimus is
primarily metabolized in the liver via the cytochrome
P450-IIIA4 system; however, tacrolimus is more sub-
ject to important drug interactions compared with
CsA.
Like CsA, tacrolimus is a prodrug and shares
similar molecular targets even though tacrolimus is
structurally dissimilar. Similar to CsA, the exact se-
quence of events that lead to the immunosuppressive
action of tacrolimus has not been elucidated. Tacroli-
245
Effects Severity Comments
1 CNI level 3 Increased peak and
AUC by 25 to 50%
Nephrotoxicity 3 CNI induced
vasoconstriction is
exacerbated by
prostaglandin
inhibition
2 CNI level 3 Slow onset, slow offset
2 CNI level 3
2 CNI level 3 Rifabutin is a less
potent hepatic enzyme
inducer than rifampin
2 CNI level 2
1 CNI level 3 Anticipate decrease in
CNI dosage
mus binds to a high-affinity intracellular FK-binding
protein (FK-BP-12). The complex of FK-BP-12 and
tacrolimus inhibits calcineurin, which interacts with a
calcium/calmodulin-dependent serine/threonine phos-
phatase. Dephosphorylation is essential for activation
of N-FAT and activation of IL-2 transcriptions. Thus,
tacrolimus exerts its immunosuppressive properties
through inhibition of transcription of IL-2 genes (45).
Nephrotoxicity, hypertension, new-onset post-
transplantation diabetes, and neurotoxicity are the
most common adverse effects of tacrolimus. These
adverse reactions have been primarily observed at
plasma concentrations of ⬎15 ng/dl but can occur at
any plasma concentration. Diabetes usually occurs at
plasma concentrations of ⬎10 ng/dl and with concom-
itant use of prednisone. Nephrotoxicity from tacroli-
mus is much less predictable than with CsA and can
occur over a wide range of plasma concentrations but
generates a pattern of nephrotoxicity similar to CsA.
Although less nephrotoxicity and fewer renal hemo-
dynamic changes were initially reported with tacroli-
mus, more recent reports have documented a very
similar incidence of nephrotoxicity compared with
similarly therapeutic doses of CsA, with an overall inci-
dence of nephrotoxicity that approaches 35 to 40%. Like
CsA, long-term administration of tacrolimus may cause
striped interstitial fibrosis and arteriolar hyalinosis. A
number of metabolic adverse reactions, such hyperkale-
mia, hyperuricemia, and hypomagnesemia, have also
been observed with the use of tacrolimus. Generally,
246
patients who receive tacrolimus require fewer antihy-
pertensive and hyperlipidemic agents compared with
CsA-treated patients, but the overall incidence of new-
onset diabetes is much higher with tacrolimus than
CsA. Alteration in peripheral insulin resistance and a
decrease in insulin release contribute to hyperglycemia
in these patients. Hirsutism and gingival hyperplasia,
which frequently are observed in CsA-treated patients,
are very rare and are not considered a true adverse
effect of tacrolimus (46 – 48).
Generic Formulations of CNIs
As the cost of health care continue to soar, it is
vital to provide a cost-effective immunosuppressive
regimen to provide adequate immunosuppression and
avoid acute rejection while decreasing toxicity and
overall cost related to immunosuppressive agents.
Since approval of the Hatch-Waxman Act in 1983,
generic drugs have provided four major benefits to the
US health care system: (1) Stimulate competition, (2)
expand dollar expenditure for other health care ser-
vices, (3) promote creation of smaller pharmaceutical
companies, and (4) reduce prices (49 –53). Today,
although generic drugs supply 75% of the US market,
they account for only 10% of total drug expenditure
because generic drugs are typically priced at 10 to
50% of innovator products. Although there are some
unproven concerns about the use of generic drugs,
most data support the use of generic immunosuppres-
sive agents for transplant patients. It is important for
nephrologists to have an understanding of generic drug
development, yet in a study of 3639 physicians nation-
wide, only 17% were able to recognize the Food and
Drug Administration standards for bioequivalency for
generic drugs (54).
According to the Food and Drug Administration,
drug products are considered AB rated when test
results provide clinical evidence that generic drugs and
innovator agents are bioequivalent. AB-rated products
ensure safety and efficacy similar to innovator prod-
ucts and are virtually the same as the brand name
product but with a lower price. For drug products to be
regarded as bioequivalent, pharmaceutical equivalence
needs to be demonstrated. Drugs are considered phar-
maceutical equivalents when products have the same
active ingredient(s), dosage form, route of administra-
tion, and strength and provide the same concentration
at the receptor side. Drug products are considered
bioequivalent when pharmaceutical equivalency has
been met and clinical evidence of similar pharmaco-
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
kinetic behavior has been proved (rate, extent of ab-
sorption, AUC, and time to maximal concentration).
Regulatory guidelines state that drug products are AB
rated when the 90% confidence interval for the ratio of
the mean response is within 80 and 125%. This is
different from variation of 80 to 125% of plasma
concentration that has been claimed by a number of
pharmaceutical companies. The use of powerful sta-
tistical criteria and two one-sided tests does not allow
any drug product with a mean plasma difference and
AUC ⬎10% to be approved as an AB-rated agent. In
a study of 2070 clinical bioequivalence studies of
generic drugs in the United States, the average differ-
ence in value of Cmax and AUC between generic and
innovator products was 4.3 and 3.5%, respectively
(55). Differences between branded drugs and generic
drugs can include variations only in shape, color, size,
expiration date, and inactive ingredients; however,
none of these factors should have any effect on drug
pharmacokinetics or pharmacodynamics of a specific
agent.
Azathioprine
Azathioprine is an imidazole analogue of 6-mer-
captopurine (6-MP) that inhibits both de novo and
salvage pathways for T and B lymphocyte prolifera-
tion. Since introduction of mycophenolate mofetil
(MMF) to the market, use of azathioprine has declined
markedly, but it is still an excellent choice for patients
who are intolerant to MMF. After oral administration,
the bioavailability of azathioprine ranges from 50 to
60% with peak plasma concentration at 2 hours. Aza-
thioprine is distributed widely to all body compart-
ments with a volume of distribution that seems to
correlate with total body weight. Liver failure may
alter the clearance of azathioprine, and dosage adjust-
ment is needed to avoid toxicity. Therapeutic drug
monitoring for azathioprine has no clinical value as a
result of the intracellular pharmacodynamic effects of
azathioprine on thiopurine nucleotides (56,57).
Adverse reactions that are associated with aza-
thioprine therapy are relatively uncommon and are
rare with dosages of ⬍2 mg/kg per d. The most
commonly encountered adverse event is myelosup-
pression. Dosage adjustment is critical for patients
with abnormal blood counts (white and red blood cells
and platelets) and in patients who take allopurinol,
because allopurinol and other xanthine oxidase inhib-
itors may predispose patients to excessive bone mar-
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
row suppression. Azathioprine has also been associ-
ated with veno-occlusive disease and pancreatitis. The
experience with azathioprine during pregnancy in kid-
ney transplantation is encouraging, and compared with
MMF, there is very limited risk for congenital anom-
alies with azathioprine (58); prednisone, CsA, tacroli-
mus, and azathioprine have the lowest risk for con-
genital malformations compared with other commonly
used immunosuppressive agents (Table 14).
MPA Derivatives
MPA is a purine antagonist that was approved in
1995 for the prevention of acute rejection in renal
transplant recipients. It is a noncompetitive inhibitor
of inosine monophosphate dehydrogenase, an enzyme
that plays a vital role in the de novo pathway of purine
biosynthesis. Both T and B cell proliferation require
inosine monophosphate dehydrogenase for activation
and maturation; therefore, mycophenolate inhibits the
rate-limiting enzymes in T and B cell biosynthesis.
MPA-based regimens have been effective at improv-
ing long-term allograft survival and reducing acute
rejection of kidney transplant patients. Although it has
become a standard of practice to prescribe MPA-based
therapy at the time of discharge, the result of clinical
studies and safety of MPA-based therapy must be
interpreted in the context of study design and dosage
of comparative agents. Different salt forms of myco-
phenolate are on the US market: MMF (CellCept [F.
Hoffman La-Roche] and generic formulations) and
mycophenolate sodium (myFortic; Novartis).
The most common adverse effect associated with
mycophenolate is gastrointestinal toxicity, which is
Table 14. Azathioprine and mycophenolate drug– drug interactions
Drug Mechanism
ACEIs Synergistic
myelosuppression
Acyclovir 1 AUC of MMF
Allopurinol Inhibits xanthene oxidase,
1 AUC of AZA
Antacids 2 absorption of MMF
Cholestyramine 2 absorption of MMF
Co-trimoxazole Synergistic
myelosuppression
Ganciclovir Synergistic
myelosuppression
Omeprazole 2 MMF drug exposure
1, Avoid combination; 2, usually avoid (use only no other alternative agents available); 3, monitor closely; 4, no action needed (the risk for adverse drug reaction is
small). ACEI, angiotensin-converting enzyme inhibitor; AZA, azathioprine.
247
reversible when the drug is discontinued or dosage is
decreased. Although the mechanism of this complica-
tion is unclear, it may be related to local or systemic
effects. Unfortunately, reduction in MPA dosage or
discontinuation of MPA for gastrointestinal toxicity is
associated with a significant risk for graft failure
(hazard ratio 2.36) (59).
After oral administration, MMF is rapidly con-
verted to MPA in the acidic environment in the stom-
ach. Unlike MMF, mycophenolate sodium is absorbed
in the lower gastrointestinal tract. The slow rate of
absorption also results in a delayed peak plasma con-
centration for mycophenolate sodium; the Cmax for
MMF occurs at 0.5 to 1.0 hours after oral administra-
tion, whereas for mycophenolate sodium, the serum
peak concentration occurs at approximately 1.5 to 3.0
hours (60).
Because mycophenolate has shown a great phar-
macokinetic variability in various patient populations,
routine mycophenolate therapeutic monitoring has
been suggested; however, data about the utility of
therapeutic drug monitoring are inconclusive. In two
separate randomized clinical trials of kidney transplant
recipients, mycophenolate therapeutic drug monitor-
ing versus fixed dosage of mycophenolate did not
show any differences in biopsy-confirmed acute rejec-
tion, mean serum creatinine concentrations, incidence
of cytomegalovirus or polyomavirus infection, or al-
lograft loss (60). A number of factors are known to
alter significantly the pharmacokinetic behavior of
mycophenolate in kidney transplant recipients. Renal
failure, hepatic dysfunction, choice of CNI, dosage of
Effects Severity Comments
Anemia, neutropenia 3 1 bone marrow toxicity
Not significant 4
Severe neutropenia 1 2 AZA dosage by 75%
2 efficacy 3
3 1 bone marrow toxicity
Anemia, neutropenia 3
Anemia, neutropenia 3
2 efficacy 3
248
prednisone, and polymorphism of the UDP glucurono-
syltransferase enzymatic system may significantly
change the free fraction concentration of mycopheno-
late. In addition, the total exposure to mycophenolate
(AUC) does not seem to correlate to trough plasma
concentration. Finally, neither the incidence of acute
rejection nor major adverse effects of mycophenolate
seem to be related to plasma concentration. These
elements make therapeutic drug monitoring of myco-
phenolate unreliable and most likely would not opti-
mize mycophenolate therapy or decrease drug toxici-
ties.
TOR Inhibitors: Sirolimus and Everolimus
Sirolimus and everolimus are novel macrolide
immunosuppressants developed for use in combina-
tion with other immunosuppressive agents for preven-
tion of acute rejection and slowing the progression of
chronic allograft nephropathy in kidney transplant
recipients. At the molecular and cellular levels, these
agents inhibit mammalian TOR (mTOR), which is an
important protein for T cell proliferation. Initially,
both sirolimus and everolimus bind to key regulatory
enzyme of FK-BP-12; this complex then binds to
mTOR, which leads to cell-cycle arrest at the G1
stage. In addition to their immunosuppressive proper-
ties, these agents seem to inhibit some of the vascular
alterations of chronic allograft nephropathy. These
agents have no effect on the calcineurin phosphatase
pathway and are suitable agents to be used in combi-
nation with low-dosage CNIs or in calcineurin avoid-
ance protocols (61).
Monitoring of sirolimus and everolimus trough
blood levels has been helpful to adjust CNIs to target
a lower plasma concentration. Sirolimus blood trough
levels should be maintained between 5 and 20 ng/ml,
and everolimus blood trough concentration should be
maintained between 3 and 8 ng/ml, depending on
institution-specific protocols (62– 65).
The most common adverse events associated
with use of sirolimus include myelosuppression, pri-
marily thrombocytopenia, hyperlipidemia, and de-
layed wound healing. Moderate to severe sirolimus
toxicity is characterized by interstitial pneumonitis,
Pneumocystis jiroveci pneumonia, and fungal infec-
tions. Despite some clinical benefits, the use of siroli-
mus as primary immunosuppression should be re-
served for patients with complications of standard CNI
protocols (66 – 68).
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Common Drug–Drug Interactions
CsA, tacrolimus, and sirolimus are most com-
monly used with one or two other agents (azathio-
prine, MMF, sirolimus, or corticosteroids) to prevent
acute rejection. The significant reduction of acute
allograft rejection and graft loss from immunologic
factors has been paralleled with an increase in predomi-
nantly cardiovascular complications (hypertension, hy-
percholesterolemia, obesity, and posttransplantation dia-
betes) and osteoporosis in kidney transplant recipients.
Because most transplant patients have several comorbid
conditions, avoidance of drug interactions is vital and
promotes allograft and patient survival. As the number
of drugs for the management of comorbid conditions
in kidney transplant recipients increases, so does the
risk for clinically relevant drug interactions. The ma-
jority of immunosuppressive drugs are substrates for
commonly used drugs for the management of hyper-
tension, hyperlipidemia, and infections (69).
The majority of clinically important immuno-
suppressive drug interactions results from induction
or inhibition of immunosuppressive drug metabo-
lism; however, other mechanisms, including phar-
macodynamic interactions, in which one agent may
alter the pharmacokinetic behavior of other drugs
(absorption, distribution, metabolism, or elimina-
tion) or have additive or synergistic toxicities, are
also important. To avoid drug– drug interactions,
both pharmacokinetic properties and pharmacody-
namic interactions should be considered (70). For
reduction of the severity of drug– drug interactions
in transplant recipients, it is crucial to identify the
site and type of drug elimination with other con-
comitant immunosuppressant medications. Age-re-
lated pharmacokinetics alterations, organ dysfunc-
tion, and comorbidities may also increase the risk
for potential drug interactions. A basic understand-
ing of pharmacokinetic and pharmacodynamic drug
interaction may improve patient outcomes and de-
crease the risk for drug toxicities. The most impor-
tant principal of understanding drug interactions is
to determine whether drug interactions are clinically
relevant and should be avoided. Although drug
interaction programs or handheld devices and appli-
cations provide an alert for drug interactions, they
often do not provide any guidelines for management
of drug interactions or take into account individual
patient factors (70) (Table 15).
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010 249

Table 15. Sirolimus drug– drug interactions

Drug Mechanism Effects Severity Comments
ACEIs Synergistic Anemia, neutropenia 3 1 bone marrow
myelosuppression toxicity
Amprenavir 1 plasma level of sirolimus Hyperlipidemia, anemia, 3
neutropenia
Bromocriptine 1 plasma level of sirolimus Hyperlipidemia, anemia, 3
neutropenia
Carbamazepine 2 intestinal absorption 2 sirolimus level 2
Cholestyramine 2 intestinal absorption 2 sirolimus level 3
Clarithromycin 1 plasma level of sirolimus Hyperlipidemia, anemia, 2 Azithromycin is
neutropenia preferred agent
Co-trimoxazole Synergistic Anemia, neutropenia 3
myelosuppression
CsA 1 plasma level of sirolimus Hyperlipidemia, anemia, 3 Give 4 hours
neutropenia after the dose
Danazol 2 intestinal absorption 2 sirolimus level 3
Diltiazem 1 plasma level of sirolimus Hyperlipidemia, anemia, 2 Amlodipine is the
neutropenia preferred agent
Erythromycin 1 plasma level of sirolimus Hyperlipidemia, anemia, 2 Azithromycin is
neutropenia preferred agent
Fluconazole 1 plasma level of sirolimus Hyperlipidemia, anemia, 2
neutropenia
Ganciclovir Synergistic Anemia, neutropenia 3
myelosuppression
Indinavir 1 plasma level of sirolimus Hyperlipidemia, anemia, 2
neutropenia
Itraconazole 1 plasma level of sirolimus Hyperlipidemia, anemia, 2
neutropenia
Metoclopramide 1 plasma level of sirolimus Hyperlipidemia, anemia, 3
neutropenia
Nicardipine 1 plasma level of sirolimus Hyperlipidemia, anemia, 2 Amlodipine is
neutropenia preferred agent
Phenobarbital 1 metabolism of sirolimus 2 sirolimus level 2
Phenytoin 1 metabolism of sirolimus 2 sirolimus level 2
Rifabutin 1 metabolism of sirolimus 2 sirolimus level 2
Rifampin 1 metabolism of sirolimus 2 sirolimus level 2
Ritonavir 1 plasma level of sirolimus Hyperlipidemia, 2
Anemia, neutropenia
Verapamil 1 plasma level of sirolimus Hyperlipidemia, 2
Anemia, neutropenia
Voriconazole 1 plasma level of sirolimus Hyperlipidemia, anemia, 2
neutropenia
1, Avoid combination; 2, usually avoid (use only no other alternative agents available); 3, monitor closely; 4, no action needed (the risk for adverse drug reaction is
small). ACEI, angiotensin-converting enzyme inhibitor.

Pharmacokinetic Drug Interactions
Many drugs may stimulate or inhibit the activity
of a variety of cytochrome P450 (CYP) enzymes,
including CYP3A4, CYP2C9, and CYP2C19. More
than 50% of all drugs are metabolized through cyto-
chrome P450 enzymes. Because these enzymes are
important in the biotransformation and metabolism of
most therapeutic agents, patients who take immuno-
suppressive drugs may metabolize these drugs at a
faster or slower rate and would be at risk for acute
rejection, allograft loss, and/or drug toxicity. Variabil-
ity in elimination and drug– drug interactions has been
observed in metabolism of a drug as a result of
polymorphism of cytochrome P450 expression, and
250
polymorphisms of cytochrome P isoenzyme and P-
glycoproteins may directly and/or indirectly influence
drug– drug interactions in transplant patients (71,72).
Immunosuppressants may also stimulate or in-
hibit metabolism or prevent enterohepatic recircula-
tion of other immunosuppressant agents (Table 16).
For example, corticosteroids at low dosages may in-
duce uridine diphosphate– glucuronosyltransferase en-
zymes. Patients who are on steroid-free protocols have
a higher incidence of myelosuppression and bone
marrow toxicities as a result of higher mycophenolate
plasma concentrations (73).
Although there is no clinically important drug
interaction between mycophenolate and tacrolimus,
CsA may inhibit recirculation of mycophenolate and
reduce MPA plasma concentrations (74). As a conse-
quence, stable patients who are on mycophenolate and
CsA may experience adverse drug reactions from
mycophenolate after switching from CsA to tacrolimus.
A list of common drug interactions between immunosup-
pressive drugs are reviewed in Table 16 (73).
CsA may augment plasma hepatic hydroxy-
methyl glutaryl–CoA reductase inhibitor (statin) con-
centrations and increase the risk for myopathy and
rhabdomyolysis. Tacrolimus has a very limited effect
on metabolism of statins, and switching patients from
tacrolimus to CsA can lead to increased risk for
statin-associated rhabdomyolysis. Patients who re-
Table 16. Pharmacokinetic drug interaction between immunosuppressive agents
Drug Interactions
CsA Mycophenolate
CsA Sirolimus
CsA Corticosteroids
CsA High-dosage corticosteroids
for rejection
Tacrolimus Mycophenolate
Tacrolimus Sirolimus
Tacrolimus Corticosteroids
Sirolimus Corticosteroids
Sirolimus Mycophenolate
Mycophenolate Corticosteroids
CYP-450, cytochrome P 450; MPA, mycophenolic acid; MPAG, mycophenolate glucuronide; P-gp, P-glycoprotein; UGT, UDP glucuronosyltransferase.
a
Pharmacodynamic drug interactions; a higher rate of myelosuppression.
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
ceive co-administration of statins, azole antifungals,
and CsA should be closely monitored (75).
Finally, St. John’s Wort can increase metabo-
lism of CsA and tacrolimus by inducing both CYP-
450 IIIA and P-glycoprotein, whereas grapefruit can
decrease metabolism of CsA and tacrolimus by
inhibiting both CYP-450 IIIA and P-glycoprotein.
Transplant patients should routinely be asked about use
of herbal supplements and other supplements in addition
to other drugs (76).
In addition to the numerous pharmacokinetic
interactions seen with maintenance immunosuppres-
sants, there is the possibility for pharmacodynamic
interactions. Pharmacodynamic drug interactions
are common and predictable and for minimization
of additive toxicities should be avoided completely
if possible; if not, then toxicity should be monitored
very closely. The use of other nephrotoxic and/or
myelosuppressive agents should be used with cau-
tion. For example, amphotericin B, aminoglyco-
sides, foscarnet, cidofovir, and nonsteroidal anti-
inflammatory drugs may potentiate the neph-
rotoxicity of CNIs and should be avoided unless it is
necessary for life-threatening situations. Use of gan-
ciclovir, valganciclovir, and co-trimoxazole in com-
bination with mycophenolate or azathioprine can
lead to an increased risk for myelosuppression in
transplant patients (69,70).
Effect Mechanism
2 MPA exposure Inhibition of enterohepatic circulation
of MPA/MPAG
1 sirolimus exposure 2 metabolism of sirolimus through
CYP-450/P-gp
2 CsA exposure 1 metabolism of CSA through CYP-
450/P-gp
1 CsA exposure 2 metabolism of CSA through CYP-
450/P-gp
7 No drug interactions
2 tacrolimus exposure 1 metabolism of tacrolimus through
CYP-450/P-gp
2 tacrolimus exposure 1 metabolism of tacrolimus through
CYP-450/P-gp
1 prednisone exposure 2 metabolism of prednisone
7 No pharmacokinetic drug
interactionsa
2 MPA exposure UGT induction, increase MPA level
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
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cyclosporine elimination. Transplantation 74: 1560 –1567, 2002
63. Oberbauer R, Segoloni G, Campistol JM, Kreis H, Mota A, Lawen J,
Russ G, Grinyó JM, Stallone G, Hartmann A, Pinto JR, Chapman J,
Burke JT, Brault Y, Neylan JF, Rapamune Maintenance Regimen
Study Group: Early cyclosporine withdrawal from a sirolimus-based
regimen results in better renal allograft survival and renal function at
48 months after transplantation. Transpl Int 18: 22–28, 2005
64. Schena FP, Pascoe MD, Alberu J, del Carmen RM, Oberbauer R,
Brennan DC, Campistol JM, Racusen L, Polinsky MS, Goldberg-
Alberts R, Li H, Scarola J, Neylan JF, Sirolimus CONVERT Trial
Study Group: Conversion from calcineurin inhibitors to sirolimus
maintenance therapy in renal allograft recipients: 24-Month efficacy
and safety results from the CONVERT trial. Transplantation 87:
233–242, 2009
65. Pascual J: Everolimus in clinical practice–renal transplantation.
Nephrol Dial Transplant 21[Suppl 3]: iii18 –iii23, 2006
66. Neff RT, Jindal RM, Yoo DY, Hurst FP, Agodoa LY, Abbott KC:
Analysis of USRDS: Incidence and risk factors for Pneumocystis
jiroveci pneumonia. Transplantation 88: 135–141, 2009
67. Otton J, Hayward CS, Keogh AM, Glanville AR, Macdonald PS:
Everolimus-associated pneumonitis in 3 heart transplant recipients.
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68. Flechner SM: Risk factors for and management of sirolimus-associ-
ated pneumonitis in kidney transplant recipients. Nat Clin Pract
Nephrol 4: 250 –251, 2008
69. Kuypers DR: Immunotherapy in elderly transplant recipients: A
guide to clinically significant drug interactions. Drugs Aging 26:
715–737, 2009
70. Manitpisitkul W, McCann E, Lee S, Weir MR: Drug interactions in
transplant patients: What everyone should know. Curr Opin Nephrol
Hypertens 18: 404 – 411, 2009
71. Wang J: CYP3A polymorphisms and immunosuppressive drugs in
solid-organ transplantation. Expert Rev Mol Diagn 9: 383–390, 2009
72. Burckart GJ: Pharmacogenomics: The key to improved drug therapy
in transplant patients. Clin Lab Med 28: 411– 422, vi, 2008
73. Kuypers DR: Influence of interactions between immunosuppressive
drugs on therapeutic drug monitoring. Ann Transplant 13: 11–18,
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74. Van Gelder T, Klupp J, Barten MJ, Christians U, Morris RE:
Comparison of the effects of tacrolimus and cyclosporine on the
pharmacokinetics of mycophenolic acid. Ther Drug Monit 23: 119 –
128, 2001
75. Kanbay M, Turgut F, Covic A, Goldsmith D: Statin treatment for
dyslipidemia in chronic kidney disease and renal transplantation: A
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76. Nowack R: Review article: Cytochrome P450 enzyme, and transport
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ton) 13: 337–347, 2008
Cardiovascular Medications
Antihypertensive Agents
Peripheral ␣ Blockers
The peripheral ␣ blockers prazosin, terazosin,
and doxazosin undergo extensive hepatic metabolism
with pharmacokinetics that are not altered by the
presence of renal insufficiency; thus, peripheral ␣
blockers do not require dosage adjustment in patients
with reduced GFR. These drugs are also not apprecia-
bly dialyzed. They are used with some regularity in the
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010 253

patient with hypertension and chronic kidney disease able in the patient with CKD unless combined with a
(CKD) in that they are useful add-on compounds for diuretic (7,8). The selection of a ␤ blocker for a patient
treatment-resistant hypertension. Use of ␣-adrenergic with CKD should occur with some knowledge of the
antagonists in the treatment of hypertension has been elimination characteristics of the drug as well as
limited by their tendency to increase plasma volume, a whether the compound has active metabolites (Table 17)
phenomenon that may be more evident at high dosages (9). Accumulation of a renally cleared ␤ blocker, such
and in patients with CKD (1). as atenolol, in a patient with CKD does not typically
improve BP control but can be associated with more
Central ␣ Agonists
frequent concentration-dependent adverse effects (9).
Central ␣ agonists, such as clonidine and guan-
In general, there is not a best ␤ blocker to use for the
facine, are used in the management of hypertension in
patient with CKD even as there is a growing appreci-
patients with CKD. Clonidine is available as a trans-
ation of the pharmacokinetic and pharmacodynamic
dermal patch, which is best absorbed from a chest or
heterogeneity for drugs in this class.
upper arm location. Transdermal clonidine is of par-
ticular utility for the treatment of the labile patient who Calcium Channel Blockers
has hypertension and requires multiple medications, Calcium channel blockers (CCBs) are commonly
the hospitalized patient who cannot take oral medica- used drugs in the patient with CKD, in part as a result
tions, the patient with prominent early morning BP of the predictability of their BP-lowering response.
surges, and/or the patient with erratic medication in- Also, coronary artery disease is common in the patient
take (2). It is also of particular utility when it is with CKD, and drugs in this class are effective anti-
necessary to supervise medication intake as can occur anginal agents. In general, the volume of distribution
in the nonadherent hemodialysis patient (3). (Vd), protein binding, and plasma half-life of CCBs
Guanfacine is predominantly hepatically cleared are comparable in patients with CKD and those with
and does not accumulate in CKD. Clonidine, unlike normal renal function with a few notable exceptions
guanfacine, undergoes modest renal clearance, and its that do not mandate dosage adjustment on the basis of
plasma half-life is somewhat prolonged in CKD, al- pharmacokinetic considerations (Table 18) (10). One
though there are no specific recommendations for
dosage adjustment in this population (4). Patients who
have CKD and suddenly stop oral clonidine can be Table 17. Elimination characteristics of ␤ blockers
expected to have less frequent rebound hypertension Active Accumulation in
relating to this delayed clearance compared with indi- Drug Metabolites Renal Disease
viduals with normal kidney function; however, this Acebutolol Yes Yes
has not been formally studied. Atenolol No Yes
Clonidine is typically dosed to BP effect and can Betaxolol No Yes
be expected to accumulate in the patient with CKD. Its Bisoprolol No Yes
use in patients with CKD seems not to be associated Carteolol Yes Yes
with so-called “paradoxical hypertension,” a phenom- Carvedilol Yes No
enon that occurs at very high plasma clonidine levels Celiprolol Yes No
Esmolol No No
related to there being sufficient peripheral ␣-receptor
Labetalol No No
stimulation such that the benefits derived from central Metoprolol No No
␣1- and ␣2-adrenergic receptors stimulation are over- Metoprolol LA No No
whelmed (5). Patients with CKD and sinus node dys- Nadolol No Yes
function are at risk for significant bradycardia with Nebivolol No No
clonidine, so its use in such patients is best avoided (6). Oxprenolol No No
Penbutolol No No
␤ Blockers Pindolol No No
␤ Blockers are commonly used drugs in the Propranolol Yes No
patient with CKD for the treatment of hypertension as Propranolol LA Yes No
well as for their cardioprotective effects. The BP- Sotalol No Yes
lowering effect of ␤ blockers is somewhat unpredict- Timolol No No
254 Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Table 18. Elimination characteristics of CCBs

Renal Failure
Normal Half-life Half-life Dosage Adjustment in
Drug Trade Name (hours)a (hours) Renal Failure
Amlodipineb Norvasc 40.0 to 50.0 50.0 No
Diltiazemc Cardizem 2.0 to 5.0 2.0 to 4.0 No
Felodipine Plendil 11.0 to 16.0 18.0 ⫾ 11.4 No
Isradipine Dynacirc 8.0 3.1 No
Nicardipine Cardene 11.5 Not available No; careful dosage titration
recommended
Nifedipine Procardia 2.0 4.0 No
Nimodipine Nimotop 2.8 22.0 No; close monitoring for BP
effect advisable
Nisoldipine Sular 15.0 Not available No
Nitrendipine 3.6 4.1 No
Verapamild Calan, Isoptin, Verelan, 3.0 to 7.0 (acute) 11.4 ⫾ 4.0 (15.2) No
Covera 8.0 to 12.0 (chronic)
a
Normal half-life values are taken from populations studied simultaneously with patients with renal failure or from comparative studies in the literature.
b
All data are from individuals with normal renal function other than for renal failure half-life.
c
Diltiazem has an active metabolite, desacetyldiltiazem.
d
Verapamil and norverapamil half-life values are reported. Acute and chronic dosing half-life values are reported in individuals with normal renal function.

exception is nicardipine, for which CYP3A4 metabo-
lism and thereby plasma clearance are decreased in
patients with CKD compared with normal individuals.
Although the mechanism of this defect in drug clear-
ance remains unclear, because enzyme activity has not
been specifically studied, this defect in plasma clear-
ance is corrected by hemodialysis, suggesting the
presence of a dialyzable inhibitor of nicardipine clear-
ance in advanced renal failure (11).
CCB-related adverse effects have to be consid-
ered when these drugs are used in the patient with
CKD. Many patients with CKD tend to be constipated,
and this can be aggravated by verapamil. Also, CCBs
can produce peripheral edema, which sometimes pre-
sents an interpretive problem in the typically already
volume-expanded patient with CKD.
Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme inhibitors (ACEIs)
are frequently administered to patients with CKD for
treatment of hypertension and their cardiorenal protec-
tive effects. The BP-lowering effect of ACEIs is gen-
erally less in volume-expanded forms of hypertension,
as is often the case in CKD, compared with other
forms of hypertension; however, addition of a diuretic
to an ACEI (or angiotensin receptor blocker [ARB])
typically improves the BP-lowering response (12).
For most ACEIs, elimination is almost exclu-
sively renal with varying degrees of filtration and
tubular secretion. There are two ACEIs with dual route
of elimination, fosinopril and trandolapril, whose ac-
tive diacid form is both hepatically and renally cleared
(13,14). This property of combined renal and hepatic
elimination minimizes accumulation in CKD once
dosing to steady state has occurred. To date, no spe-
cific adverse effect has been identified from ACEI
accumulation, although cough has been suggested but
not proved to be an ACEI concentration– dependent
adverse effect. Angioneurotic edema is a potentially
life-threatening adverse effect with ACEIs that is more
independent of ACEI dosage and is more common in
black patients (15). It is probable, though, that the
longer drug concentrations remain elevated once a
response to an ACEI has occurred, the more likely it is
that BP, renal function, and potassium handling will be
negatively affected. Some patients are very sensitive
to the effects of an ACEI, particularly those who have
an activated renin-angiotensin-aldosterone system;
thus, even minimal degrees of ACEI accumulation can
present a problem (16).
The current product label recommendations,
which suggest that ACEI dosages should be reduced in
moderate to severe CKD, vary somewhat from com-
pound to compound (Table 19). These differing dos-
age recommendations are inconsequential to the clin-
 Nephrology Self-Assessment Program - Vol 9, No 4, July 2010 255

ical use of ACEIs in patients with CKD, though,

Usual dosage titration to effect

Titrate to maximum of 40 mg

Titrate to maximum of 15 mg
Titration (mg) in Renal
Recommended Dosage
because ACEIs are typically titrated to effect. Whereas

Titrate to optimal response

Failure per Day parameters such as BP and renal function are sensitive
to the plasma concentration of an ACEI, hyperkalemia
may be less so (17). If hyperkalemia occurs with an
ACEI, then a reduced dosage or use of a nonaccumu-
lating ACEI can be considered.
Angiotensin Receptor Blockers
Like ACEIs, ARBs are generally less efficacious
in the treatment of hypertension in the presence of
CKD and oftentimes require addition of a diuretic to
maximize their BP-lowering effect (12). Most of these
(mg) in Renal Failure per Day (CrCl 0

drugs undergo significant hepatic elimination, with the

Usual Total Dosage and/or Range

2.0 (on dialysis day; CrCl ⬍15 ml/min)

exception of candesartan, telmisartan, and the E-3174

metabolite of losartan, which are 40, 60, and 50%
hepatically cleared, respectively. Irbesartan and telm-
to 10 ml/min)

isartan undergo the greatest degree of hepatic elimi-

nation among the ARBs, with each having ⬎95% of
their systemic clearance by hepatic elimination. Val-
50% of normal dose

sartan and eprosartan both are approximately 70%

No adjustment

cleared by the hepatic route (Table 20) (18). As with

ACEIs, the dosage of an ARB that is given to a patient
with CKD should be adjusted according to the level of
2.5 (1)
Same

Same
Same

Same
Same

effect, not on the basis of a predetermined plan to

maintain an arbitrary blood level (19). ARBs may
increase serum potassium values less than ACEIs in
patients with CKD (20).
3.75 (1) (CrCl ⬍40 ml/min)
(CrCl 10 to 30 ml/min)

2.0 (every other day) (CrCl

Renal Failure per Day

Direct Renin Inhibitors

and/or Range (mg) in

25% of normal dose (CrCl

75% of normal dose (CrCl
Usual Total Dosage

Aliskirin is the only compound currently mar-

keted in the United States in this class. This com-
10 to 50 ml/min)

15 to 29 ml/min)

pound is a highly specific in vitro inhibitor of both

⬍40 ml/min)
No adjustment

human and primate renin with an IC50 of 0.6

nmol/L. The capacity of this drug to reduce BP in
Table 19. Elimination characteristics of ACEIs

patients with hypertension is similar to (or slightly

2.5 (1)

0.5 (1)
5 (1)
5 (1)

better than) what is seen with standard therapeutic

dosages of various ACEIs and ARBs (21,22). Opin-
ions vary considerably on the utility of aliskiren,
ranging from enthusiasm for an antihypertensive
Prinivil, Zestril
Trade Name

agent with a “new” mechanism of action to a “so

what” attitude derived, in part, from its cost and
Monopril
Lotensin

Accupril
Capoten

Univasc
Vasotec

Aceon

Altace

Mavik

absence of outcomes data distinguishing it from

ACEIs or ARBs. There still remains the need to
CrCl, creatinine clearance.

understand better how this compound fits in the

management of hypertension and its effects on renal
Trandolapril

and cardiovascular outcomes. Aliskiren is not re-

Perindopril
Benazepril

Fosinopril

Moexipril
Lisinopril

Quinapril
Captopril

Enalapril

Ramipril

nally cleared; therefore, dosage adjustment is not

Drug

necessary for patients with CKD (23). The renal

effects of aliskiren seem similar to those of an ACEI
256
Table 20. Mode of elimination for ARBs
Drug Trade Name
Candesartan Atacand
Eprosartan Teveten
Irbesartan Avapro
Losartan Cozaar
Olmesartan Benicar
E-3174 Metabolite of losartan
Telmisartan Micardis
Valsartan Diovan
or an ARB. There seems to be an additive antipro-
teinuric effect with aliskiren and an ARB such as
losartan (24).
Antianginal Agents
Patients with CKD have a high prevalence of
coronary artery disease (CAD) and tend to have more
severe CAD and coronary calcification as well as a
worse prognosis than do patients with other cardiovas-
cular risk factors (25). Patients with CKD have gen-
erally been excluded from major cardiovascular treat-
ment trials; therefore, the interplay between the
pharmacokinetics and pharmacodynamics of various
antianginal agents in the patient with CKD is typically
inferred from data derived from patients with more
normal renal function (26). A number of antihyperten-
sive agents, particularly ␤ blockers and CCBs, are
used in the patient with symptomatic ischemic heart
disease (see the Antihypertensive Agents section).
Other antianginal agents of note include nitrates and
ranolazine, which are addressed herein.
The pharmacokinetics of isosorbide dinitrate and
its two active metabolites, isosorbide-2-nitrate and
isosorbide-5-nitrate, are not altered by the presence of
renal failure, and dosage adjustment is not required in
such patients (27). Ranolazine is primarily metabo-
lized by CYP3A4 and is a substrate of P-glycoprotein.
In severe renal failure, there is upwards of a twofold
increase in the AUC for ranolazine; because ⬍7% of
an administered dose of ranolazine is excreted un-
changed, factors other than a reduced GFR contribute
to the increase in ranolazine concentrations in renal
impairment (28).
Ranolazine has a very narrow therapeutic win-
dow and should be dosed carefully in the patient with
advanced CKD (28,29). Small increases in serum
creatinine values on the order of 0.1 to 0.2 mg/dl occur
with ranolazine without a concomitant change in blood
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Renal Hepatic
60 40
30 70 (unchanged)
1 99 (2C9)
10 90 (2C9/3A4)
35 to 50 50 to 65 (unchanged)
50 50
1 99 (unchanged)
30 70 (unchanged)
urea nitrogen values or measured GFR and most likely
represent inhibition of tubular secretion of creatinine
by ranolazine or one of its metabolites (28). Ranola-
zine also modestly increases BP in patients with severe
renal insufficiency by an as-yet-undetermined mecha-
nism (28).
Cholesterol-Lowering Agents
Abnormalities in cholesterol metabolism are
ubiquitous in practically all forms of renal disease
(30). As such, treatment with statins is important and
common in this patient population. Two subtypes of
statins are currently on the US market: Fermentation
derived, or natural, statins (lovastatin, pravastatin, and
simvastatin) and synthetic statins (atorvastatin, rosuv-
astatin, and fluvastatin).
With the exception of pravastatin, all statins
undergo extensive microsomal metabolism by CYP
enzymes. Pravastatin is eliminated through both renal
and nonrenal routes, with renal clearance accounting
for 47% of its total systemic clearance (31). CYP3A4
is an important enzyme in the metabolism of several of
the hydroxymethyl glutaryl–CoA reductase inhibitors,
including atorvastatin, lovastatin, and simvastatin;
therefore, these compounds are prone to drug– drug
interactions with CYP3A4 inhibitors, such as vera-
pamil and diltiazem (32,33).
Statins are generally well tolerated in patients
with CKD (34). The major adverse effect of statins is
myopathy, often defined as muscle pain or weakness
associated with creatine kinase levels 10 times higher
than the upper limits of normal. Myotoxicity with
statins is a concentration-dependent phenomenon. Be-
cause the symptoms that commonly are seen with
statin-related myopathy often are not different from
the musculoskeletal complaints that commonly are
seen in the patient with CKD, there should be a low
threshold for measuring creatine kinase levels under
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
these conditions. In addition, the lower level of renal
function in these patients in and of itself makes it
important that myopathy be identified early, because
the reduced renal function adversely affects the toler-
ance and risk for rhabdomyolysis (32).
Finally, the numbers of medicines that typically
are prescribed to patients with renal failure increases
the chance for drug– drug interactions and the risk for
myopathy with statins. Adhering to current recom-
mendations for statin therapy in CKD should minimize
the risk for adverse reactions to statins in these patients
(Table 21) Unfortunately, adherence to these dosage
recommendations may limit achievement of choles-
terol goals; in fact, recent clinical trials have called
into question the routine use of statins in the patient
with ESRD and may affect the overall use of these
compounds in such patients (35,36).
Triglyceride-Lowering Agents
Fibrates are a class of lipid-lowering medication
primarily used as second-line agents behind statins
Table 21. Dosage recommendations for statins in patients with normal renal function and with CKD/ESRD
Normal
Drug (mg/d) CKD/ESRD
Atorvastatin 10 to 80 Dosage adjustment in patients with renal
insufficiency is not necessary
Fluvastatin 20 to 80 Dosage adjustments for mild to
moderate renal impairment are not
necessary; caution should be exercised
with severe impairment
Lovastatin 10 to 80 In patients with CrCl ⬍30 ml/min,
dosage increases ⬎20 mg should be
carefully considered and if deemed
necessary should be supplemented
cautiously
Pravastatin 10 to 40 No comment
Rosuvastatin 5 to 40 For patients who have severe renal
impairment (CrCl ⬍30 ml/min per
1.73 m2) and are not on hemodialysis,
dosing should be started at 5 mg/d and
not exceed 10 mg/d
Simvastatin 5 to 80 Dosage adjustment should not be
necessary in mild to moderate renal
insufficiency; in patients with severe
renal insufficiency, 5 mg/d should be
the starting dosage with close
monitoring if there is any titration
Recommendations taken directly from the package inserts for individual HMG-CoA reductase inhibitors. CrCl, creatinine clearance.
257
(37). These agents are associated with a reversible rise
in serum creatinine (38,39); whether this it is due to a
real change in GFR is still debated. One proposed
explanation for this phenomenon is that fibrates in-
crease the production of creatinine, in which case a
rise in serum creatinine values would not represent a
true deterioration in renal function. An alternative
theory is that fibrates reduce the production of vaso-
dilatory prostaglandins, which could lead to a true
change in renal function (39).
Routine serum creatinine monitoring is advisable
for fibrate-treated patients, particularly for those with
preexisting renal disease. A 30% increase in serum
creatinine values in the absence of other causes of
serum creatinine change warrants discontinuation of
fibrate therapy. Serum creatinine values can take sev-
eral weeks to return to their baseline values after
discontinuation of a fibrate. There is little information
in the literature as to whether a patient who has
experienced a rise in serum creatinine with fibrate
Transplantation
No comment
No comment
In patients taking CsA, therapy should begin
with 10 mg/d and should not exceed 20
mg/d
In patients taking CsA, therapy should begin
with 10 mg and titration to higher dosages
should be done with caution
In patients taking CsA, dosage should be
limited to 5 mg/d
In patients taking CsA, therapy should begin
with 5 mg/d and not exceed 10 mg/d
258
therapy can be safely restarted on a fibrate (39,40). If
clinical circumstances dictate fibrate therapy, then gem-
fibrozil would be the preferred agent in that this com-
pound has no recognizable effect on renal function (41).
Antiarrhythmic Agents
Both atrial and ventricular rhythm disturbances
are common in patients with CKD, with as many as 13
to 27% of patients who are on long-term hemodialysis
having atrial fibrillation (42). The foremost safety
issue with therapies that are used for atrial fibrillation
is the propensity of class IA and III agents to cause
torsade de pointes arrhythmias (43). The majority of
the compounds that are used in the treatment of atrial
fibrillation have a narrow therapeutic window, and
several of them are extensively renally cleared, includ-
ing procainamide and its N-acetylated metabolite, and
newer agents such as dofetilide, flecainide, and D-
sotalol.
As an example of the likelihood of proarrythmic
events with class III agents in the setting of renal
disease, dofetilide has the following black box warn-
ing: “To minimize the risk of induced arrhythmia,
patients initiated or re-initiated on dofetilide should be
placed for a minimum of 3 days in a facility that can
provide calculations of creatinine clearance, continu-
ous electrocardiographic monitoring, and cardiac re-
suscitation.” Proarrhythmic effects of class III agents,
such as torsade de pointes, have been described as
being more common in certain patient types, including
women, and those with electrolyte disturbances such
as hypokalemia and hypomagnesemia, renal failure,
and prolongation of the QT/QTc interval (44,45).
The best measurement tool for determining the
level of renal function for appropriate dosing of class
III agents is not established. Reliance on creatinine
clearance measurements, as is the suggestion for
dofetilide, runs the risk for significantly overestimat-
ing the true GFR and dosing this compound too high;
accordingly, the use of electrocardiographic moni-
toring becomes critical to improving the safety
profile of this compound in renal disease. These
drugs probably should not be used in the advanced
stages of renal failure; dofetilide is contraindicated
in patients with a creatinine clearance of ⬍20 ml/
min. Dialysis may be useful in the setting of renal
failure and the development of torsade de pointes;
however, there is varying dialysance of the renally
cleared class III agents (46).
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
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20. Bakris GL, Siomos M, Richardson D, Janssen I, Bolton WK, Hebert
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
L, Agarwal R, Catanzaro D: ACE inhibition or angiotensin receptor
blockade: Impact on potassium in renal failure. VAL-K Study Group.
Kidney Int 58: 2084 –2092, 2000
21. Brown MJ: Aliskiren. Circulation 118: 773–784, 2008
22. Gradman AH, Kad R: Renin inhibition in hypertension. J Am Coll
Cardiol 51: 519 –528, 2008
23. Vaidyanathan S, Bigler H, Yeh C, Bizot MN, Dieterich HA, Howard
D, Dole WP: Pharmacokinetics of the oral direct renin inhibitor
aliskiren alone and in combination with irbesartan in renal impair-
ment. Clin Pharmacokinet 46: 661– 675, 2007
24. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK,
AVOID Study Investigators: Aliskiren combined with losartan in
type 2 diabetes and nephropathy. N Engl J Med 358: 2433–2446,
2008
25. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B,
Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ,
Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW: Kidney disease
as a risk factor for development of cardiovascular disease: A state-
ment from the American Heart Association Councils on Kidney in
Cardiovascular Disease, High Blood Pressure Research, Clinical
Cardiology, and Epidemiology and Prevention. Circulation 108:
2154 –2169, 2003
26. Charytan D, Kuntz RE: The exclusion of patients with chronic kidney
disease from clinical trials in coronary artery disease. Kidney Int 70:
2021–2030, 2006
27. Evers J, Bonn R, Boertz A, Cawello W, Dickmans HA, Weiss M:
Pharmacokinetics of isosorbide dinitrate, isosorbide-2-nitrate and
isosorbide-5-nitrate in renal insufficiency after repeated oral dosage.
Klin Wochenschr 67: 342–348, 1989
28. Jerling M, Abdallah H: Effect of renal impairment on multiple-dose
pharmacokinetics of extended-release ranolazine. Clin Pharmacol
Ther 78: 288 –297, 2005
29. Jerling M: Clinical pharmacokinetics of ranolazine. Clin Pharmaco-
kinet 45: 469 – 491, 2006
30. Quaschning T, Krane V, Metzger T, Wanner C: Abnormalities in
uremic lipoprotein metabolism and its impact on cardiovascular
disease. Am J Kid Dis 38[Suppl 1]: S14 –S19, 2001
31. Halstenson CE, Triscari J, DeVault A, Shapiro B, Keane W, Pan H:
Single-dose pharmacokinetics of pravastatin and metabolites in pa-
tients with renal impairment. J Clin Pharmacol 32: 124 –132, 1992
32. Sica DA, Gehr TW: 3-Hydroxy-3-methylglutaryl coenzyme A reduc-
tase inhibitors and rhabdomyolysis: Considerations in the renal fail-
ure patient. Curr Opin Nephrol Hypertens 12: 123–133, 2002
33. Molden E, Skovlund E, Braathen P: Risk management of simvastatin
or atorvastatin interactions with CYP3A4 inhibitors. Drug Saf 31:
587–596, 2008
34. Navaneethan SD, Nigwekar SU, Perkovic V, Johnson DW, Craig JC,
Strippoli GF: HMG CoA reductase inhibitors (statins) for dialysis
patients. Cochrane Database Syst Rev (3): CD004289, 2009
35. Krane V, Winkler K, Drechsler C, Lilienthal J, März W, Wanner C,
German Diabetes and Dialysis Study Investigators: Effect of atorva-
statin on inflammation and outcome in patients with type 2 diabetes
on hemodialysis. Kidney Int 74: 1461–1467, 2008
36. Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K,
Beutler J, Chae DW, Chevaile A, Cobbe SM, Grönhagen-Riska C, De
Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, Remuzzi G,
Samuelsson O, Sonkodi S, Sci D, Süleymanlar G, Tsakiris D, Tesar
V, Todorov V, Wiecek A, Wüthrich RP, Gottlow M, Johnsson E,
Zannad F, AURORA Study Group: Rosuvastatin and cardiovascular
events in patients undergoing hemodialysis. N Engl J Med 360:
1395–1407, 2009
37. Chapman MJ: Pharmacology of fenofibrate. Am J Med 83: 21–25,
1987
38. The Field Study Investigators: Effects of long-term fenofibrate ther-
apy on cardiovascular events in 9795 people with type 2 diabetes
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mellitus (the FIELD study): Randomized controlled trial. Lancet 366:
1849 –1861, 2005
39. Sica DA: Fibrate therapy and renal function. Curr Atheroscler Rep
11: 338 –342, 2009
40. Davidson MH, Armani A, McKenney JM, Jacobson TA: Safety
considerations with fibrate therapy. Am J Cardiol 99: 3C–18C, 2007
41. Evans RJ, Forland SC, Cutler RE: The effect of renal function on the
pharmacokinetics of gemfibrozil. J Clin Pharmacol 27: 994 –1000,
1987
42. Reinecke H, Brand E, Mesters R, Schäbitz WR, Fisher M, Pavenstädt
H, Breithardt G: Dilemmas in the management of atrial fibrillation in
chronic kidney disease. J Am Soc Nephrol 20: 705–711, 2009
43. Camm AJ: Safety considerations in the pharmacological management
of atrial fibrillation. Int J Cardiol 127: 299 –306, 2008
44. Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG:
Current concepts in the mechanisms and management of drug-
induced QT prolongation and torsade de pointes. Am Heart J 153:
891– 899, 2007
45. Dancey D, Wulffhart Z, McEwan P: Sotalol-induced torsades de
pointes in patients with renal failure. Can J Cardiol 13: 55–58, 1997
46. van Uum SH, van den Merkhof LF, Lucassen AM, Wuis EW,
Diemont W: Successful haemodialysis in sotalol-induced torsade de
pointes in a patient with progressive renal failure. Nephrol Dial
Transplant 12: 331–333, 1997
Diuretics
Thiazide-Type Diuretics
Thiazide diuretics are not the diuretics of choice
for patients with renal insufficiency, with the possible
exception of the thiazide-like diuretics chlorthalidone
and metolazone. This distinction among the thiazide-
type diuretics relates to the differing pharmacologic
characteristics of these compounds in that they have a
much larger volume of distribution and more extended
delivery to their sites of action in the nephron (1).
Metolazone, which is often given together with a loop
diuretic in diuretic-resistant states, is very poorly ab-
sorbed from the gastrointestinal tract, which should be
taken into account when determining the appropriate
dosage and frequency of dosing with this agent (2).
Although a large dose of a thiazide diuretic (50 to
100 mg) will initiate a diuresis in patients with mild
renal insufficiency, the response in patients with a
GFR of less than approximately 50 ml/min is generally
poor. Patients with chronic kidney disease (CKD) are
not really “resistant“ to thiazide diuretics per se;
rather, the basis for failure of a thiazide diuretic is an
insufficient potency to meet the needs of patients with
a Na⫹-retaining state. Patients who receive fixed-
dosage combination antihypertensive therapy that con-
tains a thiazide diuretic should be considered for
conversion to a loop diuretic (together with whatever
was the other component of the fixed-dosage combi-
nation) when the GFR drops below approximately 30
260
ml/min, particularly when BP control has been less
than desired (3).
Loop Diuretics
Loop diuretics are the most commonly used
diuretics in renal failure. Approximately 50% of a
dose of furosemide is excreted in the urine unchanged;
the remainder is renally conjugated to glucuronic acid.
Therefore, in patients with renal failure, the plasma
half-life of furosemide is prolonged because both uri-
nary excretion and renal conjugation are reduced. The
two other loop diuretics that are available in the United
States, bumetanide and torsemide, are largely hepati-
cally metabolized (50 and 80%, respectively), and
their half-lives do not change appreciably in renal
failure (4); however, renal insufficiency will impair
their tubular delivery. In addition to the routes of
metabolism, the pharmacokinetic features of diuretics
that assume clinical significance are bioavailability
and half-life (5). The bioavailability of loop diuretics
is not affected by renal insufficiency.
On average, furosemide is 50% absorbed but
within a range of 10 to 100% (6). This wide range
makes it a matter of some guesswork as to how much
furosemide will be absorbed in an individual patient,
and varied dosages of furosemide must be tried before
the drug is deemed ineffective. This issue is poten-
tially further complicated by the presence of bowel
wall edema in the patient with decompensated heart
failure, which may slow and diminish loop diuretic
absorption from the gastrointestinal tract after oral
administration (7). In contrast, absorption and bio-
availability of bumetanide and torsemide are nearly
complete, ranging from 80 to 100%.
Several pharmacodynamic features of diuretics
are clinically important. In patients with a creatinine
clearance of ⬍20 ml/min, delivery of a loop diuretic
into the tubular fluid is only approximately 5 to 10%
of what would be delivered in individuals with normal
GFR. Thus, a large dose must be given to attain a
threshold quantity of diuretic in the tubular fluid for
delivery to the diuretic site of action. The relation
between the rate at which the diuretic is excreted and
the response in patients with renal insufficiency is
similar to what is observed in normal individuals (4,8).
Thus, the remaining nephrons in patients with renal
insufficiency (unless there are other circumstances
leading to sodium retention, such as nephrotic syn-
drome) retain their responsiveness to diuretics; the
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
problem is delivering adequate drug amounts of the
diuretic to the site of action.
A frequently posed question for a patient with
severe renal insufficiency is, “What is the largest
single dosage of a loop diuretic beyond which there is
no additional yield?” The maximal natriuretic re-
sponse occurs with intravenous bolus dosages of 160
to 200 mg of furosemide or the equivalent dosages of
bumetanide (4 to 5 mg) and torsemide (50 to 100 mg),
and nothing is accomplished by using larger dosages.
Some patients may require dosages in the range of 160
to 200 mg several times a day to persist in their
diuresis (9). Single intravenous bolus dosages of 160
to 200 mg can cause transient tinnitus, but this effect
can be minimized by administering the dose over a
period of 20 to 30 min at a rate no greater than 4
mg/min (10). Ototoxicity caused by ethacrynic acid
seems to develop more gradually and takes longer to
resolve than that caused by furosemide or bumetanide.
Limited data suggest that bumetanide may produce a
lower incidence of ototoxicity. Finally, because poten-
tiation of the ototoxic effects of aminoglycosides and
loop diuretics is well documented, these drugs should
be co-administered cautiously (11).
Potassium-Sparing Diuretics
Potassium-sparing diuretics are to be used cau-
tiously in patients with renal failure because of the risk
for hyperkalemia. Amiloride is an organic cation that
works as an antagonist of the epithelial sodium channel;
it is both filtered and extensively secreted by the organic
cation pathway. Renal disease prolongs its plasma half-
life; accordingly, the dosage should be reduced by 50%
in patients with a creatinine clearance of ⬍50 ml/min
(12). Amiloride can compete for tubular secretion with
other organic cations, such as cimetidine, metformin, or
trimethoprim. Like all potassium-sparing diuretics, the
likelihood of its causing hyperkalemia is greatest in the
patient with CKD and diabetes (13).
Triamterene, another potassium-sparing diuretic that
also inhibits the epithelial sodium channel, is seldom given
alone but rather is typically given together with hydrocholo-
rothiazide as a fixed-dosage combination product for the
treatment of hypertension. The pharmacokinetics of triam-
terene are complex, because it is hepatically converted to an
active metabolite, which then undergoes active tubular se-
cretion. Renal disease impairs the tubular secretion of this
metabolite, and lengthening of the dosage interval to every
12 hours is suggested when the creatinine clearances is ⬍50
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
ml/min (14). Triamterene is also associated with crystalluria
and occasionally with triamterene stones (15). A final con-
sideration with triamterene is its tendency to cause acute
renal failure when given together with a nonsteroidal anti-
inflammatory drug relating to an intrinsic vasoconstrict-
ing property that is unique to triamterene or its metabo-
lites (16).
Spironolactone and the newer agent eplerenone differ
mechanistically from amiloride and triamterene in that they
are aldosterone receptor antagonists. This is the basis for
their expanding use in heart failure and therapy-resistant
hypertension (17). Whereas eplerenone is metabolized by
CYP3A4 to inactive metabolites, spironolactone is oxida-
tively metabolized to two active metabolites, canrenone and
7-␣-thiomethylspironolactone, with half-life values in the
24-hour range. The pharmacokinetics of spironolactone and
eplerenone have not been studied in the setting of renal
failure. Dosage adjustment or use of spironolactone or
eplerenone is not solely based on the level of renal function;
rather, it is governed by the likelihood of clinically relevant
hyperkalemia. Spironolactone can be given to patients with
ESRD with minimal risk (18). Spironolactone and/or its
metabolites have a prolonged potassium-sparing effect that
should be accounted for when it is prescribed. Eplerenone
should be used carefully with inhibitors of CYP3A4, such as
verapamil and diltiazem, because these compounds would
be expected to inhibit the clearance of eplerenone and
therein extend its duration of action.
Mannitol
Mannitol, an osmotic diuretic, exerts its diuretic
effect at the proximal tubule and loop of Henle. If it
goes unfiltered and instead remains in the circulation,
as in patients with reduced GFR, then it can increase
intravascular volume by an osmotic drag effect. The
convective flux that occurs with high plasma mannitol
concentrations will result in dilutional hyponatremia,
increases in serum potassium, and, if concentrations
go high enough, acute renal failure, which occurs
secondary to afferent arteriolar vasoconstriction (19).
The risks that are associated with mannitol, coupled
with the availability of other highly effective diuretics,
relegate its use to nondiuretic indications, such as
cerebral edema.
References
1. Sica DA: Chlorthalidone: Has it always been the best thiazide-type
diuretic? Hypertension 47: 321–322, 2006
2. Sica DA: Metolazone and its role in edema management. Congest
Heart Fail 9: 100 –105, 2003
261
3. Dussol B, Moussi-Frances J, Morange S, Somma-Delpero C, Mun-
dler O, Berland Y: A randomized trial of furosemide vs hydrochlo-
rothiazide in patients with chronic renal failure and hypertension.
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4. Brater DC: Diuretic therapy. N Engl J Med 339: 387–395, 1998
5. Sica DA, Gehr TW: Diuretic combinations in refractory oedema
states: Pharmacokinetic-pharmacodynamic relationships. Clin Phar-
macokinet 30: 229 –249, 1996
6. Murray MD, Haag KM, Black PK, Hall SD, Brater DC: Variable
furosemide absorption and poor predictability of response in elderly
patients. Pharmacotherapy 17: 98 –106, 1997
7. Vasko MR, Cartwright DB, Knochel JP, Nixon JV, Brater DC:
Furosemide absorption altered in decompensated congestive heart
failure. Ann Intern Med 102: 314 –318, 1985
8. Brater DC: Clinical pharmacology of loop diuretics in health and
disease. Eur Heart J 13[Suppl G]: 10 –14, 1992
9. Shankar SS, Brater DC: Loop diuretics: From the Na-K-2Cl trans-
porter to clinical use. Am J Physiol Renal Physiol 284: F11–F21,
2003
10. Rybak LP: Ototoxicity of loop diuretics. Otolaryngol Clin North Am
26: 829 – 844, 1993
11. Bates DE, Beaumont SJ, Baylis BW: Ototoxicity induced by genta-
micin and furosemide. Ann Pharmacother 36: 446 – 451, 2002
12. Spahn H, Reuter K, Mutschler E, Gerok W, Knauf H: Pharmacoki-
netics of amiloride in renal and hepatic disease. Eur J Clin Pharma-
col 33: 493– 498, 1987
13. Greenberg A: Diuretic complications. Am J Med Sci 319: 10 –24,
2000
14. Sica DA, Gehr TW: Triamterene and the kidney. Nephron 51:
454 – 461, 1989
15. Fairley KF, Woo KT, Birch DF, Leaker BR, Ratnaike S: Triam-
terene-induced crystalluria and cylinduria: Clinical and experimental
studies. Clin Nephrol 26: 169 –173, 1986
16. Favre L, Glasson P, Vallotton MB: Reversible acute renal failure
from combined triamterene and indomethacin: A study in healthy
subjects. Ann Intern Med 96: 317–320, 1982
17. Nishizaka MK, Zaman MA, Calhoun DA: Efficacy of low-dose
spironolactone in subjects with resistant hypertension. Am J Hyper-
tens 16: 925–930, 2003
18. McLaughlin N, Gehr TW, Sica DA: Aldosterone-receptor antago-
nism and end-stage renal disease. Curr Hypertens Rep 6: 327–330,
2004
19. Borges HF, Hocks J, Kjellstrand CM: Mannitol intoxication in
patients with renal failure. Arch Intern Med 142: 63– 66, 1982
Gastrointestinal Agents
Antacids are commonly used self-prescribed
medications. They consist of calcium carbonate and
magnesium and aluminum salts in various compounds
or combinations. Both magnesium- and aluminum-
containing antacids should be used sparingly, if at all,
in the patient with advanced-stage chronic kidney
disease (CKD) (1). All antacids can produce drug
interactions by changing gastric pH, thereby altering
drug dissolution of dosage forms, decreasing acid
hydrolysis of drugs, or changing renal drug clearance
by altering urinary pH. Most antacids, except sodium
bicarbonate, may decrease drug absorption by adsorp-
tion or chelation of other drugs. Antacid-related drug
interactions, based on chelation of co-administered
262
medications, can be avoided by appropriately sched-
uling medication administration times. Aluminum ab-
sorption from antacids or other aluminum-containing
compounds can be substantially enhanced by the con-
comitant intake of citrate-containing products, so these
combinations must be avoided (2).
Patients with CKD have a high prevalence of gas-
trointestinal symptoms and often are treated with acid
suppressive therapy with histamine2 (H2) receptor antag-
onists and proton-pump inhibitors. H2 receptor antago-
nists are predominantly cleared by renal mechanisms that
involve varying degrees of filtration and tubular secretion
by cationic transporters (3). On the basis of its ability to
block tubular secretion of creatinine, the first-generation
H2 receptor antagonist cimetidine has been used as a way
to have 24-hour creatinine clearance measurements more
closely approximate true GFR (4). The dosage of an H2
receptor antagonist is generally adjusted on the basis
of the level of renal function; however, concentration-
dependent adverse effects are uncommon with H2
receptor antagonists other than cimetidine, which can
cause bradyarrhythmias and confusion.
Proton-pump inhibitors are predominantly hepati-
cally cleared, and dosage adjustment is not necessary in
the patient with CKD. As is the case with H2 receptor
antagonists, sporadic cases of acute interstitial nephritis
have occurred with proton-pump inhibitors (5,6). Proton-
pump inhibitors as well as H2 receptor antagonists are
available for over-the-counter purchase. As such, unless
a patient is specifically questioned about over-the-
counter medication use, a potential cause of acute kidney
disease can go unnoticed.
Acute phosphate nephropathy is a widely recog-
nized complication of the use of phosphate laxative
preparations, such as in patients who are preparing for
colonoscopy. Advanced age, renal failure, and use of
medications such as angiotensin-converting enzyme
inhibitors and angiotensin-receptor blockers are rec-
ognized as risk factors for the development of acute
phosphate nephropathy. The presence of any of these
risk factors necessitates careful attention to avoiding
excessive dehydration in the process of bowel cleans-
ing. In so doing, the likelihood that acute phosphate
nephropathy will occur can be reduced (7–9).
References
1. Maton PN, Burton ME: Antacids revisited: A review of their clinical
pharmacology and recommended therapeutic use. Drugs 57: 855– 870,
1999
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
2. Reinke CM, Breitkreutz J, Leuenberger H: Aluminum in over-the-counter
drugs: Risks outweigh benefits? Drug Saf 26: 1011–1025, 2003
3. Gladziwa U, Klotz U: Pharmacokinetics and pharmacodynamics of
H2-receptor antagonists in patients with renal insufficiency. Clin
Pharmacokinet 24: 319 –332, 1993
4. van Acker BA, Koomen GC, Koopman MG, de Waart DR, Arisz L:
Creatinine clearance during cimetidine administration for measure-
ment of glomerular filtration rate. Lancet 340: 1326 –1329, 1992
5. Härmark L, van der Wiel HE, de Groot MC, van Grootheest AC:
Proton pump inhibitor-induced acute interstitial nephritis. Br J Clin
Pharmacol 64: 819 – 823, 2007
6. Sierra F, Suarez M, Rey M, Vela MF: Systematic review: Proton pump
inhibitor-associated acute interstitial nephritis. Aliment Pharmacol
Ther 26: 545–553, 2007
7. Sica DA, Carl D, Zfass AM: Acute phosphate nephropathy: An
emerging issue. Am J Gastroenterol 102: 1844 –1847, 2007
8. Heher EC, Thier SO, Rennke H, Humphreys BD: Adverse renal and
metabolic effects associated with oral sodium phosphate bowel prep-
aration. Clin J Am Soc Nephrol 3: 1494 –1503, 2008
9. Brunelli SM: Association between oral sodium phosphate bowel prep-
arations and kidney injury: a systematic review and meta-analysis.
Am J Kidney Dis 53: 448 – 456, 2009
Antidiabetic Agents
Multiples therapies with differing mechanisms of
action are available for the treatment of diabetes;
however, in the patient with chronic kidney disease
(CKD) there are therapy considerations related to
dosage adjustment according to level of renal function,
and certain therapies are best avoided altogether (1).
Exogenous insulin, whether it is short or long acting,
is mainly renally cleared by way of filtration and
extensive tubular secretion and cellular catabolism in
the kidney. As renal failure progresses to GFR levels
of less than approximately 30 ml/min, insulin clear-
ance begins to decrease, its half-life increases, and
insulin requirements begin to decline (2). As such,
hypoglycemic spells become more common unless
there is some reduction in administered insulin dosage.
Metformin is generally considered to be contra-
indicated in advanced CKD because of the associated
risk for lactic acidosis. It can be used at low- to
mid-range dosages in patients with creatinine clear-
ances of 30 to 60 ml/min but should be avoided with
creatinine clearances of ⬍30 ml/min unless other ther-
apy options are not available; however, few cases of
metformin-associated lactic acidosis have been re-
ported, and most have occurred in patients with other
reasons for developing lactic acidosis, such as sepsis
or renal failure. There is considerable debate, there-
fore, as to the optimal use of metformin in patients
with advanced renal disease. This is further compli-
cated by reliance on criteria for its use that are based
on serum creatinine values (contraindicated for serum
creatinine values ⬎1.5 mg/dl in men and ⬎1.4 mg/dl
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
in women) rather than actual or estimated GFR (3,4).
Although use of metformin continues to increase,
observational studies have not been able to demon-
strate an increased incidence of lactic acidosis in
metformin-treated patients, even when it is used in
populations with relative contraindications (5,6). Be-
cause the use of metformin in the patient with CKD is
in a state of conceptual evolution, the best approach is
probably to assume that in patients without other
comorbid conditions that would predispose them to
lactic acidosis, elevated serum creatinine levels should
be considered a risk factor for the development of
lactic acidosis but not an absolute contraindication to
the use of metformin.
Although the metabolism of thiazolidinediones is
unaffected by renal failure, they must be used with
caution in this context because of their volume-retain-
ing effects (7,8); however, in that the edema seen with
the thiazolidinediones is secondary to salt and water
retention, the volume-retaining effect of these com-
pounds is not a deterrent to their use in the patient with
ESRD.
First-generation sulfonylureas (acetohexamide,
chlorpropamide, tolazamide, and tolbutamide) are sel-
dom used and should be avoided in patients with
stages 3 through 5 CKD. These agents were associated
with prolonged hypoglycemia relating to parent drug
and/or active metabolite accumulation (9,10). Among
second-generation sulfonylureas, glibenclamide (gly-
buride) is oxidized to several metabolites, one of
which, 4-hydroxy-glibenclamide, is renally cleared
and has 15% of the potency of the parent compound.
Thus, the risk for hypoglycemia is increased with its
use in patients with renal dysfunction. Glipizide and
gliclazide are metabolized by the liver to several inactive
metabolites and thus generally are considered safe to be
used in patients with reduced renal function (11).
The nonsulfonylurea insulin secretagogues repa-
glinide and nateglinide can be used in renal failure
without dosage adjustments (11–13). A small amount
of nateglinide is excreted in the urine, and its active
metabolite is also renally excreted; there is a small risk
for hypoglycemia when this compound is used in
advanced renal failure (14,15). ␣-Glucosidase inhibi-
tors such as acarbose and miglitol are generally not
used in patients with advanced renal failure because
the plasma level of the parent drug and variably active
metabolites can accumulate, although the clinical sig-
nificant of such drug accumulation is not known (11).
263
There is no long-term safety information on the incre-
tin-based secretagogues, such as sitagliptin. Sitagliptin
is renally cleared and requires dosage adjustment on the
basis of the level of renal function; however, it is unclear
what the risk of sitagliptin accumulation is (16).
Treatment of the patient with late-stage renal
failure and diabetes can prove difficult in that there are
limitations and contraindications to the use of several
of the therapies that routinely are used for this disease.
Even with the change in systemic clearance of insulin
in advanced CKD and ESRD, it often is the best option
in these patients to maintain glycemic control.
References
1. Snyder RW, Berns JS: Use of insulin and oral hypoglycemic medi-
cations in patients with diabetes mellitus and advance kidney disease.
Semin Dial 17: 365–370, 2004
2. Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G: Decreased
insulin requirement in relation to GFR in nephropathic type 1 and
insulin-treated type 2 diabetic patients. Diabet Med 20: 642– 645, 2003
3. Haneda M, Morikawa A: Which hypoglycaemic agents to use in type
2 diabetic subjects with CKD and how? Nephrol Dial Transplant 24:
338 –341, 2009
4. Mani MK: Metformin in renal failure: Weigh the evidence. Nephrol
Dial Transplant 24: 2287–2288, 2009
5. Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR: Metformin,
sulfonylureas, or other antidiabetes drugs and the risk of lactic
acidosis or hypoglycemia: A nested case-control analysis. Diabetes
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fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes
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Freed MI: Pharmacokinetics of rosiglitazone in patients with varying
degrees of renal insufficiency. J Clin Pharmacol 43: 252–259, 2003
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Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn
R: Thiazolidinedione use, fluid retention, and congestive heart fail-
ure: A consensus statement from the American Heart Association and
American Diabetes Association. Diabetes Care 27: 256 –263, 2004
9. Harrower AD: Pharmacokinetics of oral antihyperglycaemic agents
in patients with renal insufficiency. Clin Pharmacokinet 31: 111–
119, 1996
10. Krepinsky J, Ingram AJ, Clase CM: Prolonged sulfonylurea-induced
hypoglycemia in diabetic patients with end-stage renal disease. Am J
Kidney Dis 35: 500 –505, 2000
11. KDOQI: Clinical practice guidelines and clinical practice recommen-
dations for diabetes and chronic kidney disease. Guideline 2: Man-
agement of hyperglycemia and general diabetes care in chronic
kidney disease. Am J Kidney Dis 49[Suppl 2]: S62–S73, 2007
12. Schumacher S, Abbasi I, Weise D, Hatorp V, Sattler K, Sieber J,
Hasslacher C: Single- and multiple-dose pharmacokinetics of repa-
glinide in patients with type 2 diabetes and renal impairment. Eur
J Clin Pharmacol 57: 147–152, 2001
13. Lubowsky ND, Siegel R, Pittas AG: Management of glycemia in
patients with diabetes mellitus and CKD. Am J Kidney Dis 50:
865– 879, 2007
14. Inoue T, Shibahara N, Miyagawa K, Itahana R, Izumi M, Nakanishi
T, Takamitsu Y: Pharmacokinetics of nateglinide and its metabolites
in subjects with type 2 diabetes mellitus and renal failure. Clin
Nephrol 60: 90 –95, 2003
264
15. Nagai T, Imamura M, Iizuka K, Mori M: Hypoglycemia due to
nateglinide administration in diabetic patient with chronic renal
failure. Diabetes Res Clin Pract 59: 191–194, 2003
16. Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W, Gottes-
diener K, Wagner J, Herman GA: Effect of renal insufficiency on the
pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor.
Diabetes Care 30: 1862–1864, 2007
Analgesic Agents
Acetaminophen
There remains some debate on the role of long-term
acetaminophen use and the development of chronic kid-
ney disease (CKD). Acetaminophen is the primary me-
tabolite of phenacetin. Despite the clearly established
association between phenacetin and analgesic nephropa-
thy, there is insufficient evidence to link habitual acet-
aminophen use to analgesic nephropathy (1,2); however,
the consistency of the results from existing epidemio-
logic studies and the observed apparent dosage-response
relationship suggest that such a relationship cannot be
completely excluded. Among 1700 healthy women who
participated in the Nurses’ Health Study in the United
States, those who consume ⬎3000 g of acetaminophen
had an odds ratio of 2.04 (95% confidence interval 1.28
to 3.24) for a decreased GFR of at least 30 ml/min per
1.73 m2 during an 11-yr period compared with women
who consumed ⱖ100 g (3). Nonetheless, single-sub-
stance acetaminophen and aspirin seem to be safe to use
for patients with diagnosed advanced stages 4 to 5 CKD
without an adverse effect on CKD progression (4).
Opioid Analgesic Agents
A growing body of literature now shows that mod-
erate to severe chronic pain is common in patients with
ESRD and affects virtually every aspect of health-related
quality of life (5). A number of narcotic analgesic agents
can potentially be used in the management of pain in
these patients, including morphine, codeine, hydromor-
phone, and oxycodone, as well as fentanyl and metha-
done. Fentanyl and methadone may be the safest agents
to use because they are hepatically metabolized and do
not have active metabolites (6,7).
Morphine use is problematic in the patient with
CKD because it is hepatically metabolized to morphine-
3-glucoronide (55%), morphine-6-glucuronide (10%),
and normorphine (4%), all of which are excreted renally,
together with 10% of the parent compound. These active
metabolites accumulate with repetitive dosing in the
patient with CKD, with the attendant risk for respiratory
depression and adverse central nervous system effects
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
(8,9). Codeine, although commonly thought of as a
“mild” narcotic analgesic, also presents problems in the
patient with CKD. Codeine has multiple metabolites, the
predominant one being codeine-6-glucoronide; both co-
deine and codeine-6-glucoronide are renally excreted
(10). There is a report of respiratory arrest attributed to
the morphine-6-glucoronide metabolite of codeine (11).
Thus, morphine and codeine are best avoided in patients
with significantly reduced GFR rather than trying to
estimate the degree to which their dosage should be
reduced on the basis of the level of renal function.
Normeperidine, a major metabolite of meperi-
dine, has approximately 50% of the potency of me-
peridine as an analgesic but two to three times its
potency as a neuroexcitatory agent and is predomi-
nantly renally cleared. Meperidine and normeperidine
toxicities are not reversed by naloxone, and it may in
certain instances exacerbate it. Because of this, mepe-
dine use should be avoided in patients with significant
renal dysfunction. Normeperidine is dialyzable; there-
fore, hemodialysis may be used for patients with
suspected normeperidine neurotoxicity (12).
References
1. Barrett BJ: Acetaminophen and adverse chronic renal outcomes: An
appraisal of the epidemiologic evidence. Am J Kidney Dis 28[Suppl
1]: S14 –S19, 1996
2. Fored CM, Ejerblad E, Lindblad P, Fryzek JP, Dickman PW, Signo-
rello LB, Lipworth L, Elinder CG, Blot WJ, McLaughlin JK,
Zack MM, Nyrén O: Acetaminophen, aspirin, and chronic renal
failure. N Engl J Med 345: 1801–1808, 2001
3. Curhan GC, Knight EL, Rosner B, Hankinson SE, Stampfer MJ:
Lifetime nonnarcotic analgesic use and decline in renal function in
women. Arch Intern Med 164: 1519 –1524, 2004
4. Evans M, Fored CM, Bellocco R, Fitzmaurice G, Fryzek JP,
McLaughlin JK, Nyrén O, Elinder CG: Acetaminophen, aspirin and
progression of advanced chronic kidney disease. Nephrol Dial Trans-
plant 24: 1908 –1918, 2009
5. Davison SN: Pain in hemodialysis patients: Prevalence, cause, sever-
ity, and management. Am J Kidney Dis 42: 1239 –1247, 2003
6. Davies G, Kingswood C, Street M: Pharmacokinetics of opioids in
renal dysfunction. Clin Pharmacokinet 31: 410 – 422, 1996
7. Dean M: Opioids in renal failure and dialysis patients. J Pain
Symptom Manage 28: 497–504, 2004
8. Conway BR, Fogarty DG, Nelson WE, Doherty CC: Opiate toxicity
in patients with renal failure. BMJ 332: 345–346, 2006
9. Sawe J, Odar-Cederlof I: Kinetics of morphine in patient with renal
failure. Eur J Clin Pharmacol 32: 377–382, 1987
10. Talbott GA, Lynn AM, Levy FH, Zelikovic I: Respiratory arrest
precipitated by codeine in a child with chronic renal failure. Clin
Pediatr 36: 171–173, 1997
11. Guay DR, Awni WM, Finlay JW, Halstenson CE, Abraham PA,
Opsahl JA, Jones EC, Matzke GR: Pharmacokinetics and pharmaco-
dynamics of codeine in end-stage renal disease. Clin Pharmacol Ther
43: 63–71, 1988
12. Hassan H, Bastani B, Gellens M: Successful treatment of normeperidine
neurotoxicity by hemodialysis. Am J Kidney Dis 35: 146 –149, 2000
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010

Nephrology Self-Assessment Program

Examination Questions
Instructions to obtain 8 AMA PRA Category 1 CreditsTM
Date of Original Release: July 2010
Examination Available Online: on or before Friday, July 9, 2010
Audio Files Available: No audio files will be available for this issue.
CME Credit Eligible Through: June 30, 2011
Answers: Correct answers with explanations will be posted on the ASN website in July 2011 when the issue is archived.
UpToDate Links Active: July and August 2010
Core Nephrology question links active: There are no core questions for this issue.
Target Audience: Nephrology Board and recertification candidates, practicing nephrologists, and internists.
Method of Participation:
● Read the syllabus that is supplemented by original articles in the reference lists, and complete the online self-assessment
examination.
● Examinations are available online only after the first week of the publication month. There is no fee. Each participant is
allowed two attempts to pass the examination (⬎75% correct).
● Your score and a list of question/s (by number) answered incorrectly can be printed immediately.
● Your CME certificate can be printed immediately after passing the examination.
● Answers and explanations are provided ONLY with a passing score on the first or second attempt.
● Your ASN transcript will be updated in 6 to 8 weeks after passing the examination.
Instructions to access the Online CME Center to take the examination and complete the evaluation:
● Login at ASN’s website: www.asn-online.org
● Click the “CME” tab at the top of the homepage
● In the left-hand column click “Online CME Center”
● Scroll down; in the center of the page click the computer screen image to “Visit the Online CME Center”
● Once you’re in the Center, click the “NephSAP” banner in the center of the page
● Select a topic and click on “Enter Activity” to the right
● Read through the instructions, and then click on “Continue” at the bottom of the page
● Click on “Examination Questions/Evaluations” to begin
● Your score and a list of question numbers answered incorrectly can be printed immediately
● Follow the prompts to retake the examination if you failed, or print your certificate and the correct answers if you passed
● You can save and finish the exam to complete at another time
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Instructions to Obtain American Board of Internal Medicine (ABIM) Maintenance of Certification
(MOC) Points:
Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria:
● Be certified by ABIM in internal medicine and/or nephrology and must be enrolled in the ABIM–MOC program
via the ABIM website (www.abim.org).
● Pass the self-assessment examination within the timeframe specified in this issue of NephSAP.
● Designate the issue for MOC points by clicking on the MOC link on the CME certificate page after passing the examination.
You will be leaving the ASN-CECity site and transferring the information directly to the ABIM in real-time.
● Provide your ABIM Certificate ID number and your date of birth.
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MOC points will be applied to only those ABIM candidates who have enrolled in the program. It is your responsibility to complete
the ABIM MOC enrollment process.

266

Volume 9, Number 4, July 2010 —Clinical Pharmacology for the Nephrologist
1. A 74-year-old man with blurred vision receives a
diagnosis of fungal endophthalmitis, and Aspergillus
fumigatus is cultured from the vitreous aspirate. His
history is complicated with diabetes, severe chronic
kidney disease (CKD; estimated GFR [eGFR] ⬍30),
diabetic retinopathy, illicit intravenous drug use, hy-
pertension, and narcotic dependence. Intravenous vori-
conazole therapy is started; after 2 days of treatment,
he complains to the home health agency that he is
seeing bright “psychedelic” colors and “flashing
lights” even when his eyes are closed. His neurologic
and eye examinations are unremarkable.
Which ONE of the following is the MOST
likely cause of these symptoms?
A. Undisclosed LSD use
B. Diabetic retinopathy
C. Accumulation of voriconazole
D. The solubilizing agent cyclodextrin, found
in voriconazole preparations
E. Migraines
2. Which ONE of the following statements re-
garding pharmacologic agents that undergo
hepatic metabolism and are not eliminated by
the kidney is CORRECT?
A. Such drugs do not require dosage adjust-
ment in patients with CKD.
B. Renal function may be relevant because of
renal elimination of active metabolites.
C. Such agents do not induce the cytochrome
P450 enzyme system in patients with CKD to
the same degree seen in patients with intact
kidney function.
D. Such drugs do not inhibit the cytochrome P450
enzyme system in patients with CKD to the
same degree seen in patients with intact kidney
function.
E. Such agents should always be chosen over
compounds that undergo renal elimination to
267
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
simplify dosing, avoid toxicity, and thereby
minimize cost.
3. The volume of distribution (Vd) of a drug can
be used to calculate both a loading dose and a
maintenance dose and may demonstrate which
ONE of the following?
A. Vd increases with ascites, or “third
spacing.”
B. Vd is not affected by uremic waste prod-
ucts and thus is irrelevant in ESRD.
C. Expect greater drug removal by hemodial-
ysis when Vd is large.
D. Vd increases with volume contraction.
E. Changes in protein binding of a drug have
no impact on Vd.
4. A patient is begun on aminoglycoside therapy for
the treatment of Gram-negative sepsis.
Aminoglycoside nephrotoxicity correlates
with which ONE of the following?
A. Supratherapeutic doses given once per day
B. High peak and low trough levels
C. Frequency of dosing
D. Post-antibiotic effect
E. Ototoxicity
5. A 45-year-old man with ESRD of unknown cause and
intermittent alcohol abuse receives hemodialysis thrice
weekly. He has had fistula stenosis detected recently,
and it required an increase in heparin use during his
dialysis treatments. He is emergently admitted for
upper gastrointestinal tract bleeding after his last dial-
ysis treatment, but endoscopic findings are inconclu-
sive. His medications include antihypertensive agents,
omeprazole, sevelamer carbonate, and sertraline for
depression. He denies recent increased use of his non-
steroidal anti-inflammatory drug as well as aspirin.
Which ONE of the following drugs is MOST
likely to contribute to his episode of gastroin-
testinal bleeding?
268
A. Increased heparin requirements at dialysis treat-
ments
B. Sevelamer
C. None of his drugs would contribute to bleeding
D. Sertraline
夝8. A 52-year-old man with diabetic nephropathy under-
6. A 32-year-old, 55-kg woman with end-stage renal
failure has undergone renal transplantation for
hypertensive nephropathy. Her urine output in the
last 24 hours ranges from 5 to 10 ml/hr. You
would like to start this patient on a cyclosporine
(CsA) immunosuppressive regimen but are con-
cerned about nephrotoxicity.
Which ONE of the following is the appropri-
ate treatment protocol for this patient?
A. Initiate CsA; renal function will return to
normal in a few days.
B. Give 100 mg of furosemide, then start
CsA at 4 to 5 mg/kg per d in two divided
doses and monitor for toxicities.
C. Consider the use of sirolimus at 10 mg/d.
D. Consider an induction therapy with polyclonal
antibodies and delay the use of CsA for 3 to 5
days.
7. A 32-year-old, 55-kg woman with end-stage renal
failure underwent renal transplantation. Two months
later, she complains of a tingling sensation in her hand
and severe hand tremors. Her weight has increased to
65 kg, BP is 160/94 (baseline before discharge was
145/85), blood urea nitrogen level is 30, serum creat-
inine level is 2.2 mg/dl (baseline 1.2 mg/dl), and
trough whole-blood (RIA monoclonal Incstar) CsA
level is 885 ng/dl. Her medications include CsA 200
mg twice daily; lisinopril 10 mg/d; prednisone 20
mg/d; fluconazole 400 mg/d; nifedipine 30 mg
twice daily; and trimethoprim/sulfamethoxazole
(TMP/SMZ) double strength (DS) Monday,
Wednesday, and Friday.
Which ONE of the following statements
BEST explains her symptoms?
A. This presentation is consistent with acute
rejection, and a biopsy is needed.
B. Use of an angiotensin-converting enzyme
inhibitor (ACEI) for the treatment of hy-
pertension could have contributed to her
renal dysfunction.
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
C. Nifedipine is excreted through the kidney
and inhibits P450 3A4 gene family and
interacts with CsA.
D. This is an iatrogenic drug toxicity most
likely as a result of drug interactions.
went a successful kidney transplant 7 months ago.
Except for one episode of rejection, which was treated
with three pulse doses of intravenous methylpred-
nisolone (500 mg), his posttransplantation course had
been unremarkable.
His current medications include tacrolimus 2 mg
twice daily, mycophenolate mofetil 1000 mg twice
daily, prednisone 15 mg/d, TMP/SMZ 1 DS tablet
three times weekly, lisinopril 10 mg/d, atorvastatin
20 mg/d, NPH insulin 32 U in the morning and 17
U in the evening, aspirin 81 mg/d, and a multivita-
min.
He now presents with a 2-day history of a nonpro-
ductive cough, intermittent right-sided pleuritic chest
pain, temperature (today 103.5°F), and rigors. He
has not traveled and has not had contacts with indi-
viduals with respiratory illnesses. He has no history
of gardening or recent contacts with construction.
His social history was noncontributory.
Which ONE of the following drugs would be
the BEST initial agent for the treatment of
his pneumonia?
A. Azithromycin
B. Erythromycin
C. Clarithromycin
D. Antituberculous therapy
9. Which ONE of the following pharmacologic
parameters is the MOST important one to
measure to adjust mycophenolate therapy?
A. Mycophenolic acid (MPA) levels at 0, 2,
and 6 hours
B. MPA/mycophenolate glucuronide concen-
tration at trough
C. Percentage of CD52 cells
D. Pharmacokinetic monitoring of MPA or
mycophenolate glucuronide is not neces-
sary for most patients.
10. A 32-year-old woman received a renal transplant.
 Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
Her postoperative course was uneventful. Her serum
creatinine was 1.1 mg/dl at the time of discharge. Her
medications at this time included tacrolimus 2 mg
twice daily; sirolimus 3 mg/d; TMP/SMZ 1 DS tablet
Monday, Wednesday, and Friday; lisinopril 10 mg/d;
simvastatin 40 mg/d; and aspirin 81 mg/d. During the
past 12 months, her renal function has progressively
worsened. Her serum creatinine is 2.0 mg/dl today,
and a biopsy did not reveal rejection but is consistent
with signs of tacrolimus nephrotoxicity.
Which ONE of the following immunosuppres-
sive agents has been used alone to decrease
nephrotoxicity?
A. Sirolimus
14. A 68-year-old man with diabetes and stage 3 CKD
B. Cyclosporine
C. Tacrolimus
D. Cyclophosphamide
夝11. Which ONE of the following is the dose-
limiting toxicity of sirolimus?
A. Hyperlipidemia
B. Acute rejection
C. Hypertension
D. Gastrointestinal complications
12. A 23-year-old female kidney transplant recipient de-
velops severe hirsutism after kidney transplantation.
Which ONE of the following agents could
replace cyclosporine for maintenance ther-
apy to avoid cosmetic adverse effects such
as hirsutism and coarsening of facial fea-
tures?
A. Thymoglobulin
B. Tacrolimus
C. Sirolimus
D. Mycophenolate
夝15. Which ONE of the following statements is
夝13. A 78-year-old woman is scheduled for a screening
colonoscopy, and her gastroenterologist has recom-
mended a standard bowel preparation protocol in-
cluding a laxative and neutral sodium phosphate
orally. She received a similar bowel-cleansing
regimen 2 years ago without incident. At that
time, an adenomatous colonic polyp was re-
moved. Her serum creatinine at its baseline is
1.5 mg/dl, and her eGFR is 52 ml/min. Her
269
medications include a diuretic, an ACEI, baby-
dosage aspirin, and a statin.
Which ONE of the following is indicated at
this time?
A. Continue with the recommended therapy.
B. Continue with the recommended bowel prep-
aration, but discontinue her diuretic and
ACEI at least 2 days before the procedure.
C. Hospitalize her for the bowel preparation,
and provide intravenous fluid replacement.
D. Recommend the use of polyethylene glycol
as the bowel-preparation agent.
has a serum creatinine level of 2.0 mg/dl, an eGFR of
40 ml/min, and significant peripheral edema. He is
being seen for a routine office visit, and he states that
he has recently seen a deterioration in his diabetes
control with a most recent hemoglobin A1c of 8.0%
compared with a previous value of 6.5%. The only
medication change had been the discontinuation of
his metformin by his primary care physician because
his serum creatinine level was elevated and that it
might be “damaging the kidney.” In its place, his
sulfonylurea dosage was doubled because he was
hesitant to start insulin.
Which ONE of the following is the BEST
advice that can be given to him about his
diabetes management?
A. Increase his dosage of the sulfonylurea,
and recheck glycemic status in 2 weeks.
B. Add a thiazolidinedione to the sulfonylurea.
C. Restart the metformin at a reduced dosage, and
recheck his glycemic status in several weeks.
D. Discontinue oral medications and instead begin
a regimen of short- and long-acting insulin.
CORRECT regarding the use of a thiazo-
lidinedione in a patient with stage 4 CKD?
A. Increased risk for lactic acidosis
B. Increased risk for developing significant
peripheral edema
C. Increased risk for hypoglycemic episodes
D. Acceleration in the rate of renal functional
decline
270
16. A 38-year-old man with an eGFR of 24 ml/min and
diabetic nephropathy is being seen for recurrent hy-
poglycemic spells. His medication regimen includes
a first-generation sulfonylurea, a loop diuretic, and an
ACEI.
Which ONE of the following should be done
to prevent additional hypoglycemic spells?
A. Change him from an ACEI to an angioten-
sin receptor blocker.
B. Increase carbohydrate intake.
C. Convert from a first-generation to a sec-
ond-generation sulfonylurea.
D. Reduce his dosage of sulfonylurea.
E. Discontinue the sulfonylurea and begin an
insulin regimen.
17. Which ONE of the following BEST relates to
the use of acetaminophen in stage 4 to 5
CKD?
A. Acetaminophen use accelerates decline in
GFR in 20% of patients.
B. Acetaminophen use leads to an increased
risk for diuretic resistant hypertension.
C. Acetaminophen is the preferred first-line
nonnarcotic analgesic.
D. Acetaminophen dosing requires adjustment
for level of eGFR.
18. A 58-year-old man with ESRD secondary to
polycystic kidney disease is seen by his primary
care physician and started on simvastatin be-
cause of his presumed high cardiovascular risk.
Approximately 3 weeks thereafter, he develops
atrial fibrillation and is placed on diltiazem for
rate control. He subsequently develops myalgias
and muscle weakness.
Which ONE of the following is the BEST
treatment approach for this patient?
A. Continue current therapy, but add coen-
zyme Q.
B. Convert from diltiazem to verapamil.
C. Switch from simvastatin to lovastatin.
D. Discontinue the simvastatin.
19. A male patient has stage 5 CKD, is not yet on
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
dialysis, and has just been started on ranolazine
for management of angina.
Which ONE of the following statements is
CORRECT regarding ranolazine therapy in
this patient?
A. Dosing is not an issue in that it is hepati-
cally cleared.
B. Ranolazine has a narrow therapeutic window,
and its clearance is diminished in renal disease.
C. Ranolazine has a narrow therapeutic win-
dow and can cause acute kidney injury.
D. Ranolazine produces a reversible 10 to
15% reduction in eGFR.
20. A 64-year-old woman with ESRD that is treated with
hemodialysis develops significant peripheral edema
upon recently starting low-dosage amlodipine. She
has residual renal function of 4 ml/min as determined
by creatinine clearance and states that the amlodipine
has helped lower her interdialytic home BP readings
from 150/86 to 138/78 mmHg.
Which ONE of the following recommenda-
tions is CORRECT?
A. Gradually reduce the patient’s target weight on
dialysis until the edema has resolved.
B. Convert to another channel blocker, such
as verapamil or diltiazem.
C. Start high-dosage loop diuretic therapy.
D. Stop the amlodipine and restart after sev-
eral days at a lower dosage.
夝21. A 34-year-old patient with ESRD from FSGS is
found at most of his dialysis sessions to enter with
marked hypertension. His last treatment was charac-
terized by a BP of 190/110 mmHg despite his achiev-
ing near target weight at entry to the session. Discus-
sion with his wife suggests that he has not been
adherent to his antihypertensive medication regimen.
Which ONE of the following would you
now recommend?
A. Transdermal clonidine
B. Performing pill counts at each dialysis
treatment visit
C. Consulting a home health care agency to
arrange medication education at home
D. Home BP monitoring
Nephrology Self-Assessment Program - Vol 9, No 4, July 2010
22. A 27-year-old patient with stage 4 CKD from FSGS
is found to have a BP of 190/110 mm Hg. You elect
to add atenolol 50 mg/d to his treatment program of
an ACEI and a dihydropyridine calcium channel
blocker, each at maximal dosage. Within 1 week, he
develops two episodes of bradycardia to 48 bpm.
When seen in the emergency department for light-
headedness, an electrocardiogram showed first-de-
gree heart block with sinus bradycardia. Serum elec-
trolytes, calcium, and magnesium values all were in
the normal range.
Which ONE of the following statements
BEST explains the cause of his clinical dis-
order?
A. Idiosyncratic response to atenolol
B. Reduced atenolol clearance
C. Atenolol interaction with a dihydropyridine
calcium channel
D. A genetic polymorphism in his hepatic
metabolism (CYP3A4) of atenolol
23. A 44-year-old patient with stage 4 CKD (eGFR 22
ml/min) as a result of hypertension and New York
Heart Association class 2 congestive heart failure has
developed increased peripheral edema. He had been
treated with a loop diuretic, in addition to his cardiac
regimen of an ACEI and eplerenone. He had been
receiving increasing dosages of furosemide but has
noted less response after an 80-mg dose. You decide
to switch his diuretic to torsemide, yet he remains
diuretic resistant.
Which ONE of the following BEST explains
his diuretic resistance?
A. Increased hepatic clearance of torsemide in
CKD
B. Reduced filtration of torsemide
271
C. Increased plasma protein binding of torsemide
D. Reduced delivery of torsemide to the as-
cending limb
E. His degree of cardiac compromise
24. A 45-year-old man with ischemic cardiomyopathy
presents with hyperkalemia of 6.2 mEq/L. He had
always manifested normal serum potassium levels.
He recently had a medication change in which he
was started on a new combination of drugs. His
serum creatinine level is 2.1 mg/dl and has been
stable for the past 12 months.
Which ONE of the following new drug com-
binations is MOST likely to have led to his
hyperkalemia?
A. Eplerenone and diltiazem
B. Eplerenone and metalozone
C. Spironolactone and torsemide
D. Spironolactone and acetazolamide
25. A 47-year-old man with stage 4 CKD secondary to
diabetic nephropathy has had progressive episodes of
vomiting. A gastrointestinal evaluation determined
that the patient had gastroparesis and was begun on
metoclopramide. During the subsequent 2 weeks, he
complained of muscle pain and manifested rigidity,
reduced reflexes, hyperthermia, and confusion. He
was admitted to the hospital and found to have the
following abnormalities on physical examination:
Temperature of 101°F and lethargy.
Which ONE of the following treatments
would you recommend at this time?
A. Hemodialysis
B. Continuous hemofiltration
C. Bromocriptine
D. Cyproheptadine