Volume 16 • Number 4 • November 2017

NephSAP
®

Nephrology Self-Assessment Program

Transplantation
Co-Editors:
John P. Vella, MD
Alexander C. Wiseman, MD

Co-Directors:
Gerald Hladik, MD
Jerry Yee, MD
 Preface
CO-DIRECTOR,
NephSAP
Gerald A. Hladik, MD
University of North Carolina at Chapel Hill NephSAPÒ is one of the premiere educational activities of the American Society of
Chapel Hill, NC
Nephrology (ASN). Its primary goals are self-assessment, education, and the provision of
CO-DIRECTOR, Continuing Medical Education (CME) credits and Maintenance of Certification (MOC) points
NephSAP for individuals certified by the American Board of Internal Medicine. Members of the ASN
Jerry Yee, MD, FASN receive NephSAP electronically through the ASN website by clicking on the NephSAP link
Henry Ford Hospital
Detroit, MI under “Education and Meetings” tab.
MANAGING EDITOR EDUCATION: Medical and nephrologic information continually accrues at a rapid pace.
Gisela Deuter, BSN, MSA Bombarded from all sides with demands on their time, busy practitioners, academicians, and
Washington, DC trainees at all levels are increasingly challenged to review and understand new and evolving
ASSOCIATE EDITORS evidence. Each bimonthly issue of NephSAP is dedicated to a specific theme, i.e., to a specific
Debbie L. Cohen, MD area of clinical nephrology, hypertension, dialysis, and transplantation, and consists of an
University of Pennsylvania School of Medicine editorial, a syllabus, and self-assessment questions, to serve as a self-study device. Over the
Philadelphia, PA
course of 24 months, all clinically relevant and key elements of nephrology will be reviewed
Richard J. Glassock, MD
Professor Emeritus, The David Geffen School of
and updated. The authors of each issue digest, assimilate, and interpret key studies published
Medicine at the University of California since the release of the previous issues and integrate this new material with the body of
Los Angeles, CA existing information. Occasionally a special edition is produced to cover an area not ordinarily
Stanley Goldfarb, MD addressed by core issues of NephSAP.
University of Pennsylvania School of Medicine
Philadelphia, PA
SELF-ASSESSMENT: Thirty, single-best-answer questions will follow the 80 to 100 pages of
Karen A. Griffin, MD, FASN
Loyola University Medical Center
syllabus text. The examination is available online with immediate feedback. Those answering
Maywood, IL 75% correctly will receive MOC and CME credit, and receive the answers to all the questions
Jay L. Koyner, MD along with brief discussions and an updated bibliography. Members will find a new area
University of Chicago
Chicago, IL
reviewed every 2 months, and they will be able to test their understanding with our quiz. This
Holly J. Kramer, MD format will help readers stay up to date in developing areas of clinical nephrology,
Loyola University Medical Center hypertension, dialysis, and transplantation, and the review and update will support those
Maywood, IL
taking certification and recertification examinations.
Ruediger W. Lehrich, MD
Duke University CONTINUING MEDICAL EDUCATION: Most state and local medical agencies as well as
Durham, NC
Kevin J. Martin, MBBCh
hospitals are demanding documentation of requisite CME credits for licensure and for staff
St. Louis University School of Medicine appointments. A maximum of 50 credits annually can be obtained by successfully completing
St. Louis, MO the NephSAP examinations. In addition, individuals enrolled in Maintenance of Certification
John P. Middleton, MD
Duke University
(MOC) through the American Board of Internal Medicine may obtain points toward MOC by
Durham, NC successfully completing the self-assessment examination of NephSAP.
Sankar D. Navaneethan, MD, MPH
Baylor College of Medicine This paper meets the requirements of ANSI/NISO Z39.48-1921 (Permanence of Paper),
Houston, TX effective with July 2002, Vol. 1, No. 1.
Asghar Rastegar, MD
Yale School of Medicine
New Haven, CT
Brad H. Rovin, MD
Ohio State University Medical Center
Columbus, OH
Manoocher Soleimani, MD
University of Cincinnati
Cincinnati, OH
Charuhas V. Thakar, MD
University of Cincinnati
Cincinnati, OH
John P. Vella, MD
Maine Medical Center
Portland, ME
Alexander C. Wiseman, MD
University of Colorado at Denver
Denver, CO

FOUNDING EDITORS
Richard J. Glassock, MD
Editor-in-Chief Emeritus NephSAPÒ
Robert G. Narins, MD Ó2017 by The American Society of Nephrology
 Volume 16, Number 4, November 2017

Editorial 295 Recipient Factors

295 Delayed Graft Function and Rejection Risk

273 Modern Hepatitis C Virus Therapy and Its Effect on
Transplantation 296 Immunosuppression
Andrew F. Malone, Daniel C. Brennan
296 Induction Therapy
Syllabus 298 Maintenance Therapy

280 NephSAP, Volume 16, Number 4, November 2017— 298 Tacrolimus

Transplantation Pharmacokinetics
300
John P. Vella, Alexander C. Wiseman
301 Extended Release Tacrolimus
280 Learning Objectives
301 Antimetabolite Therapy
280 Access to Transplantation and Outcomes
302 Belatacept
280 Patient and Graft Survival
302 Steroid Therapy
282 Ethnicity
303 Mammalian Target of Rapamycin Inhibitor Therapy
283 Physical Frailty
305 Rejection
283 Cardiovascular Outcomes
307 Temporal Dynamics
284 Obesity
307 Transfusion
284 Deceased Donor Kidney Allocation
307 Novel Rejection Mediators
285 Discarded Kidneys
308 Adherence
286 Deceased Donor Hypothermia
308 Gene Activation
286 Use of Hepatitis C Virus–Seropositive Kidneys
308 Subclinical Rejection
286 Prior Living Donors in Need of Transplantation
309 Antibody-Mediated Rejection
287 Public Health Service Increased Risk Donors
310 Immunoglobulin Subtypes
288 Living Kidney Donation
311 Histoincompatibility Strategies
288 Kidney Paired Donation
312 ABO-Incompatible Transplantation
289 Living Donor Kidney Function Assessment
314 HLA Antibody Desensitization
289 Medically Complex Living Donors
314 Novel Desensitization Strategies
290 Surgery Complications

290 Pregnancy Risk 315 Clinical Tolerance

291 Kidney Failure Risk 316 Clinical Tolerance Induction

291 Prior Living Donors and Kidney Transplantation 317 Biomarkers

292 APOL1 319 Glomerular Injury Post-Transplant

292 Other Complications 319 Proteinuria in the Post-Transplant Setting
293 Delayed Graft Function 320 Glomerular Disease: Post-Transplant Outcomes
293 Premortem AKI 320 Focal and Segmental Glomerulosclerosis
294 Predonation Interventions 321 Membranous Nephropathy
294 Procedure Times 321 APOL1 and Kidney Transplantation
 Volume 16, Number 4, November 2017

321 Complement-Mediated Glomerular Disease 340 Interventions and Outcomes

323 Infection after Transplant 342 Bone and Mineral Disorders

324 Cytomegalovirus 342 Hyperparathyroidism

324 BK Virus 343 Osteoporosis

325 HIV 345 Multiorgan Transplant

327 Hepatitis C Virus 345 Simultaneous Pancreas-Kidney Transplantation
328 Hepatitis B Virus 346 Simultaneous Liver-Kidney Transplantation
328 Epstein Barr Virus 347 Multiorgan Transplantation: Utility Considerations
329 Malignancy and Kidney Transplantation 347 Pregnancy
330 Risk Factors for Malignancy in the Transplant 349 Acid-Base and Electrolyte Disorders after Transplant
Recipient
333 Transplant Candidate Cancer Screening CME Self-Assessment Questions
334 Recipient Screening for Malignancy 350 NephSAP, Volume 16, Number 4, November 2017—
335 Cancer Management in the Transplant Recipient Transplantation

336 Cardiovascular Disease Upcoming Issues

336 Pretransplant Screening Hypertension
Debbie L. Cohen, MD and Karen A. Griffin, MD
337 Hypertension
March 2018
338 Post-Transplant Diabetes Mellitus
Primary and Secondary Glomerular Diseases
338 Hyperlipidemia Richard J. Glassock, MD and Brad H. Rovin, MD
Obesity June 2018
339
339 Nontraditional and Novel Cardiovascular Risk Interventional Nephrology and Dialysis Access
Factors under Investigation Anil Agarwal, MD, Lalathaksha Kumbar, MD and Vandana Dua Niyyar, MD
July 2018
339 Structural Parameters
Disorders of Divalent Ions, Renal Bone Disease, and Nephrolithiasis
339 Biochemical Markers
Stanley Goldfarb, MD and Kevin J. Martin, MBBCh
340 Clinical Features September 2018
 Volume 16, Number 4, November 2017

The Editorial Board of NephSAP and KSAP extends its sincere appreciation to the following reviewers. Their efforts and insights help improve
the quality of these postgraduate education offerings.
NephSAP Review Panel
Mustafa Ahmad, MD, FASN Chokchai Chareandee, MD, FASN Pedram Fatehi, MD
King Fahad Medical City University of Minnesota Stanford Medicine
Riyadh, Saudi Arabia Minneapolis, MN Palo Alto, CA
Nasimul Ahsan, MD, FASN Joline L. Chen, MD William H. Fissell, MD
University of Florida and Long Beach Veteran Affairs Vanderbilt University Medical Center
Oscar G. Johnson Veteran Affairs Healthcare System Nashville, TN
Medical Center Orange, CA
Iron Mountain, MI D. Kevin Flood, MD
Karen Ching, MD Mike O’Callaghan Federal Medical Center
Jafar Al-Said, MD, FASN Hawaii Permanente Medical Group Nellis AFB, NV
Bahrain Specialist Hospital Honolulu. HI
Manama, Bahrain Lynda A. Frassetto, MD, FASN
W. James Chon, MD University of California at
Carmichael Angeles, MD, FASN University of Arkansas for Medical Sciences San Francisco
John T. Mather Memorial Hospital Little Rock, AR San Francisco, CA
Stony Brook, NY Jason Cobb, MD Tibor Fulop, MD
Kisra Anis, MBBS Emory University School of Medicine University of Mississippi Medical Center
Jacobi Medical Center/ Atlanta, GA Jackson, MS
Albert Einstein College of Medicine Armando Coca, MD, PhD
Bronx, NY Maurizio Gallieni, MD, FASN
Hospital Clínico Universitario
University of Milano
Valladolid, Spain
Naheed Ansari, MD, FASN Milano, Italy
Jacobi Medical Center/Albert Einstein Scott D. Cohen, MD, FASN
College of Medicine Duvuru Geetha, MD, FASN
George Washington University
Bronx, NY Johns Hopkins University
Washington, DC
Baltimore, MD
Nabeel Aslam, MD, FASN Beatrice Concepcion, MD
Mayo Clinic Florida Vanderbilt University Medical Center Ilya Glezerman, MD
Jacksonville, FL Nashville, TN Memorial Sloan Kettering Cancer Center
New York, NY
Nisha Bansal, MD Gabriel Contreras, MD
University of Washington University of Miami Carl S. Goldstein, MD, FASN
Seattle, WA Miami, FL Rutgers University
New Brunswick, NJ
Krishna M. Baradhi, MD Patrick Cunningham, MD
University of Oklahoma University of Chicago Basu Gopal, MBBS, FASN
Tulsa, OK Chicago, IL Royal Adelaide Hospital
Adelaide, Australia
Emmy Bell, MD, MSPH Kevin A. Curran, MD
University of Alabama at Birmingham Kevin A. Curran, MD, PA Steven Gorbatkin, MD, PhD
Birmingham, AL Canton, TX Emory University and
Atlanta Veteran Affairs Medical Center
Bruce E. Berger, MD Rajiv Dhamija, MD
Decatur, GA
Case Western Reserve University Rancho Los Amigos National
Cleveland, OH Rehabilitation Center Aditi Gupta, MD
Downey, CA University of Kansas Medical Center
Mona B. Brake, MD
Robert J. Dole Veteran Affairs Alejandro Diez, MD Kansas City, KS
Medical Center The Ohio State University Susan Hedayati, MD
Wichita, KS Columbus, OH University of Texas Southwestern
Pooja Budhiraja, MBBS John J. Doran, MD Dallas, TX
University of Kansas Medical Center Emory School of Medicine Marie C. Hogan, MBBCh, PhD
Kansas City, KS Atlanta, GA Mayo Clinic
Ruth C. Campbell, MD Randa A. El Husseini, MD, FASN Rochester, MN
Medical University of South Carolina HealthPartners Medical Group
Susie Hu, MD
Charleston, SC St. Paul, MN
Warren Alpert Medical School of Brown
Chia-Ter Chao, MD Mahmoud El-Khatib, MD University,
National Taiwan University Hospital University of Cincinnati Rhode Island Hospital
Taipei, Taiwan Cincinnati, OH Providence, RI
Edmund Huang, MD Tingting Li, MD Todd Pesavento, MD
University of California at Washington University in St. Louis Ohio State University
Los Angeles School of Medicine St. Louis, MO Columbus, OH
Los Angeles, CA
Orfeas Liangos, MD, FASN Phuong-Thu Pham, MD
Ekambaram Ilamathi, MD, FASN Klinikum Coburg David Geffen School of Medicine at UCLA
Northwell Health, Southside Hospital Coburg, Bayern, Germany Los Angeles, CA
Bayshore, NY
Michael Lioudis, MD Pairach Pintavorn, MD, FASN
Joshua M. Kaplan, MD Cleveland Clinic Nephrology East Georgia Kidney and Hypertension
Rutgers New Jersey Medical School Cleveland, OH Augusta, GA
Newark, NJ
Ajit Mahapatra, MD
Roberto Pisoni, MD
Amir Kazory, MD The Permanente Medical Group
University of Florida Medical University of South Carolina
Santa Clara, CA
Gainesville, FL Charleston, SC
A. Bilal Malik, MBBS
Quresh T. Khairullah, MD University of Washington James M. Pritsiolas, MD, FASN
St. Clair Nephrology Seattle, WA CarePoint Health - Bayonne Medical Center
Roseville, MI Bayonne, NJ
Jolanta Malyszko, MD, PhD
Apurv Khanna, MD Medical University Paul H. Pronovost, MD, FASN
State University of New York Bialystok, Poland Yale University School of Medicine
Upstate Medical University Waterbury, CT
Syracuse, NY Ernest Mandel, MD
Brigham and Women’s Hospital Mohammad A. Quasem, MD, FASN
Yong-Lim Kim, MD, PhD Boston, MA State University of New York Medical
Kyungpook National University Hospital University
Daegu, South Korea Naveed N. Masani, MD Binghamton, NY
Winthrop University Hospital
Nitin V. Kolhe, MD, FASN Mineola, NY
Derby Teaching Hospital NHS Trust Wajeh Y. Qunibi, MD
Derby, Derbyshire, UK University of Texas
Teri Jo Mauch, MD, PhD
Health Science Center
University of Nebraska College of Medicine
Farrukh M. Koraishy, MD, PhD San Antonio, TX
Omaha, NE
St. Louis University
St. Louis, MO Hanna W. Mawad, MD, FASN Pawan K. Rao, MD, FASN
University of Kentucky St. Joseph’s Hospital and Health Center
Eugene C. Kovalik, MD
Lexington, KY Syracuse, NY
Duke University Medical Center
Durham, NC Ellen T. McCarthy, MD Hernan Rincon-Choles, MD
University of Kansas Medical Center, Cleveland Clinic Foundation
Steven Kraft, MD Cleveland, OH
Kidney Institute
Western Nephrology
Kansas City, KS
Lafayette, CO Dario Roccatello, MD
Vineeta Kumar, MD Kirtida Mistry, MBBCh San Giovanni Hospital and
University of Alabama at Birmingham Children’s National Medical Center University of Torino
Birmingham, AL Washington, DC Torino, Italy

Sarat Kuppachi, MD Lawrence S. Moffatt, MD Helbert Rondon-Berrios, MD, FASN

University of Iowa Carolinas Medical Center University of Pittsburgh
Iowa City, IA Charlotte, NC School of Medicine
Pittsburgh, PA
Norbert H. Lameire, MD, PhD David B. Mount, MD
University Hospital Brigham and Women’s Hospital, Ehab R. Saad, MD, FASN
Gent, East Flanders, Belgium Harvard Medical School Medical College of Wisconsin
Boston, MA Milwaukee, WI
Sheron Latcha, MD
Memorial Sloan Kettering Cancer Center Thangamani Muthukumar, MD Mark C. Saddler, MBChB
New York, NY Weill Cornell Medicine Mercy Regional Medical Center
New York, NY Durango, CO
Vincent Weng Seng Lee, MBBS, PhD
Westmead Hospital Mohanram Narayanan, MD Neil Sanghani, MD
Sydney, NSW Baylor Scott & White Health Vanderbilt University
Australia Temple, TX Nashville, TN

Paolo Lentini, MD, PhD Macaulay A. Onuigbo, MD Mohammad N. Saqib, MD

St. Bortolo Hospital Mayo Clinic Lehigh Valley Hospital
Bassano del Grappa, Italy Rochester, MN Allentown, PA
Oliver Lenz, MD Rosemary Ouseph, MD Hitesh H. Shah, MD
University of Miami Health System St. Louis University Hofstra Northwell School of Medicine
Miami, FL Webster Groves, MO Great Neck, NY
Michiko Shimada, MD, PhD Hung-Bin Tsai, MD Nand K. Wadhwa, MD
Hirosaki University National Taiwan University Stony Brook University
Hirosaki, Japan Hospital Taipei, Taiwan Stony Brook, NY
Shayan Shirazian, MD Katherine Twombley, MD Connie Wang, MD
Winthrop-University Hospital Medical University of South Carolina Hennepin County Medical Center
State University of New York at Charleston, SC Minneapolis, MN
Stony Brook Kausik Umanath, MD Maura A. Watson, DO
Mineola, NY Henry Ford Hospital Walter Reed National Military Medical Center
Arif Showkat, MD, FASN Detroit, MI Bethesda, MD
University of Tennessee Puchimada M. Uthappa, MBBS, FASN Dawn Wolfgram, MD
Memphis, TN Columbia Asia Hospital Medical College of Wisconsin
Mysore, Karnataka, India Milwaukee, WI
Stephen M. Sozio, MD
Johns Hopkins University School of Medicine Anthony M. Valeri, MD Sri Yarlagadda, MBBS
Baltimore, MD Columbia University Medical Center University of Kansas Medical Center
New York, NY Kansas City, KS
Ignatius Yun-Sang Tang, MD, FASN Allen W. Vander, MD, FASN Brian Young, MD
University of Illinois at Chicago Kidney Center of South Santa Clara Valley Medical Center
Chicago, IL Louisiana San Jose, CA
Ahmad R. Tarakji, MD Thibodaux, LA Mario Javier Zarama, MD
King Saud University, Jon R. Von Visger, MD, PhD Kidney Specialists of
King Khalid University Hospital The Ohio State University Minnesota, PA
Riyadh, Saudi Arabia Columbus, OH Saint Paul, MN
 Volume 16, Number 4, November 2017

Program Mission and Objectives

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

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

AMA Credit Designation Statement

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

Original Release Date

November 2017

CME Credit Termination Date

October 31, 2019

Examination Available Online

On or before Wednesday, November 15, 2017

Estimated Time for Completion

10 hours

Answers with Explanations

•Provided with a passing score after the first and/or after the second attempt
•November 2019: posted on the ASN website when the issue is archived.

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

Method of Participation
•Read the syllabus that is supplemented by original articles in the reference lists.
•Complete the online self-assessment examination.
•Each participant is allowed two attempts to pass the examination (.75% correct) for CME credit.
•Upon completion, review your score and incorrect answers and print your certificate.
•Answers and explanations are provided with a passing score or after the second attempt.
 Volume 16, Number 4, November 2017

Activity Evaluation and CME Credit Instructions

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

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

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

(MOC) Points
Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria:
• Be certified by ABIM in internal medicine and/or nephrology and enrolled in the ABIM–MOC program
• Enroll for MOC via the ABIM website (www.abim.org).
• Enter your (ABIM) Candidate Number and Date of Birth prior to completing the examination.
• Take the self-assessment examination within the timeframe specified in this issue of NephSAP.
• Upon completion, click Claim Your MOC points, the MOC points submitted will match your CME credits claimed,
check the Attestation Statement box and submit.
• ABIM will notify you when MOC points have been added to your record.

Maintenance of Certification Statement

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant
to earn up to 10 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC)
program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity
provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
MOC points will be applied to only those ABIM candidates who have enrolled in the MOC program. It is your responsibility to
complete the ABIM MOC enrollment process.

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

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

Medium or Combination of Media Used

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

Technical Support
If you have difficulty viewing any of the pages, please refer to the ASN technical support page for possible solutions. If you
continue having problems, contact ASN at email@asn-online.org.
 Volume 16, Number 4, November 2017

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

EDITORIAL BOARD for this Issue:

Gerald A. Hladik, MD, FASN—Current Employer: University of North Carolina at Chapel Hill; Honoraria: Renal Research Institute;
Scientific Advisor/Membership: ASN Co-Director, NephSAP; Board Member, Renal Research Institute
Ruediger W. Lehrich, MD—Current Employer: Duke University Medical Center
Manoocher Soleimani, MD—Current Employer: University of Cincinnati; Scientific Advisor/Membership: Editorial Board: American Journal of
Kidney Disease
John P. Vella, MD, FASN—Current Employer: Maine Nephrology Associates PA; Research Funding: Bristol-Myers Squibb, Astellas;
Scientific Advisor/Membership: UpToDate
Alexander C. Wiseman, MD—Current Employer: University of Colorado at Denver and Health Sciences Center; Research Funding:
Novartis, Alexion, Bristol-Myers Squibb, Oxford Immunotec, Quark, Astellas; Scientific Advisor/Membership: American Society of
Transplantation, American Journal of Transplantation
Jerry Yee, MD, FASN—Current Employer: Henry Ford Hospital; Consultancy: OptumHealth, Merck, Vasc-Alert, Akebia, Mallinckrodt,
CV-RX, Keryx, DynaMed/Ebsco, Abbvie; Ownership Interest: Merck, Gilead, Vasc-Alert; Honoraria: Washington University of
St. Louis, National Kidney Foundation; Patents/Inventions: Vasc-Alert, Henry Ford Hospital; Scientific Advisor/Membership: NKF:
Editor-in-Chief of Advances in CKD (journal); Editorial Board: American Journal of Nephrology, American Journal of Hypertension,
CJASN, Heart Failure Journal; Section Editor: EBSCO DynaMed, ASN Co-Director, NephSAP; Other Interests: Elsevier and NKF,
Editor-in-Chief, Advances in CKD

EDITORIAL AUTHORS:
Daniel C. Brennan, MD—Current Employer: Washington University in St. Louis; Consultancy: Alexion, CareDx, Immucor, Sanofi,
Veloxis; Research Funding: Alexion, Astellas, Bristol-Myers Squib, CareDx, Oxford Immunotec, Shire, Veloxis; Honoraria:
Alexion, Sanofi, Veloxis; Scientific Advisor/Membership: Editorial Board: Transplantation, UpToDate; Speakers Bureau:
Alexion, Astellas, Novartis, Sanofi, Veloxis
Andrew F. Malone, MBChB—Current Employer: Washington University in St. Louis; Ownership Interests: Gilead

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

Commercial Support
There is no commercial support for this issue.
 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Editorial
Modern Hepatitis C Virus Therapy and Its Effect on Transplantation
Andrew F. Malone, MB, BCh, MRCPI, and Daniel C. Brennan, MD, FACP
Division of Nephrology, Department of Medicine, Washington University School of Medicine,
St. Louis, Missouri
The hepatitis C virus (HCV) is a small, enveloped,
single-stranded RNA virus from the family Flavivir-
idae. This virus is transmitted by contact with small
amounts of blood and can also be transmitted sexually
and from mother to baby; it is estimated that 71 million
persons worldwide are infected with HCV, and it is most
prevalent in eastern European regions. Between 15% and
45% of infected persons spontaneously clear the virus
within 6 months of infection without any treatment. The
remaining 55%–85% will develop chronic HCV infection.
The risk of cirrhosis of the liver in those with chronic
HCV infection is between 15% and 30% within 20 years
(1). Infection is commonly occult, and nearly 80% of
those who become infected do not have any symptoms.
This observation renders screening for HCV important
among at-risk groups and in areas of high prevalence.
HCV and ESRD
HCV is a significant issue among patients with
ESRD. Patients on hemodialysis are at risk of infection
due to exposure at hemodialysis units, and there is
currently no vaccination for HCV in contrast to
hepatitis B virus. The prevalence of HCV likely varies
between different dialysis units due to patient behav-
iors and intravenous drug use in the surrounding
community. Seroconversion rates also vary between
dialysis units and likely reflect facility protocols and
practices. The Dialysis Outcomes and Practice Patterns
Study examined HCV infection in dialysis units by
country (2). The unadjusted prevalence of HCV in
United States centers was estimated at over 14%, with
a seroconversion rate of three per 100 patient-years
(between 1997 and 2001). Prevalence also increased
with time on dialysis, rising to over 20% after 10 years.
Perhaps the increased mortality and morbidity associ-
ated with HCV infection are more important. A nearly
20-year-old study using New England Organ Bank
samples and data showed that waitlisted patients with
273
anti–HCV-positive serology at the time of referral for
transplant (compared with anti–HCV-negative serol-
ogy patients) had a relative risk of death from all causes
of 1.41 (95% confidence interval [95% CI], 1.01 to
1.97) and had a relative risk of death due to liver
disease or infection of 2.39 (95% CI, 1.28 to 4.48). For
those HCV-positive patients who went on to get trans-
planted (compared with those who remained on di-
alysis), the relative risks of death from all causes were
4.75 (95% CI, 2.76 to 8.17) between 0 and 3 months,
1.76 (95% CI, 0.75 to 4.13) between 3 and 6 months,
0.31 (95% CI, 0.18 to 0.54) between 3 months and 4
years, and 0.84 (95% CI, 0.51 to 1.37) after 4 years (3).
Other more recent studies (but still 10 years old) have
confirmed this increased risk in dialysis patients with
HCV. A significant proportion of this risk was due to an
excess of cardiovascular-associated mortality and liver
disease–related risk (4–6).
HCV Infection in the Post-Transplant Patient
There are complications in the post-transplant
period related to HCV infection. There is an increase
in secondary infections in patients with HCV post-
transplant, and this is the second most common cause of
death after cardiovascular disease among these patients
(7–11). Extrahepatic malignancies, such as post-transplant
lymphoproliferative disorder and myeloma, have been
associated with HCV infection post-transplantation
(12–14). Furthermore, there is a direct effect of HCV on
lymphoid carcinogenesis, and regression of Hodgkin lym-
phoma with treatment of HCV has been shown (15,16).
Patients with HCV are at increased risk of post-transplant
diabetes mellitus, and post-transplant diabetes mellitus is an
independent risk factor for death and graft loss (17).
From the renal aspect, recurrence or de novo glomerular
disease is also a concern, and post-transplant HCV
infection, membranoproliferative GN (cryoglobulinemic
and noncryoglobulinemic), membranous glomerulopathy,
274
anticardiolipin-associated glomerulopathy, and acute and
chronic transplant glomerulopathy have all been de-
scribed. Whether there is an increased risk of allograft
rejection in patients with HCV infection is debated, but in
general, HCV infection likely confers an increased degree
of immunosuppression due to reduced number and
responsiveness of T-helper lymphocytes (18). Finally,
HCV infection increases the risk of hepatocellular carci-
noma and liver cirrhosis (19).
Despite the concerns for these complications,
a clear survival advantage exists with kidney trans-
plantation compared with remaining on dialysis with
HCV. Ingsathit et al. (20) performed a meta-analysis of
data reporting outcomes of HCV-positive patients who
were transplanted compared with those who were not
transplanted. This study used a random effects model
and reported a pooled risk ratio (RR) for death at 5 years
of 2.19 (95% CI, 1.50 to 3.20) for those remaining on the
waiting list compared with those transplanted.
These results and the advantage of transplantation
existed before the modern era of direct-acting antiviral
(DAA) therapy treatment of HCV infection post-
transplantation. Before the advent of DAA drugs,
treatment was rarely successful, and the use of IFN alfa is
associated with increased risk of rejection and graft loss.
Thus, treatment options were limited to ribavirin mono-
therapy; however, this strategy was controversial: im-
provement in liver histology was variable, and therapy
was limited by a dose-dependent hemolytic anemia (21).
Using HCV-Positive Donor Kidneys in the Pre-DAA
Era
There is no doubt that, even in the pre-DAA
therapy era, ESRD patients with HCV infection benefited
from kidney transplantation. However, whether this
benefit remained when kidneys from donors with HCV
were transplanted into HCV-positive recipients has
always been controversial, and this practice varies
widely. Decisions as to whether to use a kidney from
an HCV-positive donor are center specific. It is known
that transmission of HCV infection from donor to
recipient is almost 100%. Therefore, only transplantation
of HCV-positive donors to known HCV-positive recip-
ients has occurred in routine practice to date (22). HCV-
positive patients receiving an HCV-positive kidney
transplant have worse outcomes compared with HCV-
positive patients receiving an HCV-negative kidney
(23). These issues led to the questions of for whom
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
(among HCV-positive recipients) and when we should
use HCV-positive kidneys. Kucirka et al. (24) explored
the use of HCV kidneys in HCV recipients and found
that African Americans (RR, 1.56; 95% CI, 1.39 to 1.75),
patients with diabetes (RR, 1.29; 95% CI, 1.18 to 1.40),
and those at a center with long wait times (RR, 1.19 per
quartile of waiting time; 95% CI, 1.06 to 1.33, P50.002)
were more likely to receive an HCV-positive kidney.
However, those who received HCV-positive kidneys
waited 310 days less on the waitlist, and the authors
suggested that this likely offsets the higher patient and
graft loss associated with HCV-positive kidneys (24).
Modern Era of HCV Treatment: DAAs
A paradigm shift in the approach to HCV man-
agement due to the recent introduction of DAAs is likely
to make such issues outlined above irrelevant soon. In
2011, the first generation DAAs for treatment of HCV
were approved by the US Food and Drug Administra-
tion: telaprevir and boceprevir. Efficacy of these oral
protease inhibitors was tested in two trials: A New
Direction in HCV Care: A Study of Treatment-Naive
Hepatitis C Patients with Telaprevir and Serine Protease
Inhibitor Therapy 2 Study (25,26). When added to dual
therapy of pegylated IFN (peg-IFN) and ribavirin for the
treatment of HCV genotype 1 infections, these agents
enhanced sustained virologic response (SVR) rates to
about 70% but at the expense of increased toxicities.
Since 2013, there has been explosive prolifera-
tion of new oral DAAs in the clinical arena with better
tolerability, side effect profiles, and SVR rates (27–
39); also, treatment regimens are typically only 12
weeks in duration. DAAs for HCV are NS5A inhib-
itors, NS5B inhibitors, and NS3/4A protease inhibitors.
Current therapies are combinations of two or more of
these drug classes. These viral proteins are HCV-
encoded nonstructural proteins that constitute the
HCV RNA replication machinery. NS5B is an RNA-
dependent RNA polymerase, NS5A is responsible for
the assembly of the membrane-bound replication com-
plex, and NS3/4A is a serine protease, an enzyme
involved in post-translational processing and replica-
tion of HCV (40). Sofosbuvir is an NS5B inhibitor
and currently, the most commonly prescribed DAA in
combination therapy. This utilization pattern is largely
attributable to the success of the Sofosbuvir/Velpatasvir
Fixed Dose Combination for 12 Weeks in Adults With
Chronic HCV Infection (ASTRAL-1) Trial, and the
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 275

American Association for the Study of Liver Diseases

Listed are the most common DAA combinations available currently. Columns 3–13 represent HCV genotypes 1–6 and subgenotypes (1a and 1b). Each genotype is further divided into indications for C2 and C1 patients. DAA
1a, C1 1b, C2 1b, C1 2, C2 2, C1 3, C2 3, C1 4, C2 4, C1 5/6, C2/1
guidelines state that sofosbuvir/velpatasvir is the

x
only combination DAA therapy currently recom-
mended for use in all genotypes, regardless of the
presence of compensated cirrhosis (Table 1) (34,35).

x
x

x
DAAs and CKD
From the renal point of view, sofosbuvir’s
hepatic metabolite is renally eliminated by 80%;

x
x

x
however, renal elimination is not significant for all
other DAAs. All currently licensed DAA regimens

combinations with activity are marked x. Column 2 refers to FDA-recommended GFR limitations of use. FDA, Food and Drug Administration; C2, noncirrhotic; C1, cirrhotic.
can be used in patients with a GFR.30 ml/min per

x
x
1.73 m2. Two studies have examined the use of DAA
regimens in CKD patients with lower GFRs. In the

x
x
RUBY-1 Trial, 12 weeks of paritaprevir/ritonavir/
ombitasvir/dasabuvir combination therapy were used
in 20 noncirrhotic patients with drug-naı̈ve genotype

x
1 and GFR,30 ml/min per 1.73 m2 or on dialysis
(41). Genotype 1a patients also received IFN. The 12-
week post-treatment SVR was reported in 90% of

x
patients. In the C-SURFER Trial, 116 patients with
CKD stage 4/5 or ESRD on maintenance dialysis
were treated for 12 weeks with elbasvir/grazaprevir.
x
x
x

x
These patients had genotype 1 HCV, and most were
treatment naı̈ve and noncirrhotic. With this combination,
99% experienced an SVR at 12 weeks post-treatment
x
x
x

x
x
x
(42). DAAs were well tolerated in both trials, except for
ribavirin-treated patients, in whom anemia was common.
The HCV-Therapeutic Registry and Research Network
x
x

x
Table 1. Spectrum of activity of direct-acting antiviral therapy

Trial is an observational trial following patients with

renal disease on sofosbuvir-based regimens. Some reg-
imens included ribavirin, and 12.3% of regimens
1a, C2

included peg-IFN. SVR among the 73 patients with

x
x
x

x
x
x

GFR,45 ml/min per 1.73 m2 was 83%. Anemia,

worsening renal function, and serious side effects
were more common in those with reduced GFR. The
DAA Combination Recommendation

Reduce dose; ESRD

FDA Label GFR

efficacy of lower doses of sofosbuvir in patients with

Over 30 ml/min

Over 30 ml/min
Over 30 ml/min
Over 30 ml/min
Any; ESRD not

low GFR was assessed by Bhamidimarri et al. (43).

not studied

This group used 200 mg daily or 400 mg on alternate

studied

days with a standard dose of simeprevir in genotype 1

patients with GFRs,30 ml/min per 1.73 m2 or on
Any

dialysis (most had cirrhosis as well). SVRs were 75%–

ombitasvir/dasabuvir

Sofosbuvir/velpatasvir
Daclatasvir/sofosbuvir
Simeprevir/sofosbuvir

100%, with best responses in noncirrhotic genotype 1a

ombitasvir/ribavirin
Ledipasvir/sofosbuvir
Paritaprevir/ritonavir/

Paritaprevir/ritonavir/
Elbasvir/grazaprevir

patients who were not on dialysis and were treated

with sofosbuvir at 200 mg daily (43).

DAAs and HCV Treatment Post-Transplantation

HCV has been successfully treated with modern
DAA regimens in the postkidney transplant population.
276
This was first reported in 2016 in the United States and
European cohorts. In the United States study, 20
patients, primarily of genotype 1 (88%; genotype 2
was also treated) and most without cirrhosis (n516 of
20), received DAA drug therapy at a median of 888 days
post-transplant. Maintenance immunosuppression was
calcineurin inhibitors, antimetabolite agents, and pred-
nisone. Serum creatinine levels at the initiation of
treatment ranged from 0.86 to 2.18 mg/dl. All received
a sofosbuvir-based regime (primarily treatment with
sofosbuvir/simeprevir or sofosbuvir/ledipasvir), and
three patients also received ribavirin. All patients cleared
the virus and had an SVR at 12 weeks post-treatment
(44). The French group treated 25 patients for post-
transplant HCV infection. Genotypes 1a, 1b, 2, 3, and 4
were all represented, but genotype 1b was most common
(n515). The median time from transplant to the start of
DAA treatment was 146 months. All received sofosbuvir-
based regimens (simeprevir/sofosbuvir or ledipasvir/
sofosbuvir), with two patients receiving a ribavirin-based
regimen and one receiving sofosbuvir/ribavirin/peg-IFN.
All drugs except ribavirin were not dose reduced for
GFR. All patients had GFRs.30 ml/min per 1.73 m2 at
the start of therapy. The SVR at 12 weeks post-treatment
was 100% (45). In both studies, the average tacrolimus
trough levels were lower post-therapy compared with the
levels at the start of and during therapy. In both studies,
drugs were well tolerated, with no significant side effects
noted, and no rejection episodes occurred.
It is important to understand the pharmacokinet-
ics of DAAs in the setting of transplantation so that
appropriate monitoring and dose adjustments can be
made during and after therapy. Daclatasvir and
sofosbuvir are not substrates of the cytochrome P450
Table 2. Direct-acting antiviral therapy and immunosuppression drug interactions
Paritaprevira
/Ritonavir/
Immunosuppressive Sofosbuvir/ Ledipasvir/ Elbasvir/ Ombitasvir/
Agent Velpatasvir Sofosbuvir Grazoprevira Dasabuvir Simeprevira Sofosbuvir Daclatasvir
Tac A A
Ciclo A A
Myf A A
Aza A A
Everol C C
Sirol A A
According to www.hep-druginteractions.org (University of Liverpool). Tac, tacrolimus; A, no interactions; C, potential interactions; Ciclo, ciclosporin; D, do not administer; Myf,
myfortic/cellcept; Aza, azathioprine; Everol, everolimus; Sirol, sirolimus.
a
NS3/4A protease inhibitors (most Cyp 3A inhibition).
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
isoenzymes 3A4/5 or the drug transporter P-glycopro-
tein. Therefore, no clinically significant interactions
with common transplant immunosuppression drugs are
expected. All DAAs in use today as single agents or in
combination, except for sofosbuvir alone, have drug-
drug interactions that need to be monitored (Table 2).
In two previous trials of post-transplant HCV treat-
ment, tacrolimus trough levels were decreased post-
treatment by approximately 45%, despite no dose
reductions. This decrease was postulated to result from
improved hepatic enzyme function post-HCV viral
clearance.
The optimal treatment regime in post-transplant
patients is dependent on GFR and genotype, with
close monitoring of immunosuppression drug levels
required. The ideal regimen has an SVR of 100%, is
not cleared by the kidneys, treats all genotypes, and is
easily available from a cost and regulation stand-
point. No such combination currently exists. How-
ever, treatment efficacy in the post-transplant patient
with available drugs is excellent. Given the huge
disparity between the waitlist population and num-
ber of patients transplanted each year, new ways to
increase the donor pool are always welcome. Accord-
ing to the Centers for Disease Control and Prevention,
3.4 million people in the United States are living with
HCV infection (46). Using Organ Procurement Trans-
plant Network donor registration data from 2012,
2.4% of deceased donors used were HCV serology
positive (47). Approximately 50% of HCV-positive
kidneys are discarded, and about 500 of these are high-
quality kidneys (48,49). Among nonextended criteria
donor organs, HCV infection is the most likely reason
for an organ to be discarded (24).
C C C A A
D C D A A
A C A A A
A A A A A
C C C A C
C C C A A
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Can We and Should We Use HCV-Positive Donor
Kidneys in the HCV-Negative Recipient?
Recent studies have examined the feasibility of
transplanting HCV-positive kidneys into HCV-negative
donors followed by immediate treatment with DAA
regimens. The Zepatier for Treatment of Hepatitis C–
Negative Patients Who Receive Kidney Transplants
from Hepatitis C–Positive Donors (THINKER) Trial is
a single-center, open-label trial of the use of HCV-
positive kidneys in HCV-negative recipients (50). Early
results have been reported, and the trial is still ongoing.
This trial determined the safety and efficacy of using
kidneys from HCV genotype 1 viremic donors fol-
lowed by elbasvir/grazoprevir treatment. Recipients
with any liver disease, HIV, hepatitis B virus, or HCV
infection were excluded. HCV viremia post-transplant
and genotype were confirmed in study subjects post-
transplantation and before initiation of DAA therapy.
Initiation of therapy on day 3 post-transplant was
established because of the delay in confirming viremia
and HCV genotype. Elbasvir/grazoprevir is only licensed
for use in genotype 1 and 4 patients. Therefore, the
investigators limited the THINKER Trial to genotype 1
patients. Ten patients were studied, and all patients
cleared HCV and had an SVR at 12 weeks post-treatment.
Median 6-month creatinine levels and GFRs were 1.1 mg/
dl and 62.8 ml/min per 1.73 m2, respectively. One patient
had delayed graft function, two patients had transient
transaminitis, and one patient developed transient class I
de novo donor-specific antibodies.
Before using HCV-positive kidneys in HCV-
negative recipients, informed consent is required.
However, most recipients who are HCV negative have
little knowledge of their illness. One study determined
how willing an HCV-negative recipient would be to
accept an HCV-positive kidney. This study questioned
185 patients and found that 29% of patients would
accept under any conditions and that over 50% would
accept under certain conditions (51). Use of HCV-
positive kidneys in HCV-negative patients is also cost
effective on the basis of the assumption that cure rates
remain .97% (52). The cost benefit of using HCV-
positive kidneys is also suggested by a United King-
dom study (53). The elbasvir/grazoprevir combination
was likely chosen in the THINKER Trial for its
nonrenal elimination. Notably, this drug combination
is not active against genotypes 2, 3, 5, and 6. Pange-
notypic treatments that include sofosbuvir have not
277
been studied in the immediate post-transplant period.
This may represent a significant limitation in certain
regions, and 50%–70% of donors in United States
cohorts (the THINKER Trial, National Health and
Nutrition Examination Survey, and Kaiser Permanente)
are genotype 1a or 1b (54). Many insurance compa-
nies and some Medicaid programs will only approve
the use of DAA therapy for patients with advanced
biopsy-proven liver cirrhosis (Metavir fibrosis stages
2–4). This is likely due to the current high cost of
DAAs and the opinions expressed by some profes-
sional societies. Namely, those with the greatest need
should be treated first (55,56). Treatment of HCV
post-transplantation will continue to be a challenge
until payers make DAAs available to all HCV-infected
patients.
In summary, DAA agents are highly effective, and
their efficacy is established in patients with reduced
GFR, with minimal side effects. DAAs can effectively
treat HCV in the post-transplantation period, including
immediately post-transplant. Drug-drug interactions with
DAA are mild for most classes. With careful monitoring,
graft function remains stable, with rejection events un-
likely. The transplantation of HCV-positive donor kidneys
into HCV-negative recipients has the potential to increase
the donor pool, while reducing waiting list time and
dialysis-related morbidity.
Disclosures
None.
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Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Syllabus
NephSAP, Volume 16, Number 4, November 2017—Transplantation
John P. Vella, MD, FASN, FAST* and Alexander C. Wiseman, MD, FASTy
*Division of Nephrology and Transplantation, Maine Medical Center and Tufts University School
of Medicine, Portland, Maine; and yDivision of Renal Diseases and Hypertension, Transplant
Center, University of Colorado Denver, Aurora, Colorado
Learning Objectives
1. Describe current transplant outcomes, includ-
ing delayed graft function, rejection, graft, and
patient survival, and living donor outcomes
2. Discuss early outcomes associated with the
2014 changes to the Kidney Allocation System
3. Examine the spectrum of complications that
occur after transplantation, including infec-
tion, malignancy, and cardiovascular disease,
and accompanying individual diagnostic and
therapeutic strategies
4. Review the status of immunosuppression, in-
compatible transplantation, and efforts to achieve
immunologic tolerance
This syllabus reviews the major clinical studies
published between January of 2015 and January of
2017 in pertinent journals with the highest impact
factors. The authors have focused on randomized trials,
case series, and registry data whenever possible. In the
interest of brevity, case reports, basic science studies,
preclinical studies, and data published only in abstract
form have been, in general, excluded.
Access to Transplantation and Outcomes
The Scientific Registry of Transplant Recipients
(SRTR) evaluates the clinical and scientific status of
organ transplantation in the United States in close col-
laboration with the Organ Procurement and Trans-
plantation Network, which is administered by the
United Network for Organ Sharing under contract with
the Health Resources and Services Administration.
Each year, the SRTR reports on the state of trans-
plantation in the United States (1). Important findings
include the following.
280
(1) Implementation of the new Kidney Allocation
System on December 4, 2014 led to an increase
in deceased donor kidney transplants among
black candidates and those with calculated panel
reactive antibodies 98%–100% but a decrease
among candidates ages 65 years old or older.
(2) There are positive trends in graft and patient
survival for deceased and living donor kidney
transplants, but the challenge of limited kidney
supply persists.
(3) The total number of patients on the waiting list
decreased for the first time in a decade due to
fewer waiting list additions, an increased number
of removals due to medical deterioration, and an
increase in the total number of transplants.
(4) Waiting list deaths remain stable, presumably
from the removal of inactive candidates too sick
for transplantation.
Smith et al. (2) reported that the new allocation
policy is associated with increased quality-associated
life-years at lower cost compared with the old policy,
thereby yielding net benefits to the US Medicare system
totaling $271 million United States dollars in the first
year and $55 million United States dollars yearly after.
Patient and Graft Survival
The total number of kidney transplant recipients
alive with a functioning graft exceeded 200,000 within
the United States as of June of 2015, more than doubling
since 2000 (1). Although allograft function and survival
remained better for living than for deceased donor
transplants, long-term outcomes continued to improve
for both. All-cause and death-censored graft failure at
1, 3, 5, and 10 years continued to decline for living and
deceased donor transplants.
For deceased donor transplants, 10-year graft failure
for transplants in 2005 was 52.8%, which decreased from
59.2% in 1995 (Figures 1 and 2). Similarly, 10-year graft
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Figure 1. Adult deceased donor transplant recipient death-
censored graft failure rates are improving over time. Death-
censored graft failure among adult deceased donor kidney
transplant recipients. Estimates are unadjusted and computed
using Kaplan–Meier competing risk methods. Recipients are
followed to the earliest of kidney graft failure; kidney retrans-
plant; return to dialysis; death; or 6 months or 1, 3, 5, or 10
years post-transplant. Death-censored graft failure is defined as
a return to dialysis, reported graft failure, or kidney retransplant.
OPTN, Organ Procurement and Transplantation Network.
Reprinted with permission from Hart A, Smith JM, Skeans
MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL,
Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni
AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J
Transplant 17[Suppl 1]: 21–116, 2017.
failure for living donor transplants in 2005 was 37.3%,
down from 44.8% in 1995 (Figures 3 and 4). Death with
a functioning graft remained essentially constant for liv-
ing and deceased donor transplants. Five-year deceased
Figure 2. Adult deceased donor transplant recipient death with
function rates are stable over time. Death with function among
adult deceased donor kidney transplant recipients. Estimates are
unadjusted and computed using Kaplan–Meier competing risk
methods. Recipients are followed to the earliest of kidney graft
failure; kidney retransplant; return to dialysis; death; or 6
months or 1, 3, 5, or 10 years post-transplant. Death with
function is defined as death without prior graft failure, return to
dialysis, or retransplant. OPTN, Organ Procurement and Trans-
plantation Network. Reprinted with permission from Hart A,
Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh
WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ,
Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data
Report: Kidney. Am J Transplant 17[Suppl 1]: 21–116, 2017.
281
Figure 3. Adult live donor transplant recipient death with
function rates are stable or marginally improving over
time. Graft failure among adult living donor kidney
transplant recipients. Estimates are unadjusted and com-
puted using Kaplan–Meier competing risk methods. Re-
cipients are followed to the earliest of kidney graft failure;
kidney retransplant; return to dialysis; death; or 6 months
or 1, 3, 5, or 10 years post-transplant. All-cause graft
failure is defined as any of the prior outcomes before 6
months or 1, 3, 5, or 10 years. OPTN, Organ Procurement
and Transplantation Network. Reprinted with permission
from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart
DE, Cherikh WS, Wainright JL, Kucheryavaya A, Woodbury
M, Snyder JJ, Kasiske BL, Israni AK: OPTN/SRTR 2015
Annual Data Report: Kidney. Am J Transplant 17[Suppl 1]:
21–116, 2017.
donor graft survival was lowest for patients with diabetes
or hypertension as a cause of kidney failure: 70.4% and
71.8%, respectively. As previously reported, the overall
outcomes of donation after brain and cardiac death trans-
plants continue to be identical, which is reassuring (Figure
5). Such observations should not lead to complacency.
Lim et al. (3), studying donation after cardiac death
outcomes, examined the association between delayed
graft function (DGF) and graft and patient outcomes. A
greater proportion of recipients with DGF had experi-
enced overall graft loss and death-censored graft loss at
3 years compared with those without DGF (14% versus
4%; P50.04 and 11% versus 0%, P,0.01, respec-
tively). Compared with recipients without DGF, the
adjusted hazard ratio (HR) for overall graft loss at 3
years for recipients with DGF was 4.31 (95% confi-
dence interval [95% CI], 1.13 to 16.44).
The kidney donor profile index (KDPI) is a numeric
score that has been developed to assess deceased donor
kidney quality, and it is an integral part of the Kidney
Allocation System. Factors include donor age, height,
weight, creatinine, diabetes, hypertension, cause of death,
hepatitis C status, and donation after cardiac death, and they
are incorporated into a calculator (https://optn.transplant.
hrsa.gov/resources/allocation-calculators/kdpi-calculator/).
282
Figure 4. Adult live donor transplant recipient death censored graft
failure rates are improving improving over time. Death-censored
graft failure among adult living donor kidney transplant recipients.
Estimates are unadjusted and computed using Kaplan–Meier
competing risk methods. Recipients are followed to the earliest of
kidney graft failure; kidney retransplant; return to dialysis; death; or
6 months or 1, 3, 5, or 10 years post-transplant. Death-censored graft
failure is defined as a return to dialysis, reported graft failure, or
kidney retransplant. OPTN, Organ Procurement and Transplantation
Network. Reprinted with permission from Hart A, Smith JM,
Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright
JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni
AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J
Transplant 17[Suppl 1]: 21–116, 2017.
Lower scores are better. Not surprisingly, there continues to
be a marked graft survival outcome discrepancy between
the highest KDPI kidneys (.85%) compared with lower
KDPI kidneys (,85%) (Figure 5).
Figure 5. Graft survival among adult deceased donor kidney
transplant recipients associates with graft quality as measured by
the Kidney Donor Profile Index (KDPI) (lower is better). Those
who receive kidneys with a KDPI .85% have the worse long
term graft survival rates. Graft survival among adult deceased
donor kidney transplant recipients in 2010 by KDPI. Graft
survival was estimated using unadjusted Kaplan–Meier meth-
ods. The reference population for the KDRI to KDPI conversion
is all deceased donor kidneys recovered for transplant in the
United States in 2015. OPTN, Organ Procurement and Trans-
plantation Network. Reprinted with permission from Hart A,
Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh
WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ,
Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report:
Kidney. Am J Transplant 17[Suppl 1]: 21–116, 2017.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Ethnicity
Taber et al. (4) examined the outcomes of black
kidney transplant recipients, a group known to experi-
ence higher rates of graft loss for the last 40 years. They
studied 3306 non-Hispanic whites (67%) compared
with 1612 non-Hispanic blacks (33%) with 6 years of
follow-up. In the unadjusted analysis, black recipients
were significantly more likely to have overall graft loss
(HR, 1.19; 95% CI, 1.07 to 1.33) and death-censored
graft loss (HR, 1.67; 95% CI, 1.45 to 1.92) but had
lower mortality (HR, 0.83; 95% CI, 0.72 to 0.96). In
fully adjusted models, only death-censored graft loss
remained significant (HR, 1.38; 95% CI, 1.12 to 1.71).
The authors concluded that non-Hispanic black kidney
transplant recipients experience a substantial disparity
in graft loss but not mortality. Recognition that sus-
ceptibility to kidney disease has a genetic component
has been evaluated by candidate gene studies identify-
ing alterations in a variety of genes as reviewed in
a prior Nephrology Self-Assessment Program on trans-
plantation (5). Chief among them are two risk variants
of the apolipoprotein L1 gene (APOL1) in association
with nondiabetic nephropathy in blacks. Freedman
et al. (6) evaluated the impact of APOL1 positivity in
black kidney donors with data from 478 newly ana-
lyzed deceased donor recipients reported to the SRTR.
Shorter renal allograft survival in recipients of APOL1
kidneys was confirmed (HR, 2.00; 95% confidence
interval [95% CI], 1.39 to 3.02, P50.03). Combined
analysis of 1153 deceased donor kidney transplants
from black donors revealed that donor APOL1 high-
risk genotype (HR, 2.05), older donor age (HR, 1.18;
95% CI, 1.00 to 1.40), and younger recipient age (HR,
0.70) significantly impacted allograft survival adversely.
Although prolonged allograft survival was seen in many
recipients of APOL1 kidneys, follow-up serum creati-
nine concentrations were higher than those in recipients
without APOL1 renal risk variant kidneys. A competing
risk analysis revealed that APOL1 impacted renal
allograft survival but not recipient survival.
Arce et al. (7) reported that risks for graft failure
and mortality (HR, 0.69; 95% CI, 0.65 to 0.73) and all-
cause graft failure (HR, 0.79; 95% CI, 0.75 to 0.83) are
lower in Hispanics compared with non-Hispanic trans-
plant recipients. Furthermore, the association between
Hispanic ethnicity and graft failure excluding death was
significantly modified by age. Compared with non-Hispanic
whites, graft failure, excluding death with a functioning
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
graft, did not differ in Hispanics ages 18–39 years old (HR,
0.96; 95% CI, 0.89 to 1.05) or 40–59 years old (HR, 1.08;
95% CI, 1.00 to1.16) but was 13% lower in those ages $60
years old (HR, 0.87; 95% CI, 0.78 to 0.98).
Adler et al. (8) analyzed socioeconomic status
(SES) and racial/ethnic gradients between donors and
recipients. In a retrospective cohort study, traditional
demographic and socioeconomic factors as well as an
SES index were compared in 56,697 deceased kidney
donor and recipient pairs transplanted between 2007 and
2012. Kidneys were more likely to be transplanted in
recipients of the same racial/ethnic group as the donor
(P,0.001). Kidneys tended to go to recipients of lower
SES index (50.5% of the time; P,0.001), a relationship
that remained after adjusting for other available markers
of donor organ quality and SES (P,0.001).
Physical Frailty
Frailty is associated with inferior survival and
increased resource requirements among kidney transplant
candidates. Lynch et al. (9) examined US Renal Data
System data from 51,111 adult ESRD patients waitlisted
for transplant from 2000 to 2011. Frequently admitted
patients had higher subsequent resource requirements,
increased waitlist mortality, and decreased likelihood of
transplant (death after listing: 1–7 days: HR, 1.24; 95%
CI, 1.20 to 1.28; 8–14 days: HR, 1.49; 95% CI, 1.42 to
1.56; $15 days: HR, 2.07, 95% CI; 1.99 to 2.15 versus
0 days). Graft and recipient survival was inferior, with
higher admissions, although survival benefit was pre-
served. A model, including waitlist admissions alone,
performed better in predicting postlisting mortality than
estimated post-transplant survival. Similarly, McAdams-
DeMarco et al. (10) studied the association between
prospectively assessed physical frailty and postkidney
transplantation mortality and found that frailty was
independently associated with a 2.17-fold higher risk
of death (95% CI, 1.01 to 4.65; P50.05).
Physical frailty is associated with decreased
likelihood of transplantation and inferior sur-
vival after kidney transplantation.
Cardiovascular Outcomes
Cardiovascular death remains the leading cause of
mortality in kidney transplant recipients. Lim et al. (3)
283
conducted a retrospective study using health care data-
bases in Ontario, Canada to determine whether the
incidence of cardiovascular events after kidney trans-
plantation has changed over time. Recipients (n54954)
were older and had more baseline comorbidity in recent
years. A total of 445 recipients (9.0%) died or experi-
enced a major cardiovascular event within 3 years of
transplantation. There was no significant change in the
incidence of the composite outcome or death-censored
cardiovascular events over time (P50.41 and P50.92,
respectively). After adjusting for age, sex, and comor-
bidities, the risk of death or major cardiovascular event
steadily declined across the years of transplant (2006–
2009 adjusted HR, 0.70; P,0.01; referent, 1994–1997).
When recipients were matched for age, sex, and date of
cohort entry to members of the general population and to
the CKD population, the risk was lowest in the general
population and highest in the CKD population.
Shin et al. (11) analyzed 2684 primary kidney
transplant recipients who had a functioning graft at 6
months after transplantation to assess the association of
renin-angiotensin system (RAS) blockade with patient
and graft survival. RAS blockade was associated with
an adjusted HR of 0.63 (95% CI, 0.53 to 0.75) for total
graft loss, an adjusted HR of 0.69 (95% CI, 0.55 to
0.86) for death, and an adjusted HR of 0.62 (95% CI,
0.49 to 0.78) for death-censored graft failure. The
associations of RAS blockade with a lower risk of total
graft loss and mortality were stronger with more severe
proteinuria. The RAS blockade was associated with
a twofold higher risk of hyperkalemia. By comparison,
Dad et al. (12) analyzed the Folic Acid for Vascular
Outcome Reduction in Transplantation Trial database
and reported that aspirin use did not associate with
reduced risk for incident cardiovascular disease, all-
cause mortality, or kidney failure in stable kidney
transplant recipients without a history of cardiovas-
cular disease. Pihlstrøm et al. (13) investigated the
association between baseline parathyroid hormone
(PTH) levels and major cardiovascular events, renal
graft loss, and all-cause mortality. Significant asso-
ciations between PTH and all three outcomes were
found in univariate analyses. When adjusting for
a range of plausible confounders, including measures
of renal function and serum mineral levels, PTH
remained significantly associated with all-cause mor-
tality (4% increased risk per 10 U; P50.004) and
graft loss (6% increased risk per 10 U; P,0.001) but
not major cardiovascular events.
284
Obesity
The impact of pretransplant body mass index
(BMI) on long-term allograft outcomes after kidney
transplantation remains controversial. Naik et al.
(14) studied 108,654 transplant recipients and de-
termined that increasing BMI level was associated
with increased risk of long-term allograft failure. In
an adjusted model with BMI of 18.5 to ,25 kg/m2 as
referent, the subhazard ratios (SHRs) for BMI were
,18.5 kg/m2: SHR, 0.96; P50.41; 25 to ,30 kg/m2:
SHR, 1.05; P50.01; 30 to ,35 kg/m2: SHR, 1.15;
P#0.001; 35 to ,40 kg/m2: SHR, 1.21; P,0.001; and
.40 kg/m2: SHR, 1.13; P50.002. Mechanistically, it
has been suggested that obesity is often associated with
the development of an adiposity-induced inflammatory
state that induces metabolic dysfunction that increases
the risk for developing type 2 diabetes (15).
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11. Shin JI, Palta M, Djamali A, Kaufman DB, Astor BC: The association
between renin-angiotensin system blockade and long-term outcomes in
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renal transplant recipients: The Wisconsin Allograft Recipient Database
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12. Dad T, Tighiouart H, Joseph A, Bostom A, Carpenter M, Hunsicker L,
Kusek JW, Pfeffer M, Levey AS, Weiner DE: Aspirin use and incident
cardiovascular disease, kidney failure, and death in stable kidney
transplant recipients: A post hoc analysis of the Folic Acid for Vascular
Outcome Reduction in Transplantation (FAVORIT) Trial. Am J Kidney
Dis 68: 277–286, 2016 PubMed
13. Pihlstrøm H, Dahle DO, Mjøen G, Pilz S, März W, Abedini S, Holme I,
Fellström B, Jardine AG, Holdaas H: Increased risk of all-cause
mortality and renal graft loss in stable renal transplant recipients with
hyperparathyroidism. Transplantation 99: 351–359, 2015 PubMed
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Lentine KL: The impact of obesity on allograft failure after kidney
transplantation: A competing risks analysis. Transplantation 100:
1963–1969, 2016 PubMed
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sue inflammation and transplantation. Am J Transplant 16: 743–750,
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Deceased Donor Kidney Allocation
The Kidney Allocation System (KAS), a major
change to deceased donor kidney allocation implemented
by the United Network for Organ Sharing (UNOS) in
December of 2014, incorporated specific goals, which
included directing the highest quality organs to
younger, healthier recipients; increasing access to
deceased donor kidney transplantation for highly
sensitized patients, racial/ethnic minorities, and those
with an extended duration on dialysis while mitigat-
ing regional variability.
To assess the impact of this major change in
allocation policy, Stewart et al.(1) compared Organ
Procurement and Transplantation Network data 1 year
before and 1 year after implementation of the KAS.
Transplants in which the donor and recipient ages differed
by .30 years declined by 23%. Initial sharp increases in
transplants were observed for calculated panel reactive
antibody 99%–100% recipients and recipients with at
least 10 years on dialysis, with a subsequent tapering of
transplants to these groups, suggesting a bolus effect. It
was noted that kidneys were more often being shipped
over long distances, leading to longer cold ischemic
times and higher delayed graft function (DGF) rates.
Importantly, 6-month graft survival rates had not changed
significantly. Building on the prior observations, Massie
et al.(2) compared kidney distribution, transplant rates for
waitlist registrants, and recipients for the 2 years pre-
and post-KAS. Some of their key findings included an
increase in regional imports from 8.8% pre-KAS to
12.5% post-KAS and an increase in national imports
from 12.7% pre-KAS to 19.1% post-KAS (P,0.001).
The proportion of recipients .30 years older than their
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
donor decreased from 19.4% to 15.0% (P,0.001). The
proportion of recipients with calculated panel reac-
tive antibody 100% increased from 1.0% to 10.3%
(P,0.001). This latter observation is truly remarkable,
because such patients previously had low transplant
rates with markedly prolonged waiting times. The
overall deceased donor transplant rate did not change.
However, rates increased for blacks (incidence ratio
[IR], 1.19; 95% confidence interval [95% CI], 1.13 to
1.25), Hispanics (IR, 1.13; 95% CI, 1.05 to 1.20), and
candidates ages 18–40 years old (IR, 1.47; 95% CI,
1.38 to 1.57) but declined for candidates ages .50
years old (IR, 0.93; 95% CI, 0.87 to 0.98), those 51–60
years old (IR, 0.90; 95% CI, 0.85 to 0.96), and those
ages .70 years old. Of some concern, the DGF rate
increased from 24.8% pre-KAS to 29.9% post-KAS
(P,0.001). In summary, KAS has been associated
with improved access to transplantation for minorities,
younger candidates, and highly sensitized patients but
declines for older candidates as projected by preimple-
mentation modeling. DGF increased substantially. This
is of concern due to the association of DGF with in-
ferior long-term outcomes (discussed below).
Changes in United States national kidney
allocation implemented in December of 2014
have improved transplantation access for
minorities, younger candidates, and those
who are highly sensitized. This is at the ex-
pense of reduced access for older patients
and higher delayed graft function rates.
Discarded Kidneys
One of the central features of the new system was
the development of the kidney donor profile index
(KDPI), a numeric score on the basis of ten clinical criteria
that describe organ quality implemented pre-KAS in 2012
(lower score is better; calculator is available online:https://
optn.transplant.hrsa.gov/resources/allocation-calculators/
kdpi-calculator/). It is known that allograft prognosis is
inferior when the KDPI exceeds 85%, which includes
a group of donor kidneys that approximates the previous
designation of expanded criteria donors (ECDs). Bae et al.
(3) studied the discard rates of the kidneys recovered for
transplantation from the ECD era with those of the KDPI
era. There was no significant change in discard rate from
the ECD era (18.1%) to the KDPI era (18.3%) among the
285
entire population (adjusted odds ratio [aOR], 0.97; 95% CI,
1.04 to 1.10; P=0.30) or in any KDPI stratum. However,
among kidneys in which ECD and KDPI indicators were
discordant, high-risk standard criteria donor (SCD) kidneys
(with KDPI.0.85) were at increased risk of discard in the
KDPI era (aOR, 1.07; 95% CI, 1.42 to 1.89; P=0.02).
However, recipients of these kidneys were at much lower
risk of death (adjusted risk ratio, 0.56; 95% CI, 0.77 to 0.94
at 2 years post-transplant) compared with those remaining
on dialysis and waiting for low-KDPI kidneys. The authors
suggested that there might be an unexpected harmful
labeling effect of reporting a high KDPI for SCD kidneys
without the expected advantage of providing a more gran-
ular risk index. Such concerns warrant ongoing vigilance.
Stewart et al.(4) also evaluated trends in donor
characteristics with specific reference to discard kidneys.
They reported that most of the kidney discard rate rise
was explained by the broadening donor pool. However,
the presence of an unexplained residual increase sug-
gests that behavioral factors, such as programmatic risk
aversion or allocation inefficiencies, may also play a role.
Snyder et al. (5) examined whether accepting high-risk
kidneys (KDPI$0.85) is associated with transplant pro-
grams receiving inferior evaluations. Despite a clear
relationship between KDPI, graft failure, and mortality,
there was no relationship between a program’s use of
high-KDPI kidneys and subsequently receiving a poor
performance evaluation after risk adjustment. Excluding
high-KDPI donor transplants did not alter the programs
identified as underperforming, because in every case,
underperforming programs also had worse than ex-
pected outcomes among lower-risk donor transplants.
The authors concluded that there is no evidence that
programs that accept higher-KDPI kidneys are at greater
risk for poor performance evaluations, and risk aversion
may limit access to transplant for candidates while
providing no measurable benefit to program evaluations.
Therefore, do we have predictors of kidney discard?
Marrero et al.(6) performed an analysis of the Organ
Procurement and Transplantation Network database
from 2000 to 2012 of all solid organ donors. Perhaps
as expected, predictors of increased discard included
age older than 50 years old, performance of a kidney
biopsy, cytomegalovirus seropositive status, donation
after cardiac death, hepatitis B and C seropositive status,
cigarette use, diabetes, hypertension, terminal creatinine
.1.5 mg/dl, and blood type AB.
Does timing of kidney procurement impact the
discard rate? Indeed, the answer is yes given a recent
286
report by Mohan et al.(7) that studied the impact of the
day of the week of the procurement and subsequent
utilization or discard of deceased donor kidneys in the
United States. Compared with weekday kidneys, or-
gans procured on weekends were significantly more
likely to be discarded than transplanted (OR, 1.16; 95%
CI, 1.13 to 1.19), even after adjusting for organ quality
(aOR, 1.13; 95% CI, 1.10 to 1.17). Weekend discards
were of a significantly higher quality than weekday
discards, although the effect was small (KDPI: 76.5%
versus 77.3%). Considerable geographic variation was
also noted in the proportion of transplants that occurred
over the weekend (Figure 6).
Deceased Donor Hypothermia
DGF, which is reported in up to 50% of kidney
transplant recipients, is associated with increased costs
and inferior prognosis (see below). Targeting mild
hypothermia in organ donors before organ recovery
may impact DGF risk. Niemann et al.(8) enrolled
organ donors (after declaration of death by neurologic
criteria) from two large donation service areas and
randomly assigned them to one of two targeted tem-
perature ranges: 34
C to 35
C (hypothermia) or 36.5
C
to 37.5
C (normothermia). The study was terminated
early on the recommendation of an independent data
and safety monitoring board after the interim analysis
showed efficacy of hypothermia. DGF developed in 79
recipients of kidneys from donors in the hypothermia
Figure 6. There is marked geographic variation in the
proportion of deceased donor transplants that are performed
over the weekend. Geographic variation in the proportion of
deceased donor kidney transplants performed over the weekend
by state, 2000–2013. Reprinted with permission from Mohan S,
Foley K, Chiles MC, Dube GK, Patzer RE, Pastan SO, Crew
RJ, Cohen DJ, Ratner LE: The weekend effect alters the
procurement and discard rates of deceased donor kidneys in the
United States. Kidney Int90: 157–163, 2016.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
group (28%) and 112 recipients of kidneys from donors
in the normothermia group (39%; odds ratio, 0.62; 95%
CI, 0.43 to 0.92; P=0.02). The authors concluded that
mild hypothermia compared with normothermia in
organ donors after declaration of death per neurologic
criteria significantly reduced the rate of DGF among
recipients. It is now up to organ procurement organi-
zations to either repeat the study or implement the
protocols for deceased donors.
Use of Hepatitis C Virus–Seropositive Kidneys
The impact of transplanting hepatitis C virus
(HCV)–seropositive deceased donor kidneys was stud-
ied by Scalea et al.(9), who analyzed 1679 adult
allografts between 2000 and 2012. Of these, 195 hep-
atitis C virus–seropositive recipients (R+) received
kidneys from hepatitis C virus–seropositive donors
(D+) in contrast to 1418 HCV-negative recipients who
received grafts from hepatitis C virus–negative donors
(D–) and 66 R+ patients who received D– kidneys.
Death-censored graft survival in the D+/R+ population
was better than graft survival for D–/R+ patients,
despite D+/R+ patients having higher rates of hyper-
tension and black ethnicity. Waitlist times for patients
accepting HCV-seropositive grafts were 318 days (for
D+/R+ patients) versus 613 days (D–/HCV-negative
recipients) or 570 days (D–/R+). The authors reason-
ably concluded that HCV D+/R+ patients spent less
time on the transplant waitlist, which contributed to
improved death-censored graft survival compared with
D–/R+ patients.
Prior Living Donors in Need of Transplantation
The incidence of ESRD in prior living kidney
donors (PLDs) has been estimated at 30 in 10,000,
higher than four in 10,000 in the general population
(reviewed in prior issues of the Nephrology Self-
Assessment Program on transplantation). Wainright
et al.(10) investigated the early effects of the KAS on
the access of PLDs to deceased donor kidney trans-
plants. Using the Organ Procurement and Transplanta-
tion Network data, this group compared prevalent and
incident cohorts of PLDs in the 1-year periods before
and after KAS implementation. Importantly, transplant
rates were not statistically different before or after KAS
implementation for either prevalent (2.37 versus 2.29;
relative risk [RR], 0.96; 95% CI, 0.62 to 1.49) or
incident (4.76 versus 4.36; RR, 0.92; 95% CI, 0.53 to
1.60) candidates. Median waiting time to deceased
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
donor kidney transplant for prevalent PLDs in the post-
KAS cohort was 102.6 days compared with 82.3 days
in the pre-KAS cohort (P=0.98). The median KDPI for
PLD recipients was 31% with KAS versus 23% before
KAS (P=0.02). Despite a sharp decrease in the waiting
time for highly prioritized candidates with calculated
panel reactive antibodies of 98%–100% (from .7000
to 1164 days), PLDs still had much shorter waiting
times (mean of 102.6 days).
The incidence of ESRD in prior living donors
is 30 in 10,000, which is higher than that in
nondonors (four in 10,000). This risk is
mitigated to an extent in that prior donors
have ready access to transplantation.
Public Health Service Increased Risk Donors
The US Public Health Service redefined donors
previously classified by the Centers for Disease
Control as being at high risk for transmission of
hepatitis B, HCV, and HIV. These categories include
the following.
(1) People who have had sex with a person known or
suspected to have HIV, hepatitis B, or HCV
infection within the previous year.
(2) Men who have had sex with men within the
previous year.
(3) Women who have had sex with a man with a
history of having sex with men within the pre-
vious year.
(4) People who have had sex for money or drugs
within the previous year.
(5) People who have had sex with a person who had
sex in exchange for money or drugs within the
previous year.
(6) People using nonmedical injection of drugs
within the previous year.
(7) People who have sex with a person who used
nonmedical injection of drugs within the previous
year.
(8) People who have been in lockup, jail, prison, or
juvenile correctional facility for .72 consecutive
hours.
(9) Persons who have been newly diagnosed with
or treated for syphilis, gonorrhea, Chlamydia, or
genital ulcers in the preceding 12 months.
287
(10) Deceased donors whose medical/behavioral
history cannot be determined.
(11) Deceased donors whose blood specimen has
been hemodiluted.
The UNOS regulations specify that such donors
be screened for hepatitis B virus, HCV, and HIV by
both serology and nucleic acid testing (NAT). These
kidneys can only be offered as Public Health Service
Increased Risk Donor if hepatitis B virus, HCV, and
HIV testing is negative. It should be understood that
there is still risk of a false negative result should such
a donor remain within the window period after infection
but before viral nucleic acid has sufficiently amplified to
yield a positive result. Such kidneys are only offered to
recipients who have been informed of the risks and
consented to receive such a kidney. Kidneys that test
positive for HCV or hepatitis B virus can be offered to
recipients who are HCV seropositive or hepatitis B
virus positive, respectively. Kidneys from HIV-positive
donors can now be transplanted into HIV-positive recip-
ients under experimental protocols since the HIV Organ
Policy Equity Act was enacted in 2013.
Importantly, the number of such deceased donors
has increased markedly over the last decade driven by
the epidemic of opiate addiction within the United States.
Kucirka et al.(11) quantified the impact of the new
guidelines and found that 19.5% of donors were labeled
increased risk donors (IRD) compared with 10.4%,
12.2%, and 12.3% in the 3 most recent years under the
old guidelines (incidence rate ratio, 1.45; P,0.001).
Increases were consistent across organ procurement
organizations: 44 of 59 had an increase in the percent-
age of donors labeled as being at increased risk, and 14
organ procurement organizations labeled 25% of their
donors as being at increased risk under the new guidelines
(versus five organ procurement organizations under the
old guidelines). Blacks were 52% more likely to be labeled
IRD under the new guidelines (RR, 1.52; P=0.01).
The risk of transmission of disease using the prior
Centers for Disease Control and Prevention guidelines
was previously reviewed by Kucirka et al.(12). They
found that increased risk organs are discarded at higher
rates than SCD kidneys. Their estimated risk of un-
detected window period HIV infection varies by IRD
behavior category (range, 0.035–4.9 per 10,000 donors
when NAT is used), and HCV risk is higher (range,
0.027–32.4 per 10,000). Recipients who receive such
kidneys are tested at time 0 and again at defined time
288
points until the end of the first post-transplant year by
NAT. Information about recipients who test positive
needs to be shared with the UNOS Disease Transmission
Advisory Committee. Updated information on actual
disease transmission on the basis of the new criteria is
eagerly awaited.
Deceased donor kidneys procured from
individuals who meet the US Public Health
Service definitions of increased risk now
make up approximately 20% of the entire
donor pool. These donors are tested for viral
infections by both serology and NAT. Organs
from these donors can be offered for trans-
plantation when the testing is negative.
Point estimates of risk for transmission of
HIV, HCV, and hepatitis B virus are all <1%.
These kidneys tend to be from young donors
with low KDPIs and may be associated with
reduced waiting time for transplantation.
References
1. Stewart DE, Kucheryavaya AY, Klassen DK, Turgeon NA, Formica RN,
Aeder MI:Changes in deceased donor kidney transplantation one year
after KAS implementation.Am J Transplant 16:1834–1847,2016 PubMed
2. Massie AB, Luo X, Lonze BE, Desai NM, Bingaman AW, Cooper M,
Segev DL:Early changes in kidney distribution under the new allocation
system.J Am Soc Nephrol 27:2495–2501,2016 PubMed
3. Bae S, Massie AB, Luo X, Anjum S, Desai NM, Segev DL:Changes in
discard rate after the introduction of the kidney donor profile index
(KDPI).Am J Transplant 16:2202–2207,2016 PubMed
4. Stewart DE, Garcia VC, Rosendale JD, Klassen DK, Carrico BJ:
Diagnosing the decades-long rise in the deceased donor kidney discard
rate in the United States.Transplantation 101:575–587,2017 PubMed
5. Snyder JJ, Salkowski N, Wey A, Israni AK, Schold JD, Segev DL,
Kasiske BL:Effects of high-risk kidneys on Scientific Registry of Trans-
plant Recipients Program Quality Reports.Am J Transplant 16:2646–
2653,2016 PubMed
6. Marrero WJ, Naik AS, Friedewald JJ, Xu Y, Hutton DW, Lavieri MS,
Parikh ND:Predictors of deceased donor kidney discard in the United
States.Transplantation 101:1690–1697,2017 PubMed
7. Mohan S, Foley K, Chiles MC, Dube GK, Patzer RE, Pastan SO, Crew
RJ, Cohen DJ, Ratner LE:The weekend effect alters the procurement
and discard rates of deceased donor kidneys in the United States.Kidney
Int 90:157–163,2016 PubMed
8. Niemann CU, Feiner J, Swain S, Bunting S, Friedman M, Crutchfield
M, Broglio K, Hirose R, Roberts JP, Malinoski D:Therapeutic hypo-
thermia in deceased organ donors and kidney-graft function.N Engl J
Med 373:405–414,2015 PubMed
9. Scalea JR, Redfield RR, Arpali E, Leverson GE, Bennett RJ, Anderson
ME, Kaufman DB, Fernandez LA, D’Alessandro AM, Foley DP,
Mezrich JD:Does DCD donor time-to-death affect recipient outcomes?
Implications of time-to-death at a high-volume center in the United
States.Am J Transplant 17:191–200,2017 PubMed
10. Wainright JL, Kucheryavaya AY, Klassen DK, Stewart DE:The impact
of the new kidney allocation system on prior living kidney donors’
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
access to deceased donor kidney transplants: An early look.Am J
Transplant 17:1103–1111,2017 PubMed
11. Kucirka LM, Bowring MG, Massie AB, Luo X, Nicholas LH, Segev
DL:Landscape of deceased donors labeled increased risk for disease
transmission under new guidelines.Am J Transplant 15:3215–3223,
2015 PubMed
12. Kucirka LM, Singer AL, Segev DL:High infectious risk donors: what
are the risks and when are they too high?Curr Opin Organ Transplant
16:256–261,2011 PubMed
Living Kidney Donation
In 2015, 5626 living donor transplants were per-
formed, an increase from 5539 in 2014 but a decrease
from the peak of 6647 in 2004 (Figure 7) (1). This de-
cline is due to a decrease in related kidney donations,
because unrelated donations have been stable. Although
the number of paired donations has increased, this is not
enough to offset the overall decline in related donations.
Women made up 63.5% of living donors, an increase
from 59.2% in 2005. The proportion of black donors has
continued to decline over 10 years from 13.4% to 9.6%.
Laparoscopic nephrectomy made up .97% of procedures
in 2015. Readmissions after living donation, although
infrequent, are not rare, with rates of 2.5% at 6 weeks,
3.9% at 6 months, and 5.2% at 1 year. Overall, compli-
cations postnephrectomy occured in 5.3% of living donors
at 6 weeks, 7.2% of living donors at 6 months, and 8.8%
of living donors at 12 months. The distribution of body
mass index (BMI) remained relatively stable over 10
years, with a slight decrease in the proportion of donors
with BMI.35 kg/m2 (from 4.6% to 2.6%) and an
increase in the proportion with BMI530–35 kg/m2 (from
16.1% to 19.5%). From 2011 to 2015, 17 deaths within 1
year of donation were reported to the Organ Procurement
and Transplantation Network (OPTN). The most common
causes of death were medical (including donation related)
in seven and accident/homicide in five living donors.
The number of living donors has declined
in the United States, despite increasing kid-
ney paired donation (KPD).
Kidney Paired Donation
Approximately 30% of living donors are incom-
patible with their intended recipients due to either pre-
formed ABO or donor-specific antibodies. KPD is the
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Figure 7. The relationship between living donors and their
intended recipients has evolved over time with an overall
decline in those that are biologically related. Kidney paired
donation is a growing trend however still makes up a small
proportion of live donor transplants. Kidney transplants from
living donors by donor relation. Numbers of living donor
donations and characteristics recorded on the OPTN living
donor registration form. Reprinted with permission from Hart A,
Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh
WS, Wainright JL, Boyle G, Snyder JJ, Kasiske BL, Israni AK:
Kidney. Am J Transplant 16[Suppl 2]: 11–46, 2016.
most exciting novel approach gaining traction that
addresses incompatibility, while avoiding the financial
costs, adverse events, and inferior outcomes associated
with desensitization. Numerous programs have been
created to promote KPD, including those managed by the
United Network for Organ Sharing (UNOS), the National
Kidney Registry, the Alliance for Paired Donation, and
other regional or single-center initiatives. At core, these
programs promote the search for compatible living
donors when candidate recipients have living donors who
are incompatible. The concept of an open chain, often
triggered by an altruistic donor, frequently garners interest
by the popular press. The practice of shipping live donor
kidneys is now firmly established, eliminating some of
the logistic barriers previously encountered.
Flechner et al. (2) described an interesting twist
on the general concept of KPD in the description of
their Advanced Donation Program (ADP) that permits
a donor who desires to donate by a specific date but
does not yet have a matched donor to effectively “pay it
forward.” After obtaining informed consent from donor
and paired recipient, ten KPD chains were constructed
using an ADP donor. These ten ADP donors have
289
facilitated 47 transplants, and thus far, eight of their
paired recipients have received a kidney within a mean
of 178 (range, 10–562) days. Fumo et al. (3) studied
potential swaps that failed and found three primary
reasons that could be prevented by changes in protocol
or software: positive laboratory crossmatch (28%),
transplant center declined donor (17%), and pair trans-
planted outside the APD (14%). Making such changes
allowed their group to improve the success rate and the
number of transplants performed annually.
Living Donor Kidney Function Assessment
Per UNOS regulations, all living kidney donor
candidates undergo evaluation of GFR. Guidelines
recommend measured GFR (mGFR) via an endoge-
nous filtration marker or creatinine clearance rather
than eGFR by any methodology. However, measure-
ment methods are challenging, time consuming, and
costly, and they can yield variable results. Huang et al.
(4) investigated whether GFR estimated from serum
creatinine with or without sequential cystatin C was
sufficiently accurate to identify donor candidates with
high probability that mGFR is above or below thresh-
olds for clinical decision making. They combined the
pretest probability for mGFR thresholds ,60, ,70,
$80, and $90 ml/min per 1.73 m2 on the basis of
demographic characteristics from the National Health
and Nutrition Examination Survey with test perfor-
mance of eGFR (Chronic Kidney Disease Epidemiol-
ogy Collaboration) to compute post-test probabilities.
Using data from the Scientific Registry of Transplant
Recipients, 53% of recent living donors had predonation
GFR estimated from serum creatinine levels sufficiently
high to ensure $95% probability that predonation mGFR
was $90 ml/min per 1.73 m2, suggesting that mGFR may
not be necessary in a large proportion of donor candi-
dates. They developed a web-based application (http://
ckdepi.org/equations/donor-candidate-gfr-calculator/) to
compute the probability on the basis of eGFR that mGFR
for a donor candidate is above or below a range of
thresholds useful in living donor evaluation and selection.
Although intriguing, such methodology does not cur-
rently meet UNOS regulatory requirements.
Medically Complex Living Donors
Living donation has been deemed the chief
weapon in the fight to redistribute the gap between
supply and demand for kidneys given the continued
expansion of the national waiting list. Ahmadi et al. (5)
290
reviewed current guidelines pertaining to the selection
of medically complex donors with regard to older age,
obesity, hypertension, vascular anomalies/multiplicity,
nulliparous women, and minors as donors. Their summary
conclusions included the following statements: live kid-
ney donation in older donors (up to 70 years of age) seems
to be safe when outcome is compared with that of younger
donors; obese donors have comparable outcomes to lean
donors, at least in short- and midterm follow-up; given the
paucity of data pertaining to hypertensive donor safety,
caution is advised; vascular multiplicity poses no direct
danger to the donor; women of childbearing age can be
safely included as donors; and minors should only be
considered as kidney donors if no other options exist.
To facilitate decision making when a transplant
candidate has multiple living donors, Massie et al. (6)
developed a living kidney donor profile index (LKDPI)
using the same scale as the deceased donor kidney
donor profile index. Multivariate analysis indicated that
donor age over 50 years old (hazard ratio [HR] per 10
years, 1.15; 95% confidence interval [95% CI], 1.24 to
1.33), elevated BMI (HR per 10 U, 1.01; 95% CI, 1.09
to 1.16), black race (HR, 1.15; 95% CI, 1.25 to 1.37),
and cigarette use (HR, 1.09; 95% CI, 1.16 to 1.23)
as well as ABO incompatibility (HR, 1.03; 95% CI, 1.27
to 1.58), HLA B mismatches (HR, 1.03; 95% CI, 1.08 to
1.14), and DR mismatches (HR, 1.04; 95% CI, 1.09 to
1.15) were associated with greater risk of graft loss after
living donor transplantation (all P,0.05). The median
LKDPI score was 13 (1–27); 24.2% of donors had
LKDPI,0 (less risk than any deceased donor kidney),
and 4.4% of donors had LKDPI.50 (more risk than the
median deceased donor kidney). An online calculator is
available http://www.transplantmodels.com/lkdpi/.
Muzaale et al. (7) questioned whether it was possible
that living kidney donors had undetected, subclinical,
preexisting kidney disease that subsequently contrib-
uted to risk of ESRD. To test this theory, the authors
compared a cohort of 257 recipients whose donors
subsequently developed ESRD with a matched cohort
whose donors remained ESRD free. The median
follow-up time from transplantation was 12.5 years
(interquartile range, 7.4–17.9; maximum 520 years).
Recipients of allografts from donors who developed
ESRD had increased death-censored graft loss (74%
versus 56% at 20 years; adjusted HR, 1.7; 95% CI, 1.5
to 2.0; P,0.001) and mortality (61% versus 46% at 20
years; adjusted HR, 1.5; 95% CI, 1.2 to 1.8; P,0.001)
compared with matched recipients of allografts from
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
donors who did not develop ESRD. This association
was similar among related, spousal, and unrelated non-
spousal donors.
Surgery Complications
Lentine et al. (8) studied perioperative complications
associated with living kidney donation. Nephrectomies
were predominantly laparoscopic (94%). Overall, 16.8%
of donors experienced a perioperative complication,
most commonly gastrointestinal (4.4%), bleeding (3.0%),
respiratory (2.5%), surgical/anesthesia-related injuries
(2.4%), and other complications (6.6%). Major Clavien
Classification of Surgical Complications grade IV
(life threatening, organ dysfunction) or grade V (death)
affected 2.5% of donors. After adjustment for demo-
graphic, clinical (including comorbidities), procedure,
and center factors, blacks had increased risk of any
complication (adjusted odds ratio [aOR], 1.26; P50.001)
as well as Clavien grade II (requiring pharmacologic
treatment or transfusion) or higher (aOR, 1.39; P,0.001),
grade III (requiring anesthesia/surgery) or higher (aOR,
1.56, P,0.001), and grade IV or higher (aOR, 1.56;
P50.004) events. Other significant correlates of Clavien
grade IV or higher events included obesity (aOR, 1.55;
P,0.001), predonation hematologic (such as thrombo-
cytopenia; aOR, 2.78; P,0.001) and psychiatric
(aOR, 1.45; P50.04) conditions, and robotic nephrectomy
(aOR, 2.07; P50.002), whereas an annual center volume
.50 transplants (aOR, 0.55; P,0.001) was associated
with lower risk. The same group found that predonation
narcotic analgesia use was independently associated with
readmission after donor nephrectomy (9).
Postnephrectomy surgical complications
occur in approximately 17% of donors and
are more common in blacks and those
with obesity or hematologic or psychiatric
conditions. The risk of more serious compli-
cations (Clavien grade IV or higher) is 2.5%.
Pregnancy Risk
Garg et al. (10) recently reported that gestational
hypertension or preeclampsia was more common
among living kidney donors than among nondonors
(occurring in 15 of 131 pregnancies [11%] versus 38 of
788 pregnancies [5%]). The odds ratio (OR) for donors
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
was 2.4 (95% CI, 1.2 to 5.0; P50.01). Each component
of the primary outcome was also more common among
donors (OR, 2.5 for gestational hypertension and OR,
2.4 for preeclampsia). On a positive note, there were no
significant differences between donors and nondonors
with respect to rates of preterm birth (8% and 7%,
respectively) or low birth weight (6% and 4%, re-
spectively). There were no reports of maternal death,
stillbirth, or neonatal death among donors. Most women
had uncomplicated pregnancies after donation.
Gestational hypertension and preeclamp-
sia are more common in living donors than
nondonors.
Kidney Failure Risk
There have been few prospective, controlled studies
of kidney donors. Kasiske et al. (11) posited that
understanding the pathophysiologic effects of kidney
donation may be important for judging donor safety
and improving our understanding of the consequences
of reduced kidney function in CKD. In their pro-
spective, controlled, observational cohort study, this
group reported that GFR measured by plasma iohexol
clearance declined 0.3667.55 ml/min per year in 194
controls but increased 1.4765.02 ml/min per year in
198 donors (P,0.01) between 6 and 36 months. BP
was not different between donors and controls at any
visit. Urinary protein-to-creatinine and albumin-to-
creatinine ratios were not increased in donors com-
pared with controls. From 6 to 36 months postdonation,
serum parathyroid hormone, uric acid, homocysteine,
and potassium levels were higher, whereas hemoglobin
levels were lower in donors compared with controls.
The authors concluded that kidney donors manifest several
of the findings of mild CKD. However, at 36 months after
donation, kidney function continues to improve in donors
(presumably because of hyperfiltration), whereas controls
have expected age-related declines in function.
Previous reports on the risk of ESRD in prior living
kidney donors (PLDs) have been variously criticized due
to small sample size, inappropriate comparators, short
follow-up time, and incomplete data acquisition. Grams
et al. (12) studied data from almost 5 million nondonors
studied for up to 16 years compared with 52,998 living
kidney donors in the United States. For a 40-year-old
291
person with health characteristics that were like those of
age-matched kidney donors, the 15-year projections of
the risk of ESRD in the absence of donation varied ac-
cording to race and sex; the risk was 0.24% among black
men, 0.15% among black women, 0.06% among white
men, and 0.04% among white women. Risk projections
were higher in the presence of lower eGFR, higher
albuminuria, hypertension, current or former smoking,
diabetes, and obesity. The risk of ESRD was highest
among persons in the youngest age group, particularly
among young blacks. The 15-year observed risks after
donation among kidney donors in the United States were
3.5–5.3 times as high as the projected risks in the
absence of donation. Looking at this question another
way, Ross (13) reported that .325 living kidney donors
have developed ESRD and have been listed on the
OPTN/UNOS deceased donor kidney waitlist. Unfortu-
nately, because of lack of standardized data collection,
the denominator is unknown.
Anjum et al. (14) studied the causes of ESRD
among PLDs. Overall, 125,427 donors were observed
for a median of 11.0 years. The cumulative incidence of
ESRD increased from ten events per 10,000 at 10 years
postdonation to 85 events per 10,000 at 25 years
postdonation (late versus early ESRD adjusted for age,
race, and sex: incidence rate ratio, 1.3; 95% CI, 1.7 to
2.3). Early postdonation ESRD was predominantly
reported as GN; however, late postdonation ESRD was
more frequently reported as diabetes and hypertension.
Living kidney donors have a small but
significantly increased risk of ESRD com-
pared with nondonors. This is driven early
postdonation by GN and late postdonation
by diabetes and hypertension.
Prior Living Donors and Kidney Transplantation
The impact of the new Kidney Allocation System
(KAS) on the access of PLDs to deceased donor
kidney transplants was studied by Wainright et al. (15).
Using data from the OPTN, the numbers of PLDs
registered for transplantation before and after KAS
were examined (pre-KAS group: December 4, 2013 to
December 3, 2014 [n550, newly listed PLDs]; post-
KAS group: December 4, 2014 to December 3, 2015
[n539]). Transplant rates were similar before and after
292
KAS implementation for both prevalent (2.37 versus
2.29; relative risk, 0.96; 95% CI, 0.62 to 1.49) and
incident (4.76 versus 4.36; relative risk, 0.92; 95% CI,
0.53 to 1.60) candidates. Median waiting time to
deceased donor kidney transplantation for prevalent
PLDs in the post-KAS cohort was 102.6 days com-
pared with 82.3 days in the pre-KAS cohort (P50.98).
The median kidney donor profile index for PLD
recipients was 31% with KAS versus 23% before
KAS (P50.02). Despite a sharp decrease in the waiting
times for highly prioritized candidates with calculated
panel reactive antibodies of 98%–100% (from .7000
to 1164 days), PLDs still had much shorter waiting
times (102.6 days). In conclusion, the new system
continues to provide PLDs with quick access to high-
quality kidneys for transplantation.
APOL1
Individuals of black ancestry who express two
variant copies of the gene encoding apo1 (APOL1), an
HDL that binds to apoA-1, make up 13% of the black
population and are at increased risk of ESRD (16).
Limited studies suggest that the survival of allografts
from donors expressing two APOL1 risk alleles is
inferior to that of allografts with zero or one risk allele.
In living kidney donation, two case reports describe
donors expressing two APOL1 risk alleles who de-
veloped ESRD (17). Given the potential impact of
APOL1 variants on the utility and safety of kidney
transplantation and living kidney donation, the Amer-
ican Society of Transplantation convened a meeting
with the goals of summarizing the current state of
knowledge with respect to transplantation and APOL1,
identifying knowledge gaps and studies to address
these gaps, and considering approaches to integrating
APOL1 into clinical practice (16).
Other Complications
Lam et al. (18) reported an increased risk of gout
in donors compared with nondonors. They studied
1988 donors and 19,880 matched nondonors who were
followed for a median of 8.4 years. Donors compared
with nondonors were more likely to be given a diagnosis
of gout (3.4% versus 2.0%; 3.5 versus 2.1 events per
1000 person-years, respectively; HR, 1.6; 95% CI, 1.2 to
2.1; P,0.001). Similarly, donors compared with non-
donors were more likely to receive a prescription for
allopurinol or colchicine (3.8% versus 1.3%; OR, 3.2;
95% CI, 1.5 to 6.7; P50.002). Results were consistent in
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
multiple additional analyses. From a cohort of 1333
living donors with 5332 matched controls, Lin et al. (19)
reported that the overall incidence of peptic ulcer disease
was 1.74-fold higher in the living donor cohort than in
the nonliving donor cohort (2.14 versus 1.48 per 1000
person-years). This finding persisted after adjustment for
age, sex, monthly income, and comorbidities.
References
1. Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh
WS, Wainright JL, Boyle G, Snyder JJ, Kasiske BL, Israni AK: Kidney.
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2. Flechner SM, Leeser D, Pelletier R, Morgievich M, Miller K,
Thompson L, McGuire S, Sinacore J, Hil G: The incorporation of an
advanced donation program into kidney paired exchange: Initial
experience of the national kidney registry. Am J Transplant 15:
2712–2717, 2015 PubMed
3. Fumo DE, Kapoor V, Reece LJ, Stepkowski SM, Kopke JE, Rees SE,
Smith C, Roth AE, Leichtman AB, Rees MA: Historical matching
strategies in kidney paired donation: The 7-year evolution of a web-based
virtual matching system. Am J Transplant 15: 2646–2654, 2015 PubMed
4. Huang N, Foster MC, Lentine KL, Garg AX, Poggio ED, Kasiske BL,
Inker LA, Levey AS: Estimated GFR for living kidney donor evalua-
tion. Am J Transplant 16: 171–180, 2016 PubMed
5. Ahmadi AR, Lafranca JA, Claessens LA, Imamdi RM, IJzermans JN,
Betjes MG, Dor FJ: Shifting paradigms in eligibility criteria for live kidney
donation: a systematic review. Kidney Int 87: 31–45, 2015 PubMed
6. Massie AB, Leanza J, Fahmy LM, Chow EK, Desai NM, Luo X, King
EA, Bowring MG, Segev DL: A risk index for living donor kidney
transplantation. Am J Transplant 16: 2077–2084, 2016 PubMed
7. Muzaale AD, Massie AB, Anjum S, Liao C, Garg AX, Lentine KL,
Segev DL: Recipient outcomes following transplantation of allografts
from live kidney donors who subsequently developed end-stage renal
disease. Am J Transplant 16: 3532–3539, 2016 PubMed
8. Lentine KL, Lam NN, Axelrod D, Schnitzler MA, Garg AX, Xiao H,
Dzebisashvili N, Schold JD, Brennan DC, Randall H, King EA, Segev
DL: Perioperative complications after living kidney donation: A
national study. Am J Transplant 16: 1848–1857, 2016 PubMed
9. Lentine KL, Lam NN, Schnitzler MA, Hess GP, Kasiske BL, Xiao H,
Axelrod D, Garg AX, Schold JD, Randall H, Dzebisashvili N, Brennan
DC, Segev DL: Predonation prescription opioid use: A novel risk factor
for readmission after living kidney donation. Am J Transplant 17: 744–
753, 2017 PubMed
10. Garg AX, Nevis IF, McArthur E, Sontrop JM, Koval JJ, Lam NN,
Hildebrand AM, Reese PP, Storsley L, Gill JS, Segev DL, Habbous S,
Bugeja A, Knoll GA, Dipchand C, Monroy-Cuadros M, Lentine KL;
DONOR Network: Gestational hypertension and preeclampsia in living
kidney donors. N Engl J Med 372: 124–133, 2015 PubMed
11. Kasiske BL, Anderson-Haag T, Israni AK, Kalil RS, Kimmel PL, Kraus
ES, Kumar R, Posselt AA, Pesavento TE, Rabb H, Steffes MW, Snyder
JJ, Weir MR: A prospective controlled study of living kidney donors:
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12. Grams ME, Sang Y, Levey AS, Matsushita K, Ballew S, Chang AR,
Chow EK, Kasiske BL, Kovesdy CP, Nadkarni GN, Shalev V, Segev
DL, Coresh J, Lentine KL, Garg AX; Chronic Kidney Disease
Prognosis Consortium: Kidney-failure risk projection for the living
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KL, Garg AX, Segev DL: Patterns of end-stage renal disease caused by
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Wiseman AC, Chandraker A: Integrating APOL1 gene variants into
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Gallon L, Friedewald JJ: APOL1-associated end-stage renal disease in
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Kasiske BL, Lok CE, Feldman LS, Garg AX; Donor Nephrectomy
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Peptic ulcer disease in living liver donors: A longitudinal population-
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Delayed Graft Function
Delayed graft function (DGF) after kidney trans-
plantation is variably defined as the need for dialysis
during the first postoperative week, anuria, or failure of
prompt azotemia resolution. Importantly, DGF develops
in up to 25%–30% of kidney transplant recipients and is
associated with increased cost, length of stay, and inferior
long-term graft survival. There has been concern that the
Kidney Allocation System (KAS), a major change to
organ sharing implemented by the United Network for
Organ Sharing in December of 2014, may be associated
with increased DGF rates. Goals of the KAS included
directing the highest quality organs to younger/healthier
recipients and increasing access to deceased donor kidney
transplantation organs for highly sensitized patients and
racial/ethnic minorities at the expense of increased cold
ischemic time. Massie et al. (1), using national registry
data, compared kidney distribution, transplant rates, and
recipient characteristics between January 1, 2013 and
December 3, 2014 (pre-KAS) with those between De-
cember 4, 2014 and August 31, 2015 (post-KAS).
Regionally imported organs increased from 8.8% pre-
KAS to 12.5% post-KAS; national imports increased
from 12.7% pre-KAS to 19.1% post-KAS (P,0.001). In
parallel, DGF increased from 24.8% pre-KAS to 29.9%
post-KAS (P,0.001). The impact of this increase in DGF
rates nationwide on outcomes remains to be determined.
Donor, peritransplant, and recipient factors have
been implicated in the pathogenesis of DGF. For ex-
ample, Allen et al. (2) recently showed that donation
after cardiac death kidneys have inferior survival when
293
preprocurement hypotension persists (odds ratio [OR],
1.42; 95% confidence interval [95% CI], 1.06 to 1.90).
Donor hypoxia during the first 10 minutes after ex-
tubation was also associated with graft failure (hazard
ratio [HR], 1.30; 95% CI, 1.03 to 1.64), with 5-year
graft survival of 70.0% (95% CI, 64.5% to 74.8%) for
donors above the median versus 61.4% (95% CI,
55.5% to 66.7%) for those below the median. Patel
et al. (3) described the impact of premortem donor
hydroxyethyl starch (HES) use on allograft outcomes.
Kidneys from donors who received HES had a higher
crude rate of DGF (41% versus 31%; P,0.001). In this
report, independent predictors of DGF included donor age
(OR, 1.02; 95% CI, 1.01 to 1.04 per year), cold ischemia
time (OR, 1.04; 95% CI, 1.02 to 1.06 per hour), creatinine
elevation (OR, 1.5; 95% CI, 1.32 to 1.72 per mg/dl), and
HES use (OR, 1.41; 95% CI, 1.02 to 1.95). The broader
applicability of this remains unclear, because there are no
published data on the use of HES in kidney donors.
Donor, peritransplant, and recipient factors
are implicated in the pathogenesis of delayed
graft function after transplant, which in turn,
impacts patient and graft survival.
Premortem AKI
What about the use of kidneys from deceased
donors with premortem AKI? Heilman et al. (4) de-
scribed the outcome and phenotype of kidneys with and
without donor AKI. DGF was more common in the
AKI group, but eGFR, graft survival at 1 year, and
fibrosis scores at 12 months were similar for the two
groups. At 1 month, there were 898 differentially
expressed genes in the AKI group (P,0.01), but at
4 months, there were no differences. The authors
concluded that transplanting selected kidneys from
deceased donors with AKI is safe and associates with
excellent outcomes. Batra et al. (5) added to this lit-
erature by studying the clinical and histologic outcomes
related to 61 transplanted kidneys from deceased
donors with glomerular fibrin thrombi (GFT) conse-
quent on disseminated intravascular coagulation before
organ procurement. DGF occurred in 49% of the GFT
group and 39% of the control group (P50.14). Serum
creatinine values at 1, 4, and 12 months and eGFR at 12
months were similar in the two groups. Estimated 1-year
graft survival was 93.2% in the GFT group and 95.1% in
294
the control group (P50.22 by log rank test). The authors
concluded that GFT resolves rapidly after transplantation
and that transplanting selected kidneys from deceased
donors with GFT is a safe practice. Despite these
observations, deceased donor kidneys with AKI are often
discarded due to fear of poor outcomes. Hall et al. (6)
performed a multicenter study to determine associations
of AKI with kidney discard, DGF, and 6-month eGFRs.
In 1632 donors, the kidney discard risk increased for AKI
stages 1, 2, and 3 compared with no AKI, with adjusted
relative risks (aRRs) of 1.28 (95% CI, 1.08 to 1.52), 1.82
(95% CI, 1.45 to 2.30), and 2.74 (95% CI, 2.0 to 3.75),
respectively. The aRRs for DGF also increased by donor
AKI stage: aRR, 1.27; 95% CI, 1.09 to 1.49; aRR, 1.70;
95% CI, 1.37 to 2.12; and aRR, 2.25; 95% CI, 1.74 to
2.91, respectively. The 6-month eGFRs were similar
across AKI categories but lower for recipients with
DGF: 48 (interquartile range, 31–61) ml/min per
1.73 m2 versus 58 (interquartile range, 45–75) ml/min
per 1.73 m2 for no DGF (P,0.001).
What about the use of postprocurement biopsy on
outcomes? Wang et al. (7) carried out a systematic re-
view of the medical literature on the utility of procurement
and implantation biopsies for predicting post-transplant
outcomes. Between 1994 and 2014, 47 studies were re-
viewed that examined the association between pretrans-
plant donor biopsy findings and post-transplant graft
failure, DGF, or graft function. In general, study quality
was poor. All of them were retrospective or did not
indicate if they were prospective. Results were heteroge-
neous, with authors as often as not concluding that biopsy
results did not predict post-transplant outcomes. The
percentage glomerular sclerosis was the most often ex-
amined parameter, and it failed to predict graft failure
in seven of 14 studies. Of 15 proposed semiquantitative
scoring systems, none consistently predicted post-transplant
outcomes across studies. In summary, it seems that the
routine use of biopsies to help determine whether to trans-
plant a kidney is of little value in predicting outcomes.
Predonation Interventions
Preprocurement interventions to mitigate deceased
donor recipient DGF risk have yielded inconsistent
results to date. For example, preliminary reports that
donor remote ischemic preconditioning reduced DGF
have not been reproduced (8). Provocatively, Niemann
et al. (9) recently targeted mild hypothermia in organ
donors before organ recovery. Organ donors (after
declaration of death per neurologic criteria) from two large
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
donation service areas were randomly assigned to one of
two targeted temperature ranges: 34
C to 35
C (hypother-
mia) or 36.5
C to 37.5
C (normothermia). The study was
terminated early on the recommendation of an independent
data safety monitoring board after the interim analysis
showed efficacy of hypothermia. DGF developed in 79
recipients of kidneys from donors in the hypothermia
group (28%) and 112 recipients of kidneys from donors in
the normothermia group (39%; OR, 0.62; 95% CI, 0.43 to
0.92; P50.02). Feng (10), in an accompanying editorial,
describes some of the barriers that exist in conducting
research in deceased donors while issuing a cry to action:
“The astonishing benefits of therapeutic hypothermia
should inspire governmental regulatory and funding agen-
cies, basic and clinical scientists, and the entire donation
and transplantation communities to vigorously advocate
for innovative research interventions in deceased donors to
improve the quality and increase the quantity of organs
available for transplantation” (10).
Procedure Times
Perhaps intuitively, prolonged ischemia during
procurement, storage, and time to complete the vas-
cular anastomoses has long been thought to impact
DGF risk. Osband et al. (11) studied the extraction time
of 576 kidneys beginning with aortic crossclamp and
perfusion/cooling of the kidneys and ending with re-
moval of the kidneys and placement on ice on the back
table. This cohort was compared with Scientific Reg-
istry of Transplant Recipients (SRTR) data for out-
comes. Extraction time ranged from 14 to 123 minutes,
with a mean of 44.7 minutes. In SRTR-adjusted analy-
ses, longer extraction times and DGF were statistically
associated (OR, 1.19 per 5 minutes beyond 60 minutes;
95% CI, 1.02 to 1.39; P50.03). Up to 60 minutes of
extraction time, DGF incidence was 27.8%; by 120 min-
utes, it doubled to nearly 60%. Primary nonfunction rate
also rose dramatically to nearly 20% by 120 minutes of
extraction time. Heylen et al. investigated the effect of
anastomosis time on allograft outcome in 669 first
single-kidney transplantations from brain-dead donors
(12). Anastomosis time independently increased the
risk of DGF (OR per minute, 1.05; 95% CI, 1.02 to
1.07; P,0.001) and impaired allograft function after
transplantation (P,0.01). In a subgroup of transplant
recipients, protocol-specified biopsies at 3 months,
1 year, and 2 years were blindly reviewed. Prolonged
anastomosis time independently increased the risk of
post-transplant interstitial fibrosis and tubular atrophy
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
of these protocol-specified biopsies (P,0.001). Tennankore
et al. (13) similarly found that ischemia time is associated
with adverse long-term patient and graft survival after
kidney transplantation.
Recipient Factors
The prevalence of obesity is increasing globally and
associates with CKD and premature mortality. However,
the impact of recipient obesity on kidney transplant
outcomes remains unclear. Hill et al. (14) investigated the
association between recipient obesity (defined as body
mass index .30 kg/m2) and mortality, death-censored
graft loss, and DGF after kidney transplantation. A
systematic review and meta-analysis, including 17 studies
with a total of 138,081 patients, were analyzed. After
adjustment, there was no significant difference in mortal-
ity risk in obese recipients (HR, 1.24; 95% CI, 0.90 to
1.70; studies 55; n583,416). However, obesity was
associated with an increased risk of death-censored
graft loss (HR, 1.06; 95% CI, 1.01 to 1.12; studies 55;
n583,416) and an increased likelihood of DGF (OR,
1.68; 95% CI, 1.39 to 2.03; studies 54; n528,847).
Peräsaari et al. (15) examined the association of
donor-specific antibodies (DSAs) with DGF. Patients
with DSAs had a higher incidence of DGF compared
with nonsensitized patients (48% and 26%, respectively;
P,0.001). Third-party antibodies (anti-HLA antibodies
that are not donor specific) had no effect on DGF in-
cidence. The relative risk of DGF for patients with DSAs
in the multivariate analysis was 2.04 (95% CI, 1.25 to 3.34;
P,0.01). Analyses of the cumulative mean fluorescent
intensity (MFI) value of the DSAs revealed a rate of DGF
more than two times higher in patients with cumulative
values of 3000–5000 MFI compared with cumulative
values of 1000–3000 MFI (65% versus 31%; P50.04).
DSAs against any locus were associated with an elevated
DGF incidence of 44%–69% compared with patients
without DSA (27%), independent of rejection. Importantly,
neither the use of antibody induction nor nonuse of such
agents impact risk of DGF in allosensitized patients.
Schold et al. (16), in a cohort of approximately 14,000
kidney retransplant recipients reported to the SRTR,
disclosed DGF rates of approximately 22% for all groups
noted above, except alemtuzumab (27%; P50.04).
Patients with donor specific antibodies be-
fore transplant have twice the incidence of
delayed graft function after transplantation.
295
Delayed Graft Function and Rejection Risk
DGF is commonly considered to be a risk factor
for acute rejection, a biologically plausible association
given upregulation of chemokines, cytokines, and MHC
class II with AKI. However, this association has not
been uniformly observed across all studies. In addition,
the link between DGF and acute rejection may have
changed over time due to advances in immunosuppres-
sion and medical management. Wu et al. (17) conducted
a cohort study of 645 patients over 12 years to evaluate
the association of DGF and biopsy-proven acute re-
jection (BPAR) in a modern cohort of kidney transplant
recipients. The 1-, 3-, and 5-year cumulative probabil-
ities of BPAR were 16.0%, 21.8%, and 22.6% in the
DGF group, significantly different from 10.1%, 12.4%,
and 15.7% in the non-DGF group. In a multivariable
Cox proportional hazards model, the adjusted relative
HR for BPAR in DGF (versus no DGF) was 1.55 (95%
CI, 1.03 to 2.32). This association was generally robust
to different definitions of DGF. The relative HR was also
similarly elevated for T cell– or antibody-mediated
BPAR (HR, 1.52; 95% CI, 0.92 to 2.51 and HR, 1.54;
95% CI, 0.85 to 2.77, respectively). Finally, the associ-
ation was consistent across clinically relevant subgroups.
Thus, DGF remains an important risk factor for BPAR
in a contemporary cohort of kidney transplant recipients.
Interventions to reduce the risk of DGF and/or its after
effects remain of paramount importance to improve
kidney transplant outcomes.
Delayed graft function increases the risk
of allograft rejection by 50% compared
with prompt graft function.
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Crutchfield M, Enestvedt CK, Malinoski DJ: The impact of hydroxy-
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Immunosuppression
Induction Therapy
Rabbit antithymocyte globulin (rATG)–induced
lymphocyte depletion and basiliximab-induced IL-2
receptor blockade (IL2RA) are the induction strategies
in general use within the United States (1). Alemtuzumab
(AZ) use is dwindling due to restricted access by
the manufacturer. Prior randomized trials revealed
that rATG or IL2RA induction reduced early acute
rejection, prompting recommendations by the Kidney
Disease Improving Global Outcomes group that IL2RA
induction be used routinely as first-line therapy after
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
kidney transplantation, with lymphocyte-depleting
induction reserved for high-risk cases. Despite this
recommendation, most United States transplant recip-
ients receive depleting induction therapy (Figure 8). It
has been suggested that the older studies referenced by
Kidney Disease Improving Global Outcomes mainly
used outdated maintenance regimens, and specifically, no
large randomized trial has examined the effect of IL2RA
or rATG induction versus no induction in patients
receiving tacrolimus (TAC), mycophenolic acid (MPA),
and steroids (2). It has been suggested that, with this triple
maintenance therapy, the addition of basiliximab induc-
tion may achieve an absolute risk reduction for acute
rejection of only 1%–4% in standard risk patients without
improving graft or patient survival compared with no
induction. In contrast, rATG induction lowers the relative
risk (RR) of acute rejection by almost 50% versus IL2RA
in patients at higher immunologic risk.
Tanriover et al. (3) evaluated the United Network
for Organ Sharing data of transplant recipients maintained
on TAC/mycophenolate (MPA) from 2000 to 2012 to
compare outcomes of IL2RA and other induction agents.
Acute rejection within the first year and overall graft failure
within 5 years of transplantation were more common with
no induction therapy (13.3%; P,0.001 and 28%; P50.01,
respectively) with steroids and in the IL2RA category
(11.1%; P50.16 and 27.4%; P,0.001, respectively)
without steroids (Figure 8). Compared with IL2RA,
analyses showed that outcomes in the steroid group were
similar among induction categories, except that acute
rejection was significantly lower with rATG (odds ratio
[OR], 0.68; 95% confidence interval [95% CI], 0.62 to
0.74). In the no steroid group compared with IL2RA, the
probabilities of acute rejection with rATG (OR, 0.80; 95%
CI, 0.60 to 1.00) and AZ (OR, 0.68; 95% CI, 0.53 to 0.88)
were lower. rATG was associated with better graft survival
(hazard ratio [HR], 0.86; 95% CI, 0.75 to 0.99). The
authors concluded that, in deceased donor transplantation,
compared with IL2RA induction, no induction was
associated with similar outcomes when TAC/MPA/
steroids were used. However, rATG seems to offer better
graft survival over IL2RA in steroid avoidance proto-
cols. The same authors reached similar conclusions
when studying living donor transplant recipients (4).
Rituximab is a monoclonal antibody that targets
CD20 leading to B cell depletion. It is licensed for
various non-transplant indications and has been stud-
ied off label both as an induction and rescue immu-
notherapeutic. The efficacy and safety of rituximab as
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 297

Figure 8. Allograft rejection rates within the first post transplant year are lowest for those who receive lymphocyte depletion
(rabbit antithymocyte globulin [rATG] or alemtuzumab) compared with interleukin-2 receptor antibody [IL2r Ab] (basiliximab)
induction therapy versus no induction therapy. Observed frequencies of outcomes by induction type with or without steroids at
discharge. Reprinted with permission from Tanriover B, Jaikaransingh V, MacConmara MP, Parekh JR, Levea SL, Ariyamuthu
VK, Zhang S, Gao A, Ayvaci MU, Sandikci B, Rajora N, Ahmed V, Lu CY, Mohan S, Vazquez MA: Acute rejection rates and
graft outcomes according to induction regimen among recipients of kidneys from deceased donors treated with tacrolimus and
mycophenolate. Clin J Am Soc Nephrol 11: 1650–1661, 2016.

induction therapy in renal transplant patients were
evaluated by van den Hoogen et al. (5). In a double-
blind, placebo-controlled study, 280 adult kidney trans-
plant patients were randomized to either a single dose of
rituximab (375 mg/m2) or placebo. Maintenance immu-
nosuppression consisted of TAC, mycophenolate mofetil
(MMF), and steroids. The incidence of rejection was
comparable between rituximab- (23 of 138; 16.7%) and
placebo-treated (30 of 142; 21.2%; P50.25) patients.
Immunologically high-risk patients (panel reactive anti-
body .6% or retransplant) not receiving rituximab had
a significantly higher incidence of rejection (13 of 34;
38.2%) compared with other treatment groups (rituximab-
treated immunologically high-risk patients and rituximab-
or placebo-treated immunologically low-risk [panel
reactive antibody #6% or first transplant] patients:
17.9%, 16.4%, and 15.7%, respectively; P50.004).
Neutropenia (,1.53109/L) occurred more frequently
in rituximab-treated patients (24.3% versus 2.2%;
P,0.001). After 24 months, the cumulative incidence
of infections and malignancies was comparable. The
authors concluded that a single dose of rituximab was
safe as induction therapy but did not reduce the over-
all incidence of biopsy-proven acute rejection, and it
could benefit immunologically high-risk patients. Treat-
ment with rituximab was deemed safe.
AZ is a humanized anti-CD52 mAb that is infre-
quently used as induction therapy due to access restric-
tions imposed by the manufacturer (Bayer, Wayne, NJ).
Serrano et al. (6) reported a retrospective cohort study of
primary kidney transplant recipients receiving induction
with AZ (n55521) or antithymocyte globulin (n58504)
and maintenance immunosuppression as TAC and MMF
with early steroid withdrawal. The transplant eras
were subcategorized. AZ was significantly associ-
ated with inferior death-censored graft survival in the
earliest 2003–2005 era (adjusted hazard ratio [aHR],
2.21; 95% CI, 1.72 to 2.84). However, these findings
were no longer significant more recently. Patient sur-
vival and acute rejection with AZ were comparable
with antithymocyte globulin in the most recent era. The
effect of such findings is moot given the lack of general
298 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017

availability of AZ. However, it may be distributed under
research protocols by the manufacturer with institutional
review board approval.
Maintenance Therapy
Although maintenance immunosuppression man-
agement in kidney transplantation has evolved to
include a diverse repertoire of agents, TAC, mycophe-
nolate, and prednisone continue to represent the most
commonly used therapies (Figure 9) (1).
Despite this, the choice of immunosuppres-
sion regimen varies across transplant programs. Using
a database integrating national transplant registry and
pharmacy fill records, immunosuppression use after
transplant was evaluated for 22,453 patients transplanted
in 249 United States programs between 2005 and 2010
by Axelrod et al. (7). Use of triple immunosuppression
composed of TAC, MPA, or azathioprine (AZA), and
steroids varied widely (0%–100% of patients per pro-
gram), as did use of steroid-sparing regimens (0%–
77%), sirolimus-based regimens (0%–100%), and
cyclosporine-based regimens (0%–78%) (Figure 10).
Use of triple therapy was more common in highly
sensitized patients, women, and recipients with dialysis
duration .5 years. TAC has largely replaced cyclo-
sporine due to improved efficacy in preventing re-
jection, although registry data indicate that patient and
graft survival rates are equivalent when a calcineurin
inhibitor (CNI) is utilized. Sirolimus use has decreased
substantially with time. Patient and donor character-
istics explained only a limited amount of the observed
variation in regimen use, whereas center choice explained
30%–46% of the use of nontriple-therapy immunosup-
pression. The authors suggest that substantial variation in
center practice exists beyond that explained by differ-
ences in patient and donor characteristics.
Regardless of regimen, medication nonadherence
increases the risk for kidney transplant loss after trans-
plantation. Reese et al. (8) studied the utility of elec-
tronic reminders to enhance adherence in real time
using wireless-enabled pill bottles. Mean participant
age was 50 years old; 60% were men, and 40% were
black. Mean adherence rates were 78%, 88%, and 55%
in groups with reminders, reminders plus notification,
or neither (control), respectively (P,0.001 for com-
parison of each intervention with control). Interest-
ingly, mean TAC levels were not significantly different
between groups.
Tacrolimus
Long-term transplant outcomes are clearly limited,
at least in part, by adverse effects of immunosuppressive
therapies, which have led to the search for minimization
or withdrawal strategies. Many have been reported, and
although some result in improved renal function, this is
often at increased risk of rejection (9). Dugast et al. (10)
conducted a prospective, randomized, multicenter, double-
blind, placebo-controlled clinical study to analyze the

Figure 9. Immunosuppression in adult kidney transplant recipients. First post transplant year immunosuppression trends in US
transplant recipients reveals in (A) most patients receive lymphocyte depleting induction therapy (rATG or alemtuzumab), (B)
Tacrolimus has almost completely replaced cyclosporine as the calcineurin inhibitor of choice, (C) Mycophenolate has almost
completely replaced Azathioprine as the antimetabolite of choice, (D) the use of mTOR inhibitors was never widespread and has
dwindled to almost zero, and in (E) most patients continue to receive corticosteroids. One-year post-transplant data are limited to
patients alive with graft function at 1 year post-transplant. Mycophenolate includes MMF and mycophenolate sodium. Reprinted
with permission from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Boyle G, Snyder JJ,
Kasiske BL, Israni AK: Kidney. Am J Transplant 16[Suppl 2]: 11–46, 2016.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 299

Figure 10. While most patients continue to receive the combination of tacrolimus (Tac)/mycophenolate mofetil (MMF)/
Prednisone, a degree of intercenter and regional variability exists regarding the specific alternate combinations that are in use.
The graphic represents the proportion of patients who receive one of six mutually exclusive immunosuppression (ISx) regimens
during months 6–12 after transplant. Each horizontal bar represents an individual center within United States regions ordered by
the proportion of patients who received triple ISx (TAC 1 mycophenolic acid (MPA)/azathioprine (AZA) 1 prednisone [Pred];
orange). Overall percentages of regimen use at patient level across centers: TAC 1 MPA/AZA 1 Pred, 33.8%; TAC 1 MPA/AZA
(no Pred), 25.8%; TAC without MPA/AZA, 11.3%; sirolimus (SRL) based, 9.9%; cyclosporine (CSA) based, 7.8%; and other
regimens (including CSA withdrawal or other trial medications), 11.6%. Proportion of patients receiving one of six mutually
300 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017

impact of TAC withdrawal on patients .4 years post-
transplantation with baseline normal histology, stable
graft function, and no anti-HLA immunization. Only
ten of 52 eligible patients were randomized. Five patients
were assigned to the placebo arm, and five were assigned
to the TAC maintenance arm. In the TAC maintenance
arm, all patients maintained stable graft function, and
no immunologic events occurred. By contrast, all five
patients in the placebo arm had to reintroduce TAC,
because three presented with an acute rejection episode
(one humoral, one mixed, and one borderline) and two
showed anti-HLA antibodies without histologic lesion
(one with donor-specific antibodies [DSAs] and one
non-DSA). The authors concluded that TAC withdrawal
must be avoided long-term, even in highly selected stable
kidney recipients. Another nail in the TAC elimination
coffin was provided by Hricik et al. (11), who reported
the results of the Clinical Trials in Organ Transplantation-
09 Trial. This was a randomized, prospective study of
nonsensitized primary recipients of living donor kid-
ney transplants. Subjects received rATG, TAC, MMF,
and prednisone. Six months post-transplantation, subjects
without de novo DSAs, acute rejection, or inflammation
at protocol biopsy were randomized to wean off or remain
on TAC. The study was terminated prematurely because
of unacceptable rates of acute rejection (four of 14) and/or
de novo DSAs (five of 14) in the TAC withdrawal arm.
Gatault et al. (12) took a different approach and
sought to determine the efficacy and safety of two dif-
ferent doses of extended release tacrolimus (LCPT) in
steroid-free kidney transplant recipients. More rejection
episodes occurred in the lower target TAC–level group
(50% dose reduction at 6 months with target level
.3 ng/ml; group A) than the higher target-level group
B (continued full-dose therapy with target level of 7–
12 ng/ml; 11 versus three; P50.02): subclinical in-
flammation (21.4% versus 8.8%; P50.05) and DSAs
(six versus zero patients; P,0.01). The authors concluded
that TAC levels should be maintained .7 mg/L during the
first year after transplantation in low-immunologic risk,
steroid-free kidney transplant recipients receiving a moder-
ate dose of MPA.
Tacrolimus remains the single most effec-
tive immunosuppressive agent available to
prevent acute allograft rejection. Prospec-
tive elimination studies in low risk kidney
allograft recipients have yielded unaccept-
able results. Maintenance of therapeutic
levels remains of critical importance for all
transplant recipients.
Pharmacokinetics
TAC blood-level variability associates with in-
ferior graft survival (13). TAC trough blood concen-
trations for black kidney allograft recipients are lower
than those observed in white patients. This finding can
be associated with increased rejection and graft failure
risks (14). Oetting et al. (14) identified two CYP3A5
variants uniquely found in black recipients that in-
dependently associated with TAC troughs: CYP3A5*6
(rs10264272) and CYP3A5*7 (rs41303343). These
variants and various clinical factors accounted for
53.9% of the observed variance in trough levels, with
19.8% of the variance originating from demographic
and clinical factors (14). It has been suggested that
pretransplantation adaptation of the daily dose of TAC
to cytochrome genotype may be associated with im-
proved achievement of target trough levels. CYP3A4*22
is an allelic variant of the cytochrome P450 3A4 that
associates with decreased enzymatic degradatory activ-
ity, leading to reduced dosing. Pallet et al. (15) tested this
concept in a population of 186 kidney transplants, of
whom 9.3% (18 patients) were heterozygous for the
CYP3A4*22 genotype and none were homozygous (allele
frequency, 4.8%). Ten days after transplantation, 11% of
the CYP3A4*22 carriers were within the target range,
whereas among the CYP3A4*1/*1 carriers, 40% were

exclusive immunosuppression (ISx) regimens during months 6–12 after transplant. Each horizontal bar represents an individual
center within United States regions ordered by the proportion of patients who received triple ISx (TAC 1 MPA/AZA 1
prednisone [Pred]; orange). Overall percentages of regimen use at patient level across centers: TAC 1 MPA/AZA 1 Pred,
33.8%; TAC 1 MPA/AZA (no Pred), 25.8%; TAC without MPA/AZA, 11.3%; SRL based, 9.9%; cyclosporine (CSA) based,
7.8%; and other regimens (including CSA withdrawal or other trial medications), 11.6%. Reprinted with permission from
Axelrod DA, Naik AS, Schnitzler MA, Segev DL, Dharnidharka VR, Brennan DC, Bae S, Chen J, Massie A, Lentine KL:
National variation in use of immunosuppression for kidney transplantation: A call for evidence-based regimen selection. Am J
Transplant 16: 2453–2462, 2016.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
within the target range (P50.02). The authors concluded
that the CYP3A4*22 allelic variant is associated with
a significantly altered TAC metabolism, and carriers of
this polymorphism often reach supratherapeutic concen-
trations. The same group evaluated the long-term clinical
impact of the adaptation of initial TAC dosing according
to the cytochrome genotype (16). The outcomes of 236
kidney transplant recipients included in the Tactique Study
were retrospectively investigated over a period of 5 years.
These patients were randomly assigned to receive TAC at
either a fixed dosage or one determined by genotype. The
incidence rates of biopsy-proven acute rejection and graft
survival were similar between the control and the adapted
TAC dose groups. Patient deaths, cancer, cardiovascular
events, and infections were also similar, and renal function
did not change. The authors concluded that optimization
of initial TAC dose using pharmacogenetic testing did not
improve clinical outcomes. Shuker et al. (17) similarly
studied 244 living donor kidney transplant recipients.
They concluded that pharmacogenetic adaptation of the
TAC starting dose did not increase the number of patients
having therapeutic TAC exposure early after transplanta-
tion and did not lead to improved clinical outcome in
a low-immunologic risk population.
Pharmacogenetic testing is not associated
with improved outcomes after kidney
transplantation.
Extended Release Tacrolimus
The safety and efficacy of LCPT (Envarsus XR;
Veloxis Pharmaceuticals, Edison, NJ) compared with
immediate release tacrolimus (IR-Tac) twice daily after
kidney transplantation were studied by Rostaing et al.
(18). This group carried out a 2-year, double-blind,
multicenter, noninferiority design, phase 3 trial involving
543 de novo kidney recipients. Patients were randomly
assigned to LCPT (n5268) or IR-Tac (n5275), and 507
(93.4%) completed the 24-month study. LCPT tablets
were administered at 0.17 mg/kg daily, and IR-Tac was
administered twice daily at 0.1 mg/kg per day to maintain
target trough ranges (first 30 days, 6–11 ng/ml; thereafter,
4–11 ng/ml). There were no differences in efficacy failure
or adverse effects between groups, including tremor and
new-onset diabetes mellitus. Similar reports were pre-
viously reviewed in the Nephrology Self-Assessment
301
Program (NephSAP) transplantation issue regarding
other LCPT preparations.
Antimetabolite Therapy
Mycophenolate (either MMF or enteric-coated
MPA/mycophenolate) has largely supplanted AZA as a
first-line agent in primary immunosuppression. Wagner
et al. (19) performed a Cochrane review of randomized,
controlled trials to evaluate the benefits and risks of
MPA versus AZA as primary immunotherapy after
kidney transplantation. Data from 23 studies involving
3301 participants were included. MMF reduced the risk
for graft loss, including death (RR, 0.82; 95% CI, 0.67
to 1.0), and death-censored graft loss (RR, 0.78; 95%
CI, 0.62 to 0.99; P,0.05). No statistically significant
difference for MMF versus AZA treatment was found
for all-cause mortality (16 studies, 2987 participants:
RR, 0.95; 95% CI, 0.70 to 1.29). The risks for any acute
rejection (22 studies, 3301 participants: RR, 0.65; 95%
CI, 0.57 to 0.73; P,0.01), biopsy-proven acute re-
jection (12 studies, 2696 participants: RR, 0.59; 95%
CI, 0.52 to 0.68), and antibody-treated acute rejection
(15 studies, 2914 participants: RR, 0.48; 95% CI, 0.36
to 0.65; P,0.01) were reduced in MMF-treated patients.
Metaregression analysis suggested that the magnitude of
risk reduction of acute rejection may be dependent on
the control rejection rate (relative risk reduction [RRR],
0.34; 95% CI, 0.10 to 1.09; P50.08), AZA dose (RRR,
1.01; 95% CI, 1.00 to 1.01; P50.10), and use of
cyclosporine A microemulsion (RRR, 1.27; 95% CI,
0.98 to 1.65; P50.07). Pooled analyses failed to show
a significant and meaningful difference between MMF
and AZA in kidney function measures. The risk for
cytomegalovirus (CMV) viremia in 13 studies with 2880
participants was not statistically significantly different
between MMF- and AZA-treated patients (RR, 1.06;
95% CI, 0.85 to 1.32). The likelihood of tissue-invasive
CMV disease was greater with MMF therapy in seven
studies with 1510 participants (RR, 1.70; 95% CI, 1.10
to 2.61). Adverse event profiles varied. Gastrointestinal
symptoms were more likely in MMF-treated patients.
Thrombocytopenia and elevated liver enzymes were
more common during AZA therapy.
Adverse MMF-related effects often prompt dose
reduction or discontinuation, which can lead to rejection
and possibly, graft loss. McAdams-DeMarco et al. (20)
reported on risk factors for MMF dose reduction. Frailty
measures assessed included sarcopenia, weakness, ex-
haustion, low physical activity, and slowed walking
302
speed along with other patient and donor characteristics,
including longitudinal MMF doses, and graft loss in 525
kidney transplantation recipients. Frail recipients were
1.29 times (95% CI, 1.01 to 1.66; P50.04) more likely
to experience MMF dose reduction, as were deceased
donor recipients (aHR, 1.92; 95% CI, 1.44 to 2.54;
P,0.001) and older adults (age $65 versus ,65 years
old: aHR, 1.47; 95% CI, 1.10 to 1.96; P50.01). Impor-
tantly, MMF dose reduction was independently associated
with a substantially increased risk of death-censored graft
loss (aHR, 5.24; 95% CI, 1.97 to 13.98; P50.001).
MMF dose reduction after kidney trans-
plantation occurs more frequently in older
and frailer individuals and deceased donor
allograft recipients. MMF dose reduction
significantly associates with increased risk
of graft loss.
Belatacept
Belatacept is a cytotoxic T lymphocyte–associated
antigen-4 fusion protein that inhibits costimulation
that was Food and Drug Administration–approved for
prevention of kidney allograft rejection in 2011 on the
basis of the Belatacept Evaluation of Nephroprotection
and Efficacy as First-Line Immunosuppression Trial
and the Belatacept Evaluation of Nephroprotection and
Efficacy as First-Line Immunosuppression Trial Ex-
tended Criteria Donors Trial previously discussed in prior
NephSAP transplantation issues. The impact of belatacept in
a real clinical setting has been recently reported. Wen et al.
(21) performed a retrospective cohort study using registry
data comparing clinical outcomes between belatacept-
and TAC-treated adult kidney transplant recipients from
January 6, 2011 to January 12, 2014. Of 50,244 total
participants, 417 received belatacept plus TAC, 458 re-
ceived belatacept alone, and 49,369 received TAC alone at
discharge. Belatacept alone was associated with a higher
risk of 1-year acute rejection, with the highest rates as-
sociated with nonlymphocyte-depleting induction (aHR,
2.65; 95% CI, 1.90 to 3.70; P,0.001). There were no
significant differences in rejection rates between belatacept
plus TAC and TAC alone. In expanded criteria donor
allograft recipients, 1-year kidney function was higher with
belatacept plus TAC and belatacept alone versus TAC
alone (mean eGFRs 565.6, 60.4, and 54.3 ml/min per
1.73 m2, respectively; P,0.001). The incidence of new-
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
onset diabetes after transplantation was significantly
lower with belatacept plus TAC and belatacept alone
versus TAC alone (1.7%, 2.2%, and 3.8%, respectively;
P50.01). The authors suggested the addition of short-term
TAC in the first year after transplant and lymphocyte-
depleting induction may be advisable when using
belatacept. Similarly, Cohen et al. (22) performed a co-
hort study of adult kidney transplant recipients trans-
planted between May 1, 2001 and December 31, 2015
using national transplant registry data to compare patient
and allograft survival in patients discharged on belatacept
versus TAC-based regimens. They found that belatacept
was not associated with a significant difference in risk of
patient death (HR, 0.84; 95% CI, 0.61 to 1.15; P50.28)
or allograft loss (HR, 0.83; 95% CI, 0.62 to 1.11;
P50.20), despite an increased risk of acute rejection
in the first year post-transplant (OR, 3.12; 95% CI, 2.13
to 4.57; P,0.001). These findings were confirmed in
additional sensitivity analyses that accounted for use of
belatacept in combination with TAC, transplant center
effects, and differing approaches to matching.
Because of the increased incidence of rejection
seen with belatacept compared with CNI therapy, Xu
et al. (23) combined belatacept with AZ and rapamycin.
Compared with conventional immunosuppression,
lymphocyte depletion evoked substantial homeostatic
lymphocyte activation balanced by regulatory T and B
cell phenotypes. The reconstituted T cell repertoire was
enriched for CD281 naı̈ve cells, notably diminished in
belatacept-resistant CD282 memory subsets, and depleted
of polyfunctional donor-specific T cells. Importantly,
the latter cells could respond to third party and latent
herpes viruses. B cell responses were similarly favor-
able without alloantibody development and a reduction
in memory subsets, changes not seen in conventionally
treated patients. The combined belatacept with AZ and
rapamycin regimen uniquely altered the immune pro-
file, producing a repertoire enriched for CD281 T cells,
hyporesponsive to donor alloantigen, and competent in
its protective immune capabilities. The resulting repertoire
was permissive for control of rejection with belatacept
monotherapy. The broader applicability of such an ap-
proach remains to be determined.
Steroid Therapy
Haller et al. (24) performed a Cochrane review to
evaluate the benefits and harms of steroid withdrawal or
avoidance for kidney transplant recipients. Forty-eight
studies (224 reports) that involved 7803 randomized
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
participants were included. These studies evaluated
three different comparisons: steroid avoidance or with-
drawal compared with steroid maintenance and steroid
avoidance compared with steroid withdrawal. For adult
studies, there was no significant difference in patient
mortality in either studies comparing steroid withdrawal
with steroid maintenance (ten studies, 1913 participants,
death at 1 year post-transplantation: RR, 0.68; 95% CI,
0.36 to 1.30) or studies comparing steroid avoidance with
steroid maintenance (ten studies, 1462 participants, death
at 1 year post-transplantation: RR, 0.96; 95% CI, 0.52 to
1.80). Similarly, no significant difference in graft loss was
found comparing steroid withdrawal with steroid main-
tenance (eight studies, 1817 participants) or graft loss
(excluding death with functioning graft at 1 year after
transplantation: RR, 1.17; 95% CI, 0.72 to 1.92) and
comparing steroid avoidance with steroid maintenance
(seven studies, 1211 participants, graft loss excluding
death with functioning graft at 1 year after transplantation:
RR, 1.09; 95% CI, 0.64 to 1.86). The risk of acute
rejection significantly increased in patients treated with
steroids for ,14 days post-transplantation (seven studies,
835 participants: RR, 1.58; 95% CI, 1.08 to 2.30) and pa-
tients withdrawn from steroids later post-transplantation
(ten studies, 1913 participants; RR, 1.77; 95% CI, 1.20 to
2.61). There was no evidence to suggest a difference in
harmful events, such as infection and malignancy, in adult
kidney transplant recipients. The effect of steroid with-
drawal in children is unclear. The authors concluded that
steroid avoidance and withdrawal after kidney transplan-
tation significantly increase the risk of acute rejection.
Steroid avoidance and withdrawal after kid-
ney transplantation significantly increase the
risk of acute rejection.
Mammalian Target of Rapamycin Inhibitor
Therapy
The use of mammalian target of rapamycin in-
hibitor (mTORi) therapy, sirolimus and everolimus,
continues to decline due to inferior outcomes compared
with conventional immunotherapy. In parallel, new
reports of the use of such therapy are dwindling. One
of the potential complications of mTORi therapy is
proteinuria from nephrin inhibition that associates with
FSGS. Mandelbrot et al. (25) reported on a prospective,
303
randomized, double-blind, placebo-controlled study pro-
tocol that evaluated the impact of ramipril on urinary
protein excretion in renal transplant patients converted to
sirolimus from CNI treatment. Patients received ramipril
or placebo for up to 6 weeks before conversion and 52
weeks afterward. Doses were increased if patients de-
veloped proteinuria (urine protein-to-creatinine ratio
$0.5); losartan was given as rescue therapy for persis-
tent proteinuria. The primary end point was time to
losartan initiation. Of 295 patients randomized, 264 met
the criteria for sirolimus conversion (ramipril, n5138;
placebo, n5126). At 52 weeks, the cumulative rate of
losartan initiation was significantly lower with ramipril
(6.2%) versus placebo (23.2%; P,0.001). No signifi-
cant differences were observed between ramipril and
placebo for change in GFR or rejection. Treatment-
emergent adverse events were consistent with the known
safety profile of sirolimus and were not potentiated by
ramipril coadministration. Ramipril was deemed effec-
tive in reducing the incidence of proteinuria for up to 1
year after conversion to sirolimus in maintenance renal
transplant patients.
Sirolimus has antineoplastic properties compared
with CNI therapy. Yanik et al. (26) investigated
sirolimus effects on cancer incidence among kidney
recipients. Overall, the incidence was not significantly
lowered by sirolimus use (HR, 0.88; 95% CI, 0.70 to
1.11). However, the frequency of prostate cancer was
greater during sirolimus use (HR, 1.86; 95% CI, 1.15 to
3.02). Incidence of other cancers was similar or lower
with sirolimus use, with a 26% decrease overall (HR,
0.74; 95% CI, 0.57 to 0.96; excluding prostate cancer).
Results were similar after adjustment for demographic
and clinical characteristics. Despite such properties, mor-
tality rates for patients with cancer treated with mTORi are
higher than for similar patients maintained on CNI therapy
as discussed in a prior transplantation NephSAP.
There are occasional reports of the utility of
everolimus in combination with cyclosporine. Oh et al.
(27) performed an open label study to compare the
efficacy and tolerability of everolimus and reduced
exposure to cyclosporine (investigational group) with
enteric-coated mycophenolate sodium and standard ex-
posure cyclosporine (control group) in combination
with basiliximab and steroids. Rejection rates were
similar between groups (7.5% [investigational group]
versus 11.1% [control group]; P50.57). The mean
eGFRs of the investigational group at 12 months after
transplantation were significantly higher (68.1616.8
304
ml/min per 1.73 m2) than those of the control group
(60.6615.8 ml/min per 1.73 m2; P50.02). There were
no significant differences (P.0.05) in the frequency of
discontinuations or serious adverse events between
groups.
Tedesco-Silva et al. (28) studied the incidence of
CMV infection/disease in de novo kidney transplant
recipients receiving everolimus or mycophenolate with
no CMV pharmacologic prophylaxis. Patients were
randomized to receive rATG/TAC/everolimus/prednisone
(group 1), basiliximab/TAC/everolimus/prednisone (group
2), or basiliximab/TAC/mycophenolate/prednisone (group
3). Patients in group 1 had a 90% proportional reduction in
the incidence of CMV infection (4.7% versus 37.6%; HR,
0.10; 95% CI, 0.04 to 0.29; P,0.001). Group 2 had a 75%
proportional reduction in frequency of CMV infection/
disease compared with the control group (10.8% versus
37.6%; HR, 0.25; 95% CI, 0.13 to 0.48; P,0.001). No
differences were observed in the frequencies of acute re-
jection, wound-healing complications, delayed graft func-
tion, or proteinuria.
The salutary effect of mTORi therapy on GFR com-
pared with CNI therapy has been well described. Rostaing
et al. (29) provide a cautionary note. They report the results
of a randomized, open label, 12-month trial, in which
de novo kidney transplant patients received cyclosporine,
enteric-coated mycophenolate sodium, and steroids. Pa-
tients were stratified by an epithelial-mesenchymal transi-
tion profile based on their month 3 biopsies and then
randomized to start everolimus with half-dose enteric-
coated mycophenolate sodium (EC1; 720 mg/d) and
cyclosporine withdrawal (CNI2) or continue cyclospor-
ine with standard enteric-coated mycophenolate sodium
(CNI). The primary end point was progression of graft
fibrosis that developed in 46.2% (12 of 26) of CNI2/EC1
patients versus 51.6% (16 of 31) of CNI/EC1 patients
(P50.68). Biopsy-proven acute rejection and subclinical
events occurred in 25.0% and 5.1% of CNI2 and CNI
patients, respectively (P,0.001). The authors concluded
that early CNI withdrawal with everolimus initiation does
not prevent interstitial fibrosis.
The use of the mTOR inhibitors, sirolimus
and everolimus, continues to decline due
to unfavorable efficacy, adverse event and
outcome measures compared with calci-
neurin inhibition.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
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306 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017

Table 1. Updated Banff classification categories

Updated Banff Classification Categories
Category 1: Normal biopsy or nonspecific changes
Category 2: Antibody-mediated changes
Acute/active ABMR: Three features required
Histologic evidence of acute tissue injury (inflammation, TMA, ATN)
Linear C4d staining
Serologic evidence of DSA
Chronic active ABMR: Three features required
Histologic evidence of chronic tissue injury (interstitial fibrosis and tubular atrophy/TG, arterial sclerosis)
Linear C4d staining
Serologic evidence of DSA
C4d staining without evidence of rejection
Category 3: Borderline changes
Category 4: TCMR
Acute TCMR: Grades
IA. Significant interstitial inflammation (.25% of nonsclerotic cortical parenchyma, i2 or i3) and foci of moderate
tubulitis (t2)
IB. Significant interstitial inflammation (.25% of nonsclerotic cortical parenchyma, i2 or i3) and foci of severe
tubulitis (t3)
IIA. Mild to moderate intimal arteritis
IIB. Severe intimal arteritis
III. Transmural arteritis
Chronic TCMR
Chronic allograft arteriopathy
Category 5: Interstitial fibrosis and tubular atrophy
Grades
I. Mild interstitial fibrosis and tubular atrophy (#25% of cortical area)
II. Moderate interstitial fibrosis and tubular atrophy (26%–50% of cortical area)
III. Severe interstitial fibrosis and tubular atrophy (.50% of cortical area)
Category 6: Other changes not considered to be rejection
BK virus nephropathy
Post-transplant lymphoproliferative disorders
Calcineurin inhibitor nephrotoxicity
Acute tubular injury
Recurrent disease
De novo glomerulopathy (other than transplant glomerulopathy)
Pyelonephritis
Drug-induced interstitial nephritis
ABMR, antibody mediated rejection; TMA, thrombotic microangiopathy; ATN, acute tubular necrosis; TG, transplant glomerulopathy; i2 and i3, scores that represent increasing
degrees of inflammatory cell infiltrate in the interstitium; t2 and t3, scores that represent increasing degrees of inflammatory cell infiltrate in the tubules. Modified from Loupy
A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, Dragun D, de
Kort H, Gibson IW, Kraus ES, Lefaucheur C, Legendre C, Liapis H, Muthukumar T, Nickeleit V, Orandi B, Park W, Rabant M, Randhawa P, Reed EF, Roufosse C, Seshan SV, Sis B,
Singh HK, Schinstock C, Tambur A, Zeevi A, Mengel M: The Banff 2015 Kidney Meeting Report: Current challenges in rejection classification and prospects for adopting
molecular pathology. Am J Transplant 17: 28–41, 2017.

T cell–mediated rejection (TCMR) or chronic AMR. A
mixed pattern of TCMR and AMR was increasingly
recognized. The current iteration of the classification
system follows (Table 1).
Although the Banff consortium initially convened
to standardize renal histology definitions for research,
the classification is now broadly clinically utilized. To
evaluate adherence with the system, Becker et al. (3)
conducted a worldwide survey among members of
the Renal Pathology Society. A web-based survey
was sent out to all 503 current members with 153
responses. Among the 139 nephropathologists using
the borderline category, 67% use the Banff 1997
definition. Thirty-seven percent admitted to some-
times exaggerating Banff in the presence of tubulitis
to reach a diagnosis of borderline. Forty-eight percent
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
were dissatisfied with the definition of borderline.
Most of the influential manuscripts used the 1997
definition, contrary to the current one. The authors
concluded that there is considerable dissatisfaction
with the borderline category and that practice is
variable. It is unclear whether the more recent update
described above addresses these issues. Halloran et al.
(4) used microarray-derived molecular AMR scores as
a histology-independent estimate of AMR in 703
biopsies to re-evaluate AMR criteria and determine
the relative importance of various lesions. They con-
firmed that the important features for AMR diagnosis
were peritubular capillaritis (PTC), glomerulitis, glo-
merular double contours, DSA, and C4d staining. The
group questioned some features, including arterial fibro-
sis, vasculitis, and acute tubular injury.
The incidence of acute renal allograft re-
jection declined from 10% in 2009 and
2010 to 7.9% in 2013 and 2014.
Temporal Dynamics
Halloran et al. (5) used microarrays and conven-
tional methods to study rejection in 703 unselected
biopsies taken between 3 days and 35 years post-
transplant. Rejection was conventionally diagnosed in
205 biopsy specimens (28%): 67 pure TCMR, 110 pure
AMR, and 28 mixed (89 designated borderline). Using
microarrays, rejection was diagnosed in 228 biopsy
specimens (32%): 76 pure TCMR, 124 pure AMR, and
28 mixed. Molecular assessment confirmed most con-
ventional diagnoses (agreement was 90% for TCMR
and 83% for AMR), but it revealed some variation,
particularly in mixed rejection, and improved predic-
tion of graft failure. AMR was strongly associated with
increased graft loss, but TCMR was not. AMR became
common in biopsy specimens obtained .1 year post-
transplant and continued to appear in all subsequent
intervals. TCMR was common early but progressively
disappeared over time. Provocatively, TCMR defined
by molecular and conventional features was never
observed after 10 years in this cohort.
Transfusion
The purported benefits of blood transfusion pre-
transplantation (the so-called transfusion effect) have
long been overshadowed by the risk of allosensitization,
307
with adverse impact on both access to transplantation
and outcomes; thus, the current practice is transfusion
avoidance for transplants candidates. However, little is
known about the impact of post-transplant blood trans-
fusion on the sensitization of anti-HLA antibodies and
the formation of DSAs. Ferrandiz et al. (6) determined
the 1-year incidence of DSAs and AMR in kidney
transplant patients who had or had not received a blood
transfusion during the first year post-transplantation.
There were 390 non–HLA-sensitized patients who had
received an ABO-compatible kidney transplant and had
not previously or simultaneously received a nonrenal
organ transplant. A surprisingly high proportion of
patients, 64%, received a red blood cell transfusion
within the first year after transplantation, most within
the first month. Importantly, the overall 1-year in-
cidence of DSAs was significantly higher in patients
who had undergone transfusion (7.2% versus 0.7% in
patients with no transfusion; P,0.001). More impor-
tantly, AMR also occurred more often in the transfusion
group (n515; 6%) compared with the nontransfusion
group (n52; 1.4%; P50.04). Blood transfusion was an
independent predictive factor for de novo donor-specific
antibody (dnDSA) formation but not for AMR. Patients
who had a transfusion and developed DSAs were more
often treated with cyclosporine (n510; 55.5%) rather
than tacrolimus (n545; 19.4%; P,0.001). The authors
concluded that post-transplant blood transfusion may
increase immunologic risk, especially in underimmuno-
suppressed patients. Although this finding is indeed
cautionary, the generalizability of the observation is less
clear, because most transplant recipients are treated with
tacrolimus and are not transfused.
Transfusion post-transplantation may be
associated with new-onset donor specific
antibodies and increased risk of antibody-
mediated rejection.
Novel Rejection Mediators
Allocation algorithms for deceased donor kidney
transplantation often incorporate HLA mismatches at
the HLA A, B8, and DR loci but not HLA mismatches
at other loci, including HLA-DQ. Lim et al. (7) studied
the impact of HLA-DQ mismatches on renal allograft
outcomes. Seven hundred eighty-eight recipients who
308
received zero, one, or two HLA-DQ mismatched
kidneys were followed for a median of 2.8 years.
Compared with no HLA-DQ mismatched allograft
recipients, those who had received one or two HLA-
DQ mismatched kidneys experienced more rejection
(50 of 321 [15.6%] versus 117 of 467 [25%]; P,0.01),
late rejections (occurring .6 months post-transplant;
eight of 321 [2.4%] versus 27 of 467 [5.8%]; P50.03),
and AMRs (12 of 321 [3.7%] versus 38 of 467 [8.1%];
P50.01). Compared with recipients of zero HLA-DQ
mismatched kidneys, the adjusted hazard ratios [HRs]
for any and late rejections in recipients who had
received one or two HLA-DQ mismatched kidneys
were 1.54 (95% confidence interval [95% CI], 1.08 to
2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively.
Bachelet et al. (8) similarly reported that preformed
anti–HLA-Cw and anti–HLA-DP DSAs are as delete-
rious as anti–HLA-A/B/DR/DQ DSAs.
Jackson et al. (9) suggested a pathogenic role for
non-HLA antiendothelial cell antibodies (AECAs) in
allograft rejection. High-density protein arrays that
identified AECA target antigens were developed, and
four antigenic targets expressed on endothelial cells
were identified: endoglin; fms-like tyrosine kinase-3
ligand; EGF-like repeats, discoidin I-like domains 3; and
intercellular adhesion molecule 4. These AECAs were
detected in 24% of pretransplant sera by ELISA, and they
were associated with post-transplant donor-specific HLA
antibodies, AMR, and early transplant glomerulopathy.
The role of the lectin pathway of complement acti-
vation and its recognition molecules in acute rejection
and outcome after transplantation was studied by
Golshayan et al. (10). Polymorphisms and serum levels
of lectin pathway components in 710 consecutive
kidney transplant recipients together with all biopsy-
proven rejection episodes and 1-year outcomes were
studied. Low mannose binding lectin levels were
associated with a higher incidence of acute cellular
rejection during the first year, especially in recipients
of deceased donor kidneys. This association remained
significant (HR, 1.75; 95% CI, 1.18 to 2.60) in a Cox
regression model after adjustment for relevant cova-
riates. In contrast, there were no significant associa-
tions with rates of AMR, patient death, early graft
dysfunction, or loss. Such studies underscore the
multiplicity of molecules, pathways, and potential
biomarkers that continue to be elucidated. However,
these scientific observations have not yet achieved
clinical applicability.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Adherence
Nonadherence and HLA mismatch have been
independently associated with poorer long-term outcomes
post-transplantation. Wiebe et al. (11) prospectively cor-
related HLA mismatching with medication adherence
measurement via electronic monitors in medication vial
caps. Recipients were grouped by medication adherence
and high- or low-epitope mismatch load. They found that
the combination of higher epitope mismatch and poor
adherence acted synergistically to determine the risk of
rejection or graft loss. For example, nonadherent recipients
with an HLA-DR epitope mismatch experienced increased
graft loss (35% versus 8%; P,0.01) compared with
adherent recipients with low epitope mismatch.
Nonadherent patients are at increased risk
for rejection as HLA mismatches increase.
Gene Activation
Acute kidney rejection is a major risk factor for
chronic allograft dysfunction and long-term graft failure.
Ghisdal et al. (12) performed a genome-wide study to
detect loci associated with acute, biopsy-proven TCMR
occurring within the first year after kidney transplanta-
tion. In a discovery cohort of 4127 European renal
allograft recipients, Ghisdal et al. (12) utilized a DNA
pooling approach that reduced the cost of large-scale
association studies to compare an initial cohort of cases
and controls before utilizing an independent replication
cohort of 2765 allograft recipients. Two loci were
consistently and significantly associated with acute re-
jection in univariate and multivariate analyses. One locus
encompassed protein tyrosine phosphatase, receptor type
O, which encodes a receptor-type tyrosine kinase essential
for B cell receptor signaling. The other locus involved
a ciliary gene coiled-coil domain containing 67. The clinical
implications of these findings remain to be determined
Subclinical Rejection
The use of protocol biopsies is generally restricted
to patients undergoing experimental immunosuppressive
protocols, because the incidence of subclinical rejection
in patients treated with tacrolimus, mycophenolate mofetil,
and steroids is extremely low as discussed in a previous
Nephrology Self-Assessment Program transplantation
issue. That said, the impact of subclinical rejection in
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
patients taking lower-intensity immunotherapy has re-
mained unclear. Loupy et al. (13) studied whether early
recognition of subclinical rejection impacted long-term
consequences for kidney allograft survival. Participants
underwent prospective screening biopsies at 1 year post-
transplant, with concurrent evaluations of graft comple-
ment deposition and circulating anti-HLA antibodies.
Three distinct groups of patients were identified at the
1-year screening: 727 (73%) patients without rejec-
tion, 132 (13%) patients with subclinical TCMR, and
142 (14%) patients with subclinical AMR. Patients
with subclinical AMR had the poorest graft survival
8 years post-transplant (56%) compared with subclin-
ical TCMR (88%) and nonrejection (90%) groups
(P,0.001). In a multivariate Cox model, subclinical
AMR at 1 year was independently associated with a 3.5-
fold increase in graft loss (95% CI, 2.1 to 5.7) along
with eGFR and proteinuria (P,0.001). Subclinical
AMR was associated with more rapid progression to
transplant glomerulopathy. Of patients with subclinical
TCMR at 1 year, only those who subsequently devel-
oped dnDSAs and transplant glomerulopathy had a
greater risk of graft loss compared with patients without
rejection.
Antibody-Mediated Rejection
Schinstock et al. (14) retrospectively studied adult
conventional solitary kidney transplant recipients to
define histologic features associated with new-onset
dnDSA (defined by mean fluorescent intensity [MFI]
.1000). The incidence of dnDSA was 7.0% (54 of
771) over a mean follow-up of 4.261.9 years. Patients
with dnDSA had reduced death-censored allograft
survival (87.0% versus 97.0% no dnDSA; P,0.01).
AMR was present in 25.0% and 52.9% of patients at
dnDSA detection and 1 year. Patients with both classes
I and II dnDSAs had the highest rates of allograft loss.
Antibody levels correlated with the incidence of AMR.
The authors concluded that patients with dnDSA
without AMR at time of detection may benefit from
a follow-up biopsy within 1 year, because AMR can be
missed initially. Similarly, Wiebe et al. (15) studied
a consecutive cohort of 508 renal transplant recipients,
of whom 64 developed dnDSA. Recipients without
dnDSA or allograft dysfunction had an eGFR decline
of 20.65 ml/min per 1.73 m2 per year. In recipients
with dnDSA, the rate of eGFR decline was significantly
increased before dnDSA onset (22.89 versus 20.65
ml/min per 1.73 m2 per year; P,0.001) and accelerated
309
post-dnDSA (23.63 versus 22.89 ml/min per 1.73 m2
per year; P,0.001), suggesting that dnDSA is a marker
and contributor to ongoing alloimmunity. Time to 50%
post-dnDSA graft loss was greater in recipients with
subclinical versus clinical dnDSA phenotype (8.3
versus 3.3 years; P,0.001). Analysis of 1091 allograft
biopsies found that dnDSA and time independently
predicted chronic glomerulopathy but not interstitial
fibrosis and tubular atrophy.
The diagnosis of AMR in the absence of peri-
tubular capillary C4d staining has recently been in-
corporated into the Banff classification system. Ono et al.
(16) quantified allograft loss risk in patients with C4d2
AMR compared with C4d1 AMR patients and AMR-
free controls. C4d2 AMR patients were not different
from C4d1 AMR patients regarding baseline charac-
teristics, including immunologic risk factors (panel
reactive antibody, prior transplant, HLA mismatch,
donor type, DSA class, and anti-HLA/ABO incompat-
ibility). C4d1 AMR patients were more likely to have a
clinical presentation (85.3% versus 54.9%; P,0.001),
and those patients presented substantially earlier post-
transplantation (median, 14 days; interquartile range, 8–32
days versus median, 46; interquartile range, 20–191 days;
P,0.001) and were three times more common (7.8%
versus 2.5%); 1- and 2-year post–AMR-defining biopsy
graft survival rates in C4d2 AMR patients were 93.4%
and 90.2%, respectively, versus 86.8% and 82.6%, re-
spectively, in C4d1 AMR patients (P50.40). C4d2 AMR
was associated with a 2.56-fold (95% CI, 1.08 to 6.05;
P50.03) increased risk of graft loss compared with AMR-
free matched controls. No clinical characteristics reliably
distinguished C4d2 from C4d1 AMR. However, both
phenotypes are associated with increased graft loss.
The impact of subclinical AMR was recently
studied by Orandi et al. (17). This group compared 219
patients with AMR (77 subclinical; 142 clinical) with
controls matched on HLA/ABO compatibility, donor
type, prior transplant, panel reactive antibody, and age;
1- and 5-year graft survival rates in subclinical AMR
were 95.9% and 75.7%, respectively, compared with
96.8% and 88.4%, respectively, in matched controls
(P50.01). Subclinical AMR was independently asso-
ciated with a 2.15-fold increased risk of graft loss (95%
CI, 1.19 to 3.91; P50.01) compared with matched
controls but was not different from clinical AMR
(defined as AKI with DSA demonstration and patho-
logic evidence of tissue injury and C4d deposition;
P50.13). Most subclinical AMR patients were treated
310
with plasmapheresis within 3 days of their AMR-
defining biopsy. The impact of AMR on graft loss was
heterogeneous when stratified by compatible deceased
donor (HR, 4.73; 95% CI, 1.57 to 14.26; P,0.01),
HLA-incompatible deceased donor (HR, 2.39; 95% CI,
1.10 to 5.19; P50.03), compatible live donor (no AMR
patients experienced graft loss), ABO-incompatible live
donor (HR, 6.13; 95% CI, 0.55 to 67.70; P50.14), and
HLA-incompatible live donor (HR, 6.29; 95% CI, 3.81
to 10.39; P,0.001) transplant. The authors concluded
that subclinical AMR substantially increases graft loss,
and treatment seems warranted. Underscoring the re-
fractory nature of some AMR cases, the Johns Hopkins
investigators reported the utility of splenic irradiation for
refractory AMR in two patients. The generalizability of
this approach remains unknown (18).
The impact of microvascular inflammation and
extent of PTC has also been recently reported. Gupta
et al. (19) classified kidney allograft biopsies into
groups based on microvascular inflammation scores
of zero, one, two, or more. Gene expression profiles were
also assessed. The incidence of donor-specific anti-HLA
antibodies increased from 25% in group 1 to 36% in
group 2 and 54% in group 3. Acute and chronic AMRs
were significantly more frequent in group 3 (15% and
35%, respectively) compared with group 2 (3% and 15%,
respectively) and group 1 (0% and 5%, respectively).
Gene expression profiling revealed more immune activa-
tion in the third group as well. Kozakowski et al. (20)
studied the degree of PTC with allograft loss rates. They
found that a score of three (HR, 2.57; 95% CI, 1.25 to
5.28) and diffuse PTC (HR, 1.67; 95% CI, 1.1 to 2.54)
were significant impartial risk factors for allograft loss.
The development of donor specific antibody and antibody
mediated rejection, whether clinical or subclinical, im-
pacts graft survival adversely.
Immunoglobulin Subtypes
Antibodies may have different pathogenicities
per IgG subclass. Lefaucheur et al. (21) investigated
the association between anti-human HLA antibodies
IgG subclasses and rejection. This group studied 125 of
635 patients with donor-specific anti-human HLA anti-
bodies (DSAs) detected in the first year post-transplant;
51 (40.8%) patients had acute AMR, 36 (28.8%) pa-
tients had subclinical AMR, and 38 (30.4%) patients
were AMR free. The MFI of the immunodominant
donor-specific antibody (iDSA; the DSA with the highest
MFI level) was 67246464, and 41.6% of patients had
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
iDSA with C1q positivity. The distributions of iDSA
IgG1, -2, -3, and -4 subclasses among the population
were 75.2%, 44.0%, 28.0%, and 26.4%, respectively.
AMR was mainly driven by IgG3 iDSA, whereas sub-
clinical AMR was driven by IgG4 iDSA. IgG3 iDSA was
associated with a shorter time to rejection (P,0.001),
increased microcirculation injury (P50.002), and C4d
capillary deposition (P,0.001). IgG4 iDSA was associ-
ated with later allograft injury, with increased allograft
glomerulopathy and interstitial fibrosis/tubular atrophy
lesions (P,0.001 for all comparisons). IgG3 iDSA and
C1q binding iDSA were strongly and independently
associated with allograft failure.
The C1q complex is a complement protein in-
volved in the innate immune system. C1q binds to IgM
and IgG/antigen complexes, leading to activation of the
classical complement pathway. Calp-Inal et al. (22)
reported that the incidence of acute AMR was higher
in C1q1/DSA1 patients compared with C1q2/DSA1
and Cq12/DSA2 patients. In two different temporal
cohorts, the frequency of chronic AMR ranged from 36%
to 51% in C1q1/DSA1 patients. In contrast, chronic
AMR ranged from 5% to 25% in C1q2/DSA1 patients
and from 2% to 6% of DSA2 patients (P,0.001). The
authors concluded that the C1q2/DSA1 phenotype was
associated with acute and chronic AMR.
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Histoincompatibility Strategies
Approximately 30% of medically suitable living
donor candidates are incompatible with their intended
recipients due to preformed ABO or HLA antibodies.
Historically, such candidate recipients had little option
other than waiting for a suitable deceased donor offer.
Consequentially, those with highest levels of HLA anti-
bodies often incurred long waiting times with reduced
access to transplantation. To alleviate such problems, three
strategies have emerged:
• Change in kidney allocation to prioritize highly
sensitized patients,
• Kidney paired donation (KPD), and
• Desensitization to either ABO or HLA antibodies.
These approaches are not necessarily mutually
exclusive. For candidates with an incompatible donor,
KPD can improve the prospects of finding a compatible
living donor, but for many highly sensitized patients,
the probability of finding a match in the relatively
small pools of donors in such programs remains
limited. Keith and Vranic (1) suggest that desensitiza-
tion of a living donor/recipient pair with low levels of
incompatibility is another reasonable approach. Note
that desensitization has never been a large-volume
endeavor and may decline due to the prior changes in
deceased donor allocation and KPD.
An unexpectedly positive impact of the new
Kidney Allocation System (KAS), implemented De-
cember 4, 2014, is the degree of increase in allograft
recipients with the highest calculated panel reactive
antibody (cPRA) levels (2). Historically, such candi-
dates have had extremely low transplant rates and are
consistently under-represented among transplant recip-
ients relative to their prevalence on the waiting list.
Priority point allocations for cPRAs changed signifi-
cantly from a flat four-point allocation for cPRAs#80%
to a sliding scale that progressively increases priority
with cPRA elevations. Transplants among patients with
cPRAs of 99%–100% increased from 2.2% pre-KAS,
312 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017

peaked at 13.3% in the first quarter of 2015, and tapered
off to 10.1% by the end of 2015. In summary, these data
represent a 366% increase, slightly above these candi-
dates’ waitlist prevalence of 8.1% (Figure 12). Trans-
plants among candidates with cPRAs of 98% also
doubled from 1.2% pre-KAS to 2.4% post-KAS, with
no appreciable bolus effect. The greater than anticipated
effect of the KAS on high-cPRA transplants may be
explained by an underestimate of the acceptance of high-
quality regional and national offers for these highly
sensitized candidates. In some regions, the proportion
of such patients awaiting transplantation has declined
by .50%.
ABO-Incompatible Transplantation
ABO-incompatible (ABOi) living kidney trans-
plantation is a low-volume endeavor internationally
that includes a preconditioning regimen that variously
involves combinations of plasmapheresis, immunoad-
sorption (IA), intravenous Ig (IVIg), rituximab (RTX),
conventional immunosuppression, and less commonly,
splenectomy. Lo et al. (3) performed a meta-analysis of
83 published reports involving 4810 ABOi transplant
recipients. During a mean follow-up time of 28 months,
the overall graft survival rates for recipients who
received either IA or apheresis were 94.1% (95%
confidence interval [95% CI], 88.2% to 97.1%) and
88.0% (95% CI, 82.6% to 91.8%), respectively. For
those who received RTX or underwent splenectomy,
the overall graft survival rates were 94.5% (95% CI,
91.6% to 96.5%) and 79.7% (95% CI, 72.9% to
85.1%), respectively. Data on other longer-term out-
comes, including malignancy, were sparse. The authors
concluded that RTX and IA were potentially promising
preconditioning strategies before ABOi kidney trans-
plantation. However, the overall quality of evidence
and the confidence in the observed treatment effects are
low. Note that IA is not readily available in the United
States, although it has been used successfully in Europe
(see below).
Okumi et al. (4) studied changes in outcomes of
ABOi transplants during the last 25 years. Patients were
divided into four groups by transplantation era and
ABO compatibility. In the past decade, ABOi live
donor transplant and ABO-compatible (ABOc) recipi-
ents yielded almost equivalent outcomes with respect to
9-year graft survival rates: 86.9% and 92.0%, respec-
tively (hazard ratio [HR], 1.38; 95% CI, 0.59 to 3.22;
P50.46). The graft survival rate for ABO-incompatible
living kidney transplants (ABO-ILKTs) conducted
between 2005 and 2013 was superior compared with
that of ABO-ILKTs conducted between 1998 and 2004
(HR, 0.30; 95% CI, 0.13 to 0.72; P,0.01). ABO-ILKT
recipients showed substantial improvements in graft
survival rate over time. Graft survival was almost
identical over the past decade, regardless of ABO

Figure 12. There has been a marked increase in the number of deceased donor transplant recipients in the most highly
allosensitized recipients (defined as cPRA.98%) since implementation of KAS 12/4/14. There was an initial bolus effect that is
now declining. This has been at the expense of a small reduction in proportion of kidneys allocated to non sensitized individuals.
Distribution of kidney transplants by cPRA. Kidney-alone transplant recipients from January 1, 2013 to December 31, 2015.
KAS was implemented December 4, 2014. OPTN, Organ Procurement and Transplantation Network; SRTR, Scientific Registry
of Transplant Recipients. Reprinted with permission from Hart A, Gustafson SK, Skeans MA, Stock P, Stewart D, Kasiske BL,
Israni AK: OPTN/SRTR 2015 Annual Data Report: Early effects of the new kidney allocation system. Am J Transplant 17
[Suppl 1]: 543–564, 2017.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
compatibility. Similarly, Zschiedrich et al. (5) reported
excellent graft survival rates equivalent to ABOc
kidney transplantation outcome in Germany.
Patient and graft survival rates for ABO
compatible and preconditioned ABO in-
compatible transplantation are generally
equivalent.
It has been suggested that the infrequent use of
ABOi kidney transplantation in the United States may
reflect concern about the costs of necessary precondi-
tioning and post-transplant care (6). Axelrod et al. (6)
studied Medicare data for 26,500 live donor kidney
transplant recipients (2000 to March of 2011), in-
cluding 271 ABOi and 62 A2-incompatible (A2i) re-
cipients, and these data were analyzed to assess the
impact of pretransplant, peritransplant, and 3-year post-
transplant costs. Compared with ABOc transplantation,
3-year rates of patient (93.2% versus 88.15%; P,0.001)
and death-censored graft survival (85.4% versus 76.1%;
P,0.05) were lower after ABOi transplant. Excluding
the cost of organ acquisition, the average overall cost of
the transplant episode was significantly higher for ABOi
($65,080) compared with blood type A2i ($36,752) and
ABOc ($32,039) transplantation (P,0.001); ABOi trans-
plant was associated with high adjusted post-transplant
spending (marginal costs compared with ABOc: year 1,
$25,044; year 2, $10,496; year 3, $7307; P,0.01). The
authors concluded that ABOi transplantation provides
a clinically effective method to expand access to trans-
plantation, albeit with the risks of greater cost and inferior,
if acceptable, outcomes.
RTX, an mAb that targets B cell CD20, induces
lymphodepletion and is frequently a part of the ABOi
conditioning regimen. Lee et al. (7) provide a note of
caution regarding the safety of this approach after
analyzing 213 recipients (n5118 ABOc kidney trans-
plants and n595 ABOi kidney transplants) who un-
derwent living donor transplantation. The effect of
RTX dose on infectious complications in ABOi kidney
transplantation was studied; ABOi kidney transplant
patients were categorized by RTX dose: standard dose
(n576; 375 mg/m2) versus reduced RTX dose (n519;
200 mg). All participants received basiliximab induc-
tion for nondepleting IL-2 receptor blockade and were
maintained on conventional triple immunosuppression.
313
The rates of overall infectious complications among the
three groups were comparable. However, serious infections
developed in 13 of the ABOc kidney transplants
(11.0%), 20 from the standard RTX group (26.3%),
and two from the reduced RTX group (10.5%;
P50.02). Standard dose RTX was found to be an
independent risk factor for serious infections (HR,
2.59; 95% CI, 1.33 to 5.07; P,0.01). There were no
significant differences in rejection, renal function, graft
survival, and patient survival between standard and
reduced RTX groups.
IA was previously reviewed in prior editions of
the Nephrology Self-Assessment Program on trans-
plantation and continues to be reported outside of the
United States. Becker et al. (8) compared the clinical
outcomes of 34 ABOi living donor kidney recipients
who were transplanted using this protocol with those of
68 matched ABOc patients. Before desensitization, the
median titer of 34 ABOi patients was 1:64. Patients
received a median of seven preoperative IA treatments.
Twenty-four patients had a median of two additional
plasmapheresis treatments to reach the preoperative
target isoagglutinin titer of 1:8 or less. After a median
postoperative follow-up of 22 months, overall graft
survival in the ABOi group was not significantly different
from that in ABOc patients (log rank P50.20), whereas
patient survival tended to be lower (log rank P50.05).
The incidence of rejection episodes was 15% in both
groups. The ABOi recipients had a higher incidence of
BK virus replication (P50.04) and nephropathy (P50.01)
and showed colonization with multidrug-resistant bacte-
ria (P50.02) more frequently. In comparison with blood
group antigen–specific IA, nonantigen-specific IA showed
equal efficacy but was associated with cost reduction.
The histologic findings and incidence of antibody-
mediated rejection (AMR) after ABOi preconditioning
remain unclear. Masutani et al. (9) reviewed the histo-
logic findings at 3 and 12 months after ABOc and ABOi
transplantation. Subclinical acute rejection occurred in
6.9% and 9.9% of patients in the ABOc and ABOi
groups, respectively, at 3 months (P50.40) and 12.4%
and 10.1%, respectively, at 12 months (P50.50). The
cumulative incidence rates of acute rejection were
20.5% and 19.6%, respectively (P50.80). The degrees
of microvascular inflammation (MVI) and interstitial
fibrosis/tubular atrophy were comparable. Polyoma-
virus BK nephropathy was found in 2.7% and 3.0%
of patients in the ABOc and ABOi groups, respectively
(P.0.99). The incidence of other infections and the
314
graft/patient survival rates were not different. It has
been reported that C4d deposition is common after
ABOi transplantation, although the prognostic signifi-
cance remains unclear. Ishihara et al. (10) investigated
MVI scores greater than or equal to two within 1 year
after ABOi transplantation as a predictor of graft out-
come. They determined that 5-year graft survival was
significantly lower (P50.01) in MVI patients (89.8%)
than in non-MVI patients. Graft function, characterized
by serum eGFR, was also significantly worse for patients
with MVI than it was for patients without MVI from 3
months to 10 years post-transplantation (P50.05).
Multivariate analysis indicated that HLA class II mis-
match (P,0.01) was an independent marker of MVI.
The authors concluded that MVI score greater than or
equal to two is significantly associated with poor graft
outcome after ABOi kidney transplantation.
HLA Antibody Desensitization
Preconditioning regimens to permit HLA-incompatible
transplantation generally follow protocols similar in prin-
ciple to those for ABOi regimens. However, these pro-
tocols are associated with inferior outcomes; even intense
immunomodulation may not completely abrogate HLA
AMR. Schwaiger et al. (11) evaluated transplant outcomes
in 101 donor-specific antibody–positive (DSA1) deceased
donor kidney transplant recipients with a median follow-
up of 24 months who were subjected to IA-based de-
sensitization. Treatment included a single pretransplant IA
session followed by antilymphocyte antibody and serial
post-transplant IA. Three-year death-censored graft sur-
vival in DSA1 patients was significantly worse than that
in 513 DSA2 recipients transplanted during the same
period (79% versus 88%; P,0.01). Thirty-three DSA1
recipients (33%) had AMR.
Vo et al. (12) described their updated results of
IVIg and RTX in 226 highly sensitized patients who
received transplants after desensitization. Most received
alemtuzumab induction and standard immunosuppression.
Significant risks for AMR included previous transplants
and pregnancies as sensitizing events, DSA relative
intensity scores, presence of both classes I and II DSAs
at transplant, and time on the waitlist. Banff pathology
characteristics for AMR patients with or without graft
loss did not differ. C4d1 versus C4d2 AMR did not
predict graft loss (P50.09); however, thrombotic micro-
angiopathy (TMA) significantly predicted graft failure
(P50.05).
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
AMR episodes were treated with IVIg/RTX
(n525) or in more severe AMR, the addition of plasma
exchange (n520). Graft survival for patients treated
with IVIg plus RTX was superior (P50.03). Increased
mortality was seen in AMR patients experiencing graft loss
after AMR treatment (P50.004). Plasmapheresis and
eculizumab improved graft survival for TMA patients
(P50.04). The authors concluded that patients desensitized
with IVIg plus RTX who remained AMR free experienced
long-term graft and patient survival. However, AMR
patients had significantly reduced graft survival and GFRs
at 5 years, especially after development of TMA.
Jackson et al. (13) studied 256 post-transplant
HLA antibody levels in 25 recipients desensitized with
and 25 without RTX induction to determine the impact
of B cell depletion. They found significantly less HLA
antibody rebound in the RTX-treated patients (7% of
DSAs and 33% of non-DSAs) compared with in
a control cohort desensitized and transplanted without
RTX (32% DSAs and 55% non-DSAs). Importantly,
although RTX induction in HLA-incompatible recipi-
ents reduced the incidence and magnitude of HLA
antibody rebound, it did not affect DSA elimination,
AMR, or 5-year allograft survival compared with
recipients desensitized and transplanted without RTX.
Desensitization to permit HLA-incompatible
transplantation continues to be associated
with antibody-mediated rejection and infe-
rior outcomes compared with either HLA-
compatible or ABO incompatible transplants.
Novel Desensitization Strategies
The limitations of existing desensitization strate-
gies continue to drive the search for alternate options.
Bortezomib (BTZ), a proteasome inhibitor that causes
plasma cell depletion, has been studied in this regard.
Moreno Gonzalez et al. (14) studied the safety and
efficacy of 32 doses of BTZ (1.3 mg/m body surface
area) in ten highly sensitized kidney transplant candi-
dates with alloantibodies against their intended living
donor. Dose reduction was needed in two patients, and
two others completely discontinued therapy for adverse
events. Anti-HLA antibody mean fluorescence inten-
sity (MFI) values were stable before BTZ administra-
tion (P50.96) but decreased after therapy (mean
decrease, 1916; SEM5425 MFI; P,0.01). No patients
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
developed a negative crossmatch against their original
intended donor, and the cPRAs based on MFIs of 2000,
4000, and 8000 were unchanged in all patients. The
authors concluded that 32 doses of BTZ monotherapy
were not well tolerated and resulted in only a modest
reduction in anti-HLA antibodies. By way of contrast,
Woodle et al. (15) performed a prospective iterative
trial of proteasome inhibitor–based therapy for reducing
HLA antibody. Nineteen of 44 patients (43.2%) were
transplanted with low acute rejection rates (18.8%) and
de novo DSA formation (12.5%). Although the authors
concluded that proteasome inhibition–based desensiti-
zation consistently and durably reduced HLA antibody
levels and provided an alternative to IVIg-based de-
sensitization, most patients were still not transplanted.
IL-6 may also be an attractive target, because it
promotes B cell differentiation to plasma cells, is im-
portant for Ig production, and induces Th17 cells, a
subset of proinflammatory T helper cells defined by
their production of IL-17 that is related to T regulatory
cells. Tocilizumab (TCZ) is an anti–IL-6 receptor
antibody undergoing investigation as a potential treat-
ment for AMR. Vo et al. (16) performed a phase I/II
pilot study using TCZ with IVIg to assess safety and
limited efficacy for clinical AMR. Ten patients, un-
responsive to desensitization with IVIg 1 RTX, were
treated with IVIg 1 TCZ. No differences in baseline
characteristics were seen in patients not transplanted
versus transplanted. Two patients in each group de-
veloped serious adverse events: not transplanted, pul-
monary congestion with status epilepticus; transplanted,
infectious colitis with colonic perforation and Bell palsy.
Five of ten patients were transplanted. Six-month pro-
tocol biopsies showed no AMR. DSA strength and
number were reduced by TCZ treatment. Renal function
at 12 months was 60625 ml/min. The authors con-
cluded that TCZ and IVIg seem safe; however, larger
controlled studies are required.
References
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Israni AK: OPTN/SRTR 2015 Annual Data Report: Early effects of the
new kidney allocation system. Am J Transplant 17[Suppl 1]: 543–564,
2017 PubMed
3. Lo P, Sharma A, Craig JC, Wyburn K, Lim W, Chapman JR, Palmer SC,
Strippoli GF, Wong G: Preconditioning therapy in ABO-incompatible
living kidney transplantation: A systematic review and meta-analysis.
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4. Okumi M, Toki D, Nozaki T, Shimizu T, Shirakawa H, Omoto K, Inui
M, Ishida H, Tanabe K: ABO-incompatible living kidney transplants:
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Evolution of outcomes and immunosuppressive management. Am J
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5. Zschiedrich S, Kramer-Zucker A, Jänigen B, Seidl M, Emmerich F,
Pisarski P, Huber TB: An update on ABO-incompatible kidney trans-
plantation. Transpl Int 28: 387–397, 2015 PubMed
6. Axelrod D, Segev DL, Xiao H, Schnitzler MA, Brennan DC, Dharnid-
harka VR, Orandi BJ, Naik AS, Randall H, Tuttle-Newhall JE, Lentine
KL: Economic impacts of ABO-incompatible live donor kidney trans-
plantation: A national study of medicare-insured recipients. Am J
Transplant 16: 1465–1473, 2016 PubMed
7. Lee J, Lee JG, Kim S, Song SH, Kim BS, Kim HO, Kim MS, Kim SI,
Kim YS, Huh KH: The effect of rituximab dose on infectious
complications in ABO-incompatible kidney transplantation. Nephrol
Dial Transplant 31: 1013–1021, 2016 PubMed
8. Becker LE, Siebert D, Süsal C, Opelz G, Leo A, Waldherr R, Macher-
Goeppinger S, Schemmer P, Schaefer SM, Klein K, Beimler J, Zeier M,
Schwenger V, Morath C: Outcomes following ABO-incompatible kidney
transplantation performed after desensitization by nonantigen-specific
immunoadsorption. Transplantation 99: 2364–2371, 2015 PubMed
9. Masutani K, Tsuchimoto A, Kurihara K, Okabe Y, Kitada H, Okumi M,
Tanabe K, Nakamura M, Kitazono T, Tsuruya K; Japan Academic
Consortium of Kidney Transplantation (JACK) investigators: Histolog-
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Transplantation 101: 1416–1422, 2017 PubMed
10. Ishihara H, Ishida H, Unagami K, Hirai T, Okumi M, Omoto K,
Shimizu T, Tanabe K: Evaluation of microvascular inflammation in
ABO-incompatible kidney transplantation. Transplantation 101: 1423–
1432, 2017 PubMed
11. Schwaiger E, Eskandary F, Kozakowski N, Bond G, Kikić Ž, Yoo D,
Rasoul-Rockenschaub S, Oberbauer R, Böhmig GA: Deceased donor
kidney transplantation across donor-specific antibody barriers: Predic-
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1351, 2016 PubMed
12. Vo AA, Sinha A, Haas M, Choi J, Mirocha J, Kahwaji J, Peng A,
Villicana R, Jordan SC: Factors predicting risk for antibody-mediated
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patients transplanted after desensitization. Transplantation 99: 1423–
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Zachary AA: A closer look at rituximab induction on HLA antibody
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14. Moreno Gonzales MA, Gandhi MJ, Schinstock CA, Moore NA, Smith
BH, Braaten NY, Stegall MD: 32 Doses of bortezomib for desensitization
is not well tolerated and is associated with only modest reductions in anti-
HLA antibody. Transplantation 101: 1222–1227, 2017 PubMed
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Alloway RR, Brailey P, Cardi MA, Abu Jawdeh BG, Roy-Chaudhury P,
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Clinical Tolerance
The overwhelming majority of conventionally
immunosuppressed allograft recipients who stop therapy
develop symptomatic rejection and premature allograft
316
failure. However, the occasional fortunate patient who
conducts this experiment fails to undergo rejection,
having developed operational tolerance. Furthermore, it
is possible that there are more such patients who may
forego immunosuppression (IS) who never take the risk
with ongoing implications for cost and adverse effects.
The reader is reminded that the clinical trials of calcineurin
inhibitor withdrawal in low-immunologic risk allograft
recipients discussed above revealed significant rejection
risk, underscoring the importance of ongoing adherence
for most patients. For all of these reasons, the cellular and
immunologic events that underlie tolerance events are of
interest, because prospective identification could poten-
tially identify that subset of individuals who may undergo
immunotherapy reduction or withdrawal.
Baron et al. (1) collected samples and clinical
data from 96 tolerant patients from five different centers
with specific reference to measurable transcription
patterns. Common gene signatures and discriminating
biomarkers for tolerance after kidney transplantation
were identified. A robust gene signature involving
proliferation of B and CD41 T cells with inhibition
of CD14 monocyte functions was confirmed and cross-
validated with almost 92% accuracy. The data also
indicated participation of other cell subsets in tolerance.
The authors concluded that the use of the top 20
biomarkers, mostly centered on B cells, may provide
a standardized tool toward personalized medicine for
monitoring of tolerant or low-risk patients among
kidney allotransplant recipients. Chesneau et al. (2)
analyzed the role of B cells from 12 operationally
tolerant patients compared with healthy volunteers and
stable kidney transplant recipients on IS. Proliferation,
apoptosis, and type I proinflammatory cytokine produc-
tion by effector CD41CD25– T cells were measured.
They reported that B cells inhibit the CD41CD25–
effector T cell response in a dose-dependent manner.
This effect required B cells to interact with T cell targets
and was achieved through a granzyme B–dependent
pathway. Tolerant recipients harbored a higher number
of B cells expressing granzyme B and displayed a partic-
ular plasma cell phenotype. The investigators concluded
that these data provide insights into the characterization of
B cell–mediated immunoregulation in clinical tolerance.
The role of Foxp31 regulatory T cells (Tregs) in
operational tolerance was studied by Braza et al. (3).
They observed a higher proportion of CD41 T cells
with demethylated Foxp3 and a specific expansion of
CD41CD45RA– Foxp3(hi) memory Tregs exclusively
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
in tolerant patients. Taken together, the data show that
operationally tolerant patients mobilize an array of
potentially suppressive cells, including regulatory B
cells and Tregs.
Clinical Tolerance Induction
It has been lightheartedly suggested that clinical
tolerance is the “holy grail” of transplantation and
always will be. This viewpoint has been challenged by
reports from three centers in the United States with
proof of concept data that are described in greater detail
below. Note that tolerance induction is deemed exper-
imental and has met with varying degrees of success.
Rejections and graft losses, although infrequent, have
occurred using regimens that generally rely on in-
duction of either transient or persistent donor chime-
rism. This comment is made to refocus the readers’
attention on the experimental nature of these regimens
in evolution, not to undermine the importance of such
work. The three protocols below share common themes
that include the use of lymphocyte depletion, cellular
therapy with either donor bone marrow or CD34-
positive stem cells, and various combinations of con-
ventional immunotherapy that are subsequently tapered
off with time. A more recent clinical trial planned to
evaluate administration of Tregs to harness the immune
response has recently been initiated in eight European
and American centers. (4).
Leventhal and coworkers (5–7) described results
of a nonchimeric, operational tolerance protocol in
HLA-identical living donor renal transplants. Recipi-
ents given alemtuzumab and tacrolimus/mycopenolic
acid with early sirolimus conversion were repeatedly
infused with donor hematopoietic CD341 stem cells.
IS was withdrawn by 24 months. Twelve months later,
operational tolerance was confirmed by rejection-free
transplant biopsies. Five of the first eight enrollees were
initially tolerant 1 year off IS. Biopsies of three others
after total withdrawal showed Banff 1A acute cellular
rejection without allograft dysfunction. At 5 years post-
transplantation, four of five tolerant recipients remained
rejection free, whereas one developed Banff 1A re-
jection without allograft dysfunction. Significant time-
dependent increases of circulating Tregs were seen in
a more recent cohort of tolerant versus nontolerant
subjects (P,0.001). Gene expression signatures, de-
veloped using global RNA expression, were highly
associated with operational tolerance as early as 1 year
post-transplant.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Kawai et al. (8) previously reported the long-term
results of HLA-mismatched kidney transplantation
without maintenance IS in ten subjects after combined
kidney and bone marrow transplantation. All subjects
were treated with nonmyeloablative conditioning and
an 8- to 14-month course of calcineurin inhibitor
with or without rituximab. All ten subjects developed
transient chimerism, and in seven of these, IS was
successfully discontinued for 4 or more years. At the
time of publication, four subjects remained IS free for
periods of 4.5–11.4 years, whereas three required
reinstitution of IS after 5–8 years due to recurrence of
original disease or chronic antibody-mediated rejection
(AMR). Of the ten renal allografts, three failed due to
thrombotic microangiopathy or rejection. In collabora-
tion with the Massachusetts General Hospital group,
Newell et al. (9) theorized that biomarkers of transplant
tolerance could enhance the safety and feasibility of
clinical tolerance trials and potentially facilitate man-
agement of patients receiving IS. To this end, blood
from spontaneously tolerant renal transplant recipients
and patients enrolled in two interventional tolerance
trials using flow cytometry and gene expression pro-
filing was examined. They found that tolerance was
associated with increased expression of B cell–associated
genes relative to immunosuppressed patients. Moreover,
serial measurements of gene expression showed that this
pattern persisted over several years, although patients
receiving IS also displayed an increase in the two most
dominant tolerance-related B cell genes, IGKV1D-13
and IGLL-1, over time. Importantly, patients rendered
tolerant via induction of transient mixed chimerism and
those weaned to minimal IS showed similar increases in
IGKV1D-13 as did spontaneously tolerant individuals.
Collectively, these findings support the notion that
alterations in B cells may be a common theme for
tolerant kidney transplant recipients.
Scandling et al. (10) have provided iterative
reports, the most recent of which describes 38 HLA-
matched and -mismatched living kidney donor recipients
enrolled in tolerance protocols using post-transplant
conditioning with total lymphoid irradiation, enriched
CD341 hematopoietic cell, and antithymocyte globulin.
Persistent chimerism for at least 6 months was associated
with successful complete withdrawal of immunosup-
pressive drugs in 16 of 22 matched patients without
rejection episodes or kidney disease recurrence with up
to 5 years follow-up. Persistent mixed chimerism was
achieved in some haplotype-matched patients for at least
317
12 months by increasing the dose of T cells and CD341
cells infused compared with matched recipients in a dose
escalation study. Success of drug withdrawal in chimeric-
mismatched patients remains to be determined. None
of the 38 patients had kidney graft loss or graft versus
host disease in up to 14 years of observation. The au-
thors concluded that complete immunosuppressive
drug withdrawal could be achieved with the tolerance
induction regimen in HLA-matched patients with uni-
form, long-term graft survival in all patients. In a sub-
sequent publication, Scandling and coworkers (11)
contended that, although tolerance conditioning is ex-
pensive, the negation of the IS requirement may be less
costly long term. This group estimated costs for a hypo-
thetical 40-year-old two-haplotype match living donor
kidney transplant recipient. The standard IS therapy
cost is $179,000 over a patient’s lifetime, whereas the
tolerance induction cost is $88,000, yielding an expected
lifetime savings of $92,000. If all 5170 two-haplotype
match living donor kidney transplant recipients in the
United States from 2003 to 2012 had received tolerance
induction, this would have potentially yielded approxi-
mately $350 million United States dollars in aggregate
lifetime savings.
Regarding tolerance induction, kidney allografts
behave differently from heart allografts, which behave
differently from lung allografts for reasons that remain
unclear. Madariaga et al. (12) remind us that inducing
tolerance in experimental recipients of heart and lung
allografts has proven more challenging than for kidney
allografts.
Experimental tolerance induction utilizing
transient or persistent donor chimerism
has led to durable, IS-free engraftment
for a limited number of human transplant
recipients.
Biomarkers
Despite almost 20 years of research, the use of
individual biomarkers (e.g., granzyme B, perforin, kidney
injury molecule-1, and neutrophil gelatinase–associated
lipocalin) to noninvasively ascertain allograft stability or
differentiate among different causes of kidney injury has
failed to transition from the laboratory to the clinic due to
cost, availability, reproducibility, and performance
characteristics. The clinical nephrologist still utilizes
318
more conventional allograft markers, including serum
creatinine, urine protein-to-creatinine ratio, BK virus
nucleic acid testing, donor-specific antibody testing for
surveillance, and the allograft biopsy for definitive
diagnostics, with all of their associated limitations.
Overall, the increasing availability of sophisticated
and complex genomic and proteomic testing provides
novel avenues of investigation. Sigdel et al. (13) aimed to
map changes in the urine proteome after kidney trans-
plantation by comparing urine and biopsy changes in 396
transplant recipients. Blinded histologic data were used to
classify urine samples into diagnostic categories of acute
rejection (AR), chronic allograft nephropathy, BK virus
nephritis, and stable graft function. Ultimately, a minimal
set of 35 proteins was identified for its ability to segregate
the three major transplant injury clinical groups, making
up the final panel of 11 urinary peptides for AR (93% area
under the curve [AUC]), 12 urinary peptides for chronic
allograft nephropathy (99% AUC), and 12 urinary pep-
tides for BK virus nephritis (83% AUC). Thus, urinary
proteome discovery and targeted validation may identify
peptidomes that provide rapid, noninvasive differentiation
of causes of kidney transplant injury without an invasive
kidney biopsy. Modena et al. (14) examined gene
expression profiles of 234 graft biopsy samples matched
with their clinical and outcome data to study interstitial
fibrosis and tubular atrophy (IFTA). The biopsies were
divided into subphenotypes by degree of histologic in-
flammation: IFTA with AR, IFTA with inflammation, and
IFTA without inflammation. A novel analysis using gene
coexpression networks revealed that all IFTA phenotypes
were strongly enriched for dysregulated gene pathways
that were shared with the biopsy profiles of AR, including
IFTA samples without histologic evidence of inflamma-
tion. Thus, by molecular profiling, most IFTA samples
have ongoing immune-mediated injury or chronic rejection
more sensitively detected by gene expression profiling.
Venner et al. (15) used microarray analysis of
kidney transplant biopsies to identify changes of pure
AMR. In a set of 703 biopsies, 2603 transcripts were
significantly changed (P,0.05) in AMR versus all
other biopsies. In cultured cells, the transcripts strongly
associated with AMR were expressed in endothelial
cells. Pathway analysis of AMR transcripts identified
angiogenesis, with roles for angiopoietin and vascular
endothelial growth factors, leukocyte-endothelial inter-
actions, and natural killer signaling, including evidence
for CD16a Fc receptor–signaling elements shared with
T cells. These data support a model of AMR involving
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
injury repair in the microcirculation induced by cognate
recognition between antibody and CD16a that triggers
IFN-g release and antibody-dependent natural killer
cell–mediated cytotoxicity.
O’Connell et al. (16) studied gene sets to predict
renal allografts at risk of progressive injury due to fibrosis.
They prospectively collected biopsies from renal allograft
recipients (n5204) with stable renal function 3 months
after transplantation. The group identified a set of 13
genes independently predictive for the development of
fibrosis at 1 year. The gene set had high predictive
capacity (AUC, 0.967), which was superior to that of
baseline clinical variables (AUC, 0.706) and clinical and
pathologic variables (AUC, 0.806). Furthermore, routine
pathologic variables were unable to identify which histo-
logically normal allografts would progress to fibrosis
(AUC, 0.754), whereas the predictive gene set accurately
discriminated between transplants at high and low risk of
progression (AUC, 0.916). The 13 genes also accurately
predicted early allograft loss (AUC, 0.842 at 2 years and
AUC, 0.844 at 3 years). The predictive value of this gene
set was established in an independent cohort. The authors
concluded that this set of 13 genes could be used
to identify kidney transplant recipients at risk of allograft
loss before the onset of irreversible damage, potentially
allowing therapy to be modified to prevent progression to
fibrosis.
Oetting et al. (17) provide a cautionary note about
using such technology for prognostic purposes, warning
about the requirement for validation beyond the initial
dataset. One goal of a genome-wide association study
was to associate the allele(s) of a single-nucleotide poly-
morphism with phenotype. Although there have been
many successful associations documented, there have
been many more genome-wide association study–based
results that were later deemed false positives. As an
example, Pihlstrøm et al. (18) were unable to reproduce
prior study data suggesting that two single-nucleotide
polymorphisms (rs3811321 and rs6565887) associated
with serum creatinine and clinical outcome.
Allograft biomarkers have not impacted
clinical practice to date. Novel genomic
and proteomic analyses are elucidating
molecular events underlying allograft injury
and tolerance. However, broader clinical
applicability remains to be determined.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
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S, Asare S, Lim N, Stahly M, Howell M, Knechtle S, Kirk A, Marks
WH, Kawai T, Spitzer T, Tolkoff-Rubin N, Sykes M, Sachs DH, Cosimi
AB, Burlingham WJ, Phippard D, Turka LA: Longitudinal studies of
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Jones S, Jensen K, Shori A, Strober JA, Lavori P, Turnbull BB,
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Strober S: A cost analysis of tolerance induction for two-haplotype
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Glomerular Injury Post-Transplant
Proteinuria in the Post-Transplant Setting
Measures of proteinuria post-transplant may signal
de novo or recurrent glomerular disease or a manifesta-
tion of alloantibody-mediated injury, also referred to as
transplant glomerulopathy (see above). A recent study
showed the predictive value of proteinuria (measured
3 months and 1, 2, 5, and 10 years post-transplantation
and at the time of renal allograft biopsy) for graft
failure in 1518 patients followed for over 7 years post-
transplant. Protocol biopsies correlated proteinuria with
graft histology (1). Although proteinuria of 300–1000 mg/d
was associated with a twofold increased risk of graft
loss, proteinuria of 1–3 g/d was associated with a three-
fold increased risk of graft loss, independent of GFR
and histology. The predictive value, in terms of sensi-
tivity, specificity, and negative and positive predictive
values of proteinuria, was relatively low for abnormal
glomerular histology or graft loss. The best predictor for
biopsy findings of transplant glomerulopathy, glomerular
disease, and/or microcirculatory inflammation was pro-
teinuria .1 g/d measured 3 months post-transplant. The
positive predictive value of this parameter was 58.2%,
whereas the negative predictive value was 78.7%. The
research group suggested that kidney biopsy was indi-
cated when a proteinuria threshold of $1 g/d was
achieved to better characterize the nature of glomerular
injury. Beyond these modestly predictive findings, a sep-
arate retrospective study of 805 kidney transplant recipi-
ents concluded that the resolution of low-grade proteinuria
(from 0.15–1000 mg/d to ,0.15 g/d from years 1 and 2 to
years 2 and 3 post-transplant) was associated with a higher
graft survival rate compared with those with persistent
proteinuria, independent of BP (2). The combination of
persistent low-grade proteinuria and systolic BP .140
320
mmHg during the first 3 years was associated with inferior
patient survival and death-censored graft survival (60.2%
and 87.6%, respectively) compared with in normotensive
patients without proteinuria (87.9% and 97.0% with
P,0.001 and P,0.01, respectively). One potential contrib-
utor to the development of proteinuria is mammalian target
of rapamycin inhibitor (mTORi). Prevention of proteinuria
related to mTORi may be reasonably achieved using renin-
angiotensin system blockade. A prospective, randomized,
double-blind, placebo-controlled study of 264 renal trans-
plant patients converted from a calcineurin inhibitor to
sirolimus compared ramipril with placebo in primary preven-
tion of proteinuria (defined as urinary protein-to-creatinine
ratio $0.5) (3). Losartan was administered if proteinuria
was not controlled, despite uptitration of ramipril. At 52
weeks, the cumulative rate of losartan initiation was signif-
icantly lower in the ramipril arm (6.2%) than placebo
(23.2%; P,0.001), with no difference between study arms
with respect to changes in eGFR over the study period. A
recent review provides the reader with greater depth of the
topic of proteinuria in the post-transplant setting (4).
Glomerular Disease: Post-Transplant Outcomes
Patients with GN tend to have excellent outcomes
after kidney transplantation when assessed as a grouped
cohort. However, there is variation within individual
subtypes. A United States registry analysis of outcomes
in 32,131 patients with one of six GN subtypes showed
highest graft survival in IgA nephropathy and lowest graft
survival in vasculitis, the latter driven entirely due to death
as an end point rather than graft loss (5). Regarding the
hazard for death-censored graft loss, the IgA nephropathy
and vasculitis subgroups were similar (hazard ratio [HR],
0.94; P value not significant) and superior to FSGS (HR,
1.20; 95% CI, 1.12 to 1.28), membranous nephropathy
(MN; HR, 1.27; 95% CI, 1.14 to 1.41), membranoproli-
ferative GN (MPGN; HR, 1.50; 95% CI, 1.36 to 1.66),
and lupus nephritis (HR, 1.11; 95% CI, 1.02 to 1.20),
with all HRs statistically significant, compared with IgA
as reference. A European registry analysis of 41,383
patients with GN showed similar findings of highest
death-censored graft survival in the IgA subtype and
lowest survival in the MPGN subtypes (6). Addressing
the potential concern of using living donors for individ-
uals with primary GNs, all subtypes had superior graft
survival with living versus deceased donor kidney
transplant (e.g., IgA: HR, 0.74; 95% confidence interval
[95% CI], 0.59 to 0.92; FSGS: HR, 0.69; 95% CI, 0.45
to 1.06), except MPGN type I (HR, 1.08; 95% CI, 0.73
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
to 1.60) and type II (HR, 0.90; 95% CI, 0.32 to 2.52).
The authors concluded that living donation should be not
be discouraged across all GN subtypes, with informed
decision making in cases involving MPGN.
Focal and Segmental Glomerulosclerosis
The risk for recurrent of FSGS post-transplant is
substantial and frequently leads to early graft loss. In
an Australian and New Zealand Dialysis and Trans-
plant Registry analysis of 666 adults and 70 pediatric
kidney transplant recipients with ESRD eventuating
from biopsy-proven FSGS, the disorder recurred in
10.3% of cases, with a 52% 5-year graft survival versus
83% in those without recurrent disease (P,0.001) (7).
Risk factors for recurrence included younger age, non-
white ethnicity, and living donor versus deceased donor
transplant. Overall, median graft survival was still superior
with living donor transplant than deceased donor transplant
(14.8 versus 12.1 years; P,0.01), again suggesting that
living donor transplant should not be avoided in this
cohort. Recurrence rates strongly depend on etiology of
FSGS. In pediatric patients with known or suspected
genetic causes of FSGS, the post-transplant recurrence
rate is low. For example, only one of 25 patients in a
National Israeli Kidney Registry Study developed recur-
rent FSGS versus 17 of 22 patients (64%), in whom FSGS
was considered “primary/nongenetic” (8).
Treatment for recurrent post-transplant FSGS
remains a challenge. A review and meta-analysis of the
role of plasma exchange (PLEX) as a primary intervention
pooled 34 case reports and 43 case series totaling 423
patients (9). Defining remission as ,3.5 g/d (partial) or
,0.5 g/d (complete), the overall remission rate was 71%.
Neither age nor donor type were associated with remission.
Proteinuria .7 g/d was inversely associated with remission,
whereas men and early treatment within 2 weeks of
recurrence were associated with higher rates of remission.
Rituximab (RTX) administration to individuals who failed
or could not be weaned from PLEX and high-dose
calcineurin inhibitors was reported in a series of 19 patients.
Ten patients underwent RTX readministration after failure
to respond to PLEX (10): five achieved partial (n54) or
complete (n51) remission, and eight developed serious
infections within 1 year, suggesting that adding RTX to
achieve control of FSGS must be done with close monitor-
ing and expectation for infectious complications. Finally,
initial optimism regarding targeted B7-1 (putative role in
aberrant podocyte integrity) treatment with the costimulation
blockers, abatacept or belatacept, has been tempered by
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
a recent report of nine patients with recurrent, post-transplant
FSGS. All failed to respond to this therapy, despite
combination with other therapies that included PLEX and/
or immunoadsorption in all patients and RTX in most (11).
Membranous Nephropathy
Membranous Nephropathy (MN) often recurs post-
transplant but typically, with a far less aggressive course
than FSGS. In the largest and most comprehensive case
series to date, 63 recipients with biopsy-proven primary
MN pretransplant were followed for a median of 77
months post-transplant. Recurrent disease developed in
30 of 63 (48%) cases, and 16 were diagnosed by protocol
biopsy. In 17 of the 30 cases, there was progressive
proteinuria (12). Progressors were treated with RTX,
with complete or partial remission in 14 (82%) cases.
Importantly, graft and patient survival rates were not
different among those who developed recurrence versus
those who did not, similar to a concurrently transplanted
autosomal dominant polycystic kidney disease cohort.
The degree of pretransplant proteinuria was associated
with recurrence (approximately 50% recurrence rate for
proteinuria of 5–10 g/d; approximately 80% for .10
g/d). The presence of pretransplant antiphopholipase A2
receptor antibodies (anti-PLA2R Abs) was also associ-
ated with recurrence (HR, 3.76; 95% CI, 1.64 to 8.65;
P50.002). In a separate study, the positive predictive
value of pretransplant anti-PLA2R for recurrence was
83%, and negative predictive value was 42%, suggesting
a role in screening for anti-PLA2R Ab to risk stratify
recurrence. Namely, a positive value may indicate a need
for heightened surveillance, whereas a negative value
does not necessarily rule out the possibility of recurrent
disease (13). This finding was corroborated by another
single-center analysis of 16 patients (14). A more detailed
review of the value of anti-PLA2R Ab screening and
monitoring in pre- and post-transplant settings has been
recently published (15).
APOL1 and Kidney Transplantation
APOL1 gene polymorphisms (risk variants) are
enriched in blacks due to the trypanolytic effects
conferred by these ApoL1 proteins. Individuals with
two APOL1 risk variants (10%–15% of the black
population) are more likely to develop glomerular
diseases, including FSGS, HIV-associated nephropa-
thy, lupus nephritis, and hypertensive nephrosclerosis,
in the nontransplant setting (16). In the transplant setting,
recent clinical observations suggest that kidneys from
321
donors with two APOL1 risk variants may confer risk of
decreased allograft survival in the recipient. In a two-
center report of 675 kidneys transplanted, the presence
of two donor risk variants was associated with graft loss
(HR, 2.26; P50.001) (17). In an extension of this study
including an additional 478 deceased donor kidney
transplants, in whom APOL1 genotyping was per-
formed, donor APOL1 high-risk genotype was associ-
ated with inferior allograft survival (Figure 13) (HR,
2.05; 95% 95% CI 1.39 to 3.02; P,0.001) (18). Despite
this risk, most recipients maintained excellent function
(72.6% of grafts functioning for .5 years and 56.9% of
those functioning .10 years). It is possible that the risk
conferred by APOL1 risk variant donors is only loosely
approximated by the inclusion of black race in the
calculation of the deceased donor risk index that
determines the donor profile index for deceased donor
kidney allocation. A recent assessment of the impact of
substituting APOL1 status for race described the poten-
tial for refinement of risk for graft loss and may more
precisely classify the impact of black race as a donor risk
factor (19). Current understanding of the role and value
of testing for APOL1 risk variants is rapidly evolving
and includes consideration for not only recipients but
also, potential living donors. These concepts were
recently summarized in proceedings from an American
Society of Transplantation Expert Conference (20).
The presence of two APOL1 renal risk
variants in deceased donors is associated
with a 1.5- to twofold increased risk of graft
loss. APOL1 renal risk variants may explain
the disparity in allograft outcomes from
black kidney donors.
Complement-Mediated Glomerular Disease
Complement-mediated diseases, including atypi-
cal hemolytic uremic syndrome (aHUS) and C3
glomerulopathies, have high recurrence rates in renal
allografts and substantially impact graft survival. Despite
this, a recent registry analysis reported the persistence of
survival benefit of transplant in adult patients with
a diagnosis of hemolytic uremic syndrome (not explicitly
defined as aHUS) compared with those remaining on the
waiting list (5-year mortality risk with living donor: HR,
0.27; 95% CI, 0.11 to 0.65; with deceased donor: HR,
0.52; 95% CI, 0.29 to 0.94) (21). In general, data are
322 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017

Figure 13. Adjusted Kaplan–Meier survival plots (full model) in 1153 deceased donor kidney transplantations from black
donors based on donor APOL1 genotypes. Plots compare survival of kidneys from donors with two renal risk variants with
that for kidneys from donors with fewer than two renal risk variants. The numbers within the parentheses below the curves
reflect the following: (number of functioning allografts at the start of each year, number of allograft failures within
that year). Reprinted with permission from Freedman BI, Pastan SO, Israni AK, Schladt D, Julian BA, Gautreaux
MD, Hauptfeld V, Bray RA, Gebel HM, Kirk AD, Gaston RS, Rogers J, Farney AC, Orlando G, Stratta RJ, Mohan S,
Ma L, Langefeld CD, Bowden DW, Hicks PJ, Palmer ND, Palanisamy A, Reeves-Daniel AM, Brown WM, Divers J:
APOL1 genotype and kidney transplantation outcomes from deceased African American donors. Transplantation 100:
194–202, 2016.

sparse for the management of patient with complement-
mediated injury, but examples can be gleaned from the
nontransplant population. In a recent open label trial of
41 patients treated with eculizumab for aHUS, 73% had
a complete thrombotic microangiopathic response, with
15 of 19 patients dialysis dependent at initiation of
therapy discontinuing dialysis (22). Of the overall cohort,
nine patients had a history of prior kidney post-transplant
(three on dialysis); data were not reported for this small
cohort. A recent review describes current considerations
for diagnosis and management of these rare diseases in
the transplant setting (23). Pertinent recommendations
include careful consideration of C3 glomerulopathy in
any renal transplant candidate whose original disease
was reported as MPGN, mesangial proliferative GN, or
endocapillary proliferative GN. If C3 glomerulopathy
can be verified, detailed complement testing can be
performed to identify and predict the risk of recur-
rence. These recommendations may help in prediction,
but in practice, they may unfortunately not change
management. For example, when a high-risk comple-
ment mutation is identified, therapy may be considered to
prevent or treat recurrence; however, expense may limit
access to therapies, such as eculizumab, except in cases
where clinical diagnosis of aHUS has been established.
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Infection after Transplant
Infectious complications after transplant are a ma-
jor cause of morbidity and mortality and may interpose
allograft injury and graft loss (1). Newer infections,
such as Zika virus, are incompletely understood in the
transplant population (2). Only a small case series from
Brazil described the courses of two kidney and two
liver transplant recipients. All cases were identified
concurrent with confounding bacterial infections that
do not permit greater understanding of the impact of
Zika infection per se (3). Preventing common infec-
tions, such as influenza and common urinary tract
infections (UTIs), are worthy goals but have limita-
tions. After an outbreak of influenza A in one inpatient
transplant unit, 23 kidney transplant patients were
identified as at risk: 17 had adequate seasonal influenza
vaccination, of whom two tested positive without
clinical consequences. Of six unvaccinated recipients,
five developed influenza, and three died from severe
respiratory failure (4). In a study of 60 patients after
influenza vaccination, adequate seroconversion to at
least one of the three influenza antigens occurred in
63% without an increase in HLA alloantibody titers (5).
In conclusion, vaccination is less efficacious in ESRD
324
and kidney transplant populations than the general
population but is still considered valuable.
The same utility cannot be ascribed to screening
for and treating asymptomatic bacteriuria to prevent
UTI. In 112 kidney transplant recipients with at least
one episode of asymptomatic bacteriuria after the second
month, post-transplant routine screening was conducted,
with subsequent randomization in 1:1 fashion to antimi-
crobial therapy or no therapy. No difference in the acute
pyelonephritis rate at 24 months was found (7.5% versus
8.4%). There was no difference in lower UTI frequency,
allograft function, or mortality (6).
Cytomegalovirus
To prevent cytomegalovirus (CMV) infection/
disease, most transplant centers in the United States
use a CMV prophylaxis strategy using valganciclovir
for 3–6 months post-transplant. High-dose valacyclovir
has also been recommended. A randomized trial of 119
patients receiving either valganciclovir 900 mg daily
or valacyclovir 2 g four times daily showed similar efficacy
in prevention of CMV viremia at 12 months (31% versus
43%; P50.36). Notably, the valganciclovir group had
a lower incidence of acute rejection (17% versus 31%;
P50.03) and higher BK virus (BKV) viremia rates (36%
versus 18%; P50.04), supporting an additive immuno-
suppressive effect of valganciclovir (7). Conversely, im-
munosuppressive medications (specifically, sirolimus and
everolimus) may have additive antiviral effects. In the
absence of CMV prophylaxis, 288 kidney transplant
recipients were randomized to receive tacrolimus (TAC),
prednisone, and everolimus (n5102 with antithymocyte
globulin induction, n585 with basiliximab induction) or
mycophenolate (n5101 with basiliximab induction) (8).
Rates of CMV infection/disease at 12 months were 4.7%,
10.8%, and 37.6%, respectively (P,0.001 for each ever-
olimus versus mycophenolate group). This finding was
corroborated in a multicenter registry analysis of 311
pediatric kidney transplant recipients that revealed an
83% lower risk of CMV replication overall and a lower
CMV disease rate in high-risk (CMV IgG1 donor/CMV
IgG2 recipient) recipients when prescribed immuno-
suppression consisting of cyclosporine (CsA)/everolimus
versus CsA or TAC in combination with mycophenolate
(9). These findings support experimental data that docu-
ment inhibition of CMV replication by mammalian target
of rapamycin inhibition.
Monitoring for CMV infection may be warranted
even after prophylaxis in certain high-risk circumstances.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Forty-eight high-risk (CMV IgG1 donor/CMV IgG–
recipient) recipients who received thymoglobulin induc-
tion and 6 months of valganciclovir underwent CMV
PCR monitoring during prophylaxis and for 3 additional
months of surveillance (10). Nineteen (40%) developed
CMV infection: nine occurred during prophylaxis (five
were associated with suboptimal valganciclovir dosing);
six occurred during the surveillance period post-transplant,
and four occurred during the 3-month postsurveillance
period. The authors suggest that identification of viremia
can ideally permit immunosuppression adjustment and
reduce morbidity and hospitalizations.
Beyond CMV PCR monitoring, a number of other
markers that may identify CMV-specific immunity are
under study, including T cell subsets (11), chemokine
(C-C motif) ligand 8 (CCL8) (12), and single-nucleotide
polymorphisms in genes involved in CMV immune
response (13). These references are provided for the
interested reader (11–13).
BK Virus
Control of BK virus (BKV) reactivation from the
transplanted kidney remains an important challenge in
optimizing graft survival. Recent advances in the
understanding of the mechanisms that contribute to
viral reactivation include measures of BKV-specific
immunity, viral relationship to specific immunosup-
pressive agents, and contribution of donor versus
recipient pretransplant BKV exposure. In a study com-
paring BKV-specific and alloreactive T cells from 24
kidney transplant patients who developed BKV vire-
mia with those from 127 patients without BKV
(sampled pretransplant and 1, 2, and 3 months post-
transplant), changes in BKV-specific T cells from the
pre- to post-transplant period were associated with risk
for subsequent BKV replication (14). Another study of
cytokine profiles from T cell subsets from individuals
who cleared BKV versus those who did not revealed
an increase in a specific polyfunctional T cell subset that
secreted multiple cytokines only in the former group
(15). Thus, measures of T cell functionality may be
predictive of risk for BKV infection, and the likelihood
of clearance after replication has been established.
Mammalian target of rapamycin inhibitors (mTORis)
may not only preserve BKV-specific T cell immunity but
may also inhibit BKV replication in renal tubular epithelial
cells more than calcineurin inhibitors. The former hy-
pothesis was supported by a study showing reductions in
cytotoxic T cell function using CsA but not mTORi (16),
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
whereas the latter hypothesis was shown in an in vitro
study, in which sirolimus exerted inhibitory effects on
BKV replication in renal tubular epithelial cells (17). TAC
increased BKV replication and counteracted sirolimus
inhibition when the two medications were combined. This
suggests a possible advantage of mTORi compared with
TAC for prevention of BKV infection.
The measurement of pretransplant anti-BKV sero-
status from the donor and recipient has been proposed
as a measure to determine risk of post-transplant BKV
infection, analogous to measuring CMV IgG status in
donors and recipients pretransplant to define CMV risk.
Recent studies increasingly support this concept as a
potential risk stratification tool. In 407 living kidney
donor-recipient pairs, donor but not recipient BKV
seroreactivity was strongly associated with BKV vire-
mia within 1 year post-transplant. Coupling donors with
high seroreactivity with recipients of low seroreactivity
was associated with a tenfold increased risk of BKV
viremia (18). Another study of 116 donor/recipient pairs
reported that kidneys from donors with significant
serum neutralizing activity (donor positive) had a five-
fold elevated risk for BKV viremia, regardless of recip-
ient serostatus (donor positive versus donor negative:
odds ratio, 5.0; 95% confidence interval [95% CI], 1.9
to 12.7; P,0.001), and those donor-recipient pairs with
donor-positive/recipient-negative neutralizing serostatus
had the greatest risk for BKV viremia (odds ratio, 4.9;
95% CI, 1.7 to 14.6; P50.004) (19). These data together
with another study that described a correlation of spe-
cific donor-derived BKV subtypes with post-transplant
BKV infection (20) implicate donor source and immu-
nity as important risk factors for clinically significant BKV
infection post-transplant. Transplant recipients who are
seronegative for BK virus who receive seropositive grafts
(BK D1/R-) are at increased risk of BK viremia.
Other possible risk factors for BKV susceptibility
were clarified in a registry analysis using a paired
kidney analysis that identified recipient pairs receiving
kidneys from the same deceased donor. By stratifying
those cases where one of two recipients were treated
for BKV (discordant treatment) from those cases where
both recipients were treated for BKV (concordant treat-
ment), associations could be made to determine risk
invoked by the donor (concordant treatment) versus the
recipient (discordant treatment) (21). Recipient factors
that were associated with increased risk for treated
BKV infection included age ,18 or $60 years old,
men, four or more HLA mismatches, acute rejection, and
325
antibody-depleting induction therapy. Factors associated
with reduced risk included recipient diabetes and sirolimus
use. The rate of BKV infection in paired transplanted
kidneys was threefold higher than expected, implying that
donor factors, such as serostatus, are of greater impor-
tance in BKV risk.
Allograft biopsy findings and other recipient
antibodies during BKV infection and BKV may elicit
enhanced understanding of the subsequent clinical
course. Associations of de novo donor-specific anti-
bodies (DSAs) with persistent BKV viremia (22) and
increased risk of rejection with antibodies to self-
antigens fibronectin and collagen type IV with BKV
viremia (23) have recently been reported. Regarding
the risk (or association) of BKV viremia and de novo
DSA formation, in a large, single-center study, 785
patients were screened for BKV viremia, of which 132
(17%) developed BKV viremia. BKV viremia that
persisted .140 days despite immunosuppression dose
reduction was not associated with inferior graft or patient
survival. However, de novo HLA DSAs were identified
in 30% with persistent viremia compared with 23% in
those who rapidly cleared the virus and 15% in those
without BKV viremia (on multivariate analysis: hazard
ratio [HR], 2.53; 95% CI, 1.40 to 4.59; P,0.01 for the
development of de novo DSA with persistent BKV
viremia). Development of de novo DSAs generally
occurred after BKV viremia had been identified (me-
dian 344 days post-transplant versus 137 days post-
transplant, respectively). Beyond serologic assessment,
other studies have examined biopsies of BKV nephrop-
athy and found a higher frequency of allospecific T cell
clones rather than BKV-specific clones (24). These
findings highlight the interplay between BKV-related
inflammation/viral immunity and rejection/alloimmunity
and make the clinical strategy immunosuppression dose
reduction for BKV viremia a more complex decision
than previously understood.
HIV
Although kidney transplantation for HIV1 candi-
dates is associated with generally good outcomes, there is
an increased risk of acute rejection along with other donor
and recipient risk factors that may contribute to inferior
graft and patient survival compared with in the HIV–
recipient. In a recent analysis of 499 HIV1 recipients,
improvements in graft survival and mortality were
noted over time (2008–2011 versus 2004–2007). En-
couragingly, center experience (performance of less than
326
Figure 14. Three-year allograft survival was higher in the
HIV monoinfected (81%) and uninfected groups (86%) than
in the HCV monoinfected (78%) and HIV/HCV coinfected
patients (60%; P,0.001). Reprinted with permission from
Sawinski D, Forde KA, Eddinger K, Troxel AB, Blumberg
E, Tebas P, Abt PL, Bloom RD: Superior outcomes in HIV-
positive kidney transplant patients compared with HCV-
infected or HIV/HCV-coinfected recipients. Kidney Int 88:
341–349, 2015.
or more than six HIV1 transplants) was not associated
with outcomes, a point that should encourage further
expansion to a greater number of centers (25). In other
registry studies, factors that were predictive of acute
rejection included short duration of viral suppression
pretransplant (greater than twofold risk in those with HIV
RNA suppression for 6 months; 2 years versus .2 years)
(26) and nonuse of antithymocyte globulin (27). In the
latter study, antithymocyte globulin use was associated
with a 31% reduction in risk for rejection (95% CI, 0.35
to 0.99) (27). Antithymocyte globulin induction was also
associated with a reduction in delayed graft function and
graft loss and a trend to lower mortality without an
increase in risk of infection. Such data support the relative
safety and efficacy of the counterintuitive strategy of T
cell–depleting therapy in the HIV1 recipient. However,
a word of caution is offered by a single-center series that
reported that, in 38 HIV1 recipients treated with antithy-
mocyte globulin induction, pretransplant CD4 counts of
200–349 versus $350 cells per 1 mm3 were associated
with severe lymphopenia (,200 cells per mm3) at 4
weeks post-transplant (75% versus 30%; relative risk, 2.6;
95% CI, 1.3 to 5.1). The lymphopenia was associated
with a more than twofold greater rate of severe infection
during the first 6 months (28).
TAC versus CsA seems to be the preferred
calcineurin inhibitor in HIV1 kidney transplant recip-
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
ients. In a national cohort study in the United Kingdom
composed of 78 patients (31 treated with CsA and 47
treated with TAC), 1-year acute rejection rates were
58% versus 21%, respectively (HR for acute rejection
with TAC versus CsA, 0.25; 95% CI, 0.11 to 0.57;
P50.001) (29). Beyond immunosuppression, a major
factor that strongly contributes to inferior outcomes in
HIV1 recipients is coinfection with HCV. Two recent
studies highlighted that monoinfected HIV1 transplant
recipients have similar graft and patient survival
compared with HIV– reference groups (30, 31). How-
ever, coinfection with hepatitis C virus (HCV; HIV1
/HCV1) is associated with marked reductions in graft
and patient survival (Figure 14). An updated analysis
not only examined the relationship of HCV coinfection
on outcomes but also, focused on other factors that may
contribute to inferior graft loss compared with HIV–
recipients (32). In total, 526 HIV1 kidney transplant
recipients were compared with 82,236 HIV– recipients
in a registry analysis of the era from 2001 to 2013. Two
primary risk factors, HCV coinfection and more than
three HLA mismatches, were identified as risk amplifiers
when examining risk factors for graft loss (adjusted HR,
3.86; 95% CI, 2.37 to 6.30; P,0.001).
Transplant recipients co-infected with HIV
and HCV have markedly inferior graft sur-
vival rates compared with either mono-
infected or non-infected individuals.
With the passage of the HIV Organ Policy Equity
Act, HIV1 recipients may now consent in clinical trials
to receive organs from deceased donors who were
HIV1. The precedent for this originated from experi-
ences in South Africa, where an updated report of 27
HIV1 recipients of kidneys from HIV1 donors was
recently published (33). Death-censored graft survival
rates were 93%, 84%, and 84% at 1, 3, and 5 years
(median follow-up, 2.4 years). Updated reviews on
medication interactions and considerations for drug
resistance, opportunistic infection, and HIV-associated
kidney dysfunction are available (34, 35).
Although any increase in organ donation is of
benefit, an estimate of the impact on the organ shortage
in the greater Philadelphia area by examination of the
medical records of HIV-infected patients dying in
care at six HIV clinics implies a small impact locally
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 327

Table 2. Main characteristics of the approved direct-acting antivirals that are currently used for the treatment of HCV
Direct-Acting Antiviral Dose Adjustment
(Commercial Name), in Renal CNIs
Dose Category Impairment Antiviral Activity Coadministration
Sofosbuvir (Sovaldi), Nucleotide analogue Contraindicated in Genotypes 1-6 No change
tablet 400 mg, once NS5B polymerase patients with High genetic barrier
daily inhibitor GFR,30 ml/min
Simeprevir (Olysio), tablet NS3/4A protease inhibitor No change in renal Genotypes 1 and 4 Contraindicated
150 mg, once daily with impairment Low genetic barrier with CsA
food
Daclatasvir (Daklinza), NS5A inhibitor No change in renal Genotypes 1–4 No change
tablet 60 mg, once daily impairment Low genetic barrier
Ledipasvir/sofosbuvir NS5A inhibitor 1 Contraindicated in Genotypes 1 and 4–6 No change
(Harvoni), tablet nucleotide analogue patients with High genetic barrier
90/400 mg, once daily NS5B polymerase GFR,30 ml/min
inhibitor
Ombitasvir/paritaprevir/ NS5A inhibitor 1 NS3/4A No change in renal Genotypes 1 and 4 CsA: 20% of
ritonavir (Viekirax), protease inhibitor dysfunction Genetic barrier pretreatment total
tablet 12.5/75/50 mg, boosted by ritonavir depending on daily dose; TAC:
two once daily with food boosted HCV genotype 0.2 mg/72 h or
Dasabuvir (Exviera), tablet Non-nucleos(t)ide No change in renal Genotype 1 0.5 mg once weekly
250 mg, every 12 h analogue NS5B dysfunction Low genetic barrier
polymerase inhibitor
Elbasvir/grazoprevir NS5A inhibitor 1 NS3/4A No change in renal Genotypes 1 and 4 Coadministration
(Zepatier), tablet inhibitor dysfunction increases TAC
100/50 mg, once daily concentrations
Velpatasvir/sofosbuvir/ NS5A inhibitor 1 Contraindicated in Genotypes 1–6 No change
(Epclusa), tablet 100/ nucleotide analogue patients with
400 mg, once daily NS5B polymerase GFR,30 ml/min
inhibitor
CNI, calcineurin inhibitor. Modified from Cholongitas E, Pipili C, Papatheodoridis GV: Interferon-free regimens in patients with hepatitis C infection and renal dysfunction or
kidney transplantation. World J Hepatol 9: 180–190, 2017.

(four to five organ donors annually). When extrapolated
nationally, the authors estimated an additional 192
kidneys transplanted annually (36).
Hepatitis C Virus
As described above, HCV1 recipients have in-
ferior kidney graft and patient survival compared with
non–HCV-infected recipients. With the new generation
direct-acting antiviral (DAA) agents, cure for HCV is
achievable. However, until recently, there were no data
supporting their use in advanced CKD or after kidney
transplantation. In CKD, a large, multicenter, double-
blind, randomized trial (the C-SURFER Trial) using
a 12-week course of elbasvir-grazoprevir in 235 pa-
tients with creatinine clearances ,30 ml/min (n5179,
dialysis dependent) achieved viral eradication in 94%
of patients with an excellent safety profile. There were
no discontinuations due to adverse events (37). After
transplant, a number of case series are now available
that show efficacy similar to that in the general
population with a number of different DAA regimens
that include all six HCV genotypes (38, 39). One small
case series describes successful clearance of HCV in
six HIV/HCV-coinfected recipients, a population that
had been excluded from study in the C-SURFER Trial
(40). The American Association for the Study of Liver
Diseases continues to update its recommendations for
use of DAA in HCV (41). A recent review of literature
for DAA in CKD and after kidney transplant forms
a good reference (Table 2) (42). In patients with CKD,
drug-drug interactions between calcineurin inhibitors
and DAAs should always be considered and reviewed
(43). These data have encouraged the expansion of use
of HCV1 organ donors for not only HCV1 recipients,
thereby shortening the waiting time to transplant, but
also, the possibility of using HCV1 donors for HCV–
328
recipients who have no living donors and are expected
to fare poorly on dialysis and/or have an excessively
long expected waiting time for transplant when con-
sidering the candidate’s comorbidities (44). Pilot stud-
ies in this regard are underway.
Direct-acting antiviral agents can effectively
clear HCV pre- or post-transplantation. Be-
fore treating a potential transplant candidate,
carefully consider the patient’s expected
waiting time and willingness to accept
a kidney from an HCV1 deceased donor.
Hepatitis B Virus
Similar to efforts to utilize HIV1 and HCV1
deceased donors in a thoughtful manner and expand
organ utilization, recent guidelines have been published
that clarify the risk of transmission from organ donors
with serologic evidence of hepatitis B virus infection
(45). This guideline specifically reviews considerations
when using kidneys from deceased donors who are
hepatitis B surface antigen positive or hepatitis B core
antibody positive. In general, kidneys from an hepatitis
B surface antigen positive donor can be considered in
hepatitis B virus–vaccinated recipients with high hep-
atitis B surface antibody (HbSAb) titers, provided that
lifelong chronic antiviral therapy is administered.
Additionally, hepatitis B surface antigen positive donor
kidneys can be considered for recipients with low/
absent HbSAb titer with a combination of hepatitis B
immune globulin administration and continuation of
chronic antiviral therapy. Conversely, kidneys from an
hepatitis B core antibody positive donor pose negligible
risks and should be considered for all recipients, with
recommendations for a period of antiviral prophylaxis
for up to 1 year only for the recipient with low HbSAb
titer.
Epstein Barr Virus
Issues related to Epstein Barr virus infection are
discussed below.
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40. Sawinski D, Lee DH, Doyle AM, Blumberg EA: Successful posttrans-
plant treatment of hepatitis C with ledipasvir-sofosbuvir in HIV1 kidney
transplant recipients. Transplantation 101: 974–979, 2017 PubMed
41. Panel AIHG; AASLD/IDSA HCV Guidance Panel: Hepatitis C guidance:
AASLD-IDSA recommendations for testing, managing, and treating adults
infected with hepatitis C virus. Hepatology 62: 932–954, 2015 PubMed
42. Cholongitas E, Pipili C, Papatheodoridis GV: Interferon-free regimens
in patients with hepatitis C infection and renal dysfunction or kidney
transplantation. World J Hepatol 9: 180–190, 2017 PubMed
43. Badri P, Dutta S, Coakley E, Cohen D, Ding B, Podsadecki T, Bernstein B,
Awni W, Menon R: Pharmacokinetics and dose recommendations for
cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir,
and dasabuvir. Am J Transplant 15: 1313–1322, 2015 PubMed
44. Reese PP, Abt PL, Blumberg EA, Goldberg DS: Transplanting hepatitis
C-positive kidneys. N Engl J Med 373: 303–305, 2015 PubMed
45. Huprikar S, Danziger-Isakov L, Ahn J, Naugler S, Blumberg E, Avery
RK, Koval C, Lease ED, Pillai A, Doucette KE, Levitsky J, Morris MI,
Lu K, McDermott JK, Mone T, Orlowski JP, Dadhania DM, Abbott K,
Horslen S, Laskin BL, Mougdil A, Venkat VL, Korenblat K, Kumar V,
Grossi P, Bloom RD, Brown K, Kotton CN, Kumar D: Solid organ
transplantation from hepatitis B virus-positive donors: Consensus
guidelines for recipient management. Am J Transplant 15: 1162–
1172, 2015 PubMed
Malignancy and Kidney Transplantation
There is an increased risk of certain malignancies
after kidney transplant compared with in the general
330
Figure 15. Observed cumulative incidence of lung cancer
during the first 10 years after renal transplantation. All
between-group comparisons were significant by pairwise
log rank test (P,0.001). Reprinted with permission from
Opelz G, Döhler B: Influence of current and previous
smoking on cancer and mortality after kidney transplanta-
tion. Transplantation 100: 227–232, 2016.
population. Quantifying the excess risk of malignancy
specifically due to kidney transplantation and attendant
immunosuppression has been challenging. One issue is
the difficulty of accurate reporting. When comparing
malignancy rates of the Scientific Registry of Transplant
Recipients (SRTR) with those of 15 linked cancer
registries, only 36.8% of cancers were identified in
both sources, with 47.5% additional cases documented
only in cancer registries and 15.7% only identified in
the SRTR (1). Thus, malignancy data solely utilizing
the SRTR are likely an underestimate of the magnitude
of the difference. When using linked data, certain
malignancies have a clear relationship with transplanta-
tion: Kaposi sarcoma, non-Hodgkin lymphoma (NHL),
lip cancer, and nonepithelial skin cancer. Others are
linked more strongly with renal failure itself (kidney
cancer and thyroid cancer) (2). The risk of cancer in
retransplanted recipients compared with primary kid-
ney transplant recipients, again using linked databases,
is similar, except for renal cell carcinoma (RCC) of the
native kidneys (twofold increased risk; adjusted in-
cidence risk ratio [aIRR], 2.03; 95% confidence interval
[95% CI], 1.45 to 2.77), perhaps due to increased kidney
disease exposure or dialysis time (3). The incidence,
clinical consequences, and economic costs of malignancy
after transplantation are significant. When segregating
malignancies into three types, nonmelanoma skin cancer,
viral linked, and other cancers, in 67,157 recipients from
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
2000 to 2011, the incidence of nonmelanoma skin cancer
was diagnosed in 5.7%, viral-linked cancer was diagnosed
in 1.9%, and other cancers were diagnosed in 6.3%. The
mortality risk was more than three times higher in those
with viral-linked malignancy compared with individuals
who were malignancy free by 3 years. Overall, malig-
nancy accounted for 3%–5.5% of total inpatient Medicare
expenditures and 1.5%–3.3% of outpatient expenditures in
the first 3 years after transplant (4). A separate analysis
described a twofold increased risk of death in transplant
recipients after they were diagnosed with de novo cancer
compared with in the general population, despite the
competing risk of death that transplant recipients face
otherwise (5). These data help define the magnitude of the
ongoing problem of cancer in the transplant population and
support ongoing screening of CKD patients as they pass
from phases of ESRD to transplant and back to ESRD.
Risk Factors for Malignancy in the Transplant
Recipient
To define appropriate surveillance strategies, one
must first be able to identify potential risk factors in
addition to common malignancy patterns. Perhaps the
most compelling recent analysis regarding risk factor
identification and management comes from a large
registry study addressing the risk of smoking and the
benefits of smoking cessation. In 45,548 kidney trans-
plant recipients from 1995 to 2012, smoking cessation
before transplant led to a significant reduction in fre-
quency of many malignancies, most prominently lung
cancer (Figure 15 and Table 3) (6). Persistent smoking
was associated with 50% increase in all-cause graft
loss, with similar findings for death and death-censored
graft loss (P,0.001), whereas those who stopped
smoking before transplant had only a modest 10%
increase in all-cause graft loss compared with non-
smokers. Thus, smoking cessation should be strongly
recommended at the time of transplant evaluation and
while on the waiting list.
Smoking cessation before transplant is as-
sociated with a significant reduction in risk
for lung cancer and other virus-associated
malignancies after transplant.
A history of malignancy or specific types of cancer
before transplant may compel heightened screening after
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 331

Table 3. The standardized incidence ratio (SIR; the ratio of the incidence of malignancy in the kidney transplant
population to the incidence in the general population) of various malignancy subtypes during the first 10 years after
renal transplantation by smoking status

ICD10, International statistical classification of diseases and related health problems, 10th revision; CNS, central nervous system. Reprinted with permission from Opelz G,
Döhler B: Influence of current and previous smoking on cancer and mortality after kidney transplantation. Transplantation 100: 227–232, 2016.

transplant. A recent United States registry analysis
showed that pretransplant skin cancer was associated
with post-transplant malignancy (PTM) for not only skin
cancer (subhazard ratio [SHR], 2.92; 95% CI, 2.52 to
3.39) but also, solid tumors (SHR, 1.44; 95% CI, 1.04 to
1.99) and post-transplant lymphoproliferative disease
(PTLD; SHR, 1.93; 95% CI, 1.01 to 3.66) (7). The 5-
year cumulative incidence of any malignancy in those
with pretransplant skin cancer was 31.6% versus 7.4%
(P,0.001) in those with no such history. Conversely, an
Australian and New Zealand Dialysis and Transplant
Registry analysis of prior malignancy history (excluding
melanocytic skin cancers) failed to find an association
between pretransplant malignancy history and post-
transplant recurrence or a second primary malignancy
(8). A systematic meta-analysis of solid organ transplant
recipients reported an association of pretransplant malig-
nancy (of any type) with all-cause mortality (ten studies,
1.5-fold increased risk), cancer-specific mortality (three
studies, threefold increased risk), and post-transplant de
novo malignancy (seven studies, twofold increased risk)
(9). Perhaps the Australian/New Zealand data are dis-
tinctly different from the other analyses due to differ-
ences in transplant eligibility criteria or differences in
point prevalence of nonmelanoma skin cancer. Regard-
ing risk factors for specific types of PTM, the risk of
RCC was specifically studied in a linked registry analysis
of kidney transplant recipients from 1987 to 2010 (10).
There was a more than fivefold increased risk (standard-
ized incidence ratio, 5.68; 95% CI, 5.27 to 6.13) of RCC,
particularly of the papillary subtype, compared with in
the general population. Additive risk was noted with
blacks, men, increasing dialysis time, and the use of
induction therapy but was not noted with specific
maintenance immunosuppression regimen. Interest-
ingly, for colon cancer, an increased risk was present
in kidney transplant patients treated with cyclosporine
and azathioprine but not in those treated with tacrolimus
and mycophenolate, suggesting differential effects of
immunosuppression on different types of solid tumors
(11).
The question of which immunosuppression reg-
imen confers the greatest risk (or the least risk) for
development of PTM is an ongoing subject of study.
Two recent studies implicate azathioprine as a primary
offender in the development of skin cancer, but one
provocatively acquits mycophenolate use as a risk
factor. In a meta-analysis of 27 studies that evaluated
the risk of skin cancer in relation to azathioprine
treatment, there was a significant risk of squamous cell
carcinoma (SCC; hazard ratio [HR], 1.56; 95% CI,
1.11 to 2.18) but not of other types of skin cancers
(12). In a second report of solid organ transplant
recipients (not limited to kidney transplant), a matched
332 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017

Table 4. Association between induction therapy and incident virus–related cancers

Malignancy Type Cancers, N Incidencea aIRR (95% CI) P Value
NHL
No induction 377 142.1 Reference
Polyclonal 125 131.6 0.96 (0.77 to 1.20) 0.70
Muromonab-CD3 80 210.9 1.37 (1.06 to 1.76) 0.02
Alemtuzumab 15 216.2 1.79 (1.02 to 3.14) 0.04
Anti-IL2R 96 114.9 0.82 (0.65 to 1.05) 0.10
Non-NHL VRCs
No induction 164 61.8 Reference
Polyclonal 56 60.0 1.11 (0.82 to 1.53) 0.50
Muromonab-CD3 25 65.9 1.02 (0.65 to 1.58) 0.90
Alemtuzumab 4 57.6 2.05 (0.66 to 6.33) 0.20
Anti-IL2R 53 63.5 1.09 (0.78 to 1.51) 0.60
All VRCs
No induction 541 203.9 Reference
Polyclonal 181 190.6 1.01 (0.84 to 1.21) 0.90
Muromonab-CD3 104 276.8 1.26 (1.01 to 1.57) 0.04
Alemtuzumab 19 273.8 1.84 (1.11 to 3.03) 0.02
Anti-IL2R 149 178.4 0.90 (0.74 to 1.10) 0.30
aIRRs for VRCs after kidney transplantation. The number of cancers diagnosed in each stratum is shown (N). VRCs included NHL, Hodgkin lymphoma, human papillomavirus-
related cancers (cancers of the cervix, vagina, vulva, anus, penis, oropharynx, and tonsil), Kaposi sarcoma, and liver cancer. All models were adjusted for recipient age, sex, race,
retransplantation, zero HLA mismatch status, receipt of living donor kidney, and year of transplant. Only transplants completed in years with at least 20 recipients receiving the
induction therapy of interest were included: polyclonal: 1987–2009; muromonab-CD3: 1987–2003; alemtuzumab: 2001–2009; and anti-IL2R: 1995–2009. Anti-IL2R, anti–IL-2
receptor (daclizumab and basiliximab); VRC, virus-related cancer. Modified from Hall EC, Engels EA, Pfeiffer RM, Segev DL: Association of antibody induction
immunosuppression with cancer after kidney transplantation. Transplantation 99: 1051–1057, 2015.
a
Per 100,000 person-years.

control study of 170 affected patients and 324 controls,
azathioprine use again was associated with increased
risk of SCC (odds ratio, 2.67; 95% CI; 1.23 to 5.76),
whereas an inverse relationship was noted with mycophe-
nolate use with or without concomitant use of tacrolimus
(approximately 50% reduction in odds ratio) (13). The
authors concluded that the excess risk of SCC his-
torically noted with azathioprine is substantially reduced
using modern immunosuppressive regimens. Beyond
azathioprine use, the association of induction therapy
and malignancy risk has remained a question. Using
linked registry analyses, aIRRs of NHL, melanoma,
and the solid tumors lung, colorectal, kidney, and thyroid
cancers were calculated based on use of different types of
induction therapy (14). Nondepleting induction agents
(IL-2 receptor antagonists) were not associated with a
higher aIRR of any malignancy compared with kidney
transplant recipients who did not receive induction.
Conversely, muromonab-CD3 (OKT3) and alemtuzumab
were associated with an increased risk of NHL (aIRR,
1.37; 95% CI, 1.06 to 1.76 and aIRR, 1.79; 95% CI,
1.02 to 3.14, respectively). Polyclonal induction thera-
pies, such as antithymocyte globulin preparations,
were associated with an increased risk of melanoma
(aIRR, 1.50; 95% CI, 1.06 to 2.14) (Tables 4 and 5).
Both thyroid and colorectal cancer, incidence risk ratios
were also higher in the cohort treated with alemtuzumab.
In general, these data point to the safety of IL-2 receptor
antagonists, the lack of increased risk of NHL with
polyclonal depleting therapy, and the need for tailored
monitoring for other malignancies based on the specific
induction agent.
Finally, the question of the effects on PTM of
mammalian target of rapamycin inhibitors (mTORis)
has been further clarified. A large linked registry
analysis of cancer registries and national pharmacy
claims examined cancer incidence in 32,604 kidney
transplant recipients. Non-melanoma skin cancers were
excluded from this analysis (15). Overall, cancer
incidence was modestly and nonsignificantly lower
with sirolimus use (HR, 0.88; 95% CI, 0.70 to 1.11). A
second analysis that included skin cancer data from
a single-registry analysis from the Collaborative Trans-
plant Study of 78,146 primary deceased donor kidney
transplant recipients from 1999 to 2013 showed only
a reduction in the incidence of basal cell carcinoma
with mTORi (HR, 0.56; P50.004), with no reduction
in incidence or risk of any other type of tumor, including
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 333

Table 5. Associations of induction agents with nonvirus-related cancers

Malignancy Type Cancers, N Incidencea aIRR (95% CI) P Value
Lung cancer
No induction 297 111.9 Reference
Polyclonal 127 133.7 1.14 (0.91 to 1.43) 0.20
Muromonab-CD3 46 121.3 1.03 (0.75 to 1.41) 0.80
Alemtuzumab 7 100.9 0.93 (0.42 to 2.07) 0.90
Anti-IL2R 77 92.2 0.73 (0.56 to 0.95) 0.02
Kidney cancer
No induction 261 98.4 Reference
Polyclonal 121 127.4 1.08 (0.85 to 1.38) 0.50
Muromonab-CD3 34 89.6 0.93 (0.65 to 1.34) 0.70
Alemtuzumab 11 158.5 1.20 (0.63 to 2.30) 0.60
Anti-IL2R 102 122.1 1.03 (0.81 to 1.32) 0.80
Colorectal cancer
No induction 164 61.8 Reference
Polyclonal 60 63.2 1.14 (0.82 to 1.58) 0.40
Muromonab-CD3 20 52.7 0.77 (0.48 to 1.24) 0.30
Alemtuzumab 7 100.9 2.46 (1.03 to 5.91) 0.04
Anti-IL2R 47 56.3 0.88 (0.62 to 1.25) 0.50
Thyroid cancer
No induction 103 38.8 Reference
Polyclonal 26 27.4 0.65 (0.40 to 1.04) 0.07
Muromonab-CD3 5 131.8 0.32 (0.12 to 0.80) 0.01
Alemtuzumab 10 144.1 3.37 (1.55 to 7.33) 0.002
Anti-IL2R 27 32.3 0.81 (0.51 to 1.29) 0.40
Melanomab
No induction 107 68.7 Reference
Polyclonal 56 103.4 1.50 (1.06 to 2.14) 0.02
Muromonab-CD3 11 51.1 0.77 (0.41 to 1.45) 0.40
Alemtuzumab 3 81.1 1.14 (0.33 to 3.95) 0.80
Anti-IL2R 38 88.1 1.15 (0.77 to 1.72) 0.50
aIRRs for nonvirus-related cancers after kidney transplantation. The number of cancers diagnosed in each stratum is shown (N). All models were adjusted for recipient age, sex,
race, retransplantation, zero HLA mismatch status, receipt of living donor kidney, and year of transplant. Only transplants completed in years with at least 20 recipients receiving
the induction therapy of interest were included: polyclonal: 1987–2009; muromonab-CD3: 1987–2003; alemtuzumab: 2001–2009; and anti-IL2R: 1995–2009. Anti-IL2R, anti–IL-
2 receptor (daclizumab and basiliximab). Modified from Hall EC, Engels EA, Pfeiffer RM, Segev DL: Association of antibody induction immunosuppression with cancer after
kidney transplantation. Transplantation 99: 1051–1057, 2015.
a
Per 100,000 person-years.
b
Among non-Hispanic white kidney recipients.

SCC (16). A final large, longitudinal analysis from
Australia and New Zealand, where utilization of mTORi
has been higher due to its hypothesized potential
impact on skin cancer, showed a higher risk of all-cause
mortality with mTORi use during a median follow-up of 7
years (17). Taken collectively, the application of mTORi,
specifically for its antineoplastic properties in the pre-
vention of PTM, is not supported by existing data.
Transplant Candidate Cancer Screening
In general, there have been few studies specific to
the transplant candidate population to guide whether
screening practices for malignancies should be substan-
tially different from those used in the general population.
For prostate cancer screening, prostate-specific antigen
(PSA)–based screening per American Urological As-
sociation screening guidelines of 3782 men undergoing
transplant evaluation did not lead to improved patient
survival after transplant but did increase the time to
listing for those with a positive test result (18).
Furthermore, those screened had a reduced likelihood
of receiving a transplant, regardless of PSA value.
Thus, routine PSA screening should be discouraged,
because it may create an unnecessary barrier to trans-
plantation. For colon cancer, the findings of 70 patients
with ESRD undergoing colonoscopy as a function of
334
kidney transplant evaluation were compared with those
from 70 non-ESRD controls matched for age, sex, and
endoscopist (19). Adenomatous polyps were present in
54.3% of ESRD subjects versus 32.9% of controls
(P,0.01), supporting the practice of colonoscopy
screening in the candidate transplant evaluation
similar to the general population. Regarding the use
of mammography for breast cancer screening, a study
of 541 women $40 years old undergoing kidney
transplant evaluation from 2006 to 2012 showed that
patients ages 40–49 and $50 years old had similar
biopsy rates and breast malignancy (20). Although
not a cost-effectiveness analysis, these data generally
support the American Cancer Society recommenda-
tions to start annual mammogram at age 40 years old
in transplant candidates rather than the US Preven-
tative Services Task Force recommendation of bi-
ennial mammogram beginning at age 50 years old. In
cases where breast cancer is identified, genomic
profiling may be increasingly possible to identify
low-risk cancers and shorten the “disease-free in-
active status” that is often 2–5 years long without this
information (21).
Regarding dermatology clearance in individuals
who have had a prior skin cancer, there has been a
consensus report from the International Transplant Skin
Cancer Collaborative that describes a waiting time con-
struct for each skin cancer subtype based on its staging
(22). Using a 60% 5-year post-transplant survival as a
threshold for acceptable expected survival post-transplant,
the International Transplant Skin Cancer Collaborative
advocates for a 2-year waiting time for SCC that is high
risk (.2 cm, high-risk location [e.g., ear, lip, scalp, or
temple], recurrent lesion, or poorly differentiated), and
waiting times of 2 years for melanoma stage Ia, 5 years for
stage Ib, and 5–10 years for stages IIa, IIb, and IIIa;
patients with stages IIc, IIIb, IIIc, and IV would not be
candidates for transplant. Finally, the question of screen-
ing for RCC via ultrasound remains controversial. There is
clearly an increased risk of RCC in patients with ESRD as
described previously. In a surveillance study of 2642
transplant candidates who underwent renal ultrasound at
the time of evaluation followed by annual screening (23)
71 RCCs were identified (52 on initial screening),
with independent associations with men and black
race. Whether this 2%–3% detection rate warrants
such a monitoring strategy remains unanswered, and
no firm consensus has been adopted across the
transplant community.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Recipient Screening for Malignancy
As in the setting of transplant candidate malig-
nancy screening, perhaps even less has been published
specific to screening practices after transplant. A sys-
tematic review of the literature identified 13 relevant
clinical practice guidelines for all organ transplants, of
which eight were specific to kidney transplant recip-
ients (24). The reviewers noted specifically that “there
is a lack of direct evidence to support cancer screen-
ing recommendations” (24). Recommendations were
based primarily on the authors’ interpretations of risk
in the context of general population risk rather than
evidence in a transplant population, without input
from oncology specialists, primary care providers,
and public health experts. Despite these limitations, the
relationship of immunosuppression and virus-mediated
cancers is strong. The appropriate screening for Epstein
Barr virus (EBV)–related cancer remains an area of active
research.
Routine screening for EBV by PCR has been
generally ineffective in the prediction of risk for PTLD
in the adult kidney transplant population: a positive
EBV PCR is insensitive and nonspecific, hindered by
the lack of standardized assay or source (i.e., whole
blood or plasma) (reviewed in ref. 25). An additional
confounder is the increase in the number of cases of
EBV-related PTLD over time (from 10% during the
period 1990–1995 to 48% of cases during the period
2008–2013 in one large series) (26). Parenthetically,
remission rates and survival were found to be similar
whether PTLD was EBV1 or EBV–. Although the data
supporting EBV PCR screening for PTLD risk have
been inconsistent, a positive test may generally predict
an overimmunosuppressed state that is associated with
a higher malignancy risk in general. In 669 patients
screened annually with EBV PCR from whole blood (if
positive, repeated on each routine visit), 147 patients
had a persistently high EBV viral load (27). Persistent
EBV replication was associated with a 70% increase in
the risk of post-transplant cancer (of all types) during
a mean follow-up of 94 months, with an incidence of
cancer of 26.7% in 45 recipients with a persistent PCR
of .10,000 copies per 1 ml. These findings are pro-
vocative, and a standard of care regarding EBV PCR
screening remains undefined. In the absence of screen-
ing, prophylactic antiviral treatment of those at high risk
(EBV-seronegative recipients of organs from seroposi-
tive donors) has been considered a strategy in minimiz-
ing risk for PTLD. Unfortunately, a meta-analysis of 31
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
studies found no effect of this strategy on the prediction
or the incidence of PTLD (28).
Cancer Management in the Transplant Recipient
A common question in the transplant patient with
malignancy is whether altering immunosuppression is
safe and/or effective. Regarding the safety of immuno-
suppression withdrawal during chemotherapy for PTLD,
a study of 24 patients investigated immunosuppression
cessation during chemotherapy and resumption at lower
dose (calcineurin inhibitor at 50%, prednisolone #10
mg daily, no third agent) approximately 6 weeks after
chemotherapy (29). Compared with 83 matched controls,
no difference was noted in time to $25% increase in
serum creatinine. Only one patient with PTLD experi-
enced a $25% increase in serum creatinine within 6
months of withdrawal, which was associated with pro-
gressive PTLD and death. This provides some comfort in
eliminating immunosuppression for short intervals during
periods of aggressive chemotherapy. There are no recent
publications addressing immunosuppression reduction/
withdrawal/transition during treatment for solid tumors.
Novel therapeutic targets for control of a variety
of malignancies include the programmed cell death
pathway (programmed cell death protein 1 [PD-1]
ligand and its receptor PD-1) and the cytotoxic T
lymphocyte–associated antigen-4 (CTLA-4) pathway
(CTLA-4 binding to its ligand B7-1/2) (30). PD-1 is
expressed on T cells (as well as B cells, and natural
killer cells) and binds PD-1 ligand expressed by tumor
cells. This ligand binding leads to T cell exhaustion,
creating a state of immunosuppression. Like the PD-1
pathway, CTLA-4 is expressed on T cells, and ligand
binding leads to T cell exhaustion. Two mAbs to PD-1,
nivolumab and pembrolizumab, inhibit T cell exhaus-
tion and increase tumor surveillance. These agents have
shown efficacy in advanced melanoma and nonsmall cell
lung cancer, and they are under investigation in multiple
other tumor types. In transplant recipients (kidney and
other organs), these agents have been associated with
a near-universal incidence of rejection, often leading to
dialysis dependence in the kidney transplant setting (31,
32). The mAb ipilimumab binds and inhibits this CTLA-
4–induced T cell suppression. Although effective in
preventing tumor progression in metastatic disease, re-
jection has not been reported in solid organ transplant
recipients treated with ipilimumab. A recent review of
case reports was published describing 15 cases (in kidney
and liver transplants) using ipilimumab, nivolumab, and
335
pembrolizumab, with no allograft rejection with ipilimumab
(but potentially lesser antitumor effect [33] than the PD-1
mAbs [34]).
Checkpoint inhibitors targeting PD-1
(nivolumab and pembrolizumab) and CTLA-
4 (ipilimumab) are used to treat metastatic
malignancies. These agents restore T cell
function; PD-1 inhibition can place the trans-
plant at very high risk for rejection.
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mammalian target of rapamycin inhibitor and incidence of post-transplant
cancer in kidney transplant recipients. Nephrol Dial Transplant 31: 1360–
1367, 2016 PubMed
17. Badve SV, Pascoe EM, Burke M, Clayton PA, Campbell SB, Hawley
CM, Lim WH, McDonald SP, Wong G, Johnson DW: Mammalian
target of rapamycin inhibitors and clinical outcomes in adult
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1855, 2016 PubMed
18. Vitiello GA, Sayed BA, Wardenburg M, Perez SD, Keith CG, Canter
DJ, Ogan K, Pearson TC, Turgeon N: Utility of prostate cancer
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19. Saumoy M, Jesudian AB, Aden B, Serur D, Sundararajan S, Sivananthan
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20. Stoecker JB, Cote DR, Augustine JJ, Sarabu N, Schulak JA, Sanchez
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21. Mukhtar RA, Piper ML, Freise C, Van’t Veer LJ, Baehner FL,
Esserman LJ: The novel application of genomic profiling assays to
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22. Zwald F, Leitenberger J, Zeitouni N, Soon S, Brewer J, Arron S,
Bordeaux J, Chung C, Abdelmalek M, Billingsley E, Vidimos A, Stasko
T: Recommendations for solid organ transplantation for transplant
candidates with a pretransplant diagnosis of cutaneous squamous cell
carcinoma, merkel cell carcinoma and melanoma: A consensus opinion
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23. Klein JA, Gonzalez SA, Fischbach BV, Yango AF, Rajagopal A, Rice
KM, Saim M, Barri YM, Melton LB, Klintmalm GB, Chandrakantan A:
Routine ultrasonography surveillance of native kidneys for renal cell
carcinoma in kidney transplant candidates. Clin Transplant 30: 946–
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24. Acuna SA, Huang JW, Scott AL, Micic S, Daly C, Brezden-Masley C,
Kim SJ, Baxter NN: Cancer screening recommendations for solid organ
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25. Dharnidharka VR: Peripheral blood epstein-barr viral nucleic acid
surveillance as a marker for posttransplant cancer risk. Am J Transplant
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26. Luskin MR, Heil DS, Tan KS, Choi S, Stadtmauer EA, Schuster SJ,
Porter DL, Vonderheide RH, Bagg A, Heitjan DF, Tsai DE, Reshef R:
The impact of EBV status on characteristics and outcomes of post-
transplantation lymphoproliferative disorder. Am J Transplant 15:
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27. Bamoulid J, Courivaud C, Coaquette A, Crépin T, Carron C, Gaiffe E,
Roubiou C, Rebibou JM, Ducloux D: Late persistent positive EBV viral
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organ transplant recipients: A systematic review. Am J Transplant 17:
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CM, Marlton P, Gandhi MK, Campbell SB, Mollee P: Cessation of
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in cancer therapy. J Clin Oncol 33: 1974–1982, 2015 PubMed
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Pardoll DM, Taube JM, Drake CG: Tumor regression and allograft
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Cardiovascular Disease
Pretransplant Screening
There is ongoing debate regarding the utility of
testing for ischemic heart disease for risk stratification
purposes in potential kidney transplant candidates. An
updated meta-analysis of a total of 52 cohort and
randomized, controlled studies that included 7401
participants evaluated major adverse cardiac events
and cardiovascular and all-cause mortality after trans-
plant after undergoing a preoperative cardiac screening
test (1). Cardiac screening tests were either noninva-
sive (segregated by dobutamine stress echocardiogra-
phy or myocardial perfusion scintigraphy) or invasive
(angiography). The authors determined that the prog-
nostic value of an abnormal noninvasive test was
similar to that of abnormal coronary angiography for
predicting cardiovascular mortality and major adverse
cardiac events, with a trend suggesting lower all-cause
mortality in the cohort screened by angiography. Based
on these findings, the authors suggested that initial
investigation using coronary angiography is not indicated
in the absence of a conventional indication, and they did
not find superiority of one noninvasive test over another.
Disappointingly, even in large meta-analyses, such as
this one, large numbers of patients with negative test
results still have adverse cardiac outcomes, and large
numbers of patients with abnormal test results do not
have adverse cardiac outcomes; thus, the answer to the
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
question of whether any testing should be routinely
performed remains unanswered. Regarding this latter
point, the reader is referred to a review of the evidence
for screening for cardiovascular disease in kidney trans-
plant candidates (2). Despite this ongoing debate, it is
heartening to note that, even with increasing rates of
transplant of higher-risk candidates (older with more
cardiovascular events before transplant), one regional
Canadian study described that the risk of death or major
cardiovascular event post-transplant has remained stable
over time when comparing 3-year outcomes in a recent era
(2006–2009) with those from a prior era (1994–1997) (3).
Hypertension
Although renin-angiotensin-aldosterone system
(RAAS) blockade is a cornerstone of antihypertensive
management in the CKD population, the nephropro-
tective benefits have not been shown in the kidney
transplant population. Recently, a large, single-center
series; a multicenter, randomized clinical trial; and
a meta-analysis have been published that frame the
issues surrounding RAAS use after kidney transplanta-
tion. In the single-center series, 2684 primary kidney
transplant recipients from 1994 to 2010 with a function-
ing graft at 6 months were retrospectively evaluated for
RAAS agent use or nonuse in a time-dependent analysis,
and the outcomes of mortality and graft loss were as-
sessed (4). A total of 638 graft failures occurred at a
mean of 5.4 years post-transplant. RAAS blockade was
associated with a statistically significant 37% reduction
in hazard for overall graft loss (adjusted hazard ratio
[aHR], 0.63; 95% CI, 0.53 to 0.75), a 31% reduction in
hazard for death (aHR, 0.69; 95% CI, 0.55 to 0.86),
and a 38% reduction in death-censored graft failure
(aHR, 0.62; 95% CI, 0.49 to 0.78). Conversely, a
double-blind, placebo-controlled, randomized trial (the
first in kidney transplant recipients to investigate
RAAS blockade) was conducted at 14 centers and en-
rolled 213 patients .3 months post-transplant who had
eGFR$20 ml/min per 1.73 m2 and proteinuria $200
mg/24 h in a 1:1 ratio to receive placebo versus ramipril
5 mg twice daily (5). Ramipril did not reduce the
primary end point, a composite of doubling serum
creatinine, ESRD, or death. Despite .4 years of
follow-up, the absolute difference between the groups
was only 0.5% (Figure 16). Finally, a meta-analysis of
eight randomized, controlled trials (1502 participants)
with .1 year of follow-up failed to show reductions in
risk of death (risk ratio [RR], 0.96; 95% CI, 0.62 to
337
1.51), transplant failure (RR, 0.76; 95% CI, 0.49 to
1.18), or creatinine level doubling (RR, 0.84; 95% CI,
0.51 to 1.39) compared with in the control group, with
a more than twofold greater risk of hyperkalemia using
RAAS agents (6).
The small n in the case of the randomized trial, the
uncontrolled nature of the single-center trial, and the
meta-analysis inclusion of studies with generally short
follow-up summarize the difficulties in proving (or
disproving) benefit of RAAS agents in kidney trans-
plant recipients. It has been estimated that it would
require a study of over 10,000 subjects to determine if
graft failure was impacted by RAAS inhibition, a very
unlikely circumstance. A thoughtful editorial of the
Lancet Trial concludes that, although RAAS blockade
is unlikely to show a benefit in hard end points, there
are no data to suggest avoiding RAAS inhibitors (7). A
recently published expert review also concludes that no
specific antihypertensive medication has been proven
to be more efficacious than others in reducing mortal-
ity or preventing graft loss (8). As an aside, sodium
restriction remains important in the efficacy of RAAS
blockade in transplant recipients as shown in a series of
22 subjects treated with RAAS blockers whose systolic
BP declined from a mean of 140614 to 129612 mmHg
and diastolic BP declined from 8668 to 7968 mmHg
Figure 16. Ramipril versus placebo after kidney transplan-
tation. Time to the primary outcome of doubling serum
creatinine, ESRD, or death during the extension phase of the
study. Reprinted with permission from Knoll GA, Fergusson
D, Chassé M, Hebert P, Wells G, Tibbles LA, Treleaven D,
Holland D, White C, Muirhead N, Cantarovich M, Paquet M,
Kiberd B, Gourishankar S, Shapiro J, Prasad R, Cole E,
Pilmore H, Cronin V, Hogan D, Ramsay T, Gill J: Ramipril
versus placebo in kidney transplant patients with proteinuria:
A multicentre, double-blind, randomised controlled trial.
Lancet Diabetes Endocrinol 4: 318–326, 2016.
338
after initiation of a low-sodium diet (total daily sodium
intake change from164650 mmol/24 h during the regular
sodium diet to 87655 mmol/24 h) (9).
Post-Transplant Diabetes Mellitus
Post-transplant diabetes mellitus (PTDM) remains
an often-encountered clinical syndrome with strong
associations for patient and graft survival. Multiple
definitions and multiple risk factors clearly play a role
in the frequency of diagnosis of PTDM. Regarding the
incidence of PTDM, perhaps the best point of reference
is a randomized, controlled trial of 1083 patients using
the most objective definitions of diabetes (the Amer-
ican Diabetes Association definitions of hemoglobin
A1c $6.5%, fasting blood glucose $7.0 mmol/L
($126 mg/dl), 2-hour plasma glucose $11.1 mmol/L
($200 mg/dl) during an oral glucose tolerance test, or
symptomatic hyperglycemia and a random plasma
glucose $11.1 mmol/L) and examining a low-risk
population using tacrolimus-containing regimens
(rapid corticosteroid withdrawal [CSWD], predomi-
nantly white, and mean body mass index [BMI] of 25
kg/m2) that reported an incidence of PTDM of approx-
imately 17% 24 weeks post-transplant (10). Identifica-
tion of risk factors for PTDM may facilitate mitigation
of its development and/or severity. In a single-center
study of 672 patients without preexisting diabetes, 32%
developed PTDM (11). A bimodal incidence (#3 months
and .3 months post-transplant) was identified, in which
31% of early PTDM reverted, and a normal oral glucose
tolerance test and normal hemoglobin A1c at 3 months
predicted a low risk (4% incidence) of later-onset
PTDM. Obesity was strongly associated with PTDM,
but tacrolimus levels were not. In a separate series of
150 patients, visceral adipose tissue content measured
via dual energy X-ray absorptiometry scans was the
strongest predictor of PTDM 1 year after transplant
(12). In another series in which 102 of 481 (22.5%)
patients developed PTDM, with mean follow-up of
57 months post-transplant, obesity (BMI$25 kg/m2)
was the strongest predictor of PTDM followed by
planned maintenance with sirolimus, nonwhite recipi-
ent status, and older recipient age (13). A novel risk
factor for PTDM, hypomagnesemia, was reported in a
retrospective series of 948 recipients (14). A serum
magnesium of ,0.74 mmol/L at 1 month post-transplant
(1.8 mg/dl) was significantly associated with increased
risk of PTDM (hazard ratio [HR], 1.58; 95% CI, 1.07 to
2.34; P50.02) and also associated with PTDM using
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
a time-varying model (HR, 1.78; 95% CI, 1.29 to 2.45;
P,0.001) and a rolling average model (HR, 1.83; 95%
CI, 1.30 to 2.57; P50.001). The authors conjecture
that the risk of PTDM imparted by hypomagnese-
mia is due to alterations in cellular transport of glucose
and/or reduced b cell secretion of insulin. Interventional
trials are needed to determine if this association can
be remedied with magnesium supplementation. Finally,
an ongoing concern is the role of chronic corticosteroids
in the development of PTDM. In a recent report
stemming from a 5-year double-blind study compar-
ing early CSWD with corticosteroid maintenance
tapered to 5 mg/d (CCS) from 6 months onward, no
difference in PTDM rates was noted: 36.3% of CCS
patients versus 35.9% of CSWD patients were di-
agnosed with PTDM by 5 years. Notably, insulin
therapy was more prevalent in the CCS cohort versus
CSWD (11.6% versus 3.7%; P50.05) (15). Thus,
traditional risk factors (obesity) and nontraditional risk
factors (hypomagnesemia) may help predict PTDM,
whereas immunosuppression-related risk factors (low-
dose corticosteroids and tacrolimus dose/trough con-
centrations) may be less valuable.
Hyperlipidemia
As reviewed in the last Nephrology Self-Assessment
Program, the Kidney Disease Improving Global Out-
comes Clinical Practice Guideline for Lipid Manage-
ment in CKD states that “in adult kidney transplant
recipients, we suggest treatment with a statin,” implying
that all kidney transplant patients may derive benefit
from therapy, regardless of lipid profile (grade 2B
evidence) (16, 17). A recent provocative study evaluated
HDL cholesterol (HDL-C) function and its association
with cardiovascular and graft outcomes. HDL-C is
thought to protect from the development of atheroscle-
rosis in part due to its role in removal of cholesterol from
macrophage foam cells (cholesterol efflux) (18). In
a prospective study, 495 stable kidney transplant recip-
ients underwent assessment of macrophage cholesterol
efflux capacity and were followed for a mean of 7.0
years. When examined by tertile, cholesterol efflux
capacity was independently associated with increased
long-term kidney allograft survival. Interestingly, it was
not associated with cardiovascular outcomes or mortal-
ity. The association with graft survival was independent
of serum HDL-C levels, suggesting a novel potential
therapeutic target for the prevention of graft failure may
be to increase HDL-C function rather than quantity.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Obesity
Although obesity is not a traditional cardiovas-
cular risk factor, its association with PTDM, and its
frequent consideration for transplant candidacy justifies
discussion as a separate cardiovascular risk factor in
kidney transplantation. Recently published trials con-
tinue to show the survival advantage of transplantation
versus remaining on dialysis in obese candidates but
with greater clarity regarding risks. Using the United
Kingdom renal and transplant registry data from 2004
to 2010, 1- and 5-year survival rates after transplant
were superior to those of waitlisted candidates in all
BMI subgroups, including BMI535–40 and .40 kg/m2
(19). Further comparisons of obese with nonobese trans-
plant recipients (BMI518.5–25 kg/m2) showed no
differences in mortality with increasing BMI. However,
conclusions regarding the latter subgroups are difficult
to extrapolate, because only 540 of the 13,526 total
patients available for analysis had BMI.35 kg/m2.
Using statistical methodology to control for the com-
peting risk of death, a United States registry analysis of
108,654 primary kidney transplant recipients from
2001–2009 showed worse graft survival with increas-
ing BMI (20). With BMI518.5–25 kg/m2 as the
reference, the sub-HRs were 1.15 for 30–35 kg/m2
(P,0.001), 1.21 for 35–40 kg/m2 (P,0.001), and 1.13
for .40 kg/m2 (P50.002). A meta-analysis that did not
account for the competing risk of death similarly found
an increased risk of death-censored graft loss (HR,
1.06; 95% CI, 1.01 to 1.12), an increased likelihood of
delayed graft function (DGF; odds ratio, 1.68; 95% CI,
1.39 to 2.03), and no significant difference in mortality
risk in obese recipients (defined as BMI$30 kg/m2;
HR, 1.24; 95% CI, 0.90 to 1.70) (21). Taken together,
kidney transplant can be considered effective therapy
from the obese patient’s perspective compared with
dialysis, but there are higher risks of morbidity (DGF
and graft loss) than in nonobese transplant recipients
that transplant programs must reconcile.
This additive risk noted in obese patients has
prompted transplant centers to explore surgical options
to optimize outcomes. In one series, laparoscopic sleeve
gastrectomy was performed in 52 renal transplant candi-
dates with a mean BMI of 43.0 kg/m2 (range, 35.8–
67.7 kg/m2), with 29 achieving goal BMI of ,35 kg/m2
at a mean of 92 days (range, 13–420 days) and six
undergoing successful transplant (22). A single-center
series used minimally invasive robotic surgery in 67 living
donor kidney transplants for patients with BMI$40 kg/m2
339
to minimize the substantial risk of wound complications
known to occur in this patient segment (23). There were
no graft losses due to graft thrombosis or infection. The
authors compared their outcomes with registry data
(a total of 612 living donor transplants in recipients
with BMI$40 kg/m2 were performed during the period
2009–2014) and found similar rates of DGF and equiv-
alent graft function and patient survival. However, 2%
of morbidly obese recipients who underwent the open
technique had graft loss due to infection or graft thrombo-
sis. Perhaps expansion of these surgical approaches will
lead to a greater comfort in evaluating and transplanting the
obese transplant candidate.
Nontraditional and Novel Cardiovascular Risk
Factors under Investigation
Structural Parameters. Left ventricular (LV) hy-
pertrophy has been described as a risk factor for poor
cardiovascular and renal outcomes in patients with
stages 2–5 native CKD (24). After transplant, LV mass
index and left atrial volume index often improve
coincident with improvement in LV ejection fraction
(25). In a long-term follow-up study of 100 patients
from two randomized, controlled trials (mean of 8.4
years of follow-up), LV hypertrophy regression was
significantly associated with reduction in risk for
cardiovascular events and mortality, and it was associ-
ated with higher GFR (26). Beyond echocardiographic
parameters, aortic stiffness has also been proposed as
a cardiovascular risk predictor. A recent study of 1497
kidney transplant recipients evaluated aortic stiff-
ness measured by carotid-femoral pulse wave velocity
(PWV) 8 weeks after transplant, with median follow-up
of 4.2 years (27). For every 1-m/s increase in PWV up
to 12 m/s, an increase in mortality risk was identified
(HR, 1.36; 95% CI, 1.14 to 1.62; P50.001). Each
interquartile range increase was similar in magnitude
for risk of death as an age increase of 20 years. Thus,
structural assessments of LV hypertrophy and PWV
may provide greater opportunity for post-transplant risk
stratification, and intervention strategies with LV hy-
pertrophy and PWV regression as surrogate or primary
end points should be considered.
Biochemical Markers. Substudies of the Folic Acid
for Vascular Outcome Reduction in Transplantation
(FAVORIT) Trial have examined serum and urinary
markers as potential indicators of cardiovascular out-
comes. In a population of 1131 participants enriched
for adverse events from the overall cohort of 4110
340
participants, combined elevations of B-type natriuretic
peptide and cardiac troponin I exceeding clinical cutoffs
were associated with future cardiovascular adverse
events (HR, 6.3; 95% CI, 2.7 to 15.0). For kidney graft
loss, the HR was 8.8 (95% CI, 3.4 to 23.1) (28). A
separate post hoc study evaluated urine neutrophil
gelatinase–associated lipocalin, kidney injury molecule-
1, IL-18, and liver-type fatty acid binding protein as
potential biomarkers for adverse events (29). The urine
neutrophil gelatinase–associated lipocalin-to-creatinine
ratio was strongly and independently associated with all
three end points of mortality, graft loss, and cardiovascular
events. Urine kidney injury molecule-1–to-creatinine and
IL-18–to-creatinine ratios were only independently asso-
ciated with greater mortality risk.
Beyond these exploratory biomarkers, another
novel serum assay predictive of cardiovascular end points
was recently reported, a measure of vascular calcification
propensity referred to as T50. T50 represents the time point
of the half-maximal generation of secondary calciprotein
particles from primary calciprotein particles, and is a re-
flection of the capacity of serum to inhibit the amorphous-
to-crystalline transformation of calcium phosphate. In 1455
kidney transplant recipients, T50 measured at 10 weeks
post-transplant was associated with all-cause mortality,
with low (faster) versus high (slower) T50 quartile (HR,
1.60; 95% CI, 1.00 to 2.57) and cardiac mortality (HR,
3.60; 95% CI, 1.10 to 11.83) (30). These findings were
replicated in a longitudinal cohort of 699 patients with
a median follow-up of 3.1 years, in which lower T50
values were independently associated with increased
all-cause mortality and increased cardiovascular mor-
tality, independent of age, sex, eGFR, or other Fra-
mingham risk factors (31). Standardization of test
characteristics and replication of these findings are
warranted in the future.
Clinical Features. Clinical assessments of BP at the
extremes in the transplant candidate may predict kidney
allograft outcomes. Midodrine, often used for symp-
tomatic hypotension in the chronic dialysis setting, was
evaluated as a risk factor for post-transplant outcomes
by linking prescription use 1 year before transplant to
3-month and 1-year outcomes post-transplant (32).
DGF was much more common in the midodrine cohort
(32% versus 19%; P,0.05). More remarkably, at 3 months,
graft failure (5% versus 2%), death (4% versus 1%), and
acute myocardial infarction and cardiac arrest (all P,0.05)
were more common in the midodrine cohort. In the latter,
the 3-month death-censored graft failure aHR was 2.0 (95%
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
CI, 1.18 to 3.39), and the death aHR was 3.49 (95% CI,
1.95 to 6.24). These differential rates of mortality and graft
loss persisted at 1 year and are clinically meaningful given
modern transplant success rates (Figure 17). Conversely,
severe hypertension before transplant may not associate
with poor transplant outcomes. In a single-center study
comparing recipients with severe preoperative hyper-
tension, defined as systolic BP .180 mmHg or di-
astolic BP .110 mmHg (n5111), with those without
severe hypertension (n598), there were no differences
in cardiac events, patient or graft survival, or postoperative
complications, such as DGF, length of stay, or nadir of
serum creatinine (33).
Midodrine use before transplant was re-
cently identified as a risk factor for delayed
graft function, early graft loss, and death
after transplant.
Interventions and Outcomes
Applying cardioprotective principles garnered
from the general and high-risk populations to the trans-
plant population has been a challenge. For example,
aspirin use as primary cardiovascular prevention in
kidney transplant recipients with hyperhomocysteine-
mia was assessed in a post hoc analysis of 981 aspirin
users versus a matched cohort of 981 nonusers in the
FAVORIT Trial (34). After 4 years of follow-up, no
differences in risk for cardiovascular disease events,
all-cause mortality, kidney failure, composite of kid-
ney failure or mortality, or composite of primary
cardiovascular disease events or mortality were noted
with aspirin use. Thus, there is no evidence that
supports its use in primary prevention. Conversely,
the survival advantage of drug-eluting stents (DESs)
versus bare metal stents (BMS) for percutaneous
coronary intervention in the high-risk general popula-
tion was mirrored in a retrospective study of kidney
transplant recipients (35). Using propensity score–
matched registry data, 3245 kidney transplant recipi-
ents underwent percutaneous coronary intervention, in
whom a 20% lower risk of death and 14% lower risk of
death, myocardial infarction, or repeat revasculariza-
tion at 3 years of follow-up were noted with DES
versus BMS. Similarly, patency after endovascular
intervention of transplant renal artery stenosis was
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Figure 17. Incidence of complications at 3 and 12 months post-
transplant according to pretransplant midodrine use. AMI,
acute myocardial infarction. Reprinted with permission from
Alhamad T, Brennan DC, Brifkani Z, Xiao H, Schnitzler
MA, Dharnidharka VR, Axelrod D, Segev DL, Lentine KL:
Pretransplant midodrine use: A newly identified risk marker for
complications after kidney transplantation. Transplantation 100:
1086–1093, 2016.
shown to be superior with DES versus BMS, and both
were superior to percutaneous transluminal angioplasty
alone in a trial of 45 patients who underwent a total of
50 primary endovascular interventions (DES, 18; BMS,
26; percutaneous transluminal angioplasty, six) (36).
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Bone and Mineral Disorders
Hyperparathyroidism
Hyperparathyroidism is commonly recognized
after transplant, but the natural history of disease,
response to therapy, and long-term ramifications are
less well understood. To shed light on the severity and
natural history of disordered mineral metabolism after
transplant, a multicenter, prospective study cohort of
246 recipients with parathyroid hormone (PTH) levels
.65 pg/ml was intensively monitored in the first year
post-transplant (1). In those untreated, 86.2% had
persistent hyperparathyroidism .65 pg/ml, and 40%
had PTH.130 pg/ml at 1 year. In those with persistent
hyperparathyroidism, hypercalcemia rates (albumin-
corrected serum calcium .10.2 mg/dl) peaked at week
8 (48%), decreasing to 25% at 1 year. Similarly,
hypophosphatemia (,2.5 mg/dl) rates peaked at week
2 post-transplant (54%) and improved progressively
over 1 year. Fibroblast growth factor 23 reached a nadir by
the third month post-transplant. This study together with
another longitudinal study of 1237 children, in whom
hyperparathyroidism was observed in 41% of recipients
(2), provide perspectives on the need for and timing of
potential interventions in the post-transplant setting.
Potential interventions include medical (cinacalcet
and paricalcitol) and surgical (subtotal parathyroidec-
tomy) options. A recent randomized, controlled trial
compared cinacalcet with parathyroidectomy for 30
patients with hypercalcemia and hyperparathyroidism 6
months or more from time of transplantation (mean, 3.7
years) (3). After 1 year, ten of 15 patients treated with
cinacalcet had normal serum calcium levels versus 15 of
15 in the parathyroidectomy arm. The latter group had
lower PTH levels and significant increases in femoral
neck bone mineral density (BMD). In a separate single-
center, crossover trial of 43 patients that examined the
effect of a 6-month treatment with paricalcitol (1 mg/d
for 3 months and uptitrated to 2 mg/d if tolerated), PTH
declined during paricalcitol treatment from a mean of
115.6 to 63.3 pg/ml, with vertebral mineral bone density
increasing and bone turnover markers decreasing with
therapy for 6 months (4). Both a reduction in proteinuria
and an increase of serum creatinine were detected during
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
therapy. The latter observation was hypothesized to
result from decreased tubular secretion or increased
generation of creatinine rather than a true change in
GFR. In a separate 3-month study, paricalcitol increased
serum fibroblast growth factor 23 levels and slightly
increased serum KLOTHO levels, raising the possibility
of longer-term benefits from this active vitamin D
receptor analogue. This latter point is highlighted by
a follow-up study of 1840 transplant recipients recruited
in the Lescol in Renal Transplantation Trial with 6–7
years of follow-up (5). Persistent elevation in PTH.65
pg/ml was associated with a 46% (P,0.01) higher risk
of death and an 85% higher risk of graft loss (P,0.001).
Stepwise PTH elevations were associated with all-cause
mortality and graft loss in multivariate analysis. Taken
together, these findings support more aggressive monitor-
ing and management of hyperparathyroidism and its effect
on mineral metabolism.
Osteoporosis
The measure of bone integrity in CKD and after
transplant often involves noninvasive markers as surrogates
for hard end points, such as fracture or bone biopsy data.
Although dual energy X-ray absorptiometry is commonly
used to determine BMD, other novel methods include the
trabecular bone score and the in vivo microindentation
measurement that evaluates trabecular microarchitecture
and the mechanical properties of bone to predict fracture
risk. In 40 kidney transplant recipients, all three modal-
ities were compared with those in 94 healthy controls
(6). BMD by dual energy X-ray absorptiometry was
lower compared with in controls. Trabecular bone score
and bone strength did not differ from controls, despite
longstanding kidney transplant status of .10 years. This
observation suggests that declines in bone health may
not necessarily be a forgone conclusion after transplant.
That bone disease is less severe in the current
transplantation era compared with prior eras is further
supported by three recent studies from different geo-
graphic regions. A database analysis examining 21,769
patients transplanted between 2001 and 2013 disclosed
a 3.8% incidence of hip fracture: a rate of 1.54/1000
patient-years for hip fracture and a rate of 9.99/1000
patient-years for any fracture. On balance, these con-
temporary rates are approximately one half of prior re-
ports from earlier eras (7). A Canadian analysis of
fracture rates from 4821 kidney transplant recipients
from 1994 to 2008 showed a similar 10-year cumula-
tive incidence of hip fracture of 1.7% (8). Additional
343
findings included a 3-year cumulative incidence of
nonvertebral fracture of 1.6% (95% confidence interval
[95% CI], 1.3% to 2.0%), a rate higher than that in the
general population of 0.5% (95% CI, 0.4% to 0.6%;
P,0.001), which is only slightly higher than that in the
nondialysis CKD population (1.1%; 95% CI, 0.9% to
1.2%; P50.03). This may be due to changes over time in
patient management as suggested by a single-center study
from France comparing patients transplanted from 2004
to 2006 with a group transplanted from 2009 to 2011 (9).
Cinacalcet, vitamin D, and bisphosphonates were used
more frequently. Median PTH levels were lower, and
vitamin D deficiency declined from 64% to 20%, whereas
fracture incidence decreased from 9.1% to 3.1% (P50.05).
The incidence of bone fracture post trans-
plantation has declined over time concur-
rent with increasing use of prophylaxis.
Prevention of osteoporosis post-transplant remains
an active area of study. A recent meta-analysis of 12
studies evaluating the efficacy of bisphosphonates in-
cluded 621 patients and described improvements in
BMD of 6.0% at the femoral neck and 7.4% at the
lumbar spine in those taking bisphosphonates com-
pared with those not taking bisphosphonate. However,
this was not associated with a difference in fracture
incidence between groups (10). In the general population,
treatment of low bone mineral density becomes cost
effective when the 10-year probability of hip fracture
reaches approximately 3% as assessed by the Fracture
Risk Assessment Tool (11). In the post-transplant setting,
it is reasonable to consider treatment with bisphospho-
nates in individuals with suspected osteoporosis when
the 10-year probability of hip fracture reaches this
threshold in the absence of other contributing factors in
the first 12 months after transplant when the eGFR is
.30 ml/min per 1.73 m2 (12). Another potential treat-
ment for the prevention of osteoporosis and fractures
post-transplant is the receptor activator of NF-kB ligand
inhibitor denosumab. An open label, prospective, ran-
domized trial of 90 patients compared two denosumab
doses of 60 mg at 2 weeks and 6 months after transplant
with no treatment (13). At 12 months, lumbar spine BMD
increased by 4.6% in the denosumab group and decreased
by 20.5% in the control group (between-group differ-
ence, 5.1%; 95% CI, 3.1% to 7.0%; P,0.001), and total
344
Table 6. Mean lifetimes up to 10 years for SPK and KA and their differences based on graft loss and death for
recipients with ages at transplants from 18 to 55, from 18 to 39, and from 40 to 55 years old
SPK
Graft loss
Age group, 18–55 y 8.00 (0.05)
Age group, 18–39 y 7.99 (0.07)
Age group, 40–55 y 8.00 (0.08)
Death
Age group, 18–55 y 8.68 (0.04)
Age group, 18–39 y 8.77 (0.06)
Age group, 40–55 y 8.59 (0.06)
Numbers in parentheses are SEMs. Modified from Sung RS, Zhang M, Schaubel DE, Shu X, Magee JC: A Reassessment of the Survival Advantage of Simultaneous Kidney-
Pancreas Versus Kidney-Alone Transplantation. Transplantation 99: 1900–1906, 2015.
hip BMD increased by 1.9% (95% CI, 0.1% to 3.7%;
P50.04) compared with in the control group. Other
biochemical measures of bone turnover all significantly
decreased with denosumab. The safety of denosumab
within this trial was reported separately, with more
infections in the denosumab group (n5146) compared
with in the control group (n599), primarily driven by
a higher incidence of urinary tract infection/cystitis (51
versus 25 episodes in 24 denosumab-treated versus 11
control patients; P,0.01). The frequencies of opportu-
nistic viral infections, pyelonephritis, and urosepsis were
not more common (14).
The use of bisphosphonates after trans-
plant is associated with improvements in
BMD but has not been associated with
reduction in risk for fracture.
Finally, another potential contributor to the risk for
hip fracture after transplant is the frequent use of proton
pump inhibitors (PPIs). This specific risk has been de-
scribed in the general population but until recently, was
not reported in the transplant population. A case-control
study compared 231 kidney transplant patients with a first
hip fracture with 15,575 kidney transplant controls using
registry data matched for age, sex, race, and transplant
year (15). PPI use and persistence of use in the year
before fracture (the index date) were greater in the hip
fracture cohort. After multivariable adjustment, the odds
ratio of hip fracture with PPI use was 1.39 (95% CI, 1.04
to 1.84), consistent with but not higher than the risk of
PPI and fracture noted in the general population (16).
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
KA Difference between SPK and KA P Value
7.82 (0.09) 0.18 (0.09) 0.05
7.68 (0.11) 0.30 (0.13) 0.02
7.93 (0.10) 0.08 (0.12) 0.52
8.51 (0.07) 0.17 (0.08) 0.03
8.59 (0.10) 0.18 (0.11) 0.10
8.40 (0.09) 0.19 (0.11) 0.08
References
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S, Vincenti F: A prospective cohort study of mineral metabolism after
kidney transplantation. Transplantation 100: 184–193, 2016 PubMed
2. Bonthuis M, Busutti M, van Stralen KJ, Jager KJ, Baiko S, Bakkaloğlu S,
Battelino N, Gaydarova M, Gianoglio B, Parvex P, Gomes C, Heaf JG,
Podracka L, Kuzmanovska D, Molchanova MS, Pankratenko TE,
Papachristou F, Reusz G, Sanahuja MJ, Shroff R, Groothoff JW, Schaefer
F, Verrina E: Mineral metabolism in European children living with a renal
transplant: A European Society for Paediatric Nephrology/European
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try Study. Clin J Am Soc Nephrol 10: 767–775, 2015 PubMed
3. Cruzado JM, Moreno P, Torregrosa JV, Taco O, Mast R, Gómez-Vaquero
C, Polo C, Revuelta I, Francos J, Torras J, García-Barrasa A, Bestard O,
Grinyó JM: A randomized study comparing parathyroidectomy with
cinacalcet for treating hypercalcemia in kidney allograft recipients with
hyperparathyroidism. J Am Soc Nephrol 27: 2487–2494, 2016 PubMed
4. Trillini M, Cortinovis M, Ruggenenti P, Reyes Loaeza J, Courville K,
Ferrer-Siles C, Prandini S, Gaspari F, Cannata A, Villa A, Perna A,
Gotti E, Caruso MR, Martinetti D, Remuzzi G, Perico N: Paricalcitol for
secondary hyperparathyroidism in renal transplantation. J Am Soc
Nephrol 26: 1205–1214, 2015 PubMed
5. Pihlstrøm H, Dahle DO, Mjøen G, Pilz S, März W, Abedini S, Holme I,
Fellström B, Jardine AG, Holdaas H: Increased risk of all-cause
mortality and renal graft loss in stable renal transplant recipients with
hyperparathyroidism. Transplantation 99: 351–359, 2015 PubMed
6. Pérez-Sáez MJ, Herrera S, Prieto-Alhambra D, Nogués X, Vera M,
Redondo-Pachón D, Mir M, Güerri R, Crespo M, Díez-Pérez A, Pascual
J: Bone density, microarchitecture and tissue quality long-term after
kidney transplant. Transplantation 101: 1290–1294, 2017 PubMed
7. Ferro CJ, Arnold J, Bagnall D, Ray D, Sharif A: Fracture risk and mortality
post-kidney transplantation. Clin Transplant 29: 1004–1012, 2015 PubMed
8. Naylor KL, Jamal SA, Zou G, McArthur E, Lam NN, Leslie WD,
Hodsman AB, Kim SJ, Knoll GA, Fraser LA, Adachi JD, Garg AX:
fracture incidence in adult kidney transplant recipients. Transplantation
100: 167–175, 2016 PubMed
9. Perrin P, Kiener C, Javier RM, Braun L, Cognard N, Gautier-Vargas G, Heibel
F, Muller C, Olagne J, Moulin B, Ohlmann S: Recent changes in chronic
kidney disease-mineral and bone disorders and associated fractures after
kidney transplantation. Transplantation 101: 1897–1905, 2017 PubMed
10. Toth-Manikowski SM, Francis JM, Gautam A, Gordon CE: Outcomes
of bisphosphonate therapy in kidney transplant recipients: A systematic
review and meta-analysis. Clin Transplant 30: 1090–1096, 2016 PubMed
11. Tosteson AN, Melton LJ 3rd, Dawson-Hughes B, Baim S, Favus MJ,
Khosla S, Lindsay RL: National Osteoporosis Foundation Guide
Committee: Cost-effective osteoporosis treatment thresholds: the
United States perspective. Osteoporos Int 19: 437–447, 2008
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12. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD
Update Work Group: KDIGO 2017 Clinical Practice Guideline Update
for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic
Kidney Disease–Mineral and Bone Disorder (CKD-MBD). Kidney Int
Suppl 7: 39–40, 2017 PubMed
13. Bonani M, Frey D, Brockmann J, Fehr T, Mueller TF, Saleh L, von
Eckardstein A, Graf N, Wüthrich RP: Effect of twice-yearly denosumab on
prevention of bone mineral density loss in de novo kidney transplant recipients:
A randomized controlled trial. Am J Transplant 16: 1882–1891, 2016 PubMed
14. Bonani M, Frey D, de Rougemont O, Mueller NJ, Mueller TF, Graf N,
Wüthrich RP: Infections in de novo kidney transplant recipients treated
with the RANKL inhibitor denosumab [published online ahead of print
October 28, 2016]. TransplantationPubMed
15. Lenihan CR, Sukumaran Nair S, Vangala C, Ramanathan V, Montez-Rath
ME, Winkelmayer WC: Proton pump inhibitor use and risk of hip fracture in
kidney transplant recipients. Am J Kidney Dis 69: 595–601, 2017 PubMed
16. Kwok CS, Yeong JK, Loke YK: Meta-analysis: Risk of fractures with
acid-suppressing medication. Bone 48: 768–776, 2011 PubMed
Multiorgan Transplant
Simultaneous Pancreas-Kidney Transplantation
Simultaneous pancreas-kidney transplantation (SPK)
rates have remained stable over the past 2 years after
falling significantly from 2004 to 2013. The number of
active new patients on the waiting list fell over 50%
from 2004 to 2013 as transplant rates fell 25% during
the same period. This decline stabilized with 1160 patients
added to the waiting list and 719 SPK transplants
performed in 2015 (1). The waiting time to transplant
remains significantly shorter for SPK transplants than
for deceased donor transplants, with an average esti-
mated waiting time of slightly over 18 months versus
.7 years for deceased donor transplant (2). Five-year
survival was 89.6% for SPK recipients transplanted in
2010, a steady improvement over time. An ongoing
question is the relative advantage of SPK over kidney
transplant alone (KA). A recent analysis of 7308 SPK
and 4653 KA adult patients with type 1 diabetes trans-
planted in 1998–2009 simulated a randomized, con-
trolled trial by using propensity score matching and
transplant center volume to compare survival rates of SPK
versus KA (3). There was a marginal advantage in patient
survival (0.17 years) and graft survival (0.18 years) with
SPK, findings contrary to previous comparisons (Table 6).
The KA cohort was not stratified by donor type (deceased
versus living donor), suggesting that the marginal benefit
of SPK may disappear if limited to comparison with living
donor KA. Benefits of pancreas transplant beyond survival
rates have also been explored in smaller exploratory
studies. Patients with type 1 diabetes who received SPK
(n525) or living donor KA (n517) underwent angiogra-
phy, echocardiography, and computed tomography for
345
measures of coronary calcification at the time of evaluation
and again .7 years (median, 10.1 years) after transplant
(4). Coronary artery disease progression, calcification, and
systolic function were no different between groups, sug-
gesting that the addition of the pancreas transplant did not
impact these parameters, despite differences in hemoglobin
A1c levels (mean, 5.5% versus 8.3%) between groups. In
another single-center study, health-related quality of life
was assessed in 126 SPK recipients pre- and post-transplant
(mean, 5 years) (5). On multiple measures, including gastro-
intestinal quality of life, psychological status, social func-
tion, and burden of medical treatment, these measures
improved with transplant but did not improve in those with
only one organ functioning (15.9% of patients).
In 2015, 9.7% of SPK transplants were for in-
dications of type 2 diabetes mellitus (1). This reflects
recent clarifications in eligibility criteria for SPK: (1)
renal insufficiency with an eGFR,20 ml/min, (2)
requirement for insulin for treatment of diabetes, and
(3) C peptide ,2 ng/ml or C peptide .2 ng/ml with
body mass index cutoff #30 kg/m2. Patient survival in
SPK recipients with type 1 diabetes mellitus was higher
than in patients with type 2 diabetes mellitus in the most
recent registry analysis (90% versus 86.4% at 5 years)
(1), likely due to older age and comorbidity in the
type 2 diabetes mellitus cohort. Using these eligibility
criteria, with the additional criterion of pretransplant
insulin use ,1 U/kg per day, a comparison of glucose
homeostasis in seven type 2 diabetes mellitus SPK
recipients with that in nine type 1 diabetes mellitus SPK
recipients within 1 year of transplant determined no dif-
ferences in measures of insulin resistance and secretion (6).
Recurrent autoimmunity was recently shown to
contribute to pancreas allograft failure. In a cohort of
223 SPK recipients with a history of type 1 diabetes
mellitus, antibodies to the autoantigens GAD65, IA-2,
and ZnT8 were measured yearly (7). Biopsy-confirmed
type 1 diabetes mellitus recurrence (insulitis and ab-
sence of insulin staining) was found in 5.8% over a
mean follow-up of 6.264.1 years, and it strongly as-
sociated with autoantibody conversion but not with
autoantibody persistence. Recurrent autoimmunity was
not correlated with the type or degree of immunosup-
pression. Finally, for patients who experience pancreas
graft failure, outcomes of a repeat pancreas transplant
are encouraging. A recent comparison of 18 pancreas
retransplant recipients with 78 primary pancreas after
kidney transplant recipients found comparable 3-year
pancreas graft survival rates: 85.1% in both groups (8).
346
Simultaneous Liver-Kidney Transplantation
In 2016, eligibility criteria for simultaneous liver-
kidney transplants (SLKs) were developed and ap-
proved by the Organ Procurement and Transplantation
Network, and they are in the process of implementa-
tion (Table 7). This policy was in response to the
increase in SLK transplants performed over time (626
in 2015 compared with 362 in 2009). A summary of the
rationale has been recently published (9). Some of
the more controversial aspects include the definition
of CKD (,30 ml/min on one occasion with a history
of GFR,60 for 90 days) and the duration of AKI
(.6 weeks, GFR,25 ml/min, or dialysis dependence)
that permit eligibility. In the meantime, many single-
center reports and registry analyses have described the
difficulties in defining the best utility of kidneys trans-
planted to either the kidney waiting list or the more
morbid cohort of liver transplant candidates with renal
disease (10, 11). Perhaps the analysis most reflective of
clinical practice is one that compared 1884 SLK
recipients with 31,882 liver transplant alone (LTA)
recipients transplanted from 2002 to 2009. Patients
were compared based on propensity score matching
Table 7. Medical eligibility criteria for adult simultaneous liver-kidney transplantation
If the Candidate’s Transplant
Nephrologist Confirms a Diagnosis of
CKD with a measured or calculated
GFR#60 ml/min for .90 consecutive d
Sustained AKI
Metabolic disease
For the adult SLK candidate to be prioritized ahead of all KA candidates at the time of their liver offer, the candidate must meet one of the criteria related to kidney function. UNOS,
United Network for Organ Sharing; CrCl, creatinine clearance; HUS, hemolytic uremic syndrome. Modified from https://optn.transplant.hrsa.gov/media/1240/05_slk_allocation.pdf.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
and included matching for dialysis needs and serum
creatinine $2.0 mg/dl pretransplant (12). A small sur-
vival benefit of 3.7 months at 5 years was noted in
patients with pretransplant CKD (no dialysis) who had
an SLK versus an LTA. In those requiring dialysis
(acute and chronic; unspecified duration), there was no
benefit to SLK over LTA at 5 years post-transplant.
Given the difficulties in predicting who truly re-
quires a kidney transplant at the time of liver trans-
plant, a recent report described the use of native renal
biopsy before liver transplant to determine if a concur-
rent kidney transplant should be performed (13). In 59
liver transplant candidates with renal impairment of
unclear etiology, SLK transplant was recommended for
patients with .40% global glomerular sclerosis, with
interstitial fibrosis .30%, or requiring hemodialysis for
.2 months. Based on these criteria, 70% of patients
listed for transplant did not undergo SLK: 23 ultimately
underwent LTA and ten underwent SLK. Renal function
and survival were comparable at 1 year post-transplant.
Importantly, biopsy-related complications were uncom-
mon (n52). Thus, biopsy may provide useful informa-
tion to minimize unnecessary use of kidneys for SLK.
Then the Transplant Program Must Report
in the UNOS Computer System and
Document in the Candidate’s Medical Record
At least one of the following
That the candidate has begun regularly administered dialysis as an ESRD
patient in a hospital-based, independent nonhospital-based, or home setting
At the time of registration on the kidney waiting list, that the candidate’s
most recent measured or calculated CrCl or GFR is #30 ml/min
On a date after registration on the kidney waiting list, that the candidate’s
measured or calculated CrCl or GFR is #30 ml/min
At least one of the following or a combination of both of the following
for the last 6 wk
That the candidate has been on dialysis at least once every 7 d
That the candidate has a measured or calculated CrCl or GFR that is
#25 ml/min at least once every 7 d
If the candidate’s eligibility is not confirmed at least once every 7 d for
the last 6 wk, the candidate is not eligible to receive a liver and a kidney
from the same donor
A diagnosis of at least one of the following
Hyperoxaluria
Atypical HUS from mutations in factor H or factor I
Familial non-neuropathic systemic amyloidosis
Methylmalonic aciduria
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Parenthetically, the most common renal diagnoses
from these biopsies were membranoproliferative GN
(23%), IgA nephropathy (19%), and acute tubular
necrosis (19%).
Finally, the question of whether the liver is
immunoprotective for the kidney in the SLK trans-
plant setting has been asked. In a relatively large,
single-center cohort of 68 SLK recipients, 14 with
pretransplant donor-specific antibodies (DSAs), pro-
tocol post-transplant renal biopsies were performed
(14). Compared with a control group of patients who
had undergone KA (n5136), 28 KA individuals with
pretransplant DSAs experienced higher incidence rates
of antibody-mediated rejection (46.4% versus 7.1%)
and chronic transplant glomerulopathy (53.6% versus
0%). KA patients without DSAs had higher frequencies
of T cell–mediated rejection (30.6% versus 7.4%) and
decline in renal function, whereas the SLK cohort had
stable GFRs. A concurrent liver transplant was strongly
associated with lower cellular- and antibody-mediated
rejection and stable GFR, suggesting that the liver may
indeed protect against chronic immunologic injury.
Multiorgan Transplantation: Utility
Considerations
Although kidney transplant coupled with a second
organ may lead to improved outcomes for other organ
transplant cohorts, this diminishes use of kidneys for the
kidney transplant candidate. A recent paired kidney anal-
ysis evaluated kidney transplant outcomes where a kidney
was transplanted to one recipient (KA) and the contralat-
eral kidney was transplanted to an SLK (n51998) or
simultaneous heart-kidney (SHK; n5276) recipient (15).
The 5-year survival was higher in the KA cohort (81%
versus 66% in SLK; P,0.001; 84% versus 75% in SHK;
P50.02). Graft survival was significantly higher in KA
versus SLK but not SHK. The authors suggest that these
outcomes are contrary to allocation policies that are meant
to optimize survival overall but instead, favor multiorgan
transplantation. For greater details regarding allocation
issues and outcomes in multiorgan transplant, the reader
is referred to a recent review (16).
References
1. Kandaswamy R, Stock PG, Gustafson SK, Skeans MA, Curry MA,
Prentice MA, Israni AK, Snyder JJ, Kasiske BL: OPTN/SRTR 2015
Annual Data Report: Pancreas. Am J Transplant 17[Suppl 1]: 117–173,
2017 PubMed
2. Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh
WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske
BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J
Transplant 17[Suppl 1]: 21–116, 2017 PubMed
347
3. Sung RS, Zhang M, Schaubel DE, Shu X, Magee JC: A reassessment of
the survival advantage of simultaneous kidney-pancreas versus kidney-
alone transplantation. Transplantation 99: 1900–1906, 2015 PubMed
4. Lindahl JP, Massey RJ, Hartmann A, Aakhus S, Endresen K, Günther
A, Midtvedt K, Holdaas H, Leivestad T, Horneland R, Øyen O, Jenssen
T: Cardiac assessment of patients with type 1 diabetes median 10 years
after successful simultaneous pancreas and kidney transplantation
compared with living donor kidney transplantation. Transplantation
101: 1261–1267, 2017 PubMed
5. Martins LS, Outerelo C, Malheiro J, Fonseca IM, Henriques AC, Dias
LS, Rodrigues AS, Cabrita AM, Noronha IL: Health-related quality of
life may improve after transplantation in pancreas-kidney recipients.
Clin Transplant 29: 242–251, 2015 PubMed
6. Chakkera HA, Kudva YC, Chang YH, Heilman RL, Singer AL, Mathur
AK, Hewitt WR, Khamash HA, Huskey JL, Katariya NN, Moss AA,
Behmen S, Reddy KS: Glucose homeostasis after simultaneous pan-
creas and kidney transplantation: A comparison of subjects with C-
peptide-positive non-type 1 diabetes mellitus and type 1 diabetes
mellitus. Clin Transplant 30: 52–59, 2016 PubMed
7. Vendrame F, Hopfner YY, Diamantopoulos S, Virdi SK, Allende G,
Snowhite IV, Reijonen HK, Chen L, Ruiz P, Ciancio G, Hutton JC,
Messinger S, Burke GW 3rd, Pugliese A: Risk factors for type 1 diabetes
recurrence in immunosuppressed recipients of simultaneous pancreas-
kidney transplants. Am J Transplant 16: 235–245, 2016 PubMed
8. Seal J, Selzner M, Laurence J, Marquez M, Bazerbachi F, McGilvray I, Schiff
J, Norgate A, Cattral MS: Outcomes of pancreas retransplantation after
simultaneous kidney-pancreas transplantation are comparable to pancreas after
kidney transplantation alone. Transplantation 99: 623–628, 2015 PubMed
9. Formica RN, Aeder M, Boyle G, Kucheryavaya A, Stewart D, Hirose R,
Mulligan D: Simultaneous liver-kidney allocation policy: A proposal to
optimize appropriate utilization of scarce resources. Am J Transplant
16: 758–766, 2016 PubMed
10. Brennan TV, Lunsford KE, Vagefi PA, Bostrom A, Ma M, Feng S:
Renal outcomes of simultaneous liver-kidney transplantation compared
to liver transplant alone for candidates with renal dysfunction. Clin
Transplant 29: 34–43, 2015 PubMed
11. Hmoud B, Kuo YF, Wiesner RH, Singal AK: Outcomes of liver
transplantation alone after listing for simultaneous kidney: Comparison
to simultaneous liver kidney transplantation. Transplantation 99: 823–
828, 2015 PubMed
12. Sharma P, Shu X, Schaubel DE, Sung RS, Magee JC: Propensity score-
based survival benefit of simultaneous liver-kidney transplant over liver
transplant alone for recipients with pretransplant renal dysfunction.
Liver Transpl 22: 71–79, 2016 PubMed
13. Pichler RH, Huskey J, Kowalewska J, Moiz A, Perkins J, Davis CL,
Leca N: Kidney biopsies may help predict renal function after liver
transplantation. Transplantation 100: 2122–2128, 2016 PubMed
14. Taner T, Heimbach JK, Rosen CB, Nyberg SL, Park WD, Stegall MD:
Decreased chronic cellular and antibody-mediated injury in the kidney
following simultaneous liver-kidney transplantation. Kidney Int 89:
909–917, 2016 PubMed
15. Choudhury RA, Reese PP, Goldberg DS, Bloom RD, Sawinski DL, Abt
PL: A paired kidney analysis of multiorgan transplantation: Implications
for allograft survival. Transplantation 101: 368–376, 2017 PubMed
16. Stites E, Wiseman AC: Multiorgan transplantation. Transplant Rev
(Orlando) 30: 253–260, 2016 PubMed
Pregnancy
A greater understanding of the risks of pregnancy
for the kidney transplant recipient and fetus has been
advanced by recent large, single-center experiences,
voluntary registry analyses, and patient surveys. In a
single-center experience of 138 pregnancies in 89 renal
348
transplant patients from 1973 to 2013, 74% resulted in
live births (1). Of these, 61% births were premature,
52% had low birth weight, and 14% were associated
with preeclampsia. Long-term graft function (eGFR at
1, 5, and 10 years) and 10-year patient survival were
no different compared with those in a paired, nonpregnant
control group. Thus, although obstetric complications
were common, most pregnancies were successful, with
no overt risk to transplant function. A similar registry
report from Italy in 1978–2013 compared 222 successful
pregnancies with 1418 low-risk controls, with general
findings of higher rates of preterm delivery (57.3% versus
6.3%; P,0.001) and babies small for gestational age
(14.0% versus 4.5%; P,0.001) (2). In a subset of this
cohort, 121 successful pregnancies from 2000 to 2014
were compared with the same control group (n51418)
and an additional control group of 610 births in mothers
with CKD, risk for preterm delivery was similar in the
CKD and transplant cohorts, suggesting that degree of
CKD rather than transplant status was the primary
determinant for maternal-fetal outcomes (3).
Greater insight into the appropriate timing post-
transplant to pursue pregnancy for the health of the
transplant was provided by a registry analysis of 21,814
women ages 15–45 years old transplanted from 1990 to
2010 with 729 pregnancies occurring within 3 years of
transplant (4). When examining risk of death-censored
graft loss after pregnancy in years 1–3 post-transplant, an
increased risk was noted in those with pregnancies during
the first post-transplant year (hazard ratio, 1.25; 95%
confidence interval [95% CI], 1.04 to 1.50) and year 2
(hazard ratio, 1.26; 95% CI, 1.06 to 1.50) but not in year
3. Thus, current recommendations to wait at least 1 year
post-transplant before pursuing pregnancy (5) perhaps
should be tempered with the understanding that increased
risk persists into the second year post-transplant.
Beyond timing of pregnancy, the type and degree of
immunosuppression are also an important consideration
for individuals who plan to conceive or become pregnant.
Mycophenolate (MPA) is teratogenic and carries a US
Food and Drug Administration advisory to discontinue
this agent when planning for pregnancy. A recent analysis
of 382 pregnancies in patients with a history of MPA use
from the National Transplantation Pregnancy Registry
reported that birth defects and miscarriages were similar
among kidney transplant recipients who discontinued
MPA.6 versus ,6 weeks before pregnancy and during
the first trimester, whereas the risks of were significantly
increased when MPA was continued or discontinued after
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
the first trimester (6). Rather than interpret this as safe to
continue MPA during the first trimester, a more appropri-
ate interpretation is that MPA should be discontinued as
soon as awareness of pregnancy (or planning) is present.
A general guideline is that mycophenolate should be
transitioned to azathioprine .6 weeks prior to conception.
An editorial on this manuscript, which includes reference
to a separate National Transplantation Pregnancy Registry
analysis, describes pregnancy outcomes in 302 recipients
who discontinued MPA before conception and 142 who
took MPA in the first trimester. Higher incidences of
miscarriages (20% versus 48%; P,0.001) and birth defects
(5.7% versus 11.6%; P50.10) were noted in the latter
group (7). With respect to other immunosuppressive agents,
a recent study of changes in calcineurin inhibitor dose and
blood trough concentrations highlighted changes that
occur in pregnancy (8). In 75 women (88 deliveries),
cyclosporine (n560) and tacrolimus (n528) trough
concentrations fell by the second trimester compared
with 12 months before delivery. These declines necessi-
tated an increase in calcineurin inhibitor dose of 20%–25%,
a reasonable rule of thumb to expect during pregnancy.
When considering risk factors for untoward out-
comes during pregnancy, one concern is that highly
sensitized patients may be more susceptible to rejection,
posing a greater risk to graft outcomes. In a retrospective,
single-center study of 11 pregnant patients, eight had
detectable panel reactive antibody levels (.0%) (9). Two
of the eight had second trimester miscarriages, one had
a stillbirth, and after a median follow-up of 2.3 years after
delivery, three of the eight developed antibody-mediated
rejection leading to graft loss. Although impossible to
control for the many risk factors for rejection, this small
report raises concern for fetal and allograft outcomes in
sensitized patients.
Lastly, whether organ transplant immunosuppres-
sion in the father impacts pregnancy outcomes was
recently explored. A Norwegian registry analysis iden-
tified 2463 men who fathered babies of 4614 deliveries
before and 474 deliveries after solid organ transplanta-
tion (396 after kidney transplant) from 1967 to 2009 and
compared these cohorts with the general population of
2,511,506 births (10). They found no increased risk of
congenital malformations or other fetal or maternal
outcomes compared with in the general population.
Higher rates of preeclampsia (adjusted odd ratio, 7.4;
95% CI, 1.1 to 51.4) occurred in pregnancies post-
transplant compared with pretransplant. Given the wide
95% CI, this finding should be interpreted with caution.
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
References
1. Stoumpos S, McNeill SH, Gorrie M, Mark PB, Brennand JE, Geddes
CC, Deighan CJ: Obstetric and long-term kidney outcomes in renal
transplant recipients: A 40-yr single-center study. Clin Transplant 30:
673–681, 2016 PubMed
2. Piccoli GB, Cabiddu G, Attini R, Gerbino M, Todeschini P, Perrino
ML, Manzione AM, Piredda GB, Gnappi E, Caputo F, Montagnino G,
Bellizzi V, Di Loreto P, Martino F, Montanaro D, Rossini M, Castellino
S, Biolcati M, Fassio F, Loi V, Parisi S, Versino E, Pani A, Todros T;
Italian Study Group on Kidney and Pregnancy of the Italian Society of
Nephrology: Pregnancy outcomes after kidney graft in Italy: Are the
changes over time the result of different therapies or of different
policies? A nationwide survey (1978-2013). Nephrol Dial Transplant
31: 1957–1965, 2016 PubMed
3. Piccoli GB, Cabiddu G, Attini R, Gerbino M, Todeschini P, Perrino
ML, Manzione AM, Piredda GB, Gnappi E, Caputo F, Montagnino G,
Bellizzi V, Di Loreto P, Martino F, Montanaro D, Rossini M, Castellino
S, Biolcati M, Fassio F, Loi V, Parisi S, Versino E, Pani A, Todros T;
Italian Study group on Kidney and Pregnancy of the Italian Society of
Nephrology: Outcomes of pregnancies after kidney transplantation:
lessons learned from CKD. A comparison of transplanted, nontrans-
planted chronic kidney disease low-risk pregnancies: A multicenter
nationwide analysis [published online ahead of print January 21, 2017].
Transplantation doi:10.1097/TP.0000000000001645
4. Rose C, Gill J, Zalunardo N, Johnston O, Mehrotra A, Gill JS: Timing
of pregnancy after kidney transplantation and risk of allograft failure.
Am J Transplant 16: 2360–2367, 2016 PubMed
5. Kidney Disease: Improving Global Outcomes Transplant Work Group:
KDIGO clinical practice guideline for the care of kidney transplant
recipients. Am J Transplant 9[Suppl 3]: S1–S155, 2009 PubMed
6. King RW, Baca MJ, Armenti VT, Kaplan B: Pregnancy outcomes
related to mycophenolate exposure in female kidney transplant recipi-
ents. Am J Transplant 17: 151–160, 2017 PubMed
7. Moritz MJ, Constantinescu S, Coscia LA, Armenti D: Mycophenolate
and pregnancy: Teratology principles and national transplanta-
tion pregnancy registry experience. Am J Transplant 17: 581–582,
2017 PubMed
8. Kim H, Jeong JC, Yang J, Yang WS, Ahn C, Han DJ, Park JS, Park SK:
The optimal therapy of calcineurin inhibitors for pregnancy in kidney
transplantation. Clin Transplant 29: 142–148, 2015 PubMed
9. Ajaimy M, Lubetzky M, Jones T, Kamal L, Colovai A, de Boccardo G,
Akalin E: Pregnancy in sensitized kidney transplant recipients: A
single-center experience. Clin Transplant 30: 791–795, 2016 PubMed
10. Morken NH, Diaz-Garcia C, Reisaeter AV, Foss A, Leivestad T, Geiran
O, Hervás D, Brännström M: Obstetric and neonatal outcome of
pregnancies fathered by males on immunosuppression after solid organ
transplantation. Am J Transplant 15: 1666–1673, 2015 PubMed
Acid-Base and Electrolyte Disorders after Transplant
A few recent studies were published on acid-base
and electrolyte metabolism in transplantation during 2015
and 2016. A summary of key studies includes (1) me-
tabolic acidosis and transplant outcomes, (2) fluid man-
agement post-kidney transplant, and (3) a novel analysis of
the interplay of uric acid and allograft outcomes.
In a multicenter, retrospective cohort of 2318
kidney transplant recipients from 1997 to 2015, the
relationship of serum bicarbonate (total CO2 con-
centration) and outcomes was described (1) After
multivariable adjustment, total CO2 ,22 mmol/L at 3
349
months post-transplant was associated with increased
risk of death-censored graft failure (hazard ratio [HR],
1.66; 95% confidence interval [95% CI], 1.14 to 2.42),
and time-varying concentration of total CO2 ,22
mmol/L was also associated with death-censored
graft loss (HR, 3.17; 95% CI, 2.12 to 4.73) and death
(HR, 3.16; 95% CI, 1.77 to 5.62), even after control-
ling for eGFR. Whether intervention reduces this risk
is yet unproven. Further research in this area is
required (2).
Normal saline is commonly and liberally admin-
istered in the perioperative period after kidney trans-
plantation. A theoretical concern is that this practice
may provoke hyperchloremic metabolic acidosis and
the risk of hyperkalemia with need for dialysis. A
meta-analysis of lower-chloride solutions versus nor-
mal saline identified six randomized trials with 477
patients (3). No difference in risk of hyperkalemia or
delayed graft function was noted, and there were no
significant differences in rejection or graft loss. The
use of balanced electrolyte solutions was associated
with higher pH, higher bicarbonate, and lower serum
chloride concentrations. A strong case cannot be made
for the use of one solution versus the other.
The ongoing question of whether elevated uric
acid is a marker for or contributor to progressive CKD
and graft loss was addressed in a novel retrospective
analysis of 1170 transplants from 2000 to 2010 (4).
Using time-dependent marginal structural Cox propor-
tional hazards models that controlled for kidney func-
tion, with eGFR as a time-varying confounder, uric acid
was not associated with graft failure (HR, 0.90; 95% CI,
0.85 to 0.94 for every 10-mmol/L increase in uric acid),
death-censored graft loss, or death. This supports the
concept that hyperuricemia is not an independent risk
factor for progressive renal dysfunction post-transplant
but rather, is a marker for lower eGFR.
References
1. Park S, Kang E, Park S, Kim YC, Han SS, Ha J, Kim DK, Kim S, Park
SK, Han DJ, Lim CS, Kim YS, Lee JP, Kim YH: Metabolic acidosis and
long-term clinical outcomes in kidney transplant recipients. J Am Soc
Nephrol 28: 1886–1897, 2017 PubMed
2. Messa PG, Alfieri C, Vettoretti S: Metabolic acidosis in renal trans-
plantation: Neglected but of potential clinical relevance. Nephrol Dial
Transplant 31: 730–736, 2016 PubMed
3. Wan S, Roberts MA, Mount P: Normal saline versus lower-chloride
solutions for kidney transplantation. Cochrane Database Syst Rev 8:
CD010741, 2016 PubMed
4. Kim ED, Famure O, Li Y, Kim SJ: Uric acid and the risk of graft failure
in kidney transplant recipients: A re-assessment. Am J Transplant 15:
482–488, 2015 PubMed
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017

Transplantation
Claiming Credits and Evaluation Process
Accreditation Statement
The American Society of Nephrology (ASN) is accredited by the Accreditation Council for Continuing Medical Education to
provide continuing medical education for physicians.
AMA Credit Designation Statement
The ASN designates this enduring material for a maximum of 10 AMA PRA Category 1 Credits™. Physicians should claim
only the credit commensurate with the extent of their participation in the activity.
Original Release Date: November 2017
CME Credit Termination Date: October 31, 2019
Examination Available Online: On or before Wednesday, November 15, 2017
Estimated Time for Completion: 10 hours
Answers with Explanations
• Provided with a passing score after the first and/or after the second attempt
• November 2019: posted on the ASN website when the issue is archived.
Method of Participation
• Read the syllabus that is supplemented by original articles in the reference lists.
• Complete the online self-assessment examination.
• Each participant is allowed two attempts to pass the examination (.75% correct) for CME credit.
• Upon completion, review your score and incorrect answers and print your certificate.
• Answers and explanations are provided with a passing score or after the second attempt.
Activity Evaluation and CME Credit Instructions
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• Click the ASN CME Center.
• Locate the activity name and click the corresponding ENTER ACTIVITY button.
• Read all front matter information.
• On the left-hand side, click and complete the Demographics & General Evaluations.
• Complete and pass the examination for CME credit.
• Upon completion, click Claim Your CME Credits, check the Attestation Statement box, and enter the number of
CME credits commensurate with the extent of your participation in the activity.
• If you need a certificate, Print Your Certificate on the left.
For your complete ASN transcript, click the ASN CME Center banner, and click View/Print Transcript on the left.

Instructions to obtain American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) Points
Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria:
• Be certified by ABIM in internal medicine and/or nephrology and enrolled in the ABIM–MOC program
• Enroll for MOC via the ABIM website (www.abim.org).
• Enter your (ABIM) Candidate Number and Date of Birth prior to completing the examination.
• Take the self-assessment examination within the timeframe specified in this issue of NephSAP.
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check the Attestation Statement box and submit.
• ABIM will notify you when MOC points have been added to your record.

Maintenance of Certification Statement

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to
earn up to 10 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program.
Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity
provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
MOC points will be applied to only those ABIM candidates who have enrolled in the MOC program. It is your responsibility to
complete the ABIM MOC enrollment process.

350
 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
NephSAP, Volume 16, Number 4, November 2017—Transplantation
1. A 68-year-old black man with ESRD is waitlisted
for deceased donor kidney transplantation. His blood
type is A, and he has a calculated panel reactive
antibody (cPRA) level of 80%.
Since implementation of the new Kidney Allo-
cation System (KAS) by the United Network for
Organ Sharing on December 4, 2014, which
ONE of the following factors now associates
with him having an INCREASED likelihood of
receiving a deceased donor kidney compared
with the prior allocation system?
A. His race
B. His cPRA
C. His age
D. His blood type
2. A 66-year-old man is referred for kidney trans-
plantation. He has stage 5 CKD due to membranous
nephropathy (MN), and he has been maintained on
hemodialysis for 3 months. He uses a walker and
needs help to get dressed each day. His examination
shows a slow walking speed and difficulty standing
from a sitting position. He asks about his prognosis
regarding kidney transplantation.
Which ONE of the following should you tell him
about the effect of his physical function on his
transplantation outcomes?
A. It will not affect his graft survival after
kidney transplantation
B. It is associated with increased waitlist
mortality
C. It is associated with a decreased risk for
readmissions after transplantation
D. Physical therapy can mitigate the effects of
frailty on his transplant outcomes
3. A 56-year-old man with ESRD due to IgA nephrop-
athy returns for his routine yearly re-evaluation visit
with your local transplant program. He has been
listed for deceased donor transplantation for 4
years. His blood type is B. No living donors have
been identified. He previously was listed for
an expanded criteria donor kidney, and he asks
whether there are any other options to increase
his chances of receiving a deceased donor kidney
351
transplant. You begin a discussion about the bene-
fits and risks of a Public Health Service Increased
Risk Donor (PHS-IRD) kidney. He is ambivalent
about receiving a kidney from an intravenous drug
user and concerned about the risk of acquiring an
infection from the procedure.
Which ONE of the following should you tell him
about PHS-IRD kidneys?
A. Transplantation of PHS-IRD kidneys is as-
sociated with an increased waiting time
B. Kidneys from individuals with increased
risk behaviors currently make up ,10% of
all deceased donors
C. Kidneys from intravenous drug users are
never used for transplantation
D. His risk of contracting HIV, hepatitis C virus
(HCV), or hepatitis B virus from a PHS-IRD
donor is ,1%
4. A 59-year-old woman with stage 5 CKD is referred
for transplantation. She donated a kidney to her sister
18 years ago and now has advanced CKD compli-
cating diabetes mellitus and hypertension. She has
had multiple pregnancies and received several blood
transfusions after a recent gastrointestinal bleed.
Her blood type is A, and her cPRA is 9%. She is
concerned about the effect of the new KAS on her
chances of receiving a kidney. A discussion ensues
about kidney transplantation options.
Which ONE of the following should you tell her
regarding her options for kidney
transplantation?
A. The quality of decreased donor kidneys has
deteriorated since implementation of Kidney
Allocation System (KAS), with a median
kidney donor risk index of .80%
B. Prior living donors have improved access to
transplantation since implementation of KAS
C. Her projected waiting time for a deceased
donor kidney is likely to be ,4 months
D. She can be listed for transplantation only
after initiation of dialysis
5. A 63-year-old man with ESRD and HCV infection
(genotype 1) as a consequence of a remote history
352
of intravenous drug use is listed for kidney trans-
plantation. He is HCV treatment naı̈ve. He asks
whether it would be better to opt for an HCV-positive
kidney compared with a standard criteria HCV-
negative kidney. His HCV viral load is persistently
high at .450,000 IU/ml.
Which ONE of the following statements should
you tell him regarding the expected outcomes of
receiving an HCV-positive kidney and manage-
ment of HCV infection?
A. Consent to receive an HCV-positive kidney
may dramatically reduce his waiting time
B. Receipt of an HCV-positive donor kidney is
associated with worse allograft survival com-
pared with waiting for an HCV-negative donor
kidney
C. Consent to receive an HCV-positive donor
kidney is not recommended in order to avoid
infection with a virus of different genotype
D. HCV infection should be treated before
transplantation because direct-acting antivi-
ral agents are contraindicated in transplant
recipients receiving calcineurin inhibitors
6. Your transplant surgeon informs you that a de-
ceased donor kidney with premortem AKI has
been offered to a dialysis patient from an affiliated
practice. The donor was 28 years old. The terminal
serum creatinine level is 2.5 mg/dl. The preim-
plantation allograft biopsy shows fibrin thrombi.
Glomerulosclerosis is not present. Your nephrol-
ogy colleague asks you about the expected post-
transplant prognosis.
Which ONE of the following should you tell
your colleague about the expected prognosis of
transplanting this kidney?
A. The risk of delayed graft function (DGF) is
equivalent to receiving a deceased donor
kidney without AKI
B. This donor’s preimplantation kidney biopsy
predicts that DGF is certain
C. The finding of fibrin thrombi on biopsy is
associated with .10% lower allograft sur-
vival at 1 year
D. AKI in the donor kidney does not affect
allograft function at 1 year
7. A 59-year-old woman with ESRD due to polycystic
kidney disease is admitted for transplantation. She
is asymptomatic. Her physical examination shows
a body mass index (BMI) of 37 kg/m2. She has
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
a low-level donor-specific antibody targeting HLA-
A2 (mean fluorescence intensity of 1582). The flow
cytometry crossmatch is negative. She receives the
deceased donor kidney after 28 hours of cold
ischemia time. The preimplantation biopsy shows
no fibrin thrombi. Postoperatively, her urine output
is 3 L over the initial 24 hours. However, the serum
creatinine level rises from 5 mg/dl on postoperative
day 1 to a peak of 6.2 mg/dl on postoperative day 7.
She does not require dialysis, and the serum creatinine
subsequently begins to decline to 1.4 mg/dl over the
next 2 weeks.
Which ONE of the following statements about
this patient’s delayed graft function (DGF) is
CORRECT?
A. The presence of the donor-specific antibody
increases her risk of DGF
B. Her BMI does not influence her risk of DGF
C. Her DGF only affects allograft prognosis
when fibrin thrombi are seen on preimplan-
tation biopsy
D. Her DGF only affects long-term allograft
function if she develops rejection
8. A 29-year-old woman is seen in consultation to
assess her candidacy to donate a kidney to her
father. She is planning to have a family within the
next 3 years. All of her donor testing is normal. She
is ABO compatible and has a negative crossmatch
with her father. They are a one-haplotype match.
Which ONE of the following should you tell her
about her pregnancy risk after live donor
nephrectomy?
A. Pregnancy after kidney donation is more likely
to be complicated by low-birth weight infants
B. Pregnancy after kidney donation is more
likely to be complicated by preterm births
C. Pregnancy after kidney donation is associated
with an increased risk of gestational hyperten-
sion and preeclampsia
D. The risk of neonatal mortality is higher among
kidney donors compared with nondonors
9. A 23-year-old white man has been accepted as
an altruistic living donor. He is completely healthy
and does not smoke. On physical examination, his
BP is 110/80 mmHg. His creatinine clearance is 106
ml/min. He asks about his future risk of developing
kidney failure.
Which ONE of the following should you tell him
about his risk of ESRD after kidney donation?
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
A. It is higher compared with black donors
B. It is no higher than that of nondonors in the
general population
C. It is three to five times higher than non-
donors in the general population
D. It may be lower than that of older donors
10. A 32-year-old woman with ESRD due to reflux
nephropathy is seen in follow-up 6 weeks after
receiving a 6/6-antigen mismatch kidney transplant
from a living unrelated donor. She received in-
duction therapy with antithymocyte globulin and is
now maintained on tacrolimus, mycophenolic acid
(MPA), and prednisone 15 mg daily, with a plan
to taper prednisone to 5 mg daily by week 10.
Her serum creatinine concentration is 1.2 mg/dl.
She wishes to taper entirely off prednisone because
of weight gain and onset of glucose intolerance.
Which ONE of the following should you advise
her about the risks of steroid elimination after
transplantation?
A. It is associated with an increased risk of
mortality
B. It will lower her risk of infection
C. It will lower her risk of developing diabetes
mellitus
D. It will lower her risk of malignancy
E. It is associated with an increased risk of
acute rejection
11. Which ONE of the following statements about
antibody induction therapy for kidney trans-
plantation is CORRECT?
A. Basiliximab therapy associates with marked
reduction in rejection risk in tacrolimus/
mycophenolate/steroid-treated nonsensi-
tized patients
B. Rituximab induction reduces rejection risk
in nonsensitized allograft recipients
C. An alemtuzumab/prednisone-free regimen
is becoming the most widely used strategy
in the United States
D. Induction therapy associates with approxi-
mately 50% rejection risk reduction com-
pared with no induction therapy
12. Which ONE of the following statements about
use of mycophenolate after kidney transplanta-
tion is CORRECT?
A. Dose reductions stemming from adverse
effects are associated with an increased risk
of rejection and graft failure
353
B. The risk of cytomegalovirus (CMV) viremia
is greater with azathioprine compared with
mycophenolate
C. Mycophenolate is associated with a reduced
risk of mortality compared with azathioprine
D. Physical frailty does not affect the frequency
of mycophenolate adverse events
E. Dose-limiting adverse effects are more com-
monly seen in living compared with de-
ceased donor allograft recipients
13. A 38-year-old kidney transplant recipient is admit-
ted for management of an upper gastrointestinal
bleed. She is found to have a bleeding gastric ulcer
that is cauterized endoscopically. She is fatigued
but otherwise asymptomatic. Her allograft function
has been excellent since transplantation 4 months
ago, and her serum creatinine has been stable at 1.3
mg/dl. Her medications include cyclosporine, my-
cophenolate mofetil, prednisone, and valganciclo-
vir. Her hemoglobin stabilizes at 6.7–6.9 g/dl. Her
internist recommends transfusion with 1 U packed
red blood cells. You discuss the benefits and risks
of transfusion as well as transfusion methods with
her internist.
Which ONE of the following statements should
you advise about the risks and methods of
transfusion in this patient?
A. There is no risk of allosensitization, because
she is immunosuppressed
B. Blood transfusion may induce donor-specific
antibody and an increased risk of rejection
C. Leukocyte filtration will eliminate the risk of
allosensitization
D. If she receives blood, it should be CMV
negative
E. If she receives blood, it should be irradiated
14. A 48-year-old woman with ESRD due to lupus
nephritis is evaluated during her annual visit while
waitlisted for transplantation. Her cPRA is 99%
as a result of prior pregnancies and remote trans-
fusions. She has been on the waitlist for 3 years.
Her sister is her only potential living donor.
However, their complement-dependent cytotoxic-
ity crossmatch is positive. Her nephrologist con-
sults you about her candidacy for desensitization.
She has already been listed for kidney paired
donation nationally.
Which ONE of the following should you advise
about HLA antibody desensitization?
354
A. HLA antibody desensitization using plasma-
pheresis and intravenous Ig is associated with
the same excellent outcomes as desensitization
to permit ABO-incompatible transplantation
B. Treatment of subclinical rejection detected
by protocol biopsy abrogates the risk of allo-
graft failure after HLA antibody desensitization
C. The addition of rituximab to her regimen
will increase the risk of infection and ma-
lignancies at 2 years
D. HLA antibody desensitization is associated
with inferior patient and graft survival com-
pared with HLA-compatible transplantation
E. Thrombotic microangiopathy after desensi-
tization is mitigated by plasmapheresis and
does not affect allograft outcome
15. A 68-year-old woman with polycystic kidney disease
receives a kidney donor profile index .86% deceased
donor kidney. Her achieved serum creatinine level is
1.8 mg/dl. She is tolerating maintenance immuno-
suppression with tacrolimus and mycophenolate well.
In addition to serum creatinine levels, which
ONE of the following biomarkers should be
used to best monitor her allograft stability?
A. Kidney injury marker-1
B. Neutrophil gelatinase–associated lipocalin
C. Perforin
D. Granzyme B
E. Urine protein-to-creatinine ratio and/or urine
albumin-to-creatinine ratio
16. A 54-year-old woman with a history of reflux
nephropathy and recurrent urinary tract infection
is seen six months after living donor kidney trans-
plantation. She had prompt function of the allograft,
and her serum creatinine level has been stable at
1.2 mg/dl for the last six weeks. She is concerned
about her bone health because her 10-year proba-
bility of a hip fracture is estimated to be 3.2% based
on the Fracture Risk Assessment Tool (FRAXÒ).
Her immunosuppression includes tacrolimus,
mycophenolate mofetil, and prednisone. The serum
creatinine level is 1.2 mg/dl (eGFR .60 ml/min per
1.73 m2), the parathyroid hormone (PTH) level is
116 pg/ml (reference range, 12 - 88 pg/ml), the serum
calcium is 9.1 mg/dl, the phosphorus is 2.6 mg/dl, the
serum alkaline phosphatase is normal, the 25-hydroxy-
vitamin D level is 30 ng/ml (reference range 5 30–
50 ng/ml), and the 1,25-dihydroxy-vitamin D level
is 32 pg/ml (reference range 5 25–65 pg/ml).
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
Which ONE of the following is the MOST ap-
propriate management strategy for this woman?
A. No further treatment
B. Denosumab
C. A bisphosphonate
D. Teriparatide
17. A 56-year-old man has hypercalcemia and hyper-
parathyroidism 18 months after a second deceased
donor kidney transplant. Laboratory studies show
a serum creatinine of 1.0 mg/dl, a PTH of 1208 pg/ml
(reference range 512–88 pg/ml), a serum calcium of
10.6–11.2 mg/dl, a serum albumin of 4.2 g/dl, a serum
phosphorus of 1.4 mg/dl, and a serum 25-hydroxy-
vitamin D level of 35 ng/ml. A dual energy x-ray
absorptiometry scan shows a Z score of 22.1 and a T
score of 22.7, which was a significant decrease of 7.1%
compared with a previous measurement 1 year ago.
Parathyroid scintigraphy shows four enlarged glands.
Which ONE of the following is the MOST ap-
propriate next step in treatment?
A. Subtotal parathyroidectomy
B. Cinacalcet 30 mg daily and titrate until the
serum PTH level is normalized
C. Paricalcitol 1 mg/d titrated to 2 mg/d as tolerated
D. Denosumab 60 mg administered every 6
months
18. A 31-year-old woman is seen for preconception
counseling 5 years after successful kidney trans-
plantation. She is maintained on stable doses of
tacrolimus, mycophenolate mofetil (MMF), and
prednisone. She had one episode of mild acute
cellular rejection 3 months after transplantation that
responded to pulse methylprednisolone. Her serum
creatinine level has been stable in the 1.4- to 1.6-
mg/dl range over the past year, and the urine protein-
to-creatinine ratio has averaged 400 mg/d. A biopsy
2 years ago showed mild to moderate transplant
glomerulopathy with no active inflammation. At that
time, a donor-specific antibody to HLA-DQ7 was
detected with a mean fluorescence intensity of 7000.
Which ONE of the following is the MOST ap-
propriate management of her immunosuppres-
sion in preparation for and during pregnancy?
A. Transition MMF to azathioprine .6 weeks prior
to attempts to conceive and plan to increase
tacrolimus about 20%–25% during the sec-
ond trimester to maintain therapeutic levels
B. Wait until the first trimester to discontinue
mycophenolate mofetil
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
C. Transition mycophenolate mofetil to siroli-
mus now
D. Discontinue tacrolimus after pregnancy is
confirmed
19. A 54-year-old man with type 2 diabetes mellitus is
evaluated for persistent hypertension 2 years after
a living related kidney transplant. He has no prior
cardiovascular history. His medications are tacroli-
mus, sirolimus (implemented because of gastroin-
testinal intolerance to mycophenolate), prednisone,
amlodipine 10 mg daily, and hydrochlorothiazide 25
mg daily. The systolic BP has consistently been in the
150- to 159-mmHg range using home BP monitoring.
On physical examination, the BP is 158/90 mmHg.
There is no lower extremity edema. Laboratory
studies show a serum creatinine level of 0.9 mg/dl,
potassium of 4.3 mEq/L, and a urine protein-to-
creatinine ratio of 200 mg/g.
Which ONE of the following is the MOST ap-
propriate agent to add for BP control?
A. Furosemide
B. Hydralazine
C. Labetalol
D. Lisinopril
20. A 62-year-old man with ESRD due to type 2
diabetes mellitus currently maintained on hemodi-
alysis for 1 year is seen in consultation to evaluate
his candidacy for kidney transplantation. His past
medical history is significant for stable coronary
artery disease that required placement of a drug-
eluting stent in the left circumflex artery 3 years
ago. His BMI is 36.5 kg/m2.
Which ONE of the following is the MOST ap-
propriate statement regarding his expected
transplant outcome?
A. His risk of graft loss (death censored) is similar
to that of nonobese transplant recipients
B. His mortality risk is higher than nonobese
transplant recipients
C. His risk of DGF is higher than nonobese
transplant recipients
D. His mortality risk with transplant is higher
than his nonobese waitlisted counterparts
21. A 64-year-old woman with ESRD due to chronic
GN and a remote history of a transient ischemia
attack and peptic ulcer disease has been on hemo-
dialysis for 6 years. She is active on the kidney
waitlist. She suffers from hypotension during di-
alysis and requires regular use of midodrine during
355
dialysis to maintain systolic BP .90 mmHg. Her
systolic BP on nondialysis days is 90–100 mmHg.
Her medications include omeprazole, aspirin, seve-
lamer carbonate, magnesium oxide, and methoxy
polyethylene glycol epoetin-b. She had a normal
exercise stress test within the past year. An echo-
cardiogram shows severe left ventricular hypertro-
phy. Her laboratory studies are significant for a low
serum magnesium of 1.3 mg/dl.
In considering her clinical risk factors, which
ONE of the following clinical features is MOST
highly associated with graft loss after
transplant?
A. Midodrine use
B. Hypomagnesemia
C. Proton pump inhibitor use
D. Aspirin use
22. A 44-year-old man with HIV-associated nephrop-
athy has been on dialysis for 4 years. His HIV viral
load is undetectable on highly active antiretroviral
therapy, with a recent CD4 count of 480/ml and no
opportunistic infections. He wishes to pursue
kidney transplantation.
When considering his transplant referral and
management, which ONE of the following is the
MOST appropriate management?
A. Use of cyclosporine rather than tacrolimus
for maintenance immunosuppression
B. Use of thymoglobulin induction therapy
C. Referral to a transplant center with extensive
prior experience in HIV-positive transplantation
D. Avoidance of HIV-positive deceased donors
23. A 62-year-old man was found to have BK virus
(BKV) viremia (16,240 copies/ml) 6 months after
deceased donor transplant while on tacrolimus,
MPA, and prednisone. A biopsy of the allograft 6
months after transplantation showed no evidence
of rejection or BKV nephropathy. His tacrolimus
and MPA doses were initially reduced by 25%.
MPA was further reduced by an additional 50%
over the subsequent 3 months due to persistent
viremia. Over the next 3 months, BKV viremia
remained present at very low levels (1000–2000
copies/ml). Renal allograft function remained sta-
ble throughout the 6-month period, with serum
creatinine of 1.2 mg/dl.
Compared with individuals who never de-
veloped BKV viremia, which ONE of the fol-
lowing is the MOST likely clinical outcome?
356
A. Development of de novo donor-specific
antibodies
B. Graft loss due to BKV nephropathy
C. Development of a second viral infection
D. Increased mortality
24. A 55-year-old man with ESRD secondary to type
2 diabetes mellitus is evaluated for future kidney
transplantation. He has been on dialysis for 6 months,
and he has a potential living donor, his wife, who
is otherwise healthy. He is a nonsmoker. He has
a history of squamous cell skin cancer on his scalp
that was diagnosed and successfully resected with
clear margins 1 year ago. The lesion was 2.1 cm in
size. He had a 1-cm tubular adenomatous polyp
resected 2 years ago during screening colonoscopy.
He has no symptoms of urinary frequency, urgency,
or hesitancy. He does not have hematuria and has not
worked in aluminum smelting, rubber manufacture,
or leather industries. There is no family history of
colon cancer or prostate cancer.
Regarding his risk for malignancy after trans-
plant, which ONE of the following is the MOST
appropriate management recommendation?
A. An additional 1-year waiting time (total
waiting time 52 years) on the basis of prior
skin cancer history
B. Repeat colonoscopy now before proceeding
with a living donor transplant
C. Check a screening serum prostate-specific
antigen level
D. Refer him for screening cystoscopy
25. A 55-year-old man with ESRD secondary to membra-
nous nephropathy (MN) is seen to assess his candi-
dacy for kidney transplantation. He still produces urine
and has persistent proteinuria (6 g/d). An antiphospho-
lipase A2 receptor autoantibody level drawn at the time
of evaluation is negative. He is scheduled to receive
a living unrelated kidney transplant from a friend.
Which ONE of the following is the MOST ac-
curate regarding his risk for recurrent MN af-
ter transplant?
A. He has a high (.80%) likelihood of de-
veloping recurrent MN
B. The absence of anti-phospholipase A2 re-
ceptor (anti-PLA2R) antibody indicates
a low risk (,20%) of recurrent MN
C. Graft survival is significantly lower in those
who develop recurrent MN than the general
transplant population
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
D. Recurrent MN with progressive proteinuria
typically responds to rituximab
26. A 49-year-old woman with type 2 diabetes mellitus
and stage 5 CKD undergoes an evaluation for kidney
transplantation. She has no identified living donors.
She has had insulin-requiring diabetes mellitus for 18
years. Her BMI is 28 kg/m2. Laboratory studies show
an eGFR of 14 ml/min per 1.73 m2, a C-peptide level
of 3.2 ng/ml, and a hemoglobin A1c of 6.8%. She
wishes to discuss pancreas transplantation.
Which ONE of the following is the MOST ac-
curate when discussing simultaneous pancreas-
kidney (SPK) transplantation with her?
A. She is an eligible candidate for SPK
transplantation
B. SPK transplant in type 2 diabetes mellitus
recipients is associated with a higher risk of
rejection compared with in type 1 diabetes
mellitus recipients
C. SPK transplant in type 2 diabetes mellitus
recipients is associated with an increased
risk of primary nonfunction compared with
in type 1 diabetes mellitus recipients
D. SPK transplant in type 2 diabetes mellitus
recipients is associated with worse pancreas
graft survival compared with in type 1 diabetes
mellitus recipients
27. A 55-year-old woman with type 1 diabetes and ESRD
for 6 months is evaluated for kidney transplantation.
She has consistently achieved a hemoglobin A1c level
of about 7.2 %–7.8% using an insulin pump. Her
BMI is 31 kg/m2. She has not had emergency care or
third party assistance for hypoglycemia. She does not
have symptomatic cardiovascular disease. She has no
potential living kidney donors and wishes to consider
pancreas transplantation. Her C peptide is ,2 ng/ml.
Which ONE of the following should you tell her
about SPK transplantation?
A. She is not a candidate for SPK transplantation
B. SPK transplant is associated with substantial
improvements in health-related quality of
life, even in the setting of early pancreas
transplant failure
C. SPK transplant is associated with substantial
improvements in long-term survival com-
pared with kidney transplant alone
D. SPK transplant waiting time is substantially
shorter than for deceased donor kidney trans-
plant alone
Nephrology Self-Assessment Program - Vol 16, No 4, November 2017
28. In 2016, eligibility criteria for simultaneous liver-
kidney transplant were developed and approved by
the Organ Procurement and Transplantation Network.
Which ONE of the following liver transplant
candidates is NOT eligible for simultaneous
liver-kidney transplantation?
A. A 64-year-old man with stage 3 CKD
(eGFR545–50 ml/min per 1.73 m2) docu-
mented for 4 months and a recent fall in
eGFR during a period of hypovolemia to 25
ml/min per 1.73 m2
B. A 19-year-old woman with primary hyper-
oxaluria, nephrocalcinosis, and stage 5 CKD
C. A 54-year-old man with HCV infection, type
2 diabetes mellitus, an eGFR of 35–40 ml/min
per 1.73 m2, and proteinuria of 1 g/d
D. A patient with type 2 hepatorenal syndrome
with an eGFR of 15–25 ml/min per 1.73 m2
over the past 6 weeks
29. A 62-year-old man with chronic GN is to undergo
living unrelated kidney transplant. He has a history
of squamous cell carcinoma successfully treated 5
years ago. He is CMV naı̈ve (serum IgG for CMV
is negative), whereas his prospective donor is CMV
IgG positive. Other past medical history includes
chronic idiopathic diarrhea two to three times daily.
An extensive evaluation of the diarrhea was unre-
vealing. The transplant center is considering use of
357
tacrolimus combined with the mammalian target of
rapamycin inhibitor everolimus and prednisone as
initial maintenance immunosuppression.
Compared with tacrolimus/mycophenolate-
based immunosuppression, which ONE of the
following is the MOST likely clinical outcome of
using tacrolimus/everolimus/prednisone in the
absence of CMV prophylaxis?
A. Lower incidence of CMV viremia
B. Lower incidence of acute rejection
C. Lower incidence of mortality
D. Lower incidence of nonskin malignancy
30. A 62-year-old man with chronic GN is to undergo
living unrelated kidney transplant. His calculated
panel reactive antibody score is 0%, and the HLA
mismatch with the donor is four out of six. In addition
to tacrolimus/mycophenolate-based immunosup-
pression with prednisone, the transplant center
is planning use of rabbit antithymocyte globulin
for induction therapy.
Compared with induction therapy with an IL-2
receptor antagonist, which ONE of the following is
the MOST likely clinical outcome of using rabbit
antithymocyte globulin for induction therapy?
A. A lower incidence of acute rejection
B. A lower incidence of graft loss
C. A lower incidence of mortality
D. A lower incidence of malignancy