Nephrotoxicity of immune checkpoint inhibitors beyond ...

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Nephrotoxicity of immune checkpointinhibitors beyond tubulointerstitialnephritis: single-center experienceOmar Mamlouk1, Umut Selamet2, Shana Machado1, Maen Abdelrahim3, William F. Glass4, Amanda Tchakarov4,Lillian Gaber5, Amit Lahoti6, Biruh Workeneh6, Sheldon Chen6, Jamie Lin6, Noha Abdel-Wahab7,8, Jean Tayar8,Huifang Lu8, Maria Suarez-Almazor8, Nizar Tannir9, Cassian Yee10, Adi Diab10† and Ala Abudayyeh6*†

Abstract

Rationale & Objective: The approved therapeutic indication for immune checkpoint inhibitors (CPIs) are rapidlyexpanding including treatment in the adjuvant setting, the immune related toxicities associated with CPI can limitthe efficacy of these agents. The literature on the nephrotoxicity of CPI is limited. Here, we present cases of biopsyproven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potentialmechanisms of these adverse effects.

Study design, setting, & participants: We retrospectively reviewed all cancer patients from 2008 to 2018 whowere treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD AndersonCancer Center.

Results: We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male,and the median age was 64 (range 38 to 77 years). The median time to developing acute kidney injury (AKI) fromstarting CPIs was 14 weeks (range 6–56 weeks). The average time from AKI diagnosis to obtaining renal biopsy was16 days (range from 1 to 46 days). Fifteen cases occurred post anti-PD-1based therapy. ATIN was the most commonpathologic finding on biopsy (14 of 16) and presented in almost all cases as either the major microscopicfinding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immuneglomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, oramyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppressionwere used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majorityachieving complete to partial renal recovery.

Conclusions: Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsydata demonstrate that ATIN is the most common pathological finding; however it can frequently co-occurwith other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids.In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI.

Keywords: Checkpoint inhibitors, Immunotherapy, Glomerulonephritis, Acute tubulointerstitial nephritis

* Correspondence: [email protected]†Adi Diab and Ala Abudayyeh contributed equally to this work.6Division of Internal Medicine, Section of Nephrology, The University of TexasMD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1468, Houston, TX77030, USAFull list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Mamlouk et al. Journal for ImmunoTherapy of Cancer (2019) 7:2 https://doi.org/10.1186/s40425-018-0478-8

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IntroductionImmune checkpoint inhibition had a major clinical suc-cess in clinical oncology and impacted the treatmentparadigm in many cancers. The approval indications forCPI has been progressively expanding including treat-ments the adjuvant setting [1–3]. Immune related ad-verse events (irAEs) are well described toxicities thatare closely associated with CPI therapies and can in-volve any organ in the human body [4].Renal toxicity associated with CPI incidence has been

reported as low as 2% when nivolumab alone to 4.5%when combination nivolumab and ipilimumab has beenused [2, 5–7]. Guidelines for the multidisciplinary man-agement of irAEs have been published by the Society forImmunotherapy of Cancer (SITC) and the American So-ciety of Clinical Oncology (ASCO) [4, 7, 8]; however, thedata on renal management is limited and not consistent.The CPI-related renal pathologies are varied. Besides

acute tubulointerstitial nephritis, seven other biopsy-proven kidney manifestations were published as casereports of nine patients on CPIs, including lupus nephrop-athy, thrombotic microangiopathy (TMA),nephrotic syn-drome (focal segmental glomerulosclerosis (FSGS), twocases of minimal-change disease (MCD) [9], membranousnephropathy), pauci-immune glomerulonephritis [10], andtwo cases of IgA nephropathy [11–16]. The etiology of thereported kidney toxicity is not yet clear. Suggestedmechanisms include direct lymphocytic cellular infiltra-tion of renal interstitium, immune complex-mediatedkidney injury, lupus nephritis, IgA, microangiopathichemolytic anemia (TMA), or release of cytokines lead-ing to podocyte foot process effacement (minimal-change disease and focal segmental glomerulosclerosis).The current recommendations for the diagnosis and

management of renal irAEs are not comprehensive dueto the limited available data and understanding of thepathophysiology associated with renal irAEs. Therefore,we have reviewed a series of kidney biopsy cases of pa-tients on CPIs in our institution to better understandthe spectrum of injuries associated with irAEs and thetreatments that were used.

MethodsThis retrospective study was approved by the institu-tional review board in accordance with the Declarationof Helsinki. We retrospectively identified a total of6412 patients who had received FDA approved CPI’s atThe University of Texas MD Anderson Cancer Centerduring 2008–2018. In addition, we collected all kidneybiopsies (266) performed at MD Anderson in the sameperiod. Of the 6412 patients, 15 patients were biopsiedfor suspected CPI-induced nephrotoxicity. However, anadditional case in our biopsied database population thatwas treated with a non-approved CTLA-4 inhibitor

(tremelimumab) was also identified, bringing the totalcases to 16.We collected age, sex, race/ethnicity, cancer diagno-

sis, name and class of CPI used, reason for kidney biopsy,underlying comorbidities including autoimmune disease,potentially nephrotoxic medications, serum creatinine atbaseline, peak serum creatinine during AKI, date of lastfollow-up, urine sediment, proteinuria, other irAEs, sero-logic findings, and kidney biopsy findings.We defined AKI using the AKIN criteria since it was

used to define and categorize the severity of nephritis inthe ASCO practice guidelines [17].Patients’ renal functions were followed up for at least

3 months post-AKI before categorizing renal recoveryinto persistent acute kidney injury, complete renal re-covery and partial renal recovery, after creatinine hadreached a stable value. Complete recovery of renal func-tion was defined by an improvement in creatinine levelpost-AKI to a level less than 0.35mg/dL above the base-line. Partial recovery was defined by the serum creatin-ine improving to a level between the baseline plus 0.35mg/dL and less than two times the baseline value. [18]Complete remission in membranous nephropathy was

defined by the random urine protein-to-creatinine ratios< 0.2 g/g on at least three occasions along with a normalserum creatinine. [19]

ResultsPatient characteristicsSixteen patients developed AKI while on CPIs and re-quired renal biopsies over the past 10 years at our insti-tution. The characteristics of these patients, urinefindings, AKI category, and associated renal pathologyare summarized in Table 1.Most cases identified were white men (1 case was a

Hispanic man, and 4 cases were women), with a medianage of 64 years (range, 38–77 years). Renal cell carcin-oma, urothelial bladder cancer and melanoma were themost common malignancies (3 cases of RCC and 3urothelial bladder cancer and 4 cases of melanoma),followed by multiple myeloma (2 cases) and 1 case eachof chondroma, squamous cell cancer of the lung,adenocarcinoma of the lung, and Hodgkin lymphoma.Most cases occurred in the setting of nivolumab (anti-PD-1) and pembrolizumab (anti-PD-1) use (6 caseseach), a combination of nivolumab and ipilimumab(anti-CTLA-4) (2 cases), tremelimumab(anti-CTLA-4)(1 case), and atezolizumab (anti-PD-L1) (1 case). 7 pa-tients had chronic kidney disease (CKD) at baseline:5had CKD stage 3, and 2 had CKD stage 4.

Clinical featuresThe median time to development of AKI after starting aCPI was 14 weeks (range: 6–56 weeks). However, AKI

Mamlouk et al. Journal for ImmunoTherapy of Cancer (2019) 7:2 Page 2 of 13

Table

1Characteristicsof

thepatientswho

develope

dCPI-related

renalm

anifestations

andtheirlabo

ratory

andmicroscop

icfinding

sassociated

with

theCPI-related

renal

manifestations,initialthe

rapies

andtheou

tcom

esNo

Age

,years

Sex

Race

Cancertype

CPI

duratio

nCom

orbidities

Potentially

neph

rotoxic

home

med

ication

(dose;mg/day)

Baseline

Crmg/dL

PriorUA

Peak

Cr

mg/dL

Severity

ofAKI

Urin

eSedimen

tCells/HPF

Proteinu

ria

Kidn

eybiop

syInitial

Managem

ent

Renal

outcom

ePFS

Cancerstatus

Acute

tubu

lointerstitialn

ephritis

165

MW

Smolde

ring

myeloma

Pembrolizum

ab6cycles

(14weeks)

HTN

,dyslipidem

ia,

RA,G

ERD

Losartan,50

Omep

razole,20

0.8

N/A

4.83

G3

3WBC

,1RB

C,

UPC

:1

•Acute

TINwith

eosino

phils

•Acute

mild

tubu

lar

epith

elialinjury

with

tubu

litis

•5%

IFTA

CPI

discon

tinued

Dexam

ethasone

(0.6mg/kg)

Partial

recovery

17weeks

prog

ressed

toMM,

startedon

CYBORD

274

MW

Urothelial

bladde

rcancer

Nivolum

ab60

cycles

(24weeks)

CKD

stage4,

stable,attrib

uted

topriorchem

othe

rapy-

relatedne

phrotoxicity

Ibup

rofen,

PRN

2.5

N/A

7.48

G3

11WBC

,eo

sino

phil

0RB

C,

UPC

:0.8

•Acute

TINwith

neutroph

ilsand

eosino

phils

•Mod

erate

hype

rten

sive

neph

roscleosis

•Noim

mun

ecomplex

depo

sitio

n•48%

glob

alglom

erular

sclerosis

•50%

IFTA

CPI

discon

tinued

Pred

nisone

(1mg/kg)

Partial

recovery

followed

byAKI(sep

sis)

dialysis-

depe

nden

t

32mon

ths

Minim

alresidu

aldisease

368

MW

Metastatic

melanom

aNivolum

abanddabrafen

ibandtram

etinib

9cycles

(9mon

ths)

HTN

,CKD

stage2,

hypo

physitis;

hypo

thyroidism

and

adrenalinsufficiency

Fosino

pril,40

Hydralazine

,30

Hydrocortison

e,60

1.3

N/A

5.38

G3

48WBC

,7RB

C,

UPC

:0.36

•Acute

tubu

loep

ithelial

injury

•Acute

tubu

lointerstitial

neph

ritis

•Arterialand

arterio

lar

sclerosis

•IFTA

30%

andglob

alsclerosis23%

CPI

discon

tinued

Methylpredn

isolon

e(1.1mg/kg)

Infliximab

(2do

ses8weeks

apart)

Partial

recovery

15mon

thswith

noeviden

ceof

prog

ressionun

der

observation

477

MW

Papillary

urothe

lial

cancer

of urinary

bladde

r

Pembrolizum

abfor10

weeks

3do

ses

DM

CKD

stage3

Obstructive

urop

athy

(S/p

leftne

phrostom

y)

-1.5

Protein

(+1)

7.8

G4

>182WBC

9RB

Ceo

sino

phil

+1protein

ATINwith

eosino

phil

andfew

multin

ucleated

giantcells

ATN

Globalsclersosis50%

andIFTA

50%

CPI

discon

tinued.

Methypred

nisone

1mg/kg

BID

intiatedon

HDand

steroiddo

sewas

tape

red

Persistent

AKIdialysis

depe

nede

nt

2mon

thswith

noeviden

ceof

prog

ressionun

der

observatoin

555

MB

Transitio

nal

cellbladde

rcancer

Atezolizum

abarou

nd6mon

ths

Obstructiveurop

athy

s/pbilateral

neph

rostom

ytube

sCKD

stage4

GERD

Pantop

razole,40

3.3

UPC

1.2

5.8

G3

27WBC

8RB

Ceo

sino

phil

UPC

:2.7

Acute

andchronic

tubu

lointerstitial

neph

ritiswith

neutroph

ilsand

eosino

phils

Diffuse(>

95%)IFTA

CPI

discon

tinued.

norenal

recovery.

CKD

stage5

9mon

thshad

prog

ressionof

metastasis.

Deceased

Acute

tubu

lointersitialNep

hritiswith

Glomerulon

ephritis

641

MW

Squamou

scellcancer

ofthelung

Nivolum

ab4cycles

(14weeks)

Asthm

aIbup

rofendaily

for2weeks

0.8

N/A

4.52

G3

19WBC

,320RB

C,

UACR:

1025

mg/g

•Acute

focalseg

men

tal

necrotizingpauci-

immun

eGN(no

crescentsor

glob

alsclerosis):

ANCA-neg

ative

•Mild

interstitial

neph

ritis

with

outatroph

y

CPI

discon

tinued

Pred

nisone

(1mg/kg)

Rituximab

(1do

se)

Com

plete

recovery

14weeks

patient

deceased

oweto

prog

ression

ofcancer

775

MW

Metastatic

Trem

elim

umab

HTN

andCKD

stage3

Amoxicillin/

1.8

4.75

5WBC

,•Acute

focalseg

men

tal

CPI

discon

tinued

Partialrecovery

11mon

thswith


Table

1Characteristicsof

thepatientswho

develope

dCPI-related

renalm

anifestations

andtheirlabo

ratory

andmicroscop

icfinding

sassociated

with

theCPI-related

renal


rapies

andtheou

tcom

es(Con

tinued)

No

Age

,years

Sex

Race

Cancertype

CPI

duratio

nCom

orbidities

Potentially

neph

rotoxic

home

med

ication

(dose;mg/day)

Baseline

Crmg/dL

PriorUA

Peak

Cr

mg/dL

Severity

ofAKI

Urin

eSedimen

tCells/HPF

Proteinu

ria

Kidn

eybiop

syInitial

Managem

ent

Renal

outcom

ePFS

Cancerstatus

RCC

2do

ses(6weeks)

clavulanate,500

mgdaily

for5days

Hydralazine

,75

N/A

G3

67RB

C,

UPC

:1.43

pauci-immun

ene

crotizingGN

•Mild

acute

tubu

lointerestitial

neph

ritiswith

eosino

phils

•Acute

tubu

lar

epith

elialinjury

•Arterialand

arterio

larsclerosis

•IFTA

5%and

glob

alsclerosis38%

Methylpredn

isolon

e(2mg/kg)

Rituximab

(weeklyfor4do

ses)

Plasmaphe

resis

(dailyfor5sessions)

noeviden

ceof

prog

ression

unde

rob

servatoin

869

WW

Uveal

Melanom

aNivolum

aband

Ipilimum

ab(3cycles)9weeks

HTN

,DM,Stroke

CKD

stage3

GERD

Omep

razole,40

Valsartan,

801.4

No

protein

4.9

G3

15WBC

7RB

CUPC

:0.4

Granu

lomatou

sne

crotizingvasculitis

hype

rten

sive

neph

rosclerosis

Patchy

mod

erateto

severe

interstitial

inflammation

50%

glob

alglom

eulosclerosis

and30%

IFTA

Neg

ativeANCA

CPI

discon

tinued.

Pred

nisone

1mg/kg

daily

followed

byrituxim

abx1

after

oneweek

Com

plete

recovery

8mon

thswith

noeviden

ceof

prog

ression

unde

rob

servatoin

969

MW

Melanom

aIpilimum

aband

Nivolum

ab2cycles

(6weeks)

GERD,H

TN,

CKD

stage3

Olm

esartan,

40Furosemide,20

Omep

razole,20

1.4

N/A

2.40

G2

7WBC

,11

RBC,

UPC

:7.7

•IgAne

phropathy

with

focalseg

men

tal

endo

capillary

hype

rcellularity

andsclerosis

•Acute

mild

TIN

with

eosino

phils

•40%

glob

alglom

erular

sclerosis,20%

IFTA

•Mild

arterialand

arterio

larsclerosis

CPI

discon

tinued

Pred

nisone

(0.5mg/kg)

Com

plete

recovery

followed

byrelapse

19mon

thswith

noeviden

ceof

disease

onob

servation

1050

FW

Melanom

aPembrolizum

abcompleted

5do

ses(12weeks)

Asthm

a,GERD,H

TNNaproxen,

250PR

NOmep

razole,10

HCTZ,12.5

0.8

N/A

3.08

G3

6WBC

,2RB

C,

negative

dipstick

Don

e5weeks

afterAKI:

•low-grade

tubu

lointerstitialinjury

•IgAne

phropathy

(with

outpatholog

icindicatio

nof

activedisease)

•FSGS,NOS

•Very

mild

interstitial

inflammation

CPI

discon

tinued

Pred

nisone

(2mg/kg)

Mycop

heno

late

Mofetil1g

BIDInfliximab

(one

dose)

Partial

recovery

followed

byAKIattributed

to Vemurafen

ib

4weeks

prog

ression

ofmetastasis

1160

FH

RCC

Nivolum

ab6cycles

(16weeks)

GERD,and

dyslipidem

iaEsom

eprazole,40

0.8

Neg

ative

dipstick

N/A

2WBC

,3RB

C,

UPC

:9.7

•PLA2R

negativeearly

mem

branou

sGN

•FocalT-cell–rich

crescent-like

inflammation

•Acute

tubu

locentric

TINwith

T

CPI

discon

tinued

Pred

nisone

(1mg/kg)

Com

plete

recovery

20weeks

then

had

diseaseprog

ression

startedon

axitinib


Table

1Characteristicsof

thepatientswho

develope

dCPI-related

renalm

anifestations

andtheirlabo

ratory

andmicroscop

icfinding

sassociated

with

theCPI-related

renal


rapies

andtheou

tcom

es(Con

tinued)

No

Age

,years

Sex

Race

Cancertype

CPI

duratio

nCom

orbidities

Potentially

neph

rotoxic

home

med

ication

(dose;mg/day)

Baseline

Crmg/dL

PriorUA

Peak

Cr

mg/dL

Severity

ofAKI

Urin

eSedimen

tCells/HPF

Proteinu

ria

Kidn

eybiop

syInitial

Managem

ent

Renal

outcom

ePFS

Cancerstatus

cells

positivefor

CD3,CD4,CD8

1261

FW

Smolde

ring

myeloma

Pembrolizum

ab2cycles

(8weeks)

Hypothyroidism,

HTN

,dyslipidem

iaGERD

Lansop

razole,30

0.6

N/A

2.86

G3

32WBC

,1RB

C,

UPC

:0.3

•Granu

lomatou

sTIN

•C3de

positio

n(possibleearly

GN)

•Rare

sube

pitheliald

eposits

•5–10%

IFTA

•Arterialand

arterio

larsclerosis

CPI

discon

tinued

Pred

nisone

(1mg/kg)

Partial

recovery

12mon

thswith

noprog

ressionun

der

observation

1374

MW

RCC

CML

Nivolum

abwith

Axitin

ib(fo

r14

mon

ths)

andIm

atinib

(for20

mon

ths)

HTN

CKD

stage3

GERD

Omep

razole,40

1.6

N/A

2.73

G2

1WBC

,0RB

C,

UPC

:0.38

•Acute

tubu

loep

ithelial

injury

•Acute

tubu

lointerestitial

neph

ritiswith

eosino

phils

•FSGS(preservationof

foot

process)likelysecond

ary

(HTN

andpo

st-nephrectomy)

•Arterialand

arterio

lar

sclerosis(m

oderate)

•IFTA

20%

andglob

alsclerosis9%

CPI

discon

tinued

Pred

ison

e(0.8mg/kg)

Partial

recovery

12mon

thswith

eviden

ceof

prog

ression

1463

MW

Cho

ndroma

Pembrolizum

ab6cycles

(18weeks)

Coron

aryartery

disease,

hypo

thyroidism

,ne

urog

enicbladde

r

–0.5

N/A

2.25

G3

21WBC

,11

RBC,

UPC

:31

•AAtype

amyloido

sis,

•Acute

tubu

larep

ithelial

injury

•28%glob

alglom

erular

sclerosis

•5%

IFTA

CPI

discon

tinued

Methylpredn

isolon

e(1mg/kg)

Infliximab

440

mgon

edo

se

Partial

recovery

followed

byAKI(sep

sis)

26weeks

Patient

deceased

owingto

bowel

perfo

ratio

n

Cases

with

suspectedCPI

toxicity

1538

MW

Hod

gkin

Lymph

oma

Nivolum

aband

LAG-3

antib

ody

2cycles

(10weeks)

Cardiom

yopathy

s/pSC

T(9mon

thsago)

Sulfametho

xazole

andtrim

etho

prim

(800/160

mg)

3tim

espe

rweek

Valacyclovir,500

Pantop

razole,40

0.8–0.9

N/A

1.63

G1

11WBC

,1RB

C,

UPC

:0.05

Don

e4weeks

afterAKI

(firstbiop

sywas

inadeq

uate):

•Noeviden

ceof

acute

glom

erular

ortubu

larinjury

orinflammation

•IFTA

5%andglob

alsclerosis5%

CPI

was

held

then

resumed

after6weeks

alon

gwith

proton

pumpinhibitorwith

out

recurren

ceof

AKI

Com

plete

recovery

13mon

thsremains

with

complete

respon

sethen

patient

declined

furthe

rtherapy

1658

MW

Non

-small

celllung

cancer

Carbo

platin

and

Pemetrexed

for3cycles

(7weeks

adde

dto

Pembrolizum

ab(13weeks)

HTN

COPD

Amoxicillin

and

Clavulanate,

875–125mgBID

Lisino

pril20

0.5

Protein

(+1)

7.1

G3

No

pyuriaor

hematuria

UPC

0.6

ATN

NoGlomerulosclerosis

15%

IFTA

CPI

discon

tinued.

Pred

nisone

1mg/kg

Persistent

AKIdialysis

depe

nden

tde

pene

dent

9mon

thswith

norecurren

ce(with

drew

from

furthe

rtherapy)

PFSprog

ression-free

survival,M

male,

Ffemale,

Wwhite,B

black,LAG-3

lymph

ocyteactiv

ationge

ne3,

HTN

hype

rten

sion

,GERDga

stroesop

hage

alreflu

xdisease,

MM

multip

lemyeloma,RA

rheu

matoidarthritis,D

Mdiab

etes

mellitus,C

OPD

chronicob

structivepu

lmon

arydiseases,SCT

stem

celltran

splant,C

KDchronickidn

eydisease,

WBC

white

bloo

dcells,R

BCredbloo

dcells,U

Aurinalysis,U

PCurineproteinto

creatin

ineratio

,WNLwith

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occurred within 9 weeks with the use of the CTLA-4inhibitor tremelimumab or the combination of theCTLA-4 inhibitor ipilimumab and the PD-1 inhibitornivolumab. All other patients on PD-1 inhibitors hadlonger durations to development of AKI: a median of20 weeks (range, 10–56 weeks) with nivolumab aloneand 13.5 weeks (range: 8–18 weeks) with pembrolizu-mab alone.The most common urine finding was sub-nephrotic

proteinuria at time of acute kidney injury diagnosis(urine studies were done within 48 h of diagnosis in 13out of 16 cases). The median urine protein-to-creatin-ine (UPC) ratio was 0.8 g/g with a range of 0–31. 3cases had ≤0.3 g/g protein in the urine. 10 cases hadproteinuria ranging from 0.3 to 3 g/g, and 3 cases hadnephrotic-range proteinuria and hypoalbuminemia con-sistent with nephrotic syndrome and associated withrenal pathologies of AA amyloidosis, membranousglomerulonephritis, or IgA nephropathy (one case each).Prior urinalysis was not available in most of the cases(11 out of 16) to compare the acuity of reported pro-teinuria. Pyuria (> 5 white blood cells [WBC]/high--power field [HPF]) with associated biopsy finding oftubulointerstitial inflammation was present in 7 pa-tients but was absent in four patients despite histo-logical evidence of tubulointerstitial nephritis in thosepatients, there was no clear association with type ofCPI or use of steroids. Microscopic hematuria (> 3 redblood cells [RBC]/HPF) was present in eight of the pa-tients in our series, two patients had > 50 RBC/HPF witha renal pathology of pauci-immune glomerulonephritis.Among non-renal irAEs that developed during therapy

with CPI (both Anti-PD-1 and Anti -CTLA-4), the mostcommon irAE was hypothyroidism. Other irAEs weredermatitis, pnemonitis, colitis, esophagitis, adrenal insuf-ficiency, and myositis. Majority of the non renal irAEsdeveloped nephrotoxicity after or at the time of nonrenal irAE diagnosis. No correlation was observed be-tween the severity and recovery of non-renal irAE withthe renal one.Summary of observed other irAEs in patients who de-

veloped CPI related nephrotoxcity and their outcomeare included in Table 2.

Renal pathologies and their associated clinical findingsAcute tubulointerstitial nephritisTubulointerstitial inflammation was the most commonpathologic finding on biopsy, present in 14 of the 16cases as either the main microscopic finding or as a mildform of interstitial inflammation in association withother glomerular pathologies.As presented classically in the literature, our cases in-

clude 5 cases with only ATIN of which all had eosino-philic infiltration in addition to neutrophils except for

one case. 2 cases were treated with pembrolizumab, 2cases on Nivolumab, and 1 case was treated with Atezo-lizumab. 3 out of the 5 cases were also treated with ei-ther Ibuprofen or proton-pump inhibitors prior to CPIuse which are also associated with ATIN [20].

Acute tubulointersitial Nephritis & Glomerulonephritis

Pauci-immune glomerulonephritis (Fig. 1) Acute focalsegmental necrotizing pauci -immune glomeruloneph-ritis was noted in 3 cases, with nivolumab in 1 case, tre-melimumab in 1 case, and nivolumab combined withipilimumab, in 1 case. The patient on nivolumab hadnon-specific symptoms of fatigue and generalized weak-ness. Antineutrophil cytoplasmic antibody (ANCA)titer was negative.The patient who developed pauci-immune glomer-

ulonephritis related to tremelimumab had arthralgia,vasculitic rash, and pneumonitis. Serologic findingswere remarkable for positive antinuclear antibodies(1:160), positive myeloperoxidase-antineutrophil cyto-plasmic antibodies (MPO-ANCA; level > 8), negativeanti-glomerular basement membrane (anti-GBM) anti-bodies, and normal complement.The 3rd case we observed with microscopic finding

of pauci-immune granulomatous necrotizing vasculitisoccurred in a patient treated nivolumab combined withipilimumab. The patient had AKI with nonspecificsymptoms of poor appetite and fatigue. ANCA andanti-GBM titers were negative. Fungal stains and stainsfor acid-fast bacilli and BK polyomavirus were negativewhich are also associated with granulomatous tubu-lointerstitial inflammation. In all 3 vasculitis casesurine studies indicated microscopic hematuria, pyuriaand sub nephrotic proteinuria were seen.

IgA nephropathy (Fig. 2) IgA nephropathy developedin a patient receiving the combination therapy of ipili-mumab and nivolumab and in a patient receiving pem-brolizumab. Both patients had hypertension with noprior history of IgA nephropathy. No previous urinestudies were available for evaluation of prior reportedmicroscopic hematuria or proteinuria. The patient whowas receiving ipilimumab combined with nivolumab hadpreexisting stable CKD stage 3 (eGFR 55–60 mL/min/1.73m2) and had an increase in creatinine level from abaseline of 1.3 mg/dL to 2.4 mg/dL, with pyuria andhematuria (7 and 11 cells/HPF respectively) and neph-rotic range proteinuria (UPC ratio: 7.7 g/g) after com-pleting the 2nd cycle. Kidney biopsy showed IgAnephropathy with focal, segmental endocapillary hyper-cellularity and sclerosis and mild ATIN with eosinophils.The 2nd case developed AKI after receiving the 5th

cycle of pembrolizumab. Urinalysis was positive for


pyuria with no hematuria or proteinuria. Biopsy showedIgA nephropathy with focal, segmentally sclerotic glom-eruli, without evidence of active disease along with mildATIN. Of note, on the second case, the biopsy was per-formed 5 weeks after discontinuation of the CPIs andwhile the patient was on prednisone, which may accountfor the lack of significant inflammation in the biopsy.

Membranous nephropathy (Fig. 3) One patient whohad had negative urinalysis results before starting nivo-lumab developed nephrotic-range proteinuria after 6 cy-cles (16 weeks of therapy) with a UPC ratio of 9.7 g/gand no hematuria, pyuria, or significant change in eGFR.The pathology showed features of early membranousglomerulonephritis negative for anti-phospholipase -A2-receptor (PLA2R) autoantibodies with focal T cell–richcrescent-like inflammation and acute glomerulocentric-nephritis with T cells positive for CD3, CD4, and CD8.The presence of concurrent ATIN, and the patient’scomplete recovery (UPC ratio improved to < 0.5 g/g)after CPI discontinuation and steroid therapy suggestedthat the membranous nephropathy was related to CPIrather than to progression of the underlying malignancy.

The rest of the secondary serologic analysis, including thehepatitis panel, was negative.

C3 glomerulopathy One patient with smoldering mul-tiple myeloma was treated with pembrolizumab for 2cycles and then developed AKI with microscopichematuria and pyuria. The patient had granulomatoustubulointerstitial nephritis. Glomeruli were normal inappearance without inflammation. However, there wasgranular C3-only deposition on immunofluorescencewith corresponding rare, large sub-epithelial depositsby electron microscopy and normal serum C3 levels.Lack of immunoglobulin and light chain depositionwas confirmed by immunofluorescence staining ofproteinase-treated paraffin sections. The patient hadno evidence of infection and had stable free kappalight chains. These findings suggested early features ofC3 glomerulopathy.

Focal segmental glomerulosclerosis (FSGS) FSGS wasobserved in the kidney biopsy of one case treated withnivolumab as monotherapy. The patient had hyperten-sion and proteinuria, but it was less than 0.5 g per day

Table 2 Observed irAEs in patients who developed CPI related nephrotoxcity and their outcome

Patient # CPI AKI severity Assosciated irAE Relation to AKI diagnosis Renal and non renal irAE outcome

11 Nivolumab Nephroticsyndrome

Hypothyrodisim (G2) 4 weeks prior to AKI Persistent hypothyrodisimComplete remission of nephroticsyndrome

14 Pembrolizumab G3 Colitis (G3) 2 weeks prior to AKI Diarrhea and renal functionimproved partially then patientdeveloped 2nd AKI

2 Nivolumab G3 Elevated dsDNA and RNP titers At the time of AKI diagnosis Titers became undetectableafter 4 weekPartial renal recovery

6 Nivolumab G3 Hypothyrodisim (G2) 10 weeks prior to AKI Persistent hypothyrodisimComplete renal recovery

3 Nivolumab G3 Myositis 6 weeks after AKI Myosisits had resolvedPartial renal recovery

7 Tremelimumab G3 Dermatitis (G1)Pneumonitis (G2)

At the time of AKI diagnosis Dermatitis and pneumonitishad resolved within 2 weekPartial renal recovery

15 Nivolumab G1 Hypothyrodisim (G2)Esophagitis (G2)

5 weeks prior to AKI Esophagitis and AKI hadfully recoveredPersistent hypothyrodisim

10 Pembrolizumab G3 Dermatitis (G1)Pneumonitis (G2)

At the time of AKI diagnosis Dermatitis and pneumonitishad resolved within 1 weekPartial renal recovery

8 Nivolumab andIpilimumab

G3 Dermatitis (G1)Thyroditis (G3)Adrenal insuffiency (G1)

5 weeks prior to AKI Persistent hypothyrodisimand adrenal insuffiencyComplete renal recovery

Common Terminology Criteria for Adverse Events (CTCAE)Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicatedGrade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental ADLGrade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting selfcare ADLGrade 4 Life-threatening consequences; urgent intervention indicatedCPI immue Checkpoint inhibitor, AKI acute kidney injury, irAE immue related adverse events


Fig. 2 Two cases showed IgA nephropathy, one of which was characterized by segmental mesangial and endocapillary hypercellularity seen onH&E (a) and PAS stains (b), indicated by arrows. There were IgA-dominant immune complex deposits (c, IgA immunofluorescence) with numerousmesangial electron dense deposits ultra-structurally, indicated by arrows (d, electron microscopy).

Fig. 1 Two cases showed pauci-immune glomerulonephritis characterized by focal, segmental glomerulonecrosis (a, H&E) without immune complexdeposition (b, IgG immunofluorescence) and with fibrin deposition within the lesions (c, fibrinogen immunofluorescence)


(UPC ratio < 0.5 g/g) with no hematuria or significantpyuria noted on the urinalysis. Electron microscopyshowed preservation of foot processes which is suggest-ive of secondary focal segmental glomerulosclerosis.Again, acute tubulointerstitial nephritis was noted witheosinophilia.

AA amyloidosis (Fig. 4) After 18 weeks (6 cycles) ofpembrolizumab, a patient with chondroma developedAKI with nephrotic-range proteinuria (UPC ratio: 31 g/g) and severe colitis. The kidney biopsy was positive foramyloid on Congo red and thioflavin T. Immunofluor-escence was negative for light chains, and mass spec-troscopy confirmed AA amyloid. Patient was started onsteroids 48 h prior to the biopsy and could explain thelack of ATIN in the pathology although there was evi-dence of microscopic hematuria and pyuria on theurinalysis.Comparison of the characteristics and renal outcomes

of patients with renal pathologies related to CPI use be-tween the current study and the previously publishedcase reports are summarized in Table 3.

TreatmentCPIs were discontinued in 15 cases and held for 6 weeksin one case of the studied cases at the time of AKI diag-nosis. Most of the patients received steroids at the time

of AKI diagnosis except two patients. One who had mildnephritis, in whom CPI was held, and another who hadsevere kidney disease and poor residual renal function(seen in interstitial fibrosis with tubular atrophy (IFTA) >90% on biopsy). Additional immunosuppressant agentswere used as indicated by the associated glomeruloneph-ritis in the pathology. The dose, form, or duration ofsteroid treatment did not follow any guideline. The ini-tial used dose of prednisone ranged from 0.5–4 mg/kg/day. The prednisone was tapered off over 4–24 weeksdepending on the renal pathology and recurrence ofrenal disease.

Renal function and survival outcomesThree of the 5 ATIN cases all had partial renal recoveryafter prednisone and one of which had also infiliximab(2 doses). The 2 cases with no renal response, one hadpoor residual renal function from severe chronic kidneydisease with associated IFTA > 90%, CPI was held, andno steroids were given, and the other case had associatedacute tubular necrosis and remained hemodialysisdependent as of 12 weeks post AKI diagnosis despiteprednisone therapy.In our glomerulonephritis cases, membranous ne-

phropathy, granulomatous with C3 glomerular depos-ition, and focal segmental glomerulosclerosis, and oneof the 2 cases of CPI-related IgA nephropathy had

Fig. 3 A single case of membranous glomerulonephritis which showed a focal area of crescent-like inflammation and glomerulocentrictubulointerstitial nephritis (a, H&E, arrow indicates crescent like inflammation) which was T-cell rich (b, CD3 immunohistochemistry, arrowindicated CD3 positive cells). There was diffuse capillary immune complex deposition (c, IgG immunofluorescence) with numerous subepithelialelectron-dense deposits, indicated by arrows (d, electron microscopy)


complete or partial recovery after starting prednisone (0.5mg/kg-3mg/kg). The two ANCA negative pauci-immuneglomerulonephritis patients had complete recovery of renalfunction after discontinuing CPI and starting prednisoneand rituximab for treatment of pauci immune GN. The3rd patient with ANCA positive pauci immune GN under-went treatment with steroids, plasmapheresis, and rituxi-mab as indicated for creatinine > 4.0mg/dl and possiblelung involvement. The patient with AA amyloid had partialrenal recovery after steroid treatment and due to contin-ued colitis received infliximab and later progressed to AKIdue to sepsis. The second IgA case had partial renal re-sponse after steroids, mycophenolate mofetil and then onedose of infliximab due to failure of initial response.Three of the 16 cases died because of disease progres-

sion. All 13 surviving patients continued treatment, with5 being on active therapy and 8 staying on surveillance.We included the disease progression free survival

(PFS) of the 16 patients in Table 1. However, we are notable to conclude a disease response or PFS benefit inthese patients since we do not have in this current popu-lation patients who were treated with CPIs and didn’tdevelop nephrotoxicity to make such comparison.

DiscussionWe report 16 cases, 5 with typical ATIN with no associ-ated glomerulonephritis which is the most commonly

reported etiology for AKI related to CPIs [21] . However,we have also presented ATIN associated with glomerulop-athies in nine out of the 16 cases. Some of these glomeru-lopathies have not been reported in the literature to beassociated with CPI use (MPO-ANCA positive pauci-im-mune glomerulonephritis, C3 staining, or AA amyloid).The treatments of these glomerulopathies were varied andnot limited to steroids but included other immunosup-pressive medications in steroids refractory cases and as astandard of care to treat the glomerulopathies.Immunotherapy-related acute interstitial nephritis

[22, 23] could be due to the loss of tolerance of drug-specific effector T cells with the inhibition of PD-1 sig-naling. These are T cells that were primed during aprior nephritogenic drug exposure. Another proposedmechanism is the development of autoimmunity to kid-ney self-antigens after the loss of self-tolerance and po-tentiation of antigen recognition after blocking of theCTLA-4 or PD-1 pathway, which plays an importantrole in regulating peripherally and at the level of targetorgans, respectively [24].The types of nephropathies induced by the CPI class

vary tremendously, even when induced by a single agentsuch as nivolumab. For a given glomerulopathy relatedto CPIs, the severity and the response to steroids canalso differ, partly due to patient differences. Overall, thevariety of CPI-induced renal manifestations suggests

Fig. 4 In the case of amyloidosis, the glomeruli showed diffuse mesangial expansion by amorphous eosinophilic matrix, indicated by arrows (a,H&E) that showed green birefringence under polarized light by Congo red stain (b) and diffuse 3+ fluorescence (Thioflavin T stain) of deposits inglomeruli and arterioles (c). Abundant fibrils measuring 8–10 nm were identified by electron microscopy, area of dense fibril deposition within thebox, less dense fibril deposition indicated by arrows (d)


Table 3 Comparison of the characteristics and renal outcomes of patients with CPI related nephropathy between the current studyand the previously published case reportsCase Renal Manifestation Urine studies/

SerologyMalignancy Immunotherapy Therapy Response

Nephrotic syndrome cases in relation to immune checkpoint agents

Daanen et al. [13] FSGS – RCC Nivolumab D/C + steroids+MMF

Remissionfollowed byrelapse

Kitchluet al. [14]

MCD – Hodgkinlymphoma

Pembrolizumab D/C + steroids Remission(partial)

Kitchluet al. [14]

MCD – Melanoma Ipilimumab D/C + steroids Remission

Lin et al. [9] Membranous Nephropathy(PLA2R neg.)

– Melanoma Nivolumab D/C + steroids Remission(partial)

Current study (#11) Membranous Nephropathy(PLA2R neg.)

– RCC Nivolumab D/C + steroids Remission

IgA nephropathy cases in relation to immune checkpoint agents

Jung et al. [16] AKI grade 4Cellular crescents with necrosisSub-epithelial desposition.

Proteinuria andhematuria

Clear cellKidney cancer

Nivolumab D/C, steroidsand RRT

Recovery(RRT was d/cafter 5 months)

Kishi et al. [15] AKI grade 2Mesangial exp. with no crescentsor endocapillary hypercellularity

Sub nephroticproteinuria.Hematuria

Lung SCC Nivolumab D/C Remission(Complete)

Current study (#9) AKI grade 2endocapillary hypercellularity

Nephrotic rangeproteinuriaPyuria andhematuria

Melanoma Nivolumab+Ipilimumab

D/C and steroids Remissionfollowedby relapse

Current study (#10) AKI grade 3No Glomerularproliferative lesions*

No proteinuriaNo hematuria+pyuria

Melanoma Pembrolizumab D/C and steroids,MMF, and infliximab

Partial recovery

Pauci-immune GN cases in relation to immune checkpoint agents

Van den Brom et al. [12] GPA **Dysmorphic erythrocytes and proteinuriaExtra renal: Cutaneous vasculitisStable lung nodule

+PR3-ANCAC; normal

MalignantMelanoma

Ipilimumabfollowed byPembrolizumab

Cyclosporineand steroids

Remission

Cusnir et al. [10] GPAFocal proliferative GNExtra renal; Cutaneous vasculitissinusitis

+PR3-ANCAC; N/A

MalignantMelanoma

Nivolumab+Ipilimumab

steroids andrituximab

Not Stated

Current study (#6) Focal necrotizing pauci-immuneglomerulonephritis with no crescentsExtra renal; N/A

Negative ANCAC; N/AG3

NSCLC (SCC) Nivolumab D/C, steroidsand rituximab

Completerecovery

Current study (#7) Focal segmental pauci-immunenecrotizing glomerulonephritisExtra renal; N/A

+MPO-ANCAC; normalG3

mRCC Tremelimumab D/C, steroids,plasmaphresisand rituximab

Partialrecovery

Current study (#8) Granulomatous necrotizing vasculitisExtra renal; N/A

Negative ANCAC3/4 normal

UvealMelanoma

Nivolumab+Ipilimumab

D/C, steroidsand rituximab

Completerecovery

Anti-dsDNA cases in relation to immune checkpoint agents

Fadel et al. [11] AKI with proteinuriaExtramembranous and mesangialdeposits (IgG, IgM, C3, C1q)

+dsDNAC; normal

MetastaticMelanoma

Ipilimumab D/C Partial renalrecoverydsNDA;not detectable

Current study (#2) AKI with proteinuriaATIN with no I.C. deposition GN

+dsDNA and RNP Bladdercancer

Nivolumab D/C and steroids Partial renalrecoverydsNDAand RNP;not detectable

FSGS focal segemental glomerulosclerosis, MCD mininmal change disease, D/C immune checkpoint agent was discontinued, Neg Negative, PLA2R anti-phospholipase-A2 receptor, AKI acute kidney injury, I.C immune complex, GN glomerulonephritis, C, complement, Exp. expansion, AKI acute kidney injury, ATINacute tubulointerstitial nephritis, RRT renal replacement therapy, GPA granulomatosis with polyangiitis, PR3 proteinase 3, ANCA antineutrophil cytoplasmicantibodies, MPO myeloperoxidase, N/A not available, NSCLC non-small cell lung cancer, mRCC metastatic renal cell carcinoma, dsDNA double stranded DNA*Renal biospy was done 5 weeks post treatment with steroid, MMF and infliximab**Presumptive diagnosis. Renal Biopsy was not reported


multiple complex mechanisms that should be furtherelucidated.Autoantibody development was believed to explain the

variability in immune- related adverse effects [25, 26]. Weobserved one case with acute interstitial nephritis that wasrefractory to high-dose corticosteroids. The patient did re-spond partially to infliximab. This was also demonstratedin one of the IgA cases where patient was refractory tohigh dose steroids and Cellcept and finally responded afterinfliximab, suggesting that adding anti–tumor necrosisfactor alpha could have mediated some of the renal in-flammation. The treatment success may be due to inflixi-mab’s immediate action to block TNF-alpha, which isusually upregulated in patients on CPIs [23]. The renalbenefit could be direct or indirect, via a decrease in cyto-kine release that would otherwise contribute to acutetubular necrosis. However, a delayed effect of mycopheno-late mofetil use, which can take several weeks, cannot beexcluded in one of our cases [27]. Adding infliximab as asecond-line therapy for cases with irAEs that are resistantto steroids has been suggested previously [27, 28], but hasnot specifically reported in previous cases of nephritis-type irAEs.Based on the variety of renal pathologies noted in our

16 patients who developed AKI while on CPIs, we rec-ommend a kidney biopsy in patients with grade 2 orabove renal injury and/or patients with unexplained pro-teinuria of greater than one gram/day. At baseline, theurinalysis, spot protein to creatinine ratio, antinuclearantibody levels, and anti-double-stranded DNA levelscould be obtained before initiation of the CPI therapy.

LimitationsPatients with other irAEs may have also undergone treat-ment with steroids or other forms of immunosuppressionthat further ameliorate the renal dysfunction prior to therenal biopsy. In addition, because of the retrospective na-ture of the study we do lack baseline urinalysis prior to useof CPI and therefore cannot completely exclude the pres-ence of underlying renal pathologies prior to CPI use. Inaddition, although majority of our cases with renal patholo-gies were treated with anti-PD-1 agents we cannot con-clude that ATIN was more prevalent in this class ofmedications since out of the 6412 patients identified morethan half (3608) were treated with anti-PD1 agents. Neededare prospective studies with urinalysis, proteinuria evalu-ation at baseline, during CPI and pre-toxicity, at time oftoxicity and at the time of toxicity resolution to more ac-curately identify and characterize renal irAEs and responseto immune suppression, in addition to obtaining early renalconsult and renal biopsy when indicated.

AcknowledgementsNot applicable.

FundingThe University of Texas MD Anderson Cancer Center is supported inpart by the National Institutes of Health through Cancer Center SupportGrant P30CA016672.

Availability of data and materialsAll data generated or analyzed during this study are included in this publishedarticle.

Authors’ contributionsData acquisition was performed by AA, OM. US, SM. WG, AT and LGperformed the histological examination of the kidney biopsies andcontributed in writing the pathology section of the manuscript. Themanuscript preparation was performed by AA, AD, and OM and editedby US and SC. All the authors contributed to the quality control data,analysis, interpretation of data and writing and final proof of paper. Allauthors read and approved the final manuscript.

Ethics approval and consent to participateThis retrospective study was approved by the institutional review board inaccordance with the principles of the Declaration of Helsinki.

Consent for publicationInstitution consent form (MD Anderson).

Competing interestsDr. Yee is Consultant for Immatics US, Berkeley Lights, Adaptive Biotechnologies,and Torque Biologics and he is a member of Parker Institute of Immunotherapyfor support.Dr. Tannir is on an advisory board and receiving honoraria from Pfizer.,Nektar Therapeutics, and Oncorena. He is as well on an advisory boardof ARMO BioSciences and receiving honoraria from Bristol-Myers Squibb,Novartis, Exelisis, and Eiasi Med Research.Dr. Diab has research funding from NEKTAR therapeutics, Idera Therapeutics,Pfizer, and Bristol Myers Squibb.Dr. Suarez-Almazor is the recipient of a K24 career award from NIAMS (NIAMSK24 AR053593) and she has received consultant fees from Bristol Myers Squibb.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in publishedmaps and institutional affiliations.

Author details1Department of Nephrology, McGovern Medical School, The University ofTexas Health Science Center at Houston, Houston, TX, USA. 2Division ofNephrology, Department of Medicine, David Geffen School of Medicine,University of California, Los Angeles, Los Angeles, CA, USA. 3Institute forAcademic Medicine and Weill Cornell Medical College, Houston MethodistCancer Center, Houston, TX, USA. 4Department of Pathology, McGovernMedical School, The University of Texas Health Science Center at Houston,Houston, TX, USA. 5Department of Pathology, Houston Methodist Hospital,Houston, TX, USA. 6Division of Internal Medicine, Section of Nephrology, TheUniversity of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit1468, Houston, TX 77030, USA. 7Rheumatology and RehabilitationDepartment, Assiut University Hospitals, Faculty of Medicine, Assiut, Egypt.8Department of General Internal Medicine, Section of Rheumatology andClinical Immunology, The University of Texas MD Anderson Cancer Center,Houston, TX, USA. 9Department of Genitourinary Medical Oncology, TheUniversity of Texas MD Anderson Cancer Center, Houston, TX, USA.10Department of Melanoma, The University of Texas MD Anderson CancerCenter, Houston, TX, USA.

Received: 20 September 2018 Accepted: 6 December 2018

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