9/17/2018 Complications of Disclosures Immunosuppressive • Gra nt/ Re se a rc h Suppo rt fro m Shire Medications Pha rma c e utic a ls UCSF T ra nspla nt Sympo sium Se pte mb e r 20, 2018 Alliso n We b b e r, M.D. 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 Data from US unre la te d to I mmuno suppre ssio n- CNI s Renal data System 3. Co mplic a tio ns a s a re sult o f I mmuno suppre ssio n NEJM 1999;341:1725 ‐ 30 1
9/17/2018 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 Why Transplant? (a) Overall, dialysis, and transplant • 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 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. 2017 Annual Data Report 6 Volume 2, Chapter 5 Case #1 Case continued… • • Our pa tie nt is a 36 ye a r o ld ma le with E SRD He wa s no te d to b e E BV I g G po sitive a nd 3 mo nths se c o nda ry to unkno wn e tio lo g y who unde rwe nt a po st tra nspla nt wa s c o nve rte d o ff ta c ro limus o nto DDRT a t UCSF . His c o urse wa s c o mplic a te d b y b e la ta c e pt . de la ye d g ra ft func tio n re q uiring dia lysis. • His re na l func tio n b e g a n to impro ve a nd he c a me Unfo rtuna te ly 3 mo nths po st tra nspla nt he re ma ine d o ff o f he mo dia lysis. dia lysis de pe nde nt. K idne y a llo g ra ft b io psie s • His c re a tinine o n la st c he c k wa s 1.18 mg / dL . 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 o 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 2
9/17/2018 Calcineurin Inhibitor Renal Toxicities • T a c ro limus a nd Cyc lo spo rine - b a c kb o ne o f so lid o 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 o • 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 Afferent Arteriolar Isometric Vacuolization ‐ Direct Vasoconstriction Tubular Toxicity 3
9/17/2018 Thrombotic Microangiopathy ‐ Fibrin Thrombi and Schistocytes Downstream effects of Arteriolar Hyalinization/arteriosclerosis CNIs and metabolic CNIs and neurotoxicity Syndrome • • T re mo r: 35-55% o f pa tie nts Ca lc ine urin I nhib ito rs c a use the me ta b o lic • syndro me : 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, Hype rte nsio n b o ne s o f the fe e t, a nkle s, kne e . o Hype rlipide mia o • Pe riphe ra l ne uro pa thy NODAT -dire c tly to xic to isle t c e lls o CK D o 4
9/17/2018 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 Patients receiving a Data Source: Special analysis using Reference table H.12_Dialysis and H.12_Tx. Mortality among 2014 prevalent patients. (a) Dialysis first-time, kidney- patients, denominator excludes missing/unknown causes of death. (b) Transplant recipients, denominator excludes missing/unknown only transplant, causes of death. (c) Dialysis patients, denominator includes missing/unknown causes of death. (d) Transplant recipients, denominator 2002–2006 includes missing/unknown causes of death. Abbreviations: ASHD, atherosclerotic heart disease; AMI, acute myocardial infarction; combined. CHF, congestive heart failure; CVA, cerebrovascular accident. Courte urtesy o of USRDS A RDS Annual nnual Rep Report rt 2011 2011 2017 Annual Data Report 18 Volume 2, Chapter 5 Timing of Post ‐ transplant Complications of medications as a Infections result of immunosuppression Ze r o - 1 month • 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 . 5
9/17/2018 Timing of Posttransplant Infections Timing of Posttransplant Infections T wo - 6 months Be yond 6 months BK V (po lyo ma virus) Co mmunity infe c tio ns CMV P c arinii CMV re tinitis A fumigatus Crypto c o c c us Candida spe c ie s Po lyo ma virus No c ardia spe c ie s T go ndii M. T ub e rc ulo sis L mo no c yto ge ne s Atypic a l myc o b a c te rium 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 . Brennan DC, Bohl D. In: Clinical Nephrology, Dialysis and Transplantation . Case #2 Skin lesion • 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 : 6
9/17/2018 • • T he le sio n wa s b io psie d 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 Wha t is the dia g no sis? o 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 ) 7
9/17/2018 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 o 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 o 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 o me ta sta sis Cancer and Transplantation Kaposis Sarcoma • o I n a n immuno suppre sse d sta te , the me c ha nisms o f immuno - Re duc tio n o f immuno suppre ssio n ha s b e e n surve illa nc e a re a lte re d, inc re a sing the risk o f ma lig na nc y 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 o 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 . 8
9/17/2018 Our patient Summary • • Re c e ive d lo c a l ra dia tio n the ra py 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 CNI wa s sto ppe d a nd re pla c e d b y siro limus syndro me , ne phro to xic ity, ne uro to xic ity) a nd tho se • Cr is no w 1.1 mg / dL , re so lutio n o f K S 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 o 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! 9
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