Disclosures Immunosuppressive Gra nt/ Re se a rc h Suppo rt fro m - - PDF document

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Complications of Immunosuppressive Medications

UCSF T ra nspla nt Sympo sium Se pte mb e r 20, 2018 Alliso n We b b e r, M.D.

Disclosures

• Gra nt/ Re se a rc h Suppo rt fro m Shire

Pha rma c e utic a ls

Lecture

• 1. Why T

ra nspla nt?

• 2. Co mplic a tio ns/ Side e ffe c ts o f the me dic a tio ns

unre la te d to I mmuno suppre ssio n- CNI s

• 3. Co mplic a tio ns a s a re sult o f I

mmuno suppre ssio n

Data from US Renal data System

NEJM 1999;341:1725‐30

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• T

he a nnua l de a th ra te fo r a ll pa tie nts o n dia lysis wa s 2.6 time s a s hig h a s tha t fo r pa tie nts o n the wa iting list

• Annua l de a th ra te fo r pa tie nts o n the wa iting list

wa s 1.7 time s a s hig h a s tha t fo r tra nspla nt re c ipie nts

Why Transplant?

2017 Annual Data Report Volume 2, Chapter 5 6

vol 2 Figure 5.1 Adjusted all‐cause mortality by treatment modality (a) overall, dialysis, and transplant, and (b) hemodialysis and peritoneal dialysis, for period‐prevalent patients, 2001‐2015

(a) Overall, dialysis, and transplant

Data Source: Reference Tables H.2_adj, H4_adj, H.8_adj, H.9_adj, and H.10_adj; and special analyses, USRDS ESRD Database. Adjusted for age, sex, race, ethnicity, primary diagnosis and vintage. Reference population: period prevalent ESRD patients, 2011. Abbreviations: HD, hemodialysis; PD, peritoneal dialysis.

Case #1

• Our pa tie nt is a 36 ye a r o ld ma le with E

SRD se c o nda ry to unkno wn e tio lo g y who unde rwe nt a DDRT a t UCSF . His c o urse wa s c o mplic a te d b y de la ye d g ra ft func tio n re q uiring dia lysis. Unfo rtuna te ly 3 mo nths po st tra nspla nt he re ma ine d dia lysis de pe nde nt. K idne y a llo g ra ft b io psie s re ve a le d a c ute tub ula r c e ll injury, mo de ra te a rte rio sc le ro sis, no re je c tio n, iso me tric va c uo liza tio n

• f pro xima l tub ule s c o nsiste nt with CNI

to xic ity. De spite lo we ring ta c ro limus do se s, he re ma ine d dia lysis-de pe nde nt

Case continued…

• He wa s no te d to b e E

BV I g G po sitive a nd 3 mo nths po st tra nspla nt wa s c o nve rte d o ff ta c ro limus o nto b e la ta c e pt .

• His re na l func tio n b e g a n to impro ve a nd he c a me
• ff o f he mo dia lysis.
• His c re a tinine o n la st c he c k wa s 1.18 mg / dL

.

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• T

a c ro limus a nd Cyc lo spo rine - b a c kb o ne o f so lid

• rg a n tra nspla nta tio n immuno suppre ssio n
• Va so c o nstric tio n o f the Affe re nt Arte rio le
• De c re a se d filtra tio n a s a c o nse q ue nc e o f lo we r intra -g lo me rula r pre ssure
• Dire c t E

ffe c t o n T ub ule s

• T

hro mb o tic Mic ro a ng io pa thy

• Arte rio la r Hya lino sis/ va sc ula r dise a se -stripe d fib ro sis

Calcineurin Inhibitor Renal Toxicities

Afferent Arteriolar Vasoconstriction Isometric Vacuolization‐Direct Tubular Toxicity

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Downstream effects of Arteriolar Hyalinization/arteriosclerosis

Thrombotic Microangiopathy‐ Fibrin

Thrombi and Schistocytes

CNIs and neurotoxicity

• T

re mo r: 35-55% o f pa tie nts

• He a da c he , visua l a b no rma litie s a nd se izure s (PRE

S)

• Pa in syndro me : symme tric a l pa in in the lo we r limb s,

b o ne s o f the fe e t, a nkle s, kne e .

• Pe riphe ra l ne uro pa thy
• Ca lc ine urin I

nhib ito rs c a use the me ta b o lic syndro me :

• Hype rte nsio n
• Hype rlipide mia
• NODAT
• dire c tly to xic to isle t c e lls
• CK

D

CNIs and metabolic Syndrome

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Patients receiving a first-time, kidney-

• nly transplant,

2002–2006 combined.

Courte urtesy o

• f USRDS A

RDS Annual nnual Rep Report rt 2011 2011

2017 Annual Data Report Volume 2, Chapter 5 18

vol 2 Figure 5.4 Unadjusted percentages of deaths in 2014 by cause, with and without missing data, by modality among dialysis patients and transplant recipients

(b) Transplant patients, denominator excludes missing/unknown causes of death

Data Source: Special analysis using Reference table H.12_Dialysis and H.12_Tx. Mortality among 2014 prevalent patients. (a) Dialysis patients, denominator excludes missing/unknown causes of death. (b) Transplant recipients, denominator excludes missing/unknown causes of death. (c) Dialysis patients, denominator includes missing/unknown causes of death. (d) Transplant recipients, denominator includes missing/unknown causes of death. Abbreviations: ASHD, atherosclerotic heart disease; AMI, acute myocardial infarction; CHF, congestive heart failure; CVA, cerebrovascular accident.

Complications of medications as a result of immunosuppression

Ze r

• - 1 month

Timing of Post‐transplant Infections

• Wo und infe c tio ns
• L

ine se psis

• UT

I s

• Pne umo nia
• He rpe svirus
• Ora l c a ndidia sis

Brennan DC, Bohl D. In: Clinical Nephrology, Dialysis and Transplantation.

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T wo - 6 months

Timing of Posttransplant Infections

BK V (po lyo ma virus) CMV P c arinii A fumigatus Candida spe c ie s No c ardia spe c ie s T go ndii L mo no c yto ge ne s He pa titis B a nd C Histo pla smo sis Co c c idio ido myc o sis

Brennan DC, Bohl D. In: Clinical Nephrology, Dialysis and Transplantation.

Be yond 6 months

Timing of Posttransplant Infections

Co mmunity infe c tio ns CMV re tinitis Crypto c o c c us Po lyo ma virus

• M. T

ub e rc ulo sis Atypic a l myc o b a c te rium

Brennan DC, Bohl D. In: Clinical Nephrology, Dialysis and Transplantation.

Case #2

• 68 ye a r o ld g e ntle ma n with a histo ry o f HI

V a nd E SRD se c o nda ry to I GA o n HAART the ra py with unde te c ta b le VL a nd CD4 c o unt > 400 pre - tra nspla nt who pre se nte d to c linic 3 ye a rs a fte r L URT with a c o mpla int o f a b ruise o n his le g . His immuno suppre ssio n re g ime n c o nsiste d o f ta c ro limus, MMF a nd pre dniso ne , his c re a tinine wa s sta b le a t 1.6 mg / dLa nd his 6 mo nth a nd 1 ye a r ma na g e me nt b io psie s re ve a le d o nly b o rde rline c ha ng e (no re je c tio n). E xa mina tio n re ve a le d the fo llo wing :

Skin lesion

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• T

he le sio n wa s b io psie d

• Wha t is the dia g no sis?
• Co ho rt study using linke d da ta o n so lid o rg a n

tra nspla nt re c ipie nts fro m the US Sc ie ntific Re g istry

• f T

ra nspla nt Re c ipie nts (1987-2008) a nd 13 sta te a nd re g io na l c a nc e r re g istrie s

• 175,732 so lid o rg a n tra nspla nts (58.4% kidne y, 21.6%

live r, 10% he a rt 4% lung )

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Role of the Immune System in Cancer Surveillance

• I

mmuno c o mpe te nt sta te the immune syste m wo rks to pre ve nt the g ro wth a nd pro life ra tio n o f c a nc e r c e lls a nd wo rks in 3 pha se s:

• A) E

limina tio n/ immuno surve illa nc e : a c tiva tio n o f the inna te a nd a da ptive immune c e lls a nd mo le c ule s to pro te c t no rma l c e lls fro m b e c o ming tumo r c e lls whe n e xpo se d to pro -o nc o g e nic stimuli (CD4 a nd CD8 T c e lls). I f this pha se fa ils:

• B) E

q uilib rium pha se : ma intaine d in a n immune -me dia te d la te nt pe rio d

• C) e sc a pe pha se : tumo r c e lls pro g re ss to c linic a l dise a se a nd/ o r

me ta sta sis

Cancer and Transplantation

• I

n a n immuno suppre sse d sta te , the me c ha nisms o f immuno - surve illa nc e a re a lte re d, inc re a sing the risk o f ma lig na nc y

Kaposis Sarcoma

• Re duc tio n o f immuno suppre ssio n ha s b e e n

a sso c ia te d with disa ppe a ra nc e o f K S in 17% a nd 16% o f pa tie nts with muc o c uta ne o us dise a se a nd visc e ra l invo lve me nt re spe c tive ly

• T

he e limina tio n o f CNI is vita l to the tre a tme nt o f K S po st tra nspla nt

• T

he sub stitutio n o f siro limus fo r c yc lo spo rine in a to ta l

• f 17 re na l tra nspla nt pa tie nts ha s b e e n a sso c ia te d

with c o mple te re g re ssio n: T

ransplantatio n. 2004;77(5):760.

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Our patient

• Re c e ive d lo c a l ra dia tio n the ra py
• CNI

wa s sto ppe d a nd re pla c e d b y siro limus

• Cr is no w 1.1 mg / dL

, re so lutio n o f K S

Summary

• Co mplic a tio ns o f I

mmuno suppre ssio n inc lude tho se fro m uninte nde d side e ffe c ts (ie , me ta b o lic syndro me , ne phro to xic ity, ne uro to xic ity) a nd tho se a s a c o nse q ue nc e o f the inte nde d e ffe c t o f immuno suppre ssio n (infe c tio ns, ma lig na nc ie s)

• T

he “a rt” o f tra nspla nta tio n is b a la nc ing side e ffe c ts a nd finding tha t immune syste m “swe e t spo t”

• I

mmune mo nito ring a llo ws fo r individua lizing immuno suppre ssio n mo re pre c ise ly a nd is a n a re a

• f inve stig a tio n a nd re se a rc h within the fie ld o f

tra nspla nta tio n

Thank You!