Nephrology

Dear Colleagues,

It is with great pleasure that I write to you regarding recent breakthroughs in the field of

onconephrology. This is a somewhat new area of nephrology that seeks to support clinical

knowledge, education and research in the rapidly changing and intersecting worlds of oncology

and kidney diseases.

Drs. Kenar Jhaveri and Rimda Wanchoo from Northwell Health Nephrology have become

international leaders in this emerging field. Dr. Jhaveri is the Co-Editor of the 2015 textbook,

“Onconephrology: Cancer, Chemotherapy and the Kidney.” Dr. Wanchoo is Associate Editor for

the Journal of Onconephrology.

If you are like me, you have probably marveled at the rapid advances in cancer biology and

therapies in recent years. We, as nephrologists, have an urgent need to understand the renal

implications of these advances. Moreover, the renal complications of cancer, from

hypercalcemia to acute kidney injury and glomerular diseases, are extensive and knowledge on

the subject is quickly evolving. Staying up to date can be challenging, so we are very pleased to

provide you with some recent articles of interest.

Enclosed with this packet are recent key articles in Onconephrology from Northwell Health

Nephrology:

1. New England Journal of Medicine correspondence on immune checkpoint inhibitors in

the setting of kidney transplantation.

2. JAMA Oncology – BRAF mutations in melanoma and kidney complications.

3. CJASN article on multiple myeloma and the renal effects.

4. Am J Nephrology – A review of the renal effects of immune checkpoint inhibitors.

5. Kidney Int R – A review of all novel targeted therapies and their renal effects.

Enjoy, and we would love to hear back from you; your comments, ideas and anything else you

would like to discuss!

Steven Fishbane, MD Chief, Division of Kidney Diseases and Hypertension Department of Medicine, Northwell Health Vice President for Network Dialysis Services Northwell Health Professor of Medicine Hofstra Northwell School of Medicine

Northwell Health Physician Partners

Kidney and Hypertension Specialists

100/125 Community Drive, 2nd Floor

Great Neck, New York, 11021

Phone: (516) 465-8200

Fax: (516) 465-8202

Biographies of Onconephrologists

Rimda Wanchoo, MD is Assistant Professor of Medicine in the Division of

Kidney Diseases and Hypertension at Hofstra Northwell School of Medicine

in New York. She completed her residency training at St. Barnabas Medical

Center in New Jersey and subsequently her fellowship in Nephrology at the

New York Presbyterian-Weill Cornell campus and Memorial Sloan Kettering

Cancer Center. She has published in various journals and textbooks on

topics related to onconephrology in chemotherapy and targeted therapy

toxicities. In addition, her interests are in HSCT-related renal disease and paraprotein related

renal diseases. She serves as a Cancer and Kidney International Network Expert member. Her

work has been profiled in Kidney International, American Journal of Nephrology and Clinical

Journal of the American Society of Nephrologists (CJASN). She is the section editor of the

“Nephrotoxicity Corner” in the Journal of Onconephrology, as well as an associate editor for the

journal. She has given numerous talks locally and nationally on the topic of onconephrology.

She serves as the Chair of Quality for the Northwell Health Division of Kidney Diseases and

Hypertension, and is actively involved in research in onconephrology at the regional and

national level. Her other clinical interests are in glomerular diseases, dialysis and cardio-renal

diseases. She lives with her husband and two children in Manhasset, New York.

Kenar D. Jhaveri, MD is Professor of Medicine in the Division of Kidney

Diseases and Hypertension at the Hofstra Northwell School of Medicine in

New York. He completed his residency training at Yale University New

Haven Hospital in Internal Medicine and then a fellowship in Nephrology at

New York Presbyterian Hospital-Weill Cornell campus and Memorial Sloan

Kettering Cancer Center. Dr. Jhaveri's primary clinical interest is in the care

of patients with renal complications following chemotherapy and targeted

therapies and paraneoplastic glomerular diseases, as well as glomerular diseases, drug toxicities

and cardio-renal diseases. He is one of the founding members of ASN's workgroup on

onconephrology. He has published on onconephrology and has also established a presence in

the use of social media and other innovative tools (games, concept maps, role playing, creative

writing, etc.) to make nephrology a fun and exciting field. He serves as the scientific advisory

board member for the Journal of Onconephrology and on the editorial team of the American

Journal of Kidney Diseases (AJKD). He is part of the governing body of the Cancer and Kidney

International Network (CKIN) and serves as an expert member. He recently edited a Springer

textbook, “Onconephrology: Cancer, Chemotherapy and the Kidney”, a case-based approach.

He was the first editor-in-chief of the official blog of the AJKD and led its development from

2010-2016. He has a teaching-oriented blog called Nephron Power and is a columnist for the

ASN Kidney News’ section entitled "Detective Nephron". His interest in nephrology education is

vested in using creative ways of teaching nephrology to medical students, residents and

fellows. He serves as the Associate Chief for the Northwell Health Division of Kidney Diseases

and Hypertension and Site Director for the Nephrology Health Fellowship program. He is the

recipient of numerous teaching awards both locally and internationally. He lives with his wife

and two children in Searingtown, New York.

Contact us by email at kjhaveri@northwell.edu and at rwanchoo1@northwell.edu

Please visit our websites www.northwell.edu and www.nephronpower.com

You can also find us on Twitter: @HofstraKidney

Faculty Division of Kidney Diseases and Hypertension

Clinical Interests: Anemia of Kidney Disease, Chronic Kidney Disease, Cardio-Renal, Hypertension, Diabetic Kidney Disease

Steven Fishbane, MD

Vice President, Network Dialysis Services Chief, Kidney Diseases & Hypertension Director, Clinical Research, Department of Medicine Professor, Medicine, Hofstra Northwell School of Medicine

Alessandro Bellucci, MD

Executive Director, North Shore University Hospital Associate Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Chronic Kidney Disease, Electrolytes, Kidney Stones

Richard Lawrence Barnett, MD

Associate Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: ICU Nephrology

Madhu Bhaskaran, MD

Medical Director, Northwell Kidney Transplant Program Associate Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Immunosuppression Management, Renal Trans-plantation, Parenteral Nutrition

Ezra Hazzan, MD, FACP, FNKF Medical Director, LIJMC Dialysis Facilities Associate Chair, LIJMC Department of Medicine Director, Clinical Research, Department of Medi-cine Associate Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Chronic Kidney Disease, Electrolyte Disorders, Kidney Stones, Polycystic Kidney Stones, Hypertension

Holly Koncicki, MD

Assistant Professor, Medicine, Hofstra North-well School of Medicine Director, Center for Conservative Kidney Care

Clinical Interests: Cardio-Renal, Chronic Kidney Disease, Palliative Care/ Conservative Care Management

Michael Gitman, MD

Medical Director, North Shore University Hospital Assistant Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Chronic Kidney Disease, Electrolyte Disorders

Associate Chief, Kidney Diseases & Hypertension Professor, Medicine, Hofstra Northwell School of Medicine

Kenar Dinesh Jhaveri, MD, FACP, FASN, FNKF

Clinical Interests: Cardio-Renal, Glomerular Diseases, Onconephrology

Jamie S. Hirsch, MD

Assistant Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Chronic Kidney Disease, Electrolyte Disorders, Kidney Stones

Susana Hong, MD Assistant Professor, Medicine, Hofstra North-well School of Medicine

Clinical Interests: Cardio-Renal, Chronic Kidney Disease, Hypertension, Renal Artery Stenosis

Faculty Division of Kidney Diseases and Hypertension

Clinical Interests: Cardio-Renal, Chronic Kidney Disease, Electrolyte Disorders

Daniel Ross, MD

Assistant Professor, Medicine, Hofstra Northwell School of Medicine

Mala Sachdeva, MD Medical Director, True North Waldbaum Peritoneal Dialysis Program Associate Professor, Medicine, Hofstra Northwell School of Medicine

Rimda Wanchoo, MD

Assistant Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Cardio-Renal, Glomerular Diseases, Kidney Stones, Onconephrology

Pravin C. Singhal, MD, FACP

Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Chronic Kidney Diseases, Diabetic Kidney Disease, HIV and Kidney Disease, Hypertension, Glomerular Diseases

Northwell Health Physician Partners Kidney and Hypertension Specialists

100/125 Community Drive, 2nd Floor

Great Neck, New York, 11021 Phone: (516) 465-8200

Fax: (516) 465-8202

Ilene Miller, MD

Medical Director, True North Waldbaum Dialysis Unit Medical Director, Northwell Acute Units Associate Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Hypertension, Hemodialysis, Peritoneal Dialysis, Obstetric Nephrology

Anna T. Mathew, MD, MPH

Associate Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Hypertension, Chronic Kidney Disease, Hemodialysis, Peritoneal Dialysis

Lionel Mailloux, MD

Medical Director, True North Port Washington Dialysis Center Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: General Kidney Disease, Chronic Kidney Disease, Diabetic Kidney Disease, Hypertension

Clinical Interests: Chronic Kidney Disease, Glomerular Disease, Obstetric Nephrology

Hitesh H. Shah, MD, FACP, FASN Director, Nephrology Fellowship Program, North Shore University Hospital and LIJ Medical Center Combined Program Professor, Medicine, Hofstra Northwell School of Medicine

Clinical Interests: Chronic Kidney Disease, Dialysis, Glomerular Disease, Hypertension

n engl j med 376;2 nejm.org January 12, 2017 191

Preserved Renal-Allograft Function and the PD-1 Pathway Inhibitor Nivolumab

To the Editor: Inhibition of immune check-points with the use of antibodies targeting pro-grammed cell death 1 (PD-1) or monoclonal anti-bodies against cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) has been used clinically in patients with various types of cancer. In the limited number of reported cases in which these antibodies have been used in patients who have undergone kidney transplantation,1 these agents have been associated with cell-mediated and antibody-mediated rejection (see Table S2 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).

We report on a patient who received a renal transplant from a living related donor. In this patient, a regimen of a preemptive glucocorti-coid and sirolimus (a mammalian target of ra-pamycin [mTOR] inhibitor) may have prevented the adverse immune response of nivolumab in the kidney transplant.

A 70-year-old man with end-stage kidney dis-ease after bilateral nephrectomies for renal-cell cancer underwent a kidney transplantation in 2010, with one of six HLA mismatches between the recipient and the graft. The patient received basiliximab (an anti–interleukin-2 receptor anti-body) and glucocorticoid induction followed by initial immunosuppression that included a gluco-corticoid, tacrolimus, and mycophenolate mofetil.

In early 2015, the patient received a diagnosis of microsatellite-stable metastatic adenocarci-noma of the duodenum with intestinal obstruc-tion and liver metastases. He did not have a clinically significant response to treatment that included the administration of standard chemo-

therapy and discontinuation of mycophenolate mofetil, decreased doses of tacrolimus, and in-testinal stenting.

Disease progression led to the initiation of nivolumab at a dose of 3 mg per kilogram of body weight intravenously every 2 weeks begin-ning in March 2016. Prednisone at a dose of 40 mg per day was administered preemptively, and tacrolimus was replaced by sirolimus. After the initiation of nivolumab, the patient’s body weight was stable at 90 kg, the serum albumin level was 3.5 to 4.0 g per deciliter, and the serum creatinine level and estimated glomerular filtra-tion rate remained normal and stable (see Table S1 and Fig. S2 in the Supplementary Appendix). Table 1 summarizes the regimen of immuno-suppressive medications.

The patient’s donor-specific antibodies re-mained absent. In October 2016, his serum cre-

Timing* Drug and Dosage

1 Wk before Prednisone — 40 mg daily

Concurrent Prednisone — 20 mg daily; sirolimus — target goal, 4–6 ng per milliliter

1 Wk after Prednisone — 20 mg

>2 Wk and ≤6 mo after Prednisone — 10 mg/day; sirolimus — target goal, 10–12 ng per milliliter

>6 Mo after Glucocorticoid — gradually decreased to 5 mg/day; sirolimus — continued to maintain goal of 10–12 ng per milliliter

* Timing represents the initiation of the immunosuppressive regimen in relationto the administration of nivolumab.

Table 1. Immunosuppressive Regimen in a Patient Who Had Undergone Kidney Transplantation.

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 376;2 nejm.org January 12, 2017192

atinine level was 0.98 mg per deciliter (86.6 μmol per liter), and no further progression of cancer was evident on serial imaging (Fig. S1B in the Supplementary Appendix). He had no other end-organ immune-related adverse events or toxic effects.

In the limited number of patients who have received these agents,1 it appears that PD-1 in-hibitors could be more prone than CTLA-4 antago-nists to cause rejection in the transplanted kid-ney. This is especially true when the patients receive anti–CTLA-4 agents before PD-1 inhibi-tor treatment (Table S2 in the Supplementary Appendix). Blockage of the PD-1–PD-L1 interac-tion in the kidney tubular cells could impair the FOXP3+ regulatory T cell–mediated graft toler-ance.2 In some trials, administration of gluco-corticoids might have impaired the antitumor response of immune checkpoint inhibitors.3 Other studies have shown that overall survival and the time to treatment failure were not af-fected by the use of systemic glucocorticoids.4

The use of mTOR inhibitors (everolimus, tem-sirolimus, and sirolimus) has been well studied in many cancers.5 In this patient, sirolimus may have played a synergistic antitumor role in addi-tion to being an immunosuppressive agent. The effectiveness of a combination of a glucocorti-coid and sirolimus in preventing immune-related adverse events associated with PD-1 inhibitors is not known. Data from a large trial using this approach in patients who have undergone organ transplantation are lacking.

Richard Barnett, M.D. Valerie S. Barta, M.D. Kenar D. Jhaveri, M.D.Hofstra Northwell School of Medicine Hempstead, NY kjhaveri@ northwell . edu

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

1. Lipson EJ, Bagnasco SM, Moore J Jr, et al. Tumor regressionand allograft rejection after administration of anti–PD-1. N Engl J Med 2016; 374: 896-8.2. Riella LV, Paterson AM, Sharpe AH, Chandraker A. Role ofthe PD-1 pathway in the immune response. Am J Transplant2012; 12: 2575-87.3. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab inpatients with melanoma and brain metastases: an open-label,phase 2 trial. Lancet Oncol 2012; 13: 459-65.4. Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverseevents, need for systemic immunosuppression, and effects onsurvival and time to treatment failure in patients with melano-

ma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 2015; 33: 3193-8.5. Law BK. Rapamycin: an anti-cancer immunosuppressant?Crit Rev Oncol Hematol 2005; 56: 47-60.

DOI: 10.1056/NEJMc1614298Correspondence Copyright © 2017 Massachusetts Medical Society.

instructions for letters to the editor

Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere.

Letters accepted for publication will appear in print, on our website at NEJM.org, or both.

Please note the following:

• Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article.

• Letters not related to a Journal article must not exceed 400 words.

• A letter can have no more than five references and one figure or table.

• A letter can be signed by no more than three authors.

• Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.)

• Include your full mailing address, telephone number, fax number, and e-mail address with your letter.

• All letters must be submitted at authors.NEJM.org.

Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.

notices

Notices submitted for publication should contain a mailing address and telephone number of a contact person or depart-ment. We regret that we are unable to publish all notices received.

XVII INTERNATIONAL WORKSHOP ON CHRONIC LYMPHOCYTIC LEUKEMIA

The workshop will be held in New York, May 12–15. It is organized by Bio Ascend.

Contact Bio Ascend, 980 N. Michigan Ave., Suite 1400, Chi-cago, IL 60611; or call (773) 304-5019; or fax (312) 277-6893; or e-mail iwcll2017@bioascend.com; or see http://www.iwcll2017 .org.

Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Barnett R, Barta VS, Jhaveri KD. Preserved renal-allograft function and the PD-1 pathway inhibitor nivolumab. N Engl J Med 2017;376:191-2. DOI: 10.1056/NEJMc1614298

1 | P a g e   

 

Supplementary Appendix 

Preserved Renal Allograft Function While Using the PD‐1 Pathway Inhibitor Nivolumab 

              Richard Barnett 

              Valerie S. Barta 

             Kenar D. Jhaveri 

                   Nephrology,  Hofstra Northwell School of Medicine, NY,USA 

Table of Contents: 

Table S1: Lab data of trends of complete blood count, renal function and urinalysis pre and post Anti 

PD‐1 therapy……………………………………………………………………………………………page 2 

Figure S1 : Positron emission tomography–computed tomography images pre and post anti PD‐1 

therapy……………………………………………………………………………………………………page 3  

Figure S2. Serum creatinine trends over time and sirolimus levels since the start of treatment 

………………………………………………………………………………………………………………..page 4 

Table S2: Summary of patients on immune check point inhibitors and renal transplantation 

………………………………………………………………………………………………………………..page 5 

References:………………………………………………………………………………………………page 5 

 

2 | P a g e

This supplementary appendix provides additional information for the reader regarding the case

presented in the letter. Figure S1 is shown below to illustrate the effect on the tumor with the use of the

anti PD-1 agent in the letter. Table S1 trends the complete blood count, renal function and urinalysis

and Figure S2 shows a graph of the serum creatinine and sirolimus trough levels. Finally, Table S2

summarizes the literature on use of immune check point inhibitors in the renal transplant patients along

with their respective references(1-5).

Table S1

Trends of complete blood counts, renal function and Urinalysis

Lab Value (normal ranges)

Oct 2016

Sept 2016

August 2016

July 2016

May 2016

March 2016( initiation of PD-1 inhibitor)

Feb 2016

White Count(K/ul) (3.8-10.5)

12.6 10.3 12.9 12.3 12.3 10.1 10.2

Hemoglobin(g/dl) (13-17)

8.8 9.1 9.3 9.3 9.3 14.1 10.4

Hematocrit % (39-50)

31.1 29.2 28.9 28.9 28.9 35.7 34.3

Platelets(k/ul) (150-400)

483 463 499 499 421 568 213

Serum Creatinine(mg/dl)

0.98 0.92 0.75 0.82 0.8 0.9 1.1

BUN(mg/dl) 24 15 17 19 22 23 19

eGFR 82 90 93 104 91 88 89

Urine Protein/creatinine ratio

0.3 0.3

BUN: Blood Urea Nitrogen, PD: Programmed cell death; GFR: glomerular filtration rate Other lab data: Urinalysis( Oct 2016): clear, specific gravity 1.029, trace protein, negative blood, 3 white blood cells /HPF, 1 red blood cell/HPF, no casts. Urinalysis( June 2016): clear, specific gravity 1.007, trace protein, negative blood, 2 white blood cells/HPF, 2 red blood cells/HPF Urinalysis (Jan 2016-Pre PD-1 inhibitor): clear, specific gravity 1.029, 30mg/dl protein, negative blood, 0-2 red blood cells/HPF, 3-5 white blood cells/HPF. Serum BK PCR and Cytomegalovirus PCR( Oct 2016): negative

3 | P a g e

Figure S1(A,B) Pre and Post nivolumab: liver metastases

A. Positron emission tomography–computed tomography image prior to initiation of nivolumab

showing hypermetabolism associated with innumerable hepatic metastases.

B. Positron emission tomography–computed tomography image four months following treatment

of nivolumab showing resolution of the hypermetabolism associated with hepatic metastases.

4 | P a g e

Figure S2.

Serum creatinine trends over time and sirolimus levels since the start of treatment

5 | P a g e

Table S2

Summary of patients on immune check point inhibitors and renal transplantation

Immune Check Point Inhibitor( ref #)

Type of Cancer

Transplant information

Rejection(yes/no) Graft Loss(yes/no)

Cancer Outcome

Ipilumumab(#1) Melanoma DDRT No No Partial response

Ipilumumab(#1) Melanoma DDRT No No Partial response

Pembrolizumab(#2) SCC DDRT Yes(Acute cellular rejection)

Yes 85% reduction in tumor

Ipilimumab followed by Pembrolizumab(#3)

Melanoma DDRT Yes(Mixed cellular active and antibody rejection (BANFF IIA)

Yes No information

Ipilimumab followed by Nivolumab(#4)

Melanoma DDRT Yes(Acute cellular rejection BANFF IIA)

Yes Disease progression

Nivolumab(#5) NSCLC NA Yes(Acute cellular rejection ( BANFF IIB)

Yes No information

DDRT: Deceased Donor renal transplant, SCC: squamous cell carcinoma, NSCLC: Non Small Cell Lung Cancer.

Additional References:

1.Lipson EJ, Bodell MA, Kraus ES, Sharfman WH. Successful administration of ipilimumab to two kidney

transplantation patients with metastatic melanoma. J Clin Oncol. 2014 Jul 1;32(19):e69-71.

2.Lipson EJ, Bagnasco SM, Moore J Jr, Jang S, Patel MJ, Zachary AA, et al. Tumor Regression and Allograft

Rejection after Administration of Anti-PD-1. N Engl J Med. 2016 Mar 3;374(9):896-8.

3.Alhamad T, Venkatachalam K, Linette GP, Brennan DC. Checkpoint Inhibitors in Kidney Transplant

Recipients and the Potential Risk of Rejection. Am J Transplant. 2016 Apr;16(4):1332-3.

4. Spain L, Higgins R, Gopalakrishnan K, Turajlic S, Gore M, Larkin J. Acute renal allograft rejection after

immune checkpoint inhibitor therapy for metastatic melanoma. Ann Oncol. 2016 Mar 6. pii: mdw130.

6 | P a g e

5.Bollis CL,Aljadir DN, Cantafio AW. Use of the PD-1 Pathway Inhibitor Nivolumab in a Renal Transplant

Patient With Malignancy. Am J Transplant 2016: doi: 10.1111/ajt.13786

Copyright 2015 American Medical Association. All rights reserved.

Nephrotoxicity of the BRAF Inhibitors Vemurafeniband DabrafenibKenar D. Jhaveri, MD; Vipulbhai Sakhiya, MBBS; Steven Fishbane, MD

T reatment with vemurafenib, a selective BRAF inhibi-tor, has shown significant improvement in patient sur-vival compared with standard therapy in BRAF V600–

mutant metastatic melanoma.1 Similar studies have shownimprovement using another BRAF inhibitor, dabrafenibmesylate.2 No cases of acute kidney injury (AKI) have been re-ported with dabrafenib use. Acute kidney injury has been re-cently reported in a few case series with vemurafenib use.3,4

One case series included a patient who had a kidney biopsydemonstrating acute tubular necrosis as a potential mecha-nism of renal injury.4

MethodsA waiver of institutional review board review was received forthis study. We reviewed the Food and Drug Administration Ad-verse Event Reporting System (FAERS)5 quarterly legacy datafile from the third quarter of 2011 through second quarter of2014 for vemurafenib and second quarter of 2013 throughsecond quarter of 2014 for dabrafenib. Data regarding renaladverse events related to vemurafenib and dabrafenibtherapy were extracted from the database through forma-tion of a query using FAERS-assigned unique case identifi-

ers. Search terms used were “renal insufficiency, elevatedcreatinine, renal failure, renal injury, proteinuria, renalimpairment, blood creatinine increase, renal failure acute,low phosphorus, hypophosphatemia, hypercreatinemia,hyponatremia, hypokalemia, renal damage.”

ResultsA total of 132 cases of AKI in patients receiving vemurafenibtherapy were reported to the FAERS during the period re-viewed. Eighty-five patients were men, and 47, women(P < .001). The mean age of the men was 65 years, and of thewomen, 59 years (P = .04). The cases were reported fromaround the world, with France, the United States, and Ger-many reporting most of the cases. Fourteen cases of electro-lyte disorders were reported (6 cases of hypokalemia and 8cases of hyponatremia). The most common indication was fortreatment of malignant melanoma.

Thirteen cases of AKI in patients receiving dabrafenibtherapy were reported to the FAERS during the period re-viewed. Twelve patients were men. The mean age of the menwas 55 years, and of the women, 75 years (P = .002). Eight casesof electrolyte disorders were reported (2 cases of hypokale-

IMPORTANCE The selective BRAF inhibitors vemurafenib and dabrafenib have shownsignificant improvement in patient survival compared with standard therapy in BRAFV600–mutant metastatic melanoma.

OBSERVATIONS We reviewed Food and Drug Administration Adverse Event Reporting System(FAERS) data for both agents for renal toxic effects. From July 2011 through June 2014, 132cases of acute kidney injury in patients receiving vemurafenib therapy were reported. Renalinjury was more common in men (85 men vs 47 women; P < .001). From April 2013 throughJune 2014, 13 cases of renal injury in patients receiving dabrafenib therapy were reported (12men and 1 woman). Hypokalemia (6 cases in patients receiving vemurafenib and 2 cases inpatients receiving dabrafenib) and hyponatremia (8 and 6 cases, respectively) were alsoreported.

CONCLUSIONS AND RELEVANCE Vemurafenib seems to be more nephrotoxic than dabrafenib.This renal toxicity seems to be more prevalent among male patients with melanoma. On thebasis of the few published case reports, the mode of injury seems to be tubular interstitialinjury. Our findings suggest a need to monitor renal function and electrolyte levels in allpatients who receive these drugs. Dermatologists, oncologists, and nephrologists need to beaware of this potential hazard.

JAMA Oncol. 2015;1(8):1133-1134. doi:10.1001/jamaoncol.2015.1713Published online June 25, 2015.

Author Affiliations: Division ofNephrology, Hofstra North Shore LIJSchool of Medicine, North ShoreUniversity Medical Center, LongIsland Jewish Medical Center, GreatNeck, New York.

Corresponding Author: Kenar D.Jhaveri, MD, Nephrology, HofstraNorth Shore LIJ School of Medicine,North Shore University MedicalCenter and Long Island JewishMedical Center, 100 Community Dr,Great Neck, NY 10021(kdj200@gmail.com).

Research

Brief Report

jamaoncology.com (Reprinted) JAMA Oncology November 2015 Volume 1, Number 8 1133

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://oncology.jamanetwork.com/ by a Northwell Health User on 04/26/2016

Copyright 2015 American Medical Association. All rights reserved.

mia and 6 cases of hyponatremia). Contrary to prior reports,no cases of hypophosphatemia were found.2

DiscussionAlthough the FAERS reporting system is an unsophisticateddatabase with scant demographic information, the number ofAKI cases reported with BRAF inhibitor therapy is still alarm-ing. Vemurafenib appears to be more nephrotoxic than dab-rafenib. This renal toxicity seems to be more prevalent amongmale patients with melanoma. On the basis of the few pub-lished case reports,4 we believe that the mode of injury seemsto be tubular interstitial injury. Proteinuria was not reported.

ConclusionsThis FAERS reporting system signal of renal injury with BRAFinhibitor therapy is important because this class of drugs con-fers significant survival benefit in patients with melanoma. Onthe basis of our findings, there is a heightened need to moni-tor renal function and electrolyte levels in all patients who re-

ceive these drugs. Dermatologists, oncologists, and nephrolo-gists need to be made aware of this potential hazard. Kidneybiopsies are needed to elucidate the mechanism behind thetoxicity. We urge large cancer centers to look into close fol-low-up of patients with renal injury from these agents and todetermine outcomes.

ARTICLE INFORMATION

Accepted for Publication: April 30, 2015.

Published Online: June 25, 2015.doi:10.1001/jamaoncol.2015.1713.

Author Contributions: Drs Jhaveri and Sakhiya hadfull access to all of the data in the study and takeresponsibility for the integrity of the data and theaccuracy of the data analysis.Study concept and design: Jhaveri, Fishbane.Acquisition, analysis, or interpretation of data: Allauthors.Drafting of the manuscript: Jhaveri, Sakhiya.Critical revision of the manuscript for importantintellectual content: All authors.Statistical analysis: Sakhiya.

Administrative, technical, or material support:Sakhiya, Fishbane.Study supervision: Jhaveri.

Conflict of Interest Disclosures: None reported.

REFERENCES

1. Chapman PB, Hauschild A, Robert C, et al;BRIM-3 Study Group. Improved survival withvemurafenib in melanoma with BRAF V600Emutation. N Engl J Med. 2011;364(26):2507-2516.

2. Hauschild A, Grob JJ, Demidov LV, et al.Dabrafenib in BRAF-mutated metastatic melanoma:a multicentre, open-label, phase 3 randomisedcontrolled trial. Lancet. 2012;380(9839):358-365.

3. Uthurriague C, Thellier S, Ribes D, Rostaing L,Paul C, Meyer N. Vemurafenib significantlydecreases glomerular filtration rate. J Eur AcadDermatol Venereol. 2014;28(7):978-979.

4. Launay-Vacher V, Zimner-Rapuch S, Poulalhon N,et al. Acute renal failure associated with the newBRAF inhibitor vemurafenib: a case series of 8patients. Cancer. 2014;120(14):2158-2163.

5. FDA Adverse Event Reporting System (FAERS).http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm.Accessed March 18, 2015.

At a Glance

• Use of the selective BRAF inhibitors vemurafenib and dabrafenibhas shown significant improvement in patient survival comparedwith standard therapy in BRAF V600–mutant metastaticmelanoma.

• A review of Food and Drug Administration Adverse EventReporting System (FAERS) data for both agents revealed asubstantial number of renal toxic effects.

• A total of 132 cases of acute kidney injury in patients receivingvemurafenib therapy and 13 cases in patients receivingdabrafenib therapy were reported; the renal injury was morecommon in male patients.

• Hypokalemia and hyponatremia were also reported in patientswho had received each agent.

• There is a heightened need to monitor renal function andelectrolyte levels in all patients who receive these drugs.

Research Brief Report Nephrotoxicity of the BRAF Inhibitors Vemurafenib and Dabrafenib

1134 JAMA Oncology November 2015 Volume 1, Number 8 (Reprinted) jamaoncology.com

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://oncology.jamanetwork.com/ by a Northwell Health User on 04/26/2016

Mini-Review

Renal Toxicities of Novel Agents Used for Treatment ofMultiple Myeloma

Rimda Wanchoo,* Ala Abudayyeh,† Mona Doshi,‡ Amaka Edeani,§ Ilya G. Glezerman,| Divya Monga,¶

Mitchell Rosner,** and Kenar D. Jhaveri*

AbstractSurvival for patients with multiple myeloma has significantly improved in the last decade in large part due to thedevelopment of proteasome inhibitors and immunomodulatory drugs. These next generation agents with novelmechanisms of action as well as targeted therapies are being used both in the preclinical and clinical settings forpatients with myeloma. These agents include monoclonal antibodies, deacetylase inhibitors, kinase inhibitors,agents affecting various signaling pathways, immune check point inhibitors, and other targeted therapies. In somecases, off target effects of these therapies can lead to unanticipated effects on the kidney that can range fromelectrolyte disorders to AKI. In this review, we discuss the nephrotoxicities of novel agents currently in practice aswell as in development for the treatment of myeloma.

Clin J Am Soc Nephrol ▪: ccc–ccc, 2016. doi: 10.2215/CJN.06100616

IntroductionTreatment of multiple myeloma (MM) has significantlyimproved in recent decades. Whereas alkylating agentsin combination with steroids were the standard of carefor several years, novel immunomodulatory agents(IMiD) and targeted therapies have changed the treat-ment paradigms and outcomes for this disease (Figure1). Table 1 lists the novel agents and their mechanismsof action.

Three percent of all kidney biopsies performed haveparaprotein-mediated kidney disease. In addition,some novel MM therapies have also been reportedto cause kidney injury. These adverse effects are likelyto have negative effects on prognosis and may limitthe ability of the patient to receive effective treatment.Given myeloma itself can lead to kidney disease,distinguishing between myeloma-related kidney dis-ease and drug toxicity is difficult without a kidneybiopsy. Thrombocytopenia at the time of presentationoften precludes a kidney biopsy. In this review, wediscuss novel agents being used in the treatment ofMM and their related nephrotoxicities. Table 2 (Foodand Drug Administration [FDA] approved agents)and Table 3 (agents in clinical trials for MM)provide a summary of the detailed kidney toxicitiesof all agents used in MM classified by their mecha-nism of action.

Alkylating Agents, Anthracyclines, andPlatinum-Based Therapies

Combination cytotoxic therapies were commonregimens for treatment of MM before the arrivalof newer agents, especially in patients with hightumor burden and frequent relapses (1–5). Aggressivecytoreduction with a combination chemotherapeutic

regimen such as steroids, cyclophosphamide, etoposide,and cisplatin (DCEP) (6) with or without bortezomib(V-DCEP) (5) or a combination such as bortezomib,thalidomide, steroids, cisplatin, doxorubicin, cyclo-phosphamide, and etoposide (VTD-PACE) (7) is a rea-sonable salvage regimen. Cisplatin is the mostnephrotoxic of the traditional chemotherapies usedfor MM (1) known to cause dose dependent acutetubular necrosis. Besides acute tubular necrosis, it isknown to cause hypomagnesemia, fanconi syndrome,thrombotic microangiopathy (TMA), and salt wastingsyndrome (Table 2). Given the scope of this article,nephrotoxicities of traditional chemotherapy agentsused in MM (alkylating agents, anthracyclines,and platinum-based therapies) will not be discussed(1–4,8).

Proteasome InhibitorsProteasomes are enzyme complexes responsible for

degradation of intracellular proteins and clearing themisfolded/unfolded and cytotoxic proteins, and arecritical for the maintenance of protein homeostasiswithin a cell. It has been hypothesized that cancer cellsare more dependent on proteasomes for clearance ofabnormal or mutant proteins. In fact, several pre-clinical studies have shown that malignant cells aremore sensitive to proteasome inhibition than normalcells (9).

BortezomibBortezomib is a proteasome inhibitor (PI) used for

treatment of MM (10,11). In terms of nephrotoxicity,five cases of TMA have been reported with this agentthus far (12–15). However, these TMA cases are com-plex and the causality between bortezomib and these

*Division ofNephrology, HofstraNorthwell School ofMedicine, Great Neck,New York; †Division ofInternal Medicine,Section of Nephrology,The University of TexasMD Anderson CancerCenter, Houston, Texas;‡Division ofNephrology, WayneState University Schoolof Medicine, Detroit,Michigan; §KidneyDiseases Branch,National Institute ofDiabetes, Digestive andKidney Disease,National Institutes ofHealth, Bethesda,Maryland; |Departmentof Medicine, RenalService, Memorial SloanKettering Cancer Centerand Department ofMedicine, Weill CornellMedical Center, NewYork, New York;¶Nephrology Division,University of MississippiMedical Center,Jackson, Mississippi;and **Division ofNephrology,Department ofMedicine, University ofVirginia Health System,Charlottesville, Virginia

Correspondence:Dr. Kenar D. Jhaveri,Division of Nephrology,Hofstra NorthwellSchool ofMedicine, 100Community Drive,Great Neck, NY 11021.Email: kjhaveri@northwell.edu

www.cjasn.org Vol ▪ ▪▪▪, 2016 Copyright © 2016 by the American Society of Nephrology 1

. Published on September 21, 2016 as doi: 10.2215/CJN.06100616CJASN ePress

events is not definitive. For example, Morita et al. reportedthe onset of TMA 8 days after commencing treatment withbortezomib and steroids in a patient with MM who hadundergone a sequential autologous and allogenic stem cell

transplant (12). In another case, Moore et al. reported acase of TMA in a newly diagnosed myeloma patient thatoccurred 2 days after treatment with bortezomib andwhich resolved spontaneously in a few days (13). In this

Figure 1. | Four classes of agents that can be used to treat multiple myeloma. Akt, serine-threonine protein kinase B; BRAF, v-Raf murinesarcoma viral oncogene homolog B; HDAC, histone deactylase; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin;PD, programmed cell death protein; SLAMF7, signaling lymphocytic activation molecule F7.

Table 1. Novel antimyeloma agents in the market or in development and their mechanism of action

Class Name of Drug Mechanism of Action

Proteasome inhibitors Bortezomib, Carfilzomib,Ixazomib

Inhibiting the ubiquitin-proteasomesystem regulating the growth of normaland tumor cells

Immunomodulatory drugs Thalidomide, Lenalidomide,Pomalidomide

Enhance antimyeloma immune response

HDAC inhibitors Vorinostat, Panobinostat Epigenetic modulatorsmTOR inhibitors Temsirolimus, Everolimus Inhibiting the intracellular signaling

kinasesImmune check pointinhibitors

Nivolumab, Pembrolizumab Enhance the immune response to cancercells and specificallyPD1andPD1 ligandresponses

BRAF inhibitors Vemurafenib, Dabrafenib Target a specific gene mutation in somecases of myeloma

MEK inhibitors Tramatenib, Selumetinib Inhibition of overactive MAPK/ERKpathway

SLAMF7 inhibitors Elotuzumab Myeloma cell membrane bound SLAMreceptor inhibitors

Anti–IL-6 agents Siltuximab Myeloma cell membrane bound IL-6receptor inhibitors

Anti-KIR agents Lirilumab Improves immune response to cancer cellsCD38 antibody Daratumumab Myeloma cell membrane bound cd38

receptor inhibitorsAkt inhibitors Perifosine Intracellular signaling kinase inhibitors

HDAC, histone deactylase; mTOR,mammalian target of rapamycin; PD, programmed cell death protein; BRAF, v-Rafmurine sarcomaviral oncogene homolog B; MEK, mitogen-activated protein kinase; MAPK, mitogen-activated protein kinases; ERK, extracellularsignal-regulated kinases; SLAMF7, signaling lymphocytic activation molecule F7; KIR, killer Ig receptor; Akt, serine-threonine proteinkinase B.

2 Clinical Journal of the American Society of Nephrology

particular case, ADAMTS13 activity was low initially aftertreatment and remained low with bortezomib rechallenge,even though TMA did not reoccur (13). Three other casesreported in the literature (14,15) report TMA after multipledoses of the agent. Unfortunately, none of these cases hadbiopsy-proven kidney disease and most of the diagnoseswere made clinically. A mechanistic link between PI andTMAmay be mediated by the inhibition of the ubiquitinationof IkB which prevents NF-kB from entering the nucleus andultimately leads to decreased vascular endothelial growthfactor production which has been linked to the develop-ment of TMA (16–19). In addition, a case of acute interstitial

nephritis (AIN) with granuloma formation has been reportedwith bortezomib (20).

CarfilzomibCarfilzomib is a tetrapeptide epoxyketone PI approved

for the treatment of relapsed refractory MM (21). In a phase2 study of this drug in 266 patients, AKI was reported in25% of the patients. Although the majority of the kidneyadverse effects were mild, progressive kidney disease wasreported in 3.8% of patients, leading to discontinuation ofthe drug in two patients (22). There are now additionalcases of AKI from carfilzomib reported in the literature

Table 2. Summary of known renal toxicities of Food and Drug Administration approved antimyeloma agents

Class/Drug Name Published Toxicitiesin the Literature CKD Dosing ESRD Dosing

Traditionalchemotherapy

Cisplatin ATN, TMA,hypomagnesemia,fanconi syndrome,renal salt wasting

Reduce dose by 25%(46–60 ml/min CrCl)

HD: Reduce dose by 50%and administer after HD;CAPD: reduce dose by50%; CRRT: reduce doseby 25%

Reduce dose by 50%(10–45 ml/min CrCl)

Melphalan AKI, hyponatremia Reduce dose by 15%(46–60 ml/min CrCl)

Limited data

Reduce dose by 25%(10–45 ml/min CrCl)

Cyclophosphamide Hemorrhagic cystitis,hyponatremia

No dosing adjustmentneeded

HD: reduce dose by 50%and administer after HD;

CAPD: reduce dose by25%; CRRT: noadjustment needed

Anthracyclines Collapsingglomerulopathy,FSGS, minimalchange disease,TMA

No dosing adjustmentneeded

No dosing adjustmentneeded

ImmunomodulatorsLenalidomide AKI, AIN, fanconi

syndrome, minimalchange disease

10 mg daily (30–60 ml/minCrCl)

HD: 5 mg daily after HD

15 mg every 48 h (10–29ml/min CrCl)

Pomalidomide AKI, crystalnephropathy

CrCl,45ml/min avoid use Insufficient data

Proteasome inhibitorsBortezomib TMA Reduce dose if

GFR,20 cc/minDose after dialysis andconsider dose reduction(but insufficient data)

Carfilzomib TMA, prerenal, tumorlysis like syndrome,ATN

No dose adjustment Dose after dialysis

Ixazomib None reported Insufficient data Insufficient dataHDAC inhibitorsPanobinostat None reported No dose adjustment Insufficient data

SLAMF7 inhibitorsElotuzumab AKI No dose adjustment No dose adjustment

Anti-CD38 agentsDaratumumab None reported No dose adjustment No dose adjustment

ATN, acute tubular necrosis; TMA, thrombotic microangiopathy; CrCl, creatinine clearance; HD, hemodialysis; CAPD, continuousautomated peritoneal dialysis; CRRT, continuous RRT; AIN, acute interstitial nephritis; HDAC, histone deactylase; SLAMF7, signalinglymphocytic activation molecule F7.

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Nephrotoxicities of Multiple Myeloma Treatments, Wanchoo et al. 3

Tab

le3.

Summaryofkn

ownrenal

toxicities

ofan

timyelomaag

ents

(notFo

odan

dDrugAdministrationap

prove

dto

trea

tmye

loma)

curren

tlyin

clinical

trials

Class/DrugNam

ePu

blishe

dTox

icitiesin

theLiterature

Trial

Stag

eCKD

Dosing

ESR

Ddosing

mTORinhibitors

Tem

sirolim

usProteinu

ria,

FSGS,

ATN

Phase2trials

Nodosead

justmen

tInsu

fficien

tdata

Eve

rolim

usProteinu

ria

Phase1trials

Individualized

dosingon

theba

sisof

therap

eutic

drugmon

itoring

Insu

fficien

tdata

Sirolim

usFS

GS,

TMA,A

TN

Phase1trials

Individualized

dosingon

theba

sisof

therap

eutic

drugmon

itoring

Insu

fficien

tdata

BRAFinhibitors

Vem

urafen

ibAIN

,ATN,subn

ephrotic

proteinu

ria,

hypo

kalemia,hyp

onatremia,fan

coni

synd

rome

Phase2trials

Nodosead

justmen

tbut

also

notwellstudied

Insu

fficien

tdata

Dab

rafenib

AKI,AIN

,hyp

opho

spha

temia

Phase2trials

Nodosead

justmen

tInsu

fficien

tdata

HDACinhibitors

Vorinostat

Non

ereported

Phase3trials

Nodosead

justmen

tInsu

fficien

tdata

MEK

inhibitors

Trametinib

Hyp

ertens

ion,

hypon

atremia,A

KI

Phase2trials

Nodo

sead

justment,for

,30

cc/m

in–no

tstudied

Insu

fficien

tdata

Immunech

eck

pointinhibitors

Nivolumab

AIN

,hyp

onatremia

Phase3trials

Nodosead

justmen

tInsu

fficien

tdata

Pembrolizumab

AIN

,hyp

onatremia

Phase3trials

Nodosead

justmen

tInsu

fficien

tdata

Anti–IL-6

agen

tsSiltuximab

Hyp

erka

lemia,H

yperurecemia

Phase2trials

Nodosead

justmen

tif

GFR

.15

cc/min

Insu

fficien

tdata

Anti-K

IRag

ents

Lirilu

mab

AKI,hy

pop

hosp

hatemia

Phase1trials

Nodataav

ailable

Nodataav

ailable

Aktinhibitors

Perifosine

Hyp

opho

spha

temia

Phase3trials

Nodataav

ailable

Nodataav

ailable

mTOR,m

ammaliantarget

ofrapam

ycin;A

TN,a

cute

tubu

larne

crosis;T

MA,throm

boticmicroan

giop

athy

;BRAF,

v-Raf

murinesarcom

aviralo

ncog

eneho

molog

B;A

IN,a

cute

interstitial

neph

ritis;HDAC,h

istone

deactylaseinhibitors;M

EK,m

itog

en-activated

proteinkina

se;K

IR,k

iller

Igreceptor;A

kt,serine-threon

ineproteinkina

seB.

4 Clinical Journal of the American Society of Nephrology

(23–27). The possible mechanisms listed are diverse andsummarized in Table 2. They range from prerenal insults,tumor lysis–like phenomenon, to biopsy-proven TMA(23–26). In the initial two cases (23,24), AKI was transientand was clinically consistent with a ‘prerenal’ insult. Inaddition, in one of the cases, N-acetylcysteine was helpfulin ameliorating the severity of the carfilzomib-mediatedkidney injury when the patient was rechallenged with thechemotherapy agent (24). Similar to bortezomib, carfilzomibhas been associated with TMA with four reported cases inthe literature (27–29). In the case published by Sullivan et al.(28), the patient developed TMA within a few months afterreceiving carfilzomib. The patient did not undergo a kidneybiopsy and received three sessions of plasmapheresis forpresumed thrombotic thrombocytopenic purpura, whichwas stopped once the ADAMTS13 levels returned to thenormal range. Given the clinical improvement with stop-ping the drug and initiation of plasmapheresis, the authorsspeculate that plasmapheresis expedited the removal of pro-tein-bound carfilzomib or another offending agent. Twomore cases of biopsy-proven TMA with carfilzomib havebeen reported by Qaquish et al. (29). Both patients receivedplasmapheresis for several days with no improvement in therenal or hematologic parameters. ADAMTS13 levels weremeasured in both patients and were reported in the normalrange. Interestingly, the authors measured von Willebrandfactor multimers in the peripheral blood plasma samplesand showed that none of the patients treated with carfilzomibaccumulated ultra large von Willebrand factor multimersafter treatment with carfilzomib. The authors speculate thatcarfilzomib, similar to bortezomib, causes TMA through adose-dependent toxic mechanism in which plasmapheresisis unlikely to show any clinical benefit.Recently, Yui et al. published the largest case series of PI

induced TMA (30). The series by Yui et al. describes 11 pa-tients from six centers around the world that developedTMA after either carfilzomib (eight cases) and or bortezomib(three cases) treatment. Six patients were diagnosed within21 days of the initiation of the drug and the rest 6–17 monthslater. Diagnosis was made on the basis of lab values of lac-tate dehydrogenase, haptoglobin, schistocytes on bloodsmear, and presence of thrombocytopenia and anemia. Me-dian creatinine was 3.12 mg/dl and five patients requireddialysis. Two patients underwent a kidney biopsy whichconfirmed TMA. Four patients were treated with plasma-pheresis and three with eculizumab. Eight of the 11 patientshad complete resolution of TMA after discontinuation of thePI. Autoantibodies to the ADAMTS13 was an unlikely causeof the TMA in this series of patients given the normalADAMTS13 levels. Yui et al. have suggested an immune-mediated mechanism accounting for the early onset TMA(,21 days) and dose-dependent toxicity for those casesthat happen later during the course of treatment (30).A recent phase 3 trial that studied carfilzomib versus low

dose steroids with optional cyclophosphamide in relapsedMM (FOCUS) found grade 3 AKI in 8% in the carfilzomibarm compared with 3% in the control (31). Renal adverseevents occurred more frequently in patients within thecarfilzomib group compared with placebo (24% versus9%). Overall, these events occurred more frequently inpatients with lower creatinine clearance ,30 ml/minand the majority of them had known renal manifestations

of MM. In addition, hypertension (HTN) occurred in 15% ofcarfilzomib patients compared with 6% of the control (31).Bortezomib, a boronate peptide, is a reversible inhibitor

of the chymotrypsin-like activity of the 26S proteasome,whereas carfilzomib, a tetrapeptide epoxyketone PI, bindsirreversibly and inhibits the chymotrypsin-like activity ofthe 20S proteasome. This structural difference could per-haps explain the different kidney-related side effects ofthese agents. Recent animal studies and clinical case reportswith carfilzomib revealed that the drug increased the restingvasoconstricting tone and amplified the spasmogenic effectof different agents and also led to impairment of vasodilationby inducing endothelial dysfunction (32–35). Given the in-formation from the FOCUS trial, and several more cases ofHTN and TMA reported with carfilzomib as compared withbortezomib, it appears that carfilzomib is more nephrotoxicthan bortezomib (31–35).

IxazomibIxazomib is a novel oral PI that is active in both the

relapsed refractory setting and in newly diagnosed MM.On the basis of a recent randomized controlled trial inrelapsed MM, ixazomib was recently approved in the UnitedStates for the treatment of relapsed myeloma. No knownrenal toxicities have been reported with this agent (36).

Immunomodulators (Thalidomide, Lenalidomide, andPomalidomide)IMiDs, which include thalidomide, lenalidomide, and

pomalidomide, are used for treatment of relapsed orrecurrent myeloma. Their exact mechanism of action isunknown; however, they likely act via a variety of mech-anisms including immune-modulation, antiangiogenic,anti-inflammatory, and antiproliferative effects (37). Tha-lidomide, the first generation IMiD, is metabolized vianonenzymatic hydrolysis and only ,1% of unchangeddrug is excreted in the urine (38). In the initial reportshowing thalidomide activity against MM, eight out of84 patients had a .50% in serum creatinine. In these cases,the kidney injury was believed to be due to progression ofunderlying disease and not related to the drug (39). Inclinical practice, the use of thalidomide has not been asso-ciated with nephrotoxicity.The second generation IMiD lenalidomide has shown

effectiveness against MM in two pivotal trials (40,41). Therewere no reports of kidney toxicity in either study althoughWeber et al. reported that 6.2% of patients in the lenalidomidegroup developed hypokalemia versus 1.1% in the placebogroup (40). After lenalidomide was approved for treatmentof MM, a number of reports have linked it to kidney dys-function (42–47). In most patients, kidney disease devel-oped without evidence of malignancy progression.Furthermore, one patient developed fanconi syndrome(42) and one patient had a drug reaction with eosinophilia,rash, and systemic symptoms (DRESS syndrome) (45). Acase of minimal change disease was reported in a patientwith Waldenström macroglobulinemia being treated withlenalidomide (47). The largest series of AKI associated withthis drug was noted by Specter et al. (46), when they studiedpatients with amyloidosis. Twenty-seven of 41 patients(66%) studied at a single center with light chain amyloidosis

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Nephrotoxicities of Multiple Myeloma Treatments, Wanchoo et al. 5

developed kidney dysfunction during lenalidomide treat-ment. The kidney dysfunction was severe in 13 of these pa-tients (32%); four of whom required initiation of dialysis(10%). The median time to kidney dysfunction after startinglenalidomide was 44 days (interquartile range, 15–108 days).Four of eight patients without underlying renal amyloidosisdeveloped kidney dysfunction. Patients with severe kidneydysfunction were older and had a higher frequency of un-derlying renal amyloidosis, greater urinary protein excre-tion, and lower serum albumin (46).Pomalidomide is another second generation IMiD. Of the

three trials addressing its efficacy in MM, only one studyreported high incidence of grade 3–4 kidney toxicity (11%)(48–50). One case of AKI and crystal nephropathy wasattributed to pomalidomide. However, confounding fac-tors included concurrent use of levofloxacin which mayhave contributed to both AKI and crystal formation (51).In summary, both lenalidomide and pomalidomide have

been associated with kidney dysfunction; however, clini-cians must be careful when assessing patients with wors-ening kidney disease on IMiD as a number of other causesincluding progression of MM could be responsible fordecline in kidney function.

BRAF Inhibitors (Vemurafenib and Dabrafenib)The discovery of mutations in the BRAF oncogene led

to an era of targeted therapy in patients with malignantmelanoma, colorectal cancer, and lung cancer (52–55).BRAF mutations lead to constitutive activation of themitogen-activated protein kinase (MAPK) pathway, result-ing in enhanced gene transcription, cellular proliferation,and oncogenic activity. The most common mutation encoun-tered in patients with melanoma is V600E. Discovery of thismutation led to the approval of vemurafenib and dabrafenibfor treatment of BRAF V600E mutation–positive melanomas.Use of these drugs in MM is limited to small studies (56,57).This is partly due to the low prevalence (,10%) of the BRAFV600E mutation in patients with myeloma (56–58).Extrapolating the data from the use of BRAF inhibitors in

melanoma patients, one can predict that this class of drugsmay lead to adverse kidney outcomes in patients with MM.Specific toxicities have included tubular and interstitialdamage (acute as well as chronic). The onset of injuryvaries, with some cases being reported within a few weeksof drug initiation and others occurring after a 1–2 monthperiod. The kidney injury within weeks of drug initiationis likely allergic interstitial nephritis, whereas that occur-ring at a later period may be tubular toxicity (59–63). Over-all, vemurafenib has a much higher rate of associatedkidney injury as compared with dabrafenib (63). A recentreview on this topic summarizes the kidney toxicities as-sociated with BRAF inhibitors when used in melanomapatients (64).

MAPK Enzymes Mitogen-Activated Protein KinaseKinase Enzymes InhibitorsMAP2K kinases (MEK1 and MEK2) are attractive ther-

apeutic targets in several cancers because they are essentialin the mitogen-activated protein kinase kinase enzymes(MEK)/MAPK pathway which when dysregulated leads

to increased cell survival and metastasis (65,66). Trametinib(MEK inhibitor), by itself, has not been associated with neph-rotoxicity. Monotherapy with this agent can lead to HTN,but cases of AKI and hyponatremia were noted more fre-quently in patients treated with combined trametinib anddabrafenib in patients with melanoma (67). Kidney toxicitymay result from a combination effect with the BRAF inhib-itors rather than a solo effect of an MEK inhibitor (68).In MM, the MEK inhibitor AZD6244 (Selumetinib, ARRY-

142886) has demonstrated in vitro and in vivo activity againstmyeloma cells (69–71). The most common toxicities associ-ated were anemia, neutropenia, thrombocytopenia, diarrhea,fatigue, increased creatine phosphokinase, limb edema, andacneiform rash. There were three deaths (two from sepsisand one from AKI). Although the data are limited, kidneytoxicities appear to be uncommon with this agent.

Signaling Lymphocytic Activation Molecule F7Elotuzumab is a fully humanized IgG1 monoclonal

antibody targeted against signaling lymphocytic activationmolecule F7 (SLAMF7, also called CS1 [cell-surface glyco-protein CD2 subset 1]) (72,73). CS1 belongs to a family oflymphocytic activation molecule surface glycoproteins. Ithas been shown that CS1 expression is present in malig-nant plasma cells at the gene and protein levels. In addi-tion, high levels of CS1 were noted in patients withmonoclonal gammopathies of undetermined significance,smoldering myeloma, plasmacytomas, and MM (72,73),making CS1 a compelling target for immunotherapy forMM. Interestingly, the expression of SLAMF7 was presentin .95% of myeloma cells regardless of the cytogenetics ofthe myeloma cells (73).Elotuzumab promotes death of myeloma cells by CS1-CS1

interaction between natural killer (NK) cells and myelomacells (72). Elotuzumab was studied in 35 patients withrelapsed/refractory MM (74). Although 44.1% of the studypatients had serious adverse events, AKI was noted in onlytwo patients (5.9%). One of the patients had severe AKI thatrequired hemodialysis (74). It was also studied in combina-tion with lenalidomide (75) with favorable results and AKIwas not reported in that particular study. Further phase 3studies have been initiated (76,77) with no known nephro-toxicities reported thus far.

Akt/Mammalian Target of Rapamycin PathwayInhibitorsThe phosphatidylinositol-3-kinase family is made up of a

group of serine/threonine and lipid kinases that serve as theintracellular initiation point for several signaling cascadessuch as the G-coupled protein receptor. Through the pro-duction of phospho-inositol triphosphate3, the phosphory-lated form of membrane-bound phosphoinositides, thesepathways activate Akt, a serine-threonine kinase that hasbeen implicated in oncogenesis (78,79). In one of these path-ways, Akt indirectly activates the mammalian target ofrapamycin (mTOR) pathway through the activity of thetuberous sclerosis complex 1/2. mTOR includes two distinctprotein complexes, mTOR complex 1 and 2 (mTORC1 andmTORC2). Thus, Akt leads to activation of mTORC1 whichsubsequently leads to increased cellular proliferation.

6 Clinical Journal of the American Society of Nephrology

mTORC2 has been shown to be important in the regula-tion of cytoskeletal integrity (including that of the glomer-ular podocyte) (80–83). In one study higher levels ofactivated, phosphorylated Akt correlated with more ad-vanced MM (84).Perifosine is an alkylphospholipid that inhibits the

Akt pathway (decreases Akt phosphorylation) leading toapoptosis of MM cells and also enhances the cytotoxiceffects of other agents such as bortezomib (85,86). PotentAkt inhibitors are showing promise and are in develop-ment for the potential treatment of MM as well as severalother cancers (87–90). Interestingly, and for unclear rea-sons, perifosine use was associated with a high rate ofhypophosphatemia in the phase 1 trial (87).mTOR inhibitors such as rapamycin, everolimus, and

others have shown preclinical promise in the therapy ofMM especially when combined with other therapies, withpartial response rates as high as 33% (91–93). The extensiveexperience with mTOR inhibitors in solid organ transplan-tation as well as recent advances in the understanding ofthe role of the Akt/mTOR pathway in maintenance ofpodocyte viability leads to concerns about short- andlong-term kidney toxicities with these agents (80,81). Re-cently, Canaud and colleagues identified the Akt pathwayas critical to the maintenance of podocyte structure andintegrity when under stress (such as with reduced nephronnumbers) (80). Mechanistically, this pathway may accountfor the clinical observation of proteinuria with mTOR in-hibitors (i.e., mTORC2 inhibition may decrease the amountof active, phosphorylated Akt and thus alter cytoskeletalintegrity and promote podocyte apoptosis). Theoretically,the risk of proteinuria and podocyte injury could also beassociated with Akt inhibitors as well as mTOR inhibitors,especially if these are not isoform specific. Ischemicpreconditioning which experimentally protects the kidneytubules against subsequent ischemia-reperfusion may alsorely on the Akt pathway (94). So far, the clinical experiencewith Akt inhibitors is limited to small trials with perifosine(95) with no reported nephrotoxicities.Proteinuria and, more rarely, kidney dysfunction have

been reported in patients taking mTOR inhibitors (96). Thephenomena appear to be dose-dependent and reversiblewith cessation of the medication. The actual incidence ofmTOR-induced proteinuria is likely low on the basis ofanalyses of clinical trial data. For instance, in 94 patientsenrolled in four sirolimus trials there was one case ofnephrotic-range proteinuria which remitted with drugwithdrawal (97). In trials of everolimus for treatment oftuberous sclerosis–associated subependymal giant-cell as-trocytomas and angiomyolipomas, the rate of proteinuriawas 4% with drug and 8% with placebo treated patients(98). In terms of longer-term use and changes in GFR, ex-tensive use in patients with calcineurin-inhibitor–inducedrenal allograft dysfunction has shown that mTOR inhibi-tors do not appear to be associated with any increased riskof kidney dysfunction (99–101). However, there are occa-sional case reports of mTOR inhibitor–associated glomer-ulopathy and acute tubular necrosis with newer agentssuch as temsirolimus, as well as an increased incidencein mTOR-associated rises in serum creatinine in a trial oftemsirolimus versus IF-a or both in patients with ad-vanced renal cell cancer (102,103).

More recently, dual mTORC1/2 kinase inhibitors arebeing studied in clinical trials. The advantage of thesenewer agents is that the mTORC2 activation of Akt is alsoinhibited by these agents and thus they may lead to moreeffective inhibition of cancer cell proliferation (104). Thusfar, no kidney toxicity has been described with theseagents but given the mechanisms of action, vigilance forthese toxicities should be high.

Anti–IL-6 Monoclonal Antibodies in MMIL-6 plays a critical role in the pathogenesis of MM. It is

both an autocrine and paracrine growth factor contributingto the proliferation of myeloma cells as well as beinginvolved in the inhibition of tumor cell apoptosis (105).Thus, blockade of IL-6 would seem a logical antimyelomadrug strategy and this has been achieved with chimericanti–IL-6 monoclonal antibodies. Phase 2 studies withsiltuximab, an anti–IL-6 monoclonal antibody, in patientswith refractory or relapsed MM have been reported(106,107). Of note, siltuximab has received FDA approvalfor the treatment of Castleman disease where the drug hasshown efficacy (108).Specific kidney toxicity of siltuximab has not been

reported. However, several electrolyte disorders appearto be more common in patients taking this medication ascompared with placebo or other agents, at least in one trial.For instance, hyperuricemia (13%) and hyperkalemia (4%)were seen in the trial with siltuximab in Castleman disease(109). However, these adverse events were not reportedin other trials (106,107). Given the limited experiencewith this drug, more studies will be needed to confidentlyexclude kidney-specific adverse effects.

Programmed Cell Death–1 and Ligand Target in MMThis pathway includes two proteins called programmed

death–1 (PD-1), which is expressed on the surface of im-mune cells, and programmed death ligand–1 (PD-L1),which is expressed on cancer cells. When PD-1 andPD-L1 join together, they form a biochemical “shield” pro-tecting tumor cells from being destroyed by the immunesystem. Anti–PD-1 agents are humanized monoclonal an-tibodies that bind the PD-1 molecule, which are present ontumor infiltrating lymphocytes and regulatory T cells.They prevent the engagement of PD-1 to its ligand ontumor cells (PD-L1 and PD-L2) thereby asserting antineo-plastic activity. The object of blocking programmed celldeath is to restore the activation of the immune systemdirected to tumor cells. These immune check point inhib-itors are being considered for treatment of MM (110).Nivolumab was the first anti–PD-1 antibody, tested ini-

tially in melanoma. In December 2014, the FDA granted anaccelerated approval to nivolumab for the treatment ofpatients with unresectable or metastatic melanoma andrenal cell cancer (111,112). In one trial (111), there wasan increased incidence of elevated creatinine noted in thenivolumab-treated group as compared with the chemo-therapy-treated group (13% versus 9%). Steroids helpedresolve the renal dysfunction in 50% of the cases. TheFDA label has recommendations (113) to start steroids asthe creatinine rises with the presumption that AKI is

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Nephrotoxicities of Multiple Myeloma Treatments, Wanchoo et al. 7

immune-mediated. Only recently, there were severalbiopsy-proven cases of AIN related to nivolumab describedin two case series (114,115). All patients were also onother drugs (proton pump inhibitors, nonsteroidal anti-inflammatory drugs) linked to AIN, but in most cases, theuse of these drugs preceded anti–PD-1 antibody therapy.The authors believe that PD-1 inhibitor therapy may releasesuppression of T cell immunity that normally permits renaltolerance of drugs known to be associated with AIN.Pembrolizumab (MK-3475) is another monoclonal anti-

body therapy designed to directly block the interactionbetween PD-1 and its ligands. This drug has been used inmelanoma and hematologic malignancies since 2014 (116).In the initial trials, AIN was confirmed by kidney biopsyin two out of three patients with AKI. All three patientsfully recovered kidney function after treatment with high-dose corticosteroids ($40 mg prednisone or equivalent perday) followed by a corticosteroid taper (116–119). Shiraliet al. (114) and Cortazar et al. (115) reported several biopsy-proven cases of AIN with this agent. Given the immune-mediated mechanism of action of this drug, AIN will likelybe seen when these agents are used to treat MM as well.

Anti–Killer Ig-Like Receptor Agents in MyelomaNK cells, members of the innate immune system, are

important players of host immunity in controlling variouscancers. NK cell function, including cytotoxicity andcytokine release, is governed by a balance between signalsreceived from surface inhibitory and activating receptors(120). Class 1 HLA molecules, present in all tissue types,bind to the inhibitory killer Ig-like receptors (KIRs) on NKcells to prevent inadvertent activation against normal tis-sues (121). Upon malignant transformation of cells, HLAclass 1 expression is reduced or lost, resulting in escapefrom antitumor T cells. However, a mature NK cell canstill be activated due to lack of binding of inhibitoryKIRs by MHC class 1, resulting in unsuppressed activatingsignals (122). NK cells directly kill tumor cells via differentpathways including release of cytoplasmic granules con-taining perforin and granzyme which cause cell lysis, orvia release of TNF leading to cell apoptosis (123). Lirilumab,or IPH2101 (formerly 1–7F9), is a human, IgG4 monoclonalantibody against common inhibitory KIRs (KIR2DL-1, -2,and -3), that blocks KIR-ligand interaction and augmentsNK cell killing of tumor cells. So far, this new agent hasbeen tried in treatment of refractory or relapsed myelomaas a single agent (124) and in combination with otherimmune-modulating agents (125).One patient with a 10-year history of MM and seven

prior lines of therapy developed kidney failure requiringdialysis after receiving the first dose of 0.075 mg/kg of theIPH2101. It was thought to be related to the study drug ordisease progression. The same patient also developedhyperkalemia and hyperuricemia. None of the patientsdeveloped autoimmunity. IPH2101 has been used withlenalidomide in 15 patients with myeloma at varying doses(113). No cases of AKI were reported, but one patient de-veloped hypophosphatemia. Studies using this agent intreatment of other hematopoietic and metastatic solidorgan cancers are underway. In summary, there is limitedclinical data regarding use of anti-KIR antibodies. Kidney

toxicity appears to be rare but until additional data areobtained it would be prudent to pay attention to kidneyfunction and electrolytes including serum uric acid andphosphorus when using these agents.

Other Agents against MMLin et al. described relatively high expression of CD38

on myeloma cells (126); this in combination with itsrole in cell signaling identified CD38 as a potential thera-peutic antibody target for the treatment of MM. A human-ized anti-CD38 monoclonal antibody, SAR650984, iscurrently in clinical development (127,128), whereasdaratumumab, a human IgG1k monoclonal antibodyagainst CD38, was recently approved by the FDA fortreatment of previously treated MM (129). So far, clinicaltrials have not reported any clinically significant kidneyadverse events associated with the use of CD38 monoclonalantibodies.A typical characteristic of human cancers, including

MM, is the deregulation of DNA methylation and post-translational modifications, especially histone acetylation,leading to deregulation of gene transcription (130). Thehistone acetyltransferases and histone deacetylases(HDACs) act in opposition to each other to regulate acet-ylation levels of histones and nonhistone proteins (130).HDAC inhibitors (HDACi) inhibit the removal of acetylgroups by HDAC enzymes, leading to maintenance of his-tone and nonhistone protein acetylation, accumulation ofhistones and other proteins, and reactivation of epigenet-ically silenced tumor suppressor genes, causing cell-cyclearrest and apoptosis (131). Two HDACi have been ap-proved for various cancers in the United States: vorinostat(132) for cutaneous T cell lymphoma and panobinostat forMM (133). Completed clinical trials so far have not report-ed any clinically significant kidney adverse effects associ-ated with HDACi use; there is, however, significantpreclinical evidence supporting the beneficial effects ofHDACi in various models of kidney disease. In vitro,HDACs are implicated in renal fibrogenesis, possiblythrough inflammatory and profibrotic gene regulationsand cell signaling pathways; there is also evidence for aregulatory role of HDACs in the pathogenesis of polycys-tic kidney disease (134). Wang et al. (135) demonstrated anupregulation of HDACs in podocytes treated with ad-vanced glycation end products, high glucose, and TGF-b(common detrimental factors in diabetic nephropathy),suggesting a contribution of HDACs to podocyte injury.Liu et al. demonstrated that HDAC inhibition attenuateddevelopment of renal fibrosis and suppressed activationand proliferation of renal interstitial fibroblasts (136).These studies suggest a future potential for HDAC inhibi-tion in treatment of renal diseases.

FDA Adverse Event Reporting System DatabaseReview of Antimyeloma AgentsAs part of this review, we evaluated all kidney toxicities

reported with the novel antimyeloma agents discussedabove to the FDAAdverse Event Reporting System (FAERS),from the third quarter of 2011 to the second quarter of 2015.Table 4 summarizes our findings. Lenolidomide, everolimus,and bortezomib were the top three offenders with AKI as the

8 Clinical Journal of the American Society of Nephrology

Tab

le4.

Commonreported

renal

adve

rsereac

tionsto

theFo

odan

dDrugAdministrationAdve

rseEv

entRep

ortingSy

stem

datab

asefrom

thethirdquarterof2011to

thefirstquarterof2015

foran

timyelomaag

ents

discu

ssed

inthisreview

DrugNam

eRen

alIm

pairmen

taHyp

okalem

iaHyp

onatremia

Hyp

omag

nesemia

Hyp

erka

lemia

Hyp

opho

spha

temia

Hyp

erna

trem

iaGrand

Total

Len

alidom

ide

881b

136

6133

2528

811

72Eve

rolim

us58

6b52

3523

2419

474

3Bortezo

mib

325b

6551

1025

249

509

Sirolim

us24

9b8

132

97

028

8Vem

urafen

ib17

6b11

182

40

022

8Po

malidom

ide

113b

410

23

01

133

Carfilzom

ib85

b12

82

89

013

0Vorinostat

44b

2626

010

162

124

Dab

rafenib

32b

213

20

10

50Trametinib

28b

111

30

10

44Nivolumab

20b

514

24

10

44Pe

mbrolizumab

163

19b

01

00

39Pa

nobino

stat

11b

23

12

20

22

The

reareim

portan

tlim

itations

withtheFo

odan

dDrugAdministrationAdve

rseEve

ntRep

orting

System

datab

ase.The

even

tsarereportedby

prov

idersan

d/or

patien

tsan

dtherecouldbe

areporting

bias.Inad

dition,

nota

lldem

ographican

dco

morbidityinform

ationisav

ailableto

help

iden

tify

ifothe

rne

phr

otox

icrisk

factorsarepresent,such

as:u

seof

nons

teroidal

anti-

inflam

matoryag

ents,h

istory

ofhy

perten

sion

ordiabe

tesmellitus

,kno

wnkidne

ydisease,recen

tuse

ofcontrastag

ent,or

recent

useof

stan

dardch

emothe

rapy

that

couldbe

neph

rotoxic.Most

impo

rtan

tly,

itisno

tpossibleto

determineifan

even

tistrulycaus

edby

thedrugas

oppo

sedto

theun

derlyingdisease

orconc

omita

ntmed

ications.

a Ren

alim

pairmen

tcom

prises

proteinu

ria,

ARF,

AKI,elev

ated

creatinine

,hyp

ercreatine

mia,a

ndne

phritis.S

elum

etinib

andSiltux

imab

had,2ev

ents

repo

rted

totaltotheFo

odan

dDrug

Administrationhe

nceareno

tlisted.

bMostc

ommon

repo

rted

reaction

.

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Nephrotoxicities of Multiple Myeloma Treatments, Wanchoo et al. 9

most common finding reported, possibly due to muchgreater use of these drugs. Importantly, the toxicities re-ported here are not just for when these agents are used inMM, but for other cancer treatments as well. Despite the lim-itations of FAERS (Table 4), it still provides valuable informa-tion regarding the renal adverse effects of these therapies.

ConclusionsThe use of novel targeted therapies has led to significant

improvements in survival and overall prognosis with manymalignancies. However, there is evolving knowledge ofrenal adverse events with these agents. Timely recognitionof these toxicities can aid in the proper management ofpatients with myeloma. In this review, we recognized thatthere are multiple ways novel antimyeloma therapies canaffect renal function. In addition, newer targeted agents areentering clinical trials. With the advent of novel targetedtherapies and their use in myeloma, nephrologists andhematologists need to be more vigilant of the renal toxicitypotential of these agents.

AcknowledgmentsWe thank Dr. Vipulbhai Sakhiya for the information provided

from the Food and Drug Administration Adverse Event ReportingSystem regarding the agents. We thank Chin Y. Liu, director, On-cology Pharmacy Residency Karmanos Cancer Center, for her helpin the dosing section of the manuscript.

DisclosuresA.E.’s work is supported by the Intramural Research Program of

theNational Institute ofDiabetes andDigestive andKidneyDiseases,National Institutes of Health. A.A., M.D., A.E., I.G.G., D.M., M.R.,and K.D.J. are members of the American Society of NephrologyOnconephrology Forum. R.W. is an expert member of Cancerand Kidney International Network (CKIN) and K.D.J. is part ofthe governing body of CKIN. I.G.G. was funded in part throughthe National Institute of Health (Bethesda, MD)/National CancerInstitute (Bethesda, MD) Cancer Center Support Grant P30CA008748; I.G.G. owns Pfizer Inc. stock and served on the AdvisoryBoard for Astra Zeneca Inc.

References1. Perazella MA, Moeckel GW: Nephrotoxicity from chemother-

apeutic agents: clinical manifestations, pathobiology, andprevention/therapy. Semin Nephrol 30: 570–581, 2010

2. Barisx S, Ozdil M, Topal N, Do�gru O, Ozdemir N, Sever L,Albayram S, Kilicaslan I, Celkan T: Acute promyelocyticleukemia treated with idarubicin complicated by focalsegmental glomerulosclerosis. J Pediatr Hematol Oncol 32:e82–e84, 2010

3. Mohamed N, Goldstein J, Schiff J, John R: Collapsing glomer-ulopathy following anthracycline therapy. Am J Kidney Dis 61:778–781, 2013

4. Guo J, Ananthakrishnan R, QuW, Lu Y, Reiniger N, Zeng S, MaW, Rosario R, Yan SF, Ramasamy R, D’Agati V, Schmidt AM:RAGE mediates podocyte injury in adriamycin-inducedglomerulosclerosis. J Am Soc Nephrol 19: 961–972, 2008

5. Trieu Y, Trudel S, Pond GR,Mikhael J, JaksicW, ReeceDE, ChenCI, Stewart AK: Weekly cyclophosphamide and alternate-dayprednisone: an effective, convenient, and well-tolerated oraltreatment for relapsed multiple myeloma after autologous stemcell transplantation. Mayo Clin Proc 80: 1578–1582, 2005

6. Park S, Lee SJ, Jung CW, Jang JH, Kim SJ, KimWS, Kim K: DCEPfor relapsed or refractory multiple myeloma after therapy withnovel agents. Ann Hematol 93: 99–105, 2014

7. Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K,Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y,Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D,Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr:Incorporating bortezomib into upfront treatment for multiplemyeloma: early results of total therapy 3. Br J Haematol 138:176–185, 2007

8. Leung N, Slezak JM, Bergstralh EJ, Dispenzieri A, Lacy MQ,Wolf RC, Gertz MA: Acute renal insufficiency after high-dosemelphalan in patientswith primary systemic amyloidosis duringstem cell transplantation. Am J Kidney Dis 45: 102–111, 2005

9. Dou QP, Li B: Proteasome inhibitors as potential novel anti-cancer agents. Drug Resist Updat 2: 215–223, 1999

10. Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J: Theproteasome inhibitor PS-341 in cancer therapy.Clin Cancer Res5: 2638–2645, 1999

11. Richardson PG, Sonneveld P, Schuster MW, Irwin D,Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, LonialS, Goldschmidt H, Reece D, San-Miguel JF, Blade J, BoccadoroM, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB,Schenkein D, Anderson KC; Assessment of Proteasome Inhibitionfor Extending Remissions (APEX) Investigators: Bortezomib orhigh-dose dexamethasone for relapsedmultiplemyeloma.NEnglJ Med 352: 2487–2498, 2005

12. Morita R, Hashino S, Shirai S, Fujita N, Onozawa M, Kahata K,Kondo T, Imamura M, Asaka M: Thrombotic microangiopathyafter treatment with bortezomib and dexamethasone in a pa-tient with multiple myeloma. Int J Hematol 88: 248–250, 2008

13. Moore H, Romeril K: Multiple myeloma presenting with a feverof unknown origin and development of thrombotic throm-bocytopenic purpura post-bortezomib. Intern Med J 41: 348–350, 2011

14. MehtaN, SaxenaA,NiesvizkyR: Bortezomib-induced thromboticthrombocytopaenic purpura [published online ahead of printAugust1,2012].BMJCaseRepdoi:10.1136/bcr-2012-006461,2012

15. Chan KL, Filshie R, Nandurkar H, Quach H: Thromboticmicroangiopathy complicating bortezomib-based therapy formultiple myeloma. Leuk Lymphoma 56: 2185–2186, 2015

16. Greenberger S, Adini I, Boscolo E, Mulliken JB, Bischoff J: Tar-geting NF-kB in infantile hemangioma-derived stem cellsreduces VEGF-A expression. Angiogenesis 13: 327–335, 2010

17. Shibata A, Nagaya T, Imai T, Funahashi H, Nakao A, Seo H:Inhibition of NF-kappaB activity decreases the VEGF mRNAexpression in MDA-MB-231 breast cancer cells. Breast CancerRes Treat 73: 237–243, 2002

18. Thapa RJ, Chen P, Cheung M, Nogusa S, Pei J, Peri S, Testa JR,Balachandran S: NF-kB inhibition by bortezomib permits IFN-g-activatedRIP1kinase-dependentnecrosis in renal cell carcinoma.Mol Cancer Ther 12: 1568–1578, 2013

19. Lodhi A, Kumar A, Saqlain MU, Suneja M: Thromboticmicroangiopathy associated with proteasome inhibitors.Clin Kidney J 8: 632–636, 2015

20. Cheungpasitporn W, Leung N, Rajkumar SV, Cornell LD, SethiS, Angioi A, Fervenza FC: Bortezomib-induced acute interstitialnephritis. Nephrol Dial Transplant 30: 1225–1229, 2015

21. Kortuem KM, Stewart AK: Carfilzomib. Blood 121: 893–897,2013

22. Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S,Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, BuadiF, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E,Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S: A phase2 study of single-agent carfilzomib (PX-171-003-A1) in patientswith relapsed and refractory multiple myeloma. Blood 120:2817–2825, 2012

23. Jhaveri KD, Chidella S, Varghese J, Mailloux L, Devoe C:Carfilzomib-related acute kidney injury. Clin Adv HematolOncol 11: 604–605, 2013

24. Wanchoo R, Khan S, Kolitz JE, Jhaveri KD: Carfilzomib-relatedacute kidney injury may be prevented by N-acetyl-L-cysteine. JOncol Pharm Pract 21: 313–316, 2015

25. Shely RN, Ratliff PD: Carfilzomib-associated tumor lysis syn-drome. Pharmacotherapy 34: e34–e37, 2014

26. LibermanV,D’Agati VD,MasaniN,Drakakis J,Mattana J: AcuteTubular Necrosis in a Patient With Myeloma Treated WithCarfilzomib. KI Reports 1: 89–92, 2016

10 Clinical Journal of the American Society of Nephrology

27. SullivanMR, Danilov AV, Lansigan F, Dunbar NM: Carfilzomibassociated thrombotic microangiopathy initially treated withtherapeutic plasma exchange. J Clin Apher 30: 308–310, 2015

28. Hobeika L, Self SE, Velez JC: Renal thrombotic microangiopathyand podocytopathy associated with the use of carfilzomibin a patient with multiple myeloma. BMC Nephrol 15:156, 2014

29. Qaqish I, SchlamI,ChakkeraH,FonsecaR,Adamski J:Carfilzomib:A cause of drug induced thrombotic microangiopathy. TransfusApheresis Sci 54: 401–404, 2016

30. Yui JC, Van Keer J, Weiss BM, Waxman AJ, Palmer MB, D’AgatiVD, Kastritis E, DimopoulosMA, Vij R, Bansal D,Dingli D, NasrSH, Leung N: Proteasome inhibitor associated thromboticmicroangiopathy. Am J Hematol 91: E348–E352, 2016

31. Hajek R,Masszi T, PetrucciMT, PalumboA, Rosi~nol L, Nagler A,YongKL,Oriol A,Minarik J, Pour L, DimopoulosMA,Maisnar V,Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, HardanI, Jenner M, Calbecka M, David M, de la Rubia J, Drach J,Gasztonyi Z,Gornik S, Leleu X,MunderM,OffidaniM, ZojerN,Rajangam K, Chang YL, San-Miguel JF, Ludwig H: A random-ized phase III study of carfilzomib vs low-dose corticosteroidswith optional cyclophosphamide in relapsed and refractorymultiple myeloma (FOCUS) [published online ahead of printJuly 15, 2016]. Leukemia doi:10.1038/leu.2016.176, 2016

32. Meiners S, Ludwig A, Lorenz M, Dreger H, Baumann G, StanglV, Stangl K: Nontoxic proteasome inhibition activates a pro-tective antioxidant defense response in endothelial cells. FreeRadic Biol Med 40: 2232–2241, 2006

33. Stangl V, LorenzM,Meiners S, Ludwig A, BartschC,MoobedM,Vietzke A, Kinkel HT, Baumann G, Stangl K: Long-term up-regulation of eNOS and improvement of endothelial functionby inhibition of the ubiquitin-proteasome pathway. FASEB J 18:272–279, 2004

34. Scarabelli TM, Chen-Scarabelli C, Gavazzoni M, Sahni G,Saravolatz L, Raddino R, Narula J: Cardiovascular effects ofcarfilzomib, a new proteosome inhibitor, on coronary re-sistencies, vascular tone and vascular reactivity [publishedonline ahead of print March 17, 2015]. J Am Coll Cardiol doi:10.1016/S0735-1097(15)62143-X

35. Chari A, Hajje D: Case series discussion of cardiac and vascularevents following carfilzomib treatment: possible mechanism,screening, and monitoring. BMC Cancer 14: 915, 2014

36. FDA approves Ninlaro, new oral medication to treat multiplemyeloma. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473771.htm. AccessedAugust 2, 2016

37. Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, SmythMJ, Prince HM: Mechanism of action of immunomodulatorydrugs (IMiDS) in multiple myeloma. Leukemia 24: 22–32, 2010

38. Chung F, Lu J, Palmer BD, Kestell P, Browett P, Baguley BC,Tingle M, Ching LM: Thalidomide pharmacokinetics andmetabolite formation in mice, rabbits, and multiple myelomapatients. Clin Cancer Res 10: 5949–5956, 2004

39. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P,Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M,Zeddis J, Barlogie B: Antitumor activity of thalidomide inrefractory multiple myeloma. N Engl J Med 341: 1565–1571, 1999

40. Weber DM, Chen C, Niesvizky R, Wang M, Belch A,Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-KhanAA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD;Multiple Myeloma (009) Study Investigators: Lenalidomide plusdexamethasone for relapsedmultiplemyeloma inNorth America.N Engl J Med 357: 2133–2142, 2007

41. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL,Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R,Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB,Knight RD; Multiple Myeloma (010) Study Investigators:Lenalidomide plus dexamethasone for relapsed or refractorymultiple myeloma. N Engl J Med 357: 2123–2132, 2007

42. Glezerman IG, Kewalramani T, Jhaveri K: Reversible Fanconisyndrome due to lenalidomide. NDT Plus 1: 215–217, 2008

43. Batts ED, Sanchorawala V, Hegerfeldt Y, Lazarus HM: Azotemiaassociated with use of lenalidomide in plasma cell dyscrasias.Leuk Lymphoma 49: 1108–1115, 2008

44. Lipson EJ, Huff CA, Holanda DG, McDevitt MA, Fine DM:Lenalidomide-induced acute interstitial nephritis. Oncologist15: 961–964, 2010

45. Shaaban H, Layne T, Guron G. A case of DRESS (drug reactionwith eosinophilia and systemic symptoms) with acute interstitialnephritis secondary to lenalidomide. J Oncol Pharm Pract 20:302–304, 2013

46. Specter R, Sanchorawala V, Seldin DC, Shelton A, Fennessey S,Finn KT, Zeldis JB, Dember LM: Kidney dysfunction duringlenalidomide treatment for AL amyloidosis. Nephrol DialTransplant 26: 881–886, 2011

47. Jamme M, Galichon P, Hertig A: Minimal change disease andlenalidomide. Am J Kidney Dis 62: 844, 2013

48. Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R,Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K,Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J,Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z,Anderson KC: Pomalidomide alone or in combination withlow-dose dexamethasone in relapsed and refractory multiplemyeloma: a randomized phase 2 study. Blood 123: 1826–1832, 2014

49. San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M,Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C,Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A,Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C,Zaki M, Dimopoulos M: Pomalidomide plus low-dose dexa-methasone versus high-dose dexamethasone alone for patientswith relapsed and refractory multiple myeloma (MM-003): arandomised, open-label, phase 3 trial. Lancet Oncol 14: 1055–1066, 2013

50. Leleu X, AttalM, Arnulf B,Moreau P, Traulle C,Marit G,MathiotC, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B,Stoppa AM, Hennache B, Brechignac S, Meuleman N,Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L,Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, FermandJP, Avet-Loiseau H, Facon T; Intergroupe Francophone duMyelome: Pomalidomide plus low-dose dexamethasone isactive and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone duMyelome 2009-02. Blood 121: 1968–1975, 2013

51. Baird P, Leung S, Hoang H, Babalola O, Devoe CE, WanchooR, Jhaveri KD: A case of acute kidney injury from crystalnephropathy secondary to pomalidomide and levofloxacinuse. J Oncol Pharm Pract 22: 357–360, 2016

52. Andrulis M, Lehners N, Capper D, Penzel R, Heining C,Huellein J, Zenz T, von Deimling A, Schirmacher P, Ho AD,Goldschmidt H, Neben K, Raab MS: Targeting the BRAF V600Emutation in multiple myeloma. Cancer Discov 3: 862–869,2013

53. Bonello L, Voena C, Ladetto M, Boccadoro M, Palestro G,Inghirami G, Chiarle R: BRAF gene is not mutated in plasma cellleukemia and multiple myeloma. Leukemia 17: 2238–2240,2003

54. Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, MartelliMP, Pucciarini A, Bigerna B, Pacini R, Wells VA, Sportoletti P,Pettirossi V,Mannucci R, Elliott O, Liso A, Ambrosetti A, PulsoniA, Forconi F, Trentin L, Semenzato G, Inghirami G, Capponi M,Di Raimondo F, Patti C, Arcaini L, Musto P, Pileri S, Haferlach C,Schnittger S, Pizzolo G, Foa R, Farinelli L, Haferlach T,Pasqualucci L, Rabadan R, Falini B: BRAF mutations in hairy-cell leukemia. N Engl J Med 364: 2305–2315, 2011

55. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R,MillwardM, Rutkowski P, Blank CU,MillerWH Jr, Kaempgen E,Martın-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V,Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME,Goodman V, Chapman PB: Dabrafenib in BRAF-mutatedmetastatic melanoma: a multicentre, open-label, phase 3randomised controlled trial. Lancet 380: 358–365, 2012

56. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C,Schinzel AC, Harview CL, Brunet JP, Ahmann GJ, Adli M,Anderson KC, Ardlie KG, Auclair D, Baker A, Bergsagel PL,Bernstein BE, Drier Y, Fonseca R, Gabriel SB, Hofmeister CC,Jagannath S, Jakubowiak AJ, Krishnan A, Levy J, Liefeld T, LonialS, Mahan S, Mfuko B, Monti S, Perkins LM, Onofrio R, Pugh TJ,Rajkumar SV, Ramos AH, Siegel DS, Sivachenko A, Stewart AK,

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Nephrotoxicities of Multiple Myeloma Treatments, Wanchoo et al. 11

Trudel S, Vij R, Voet D, Winckler W, Zimmerman T, Carpten J,Trent J, Hahn WC, Garraway LA, Meyerson M, Lander ES, GetzG, Golub TR: Initial genome sequencing and analysis of mul-tiple myeloma. Nature 471: 467–472, 2011

57. Rustad EH, Dai HY, Hov H, Coward E, Beisvag V, Myklebost O,Hovig E, Nakken S, Vodak D, Meza-Zepeda LA, Sandvik AK,Wader KF,Misund K, Sundan A, Aarset H,WaageA: BRAFV600Emutation in early-stage multiple myeloma: good response tobroad acting drugs and no relation to prognosis. Blood Cancer J5: e299, 2015

58. O’Donnell E, Raje NS: Targeting BRAF in multiple myeloma.Cancer Discov 3: 840–842, 2013

59. Uthurriague C, Thellier S, Ribes D, Rostaing L, Paul C, Meyer N:Vemurafenib significantly decreases glomerular filtration rate. JEur Acad Dermatol Venereol 28: 978–979, 2014

60. Regnier-Rosencher E, Lazareth H, Gressier L, Avril MF, ThervetE, Dupin N: Acute kidney injury in patients with severe rash onvemurafenib treatment formetastaticmelanomas.Br JDermatol169: 934–938, 2013

61. Launay-Vacher V, Zimner-Rapuch S, Poulalhon N, Fraisse T,Garrigue V, Gosselin M, Amet S, Janus N, Deray G: Acuterenal failure associated with the new BRAF inhibitorvemurafenib: a case series of 8 patients. Cancer 120: 2158–2163, 2014

62. Teuma C, Perier-Muzet M, Pelletier S, Nouvier M, Amini-AdlM,Dijoud F, DuruG, Thomas L, FouqueD, Laville M,Dalle S: Newinsights into renal toxicity of the B-RAF inhibitor, vemurafenib,in patients with metastatic melanoma. Cancer ChemotherPharmacol 78(2): 419–426, 2016

63. Jhaveri KD, Sakhiya V, Fishbane S: BRAF inhibitor relatednephrotoxicity, JAMA Oncol 1: 1133–1134, 2015

64. Wanchoo R, Jhaveri KD, Deray G, Launay-Vacher V: Renal ef-fects of BRAF inhibitors: a systematic review by the Cancer andthe Kidney International Network. Clin Kidney J 9: 245–251,2016

65. Huynh H, Soo KC, Chow PK, Tran E: Targeted inhibition of theextracellular signal-regulated kinase pathway with AZD6244(ARRY-142886) in the treatment of hepatocellular carcinoma.Mol Cancer Ther 6: 138–146, 2007

66. Hainsworth JD, Cebotaru CL, Kanarev V, Ciuleanu TE,Damyanov D, Stella P, Ganchev H, Pover G, Morris C, TzekovaV: A phase II, open-label, randomized study to assess the effi-cacy and safety of AZD6244 (ARRY-142886) versus pemetrexedin patients with non-small cell lung cancer who have failed oneor two prior chemotherapeutic regimens. J Thorac Oncol 5:1630–1636, 2010

67. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF,Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N,Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K,Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, AllredA, Ouellet D, Kim KB, Patel K, Weber J: Combined BRAF andMEK inhibition in melanoma with BRAF V600 mutations. NEngl J Med 367: 1694–1703, 2012

68. Jansen YJ, Janssens P, Hoorens A, Schreuer MS, Seremet T,Wilgenhof S, Neyns B: Granulomatous nephritis and dermatitisin a patient with BRAF V600E mutant metastatic melanomatreated with dabrafenib and trametinib. Melanoma Res 25:550–554, 2015

69. Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF,RumizenM, Burger P,Morrison A, Podar K, ChauhanD, TassoneP, Richardson P, Munshi NC, Ghobrial IM, Anderson KC: Tar-geting MEK induces myeloma-cell cytotoxicity and inhibitsosteoclastogenesis. Blood 110: 1656–1663, 2007

70. Breitkreutz I, RaabMS,Vallet S,Hideshima T, RajeN,ChauhanD,Munshi NC, Richardson PG, Anderson KC: Targeting MEK1/2blocks osteoclast differentiation, function and cytokine secretionin multiple myeloma. Br J Haematol 139: 55–63, 2007

71. Holkova B, Zingone A, KmieciakM, Bose P, Badros AZ, VoorheesPM, Baz R, Korde N, Lin HY, Chen JQ, HermannM, Xi L, RaffieldM, Zhao X, Wan W, Tombes MB, Shrader E, Weir-Wiggins C,Sankala H, Hogan KT, Doyle A, Annunziata CM, Wellons M,Roberts JD, Sullivan D, Landgren O, Grant S: A Phase II Trialof AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2Inhibitor, in Relapsed/Refractory Multiple Myeloma. Clin CancerRes 22: 1067–1075, 2016

72. Tai YT, DillonM, SongW, LeibaM, Li XF, Burger P, Lee AI, PodarK, Hideshima T, Rice AG, van Abbema A, Jesaitis L, Caras I, LawD, Weller E, Xie W, Richardson P, Munshi NC, Mathiot C, Avet-Loiseau H, Afar DE, Anderson KC: Anti-CS1 humanizedmonoclonal antibodyHuLuc63 inhibits myeloma cell adhesionand induces antibody-dependent cellular cytotoxicity in thebone marrow milieu. Blood 112: 1329–1337, 2008

73. Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, ShumBP, Huseni M, Powers D, Nanisetti A, Zhang Y, Rice AG, vanAbbemaA,WongM, LiuG, Zhan F,DillonM,Chen S, Rhodes S,Fuh F, Tsurushita N, Kumar S, Vexler V, Shaughnessy JD Jr,Barlogie B, van Rhee F, Hussein M, Afar DE, Williams MB:CS1, a potential new therapeutic antibody target for the treat-ment of multiple myeloma. Clin Cancer Res 14: 2775–2784,2008

74. Zonder JA, Mohrbacher AF, Singhal S, van Rhee F, BensingerWI, Ding H, Fry J, Afar DE, Singhal AK: A phase 1, multicenter,open-label, dose escalation study of elotuzumab in patientswith advanced multiple myeloma. Blood 120: 552–559, 2012

75. Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A,Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK,Jagannath S: Elotuzumab in combination with lenalidomideand low-dose dexamethasone in relapsed or refractory multiplemyeloma. J Clin Oncol 30: 1953–1959, 2012

76. Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S,Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H,Belch A, Reece D, BeksacM, Spencer A, Oakervee H, OrlowskiRZ, Taniwaki M, Rollig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V,Anderson KC, Richardson P; ELOQUENT-2 Investigators:Elotuzumab Therapy for Relapsed or Refractory MultipleMyeloma. N Engl J Med 373: 621–631, 2015

77. Lonial S, Dimopoulos MA, Palumbo A, White D, Grosicki S,Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen-Nativ H, Belch A, Reece DE, Beksac M, Taniwaki M, Rollig C,Singhal AK, Katz J, Bleickardt EW, Poulart V, Richardson PG:ELOQUENT-2: a phase 3, randomized, open-label study oflenalidomide/dexamethasone with/without elotuzumab inpatients with relapsed/refractory multiple myeloma. Presentedat the 2015 Annual Meeting of the American Society of ClinicalOncology (ASCO), Chicago, IL, May 29–June 2, 2015

78. Liu P, ChengH,Roberts TM,Zhao JJ: Targeting thephosphoinositide3-kinasepathway incancer.NatRevDrugDiscov8:627–644,2009

79. Westin JR: Status of PI3K/Akt/mTOR pathway inhibitors inlymphoma. Clin LymphomaMyeloma Leuk 14: 335–342, 2014

80. Canaud G, Bienaime F, Viau A, Treins C, Baron W, Nguyen C,Burtin M, Berissi S, Giannakakis K, Muda AO, Zschiedrich S,Huber TB, Friedlander G, Legendre C, Pontoglio M, Pende M,Terzi F: AKT2 is essential to maintain podocyte viability andfunction during chronic kidney disease. Nat Med 19: 1288–1296, 2013

81. Swaminathan S, Rosner MH: The podocyte under stress: AKT2to the rescue. Am J Kidney Dis 63: 555–557, 2014

82. O’Reilly KE, Rojo F, SheQB, Solit D, Mills GB, Smith D, LaneH,Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N: mTORinhibition induces upstream receptor tyrosine kinase signalingand activates Akt. Cancer Res 66: 1500–1508, 2006

83. SarbassovDD, Ali SM, Sengupta S, Sheen JH,Hsu PP, Bagley AF,Markhard AL, Sabatini DM: Prolonged rapamycin treatmentinhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159–168, 2006

84. Hsu J, Shi Y, Krajewski S, Renner S, FisherM, Reed JC, Franke TF,Lichtenstein A: TheAKT kinase is activated inmultiplemyelomatumor cells. Blood 98: 2853–2855, 2001

85. Hideshima T, Catley L, Raje N, Chauhan D, Podar K, MitsiadesC, Tai YT, Vallet S, Kiziltepe T, Ocio E, Ikeda H, Okawa Y,Hideshima H, Munshi NC, Yasui H, Richardson PG, AndersonKC: Inhibition of Akt induces significant downregulation ofsurvivin and cytotoxicity in human multiple myeloma cells. Br JHaematol 138: 783–791, 2007

86. Hideshima T, Catley L, YasuiH, Ishitsuka K, RajeN,Mitsiades C,Podar K, Munshi NC, Chauhan D, Richardson PG, AndersonKC: Perifosine, an oral bioactive novel alkylphospholipid, in-hibits Akt and induces in vitro and in vivo cytotoxicity in humanmultiple myeloma cells. Blood 107: 4053–4062, 2006

12 Clinical Journal of the American Society of Nephrology

87. Jakubowiak AJ, Richardson PG, Zimmerman T, Alsina M,Kaufman JL, Kandarpa M, Kraftson S, Ross CW, Harvey C,Hideshima T, Sportelli P, Poradosu E, Gardner L, Giusti K,Anderson KC: Perifosine plus lenalidomide and dexamethasonein relapsed and relapsed/refractory multiple myeloma: a Phase IMultiple Myeloma Research Consortium study. Br J Haematol158(4): 472–480

88. Richardson PG, Wolf J, Jakubowiak A, Zonder J, Lonial S, IrwinD, Densmore J, Krishnan A, Raje N, Bar M, Martin T,Schlossman R, Ghobrial IM, Munshi N, Laubach J, Allerton J,Hideshima T, Colson K, Poradosu E, Gardner L, Sportelli P,Anderson KC: Perifosine plus bortezomib and dexamethasonein patients with relapsed/refractory multiple myeloma pre-viously treated with bortezomib: results of a multicenterphase I/II trial. J Clin Oncol 29: 4243–4249, 2011

89. Keane NA, Glavey SV, Krawczyk J, O’Dwyer M: AKT as a ther-apeutic target in multiple myeloma. Expert Opin Ther Targets18: 897–915, 2014

90. Mimura N, Hideshima T, Shimomura T, Suzuki R, Ohguchi H,Rizq O, Kikuchi S, Yoshida Y, Cottini F, Jakubikova J, Cirstea D,GorgunG,Minami J, Tai YT, Richardson PG, Utsugi T, Iwama A,Anderson KC: Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulumstress induced by proteasome inhibition. Cancer Res 74(16):4458–4469, 2014

91. de la Puente P, Muz B, Azab F, Luderer M, Azab AK: Molecu-larly targeted therapies in multiple myeloma [publishedonline ahead of print April 16, 2014]. Leukemia Res Treatdoi: 10.1155/2014/976567

92. Ghobrial IM, Weller E, Vij R, Munshi NC, Banwait R, BagshawM, Schlossman R, Leduc R, Chuma S, Kunsman J, Laubach J,Jakubowiak AJ, Maiso P, Roccaro A, Armand P, Dollard A,Warren D, Harris B, Poon T, Sam A, Rodig S, Anderson KC,Richardson PG: Weekly bortezomib in combination withtemsirolimus in relapsed or relapsed and refractory multiplemyeloma: a multicentre, phase 1/2, open-label, dose-escalationstudy. Lancet Oncol 12: 263–272, 2011

93. Bendell JC, Kelley RK, Shih KC, Grabowsky JA, Bergsland E,Jones S, Martin T, Infante JR, Mischel PS, Matsutani T, Xu S,Wong L, Liu Y, Wu X, Mortensen DS, Chopra R, Hege K,Munster PN: A phase I dose-escalation study to assess safety,tolerability, pharmacokinetics, and preliminary efficacy of thedual mTORC1/mTORC2 kinase inhibitor CC-223 in patientswith advanced solid tumors or multiple myeloma. Cancer 121:3481–3490, 2015

94. Jang HS, Kim J, Kim KY, Kim JI, Cho MH, Park KM: Previousischemia and reperfusion injury results in resistance of thekidney against subsequent ischemia and reperfusion insult inmice; a role for the Akt signal pathway.Nephrol Dial Transplant27: 3762–3770, 2012

95. Richardson PG, Eng C, Kolesar J, Hideshima T, Anderson KC:Perifosine, an oral, anti-cancer agent and inhibitor of the Aktpathway: mechanistic actions, pharmacodynamics, pharma-cokinetics, and clinical activity. Expert Opin Drug MetabToxicol 8: 623–633, 2012

96. Stallone G, Infante B, Pontrelli P, Gigante M, Montemurno E,Loverre A, Rossini M, Schena FP, Grandaliano G, Gesualdo L:Sirolimus and proteinuria in renal transplant patients: evidencefor a dose-dependent effect on slit diaphragm-associated pro-teins. Transplantation 91: 997–1004, 2011

97. Somers MJG, Paul E: Safety considerations of mammalian targetof rapamycin inhibitors in tuberous sclerosis complex and renaltransplantation. J Clin Pharmacol 55: 368–376, 2015

98. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, FrostM, Belousova E, Sauter M, Nonomura N, Brakemeier S, deVries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, LincyJ, Lebwohl D, Budde K: Everolimus for angiomyolipomaassociated with tuberous sclerosis complex or sporadiclymphangioleiomyomatosis (EXIST-2): amulticentre, randomised,double-blind, placebo-controlled trial. Lancet 381: 817–824, 2013

99. Morales JM, Campistol JM, Kreis H,MouradG, Eris J, Schena FP,Grinyo JM, Nanni G, Andres A, Castaing N, Brault Y, Burke JT:Sirolimus-based therapy with or without cyclosporine: long-term follow-up in renal transplant patients. Transplant Proc 37:693–696, 2005

100. Gonwa TA, Hricik DE, Brinker K, Grinyo JM, Schena FP; SirolimusRenal Function Study Group: Improved renal function in sirolimus-treated renal transplantpatients after early cyclosporineelimination.Transplantation 74: 1560–1567, 2002

101. Gaber AO, Kahan BD, Van Buren C, Schulman SL, Scarola J,Neylan JF; Sirolimus High-Risk Study Group: Comparison ofsirolimus plus tacrolimus versus sirolimus plus cyclosporine inhigh-risk renal allograft recipients: results from an open-label,randomized trial. Transplantation 86: 1187–1195, 2008

102. Izzedine H, Boostandoot E, Spano JP, Bardier A, Khayat D:Temsirolimus-induced glomerulopathy. Oncology 76: 170–172, 2009

103. HudesG,CarducciM, Tomczak P,Dutcher J, Figlin R, Kapoor A,Staroslawska E, Sosman J, McDermott D, Bodrogi I, KovacevicZ, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E,O’Toole T, Lustgarten S,Moore L,Motzer RJ; Global ARCCTrial:Temsirolimus, interferon alfa, or both for advanced renal-cellcarcinoma. N Engl J Med 356: 2271–2281, 2007

104. Markman B,Dienstmann R, Tabernero J: Targeting the PI3K/Akt/mTOR pathway–beyond rapalogs. Oncotarget 1: 530–543,2010

105. Kishimoto T: The biology of interleukin-6. Blood 74: 1–10, 1989106. Voorhees PM, Manges RF, Sonneveld P, Jagannath S, Somlo G,

KrishnanA, Lentzsch S, Frank RC, Zweegman S,Wijermans PW,Orlowski RZ, Kranenburg B, Hall B, Casneuf T, Qin X, van deVelde H, Xie H, Thomas SK: A phase 2 multicentre study ofsiltuximab, an anti-interleukin-6 monoclonal antibody, inpatients with relapsed or refractory multiple myeloma. Br JHaematol 161: 357–366, 2013

107. Orlowski RZ, Gercheva L, Williams C, Sutherland H, RobakT, Masszi T, Goranova-Marinova V, Dimopoulos MA,Cavenagh JD, Spi�cka I, Maiolino A, Suvorov A, Blade J,Samoylova O, Puchalski TA, Reddy M, Bandekar R, van deVelde H, Xie H, Rossi JF: A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb)and bortezomib versus bortezomib alone in patients withrelapsed or refractory multiple myeloma. Am J Hematol 90:42–49, 2015

108. Deisseroth A, Ko CW, Nie L, Zirkelbach JF, Zhao L, Bullock J,Mehrotra N, Del Valle P, Saber H, Sheth C, Gehrke B, Justice R,Farrell A, Pazdur R: FDA approval: siltuximab for the treatmentof patients with multicentric Castleman disease. Clin CancerRes 21: 950–954, 2015

109. van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fossa A,Simpson D, Capra M, Liu T, Hsieh RK, Goh YT, Zhu J, Cho SG,Ren H, Cavet J, Bandekar R, Rothman M, Puchalski TA, ReddyM, van de Velde H, Vermeulen J, Casper C: Siltuximab formulticentric Castleman’s disease: a randomised, double-blind,placebo-controlled trial. Lancet Oncol 15: 966–974, 2014

110. Kearl TJ, Jing W, Gershan JA, Johnson BD: PD-1/PD-L1 Blockadeafter Transient Lymphodepletion to Treat Myeloma. J Immunol190: 5620–5628, 2013

111. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L,Hassel JC, Rutkowski P,McNeil C, Kalinka-Warzocha E, SavageKJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H,Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C,Sharkey B,Waxman IM, Atkinson V, Ascierto PA: Nivolumab inpreviously untreatedmelanomawithout BRAFmutation.NEnglJ Med 372: 320–330, 2015

112. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ,Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER,Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P,Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA,Kollmannsberger C, Larkin J, RavaudA, Simon JS, Xu LA,WaxmanIM, Sharma P; CheckMate 025 Investigators: Nivolumab versusEverolimus inAdvancedRenal-CellCarcinoma.NEngl JMed373:1803–1813, 2015

113. Nivolumab Package Insert. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf. AccessedJan 1, 2016

114. Shirali AC, Perazella MA, Gettinger S: Association of AcuteInterstitial Nephritis With Programmed Cell Death 1 InhibitorTherapy in Lung Cancer Patients. Am J Kidney Dis 68: 287–291,2016

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Nephrotoxicities of Multiple Myeloma Treatments, Wanchoo et al. 13

115. Cortazar FB, Marrone KA, Troxell ML, Ralto KM, Hoenig MP,Brahmer JR, Le DT, Lipson EJ, Glezerman IG, Wolchok J, CornellLD, Feldman P, StokesMB, Zapata SA,Hodi FS,Ott PA, YamashitaM, Leaf DE: Clinico-pathological features of acute kidney injuryassociated with immune checkpoint inhibitors. Kidney Int 90:638–647, 2016

116. Pembrolizumab package insert. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf. AccessedJan 1, 2016

117. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L,Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P,NeynsB,BlankCU,HamidO,MateusC, Shapira-FrommerR,KoshM, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006investigators: Pembrolizumab versus Ipilimumab in AdvancedMelanoma. N Engl J Med 372: 2521–2532, 2015

118. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O,Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, CranmerLD, Blank CU,O’Day SJ, Ascierto PA, Salama AK, Margolin KA,LoquaiC, Eigentler TK,Gangadhar TC,CarlinoMS,Agarwala SS,Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R,Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN,Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A:Pembrolizumab versus investigator-choice chemotherapy foripilimumab-refractory melanoma (KEYNOTE-002): a randomised,controlled, phase 2 trial. Lancet Oncol 16: 908–918, 2015

119. Min L, Hodi FS: Anti-PD1 following ipilimumab for mucosalmelanoma: durable tumor response associated with severehypothyroidism and rhabdomyolysis. Cancer Immunol Res 2:15–18, 2014

120. Farag SS, Caligiuri MA: Human natural killer cell developmentand biology. Blood Rev 20: 123–137, 2006

121. Rezvani K, Rouce RH: The Application of Natural Killer CellImmunotherapy for the Treatment of Cancer. Front Immunol 6:578, 2015

122. Campbell KS, Hasegawa J: Natural killer cell biology: an updateand future directions. J Allergy Clin Immunol 132: 536–544,2013

123. BradleyM, Zeytun A, Rafi-Janajreh A, Nagarkatti PS, NagarkattiM: Role of spontaneous and interleukin-2-induced natural killercell activity in the cytotoxicityand rejection of Fas+andFas- tumorcells. Blood 92: 4248–4255, 1998

124. BensonDM Jr, Hofmeister CC, Padmanabhan S, SuvannasankhaA, Jagannath S, Abonour R, Bakan C, Andre P, Efebera Y, TiollierJ, Caligiuri MA, Farag SS: A phase 1 trial of the anti-KIR antibodyIPH2101 in patients with relapsed/refractory multiple myeloma.Blood 120: 4324–4333, 2012

125. Benson DM Jr, Cohen AD, Jagannath S, Munshi NC, Spitzer G,Hofmeister CC, Efebera YA, Andre P, Zerbib R, Caligiuri MA: APhase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomidein Patients with Relapsed/Refractory Multiple Myeloma. ClinCancer Res 21: 4055–4061, 2015

126. Lin P, Owens R, Tricot G, Wilson CS: Flow cytometricimmunophenotypic analysis of 306 cases of multiple myeloma.Am J Clin Pathol 121: 482–488, 2004

127. Martin TG, Hsu K, Strickland SA et al. A phase I trial ofSAR650984, a CD38 monoclonal antibody, in relapsed or re-fractory multiple myeloma. J Clin Oncol 32: 5s (abstr 8532),2014

128. Martin TG, Hsu K, Charpentier E, Vij R, Baz RC, Benson DM,Lendvai N: A phase Ib dose escalation trial of SAR650984(Anti-CD38 mAb) in combination with lenalidomide anddexamethasone in relapsed/refractory multiple myeloma. JClin Oncol 32: 5s (abstr 8512), 2014

129. “FDA approves Darzalex for patients with previously treatedmultiple myeloma” November 16, 2015. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm472875.htm. Accessed June 20, 2016

130. Ropero S, Esteller M: The role of histone deacetylases (HDACs)in human cancer. Mol Oncol 1: 19–25, 2007

131. Laubach JP, Moreau P, San-Miguel JF, Richardson PG: Panobinostatfor the Treatment of Multiple Myeloma. Clin Cancer Res 21:4767–4773, 2015

132. Available at: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm094952.htm.Accessed June 20, 2016

133. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htm. Accessed June 20, 2016

134. Liu N, Zhuang S: Treatment of chronic kidney diseases withhistone deacetylase inhibitors. Front Physiol 6: 121, 2015

135. Wang X, Liu J, Zhen J, Zhang C, Wan Q, Liu G, Wei X, ZhangY, Wang Z, Han H, Xu H, Bao C, Song Z, Zhang X, Li N, Yi F:Histone deacetylase 4 selectively contributes to podocyteinjury in diabetic nephropathy. Kidney Int 86: 712–725,2014

136. Liu N, He S, Ma L, PonnusamyM, Tang J, Tolbert E, Bayliss G,Zhao TC, Yan H, Zhuang S: Blocking the class I histonedeacetylase ameliorates renal fibrosis and inhibits renalfibroblast activation via modulating TGF-beta and EGFRsignaling. PLoS One 8: e54001, 2013

Published online ahead of print. Publication date available at www.cjasn.org.

14 Clinical Journal of the American Society of Nephrology

E-Mail karger@karger.com

In-Depth Topic Review

Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review

Rimda Wanchoo   a Sabine Karam   c Nupur N. Uppal   a Valerie S. Barta   a Gilbert Deray   d Craig Devoe   b Vincent Launay-Vacher   d, e Kenar D. Jhaveri   a  on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors 

a   Division of Kidney Diseases and Hypertension, Hofstra Northwell School of Medicine, Great Neck , and b   Division of Hematology and Oncology, Hofstra Northwell School of Medicine and Northwell Cancer Institute, New Hyde Park , USA; c   Department of Medicine, University of Balamand, Faculty of Medicine, Beirut , Lebanon; d   Nephrology Department, Pitié-Salpêtrière University Hospital, and e   Service ICAR, Pitié-Salpêtrière University Hospital, Paris , France

verse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3–10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2–3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9–29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of im-mune checkpoint inhibitors is extremely important.

© 2017 S. Karger AG, Basel

Introduction

Immune checkpoint inhibitors (ICI) are increasingly being used in the treatment of several malignancies. Im-mune surveillance of cancer occurs through the activity of both the innate and adaptive immune systems, where-by malignant cells are detected and eliminated in their earliest stages [1] . However, tumors escape this process

Key Words

Renal failure · Acute interstitial nephritis · Ipilimumab · Nivolumab · Onconephrology · Pembrolizumab · Targeted therapies

Abstract Background: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-pro-grammed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patient’s own immune sys-tem against the tumor rather than targeting the cancer di-rectly. These therapies have demonstrated a significant ben-efit in the treatment of melanomas and other cancers. Summary: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimum-ab-, pembrolizumab-, and nivolumab-induced kidney toxic-ity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system data-base were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hypo-natremia were toxicities caused by ipilimumab. The main ad-

Published online: January 12, 2017 NephrologyAmerican Journal of

Kenar D. Jhaveri, MD Professor of Medicine, Nephrology, Northwell Health Hofstra Northwell School of Medicine Great Neck, NY 11021 (USA) E-Mail kjhaveri   @   northwell.edu

© 2017 S. Karger AG, Basel

www.karger.com/ajn

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Adverse Renal Effects of ICIs Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

161

by employing several mechanisms to avoid or actively suppress anticancer immune responses [2, 3] . Enhancing anti-tumor T-cell immunity with checkpoint inhibitor antibodies such as anti-cytotoxic T-lymphocyte-associ-ated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1) has shown significant clinical benefits in tumor regression and prolonged stabilization of many solid tu-mors and is now FDA approved for use in non-small cell lung cancer, melanoma, and renal cell cancer. Figure 1 describes CTLA-4 and PD-1 signaling networks in ho-meostasis and Figure 2 summarizes the mechanism of action of CTLA-4 and PD-1 antagonists in malignancy. The T-cell receptor (TCR) interacts with the major his-tocompatibility complex in association with antigen on the antigen presenting cell (APC). The cell surface mol-

ecule CD28 mediates a positive co-stimulatory signal to the T cell via interaction with B7 receptors on the APC. The CTLA-4 is then upregulated on the T cell, which in turn competes with the B7-CD28 ligand molecule. CTLA-4 upregulation leads to an inhibitory signal and induces T-cell arrest. CTLA-4 activation puts the “brakes” on the immune system [4] . Ipilimumab is a monoclonal antibody that has anti-tumor activity by targeting CTLA-4 and activating the immune system. The inhibitory re-ceptor PD-1 is a cell surface molecule with a single immunoglobulin super-family domain. It is expressed on activated T cells, B cells, natural killer T cells, mono-cytes, and dendritic cells [5–7] . PD-1 has 2 ligands: PD-ligand-1 (L1) and ligand-2 (L2). Tumor expression of PD-L1 is thought to be one mechanism of immune

Fig. 1. CTLA-4 and PD-1 signaling networks at homeostasis. Integration of both positive and negative costimulatory signals during and after the initial T-cell activation will determine the fate and intensity of the alloimmune response. The first step in antigen (Ag) recognition is the binding of the antigen to major histocom-patibility complex (MHC) molecules on the antigen presenting cell (APC) and creating a complex with the T cell receptor (TCR) located on the T cell. This is followed by the interaction of the CD28 molecule with B7 (CD 80/86) initiating a co-stimulatory signal leading to further T-cell stimulation (this is in addition to other co-stimulatory molecules not depicted here). As a negative

feedback process to prevent overstimulation, T-cell activation leads to the upregulation of the CTLA-4 molecule, which com-petes with the B7-CD28 ligand and in turn leads to T-cell arrest, thus providing brakes to the immune system. Similarly, binding of the PD-1 molecule with PD-L1 and PD-L2 leads to an inhibi-tory signal with decreased effector T-cell function, suppressing immune surveillance and permitting neoplastic growth. It has to be noted that the majority of data supports the role of increased PD-L1 expression in human tumors and serves as the biomarker to consider PD-1 inhibitors for treatment. The role of PD-L2 in specific tumor immunology in humans is not well defined.

Colo

r ver

sion

avail

able

onlin

e

PD-1 and PD-L1CTLA-4

CTLA-4

CD28

Ag

B7

B7Co stimulation

MHC

Dendriticcell

Inhibitory signals

Inhibitory signals

T-lymphocyteT-lymphocyte

T Lc receptor

Activation(cytokines secretion,

proliferation, migration to the tumor)

Tumoral microenvironmentLymph node

Immune checkpoints (normal physiology)

PD-1

PD-1PD-L1

PD-L2

MHCTumor

cell

APC

T Lcreceptor

PD-1 and PD-L1CTLA-4

CTLA-4

CD28

Ag

B7

B7Co stimulation

MHC

Dendriticcell

Inhibitory signals

Inhibitory signals

T-lymphocyteT-lymphocyte

T Lc receptor

Activation(cytokines secretion,

proliferation, migration to the tumor)

Tumoral microenvironmentLymph node

Immune checkpoints (normal physiology)

PD-1

PD-1PD-L1

PD-L2

MHCTumor

cell

APC

T Lcreceptor

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Wanchoo    et al. Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

162

evasion by cancer cells. The role of PD-L2 in cancer im-munology is far less clear [6, 7] . Monoclonal antibodies directed against PD-1 prevent the engagement of PD-1 with its ligands, leading to T-cell stimulation. They assert anti-neoplastic activity by rescuing the T cell from apop-totic death, thus allowing it to continue its attack on tu-mor cells [5] . Nivolumab and pembrolizumab are 2 monoclonal antibody therapies designed to directly block the interaction between PD-1 and its ligands and have been successfully used in treatment of melanoma, lung cancer, renal cancer, and hematological malignan-cies since 2014 [8–10] .

Immune-related toxicities (colitis, dermatitis, pneu-monitis, hepatitis, and thyroiditis) are common with ICI [4, 5] . This narrative review summarizes all published contributions related to ipilimumab-, pembrolizumab-, and nivolumab-induced renal toxicities. In addition, pri-mary data from clinical trials, and FDA adverse reporting system was reviewed [11].

Incidence To better understand recently published contributions

related to ipilimumab-, pembrolizumab-, and nivolum-ab-induced renal toxicities, a Medline, Embase, and Scopus search of indexed manuscripts was conducted. A total of 17 articles and original investigations that includ-ed over 100 patients with renal outcomes secondary to the 3 agents were reviewed. In addition, details of all case re-ports reviewed can be found in online supplementary Tables 1–5 (for all online suppl. material, see www.karger.com/doi/10.1159/000455014).

Cortazar et al. [12] analyzed data from published phase 2 and 3 clinical trials of patients with adverse renal outcomes and found the overall incidence of acute kid-ney injury (AKI) to be 2.2% among a total of 3,695 pa-tients. The incidence of grade III or IV (National Cancer Institute Common Terminology Criteria for adverse events) AKI or need for dialysis was 0.6% [12] . AKI oc-curred more frequently in patients who received combi-

Fig. 2. Ipilimumab or CTLA-4 antagonist binds to the CTLA-4 molecule and prevents it from binding to B7, leading to the sus-tained activation of the T cell (lifting the foot off the brakes). PD- 1 inhibitors bind to the PD-1 molecule preventing its interaction with PD-L1/L2, thus leading to continued T-cell stimulation

(pressing on the accelerator). It has to be noted that the majority of data supports the role of increased PD-L1 expression in human tumors and serves as the biomarker to consider PD-1 inhibitors for treatment. The role of PD-L2 in specific tumor immunology in humans is not well defined.

Colo

r ver

sion

avail

able

onlin

e

Anti-PD-1 and anti-PD-L1Anti-CTLA-4

CTLA-4

CD28

Ag

B7

B7Co stimulation

MHC

Dendriticcell

Inhibitory signals

Inhibitory signals

T-lymphocyteT-lymphocyte

T Lcreceptor

T Lc receptor

Tumoral microenvironmentLymph node

Immune checkpoints and their inhibitors

PD-1

PD-1PD-L1

PD-L2

MHCTumor

cell

APC

Activation(cytokines secretion,

proliferation, migration to the tumor)

Anti-PD-1 and anti-PD-L1Anti-CTLA-4

CTLA-4

CD28

Ag

B7

B7Co stimulation

MHC

Dendriticcell

Inhibitory signals

Inhibitory signals

T-lymphocyteT-lymphocyte

T Lcreceptor

T Lc receptor

Tumoral microenvironmentLymph node

Immune checkpoints and their inhibitors

PD-1

PD-1PD-L1

PD-L2

MHCTumor

cell

APC

Activation(cytokines secretion,

proliferation, migration to the tumor)

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Adverse Renal Effects of ICIs Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

163

nation therapy with ipilimumab and nivolumab (4.9%) than in patients who received mono-therapy with ipili-mumab (2.0%), nivolumab (1.9%), or pembrolizumab (1.4%) [12] . A recent abstract reported an incidence of renal events as high as 13.9% with the use of these agents in routine practice in the United States, being associated with the highest toxicity-induced costs ($8,854) [13] . Our unpublished data [14] analyzed 211 patients who received ipilimumab, nivolumab, or pembrolizumab. Ninety-nine patients had a serum creatinine available for analysis. AKI stage 1 (based on AKI network criteria) developed in 29% (11/38) of patients who were given ipilimumab and in 24.5% (15/61) of patients who were given PD-1 inhibitors. AKI stage 2 developed in 5% (2/38) of patients who were given ipilimumab and 10% (6/61) of patients who were given PD-1 inhibitors. In summary, while initial studies had quoted a small inci-dence of AKI with ICI use, recent unpublished emerging data suggest a higher incidence rate of AKI (9.9–29% range) with ICI.

Ipilimumab Ipilimumab is a monoclonal antibody that has anti-

tumor activity by targeting CTLA-4 and activating the immune system. Cell-mediated immune response lead-ing to inflammatory cell infiltrates with and without granulomas has been reported [15, 16] . Cases of acute in-terstitial nephritis (AIN) in the initial trials, arising 2–12 weeks post drug administration have been reported and one of them demonstrated granulomas [12, 17–22] . The largest series of biopsy-proven cases of AKI was re-ported by Cortazar et al. [12] . Pathology revealed AIN in most cases with varying degrees of foot process efface-ment. In addition, cases of nephrotic syndrome [7, 19] in the form of minimal change disease and membranous ne-phropathy have been reported. Out of a total of 13 cases that were noted to have renal injury associated with ipili-mumab, there was no specific gender predilection noted (online suppl. Table 1). Most of the AKI occurred 6–12 weeks following the start of treatment, with the longest interval being 26 weeks. Eleven out of 13 patients who had AIN or podocytopathy received steroids. Two patients did not receive steroids and had no renal recovery. Of the 11 patients treated, 2 had complete recovery of renal function, 7 patients had partial improvement in renal function, and 2 patients remained dialysis dependent with no improvement. Steroids administered differed in their forms and dosages. Patients who developed AKI earlier in the course responded to steroids in a better way and needed less dialysis.

Ipilimumab has also been associated with electrolyte disturbances. Two cases of ipilimumab-induced hypona-tremia [23, 24] due to panhypopituitarism from ipilim-umab related hypophysitis have been reported. The inci-dence of hypophysitis in patients treated with this agent is close to 17% in clinical trials [23] . Mechanistically, a loss of adrenocorticotrophic hormone-secreting cortico-trophs leads to a secondary adrenal insufficiency and loss of regulatory effects of cortisol on arginine vasopressin. This could be the mechanism leading to the hyponatre-mia. In summary, anti CTLA-4 antagonists may result in AIN, podocytopathy, or hyponatremia related to panhy-popituitarism.

Pembrolizumab Pembrolizumab [25] is a humanized monoclonal im-

munoglobulin G4 (IgG4) kappa antibody directed against the PD-1. Initial reports did not mention any re-nal toxicity [26] associated with pembrolizumab. In re-cent phase 1 [27] and phase 2 trials [28] , AKI in the form of nephritis was reported with an incidence as high as 6.7% [27] . In the KEYNOTE1 trial, AKI was reported to be present in 2 out of 495 patients and hyperkalemia in 4 patients [10] . A recent study using this agent in lung can-cer reported an increase in creatinine in 1.7% of the pa-tients who received 2 mg/kg of pembrolizumab and 2% in patients who received the higher dose, but none of the patients on standard chemotherapy (docetaxel) [29] de-veloped AKI. Online supplementary Table 2 summarizes more recent case reports of renal toxicities caused by this agent [12, 30, 31] . Overall, the 4 cases [12, 31] of biopsy-proven AIN reported with this agent were in the time frame of 1–12 months. There was no gender preference. Three patients responded to steroids with complete re-mission and 1 patient required dialysis and had partial remission with steroids. Steroids used were variable from intravenous forms to oral steroids for 1–3 months time frame.

Nivolumab In the early phase I trials, nivolumab was thought to be

innocuous from a renal standpoint [9, 32, 33] . As report-ed events accumulated, it is now thought that renal ad-verse events are frequently associated [34] with nivolum-ab. In a phase I dose-escalation cohort expansion trial in patients with advanced NSCLC, adverse renal events were reported to be present in 3% of the cases [35] . Two additional phase 2 trials also reported several renal ad-verse events [8, 36] . In another phase 3 study, nivolumab monotherapy was compared with docetaxel monothera-

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Wanchoo    et al. Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

164

py in patients in whom disease had progressed during or after one prior platinum-containing chemotherapy regi-men. Among treatment-related select adverse events, 3% of the patients on nivolumab had an increase in creatinine as compared to 2% of the patients on docetaxel. Further-more, one case of interstitial nephritis was also reported in the nivolumab group [9] . Regarding trials in patients with melanoma, both AKI and hyponatremia have been reported [37–43] . Online supplementary Table 3 summa-rizes the recent case reports of renal toxicities with this agent. Four cases were reported in 2 recent publications [12, 31] . All 4 cases showed biopsy-proven AIN (most within 6–10 months following initiation of treatment). Figure 3 illustrates the pathology noted in a case of nivolumab-associated AIN. In summary, similar to pem-brolizumab, AKI appears to develop late during the treat-ment phase, usually in the 6–12 months period. No gen-der preferences were noted and steroid treatment nor-malized renal function in 75% of the cases.

Combined CTLA-4 and PD-1 Inhibitor Therapy Combination therapy with ipilimumab and nivolum-

ab appears to increase the incidence and severity of ad-verse events as compared to the use of nivolumab alone. In a randomized, double-blind phase 1 dose-escalation study, comparing nivolumab in combination with ipili-mumab with standard-of-care ipilimumab monotherapy as a first-line treatment in patients with advanced mela-noma, 4 adverse renal events among 94 patients that re-

ceived the combination therapy were reported, including a grades 3–4 event. Three of them who were managed with immunomodulatory therapy achieved complete resolution. No renal events were reported in the ipilim-umab monotherapy group [39] . In another phase 1 trial where these 2 drugs were combined in patients with ad-vanced melanoma, and administered either concurrently or sequentially, a rise in creatinine was noted in 7 out of the 53 patients who received the concurrent therapy. Conversely, none of the patients who received the se-quential therapy developed an adverse renal event [40] . In a randomized, double-blind, multicenter, phase 3 tri-al (CheckMate 067) that was conducted to evaluate the safety and efficacy of nivolumab alone or nivolumab combined with ipilimumab in comparison with ipilim-umab alone in patients with previously untreated meta-static melanoma, 3 out of the 313 (0.9%) patients treated with nivolumab alone developed a renal adverse event as compared to 17 out 313 (5%) treated with ipilimumab and nivolumab and 8 out of 311 (2.5%) treated with ipi-limumab alone [41] . Cortazar et al. [12] , Shirali et al. [31], and Murakami et al. [42] reported a total of 6 cases of ipilimumab and nivolumab combination therapy used in melanoma treatment, leading to biopsy-proven granulo-matous or diffuse AIN. All were male, and 4 of the 6 pa-tients had only partial recovery with steroids while 1 pa-tient had complete recovery. The time frame ranged from 5 to 33 weeks. It appears that the injury might be more severe due to granuloma formation and perhaps

a b

Fig. 3. a , b A 70-year-old Caucasian female who had completed chemotherapy 6 months ago for metastatic non-small cell lung cancer, 3 months ago was given a Pd1 inhibitor (Nivolumab), now presented with AKI where the baseline creatinine of 1.0 rose to 5.0 mg, urinalysis showed microhematuria and less than 1 g pro-teinuria with some white cell casts. There was no peripheral eo-

sinophilia, rash or fever a , b H&E staining showing ×200 and ×600 magnification, respectively, illustrating renal cortical tissue show-ing diffuse, mild to moderate, active interstitial inflammation, mild edema, and frequent tubulitis and tubular epithelial injury, composed of activated lymphocytes, a few macrophages, and fre-quent eosinophils.

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Adverse Renal Effects of ICIs Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

165

less responsive to steroids, and 1 patient required dialy-sis. Online supplementary Table 4 summarizes the renal effects of combined therapy.

FDA Adverse Event Reporting System Database Review of Renal Toxicities with ICI As part of this review, we evaluated all renal toxicities

with the above-mentioned ICI reported to the FDA ad-verse event reporting system from the 3rd quarter of 2011 to the 2nd quarter of 2015. Table 1 summarizes our find-ings. Renal failure was the most commonly reported event followed by hyponatremia consistent with the re-viewed literature findings. Renal failure and hyponatre-mia were also reported with PD-1 inhibitors. Ipilimumab has been in use since 2011 and PD-1 inhibitors since 2014 possibly confounding the increased rate of renal events seen with ipilimumab.

Clinical Features and Mechanism of Injury While hematuria (16%), eosinophilia (21%), and wors-

ening HTN (11%) were noted in some patients, rising se-rum creatinine (100%) and pyuria (68%) [12, 31] may be the only clinical clue in a large majority of the cases. As noted above, nephrotic syndrome is a rare finding in CTLA-4 antagonists.

CTLA-4 regulates peripheral tolerance by modulating the interaction between APC and T cells in secondary lymphoid organs. CTLA-4 deficiency was reported to trigger the early onset of severe lymphoproliferative au-toimmune syndromes both in human and mouse via tis-sue self-antigen-specific T-cell activation [1] . With CTLA-4 blockade, regulatory T cells (Tregs) lose their suppressive capacity and an uncontrolled activation of

auto-reactive T cells occurs. Those cells then migrate and infiltrate the kidney. On the other hand, PD-1 contrib-utes to tolerance primarily at the level of target organs. In the renal tissue, there is upregulation of PD-L1 by re-nal cells, which will bind and signal through PD-1 ex-pressed by T cells, trying to prevent those cells from pro-liferating and damaging the tissue. However, when the self-reactive T cells have their PD-1 receptor blocked by the antibody, the PD-1/PD-L1 signaling will be inter-rupted and T cells will further proliferate and cause cy-totoxic injury to the kidney [43] . In addition, PD-L1- and L2-deficient mice have also accelerated ischemic reper-fusion renal injury [44] . PD-Ligands are essential in pre-venting inflammatory responses of the immune system in the target organs such as the kidney [45, 46] . Also, PD-1-knockout mice spontaneously developed glomerulo-nephritis [47, 48] . The heterogeneity of the time course and delayed response are suggestive of a mechanism dis-tinct from typical drug-induced AIN. It is possible that ICIs-induced AIN may be due to “reprogramming” of the immune system, leading to the loss of tolerance against endogenous kidney antigens, as opposed to a de-layed type hypersensitivity reaction [12] . This might be why some of the cases had a long latency time period be-fore AIN occurred. Thus, anti-PD-1 therapy may drive an autoimmune variant of interstitial nephritis, similar to the induction of autoimmune diabetes, possibly medi-ated by the loss of peripheral tolerance to self-reactive T cells [49] . The disruption of PD-1 signaling might also break tolerance to drug-specific effector T cells that are critical to the pathogenesis of AIN [50] . As a result, anti-PD-1 therapy reactivates exhausted drug-specific T cells primed by the exposure to nephritogenic drugs, includ-

Table 1. Common reported renal adverse events to the FDA adverse reporting database (FAERS) from 2011 3rd quarter to 1st quarter of 2015

Drug name Renal impairment* Hypokalemia Hyponatremia Hypomagnesemia Hyperkalemia Hypophosphatemia Hypernatremia Grand

total

Ipilimumab 220 64 159 8 19 13 0 483Nivolumab 20 5 14 2 4 1 0 44Pembrolizumab 16 3 19 0 1 0 0 39

The numbers in the cell represent the total number of events of each category for the 3 immune check point inhibitors.* Renal impairment comprises proteinuria, renal failure acute, acute kidney injury, elevated creatinine, hypercreatinemia, and nephritis.** Bolded numbers represents most common reported reaction.*** The search terms used for the FAERS database were “renal impairment, proteinuria, renal failure acute, acute kidney injury, elevated creatinine, hypercreatinemia nephritis, hyponatremia, hypokalemia, hypernatremia, hyperkalemia, hypophosphatemia, hypocalcemia, hypercalcemia, hypomagnesemia, and hypertension.” There are important limitations with the FAERS database. The events are reported by providers and/or patients and there could be a reporting bias. In addition, not all demographic and comorbidity information is available to help identify if other nephrotoxic risk factors are present.

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Wanchoo    et al. Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

166

ing proton pump inhibitors and nonsteroidal anti-in-flammatory drugs but subsequently inhibited by PD-1 signaling. Either scenario resulted in increased effector T-cell migration and function, leading to clinically sig-nificant renal injury. Shirali et al. [31] and Cortazar et al. [12] had the largest series of AIN reported with both the PD-1 inhibitors. In the Shirali et al. [31] study, all 6 pa-tients (4 on nivolumab and 2 on pembrolizumab) were also on other drugs (proton pump inhibitors, nonsteroi-dal anti-inflammatory drugs) linked to AIN, but in most cases, the use of these drugs preceded anti-PD-1 anti-body therapy. It is possible that PD-1 inhibitor therapy may release the suppression of T-cell immunity that nor-mally permits renal tolerance to drugs known to be as-sociated with AIN. Dual PD-1/CTLA-4 blockade syner-gistically might break the tolerance by unleashing the quiescent, tissue-specific, self-reactive T cells, which ex-press high levels of PD-1. Table 2 summarizes the differ-ences in the 2 classes of agents.

ICIs in Kidney Transplantation Several cases of kidney injury have now been reported

when the 3 agents discussed above were used in kidney transplant patients. Although Lipson et al. [51] had ini-tially reported the successful administration of ipilimum-ab to 2 kidney transplantation patients with metastatic melanoma without any signs of rejection, they recently reported a case of tumor regression but allograft rejection after administration of pembrolizumab [52] . In addition, 3 cases of rejection were reported with the use of nivolum-ab in kidney transplant patients with melanoma [53–55] . Online supplementary Table  5 summarizes all 6 cases. Based on the 6 cases, it appears that PD-1 inhibitors could be more prone to causing rejection in the transplanted kidney compared to CTLA-4 antagonists, especially when the patients have received anti CTLA-4 agents prior to PD-1 inhibitor treatment. This may be because PD-1–PD L1 interaction in the kidney tubular cells leads to the in-duction of FOXP3+ regulatory T cells, which play an es-

Table 2. Renal effects of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antagonists and the programmed death-1 (PD-1) in-hibitors

Agents CTLA-4 antagonists (ipilimumab) PD-1 inhibitors (nivolumab and pembrolizumab)

Mechanistic differences

1. Limits T-cell response early in the immune response in lymphoid tissues

2. Expressed by T cells3. CTLA-4 ligands expressed by antigen-presenting cells

1. Limits T-cell response later in the immune response, primarily in peripheral tissues

2. Expressed by T cells and other immune cells3. PD-1 ligands expressed by antigen-presenting cells and

other immune cells and can be inducibly expressed in non-immune cells including tumor cells

Cancer Metastatic melanoma**, lung cancer*, renal cell cancer*, prostate cancer*, cervical cancer*, colorectal cancer*, pancreatic cancer*, ovarian cancer*, urothelial cancer* Metastatic melanoma**, non small cell lung cancer **,

gastric cancer*, head and neck cancer*, urothelial cancer*, colorectal cancer*, gliobastoma*, pancreatic cancer*, hematologic malignancies*

Onset of AIN AIN appears 6–12 weeks after initiation of therapy, with longest duration being 26 weeks. Late onset associated with more severe AKI requiring renal replacement therapy

AIN appears 3–12 months after initiation of therapy

Glomerular findings

Podocytopathy (membranous nephropathy and minimal change disease) and thrombotic microangiopathy reported

No cases of podocytopathy reported

Gender No gender preferences No gender preferences

Electrolyte disorders

Hyponatremia cases related to hypophysitis (secondary adrenal insufficiency)

Hyponatremia is rare

Transplant In renal transplant patients, 2 cases reported no rejection when given as a solo agent

When given– patients had rejection especially following use with CTLA-4 inhibitors (4 cases reported), likely due to loss of tolerance

AIN, acute interstitial nephritis.** FDA approved, * in phase 2 or 3 clinical trials.

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Adverse Renal Effects of ICIs Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

167

sential role in maintaining graft tolerance and minimizing the chance of rejection [44] . In a recently published case [56] , we presented a novel strategy to prevent rejection in the transplant patients receiving PD-1 inhibitors using preemptive steroids and sirolimus. The organ transplant community should be aware of the potential risk of rejec-tion in kidney transplant recipients with the use of ICI.

CKIN Recommendations

In our opinion and based on available clinical trial data, AKI is a known complication of ICI. A renal consultation should be sought early and a kidney biopsy performed, if the risk associated with the procedure is low. All potential causes of AKI (pre renal, ATN, obstruction) should be evaluated. If AKI is confirmed on a kidney biopsy as AIN or a podocytopathy, we recommend the discontinuation of the checkpoint inhibitor and a course of corticosteroids. However, we cannot recommend a definitive dose and du-ration of steroid therapy. Based on cases reported, predni-sone 1 mg/kg tapered over a period of 1–2 months may be sufficient. We additionally recommend close monitoring of the serum creatinine. Rechallenge with ICI therapy may be reasonable if other potentially offending agents (nonste-roidal anti-inflammatory drugs, proton pump inhibitors) are withdrawn and AIN has resolved. With this approach, serum creatinine should be monitored bi-weekly, with the reinstitution of steroids at the first sign of AKI from AIN without another cause. For patients on ipilimumab, renal function monitoring should be more frequent in the first 3 months, as the injury appears to happen earlier in the treat-ment course. For the PD-1 inhibitors, the injury usually happens later, so monitoring serum chemistries on a more frequent basis might be more prudent.

In kidney transplant recipients who develop malig-nancy post transplantation, these agents should be used with caution. It is important to consult with a transplant nephrologist before modifying immunosuppressive agents. The moderate reduction of immunosuppression may be warranted along with close monitoring of renal function. Conversion of tacrolimus to sirolimus and higher prednisone dose may be a reasonable treatment regimen to prevent rejection, and at the same time does not appear to minimize the efficacy of CTLA-4 or PD-1 antibodies against malignancy. The authors reiterate that there are no substantial data available to support this pre-ventive strategy and more evidence is needed. A close col-laboration between oncologists, hematologists, and trans-plant nephrologists is strongly encouraged in this setting.

Summary

Checkpoint inhibitor-related renal toxicity is an im-mune-mediated process. While initial studies noted a small incidence of AKI (2–3%), recent data suggest a high-er incidence rate closer to 13–29% with ICI [12–14] . AIN is the most common biopsy finding reported. Ipilimumab has been associated with AIN and podocytopathies such as lupus like nephritis, minimal change disease, and TMA. Hyponatremia related to hypophysitis has been reported as well. The time of onset is 2–3 months in a majority of the cases. Most cases are responsive to steroids if identified early in the course of renal injury. Few patients may re-main dialysis dependent. The renal injury related to anti PD-1 therapy is AIN. It usually appears later, 3–10 months into treatment. Steroids are also effective in the treatment of this immune-mediated adverse effect. When both CTLA-4 and PD-1 inhibitor drugs are combined, granu-lomatous or diffuse AIN can be found on kidney biopsy with partial response to steroids. While biopsy-proven in-terstitial nephritis related to these drugs is a complication associated with some degree of morbidity, one must keep in mind common causes of AKI in cancer patients such as volume depletion, dehydration, and sepsis. On the con-trary, there is a potential for the under-recognition of ne-phritis due to the use of steroids for other non-renal com-plications such as dermatitis and colitis associated with these agents. Based on the 6 cases in the transplant litera-ture, it appears that PD-1 inhibitors could be more prone to causing rejection in the transplanted kidney compared to CTLA-4 antagonists. This is especially true when the patients have received anti CTLA-4 agents prior to PD-1 inhibitor treatment. These cases have been successfully managed with either discontinuation of the drug and sim-ple observation and/or with use of systemic steroids. In organ transplant patients, a preventive strategy might be needed to minimize the chance of rejection when these agents are used for treatment of post-transplant cancers.

A close collaboration between oncologists, hematolo-gists, and nephrologists is strongly encouraged. More in-vestigation and database creation might be necessary to better understand the mechanism behind the renal dis-ease associated with ICIs.

Disclosure Statement

The results presented in this paper have not been published previously in whole or part, except in the abstract format.

This work was part of a C-KIN working group on ICIs-related renal toxicities. V.L.-V. and G.D. have received unrestricted edu-

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Wanchoo    et al. Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

168

cational grants and honoraria from Roche for last 3 years. V.L.-V. received unrestricted educational grants from Amgen, Leo Pharma, Merck, Pierre Fabre Oncologie, Takeda, Teva for the last 3 years. K.D.J. serves on the American Society of Nephrology Oncone-phrology Forum. V.L.-V. is the current President of C-KIN. G.D. and K.D.J. serve on the Governing Body of C-KIN and R.W. is an expert member of C-KIN.

Acknowledgment

We thank Dr. Matthew A. Sparks, Duke University for his crit-ical review of the manuscript. We thank Dr. Surya V. Seshan, Wei-ll Cornell Medical Center for providing the pathology figures found in this manuscript.

References

1 Iannello A, Thompson TW, Ardolino M, Mar-cus A, Raulet DH: Immunosurveillance and immunotherapy of tumors by innate immune cells. Curr Opin Immunol 2016; 38: 52–58.

2 Smyth MJ, Dunn GP, Schreiber RD: Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor de-velopment and shaping tumor immunoge-nicity. Adv Immunol 2006; 90: 1–50.

3 Zitvogel L, Tesniere A, Kroemer G: Cancer despite immunosurveillance: immunoselec-tion and immunosubversion. Nat Rev Immu-nol 2006; 6: 715–727.

4 Barbee MS, Ogunniyi A, Horvat TZ, Dang TO: Current status and future directions of the immune checkpoint inhibitors ipilimum-ab, pembrolizumab, and nivolumab in oncol-ogy. Ann Pharmacother 2015; 49: 907–937.

5 Luke JJ, Ott PA: PD-1 pathway inhibitors: the next generation of immunotherapy for ad-vanced melanoma. Oncotarget 2015; 6: 3479–3492.

6 Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye N, et al: IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res 2011; 71: 5393–5399.

7 Tang PA, Heng DY: Programmed death 1 pathway inhibition in metastatic renal cell cancer and prostate cancer. Curr Oncol Rep 2013; 15: 98–104.

8 Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al: Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373: 1627–1639.

9 Brahmer J, Reckamp KL, Baas P, Crinò L, Eb-erhardt WE, Poddubskaya E, et al: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373: 123–135.

10 Garon EB, Rizvi NA, Hui R, Leighl N, Balma-noukian AS, Eder JP, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372: 2018–2028.

11 FDA Adverse Event Reporting System (FAERS). http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Sur-veillance/AdverseDrugEffects/default.htm (accessed March 18, 2016).

12 Cortazar FB, Marrone KA, Troxell ML, Ralto KM, Hoenig MP, Brahmer JR, et al: Clinico-pathological features of acute kidney injury associated with immune checkpoint inhibi-tors. Kidney Int 2016; 90: 638–647.

13 Mason NT, Khushalani NI, Weber JS, Anto-nia SJ, McLeod HL: Modeling the cost of im-mune checkpoint inhibitor-related toxicities. J Clin Oncol 2016; 34(suppl):abstr 6627.

14 Hirsch J, Wanchoo R, Devoe C, Jhaveri KD: Incidence of AKI in immune checkpoint in-hibitors, single center study. J Am Soc Nephrol 2016; 27: 763.

15 Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al: The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic mela-noma from the ipilimumab network. PLoS One 2013; 8:e53745.

16 Thajudeen B, Madhrira M, Bracamonte E, Cranmer LD: Ipilimumab granulomatous in-terstitial nephritis. Am J Ther 2015; 22:e84–e87.

17 O’Day SJ, Maio M, Chiarion-Sileni V, Gajew-ski TF, Pehamberger H, Bondarenko IN, et al: Efficacy and safety of ipilimumab monother-apy in patients with pretreated advanced mel-anoma: a multicenter single-arm phase II study. Ann Oncol 2010; 21: 1712–1717.

18 Forde PM, Rock K, Wilson G, O’Byrne KJ: Ipilimumab-induced immune-related renal failure – a case report. Anticancer Res 2012; 32: 4607–4608.

19 Fadel F, El Karoui K, Knebelmann B: Anti-CTLA4 antibody-induced lupus nephritis. N Engl J Med 2009; 361: 211–212.

20 Voskens C, Cavallaro A, Erdmann M, Dippel O, Kaempgen E, Schuler G, et al: Anti-cyto-toxic T-cell lymphocyte antigen-4-induced regression of spinal cord metastases in asso-ciation with renal failure, atypical pneumo-nia, vision loss, and hearing loss. J Clin Oncol 2012; 30:e356–e357.

21 Izzedine H, Gueutin V, Gharbi C, Mateus C, Robert C, Routier E, et al: Kidney injuries re-lated to ipilimumab. Invest New Drugs 2014; 32: 769–773.

22 Kidd JM, Gizaw AB: Ipilimumab-associated minimal-change disease. Kidney Int 2016; 89: 720.

23 Barnard ZR, Walcott BP, Kahle KT, Nahed BV, Coumans JV: Hyponatremia associated with Ipilimumab-induced hypophysitis. Med Oncol 2012; 29: 374–377.

24 Chodakiewitz Y, Brown S, Boxerman JL, Brody JM, Rogg JM: Ipilimumab treat-ment associated pituitary hypophysitis: clin-ical presentation and imaging diagno-sis.  Clin Neurol Neurosurg 2014; 125: 125–130.

25 Pembrolizumab package insert. http://www.accessdata . fda .gov/drugsat fda_docs/label/2014/125514lbl.pdf (last accessed January 1, 2016).

26 Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, et al: Phase I study of pembrolizumab (MK-3475; Anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 2015; 21: 4286–4293.

27 Robert C, Ribas A, Wolchok JD, Hodi FS, Ha-mid O, Kefford R, et al: Anti-programmed-death-receptor-1 treatment with pembroli-zumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014; 384: 1109–1117.

28 Ribas A, Puzanov I, Dummer R, Schaden-dorf D, Hamid O, Robert C, et al: Pembroli-zumab versus investigator-choice chemo-therapy for ipilimumab-refractory melano-ma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015; 16: 908–918.

29 Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al: Pembrolizumab ver-sus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387: 1540–1550.

30 Min L, Hodi FS: Anti-PD1 following ipilim-umab for mucosal melanoma: durable tumor response associated with severe hypothyroid-ism and rhabdomyolysis. Cancer Immunol Res 2014; 2: 15–18.

31 Shirali AC, Perazella MA, Gettinger S: Asso-ciation of acute interstitial nephritis with pro-grammed cell death 1 inhibitor therapy in lung cancer patients. Am J Kidney Dis 2016; 68: 287–291.

32 Nivolumab Package Insert. http://www.access data.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf (last accessed January 1, 2016).

33 Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al: Sur-vival, durable tumor remission, and long-term safety in patients with advanced mela-noma receiving nivolumab. J Clin Oncol 2014; 32: 1020–1030.

34 Eigentler TK, Hassel JC, Berking C, Aberle J, Bachmann O, Grünwald V, et al: Diagnosis, monitoring and management of immune-re-lated adverse drug reactions of anti-PD-1 anti-body therapy. Cancer Treat Rev 2016; 45: 7–18.

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Adverse Renal Effects of ICIs Am J Nephrol 2017;45:160–169 DOI: 10.1159/000455014

169

35 Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al: Overall survival and long-term safety of nivolumab (anti-pro-grammed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treat-ed advanced non-small-cell lung cancer. J Clin Oncol 2015; 33: 2004–2012.

36 Rizvi NA, Mazières J, Planchard D, Stinch-combe TE, Dy GK, Antonia SJ, Horn L, et al: Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for pa-tients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015; 16: 257–265.

37 Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al: Survival, durable tumor remission, and long-term safety in patients with advanced mela-noma receiving nivolumab. J Clin Oncol 2014; 32: 1020–1030.

38 Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed af-ter anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; 16: 375–384

39 Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al: Nivolum-ab and ipilimumab versus ipilimumab in un-treated melanoma. N Engl J Med 2015; 372: 2006–2017.

40 Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al: Nivolum-ab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: 122–133.

41 Larkin J, Hodi FS, Wolchok JD: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373: 23–34.

42 Murakami N, Borges T, Yamashita M, Riella L: Severe acute interstitial nephritis after com-bination immune-checkpoint inhibitor ther-apy for metastatic melanoma. Clin Kidney J 2016; 9: 411–417.

43 Vandiver JW, Singer Z, Harshberger C: Se-vere hyponatremia and immune nephritis fol-lowing an initial infusion of nivolumab. Tar-get Oncol 2016; 11: 553–556.

44 Riella LV, Paterson AM, Sharpe AH, Chan-draker A: Role of the PD-1 pathway in the im-mune response. Am J Transplant 2012; 12: 2575–2587.

45 Jaworska K, Ratajczak J, Huang L, Whalen K, et al: Both PD-1 ligands protect the kidney from ischemia reperfusion injury. J Immunol 2015; 194: 325–333.

46 Menke J, Lucas JA, Zeller GC, et al: Pro-grammed death 1 ligand (PD-L) 1 and PD-L2 limit autoimmune kidney disease: distinct roles. J Immunol 2007; 179: 7466–7477.

47 Waeckerle-Men Y, Starke A, Wuthrich RP: PD-L1 partially protects renal tubular epithe-lial cells from the attack of CD8+ cytotoxic T cells. Nephrol Dial Transplant 2007; 22: 1527–1536.

48 Nishimura H, Nose M, Hiai H, Minato N, Honjo T: Development of lupus-like autoim-mune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunore-ceptor. Immunity 1999; 11: 141–151.

49 Hughes J, Vudattu N, Sznol M, et al: Precipi-tation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 2015; 38:e55–e57.

50 Spanou Z, Keller M, Britschgi M, et al: In-volvement of drug-specific T cells in acute drug-induced interstitial nephritis. J Am Soc Nephrol 2006; 17: 2919–2927.

51 Lipson EJ, Bodell MA, Kraus ES, Sharfman WH: Successful administration of ipilimum-ab to two kidney transplantation patients with metastatic melanoma. J Clin Oncol 2014; 32:e69–e71.

52 Lipson EJ, Bagnasco SM, Moore J Jr, Jang S, Patel MJ, Zachary AA, et al: Tumor regres-sion and allograft rejection after administra-tion of anti-PD-1. N Engl J Med 2016; 374: 896–898.

53 Alhamad T, Venkatachalam K, Linette GP, Brennan DC: Checkpoint inhibitors in kidney transplant recipients and the potential risk of rejection. Am J Transplant 2016; 16: 1332–1333.

54 Spain L, Higgins R, Gopalakrishnan K, Tura-jlic S, Gore M, Larkin J: Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma. Ann Oncol 2016; 27: 1135–1137.

55 Boils CL, Aljadir DN, Cantafio AW: Use of the PD-1 pathway inhibitor nivolumab in a renal transplant patient with malignancy. Am J Transplant 2016; 16: 2496–2497.

56 Barnett R, Barta VS, Jhaveri KD: Preserved re-nal allograft function while using the PD-1 pathway inhibitor nivolumab. N Engl J Med 2017; 376: 191–192 .

Dow

nloa

ded

by:

96.2

32.1

00.2

9 -

1/12

/201

7 10

:36:

38 A

M

Adverse Renal Effects of Novel Molecular

Oncologic Targeted Therapies: A Narrative

Review

Kenar D. Jhaveri1, Rimda Wanchoo1, Vipulbhai Sakhiya1, Daniel W. Ross1 and

Steven Fishbane1

1Department of Internal Medicine, Division of Kidney Diseases and Hypertension, Hofstra Northwell School of Medicine,

Northwell Health, Great Neck, New York, USA

Novel targeted anti-cancer therapies have resulted in improvement in patient survival compared to

standard chemotherapy. Renal toxicities of targeted agents are increasingly being recognized. The inci-

dence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here

we review the adverse renal effects associated with a selection of currently approved targeted cancer

therapies, directed to EGFR, HER2, BRAF, MEK, ALK, PD1/PDL1, CTLA-4, and novel agents targeted to

VEGF/R and TKIs. In summary, electrolyte disorders, renal impairment and hypertension are the most

commonly reported events. Of the novel targeted agents, ipilumumab and cetuximab have the most

nephrotoxic events reported. The early diagnosis and prompt recognition of these renal adverse events

are essential for the general nephrologist taking care of these patients.

Kidney Int Rep (2017) 2, 108–123; http://dx.doi.org/10.1016/j.ekir.2016.09.055

KEYWORDS: AKI; chemotherapy; hypokalemia; hyponatremia; nephrotoxicity; onconephrology; renal failure; targeted

therapy

ª 2016 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-

NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

In the past decade, advances in cell biology have ledto development of anticancer agents that target

specific molecular pathways. The National CancerInstitute (NCI) defines targeted therapies as “drugs orsubstances that block the growth and spread of cancerby interfering with specific molecules involved intumor growth and progression.”1 Targeted therapiesare commonly used in cancer treatment, and it is vitalthat their renal toxicities be recognized and investi-gated. Adverse renal effects of targeted therapiesoccur through several complex mechanisms. Wideranges of toxicities affecting various parts of thenephron have been reported with the novel targetedtherapies. Recognition of adverse renal effects of theseagents in a timely manner is extremely important foroptimal patient care. Table 1 summarizes the onco-logical indications for the major targeted therapiesdiscussed in this review. Figure 1 summarizes therenal toxicities that are associated with novel classes

of targeted therapies and their effects on various partsof the nephron.

FDA ADVERSE REPORTING SYSTEM REVIEW

A recent study by our group had reviewed the Foodand Drug Administration (FDA) Adverse EventReporting System (FAERS) data from 2011 to 2015 andfound a high number of renal adverse events withnovel targeted therapies.2 The total number of renaladverse events reported was 2943. Of the 3 categoriesof events, 1390 (47.3%) were metabolic disturbances,1243 (42.2%) were renal impairment, and 310 (10.5%)were hypertension (HTN). Ipilumumab and cetuximab,with 508 and 467 events respectively, were the mostcommon targeted therapies associated with reportednephrotoxicities. The rate of adverse events weresimilar between men (n ¼ 1369) and women (n ¼1305).2 Renal impairment was reported in 636 menand 522 women (P < 0.001). Metabolic disturbanceswere reported in 620 men and 639 women (P ¼ 0.5).HTN was reported with 113 men and 144 women(P ¼ 0.053).2 The most common electrolyte abnormalitywas hypokalemia (n ¼ 539). This analysis indicates thatelectrolyte abnormalities are the most common renal ormetabolic toxicity. Overall, for all renal events, therewas no difference in the incidence between men andwomen. However, men seem to have a higher risk of

Correspondence: Kenar D. Jhaveri, Associate Professor of

Medicine, Hofstra Northwell School of Medicine, Northwell

Health, Division of Kidney Diseases and Hypertension, 100 Com-

munity Drive, Great Neck, New York 11021, USA. E-mail: kjhaveri@

northwell.edu

Received 8 July 2016; revised 13 September 2016; accepted 14

September 2016; published online 21 September 2016

108 Kidney International Reports (2017) 2, 108–123

REVIEW

developing renal impairment with targeted therapiescompared to women. No such gender difference existsin standard chemotherapy-related acute kidney injury(AKI). There was no difference in gender for electrolytedisorders and HTN associated with targeted therapies.2

Hypokalemia, hypophosphatemia, hypomagnesemia,and hyponatremia are concerns in patients receivingtargeted therapies.

There are important limitations that one must keepin mind when using the FAERS database. The eventsare reported by providers and/or patients and thereforecould have a reporting bias. In addition, not all de-mographic and comorbidity information is available tohelp identify whether other nephrotoxic risk factorsare present, such as use of nonsteroidal anti-inflammatory agents, history of HTN or diabetes mel-litus, known chronic kidney disease (CKD), recent useof contrast agent, or recent use of standard chemo-therapy that could be nephrotoxic. Most importantly,it is not possible to determine whether an event is truly

caused by the drug as opposed to the underlying dis-ease or concomitant medications or by prior chemo-therapies administered to these patients. In addition,we cannot get an accurate assessment of incidence rate,as we do not have complete information on the totalnumber of patients who have actually received theseagents.

In this narrative review, we discuss the renaladverse events of a few novel anti�vascular endothe-lial growth factor (VEGF) and tyrosine kinase inhibitors(TKI) but focus more on the other novel targetedtherapies used in cancer patients. We also compare thepublished renal adverse data to the FDA-reportedevents, providing a comprehensive overview on thetoxicities.

VEGF AND VEGF RECEPTOR BLOCKADE

A hypothesis that tumor growth is angiogenesis depen-dent led to the development of antiangiogenic drugs.3

These drugs target the VEGF or VEGF receptor

Table 1. Approved hematology and oncology indications for targeted therapies along with dosing in CKD and ESRDGeneric name of targetedtherapy (trade name) Target Cancer Renal excretion

Dose adjustment forGFR 30--90 ml/min/1.73 m2

Dialysis doseadjustment

Afatineb (Gilotrif) EGFR TKI Metastatic NSCLC <5% No No data

Axitinib (Inlyta) Multi target TKI Pancreatic cancer, RCC, CML <25% No No

Aflibercept (Eylea or Zaltrap) VEGF Colorectal cancer No No No

Bevacizumab (Avastin) VEGF Colorectal cancer, NSCLC, RCC, breast cancer,epithelial ovarian cancer, GBM

No No No

Bosutinib (Bosulif) BCR-ABL TKI CML No Reduce dose to 300 mg once daily No data

Cetuximab (Erbitux) EGFR Colorectal cancer, head and neck SCC No No No

Crizotinib (Xalkori) ALK NSCLC No No No

Dabrafenib (Tafinlar) BRAF Melanoma <25% No No data

Dasatinib (Sprycel) BCR-ABL TKI CML <5% No No data

Erlotinib (Tarceva) EGFR TKI NSCLC, pancreatic cancer <10% No No

Gefitinib (Iressa) EGFR TKI NSCLC <5% No No

Ibrutinib (Imbruvica) Bruton kinase TKI CLL, mantle cell lymphoma No No data No data

Imatinib (Gleevac) BCR-ABL TKI Gastrointestinal stromal tumors, CML <15% No No

Ipilimumab (Yervoy) CTLA4 Melanoma No No No data

Lapatinib (Tykerb) ERBB2 Breast cancer <5% No No

Nivolumab (Opdivo) PD-1 Melanoma, NSCLC, Hodgkin lymphoma, RCC No No No data

Nilotinib (Tasigna) BCR-ABL TKI CML No No No data

Panitumumab (Vectibix) EGFR Colorectal cancer No No No

Pazopanib (Votrient) Multitarget TKI RCC, soft tissue sarcoma <4% No No

Pembrolizumab (Keytruda) PD-L1 Melanoma, NSCLC, Hodgkin lymphoma No data No No

Pertuzumab (Perjeta) ERBB2 Breast cancer No No No data

Ponatanib (Iclusig) BCR-ABL TKI CML, ALL No No No data

Regorafenib (Stivarga) Multitarget TKI Colorectal cancer, gastrointestinal stromal tumors <20% No No

Sorafenib (Nexavar) Multitarget TKI RCC, hepatocellular carcinoma, thyroid carcinoma <20% No No

Sunitinib (Sutent) Multitarget TKI RCC, gastrointestinal stromal tumors,pancreatic neuroendocrine tumors

<20% No No

Trametinib (Mekinist) MEK Melanoma <20% No No data

Trastuzumab (Herceptin) ERBB2 Breast cancer No No No

Vandetanib (Caprelsa) Multitarget TKI Medullary thyroid cancer <25% No No data

Vemurafenib (Zelboraf) BRAF Melanoma, thyroid cancer, colorectal cancer <5% No No data

ALK, anaplastic lymphoma kinase; ALL, acute lymphocytic leukemia; BCR-ABL, breakpoint cluster region–abelson; CLL, chronic lymphocytic leukemia; CML, chronic myelogenousleukemia; CTLA, cytotoxic T lymphocyte antigen�4; EGFR, epidermal growth factor receptor; GBM, gliobastoma multiforme; MEK, mitogen-activated protein kinase; NSCLC, non�small-cell lung cancer; PD, programmed cell death; RCC, renal cell carcinoma; SCC, squamous cell cancer; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.Information obtained from package inserts of agents, clinical trials, and published case reports.No data available for most agents for dose adjustments for GFR < 30 ml/min/1.73 m2 except vandetanib, which requires dose adjustment.

KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies REVIEW

Kidney International Reports (2017) 2, 108–123 109

(VEGFR). The VEGF ligand inhibitors (bevacizumaband aflibercept) bind to the VEGF molecule, preventingit frombinding to the receptor and inhibiting endothelialcell proliferation and vessel formation. Bevacizumab andaflibercept can produce asymptomatic albuminuria,nephrotic syndrome, and thrombotic microangiopathy(TMA).4 Eremina et al. showed that podocyte-specificknockout of the VEGF gene resulted in renal limitedTMA.5 Most drugs that target the VEGF pathway canpresent with 1 of the known renal toxicities. HTNfrequently accompanies proteinuria. Although protein-uria appears to be an effect common to all agents targetedat the VEGF pathway, the factors associated with theoccurrence and severity of the proteinuria are un-known.4 Pre-existing renal disease (including higherbaseline urinary protein levels and hypertension) andrenal cell carcinoma (as compared to other malignantdiseases) may be predisposing factors.4 Table 2 summa-rizes the known renal toxicities of VEGF-inhibitoryagents. The HTN associated with anti-VEGFagents is mediated via several mechanisms. Decreasednitrous oxide leading to endothelial dysfunction andcapillary rarefaction, pressure natriuresis, and decreasedlymph-angiogenesis leading to volume overload areproposed mechanisms that cause the HTN,6 but some-times additional classes of agents are required for man-agement. Choice of antihypertensive agents should be

individualized, with angiotensin-converting enzymeinhibitor (ACEI) or angiotensive receptor blocker (ARB)inhibition as first-line options and calcium channelblockers as a reasonable second choice. Centrally actingantihypertensive or diuretic agents may be added toadequately control blood pressure. Close follow-up iscritical for appropriate titration, and if the blood pres-sure cannot be maintained below 140/90 mm Hg (or 130/89 mm Hg in certain high-risk groups), then promptreferral to a hypertension specialist is indicated. If pa-tients develop hypertensive crisis or encephalopathy,the cancer therapy needs to be discontinued. The pro-teinuria associated with these agents is due to disruptionof the glomerular filtration barrier.7,8 A kidney biopsysample usually shows renal limited TMA and in somecases minimal change disease (MCD) or focal segmentalglomerulosclerosis (FSGS).9 Treatment can be continuedin most cases involving non�nephrotic-range protein-uria, and HTN and proteinuria can be aggressivelymanaged with ACEIs or ARBs. Since treatmentoptions and prognosis might be influenced by kidneyhistological findings, a kidney biopsy is usually recom-mended whenever feasible. The decision to stopanti-VEGF therapy or to switch to alternative agentsshouldbemade in the setting of significant proteinuria ina multidisciplinary setting. Nephrotic-range protein-uria and TMA are generally considered reasons to

Figure 1. Summary of renal adverse events noted with targeted therapies. ALK, anaplastic lymphoma kinase; BCR-ABL, breakpoint clusterregion–abelson; CTLA, cytotoxic T lymphocyte antigen�4; EGFR, epidermal growth factor receptor; HER-2, human epidermal growth factor�2;PD, programmed cell death; TKI, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor.

REVIEW KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies

110 Kidney International Reports (2017) 2, 108–123

discontinue the offending agent.10 Recent in-depth re-views on anti-VEGF agents that induced kidney dis-ease4,10 exist in the literature, and this review will notfocus on those agents.

TYROSINE KINASE INHIBITORS

An important mechanism in signal transductionpathways in cells is protein phosphorylation, which iscarried out by protein kinases. These kinases regulatethe proliferation, differentiation, migration, meta-bolism, and antiapoptotic signaling of cells. The mostimportant kinases are the serine/threonine and tyro-sine kinases, which are characterized by their abilityto catalyze the phosphorylation of serine/threonine ortyrosine amino acid residues in proteins respectively.There are 2 types of tyrosine kinases: cellular andreceptor tyrosine kinases.11 Imatinib is a cellulartyrosine kinase inhibitor (TKI) that is designed totarget the fusion protein breakpoint cluster region–abelson (BCR-ABL) and members of the SRC tyrosinekinase family. Receptor TKIs are designed to target theepidermal growth factor (EGFR), platelet-derivedgrowth factor (PDGFR), and the VEGFR tyrosine ki-nase families. These could target single receptors suchas EGFR (gefitinib) or could be multikinase ormultitarget TKIs and target many receptors such assunitinib, which targets VEGFR,1–3 PDGFR, kit, Flt3and RET.11 Figure 2 is a simplified version of thedifferent types of TKIs used in cancer treatment.

Receptor TKIs: TKIs of the PDGFR Family

PDGFR inhibitors are in clinical development forcancer therapy; most are directed against severaltyrosine kinases. Examples of these agents are les-taurtinib and tandutinib, which are used for treatmentof leukemia and pancreatic cancer, respectively. Sincethey are in phase I and II trials, they will not bediscussed here.12

Receptor TKIs: TKIs of the VEGFR Family

Sunitinib and sorafenib inhibit angiogenesis and cellproliferation by targeting multiple receptor kinases,including VEGFRs, PDGFRs, c-KIT, and others.13

Similar to anti-VEGF agents, these agents are potentinhibitors of angiogenesis and lead to adverse effectssimilar to them. TKIs (sunitinib, sorafenib, pazopanib,axitinib, cabozantinib, lenvatinib, and vandetanib)block the intracellular domain of the VEGFR. Sunitinib,sorafenib, pazopanib, and axitinib have known effectsof HTN, proteinuria, TMA, and chronic, and acuteinterstitial nephritis.4,13 Sorafenib also is known tocause hypophosphatemia and hypocalcemia. This effecthas been linked to pancreatic dysfunction from thedrug, leading to vitamin D malabsorption and sec-ondary hyperparathyroidism.14 Hence, patients on thisagent should be screened for vitamin D, phosphorous,and calcium levels. Since the advent of antiangiogenicagents, newer agents with other molecular targets1

have been approved. The renal toxicities VEGFR-related TKIs are well described in the nephrology andoncology literature and are not discussed in furtherdetail in this review; however, the renal toxicities ofthe newer targeted therapies are limited to case reportsor series. In this review, we discuss 2 novel VEGF-receptor�based TKI agents with emerging data,namely, regorafenib and vandetanib.

Regorafenib

Regorafenib is associated with several electrolyte ab-normalities, including hypophosphatemia, hypocalce-mia, hyponatremia, and hypokalemia.2,15,16 Theseabnormalities are usually mild to moderate and do notrequire dose reductions or treatment interruptions.Initial trials reported the incidence of HTN to bearound 28%, of which 7% were listed as grade 3.15 Theincidence of proteinuria was lower at 7%, and 1%were grade 3.15 A recent trial found HTN in 11% ofpatients and hypophosphataemia in 7% of patients.16

According to Yilmaz et al., the HTN associated withregorafenib may not be a dose-dependent effect.17 Asystematic review by Wang et al. evaluated 1069 pa-tients (regorafenib, n¼ 750; controls, n¼ 319) from 5clinical trials. The overall incidence of all-grade HTNwas 44.4% (95% confidence interval [CI] 30.8%–59.0%).18 The use of regorafenib in cancer patients was

Table 2. Tyrosine kinase inhibitors and VEGF inhibitorydrug�related renal toxicitiesAgent Reported nephrotoxicity References

VEGF/R antibodies

Bevacizumab HTN, proteinuria, preeclampsia-likesyndrome, renal limited TMA

4–10

Aflibercept HTN, proteinuria 4–10

Receptor TKIs, VEGF family

Sunitinib HTN, proteinuria, MCD/FSGS, AIN,chronic interstitial nephritis

7, 9, 13

Pazopanib HTN, proteinuria 7, 9

Axitinib HTN, proteinuria 7, 9

Sorafenib HTN, proteinuria, MCD/FSGS, AIN, chronicinterstitial nephritis, hypophosphatemia

7, 9, 13, 14

Regorafenib HTN, hypophosphatemia,hypocalcemia, proteinuria, AKI

2, 17, 18

Vandetanib HTN, hypokalemia, hypocalcemia 2, 19

Cellular TKIs, BCR-ABL

Imatinib ATN, Rhabdomyolysis,hypophosphatemia

2, 26–29, 32–34

Nilotinib HTN 7, 9, 37

Ponatinib HTN 7, 9

Dasatinib Rhabdomyolysis, ATN, proteinuria, TMA 40–46

Bosutinib Hypophosphatemia 47

AIN, acute interstitial nephritis; AKI, acute kidney injury; FSGS, focal segmentalglomerulosclerosis; HTN, hypertension; MCD, minimal change disease; TKI, tyrosinekinase inhibitor; TMA, thrombotic microangiopathy; VEGF, vascular endothelial growthfactor; VEGF/R, vascular endothelial growth factor/receptor.

KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies REVIEW

Kidney International Reports (2017) 2, 108–123 111

associated with a significantly increased risk of all-grade HTN (relative risk [RR] ¼ 3.76, 95% CI ¼2.35–5.99).18 Our analysis of FAERS data found 125cases of regorafenib-related renal toxicity. Similar tothe published literature, HTN was the most commonadverse event (57 cases), followed by AKI (40 cases) andhypophosphatemia (8 cases). It is interesting that AKIhas not been described in prior studies with thisagent.2 Given the lack of published biopsy-provencases, pathophysiology is not easy to elicit inregorafenib-induced AKI. The mechanism of hypo-phosphatemia might be similar to that of sorafenib, asdiscussed above.

Vandetanib

Vandetanib is a receptor TKI that inhibits many tar-gets including VEGFR2, EGFR, and RET. According toinitial studies, it has been associated with a number ofelectrolyte disturbances, such as hypocalcemia, hy-pokalemia, hyponatremia, and hypercalcemia.19,20

HTN has also been reported in close to 10% ofpatients.19,21 Data from a phase 2 trial of vandetanib inlocally advanced or metastatic differentiated thyroidcancer confirmed that HTN is frequently seen innearly 34% of cases.22 Electrolyte disturbances,namely hypokalemia and hypocalcemia, were seen at alower rate (4%).20 Vandetanib also been shown tohave an inhibitory activity on several human renaltransporters, such as MATE-1 and MATE-2, which areresponsible for the clearance of multiple drugs andtoxins. Inhibition of MATE-1 and MATE-223 at the

apical membrane of the tubular cells might lead toincreased concentrations of the drug within renalcells, resulting in worsening of renal toxic effects ofother drugs; especially cisplatin.24 Despite this, aMedline search did not reveal any published case re-ports or series of any specific postmarketing renaladverse events. In the FAERS analysis, a total of 57cases were found, with a majority of AKI (30 cases),followed by HTN (21 cases), and the remainder elec-trolyte disorders.2

TKIs of the EGFR Family

Afatinib, erlotinib, and gefitinib are small-moleculeinhibitors of the tyrosine kinase domain of the EGFR,which are used in the treatment of non�small-cell lungcancer. Monoclonal antibodies targeting the EGFR(cetuximab, panitumumab) are also used as targetedtherapies. Given their widely known association withelectrolyte disorders, both variants of EGFR inhibitorsare discussed below in a different section.

Cellular TKIsImatinib

Imatinib is a potent inhibitor of BCR-ABL fusion protein,and platelet-derived growth factors. It is a TKI that isclassically used in chronic myelogenous leukemia (CML)and gastric stromal tumors. In 1 study of patients withCML, AKI was seen in 7% of patients and CKD in 12%.25

Potential mechanisms of injury appear to be tumor lysissyndrome, biopsy-proven acute tubular damage, and orFanconi syndrome.26–30 Renal injury appears to be dose

TKI

Receptor based

VEGFR

PDGFR

EGFR

Cellular based

BCR-ABL

Bruton’s Kinase Ibrutinib

Imatinib, Nilotinib,Ponatinib, Dasatinib,Bosutinib

Afatinib, Erlotinib,Gefitinib

Lestaurtinib, Tandutinib

Sunitinib, Sorafenib,Pazopanib, Axitinib,Cabozantinib,Lenvatinib, Vandetanib

Figure 2. Simplistic view of various tyrosine kinases available for treatment of cancer. There are 2 types of tyrosine kinases: cellular andreceptor tyrosine kinases. Receptor tyrosine kinase inhibitors (TKIs) are designed to target the epidermal growth factor (EGFR), platelet-derivedgrowth factor (PDGFR), and vascular endothelial growth factor receptor (VEGFR) tyrosine kinase families. These could target single receptorssuch as EGFR (gefitinib) or could be multikinase or multitarget TKIs and target many receptors such as sunitinib, which targets VEGFR,1–3

PDGFR, kit, Flt3, and RET. The figure represents the predominant receptor involved as the target.

REVIEW KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies

112 Kidney International Reports (2017) 2, 108–123

dependent, as seen with renal cell cancer treatment,31 inwhich higher doses are associated with higher incidenceof tubular damage. Interestingly, rhabdomyolysis hasbeen reported with this agent.32,33

A common electrolyte abnormality reported withimatinib is hypophosphatemia. In 1 case series,hypophosphatemia was associated with low calciumand 25-OH vitamin D levels,34 with an incidence closeto 10%. This may be related to inhibition of renaltubular reabsorption of phosphorus.35 The mechanismunderlying phosphaturia is unclear. The FAERSreport2 found 44 cases of imatinib-related renaltoxicity, and 25 events were AKIs, in line with pub-lished literature. We found only 1 reported case ofhypophosphatemia reported to the FDA. In addition,there were 5 cases of HTN, 3 of hypokalemia, and 4 ofhyponatremia that are not described in the literature.Interestingly, based on rat models, imatinib may haverenal-protective effects. Reduced expression of trans-forming growth factor�b1 (TGF-b1) in the renal cor-tex leads to suppression of proteinuria, improvedrenal function, attenuation of glomerulosclerosis andtubule-interstitial injury.36

Nilotinib

Nilotinib is an inhibitor of BCR-ABL kinase, c-KIT, andPDGFR. It has been associated with HTN in 10% ofcases.37 Interestingly, in animal studies, nilotinibsignificantly decreased renal cortical expression ofprofibrogenic genes, such as IL-1b and monocytechemotactic protein�1, which correlated closely withtubulointerstitial damage; in addition, nilotinib treat-ment significantly prolonged survival of the rats.38

Ponatinib

Ponatinib is a BCR-ABL TKI, along with other targetssuch as PDGFR, SRC kinases, and VEGFR. Given itsactivity on VEGFR, the toxicities of anti-VEGF agentscan be applied to this agent. HTN might be commonfinding with this agent.

Dasatinib

Dasatinib is a second-generation TKI used in imatinib-resistant CML.39 It has effects on the BCR-ABL targetand other targets such as the PDGFR and c-KIT. Thereare 3 published case reports of AKI with this drug.40–42

One case report of TMA43 and 1 case report causingrhabdomyolysis44 similar to that with imatinib havebeen reported. A possible mechanism of action could bedirect tubular toxicity, as noted in 1 of the publishedcases with a kidney biopsy.40

There is a 5% incidence of proteinuria with thisagent.39 A case of biopsy-proven renal limited TMAand another case with clinical TMA has been reportedwith this agent.45,46 A possible mechanism for thisinjury is through inhibition of the Src family kinases

that are required for VEGF signaling. It is possible thatthe kidney injury could be similar to that with otherVEGF inhibitors. Of the TKIs that affect the BCR-ABLpathway, this is the only agent associated with pro-teinuric disease. Switching to imatinib or nilotinibmight be optimal for patients who develop proteinuriaon dasatinib.

Bosutinib

Bosutinib is a TKI approved for treatment of refractoryCML. Hypophosphatemia and a decline in GFR havebeen reported during therapy with bosutinib.47 Nocases of renal toxicities with this agent have beenreported in the literature.

Other TKIsIbrutinib

Ibrutinib is a TKI that irreversibly binds to and inhibitsthe Bruton tyrosine kinase. It is currently approved forthe treatment of chronic lymphocytic leukemia (CLL)and mantle cell lymphoma. In 1 study, 23% of patientsdeveloped elevated serum creatinine and edema.48 Of thepatients, 18% developed HTN as well.48 In anotherstudy of patients with mantle cell leukemia, 35% hadincreases in serum creatinine frombaseline. Therewere 4cases of grade 3 AKI, but all were confounded by pre-existing HTN and renal dysfunction, and concurrentdehydration as well.49 Four patients also developed tu-mor lysis syndrome, leading to electrolyte abnormalitiesand AKI in this study.49 Patients receiving ibrutinibshould undergo periodic creatinine level monitoring andshould maintain hydration.49 The mechanism of thisinjury is unclear at this point, but tumor lysis syndromecould be a possible mechanism. No biopsy-proven caseshave been reported in the literature. In unpublished dataon cardiac effects of ibrutinib, 23% of the patientsdeveloped new-onset systolic HTN with increases insystolic blood pressure >20 mm Hg. The mechanism ofthe HTN is also unclear.

EPIDERMAL GROWTH FACTOR RECEPTORL1

TARGET INHIBITORS

These therapies target the epidermal growth factorreceptor�1 (EGFR). They include 2 monoclonal anti-bodies, namely, cetuximab and panitumumab. OtherEGFR therapies include 3 small-molecule TKI, namely,erlotinib, gefitinib, and afatinib. Table 3 summarizesdata reported in the literature and prior clinical trialsinvestigating these 5 agents.

Cetuximab

This monoclonal antibody against EGFR 1 is known tocause hypomagnesemia.50 This happens as a result ofreduction in the transport of transient receptor poten-tial melastatin (TRPM) 6/7 ion channels to the apical

KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies REVIEW

Kidney International Reports (2017) 2, 108–123 113

membrane of the distal renal tubule.51 Filtered mag-nesium (Mg) is reabsorbed mainly in the thickascending limb of Henle and the distal tubule, wheremost of the EGFR is located in the kidney. Epidermalgrowth factor is an autocrine paracrine hormone thatregulates renal Mg reabsorption by regulating theactivity and transport of TRPM6.51 Blocking EGFRwith cetuximab blunts the movement of TRPM6/7channel, which leads to renal Mg wasting and hypo-magnesemia. The main risk factors for developinghypomagnesemia are duration of treatment, age, andbaseline Mg values.52 Low Mg levels may lead to hy-pokalemia, hypocalcemia, and cardiac arrhythmias.53

The literature review revealed multiple studies thathave reported hypomagnesemia as an adverse effect ofthis agent.54,55 Severe grade 3 (<0.9–0.7 mg/dl) or 4(<0.7 mg/dl, <0.3 mmol/l, life-threatening conse-quences) hypomagnesemia has been seen in 36% and27% of patients treated with cetuximab.56 Anotherstudy showed the incidence of hypomagnesemia to beclose to 10% to 15%.30 A more recent study revealedan incidence rate of hypomagnesemia with cetuximabto be close to 30%. Of the cases, 22% were grade 1(i.e., below the lower limit of normal to 1.2 mg/dl).57

There was no statistically significant correlationbetween Mg level and patient age, duration of treat-ment, localization of primary tumor or metastases, andnumber of metastases. However, there was an upwardtrend in a logistic regression model showing that therisk of developing hypomagnesemia increases withage.57 Management of EGFR inhibitor�induced hypo-magnesemia is summarized by Fakih in a review.58 Onehas to ensure that the patient is not on any otheroffending medication, such as thiazide diuretics orproton pump inhibitors. For patients with grade 1 or 2hypomagnesemia, oral Mg may be sufficient afterdiscontinuation of cetuximab. Testing for Mg levelsshould be performed every 2 to 3 weeks. For patientswho cannot tolerate oral Mg, i.v. Mg up to 4 g can begiven. Amiloride (Mg-sparing diuretic) has been tried inunpublished case reports, with success in treating thehypomagnsemia.59 For grades 3 and 4 hypomagnesemia,

patients should receive 6 to 10 g of magnesium sulfatedaily to twice weekly if possible. An initial strategy ofi.v. replacement and every other day monitoring ofmagnesium levels can help guide frequency. An alter-native strategy for patients requiring frequentmagnesium infusions may be to consider a 2-monthstop-and-go approach to cetuximab treatment.58

In our review of the literature, we also found 1 clinicaltrial that reported renal failure in 2% of patients,60 1published case report of a diffuse proliferative glomer-ulonephritis,61 and another case report of nephroticsyndrome.62 In our review of the FAERS, we found 467individuals who had experienced renal events.2 This isthe second highest number of events for any of the tar-geted therapies. Although the literature search revealedhypomagnesaemia as the most commonly reportedtoxicity,54,55 FAERS data suggest a high degree of renalimpairment with cetuximab.2 A total of 172 cases of AKIwith this agent were reported to FAERS.2 This was fol-lowed by hypokalemia in 113 cases; hyponatremia, 78cases; hypomagnesaemia, 58 cases; and HTN, 24 cases.AKI might be an important finding that needs to bestudied further, as prior reviews do not discuss this indetail.53 The cause of AKI is not reported in the FAERSdatabase. EGFR, which is mainly expressed in the distaland collecting tubules, is involved in maintainingtubular integrity. EGFR activation leads to growth andgeneration of tubular epithelial cells after acute tubularnecrosis.63 In patients prone to experiencing renalinjury, treatment with anti-EGFR agents might be a“second hit” for development of AKI.

Panitumumab

Panitumumab is a monoclonal antibody similar tocetuximab. In the original trials, this agent was notassociated with any nephrotoxic effects.64 However, ina recent phase 3 trial, for head and neck cancer, therewas a high incidence of hypomagnesemia (12%) andhypokalemia (10%).65 Hypomagnesemia was reportedin 36% of patients who were treated with pan-itumumab in a phase 3 trial for colorectal cancer.66 TheFAERS review found 337 renal adverse events with thisagent. The majority of the cases were of hypomagne-semia (103 cases), followed by hypokalemia (85 cases)and AKI (82 cases). Overall, there should be close Mg-monitoring strategies in patients receiving EGFRagents.67 Treatment strategies are similar to that forcetuximab-induced hypomagnesemia.

Erlotinib

Compared to cetuximab and pantumumab, the nextfew agents discussed here (erlotinib, gefitinib, andafatinib) are TKIs that affect the EGFR. Erlotinib is asmall-molecule TKI that blocks the activity of the

Table 3. Summary of renal toxic events with EGFR targeting agentsDrug Renal adverse events reported References

Cetuximab(monoclonal antibody)

Hypomagnesaemia, hypokalemia,AKI, hyponatremia, glomerulonephritis

2, 52–58

Panitumumab(monoclonal antibody)

Hypomagnesaemia, AKI, hypokalemia 2, 53, 65, 66

Erlotinib (anti-EGFR TKI) AKI, hypomagnesemia, hypophosphatemia 2, 53, 68, 69

Afatinib (anti-EGFR TKI) AKI, hypokalemia, hyponatremia 2, 53

Gefitinib (anti-EGFR TKI) AKI, hypokalemia, fluid retention,minimal change disease, proteinuria

2, 53, 72–74

AKI, acute kidney injury; EGFR, epidermal growth factor receptor; TKI, tyrosine kinaseinhibitor.

REVIEW KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies

114 Kidney International Reports (2017) 2, 108–123

EGFR tyrosine kinase, a key regulator of intracellularsignaling pathways crucial for cancer cell survival.Our literature search revealed no data on nephrotox-icity with this agent. Erlotinib can influence magne-sium handling, but its effect on the systemicmagnesium concentration seems less potent than thatobserved with antibody-based EGFR inhibitors. Ani-mal data suggest that typical human dosages of erlo-tinib are unlikely to severely affect serum magnesiumconcentrations.68 Although erlotinib can cause hypo-magnesemia, the magnesium stearate supplementationpresent as part of the erlotinib tablet might alleviatethe deficiency. Counter to data reported in the liter-ature, our FAERS analysis found 63 cases of AKI andonly 8 cases of hypomagnesemia. Further research isneeded to clarify the association between erlotinib andAKI.2 At this time, the mechanism of AKI is unclear.

The FAERS analysis also revealed 3 cases of hypo-phosphatemia with erlotinib.2 A small phase 1 trial of17 patients who used sorafenib and erlotinib for solidtumors found a 76% incidence (13 of 17 patients) ofhypophosphatemia.69 A more recent, small phase 1 studyof 25 patients using erlotinib in gliomas found a 30%incidence of hypophosphatemia.70 The mechanism oferlotinib-induced hypophosphatemia is unclear, butmight involve sodium phosphate cotransporters in theproximal tubule.53

Gefitinib

Similar to erlotinib, gefitinib is also a small-molecule TKI.A literature review revealed fluid retention in 6.6% ofpatients.71 In addition, 1 case of AKI and another case ofnephrotic syndrome (due to an autoimmune response tothe agent) have also been reported.72,73 More recently, abiopsy-proven case of MCDwas reported that respondedto drug withdrawal and a switch to erlotinib.74 Fifteencases of renal adverse events were noted in the FAERSreview,2 including 7 cases of AKI7, 4 cases of hypokale-mia, and 2 cases of hyponatremia, but no cases ofhypomagnesemia.

Afatinib

In the initial trials of afatinib, there was a 34% inci-dence of hypokalemia.75 No published cases of anynephrotoxicities with this agent are reported in theliterature. In the FAERS, there were 26 cases of AKI,followed by 6 cases of hypokalemia and 5 cases ofhyponatremia.2

HUMAN EPIDERMAL GROWTH FACTORL2

(HER-2) TARGET INHIBITORS

HER-2 is a membrane receptor that is overexpressed inmany forms of breast and gastric cancers. This receptoris part of the EGFR family.

Trastuzumab

Trastuzumab is a recombinant humanized monoclonalantibody that binds to the receptor tyrosine-kinase erbB-2 (ERBB-2) on tumor cells and induces antibody-mediated cellular toxicity in cells that overexpress thisprotein. The drug alone does not cause renal toxicity, butit can lead to cardiac toxicity and subsequently cardio-renal syndrome.76 One study illustrated that GFR < 78ml/min/1.73 m2 was the strongest predictor of cardiactoxicity.76 In addition, in the TANDEM study, thecombination of trastuzumab and anastrozole was asso-ciated with a higher incidence of HTN compared toanastrozole alone.77 In the TOGA study, the arm that hadtrastuzumab with standard chemotherapy had a higherincidence of renal toxicity compared to the arm withstandard chemotherapy alone.78 More recently, a case oftumor lysis syndrome has been reported with thisagent.79 In addition, there have now been a few cases offetal nephrotoxicity with renal impairment noted witholigohydramnios and anhydramnios. In these cases,there was spontaneous improvement of renal function inthe fetus after stopping traztuzumab.80–82 Additionalreview of the literature found no published cases ofhypokalemia or hypomagnesemia, but there are 3 pub-lished cases of hyponatremia. In each of the 3 cases, otherpotentially hyponatremia-causing chemotherapies werealso involved.83–85 The FDA analysis indicated a largenumber of cases reported of renal toxicity in the FAERSdatabase.2 Reports included 124 cases ofAKI, 112 cases ofhypokalemia, 52 cases of HTN, 24 cases of hypomagne-semia, 28 cases of hyponatremia, and 11 cases of hypo-phosphatemia.Most of the cases were females, as cancerstreated relate mainly to women.2 It is important tomonitor renal function, electrolytes, and blood pressurein these patients, as AKI was reported to the FAERSdatabase in a number of cases. Given its known cardiactoxicity, it is possible that the cases of AKI might berelated to a cardio-renal syndrome physiology and theelectrolyte disorders related to diuretic use.

Pertuzumab

Pertuzumab is a recombinant humanized monoclonalantibody that targets the extracellular dimerizationdomain of the ERBB-2. No published cases or reports ofrenal toxicity are reported in the literature or fromclinical trials. Our FAERS analysis found a total of 100cases; AKI (46 cases) and hypokalemia (26 cases) werethe top 2 causes.2

Lapatinib

Lapatinib is a dual tyrosine kinase inhibitor that in-terrupts both the EGFR and ERBB-2 pathways. In aphase 2 trial with this agent, 7 patients experiencedtreatment-related grade 3 toxicity, and 2 of them

KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies REVIEW

Kidney International Reports (2017) 2, 108–123 115

developed hyponatremia.86 Our literature searchrevealed no published reports of this agent leading toAKI or any electrolyte disorders. Our analysis demon-strated a total of 171 cases reported in the FAERSdatabase. Most cases were of hypokalemia (61 cases)and AKI (48 cases). There were a few cases of HTN,hypomagnesemia, and hyponatremia as well.2

BRAF TARGET INHIBITORS

Advanced melanoma has traditionally been unrespon-sive to standard chemotherapy agents and formerlyhad a dismal prognosis. Genetically targeted small-molecule inhibitors of the oncogenic BRAF V600mutation or a downstream signaling partner (mitogen-activating protein kinase [MEK]) are effective treatmentoptions for the 40% to 50% of patients with melanomawho harbor mutations in BRAF. Selective BRAF andMEK inhibitors induce frequent and dramatic objectiveresponses and markedly improve survival comparedwith cytotoxic chemotherapy.87–89 In the last decadeafter discovery of this mutation, drugs such asvemurafenib and dabrafenib have been approved bythe FDA and the European Medicines Agency for thetreatment of V-600 mutated melanomas. Although theinitial trials did not signal any renal toxicities with theBRAF inhibitors, recent case reports, case series, andthe FDA adverse reporting systems have uncoveredsignificant nephrotoxicities with these agents.87–89

Vemurafenib

In the initial phase III trial, 51 patients developededema, but there were no reports of proteinuria. Therewere also no reported cases of AKI.87 In 2013, in a letterto the editor, Uthurriague et al. were the first to reportAKI. They reviewed 16 patients who were on this agentfor more than 8 months.88 Fifteen patients experiencedsignificant decline in GFR at 1 month, with a meanreduction of 29 ml/min, and this decline persisted for3 months. Since then, multiple publications havehighlighted renal toxicities in various forms with thisagent, but mostly AKI and biopsy-proven ATN.89–94

Although biopsy-proven tubular toxicity93 has beenthe mechanism of injury likely causing the AKI, arecent study showed that vemurafenib induces a dualmechanism of increase in plasma creatinine with bothan inhibition of creatinine tubular secretion and slightrenal function impairment. However, this adverseeffect is mostly reversible when vemurafenib is dis-continued, and should not lead physicians to discon-tinue the treatment if it is effective.95 Table 4summarizes all known toxicities with this agent.Our analysis of the FAERS database was reportedseparately.94 In that publication, 132 cases of AKI werereported in association with vemurafenib during the

timeframe reviewed. The toxicity was more common inmen.2,93,94

Dabrafenib

The European summary of product characteristics ofthe drug reports that renal failure has been identified inless than 1% of patients treated with dabrafenib.96

Recently, 1 case of biopsy-proven acute interstitialnephritis was reported with this agent,97 whichresponded to steroid treatment. The FDA data that weanalyzed were reported separately.94 Most of the casesreported to the FAERS in that timeframe were AKI.94

Contrary to prior publications that had shown a 7%incidence of hypophosphatemia,96 no cases of hypo-phosphatemia were found in the FAERS database.94

Our group recently summarized the toxicities of theBRAF agents, and that review provides more details.98

MITOGEN-ACTIVATED PROTEIN KINASE

ENZYMES MEK1 AND/OR MEK2 (MEK)

INHIBITORS

Trametinib

There have been no published cases of nephrotoxicitywith trametinib. Monotherapy with this agent can leadto hypertension, but cases of AKI and hyponatremiawere noted more frequently in patients treated withcombined trametinib and dabrafenib.99 Our analysisfound similar results of a small number of cases of AKI(28 cases) and hyponatremia (11 cases) with this agent.Any renal toxicity may result from a combination ef-fect with the BRAF inhibitors rather than a sole effectof an MEK inhibitor.97

ANAPLASTIC LYMPHOMA KINASE (ALK)

TARGET INHIBITORS

Crizotinib

Crizitonib is an inhibitor of the anaplastic lymphoma ki-nase (ALK) indicated in patientswith non�small-cell lungcancer (NSCLC) who have ALK fusions. No renal adverseevents were reported in earlier clinical trials.100 However,a recent study did report AKI in a patient treated withthis agent.101Abiopsy-proven case ofATNwas publishedfrom France that was attributed to crizotinib.102

A recent analysis from the University of Coloradolooked at 38 patients with NSCLC who were treatedwith this agent. The mean GFR decreased by 23.9%

Table 4. BRAF inhibitor�related toxicity summary2,88-95,97,98

Allergic interstitial disease

Acute tubular necrosis

Proximal tubular damage (Fanconi syndrome)

Hypophosphatemia

Hyponatremia

Hypokalemia

Sub�nephrotic range proteinuria

REVIEW KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies

116 Kidney International Reports (2017) 2, 108–123

compared to baseline, and this was seen in the first2 weeks of therapy. Close to 84% of the patientsrecovered renal function after cessation of therapy. Theinvestigators thought that the rapid reversibility raisedthe possibility that the drug led to a defect in tubularsecretion of creatinine rather than a true drop in GFR.The study did not report biopsy data.103 In addition,renal cysts have been reported with crizotinib. Thecysts tend to be reversible and occur in 4% of pa-tients.104,105 A series from Taiwan found changes inrenal cysts in 22% of patients who received this agent.Crizotinib not only appears to be associated with for-mation of new cysts but can also lead to progression ofprior existing cysts.106 The molecular mechanism bywhich crizotinib increases risk of developing renalcysts in currently unknown. In the FAERS analysis,2

consistent with the published reports, 88 cases ofrenal impairment were noted. In addition, we foundevidence of electrolyte disorders as well (hyponatremia,24 cases; hypokalemia, 13 cases). There is no evidenceof those disorders reported in the existing literature. Insummary, besides AKI, renal cyst formation and pro-gression, hyponatremia and hypokalemia also need tobe considered with crizotinib. A recent review on thistopic summarizes the renal injury in depth.107

IMMUNE CHECKPOINT INHIBITOR:

PROGRAMMED CELL DEATHL1 AND LIGAND

TARGET (PD-1 AND PDL-1)

Cancer immunotherapy has revolutionized the treat-ment of cancer by targeting the immune system ratherthan the cancer. This pathway includes 2 proteinscalled programmed death�1 (PD-1), which is expressedon the surface of immune cells, and programmed deathligand�1 (PD-L1), which is expressed on cancer cells.The PD-1 molecule is expressed in activated T cells, Bcells, natural killer T cells, monocytes, and dendriticcells. It has 2 ligands, PD-ligand 1 (L1) and PD-ligand 2(L2). When PD-1 and PD-L1 bind to each other, abiochemical “shield” is formed, which leads to T-cellinactivation and protection of the tumor cells frombeing destroyed by the immune system. Monoclonalantibodies directed against PD-1 constitute a class ofdrugs that prevent engagement of PD-1 to its li-gands,108,109 rescuing the activated T-cell fromapoptotic death and thus allowing it to continue itsattack on tumor cells. Nivolumab and pembrolizumabare 2 monoclonal antibody therapies designed todirectly block the interaction between PD-1 and itsligands in the treatment of melanoma, lung cancer,renal cancer, and hematological malignancies, and havebeen used since 2014.110 The objective of blockingprogram cell death is to restore the activation of the

immune system, directed to tumor cells. These agentsare referred to as immune checkpoint inhibitors.108-110

Nivolumab

Nivolumab was the first anti�PD-1 antibody, testedinitially in melanoma. In December 2014, the FDAgranted an accelerated approval to nivolumab for thetreatment of patients with unresectable or metastaticmelanoma.111 Since then, this agent has also beenapproved for use in renal cell cancer.112 In 1 trial,111

there was an increased incidence of elevated creatininenoted in the nivolumab-treated group as compared tothe chemotherapy-treated group (13% vs. 9%). Steroidshelped to resolve the renal dysfunction in 50% of thecases. The FDA label113 has guidelines to start steroids ifthe creatinine rises rapidly. Recently, there were 4biopsy-proven cases of acute interstitial nephritis (AIN)related to nivolumab described in a case series.114 Allpatients in this series were also taking other drugs(proton pump inhibitors, nonsteroidal anti-inflammatorydrugs) linked to AIN, but in most cases, the use of thesedrugs long preceded anti�PD-1 antibody therapy.Treatment with steroids resolved the AIN in most cases,and rechallenge with nivolumab in 1 case resulted inrecurrence of AIN. Cortazar et al. reported an additionalcase of diffuse AIN with this agent.115 Steroids wereadministered, with no response. The authors think thatthe PD-1 inhibitor therapy may release suppression of T-cell immunity that normally permits renal tolerance ofdrugs known to be associated with AIN.114,115 The AKIappears late, usually in the 6- to 12-month period.Hyponatremia has also been reported with this agent, in25% of the cases. The underlying mechanism remainsunclear.2,113 In the FAERS analysis,2 we found 20 casesof AKI, 14 of hyponatremia, and 5 of hypokalemiaassociated with nivolumab.

Pembrolizumab

Pembrolizumab (MK-3475) is another monoclonal anti-body therapy designed to directly block the interactionbetween PD-1 and its ligands. This drug has been usedin melanoma and hematological malignancies since2014. In the initial trials, acute interstitial nephritis wasconfirmed by kidney biopsy in 2 of 3 patients withAKI. All 3 patients fully recovered renal function withtreatment with high-dose corticosteroids ($40 mgprednisone or equivalent per day) followed by acorticosteroid taper.116,117 The Keynote-2 study118 re-ported grade 3 to 4 adverse events that includedgeneralized edema and myalgia (each in 2 patients[1%]) in those given pembrolizumab 2 mg/kg, andhypopituitarism and hyponatremia (each in 2 patients[1%]) in those given pembrolizumab 10 mg/kg. The

KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies REVIEW

Kidney International Reports (2017) 2, 108–123 117

literature is scant, but recently, Shirali et al. reported 2biopsy-proven cases of AIN with this agent.114 Onecase of rhabdomyolysis and AKI has been reported,119

and renal failure occurred in 2% of the patients in arecent review.115 Cortazar et al.115 reported 2 additionalcases of AIN, 1 case that presented at 3 weeks andanother at 33 weeks after drug initiation. Both patientsreceived steroids; 1 patient responded partially andrequired dialysis, and the other patient responded withcomplete recovery. Overall, the 4 cases of biopsy-proven AIN reported with this agent were in thetimeframe of 1 month to 12 months. Of the case pa-tients, 75% responded to steroids with completeremission, and 1 patient required dialysis and hadpartial remission with steroids. The steroids used werevariable, from i.v. forms to oral steroids for a 1- to 3-month timeframe. Compared to cases reported in theliterature, the FAERS analysis found 19 cases ofhyponatremia and 16 cases of AKI. There were also 4reports of hypokalemia and hyperkalemia. It is possiblethat the electrolyte disorders are related to hypopitu-itarism. Given the immune-mediated mechanism ofaction of this drug, the kidney can be a potential targetand can lead to AIN.

IMMUNE CHECKPOINT INHIBITOR:

CYTOTOXIC T LYMPHOCYTE ANTIGENL4

(CTLA-4) AS A TARGET

Ipilimumab

Ipilimumab is a monoclonal antibody that has antitumoractivity by targeting CTLA-4 and activating the immunesystem. This agent is also considered an immunecheckpoint inhibitor. A member of the Ig family, CTLA4is expressed on CD4þ T-helper cell surface and trans-mits an inhibitory signal to T cells. Blocking of CTLA-4prevents this signal and improves antineoplasticresponse. Ipilimumab is an antibody that binds to hu-man CD152 and enhances T-cell response, especiallyagainst tumor cells. Migration of activated T cells intothe kidney leads to AKI. Cell-mediated immune responseleading to inflammatory cell infiltrates with and withoutgranulomas have been reported.120,121 At least 12 casesof AIN in the initial trials, arising 2 to 12 weeks afterdrug administration, have been reported, and 1 of themdemonstrated granulomas.115,121–124 The largest seriesof 6 cases of AIN was reported by Cortazar et al.115

Pathology revealed AIN in most cases, with varyingdegrees of foot process effacement. Cortazar et al.also reported 1 additional case of thrombotic micro-angiopathy (TMA) related to ipilumumab.115 In aphase III study conducted in patients with melanomarecently,125 no renal toxic effects were reported. Basedon our review of the literature, 2 cases of nephroticsyndrome126,127 have also been reported, 1 patient with a

lupus-like nephritis with a membranous pattern ofinjury126 and the other with minimal change in dis-ease.127 The electrolyte disorders are not well reported inthe literature with this agent. Two cases of hypona-tremia have been published.128 A possible cause ofhyponatremia is a syndrome of inappropriate antidi-uretic hormone from hypophysitis. This complicationrelated to the agent has now been well reported.129,130 Inthe FAERS analysis,2 ipilumimub, with 508 events, hadthe highest number of reports of renal events of allrecently used targeted therapies. Most were AKI, fol-lowed by hyponatremia and hypokalemia. Hypona-tremia related to this agent should prompt considerationof a pituitary-related disorder. In summary, ipilimumabis clearly nephrotoxic, with many cases of AKI andelectrolyte disorders reported in the literature andFAERs reports. Most of the AKI occurred at 6- to12-weeks’ time following the start of treatment with thisagent. Steroids remitted most cases of AIN with thisagent. Some patients had partial remission, and a fewrequired dialysis as well. AKI likely falls underan immune-mediated mechanism of injury, as notedwith other immune checkpoint inhibitors. Hence, cor-ticosteroids remain the mainstay of treatment for AINrelated to ipilumumab therapy. In the literature of casesreviewed, steroids were administered in various form;some patients received oral prednisone 60 mg daily andtapered over 3 months, and some received i.v. solume-drol ranging from 250 mg to 500 mg for 3 to 4 days andthen tapered to oral steroids.

Table 5 compares the renal toxicities of both immunecheckpoint inhibitor classes (CTLA-4 antagonists andPD-1 inhibitors). For both immune checkpoint inhibitors(anti�PD-1 and CTLA-4), if AKI is confirmed on a kid-ney biopsy as AIN or a podocytopathy, we wouldrecommend checkpoint inhibitor discontinuation and acourse of corticosteroids. However, we cannot recom-mend a definitive dose and duration of steroid therapy.Based on cases reported, prednisone 1 mg/kg with a 1- to2-month taper may be sufficient. We additionallyrecommend weekly creatinine monitoring for 1 monthafter completing steroids. Rechallenge with immunecheckpoint therapy may be reasonable if other

Table 5. Comparison of renal toxicities of CTLA-4 antagonists andPD-1 inhibitors2,114,115,121,122,124,126-128

ToxicityCTLA-4 antagonists

(ipilimumab)PD-1 inhibitors

(nivolumab and pembrolizumab)

Onset of AIN AIN appears 6–12 weeksafter initiation of therapy

AIN appears 3–12 mo afterinitiation of therapy

Glomerular findings Podocytopathy reported No cases ofpodocytopathy reported

Electrolyte disorders Hyponatremia casesrelated to hypophysitis

Hyponatremia is rare

AIN, acute interstitial nephritis; CTLA-4, cytotoxic T lymphocyte antigen�4; PD-1,programmed cell death–1.

REVIEW KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies

118 Kidney International Reports (2017) 2, 108–123

potentially offending agents are withdrawn and AIN hasresolved. With this approach, serum creatinine shouldbe monitored regularly, with reinstitution of steroids atthe first sign of AKI from AIN without another cause.For patients on ipilimumab, renal function monitoringshould be more frequent in the first 3 months, as theinjury appears to occur earlier in the treatment course.For the PD-1 inhibitors, the injury usually happenslater, so monitoring serum chemistries on a monthlybasis might be more prudent.

DOSING OF TARGETED THERAPIES IN CKD

AND DIALYSIS

Because the majority of the targeted therapies areassociated with renal toxicity, dosing in CKD andpatients on dialysis is of great importance. As noted inprior chemotherapy trials, most trials excluded patientson dialysis or with severe CKD (GFR < 30). This limitsunderstanding of dosing in CKD and dialysis. InTable 1, we summarize the existing published literatureon dosing of these agents in CKD and dialysis (wher-ever data are available).

CONCLUSIONS

The use of novel targeted therapies has led to signifi-cant improvement in survival and overall prognosiswith many malignancies. However, there is evolvingknowledge on renal adverse events with these agents.Timely recognition of these toxicities can aid in theproper management of cancer patients. In this studyand review, we recognized that there are multiple waysin which targeted therapies can have an impact on

renal function. Table 6 summarizes our recommendedmonitoring strategy for patients receiving these agents.In addition, newer targeted agents are entering clinicaltrials. It is exceedingly difficult to keep up with all thenew drugs along with their associated renal toxicities.Therefore, it is important that the medical communityadvocates for an international database registry fortargeted therapies and their renal adverse effects.

DISCLOSURE

KDJ serves on the American Society of Nephrology (ASN)

Onconephrology Forum. KDJ and RW are expert members

of the Cancer and Kidney International Network, and KDJ

serves on the Governing Board of Cancer and Kidney

International Network. All other authors declare no

competing interests.

ACKNOWLEDGMENTS

We thank Drs. Mark Perazella, Valerie Barta, and Mr. Adriel

Sanchez for creation of figures.

REFERENCES

1. National Cancer Institute. Targeted therapy. Available at:

http://www.cancer.gov/about-cancer/treatment/types/targeted-

therapies. Accessed January 1, 2016.

2. Jhaveri KD, Sakhiya VB, Wanchoo R, et al. Renal effects of

novel anti cancer targeted therapies: a review of the

FDA Adverse Event Reporting System. Kidney Int. 2016;90:

705–707.

3. Folkman J. Tumor angiogenesis: therapeutic implications.

N Engl J Med. 1971;285:1182–1186.

4. Gurevich F, Perazella MA. Renal effects of anti-angiogenesis

therapy: update for the internist. Am J Med. 2009;122:

322–328.

5. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibi-

tion and renal thrombotic microangiopathy. N Engl J Med.

2008;358:1129–1136.

6. Pande A, Lombardo J, Spangenthal E, Javle M. Hyperten-

sion secondary to anti-angiogenic therapy: experience with

bevacizumab. Anticancer Res. 2007;27:3465–3470.

7. Izzedine H, Sène D, Hadoux J. Thrombotic microangiopathy

related to anti-VEGF agents: intensive versus conservative

treatment? Ann Oncol. 2011;22:487–490.

8. Izzedine H, Massard C, Spano JP, et al. VEGF signalling

inhibition-induced proteinuria: mechanisms, significance

and management. Eur J Cancer [Oxford, England: 1990].

2010;46:439–448.

9. Izzedine H, Escudier B, Lhomme C. Kidney diseases associ-

ated with anti-vascular endothelial growth factor (VEGF): an

8-year observational study at a single center. Medicine.

2014;93:333–339.

10. Izzedine H, Rixe O, Billemont B, et al. Angiogenesis inhibitor

therapies: focus on kidney toxicity and hypertension. Am J

Kidney Dis. 2007;50:203–218.

11. Broekman F, Giovannetti E, Peters GJ. Tyrosine kinase in-

hibitors: multi-targeted or single-targeted? World J Clin

Oncol. 2011;2:80–93.

Table 6. Recommended routine physical examination, imaging, andserum and urine monitoring with various targeted therapies

Blood pressure monitoringa

Peripheral edema examinationb

Serum creatinine

Serum potassium

Serum phosphorus

Serum sodium

Serum calcium

Serum magnesiumc

Complete blood count

Urinalysis evaluation for cells and casts

Urine protein/creatinine ratioa

LDHa

Haptoglobina

CKd

Renal sonogram for cyst evaluationb

BCR-ABL, breakpoint cluster region–abelson; CK, creatinine kinase; LDH, lactatedehydrogenase.Most targeted therapies require all the tests listed below, and a few require extra teststhat are labeled with the legend below.aAnti�vascular endothelial growth factor (VEGF) agents, tyrosine kinase inhibitors,cytotoxic T lymphocyte antigen�4 (CTLA-4) inhibitor.bCrizitonib.cEpidermal growth factor (EGFR) inhibitors.dBCR-ABL tyrosine kinase inhibitors.

KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies REVIEW

Kidney International Reports (2017) 2, 108–123 119

12. Dai Y. Platelet-derived growth factor receptor tyrosine ki-

nase inhibitors: a review of the recent patent literature.

Expert Opin Ther Patents. 2010;20:885–897.

13. Jhaveri KD, Flombaum CD, Croog K, Glezerman IG. Neph-

rotoxicities associated with the use of tyrosine kinase in-

hibitors: a single-center experience and review of the

literature. Nephron Clin Pract. 2011;117:c312–c319.

14. Bellini E, Pia A, Brizzi MP. Sorafenib may induce hypo-

phosphatemia through a fibroblast growth factor-23 (FGF23)-

independent mechanism. Ann Oncol. 2011;22:988–990.

15. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib

monotherapy for previously treated metastatic colorectal

cancer (CORRECT): an international,multicentre, randomised,

placebo-controlled, phase 3 trial. Lancet. 2013;381:303–312.

16. Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care

versus placebo plus best supportive care in Asian patients

with previously treated metastatic colorectal cancer

(CONCUR): a randomized, double-blind, placebo-controlled,

phase 3 trial. Lancet Oncol. 2015;16:619–629.

17. Yilmaz B, Kemal Y, Teker F, et al. Single dose regorafenib-

induced hypertensive crisis. Exp Oncol. 2014;36:134–135.

18. Wang Z, Xu J, Nie W, et al. Risk of hypertension with

regorafenib in cancer patients: a systematic review and

meta-analysis. Eur J Clin Pharmacol. 2014;70:225–231.

19. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in

patients with locally advanced or metastatic medullary thy-

roid cancer: a randomized, double-blind phase III trial. J Clin

Oncol. 2012;30:134–141.

20. Lee JS, Hirsh V, Park K, et al. Vandetanib versus placebo in

patients with advanced non-small-cell lung cancer after prior

therapy with an epidermal growth factor receptor tyrosine

kinase inhibitor: a randomized, double-blind phase III trial

(ZEPHYR). J Clin Oncol. 2012;30:1114–1121.

21. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in

locally advanced or metastatic differentiated thyroid cancer:

a randomized, double-blind, phase 2 trial. Lancet Oncol.

2012;13:897–905.

22. Chrisoulidou A, Mandanas S, Margaritidou E, et al. Treat-

ment compliance and severe adverse events limit the use of

tyrosine kinase inhibitors in refractory thyroid cancer. Oncol

Targets Ther. 2015;8:2435–2442.

23. Morrissey KM, Stocker SL, Wittwer MB, et al. Renal trans-

porters in drug development. Annu Rev Pharmacol Toxicol.

2013;53:503–529.

24. Shen H, Yang Z, Zhao W, et al. Assessment of vandetanib as

an inhibitor of various human renal transporters: inhibition

of multidrug and toxin extrusion as a possible mechanism

leading to decreased cisplatin and creatinine clearance.

Drug Metab Dispos. 2013;41:2095–2103.

25. Marcolino MS, Boersma E, Clementino NC, et al. Imatinib

treatment duration is related to decreased estimated

glomerular filtration rate in chronic myeloid leukemia pa-

tients. Ann Oncol. 2011;22:2073–2079.

26. Gafter-Gvili A, Ram R, Gafter U, et al. Renal failure associ-

ated with tyrosine kinase inhibitors—case report and review

of the literature. Leuk Res. 2010;34:123–127.

27. Pou M, Saval N, Vera M, et al. Acute renal failure secondary

to imatinib mesylate treatment in chronic myeloid leukemia.

Leuk Lymphoma. 2003;44:1239–1241.

28. Foringer JR, Verani RR, Tjia VM, et al. Acute renal failure

secondary to imatinib mesylate treatment in prostate can-

cer. Ann Pharmacother. 2005;39:2136–2138.

29. Francois H, Coppo P, Hayman JP, et al. Partial Fanconi

syndrome induced by imatinib therapy: a novel cause of

urinary phosphate loss. Am J Kidney Dis. 2008;51:298–301.

30. Takikita-Suzuki M, Haneda M, Sasahara M, et al. Activation

of Src kinase in platelet-derived growth factor-B-dependent

tubular regeneration after acute ischemic renal injury. Am

J Pathol. 2003;163:277–286.

31. Vuky J, Isacson C, Fotoohi M, et al. Phase II trial of imatinib

(Gleevec) in patients with metastatic renal cell carcinoma.

Investig New Drugs. 2003;24:85–88.

32. Penel N, Blay JY, Adenis A. Imatinib as a possible cause

of severe rhabdomyolysis. N Engl J Med. 2008;358:

2746–2747.

33. Gordon JK, Magid SK, Maki RG, et al. Elevations of creatine

kinase in patients treated with imatinib mesylate (Glee-

vecTM). Leuk Res. 2010;34:827–829.

34. Berman E, Nicolaides M, Maki RG, et al. Altered bone and

mineral metabolism in patients receiving imatinib mesylate.

N Engl J Med. 2006;354:2006–2013.

35. O’Sullivan S, Horne A, Wattie D, et al. Decreased bone

turnover despite persistent secondary hyperparathyroidism

during prolonged treatment with imatinib. J Clin Endocrinol

Metab. 2009;94:1131–1136.

36. Iyoda M, Shibata T, Wada Y, et al. Long- and short-term

treatment with imatinib attenuates the development of

chronic kidney disease in experimental anti-glomerular

basement membrane nephritis. Nephrol Dial Transplant.

2013;28:576–584.

37. Bondon-Guitton E, Combret S, Pérault-Pochat MC. Cardio-

vascular risk profile of patients with peripheral arterial

occlusive disease during nilotinib therapy. Target Oncol.

2016;11:549–552.

38. Iyoda M, Shibata T, Hirai Y, Kuno Y, Akizawa T. Nilotinib

attenuates renal injury and prolongs survival in chronic

kidney disease. J Am Soc Nephrol. 2011;22:1486–1496.

39. Steinberg M. Dasatinib: a tyrosine kinase inhibitor for the

treatment of chronic myelogenous leukemia and Philadelphia

chromosome-positive acute lymphoblastic leukemia. Clin

Ther. 2007;11:2289–2308.

40. Ozkurt S, Temiz G, Acikalin MF, Soydan M. Acute renal

failure under dasatinib therapy. Ren Fail. 2010;1:147–149.

41. Kaiafa G, Kakaletsis N, Savopoulos C, et al. Simultaneous

manifestation of pleural effusion and acute renal failure

associated with dasatinib: a case report. J Clin Pharm Ther.

2013;1:102–105.

42. Holstein SA, Stokes JB, Hohl RJ. Renal failure and recovery

associated with second-generation Bcr-Abl kinase inhibitors

in imatinib-resistant chronic myelogenous leukemia. Leuk

Res. 2008;2:344–347.

43. Martino S, Daguindau E, Ferrand C, et al. A successful renal

transplantation for renal failure after dasatinib-induced

thrombotic thrombocytopenic purpura in a patient with

imatinib-resistant chronic myelogenous leukaemia on nilo-

tinib. Leuk Res Rep. 2013;1:29–31.

44. Uz B, Dolasik I. An unexpected and devastating adverse event

of dasatinib: rhabdomyolysis. Leuk Res Rep. 2015;5:1–2.

REVIEW KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies

120 Kidney International Reports (2017) 2, 108–123

45. Wallace E, Lyndon W, Chumley P, et al. Dasatinib-induced

nephrotic-range proteinuria. Am J Kidney Dis. 2013;6:

1026–1031.

46. Hirano T, Hashimoto M, Korogi Y, et al. Dasatinib-induced

nephrotic syndrome. Leuk Lymphoma. 2015;3:726–727.

47. Pfizer Labs. Bosulif (bosutinib) [prescribing information].

New York, NY: Pfizer Labs; 2015.

48. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with

ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J

Med. 2013;369:32–42.

49. Wang ML, Blum KA, Martin P, et al. Long-term follow-up of

MCL patients treated with single-agent ibrutinib: updated

safety and efficacy results. Blood. 2015;126:739–745.

50. Petrelli F, Borgonovo K, Cabiddu M, et al. Risk of anti EGFR

monoclonal antibody related hypomagnesemia: systematic

review and pooled analysis of randomized studies. Exp Opin

Drug Saf. 2012;11(suppl):S9–S19.

51. Voets T, Nilius B, Hoefs S, et al. TRPM6 forms the Mg2þ

influx channel involved in intestinal and renal Mg2þ

absorption. J Biol Chem. 2004;279:19–25.

52. Fakih MG, Wilding G, Lombardo J. Ceuximab induced

hypomagnesaemia in patients with colorectal cancer. Clin

Colorectal Cancer. 2006;6:152–156.

53. Izzedine H, Bahleda R, Khayat D. Electrolyte disorders

related to EGFR-targeting drugs. Crit Rev Oncol Hematol.

2010;73:213–219.

54. Chen P, Wang L, Li H, et al. Incidence and risk of hypo-

magnesemia in advanced cancer patients treated with

cetuximab: a meta-analysis. Oncol Lett. 2013;5:1915–1920.

55. Cao Y, Liao C, Tan A, et al. Meta-analysis of incidence and

risk of hypomagnesemia with cetuximab for advanced

cancer. Chemotherapy. 2010;56:459–465.

56. Schrag D, Chung KY, Flombaum CD, Saltz L. Cetuximab

therapy and symptomatic hypomagnesemia. J Natl Cancer

Inst. 2005;97:1221–1224.

57. Streb J, Püsküllüo�glu M, Glanowska I, et al. Assessment of

frequency and severity of hypomagnesemia in patients with

metastatic colorectal cancer treated with cetuximab, with a

review of the literature. Oncol Lett. 2015;10:3749–3755.

58. Fakih M. Management of anti-EGFR targeting monoclonal

antibody induced hypomagnesemia. Oncology [Williston

Park]. 2008;22:74–76.

59. Vij R, Sachdeva M. Severe electrolyte abnormalities after

cetuximab—management challenge. Am J Kidney Dis. 2010;

55(4):617–772.

60. Harari PM. Epidermal growth factor receptor inhibition stra-

tegies in oncology. Endocr Relat Cancer. 2004;11:689–708.

61. Sasaki K, Anderson E, Shankland SJ, Nicosia RF. Diffuse

proliferative glomerulonephritis associated with cetuximab,

an epidermal growth factor receptor inhibitor. Am J Kidney

Dis. 2013;61:988–991.

62. Ito C, Fujii H, Ogura M, et al. Cetuximab-induced nephrotic

syndrome in a case of metastatic rectal cancer. J Oncol

Pharm Pract. 2013;19:265–268.

63. Nakapoulou L, Stefanaki K, Boletis J, et al. Immunohis-

tochemial study of epidermal growth factor receptor in

various types of renal injury. Nephrol Dial Transplant.

1994;9:764–769.

64. Rowinsky EK, Schwartz GH, Gollob JA, et al. Safety, phar-

macokinetics and activity of ABX-EGF, a fully human anti-

epidermal growth factor receptor monoclonal antibody in

patients with metastatic renal cell cancer. J Clin Oncol.

2004;22:3003–3015.

65. Vermorken JB, Stohlmacher-Williams J, Davidenko I, et al.

Cisplatin and fluorouracil with or without panitumumab

in patients with recurrent or metastatic squamous cell

carcinoma of the head and neck (SPECTRUM): an open

label phase 3 randomized trial. Lancet Oncol. 2013;14:

697–710.

66. Van Cutsem E, Peeters M, Siena S, et al. Open label phase III

trial on panitumumab plus best supportive care compared

with best supportive care alone in patients with chemo-

therapy refractory metastatic colorectal cancer. J Clin Oncol.

2007;25:1658–1664.

67. do Pazo-Oubiña F, Estefanell-Tejero A, Riu-Viladoms G.

Magnesium monitoring practice in monoclonal anti-

epidermal growth factor receptor antibodies therapy.

J Clin Pharm Ther. 2013;38:101–103.

68. Dimke H, Van der Wijst J, Alexander TR, et al. Effects of the

EGFR inhibitor erlotinib on magnesium handling. J Am Soc

Nephrol. 2010;21:1309–1316.

69. Duran I, Hotté SJ, Hirte H, et al. Phase I targeted combination

trial of sorafenib and erlotinib in patients with advanced

solid tumors. Clin Cancer Res. 2007;13:4849–4857.

70. Broniscer A, Baker SJ, Stewart CF, et al. Phase I and phar-

macokinetic studies of erlotinib administered concurrently

with radiotherapy for children, adolescents, and young

adults with high-grade glioma. Clin Cancer Res. 2009;15:

701–707.

71. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in

previously treated non-small-cell lung cancer (INTEREST): a

randomized phase III trial. Lancet. 2008;372:1809–1818.

72. Wan HL, Yao NS. Acute renal failure associated with gefiti-

nib therapy. Lung. 2006;184:249–250.

73. Kumasaka R, Nakamura N, Shirato K, et al. Side effects of

therapy: case 1. Nephrotic syndrome associated with gefi-

tinib therapy. J Clin Oncol. 2004;22:2504–2505.

74. Maruyama K, Chinda J, Kuroshima T, et al. Minimal

change nephrotic syndrome associated with gefitinib and

a successful switch to erlotinib. Intern Med. 2015;54:823–

826.

75. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo

for patients with advanced, metastatic non-small-cell lung

cancer after failure of erlotinib, gefitinib, or both, and one or

two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 ran-

domized trial. Lancet Oncol. 2012;13:528–538.

76. Russo G, Cioffi G, Di Lenarda A, et al. Role of renal function

on the development of cardiotoxicity associated with

trastuzumab-based adjuvant chemotherapy for early breast

cancer. Intern Emerg Med. 2012;7:439–446.

77. Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab

plus anastrozole versus anastrozole alone for the treat-

ment of postmenopausal women with human epidermal

growth factor receptor 2-positive, hormone receptor-

positive metastatic breast cancer: results from the ran-

domized phase III TAnDEM study. J Clin Oncol. 2009;27:

5529–5537.

KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies REVIEW

Kidney International Reports (2017) 2, 108–123 121

78. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab

in combination with chemotherapy versus chemotherapy

alone for treatment of HER2-positive advanced gastric or

gastro-oesophageal junction cancer (ToGA): a phase 3,

open-label, randomised controlled trial. Lancet. 2010;376:

687–697.

79. Taira F, Horimoto Y, Saito M. Tumor lysis syndrome

following trastuzumab for breast cancer: a case report and

review of the literature. Breast Cancer. 2015;22:664–668.

80. Gottschalk I, Berg C, Harbeck N, et al. Fetal renal insuffi-

ciency following trastuzumab treatment for breast cancer in

pregnancy: case report and review of the current literature.

Breast Care (Basel). 2011;6:475–478.

81. Bader AA, Schlembach D, Tamussino KF, et al. Anhy-

dramnios associated with administration of trastuzumab

and paclitaxel for metastatic breast cancer during preg-

nancy. Lancet Oncol. 2007;8:79–81.

82. Watson WJ. Herceptin (trastuzumab) therapy during preg-

nancy: association with reversible an-hydramnions. Obstet

Gynecol. 2005;105:642–651.

83. Yasuhara H, Imagawa A, Koike N, et al. A case of renal salt-

wasting syndrome during chemotherapy for advanced

gastric cancer. Gan To Kagaku Ryoho. 2015;42:225–227.

84. Kolarich AR, Reynolds BA, Heldermon CD. Ado-trastuzamab

emtansine associated hyponatremia and intracranial hem-

orrhage. Acta Oncol. 2014;53:1434–1436.

85. Turner N, Stewart J, Barnett F, White S. Syndrome of inap-

propriate anti-diuretic hormone secretion secondary to

carboplatin after docetaxel-carboplatin-trastuzumab combi-

nation for early stage HER-2 positive breast cancer. Asia Pac

J Clin Oncol. 2012;8:e9–e11.

86. de Souza JA, Davis DW, Zhang Y, et al. A phase II study of

lapatinib in recurrent/metastatic squamous cell carci-

noma of the head and neck. Clin Cancer Res. 2012;18:

2336–2343.

87. US Food and Drug Administration. Zolboraf. Highlights of pre-

scribing information. Available at: http://www.accessdata.fda.

gov/drugsatfda_docs/label/2011/202429s000lbl.pdf. Accessed

July 2016.

88. Uthurriague C, Thellier S, Ribes D, et al. Vemurafenib

significantly decreases glomerular filtration rate. J Eur Acad

Dermatol Venerol. 2014;28:978–979.

89. Regnier-Rosencher E, Lazareth H, Gressier L, et al. Acute

kidney injury in patients with severe rash on vemurafenib

treatment for metastatic melanomas. Br J Dermatol.

2013;169:934–938.

90. Launay-Vacher V, Zimner-Rapuch S, Poulalhon N, et al.

Acute renal failure associated with the new BRAF inhibitor

vemurafenib: a case series of 8 patients. Cancer. 2014;120:

2158–2163.

91. Yorio JT, Mays SR, Ciurea AM, et al. Case of vemurafenib-

induced Sweet’s syndrome. J Dermatol. 2014;41:817–820.

92. Denis D, Franck N, Fichel F, et al. Fanconi syndrome induced

by vemurafenib: a new renal adverse event. JAMA Derma-

tol. 2015;151:453–454.

93. Teuma C, Perier-Muzet M, Pelletier S, et al. New insights into

renal toxicity of the B-RAF inhibitor, vemurafenib, in patients

with metastatic melanoma. Cancer Chemother Pharmacol.

2016. http://dx.doi.org/10.1007/s00280-016-3086-7.

94. Jhaveri KD, Sakhiya V, Fishbane S. BRAF inhibitor related

nephrotoxicity. JAMA Oncol. 2015;1:1133–1134.

95. Hurabielle C, Pillebout E, Stehlé T, et al. Mechanisms un-

derpinning increased plasma creatinine levels in patients

receiving vemurafenib for advanced melanoma. PLoS One.

2016;11:e0149873.

96. US Food and Drug Administration. Tefinlar. Highlights of pre-

scribing information. Available at: http://www.accessdata.fda.

gov/drugsatfda_docs/label/2013/202806s000lbl.pdf. Accessed

July 2016.

97. Jansen YJ, Janssens P, Hoorens, et al. Granulomatous

nephritis and dermatitis in a patient with BRAF V600E

mutant metastatic melanoma treated withdabrafenib and

trametinib. Melanoma Res. 2015;25:550–554.

98. Wanchoo R, Jhaveri KD, Geray D, Launay-Vacher V. Renal

effects of BRAF inhibitors. A review by the Cancer and the

Kidney International Network (C-KIN). Clin Kidney J. 2016.

http://dx.doi.org/10.1093/ckj/sfv149.

99. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and

MEK inhibition in melanoma with BRAF V600 mutations.

N Engl J Med. 2012;367:1694–1703.

100. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of

crizotinib in patients with ALK-positive non small cell lung

cancer: updated results from a phase 1 study. Lancet Oncol.

2012;13:1011–1019.

101. Martín Martorell P, Huerta Alvaro M, Solís Salguero MA,

Insa Molla A. Crizotinib and renal insufficiency: a case report

and review of the literature. Lung Cancer. 2014;84:310–313.

102. Gastaud L, Ambrosetti D, Otto J, et al. Acute kidney injury

following crizotinib administration for non small cell lung

carcinoma. Lung Cancer. 2013;82:362–364.

103. Brosnan EM, Weickhardt AJ, Lu X, et al. Drug induced

reduction in estimated glomerular filtration rate in patients

with ALK-positive non-small cell lung cancer treated with

the ALK inhibitor crizotinib. Cancer. 2014;120:664–674.

104. Lin YT, Wang YF, Yang JC, et al. Development of renal cysts

after crizotinib treatment in advanced ALK-positive non

small cell lung cancer. J Thorac Oncol. 2014;9:1720–1725.

105. Klempner SJ, Aubin G, Dash A, Ou SH. Spontaneous

regression of crizotinib associated complex renal cysts

during continuous crizotinib treatment. Oncologist. 2014;19:

1008–1010.

106. Schnell P, Barlett CH, Solomon BJ, et al. Complex renal

cysts associated with crizotinib treatment. Cancer Med.

2015;4:887–896.

107. Izzedine H, El-fekih RK, Perazella MA. The renal effects of

ALK inhibitors. Invest New Drugs. 2016;34:643–649.

108. Luke JJ, Ott PA. PD-1 pathway inhibitors: the next genera-

tion of immunotherapy for advanced melanoma. Onco-

target. 2015;6:3479–3492.

109. Terme M, Ullrich E, Aymeric L, et al. IL-18 induces

PD-1-dependent immunosuppression in cancer. Cancer Res.

2001;71:5393–5399.

110. Tang PA, Heng DY. Programmed death 1 pathway inhibition

in metastatic renal cell cancer and prostate cancer. Curr

Oncol Rep. 2015;15:98–104.

111. Robert C, Long GV, Brady B, et al. Nivolumab in previously

untreated melanoma without BRAF mutation. N Engl J Med.

2015;372:320–330.

REVIEW KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies

122 Kidney International Reports (2017) 2, 108–123

112. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab

versus everolimus in advanced renal-cell carcinoma. N Engl

J Med. 2015;373:1803–1813.

113. Bristol-Myers Squibb. Nivolumab package insert. Available

at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2

014/125554lbl.pdf. Accessed January 1, 2016.

114. Shirali A, Perazella MA, Gettinger S. Association of acute

interstitial nephritis with programmed cell death (PD)-1 in-

hibitor therapy in lung cancer patients. Am J Kidney Dis.

2016; pii: S0272-6386(16)30025-7.

115. Cortazar FB, Marrone KA, Troxell ML, et al. Clinicopatho-

logical features of acute kidney injury associated with

immune checkpoint inhibitors. Kidney Int. 2016. pii: S0085-

2538(16)30164-8.

116. Merck Sharp & Dohme. Pembrolizumab package insert.

Available at: http://www.accessdata.fda.gov/drugsatfda_

docs/label/2014/125514lbl.pdf. Accessed January 1, 2016.

117. Robert C, Schachter J, Long GV, et al. Pembrolizumab

versus ipilimumab in advanced melanoma. N Engl J Med.

2015;372:2521–2532.

118. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus

investigator-choice chemotherapy for ipilimumab-refractory

melanoma (KEYNOTE-002): a randomized, controlled, phase

2 trial. Lancet Oncol. 2015;16:908–918.

119. Min L, Hodi FS. Anti PD-1 following ipilimumab for mucosal

melanoma: durable tumor response associated with severe

hypothyroidism and rhabdomyolysis. Cancer Immunol Res.

2014;2:15–18.

120. Voskens CJ, Goldinger SM, Loquai C, et al. The price of tu-

mor control: an analysis of rare side effects of anti-CTLA4

therapy in metastatic melanoma from ipilimumab network.

PLoS One. 2013;8:e53745.

121. Izzedine H, Gueutin V, Gharbi C, et al. Kidney injuries related

to ipilimumab. Invest New Drugs. 2014;32:769–773.

122. Thajudeen B, Madhrira M, Bracamonte E. Ipilimumab

granulomatous interstitial nephritis. Am J Ther. 2015;22:

e84–e87.

123. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and

safety of ipilimumab monotherapy in patients with pre-

treated advanced melanoma: a multicenter single-arm

phase II study. Ann Oncol. 2010;21:1712–1717.

124. Forde PM, Rock K, Wilson G, O’Byrne KJ. Ipilimumab-

induced immune-related renal failure—a case report.

Anticancer Res. 2012;32:4607–4608.

125. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus

dacarbazine for previously untreated metastatic melanoma.

N Engl J Med. 2011;364:2517–2526.

126. Fadel F, El Karoui K, Knebelmann B. Anti CTLA-4 antibody

induced lupus nephritis. N Engl J Med. 2009;361:211–212.

127. Kidd J, Gizaw A. Ipilimumab associated minimal change

disease. Kidney Int. 2016;89:720.

128. Barnard ZR, Walcott BP, Kahle KT, et al. Hyponatremia

associated with ipilimumab-induced hypophysitis. Med

Oncol. 2012;29:374–377.

129. Min L, Hodi FS, Giobbie-Hurder A, et al. Systemic

high-dose corticosteroid treatment does not improve

the outcome of ipilimumab-related hypophysitis: a

retrospective cohort study. Clin Cancer Res. 2015;21:

749–755.

130. Chodakiewitz Y, Brown S, Boxerman JL, et al. Ipilimumab

treatment associated pituitary hypophysitis: clinical pre-

sentation and imaging diagnosis. Clin Neurol Neurosurg.

2014;125:125–130.

KD Jhaveri et al.: Adverse Renal Effects of Oncologic Targeted Therapies REVIEW

Kidney International Reports (2017) 2, 108–123 123

Northwell Health Onconephrology Publications

Glezerman I , Jhaveri KD, Watson T et al. Chronic Kidney Disease, Thrombotic microangiopathy and

hypertension following T-cell depleted hematopoietic stem cell transplantation. Biol Blood Marrow

Transplant: 2010:16(7):976-984.

Jhaveri KD, Glezerman I, Kroog G, Flombaum CD. Nephrotoxicities Associated With the Use of

Tyrosine Kinase Inhibitors: A Single Center Experience and Review of the Literature. Nephron Clin

Pract 2011; 117:c312-c319

Jhaveri KD, Flombaum C, Shah M, Latcha S. A retrospective observational study on the use of

capecitabine in patients with severe renal impairment (GFR <30 mL/min) and end stage renal disease on

hemodialysis.J Oncol Pharm Pract. 2012 Mar;18(1):140-7.

Jhaveri KD, Shah HH, Calderon K, Campenot E, Radhakrishnan J. Glomerular Diseases in Cancer

patients. Kidney Int 2013: 84(1):34-44

Hazzan AD, Shah HH, Hong S, Sakhiya V, Wanchoo R, Fishbane S. Treatment with erythropoiesis-

stimulating agents in chronic kidney disease patients with cancer. Kidney Int. 2014 Jul;86(1):34-9.

Jhaveri KD, Shah HH, Kadiyala A, Patel C, Stokes M, Radhakrishnan J. Glomerular diseases

associated with cancer, chemotherapy and hematopoietic stem cell transplantation. Adv Chronic Kidney

Dis 2014:21:1:48-55.

Jhaveri KD, Sakhiya V, Fishbane S. Nephrotoxicites of the BRAF inhibitors: Vemurafenib and

dabrafenib. JAMA Oncol 2015: 1;1(8):1133-4.

Jhaveri KD, Chidella S, Varghese J, Mailloux L, Devoe C. Carfilzomib induced kidney injury. Clin

Adv Hematol Oncol. 2013:11:9:1-3.

Jhaveri KD, Chidella S, Allen S, Fishbane S. Clofarabine-induced renal injury. J Oncol Pharm Pract

2013: 20(4):305-8.

Wanchoo R, Khan S, Kolitz JE, Jhaveri KD. Carfilzomib related acute kidney injury may be prevented

by N-acetyl cysteine. J Oncol Pharm Pract 2015: 2(4): 313-16

Thakkar J, Wanchoo R, Jhaveri KD. Onconephrology abstracts and publication trends: time to

collaborate. Clin Kidney J 2015: 8(5):629-31

Jhaveri KD, Wanchoo R. Carfilzomib induced nephrotoxicity. Kidney Int. 2015:88:(1):199-200

Wanchoo R, Jhaveri KD, Deray G, Launay-Vacher V. Renal effects of BRAF inhibitors: a systematic

review by the Cancer and Kidney International Network Clin Kidney J 2016: doi:10.1093/ckj/sfv149

Motwani S, Herilitz L, Monga D, Jhaveri KD, Lam A. Paraprotein-related KidneyDiseases:

Amyloidosis, Light Chain Deposition Disease, And Other Entities. Clin J Am Soc Neph 2016: 7;

11(12):2260-2272.

Jhaveri KD, Wanchoo R, Sakhiya VB, Ross D, Fishbane S. Adverse Renal Effects of Novel Molecular

Oncologic Targeted Therapies: A Narrative Review. Kidney Int Rep 2016:

http://dx.doi.org/10.1016/j.ekir.2016.09.055

Wanchoo R, Devoe C, Jhaveri KD. BRAF inhibitors - do we need to worry about kidney injury? Expert

Opin Drug Saf. 2016 May;15(5):579-81.

Jhaveri KD, Sakhiya V, Wanchoo R, Ross D, Fishbane S. Renal effects of novel anti-cancer targeted

therapies, A review of the FDA Adverse Event Reporting System. Kidney Int 2016:90:3:706-7

Wanchoo R, Abudayyeh A, Doshi M, Edeani A, Glezerman IG, Monga D, Rosner M, Jhaveri KD.Renal

Toxicities of Novel Agents Used for Treatment of Multiple Myeloma. Clin J Am Soc Nephrol. 2017 Jan

6;12(1):176-189

Wanchoo R, Reilla LV, Uppal NN, Lopez C, Nair V, Devoe C, Jhaveri KD. Immune check point

inhibitors in the cancer patient with an organ transplant. J O Onconeph 2017: doi.10.5301/jo-n.5000006

Barnett R, Barta VS, Jhaveri KD: Preserved renal allograft function while using the PD-1 pathway

inhibitor nivolumab. N Engl J Med 2017:376:2:191-192

Wanchoo R, Karam S, Uppal NN, Barta VS, Deray G, Devoe C, Launay-Vacher V, Jhaveri KD.

Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review Am J Nephrol 2017: DOI:

10.1159/000455014

1st ed. 2015, XXI, 376 p. 37 illus., 27 illus. incolor.

Printed book

Hardcover▶ 119,99 € | £108.00 | $149.00▶ *128,39 € (D) | 131,99 € (A) | CHF 135.50

eBook

Available from your library or▶ springer.com/shop

MyCopy

Printed eBook for just▶ € | $ 24.99▶ springer.com/mycopy

Order online at springer.com ▶ or for the Americas call (toll free) 1-800-SPRINGER ▶ or email us at:customerservice@springer.com. ▶ For outside the Americas call +49 (0) 6221-345-4301 ▶ or email us at:customerservice@springer.com.

The first € price and the £ and $ price are net prices, subject to local VAT. Prices indicated with * include VAT for books; the €(D) includes 7% forGermany, the €(A) includes 10% for Austria. Prices indicated with ** include VAT for electronic products; 19% for Germany, 20% for Austria. All pricesexclusive of carriage charges. Prices and other details are subject to change without notice. All errors and omissions excepted.

K. Jhaveri, A.K. Salahudeen (Eds.)

OnconephrologyCancer, Chemotherapy and the Kidney

▶ Covers the pathophysiology and management of kidney diseases incancer patients

▶ Case based resource features the latest evidence and clinicalapproaches

▶ Fills a significant knowledge gap for nephrologists, hematologistsand oncologists

This case based resource focuses on kidney disease in patients with cancer.  Chapterscover the pathophysiology and management of specific kidney diseases in cancerpatients, as well as the impact of chemotherapy, toxicity of organ and stem celltransplantation and other emerging therapies.  Filling a significant knowledge gap in thisburgeoning field, Onconephrology features the latest evidence and clinical approaches forthe beginner or experienced practitioner.       

Northwell Health Physician Partners

Kidney and Hypertension Specialists

100/125 Community Drive, 2nd Floor

Great Neck, New York, 11021

Phone: (516) 465-8200

Fax: (516) 465-8202