B Y T TRNG I HC DC H NI KHO ST KHA LUN TT NGHIP DC S H NI - 2014
B Y TTRNG I HC DC H NI KHO ST KHA LUN TT NGHIP DC S Ngi hng dn:
1.TS. V nh Ha 2. Ni thc hin: 1.Bnh vi2.B mn Dc lm sng H NI-2014 LI
CM N Li u tin, ti xin chn thnh by t lng knh trng v bit n su sc ti
hai ngi thy: PGS.TS. nguyn trng khoanh vin b mn Dc Lm Sng trng i hc
Dc H Ni trc tip hng dn, ch bo, to iu kin v tn tnh gip ti hon thnh
kho lun tt nghip.Ti xinchnthnhcmnccthycgiocabmnDc LmSngtrngihcDcHNi
nhngngithysnsngchias nhngkhkhn,vngmccatitrongsutqutrnhhctp.Ti xin
trn trng gi li cm n n ton th, , cn b, cngnhnvin-T ,phngKhoch tng
gip,toiukinthunlinhtchoti trongsutqutrnhnghincu. . Cui ckhng th hon
thnh nu thiu s ng vin, gip ca gia nh, bn b. . Li cm n c bitv
nghanht,tsinh r 23 nm qua.Ti xin chn thnh cm n! H Ni, ngy 13 thng
05 nm 2014 Sinh vin 1 N2 1.1. Ghp thn v iu tr CMD trong ghp thn2
1.2. Phc cm ng induction therapy3 1.2.1 La chn phc cm ng: ATG v
basiliximab3 1.2.2 Liu lng v ng dng4 1.2.3 Tc dng khng mong mun5
1.2.4 Tng tc thuc thuc, thuc thc n, nc ung5 1.3. Phc duy tr
maintenance therapy6 (calcineurin inhibitors CNI)6 1. antimetabolic
agents12 1.3.3 Corticosteroid16 1.4. iu tr thi ghp cp tnh17 acute
cellular rejection17 acute antibody-mediated rejection18 20 20
2.1.1 Tiu chun la chn20 2.1.2 Tiu chun loi tr20 20 2.2.1 Thit k
nghin cu20 2.2.2 Phng php x l s liu23 24 24 25 3.2.1 Phc cm ng25
3.2.2 Phc duy tr25 29 3.3.1 Chc nng lc ca thn ghp sau ghp thn29
3.3.2 Theo di cc thng s huyt hc lin quan n hng cu32 3.3.3 Tng huyt
p sau ghp thn34 35 3.4.1 Tiu chy35 3.4.2 Tng ng huyt khi pht sau
ghp36 3.4.3 Tng men gan sau ghp36 3.4.4 Nhim khun39 3.4.5 Huyt khi
sau ghp39 40 4.1 Bn lun c im i tng nghin cu40 4.2 Bn lun kt qu kho
st phc c ch min dch40 4.3 Bn lun kt qu kho st s hi phc chc nng thn
sau ghp43 4.4 Bn lun kt qu kho st cc bin c bt li ghi nhn sau ghp44
4.5 Hn ch ca nghin cu46 47 5.1 Kt lun47 5.2 xut48 TI LIU THAM KHO50
aAMRacuteantibody-mediated rejection ACR acute cellular rejection
ATN acute tubular necrosis AUC area under curve BN
BPARThighpcptnhcbngchngsinhthitbiopsyprovenacute rejection
CMVCytomegalovirus CNI calcineurin inhibitors CrCl Creatinin
clearance CV coefficient variability DGF delayed graft function DSA
donor specific antibody TB GPKD GTLN GTNN HCTHematocrit HDT
HGBHemoglobin HLA Human leukocyte antigen HPLC/MSHigh-performance
liquid chromatography/Mass spectrometry IL2 RA
2interleukin2receptors antagonists IV intravenous ) IVIg
MMFMycophenolate mofetil MPAAcid mycophenolic Ni(i=1,2,3) NODAT new
onset diabetes after transplantation NSAID Non-steroidal
anti-inflammatory drug O oralPE/PP plasmapheresis/plasma exchange
PLPh lc RBC red blood cell RCTTh randomised control trial RLTH SCr
serum creatinin SD standard deviation TGCT THA TNTThn nhn to
Tr.Trang CMD WBC white blood cell Xmean YNLS 1 2 3. 4 5 tacrolimus
6 7 8mus 9 10 2007 11 12 13 14 15 16 17 18 19 ) ng 20 21 22 23 24
Bng 25 26 (BN 02). Bng
27Tngtccatacrolimusvimethylprednisolone,nicardipinv
omeprazol/esomeprazol theo Micromedex. 1 2 0 3 0 4 5SCr. 6 (BN 02)
7 IV v SCr (BN 03) 8 93,2 x 103CP/ml N9 10(+) 11 12 . 13(ACR) 14 15
16 1 T VN Suythn mn tnh(CKD chronicrenal failure)haybnhthngiai
oncui (ESRD endstagerenaldisease)ccoilvnsckhectnhtoncu. iu tr suy
thn mn hin nay bao gm hai nhm phng php: iu tr bo tn v iu tr thay th
thn suy (bao gm lc mu ngoi thn v ghp thn), ty thuc vo giai on suy
thn [1]. Cho n nay, ghp thn vn l la chn iu tr di hn c u tin hn cho
phn ln bnh nhn suy thn mn tnh giai on cui, do kh nng ci thin ng k
cht lng cuc sng ca ngi bnh. Ti bnh vinBch Mai mttrongs nhng bnhvin
u ngnhca cnc,theothngkkhngchnh thccakhoa thn tit niu,tnh nnm 2014 c
24 trng hpcthc hin ghp thn hoc chm sc sau ghp thn ti vin.Tuy nhin,
hn ch c bn ca ghp thn l s ph thuc vo ngun cho thn v khnng
hahpmindchgiangichovnginhnthn.Saughpthn,
ngibnhvnphisdngccthucchngthighp,chiphghpviutr
chngthighpcao[1].Cckhuynco lin quan nvics dngthuc cch min dch (CMD)
thng phc tp, do s kt hp ca nhiu nhm thuc v s la chn phc iu tr thng
da trn cn nhc li ch nguy c [19]. Ti bnh vin
BchMai,chacnghincunocthchinnhmkhosthiuqu cng nh tc dng khng mong
mun ca phc thuc CMD ang c p dng trn cc bnh nhn sau ghp thn. Vi thc
trng , chng ti tin hnh thc hin ti khosttnhhnhs dngthuc c chmin dch
trn bnhnhn ghp thn ti khoa thn tit niu, bnh vin Bch Mai vi 3 mc tiu
c th nh sau: -Khost phc CMDcm ngv duy tr vi cctiuch: lachnthuc,thi
im dng thuc, liu dng, ng dng v theo di hiu qu iu tr (i
vichtcchcalcineurin)tronggiaionngaysaughpthntibnhvin Bch Mai-Kho st
s hi phc mt s chc nng ca thn ghp trong giai on ni trn. -Kho st t l
gp v x tr cc bin c bt li xut hin trong giai on ni trn. 2 CHNG I.
TNG QUAN 1.1. Ghp thn v iu tr CMD trong ghp thn Ghpthn
cchnhchottcccbnh nhnsuythngiaioncuido btknguynnhn no [2]. C
banguynnhngy suythngiai on cuithch hp nhtchoghpthnlvimcuthn mn,
bnhthn doitho ng, bnh thndotnghuytp.Baloinguynnhnnychim70%sbnhnhnc
ghp thn ti M [2],[16]. Trc khi ghp thn, bnh nhn c nh gi cc nguy c
min dch nhm gip phn tng v xc nh sm cc kt qu u ra ngn hn v
dihncathnghp[79].Snhginybaogmkimtravhahpnhm
muABO,phchphahpmHLA,xtnghimPRAvphnngcho (crossmatch) [79]. Vai tr
ca cc yu t ni trn trong bnh sinh ca qu trnh thi ghp c cp r hn trong
bng 1, trang 1 (tr.1), ph lc 1 (PL1).
Trongaphncctrnghp,ngaysauphuthutthnhcng,sclccu
thncathnghpcthtrvgnnhbnhthng[16].Tuynhinmts
bnhnhn,thnghpcthgpstrhonchcnng(delayedgraftfunction DGF), c nh ngha
l s cn thc hin lc mu trong vng 7 ngy u sau ghp hoccreatinin
mukhnggimxung di4mg/dL hay30% sovigitr trc
ghp.NguynnhnnguynphtcaDGFlhoitngthncp(acutetubular necrosis
ATN).DGFlmgiatngthigiannmvin,tngchiphiutr,kh kim sot phc CMD, bnh
nhn chm hi phc v gim t l sng st ca thn ghp. Ngoi ra, c th cn nhiu
tun sau ghp hi phc cc bin chng khc ca suythn mnnhthiu mu, mtcn
bngcalci phosphat vrilonlipid mu [16]. Ngoi tr cc trng hp ghp thn t
anh ch em sinh i cng trng, a phn
ccbnhnhnghpthnuphisdngccthucCMDngnngathi ghp [19].Mc tiuca phc
CMDlcn bng giali chnitrnv nguy c gp cc tc dng bt li c lin quan, c
bit l nguy c nhim trng e da tnh mng v u c tnh [16]. Tip cn c bn ca
iu tr CMD l la chn phc bao 3 gm nhiu thuc nhm hip ng tc dng, gim
liu cc tc nhn, t gim thiu mcnngca cctcdngbtlilin quannliu [16]. Nhn
chung, c th chia phc CMD tng th thnh 3 phc nh: phc cm ng, phc duy
trv phc iutrthighpcp tnh.Chititvcc phc nyc cp di y.1.2. Phc cm ng
induction therapy Phc cm ng l mt iu tr s dng tc nhnsinh hc(bng 2
tr.1, PL1), cthltcnhnlmsuyyutbolymphohoccchththinterleukin-2
(IL2-RA), c bt u trc, ti thi im ghp hoc ngay sau ghp. Mc tiu ca phc
cm ng l lm suyyu hoc iu chnh p ng ca t bo T thi im khng nguyntrnh
din victh. Ngoi ra, phc cm nglmtnghiu qu cavicdngthuccchmin
dchdolmgimthighpcp,hocchophp gim liu cc thnh phn khc ca phc nh cht
c ch calcineurin (CNI) hoc corticosteroid [19]. Nhiu RCTv phntch
meta chra rng phc cm ng sdngkhng th sinh hc em li li ch vt tri
trong vic lm gim t l thi ghp v suy thn sau
ghpsovivickhngsdngphccmng[3],[30],[66],[67],[74],[77] (bng 4 tr.3,
PL1). Cc khng th ny, do thng c khuyn co mnh m bi
ccHDT,vimcbngchngcao tronggiaionkhiuiutrCMD [19],[74].1.2.1 La chn
phc cm ng: ATG v basiliximab Hin nay,vic lachntc nhn nocho phc cmng
ctc dngti uvnchar rng [74][41].Tuynhin,alemtuzumabvrituximab
cthkhng c li khi c s dng lm phc cm ng trn bnh nhn ghp thn [74].
Chnh vvy,khuyncotrongccHDTthngdatrnATGhocbasiliximab
[19],[74].Miynht,RCTdoPilch NA vcsthchin(2014)trn200bnh nhn nhm so
snh mc an ton v hiu qu ca phc cm ng IL2-RA (n
=98)vrATG(n=102)trnnnphcCMDhini(tacrolimus+ mycophenolat +
corticosteroids) cho thy khng c s khc bit gia 2 tc nhn v 4
tlthighpcptnh haychcnngthnthhinquathanh thicreatinin thi im 1 nm
sau ghp [53]. Mt phn tch meta thc hin nm 2010 trn 6 RCT (853 bnh
nhn) cng cho thy gia hai tc nhn khng c s khc bit v t l thi
ghpcpcbngchngsinhthit,DGF,ghpthtbivtvong.Tuynhin, basiliximab c t l
nhim trng thp hn v do , c th s an ton hn nu c la chn cho bnh nhn
ghp thn [38].Theo KDIGO2009, lachn phc cm ng ph hpchocc itng bnh
nhn khc nhau, cn cn c vo nguy c gp thi ghp cp tnh ca i tng bnh nhn
(bng 3 tr.2, PL1). HDT ny gi ch s dng cc tc nhn gy suy yu t bo
lympho nhm bnh nhn nguy c cao, bi li ch t s gim xut hin
thighpcptnhcnbngvistngnguycnhimtrngnng[19].Trong nhng trng hp khc,
IL-2 RA nn c la chn lm phc cm ng u tay,
dolmgimtlthighpcptnhvghpthtbi,ngthikhnglmtng nguy c gp cc bin c bt
li [19].UpToDatekhngngthunviquanimtrn[74].TheoHDTny,c nhng bng chng
cho thy rATG-thymoglobulin vt tri hn IL-2 RA v placebo c cc bnh nhn
c nguy c min dch thp v cao, do cc tc gi thng s dng
rATG-thymoglobulin mt tc nhn gy suy yu lympho bo, hn l IL-2 RA
asbnhnhnghpthn,ngoitrcctrnghpkhngdungnprATG-thymoglobulin (THA, gim
bch cu thp hn 2000/mcL v/hoc tiu cu thp hn 75000/mcL) haybnh nhnghp
thn c thc hinghpcctngkhc(gan,phi, tim) v ang s dng cc tc nhn CMD
[74].1.2.2 Liu lng v ng dng
Vichnhdphngthighpthncptnh,rATGngtnhmchnn dng vi liu t 1 n 1,5
mg/kg/ngy trong vng t 3 n 9 ngy sau ghp, tng ng vi tng liu tch ly t
3 n 13,5 mg/kg [61]. Tng liu tch ly rATG cha c lm r, v c th c s khc
bit gia cc n v iu tr [74]. Tuy nhin tng liu tch ly di 3 mg/kg c th
km hiu qu hn, v liu cao trn 6 mg/kg c th khng cn thit bnh nhn ghp
thn [74]. Mt s phc s dng liu thp hn 5 nhng bnh nhn c nguy c min dch
thp v liu cao hn nhng bnhnhn
nhnthnghptngichotvonghoccyutnguyckhccathighp [74]. Vi basiliximab,
mc liu chun i vi ngi trngthnh l 40mg tim tnh mch,chialm2liu20mg.Liu
utinvokhong2gitrckhitinhnh phuthut.Liu20mgthhaivo ngyth4sau
ghp[52],[74].Nndngliu th hai nu c biu hin qu mn nng hoc gp cc bin
chng sau ghp nh ghp tht bi [52].1.2.3 Tc dng khng mong mun
Phnlncctc dngkhngmongmuncarATGldoskhngchiu trn t bo lympho T gy ra,
bao gm c ch ty xng (thng gp v ph thuc
liu)gygimbchcu,thiumuvgimtiucu[19].Cntheodislng bchcu v tiucu
trongvsaukhi iutrvirATG[61]. Bnhnhnbthiu mu bt sn, gim bch cu trung
tnh mc nng cn phi c theo di rt cn thn, c bin php d phng - iu tr st
v nhim trng thch hp, km theo h tr
truyntiucuy[61].Cctcdngbtlikhcbaogmsockphnv,tt
huytp,tnghuytp,nhptim nhanh,khth,nimay,phtban[19],[61]. Phn ng st
do tim truyn thng gp nht vo nhng liu u tin, v c th x
trbngcchchobnhnhndng paracetamol, diphenhydramin v corticosteroid
trckhitruynkhngth[19],[61].CnggingnhcctcnhnCMDkhc, rATG lm tng nguy
c nhim trng (c bit l nhim virus) v u c tnh [19],[61].
Vibasiliximab,ctngitcctcdngbtlicboco.Khcvi
rATG,basiliximabkhnggyraccphnngtimtruyn[19].Tuynhingiai
onhumarketting,cmtslnglnbocovphnngqumnvi basiliximab, bao gm pht
ban, ni m ay, nga, ht hi, th kh kh, co tht ph qun, kh th
[19],[52].1.2.4 Tng tc thuc thuc, thuc thc n, nc ung Khngghinhntng
nogiarATG/basiliximabvithcn,ncungv cc loi thuc ung khc [52],[61]. 6
1.3. Phc duy tr maintenance therapy iutrcchmindchduytrcthc
hingnnhttccctrng hpghpthnnhmngnchnthighpcptnhvghpthtbi[19],[22]. V
nguycthighpcptnhvghpthtbicaonhttrongbathngutinsau ghp,cn m botcdng
c ch min dch mccao nhttronggiai on ny [22].Tuynhin,
nguycthighpcptnhgim dntheothigian, do cth gim dn liu cc tc nhn c ch
min dch duy tr nhm gim thiu cc tc dng bt li [16],[22].Mc d vn cha
xc nh c phc duy tr ti u trong ghp thn, hu ht cctrungtmcyghp hin
nayang s dng mt phc duytr vi3 tcnhn
gm:chtcchcalcineurin(cyclosporin/tacrolimus),chtkhngchuynha
(azathioprin/mycophenolat mofetil/natri mycophenolat) v prednison
[22]. 1.3.1. Cht c ch calcineurin (calcineurin inhibitors CNI)
1.3.1.1 Hiu qu iu tr ca cc CNI S ra i ca cc CNI ci thin ng k kt qu
ca ghp tng, v t l bnh nhnsngstvthnghpsngst [16].Vvy,cho
nnay,CNIvnlthnh phn trung tm ca hu ht cc phc CMD duy tr, mc d cc
phc khng bao gmtacrolimus hay cyclosporin vn ccoilltng trong min
dch hc sau ghp, v y l cch trc tip nht lm gim cc bin chng lin quan n
bnh thn gy ra bi CNI [16]. So vi cyclosporin, tacrolimus c hiu qu
hn trong vic gims tthighpcptnhvmcnngcatthighp[33],[78],[81] (bng 5
tr.4, PL1). Tacrolimushinnaycsdngvihaidng:dngtruynthng(Prograf) dng
2 ln/ngy v dng gii phng ko di (Advagraf) dng 1 ln/ngy. Kramer v cs
tin hnh mt RCT ko di 1 nm nhm kim chng hiu qu v an ton ca 2 dng
tacrolimus khi cs dng cng mycophenolat mofetil v steroidtrn bnh nhn
ghp thn khng c phc cm ng vi cc khng th [34]. Kt qu cho thy gia hai
nhm khng c s khc bit no v chc nng thn ghp (th hin qua t l
DGF,gitrSCrvCrClvGFRctnh)cngnhtlthighpcptnhc 7 bngchngsinh
thit.Nhvy,tacrolimusdnggii phngkodichiuqu iu tr tng ng vi dng truyn
thng [34]. Kt lun ny cng c cng nhn bi mt s RCT khc [63],[70].
1.3.1.2 Tc dng khng mong munc tnh thn (calcineurin inhibitor
nephrotoxicity) ctnhthnlADRthnggpttcccbnhnhnghptngsdng phc CMD c
CNI [8],[75], thng c chia lm 2 dng [8],[47],[75]:+ c tnh cp tnh: gp
giai on sm, c th o ngc c v ph thuc liu (tuy nhin vn c trng hp bnh
nhn c nng mu trong khong ch gp c tnh). + c tnh mn tnh: ph bin hn,
thng khng hi phc v do c coi l gt chn Achilles ca cc phc CMD hin hnh
[47]. Cc biu hin lm sng ca c tnh thn bao gm tng creatinin mu, tng
nit ure mu, tng kali mu, protein niu mc trung bnh, gim o thi natri
[??]. C ch ca c tnh thn ccho l doa tn thng tiu ng mch thn, ng thn v
cu thn [47] (bng 6 tr.5, PL1). Rt kh chn on phn bit c tnh thn bnh
nhnghpthnvicc dngtnthng khc cathnghp, cbitlthi
ghpcptnh[8],[75].cimcamusinhthitccoilchunvngtrong chn on [8],[75],
tuy nhin cng khng phi lun hiu qu trong mi trng hp [75], v c tnh thn
khng c tn thng m hc no c trng [8],[27]. Vic kt hp gia c im tn thng
v s loi tr cc nguyn nhn khc c th gip cho chn on xc nh c chnh xc hn
[47]. Mcdcyclosporin vtacrolimus khngcmiquan h nov mtcu trc,
cnhngnghincuchngminhrngchaithucucctnhthnvi
nhngtnthngmhctngtnhau[8],[47].Mttrongnhngnguynnhn c xut,lcch
CMDcaccCNI cngchnhlcch gyrac tnh thn [47].c tnh ngoi thn (non-renal
toxicity of calcineurin inhibitors) 8 Miynht,mttngquanhthngvphntch
meta (trn 11 RCT v 2
nghincuthuntp)doCellineCA.vcsthchinchrarng,sovi cyclosporin, iu tr
vi tacrolimus lm gim c ngha nguy c ri lon lipid mu, nhng li lm tng
c ngha nguy c i tho ng khi pht sau ghp thn (new onset diabetes
after transplantation NODAT) [5]. Kt qu ny ng thun vi cc tng quan h
thng khc [23],[33],[78]. Ngoi ra, iu tr vi tacrolimus c th lm tng
nguy c gp mt s ADR nh run, nhc u, tiu chy, kh tiu, nn ma [78]. Khng
c s khc bit no gia 2 iutrvnguycCMV,nhimtrngnichung,uctnh,tbchhuyt
(lymphoceles) [5],[78].So snhgia hai dngbochcatacrolimus,
mtsRCTchrarng hai dngnycantontngngnhau[34],[63],[70] (bng7 tr.6,
PL1). Tuy nhin, so vi dng truyn thng, tacrolimus dng GPKD c u im hn
l dng 1 ln/ngy,docthcithinvntunthiutrkhi bnhnhnphidng thuc lu di
[20]. 1.3.1.3 Tng tc thuc thuc v thuc thc n, nc ung Tng tc hp thu:
D liu in vitro gi rng cc cht lm tng pH ca ng
tiuha,nhccantacidchamagnesi,calciumhocnhm;natribicarbonat, v
magnesioxidcthgyrasph hycutrc thucquatrunggian pH,hocs hp ph vt l
tacrolimus dn n gim hp thu [16],[72]. V vy, chng nn c dngcch xa
tacrolimust nht 2gi ngnnga tngtc [16]. Mtstcgi
chorng,ttnhttrnhdngccdnchtnynucth[72].Tacrolimusv
cyclosporincngcghinhnlctngtcvi thcn.Tc ,mchp
thucatacrolimusgimkhicmtthcn[16],[72].Banchmlngcht bo cao c th gy
chm tho rng d dy, gim nng mu v nh hng n cc thng s dc ng hc khc ca 2
thuc [16],[72].TngtcchuynhaxyrakhthngxuynviccCNI, do chng l cc ccht
caCYP3A4vglycoprotein P.Cc cht c chCYP3A4(nh diltiazem,
erythromycin,ccazolchngnm,omeprazol)cthtngnngthucc 9 ngha,trongkhi
mtschtcm ngCYP3A4,nhphenytoin,rifampin hoccc dn cht trong nc bi
chm, c th lm gim nng thuc c ngha. Mt s
trungtmlidngnhngtngtcnybngcchthngknccchtc ch CYP3A4 gim liu v gi
thnh iu tr, trong khi vn duy tr c nng ch [16].CNI cng l cc cht c ch
CYP3A4 [16].S c ch ca chng ln CYP3A4 c th gp vi cc cht nn yu hn, nh
cht c ch HMG-CoA reductase. Do , s dng ng thi CNI v statin c th lm
tng nng cacc statin, tng nguy cgp bin c btli,c bit l
trncvn[16].Ngoira,sgimchuynha rosuvastatinkhis dng
ngthivicyclosporin (tngtcchngch nh)cn lm tng nguy c gp c tnh trn
thn khi s dng cp phi hp ny [83].
Ngoicctngtcdcnghc,ccCNIcncthcmtstngtc
dclchc.Chnghn,nguyctngctnhtrnthnkhiphihpCNIvi NSAID [72],[83], nguy
ctngkalimukhiphihpvithuclitiugikali [83]. Tuy nhin, cc tng tc dc lc
hc thng kh kim chng [72] v nu s s dng cc thuc ny l bt buc, cn theo
di cht ch tnh trng lm sng v cn lm sng [72],[83]. 1.3.1.4 Liu dng v
ng dng. LiukhiucaccCNIctnhtondatrntrnglngcth
[6],[7],[16],[49],[50].Vicyclosporin,liukhiungungdaongtrong khong
10 n 15 mg/kg/ngy chia 2 ln cch nhau 12 gi. Khi sdng vi thuc CMD
khc (phc b 3, 4), cyclosporin c th s dng liu thp hn (chng hn khi u
vi 3-6 mg/kg chia lm 2 ln). Thi im bt u dng thuc c khuyn co bi nh
sn xut l trong vng 12 gi trc khi phu thut v duy trliu khi u ny 1 n
2 tun sau m [49],[50].KhongliungungcaTacrolimus(Prograf, Advagraf-
Astellas)lt 0,2 n 0,3mg/kg/ngychia2lncchnhau 12gi ivi dng
truynthngv dng 1 ln duy nht vo bui sng i vi dng GPKD [6],[7]. Thi
im khi u dng thuc l trong vng 24h sau khi hon tt phu thut.10 Trong
trng hp khng dng c ng ung (kh nng hp thu km do gp
nhngtrilontiuha[50]),cthdngccchphmngtim.Chng
hn,dungdchtimSandimmun(Norvatis)truynlintnhmchchm2n5
mg/kg/ngytrongvng2n6gi;dungdchtimPrograf5mg/ml(Astellas) truyn lin
tc 24 gi vi khong liu 0,05 0,10 mg/kg/ngy. Sau liu u, cc liu tip
theo s c hiu chnh da trn nng thuc trong mu. Vn ny c bn lun r hn phn
sau. 1.3.1.5 Theo di hiu qu iu tr CNI
Mtslnglnccnghincu,kcccnghincucanhsnxutnh
Astellas,khuynnghmtcchmnhmstheodinngmuca
tacrolimustiuhahiuquvngnchnphnngchi[75].Vi cyclosporin,mcdkhngc RCT
nososnhvictheodivkhngtheodi hiu qu iu tr, nhng thc t, cc khong nng
ch khc nhau s nh hng khc nhaunhiuquvctnhcathuc,dovictheodiiutrc
khuyn ngh mnh m [19]. Hiu qu iu tr ca 2 CNI c gim st thng qua nh
lng nng thuc trong mu. Theo KDIGO 2009, vic nh lng ny nn c tin hnh:
- Hng ngytronggiai onngaysaughpthn,chotikhi t ckhong nng ch. - Bt c
khi no c s thay i thuc hoc tnh trng lm sng ca bnh nhn c th gy ra nh
hng n nng mu. - Btckhinocssuygimchcnngthnlinquannctnhthn hoc thi
ghp. Theo di hiu qu iu tr vi tacrolimus.
Mcdcnnhiutranhcinhngchonnay,nngytrongmuton phn (ly mu trc khi ung
liu tip theo) vn l thng s c s dng rng ri nht theo di hiu qu
iutrcatacrolimus [75](bng 8tr.7, PL1).Cnhiu phng phpnhlngkhc nhau,
ph bin nhtl ccphng php min dch. Ngoi racncth
nhlngbngscklnghiunngcaokthpkhiph 11 (HPLC/MS) [16],[75]. Cn lu rng
khong nng ch khng ging nhau gia cc phng php khc nhau [75]. Cc phng
php min dch s nh lng c cc
chtchuynhacatacrolimus[16].Trongkhi,HPLC/MSschnhlng
tacrolimus.Do,nngchsthphnccphngphpchiunh HPLC/MS khong 20 25% so vi
cc phng khng c hiu [16].
Theohinghngthunccchuyngiachuunm2007,khitacrolimus c s dng phi hp vi
mycophenolat, corticosteroid v cm ng bi khng th IL-2
RA,nnduytrnngytacrolimustrongkhongt3n7 ng/ml(o bng cc phng php min
dch) [75] (bng 10). Cng c kin cho rng nng y ch trong mu ton phn ca
tacrolimus nn c duy tr mc 8 10 ng/ml trong 3 thng u tin, sau gim cn
3 n 7 ng/ml [22]. Khi s dng cng vi khng th gy suy yu t bo lympho,
nng y ch duy tr mc 7 10 ng/ml trong thng u tinv gim cn 3 7 ng/ml
nhng thng sau [22]. Cc yu t cthnh hng n nng y hayliutacrolimus cn t
duytrnng y ch c trnh by c th bng 9 tr.8, PL1. Bng 10. Nng y
tacrolimus (phng php min dch) trn bnh nhn ghp thn theo hi ngh ng
thun chu u nm 2007 [75] Thi gian (thng) (1)(2)(3)MMF + gim steroid
Cht c ch mTORPhc b ba 0 310 153 75 10/10 1510 153 7 3 125 153 75
10/10 158 123 7 >125 103 75 10/8 125 103 7 (1): khng s dng phc
cm ng; (2): cm ng vi IL-2 RA; (3): cm ng vi khng th a dng/rATG.Theo
di hiu qu iu tr vi cyclosporin Sovinngy,nngcyclosporin2gisau
ungthuc(C2,nng nh[16])tngquanchtchhnvisphinhimthucvhintngthi ghp
[16],[22], khi mt s nghin cu ch ra C2 cao hn lm gim t l thi ghp cp
tnh trong nm u sau ghp [22]. Khong C2 khuyn co trong cc HDT v tng
quan c trch dn trong bng 11 tr.10, PL1. 12 1.3.2 Cc tc nhn khng
chuyn ha antimetabolic agents
Cctcnhnkhngchuynhabaogmazathioprinvmycophenolat
mofetil/mycophenolatnatri.Tcnhnkhngchuynhacsdngtrngn 90% cc trng hp
ghp thn M [22]. Trong , mycophenolat c a chung hn nhng cng c gi
thnh cao hn so vi azathioprin [19],[22]. 1.3.2.1 So snh hiu qu iu
tr gia mycophenolat v azathioprine
CcRCTsosnhhiuquiutrcamycophenolat v azathioprin cnhiu im khng ng
thun [19]. Vi phc c cyclosporin, mt s lng ln cc th
nghimatrungtmchrarngtlthighpcptnhthphnvi mycophenolat [22]. Tuy
nhin,ccthnghimnykhngphhpvithctin lmsng hinti, dos dng dng bochcca
cyclosporin [22].Gn y,cc
thnghimlmsngviphccyclosporindngvinhtngchrarng mycophenolat khng vt
tri hn so vi azathioprine c v li ch ngn hn v di hn [55],[56]. so
snh hiu quca hai tc nhn khng chuyn ha trong phc CMD phi
hpvitacrolimus,MillerJ.Vcs tin hnh mtth nghim ngu nhin,
nhnm,atrungtmM,vi3nhmsongsong:tacrolimus(TAC)+
mycophenolatmofetile(MMF)1g/ngy;TAC+ MMF2g/ngyvTAC+azathiopirine
(AZA) [44].Kt quchothytlBPARthi im 6thngv 12 thng sau ghp thp hn c
ngha nhm MMF 2g/ngy (7%) so vi AZA (29%, p 0%ng thun phn ln 6C mt
DSAng thun phn ln 7Bt tng ng nhm mung thun phn ln 8Thn ghp khi pht
chc nng chm (DGF)ng thun phn ln 9Thi gian thiu mu lnh > 24hNghin
cu n l 3 BNG 4. PHN TCH META SO SNH LI CH CA PHC CM NG V PLACEBO Tc
giTc nhnKt qu u ra Webster ACv cs [77] IL-2 RAThi ghp cp tnh gim c
ngha thi im 6 thng (RR = 0.66) v 1 nm (RR =0.67) nhm IL2-RA. T l
ghp tht bi thi im 1 nm, 3 nm khng c skhc bitgia 2 nhm. thi im 1 nm,
t l nhim cytomegalovirus (CMV) v u c tnhkhng c s khc bit.Keown Pv
cs [30] Basiliximab- thi im 6 thng, basiliximab lm gim nguy c tng i
v tuyt i ca 2 tiu ch: thi ghp cp tnh trn lm sng (ARR = 15.6%; NNT =
6) v thi ghp cp tnh c bng chng sinh thit BPAR (ARR =11.7%, NNT = 9)
tt c cc phc iu tr.- C mt s gim ng thi nguy c ghp tht bi, nhng khng
c ngha thng k (p = 0.14).Adu Dvcs [3] IL-2RA- IL-2 RA gim c ngha
nguy c thi ghp cp tnh thi im 6 thng (OR = 0.51).- Khng c s khc bit
no v t l ghp tht bi, t vong, nhim khun, nhim CMV hoc nguy c u c tnh
thi im 1 nm so vi placebo.Szczech LAvcs [67] Khng th khng lympho
Vic s dng phc cm ng vi khng th khng lympho c li (gim t l ghp tht bi
38%) thi i m2 nm, c bit l cc bnh nhn c gii mn cm trc ghp. Mc d li
ch quan st thy ca phc ny gim dn theo thi gian, nhm bnh nhn c gii mn
cm trc ghp vn tip tc c li thi im 5 nm. Szczech LAvcs [66] Khng th
khng lympho Cc gi tr OR tng hp (t m hnh c nh nh hng v m hnh nh hng
ngu nhin) v 1 gi tr RR t phn tch hi qui thi im 2 nm c s dng nh gi
tc ng ca phc cm ng ln kh nng sng ca thn ghp. 2 gi tr OR tng hp u l
0.66 (P = 0.03) v RR 0.69 (P = 0.03), ch ra mt tc ng c li ca phc cm
ng ln kh nng sng ca thn ghp.T l sng st ca thn ghp l 85.6% nhm c dng
phc cm ng v 79.6% nhm khng c phc cm ng. 4 BNG 5. SO SNH HIU QU IU
TR V TC DNG BT LI CA CYCLOSPORINE V TACROLIMUS Tn tc giKt qu cng b
WebsterAvcs [78]. thi im 6 thng, t l ghp tht bi gim c ngha nhm bnh
nhn iu tr bng tacrolimus, v kt qu ny khng c xu hng thay i sau 3 nm.
thi im 1 nm, bnh nhn c iu tr vi Tacrolimus c t l i tho ng cn iu tr
bng insulin, run, nhc u, tiu chy, kh tiu, nn ma cao hn so vi nhm iu
tr bng cyclosporin. Ngc li, bnh nhn iu tr bng cyclosporin c t l to
bn v cosmetic side effects cao hn c ngha. Khng c s khc bit v t l
nhim trng v u c tnh. KnollGAvcs [33]. thi im 1 nm, khng c s khc bit
c ngha no gia 2 nhm v t l ghp tht bi v t vong nhng tacrolimus lm
gim c ngha s t thi ghp cp tnh cng nh s s dng khng th khng lympho iu
tr thi ghp. Tuy nhin tacrolimus lm tng t l NODAT sau ghp cao hn c
ngha so vi cyclosporin R.Woodroffev cs [81] So snh tacrolimus v
cyclosporine(Sandimmune): thi im 12 thng, khng c s khc bit v t l t
vong do mi nguyn nhn hay ghp tht bi, nhng tacrolimus lmgim c ngha t
l BPAR so vi sandimmune. V bin c bt li, tacrolimus lm tng c ngha
nguy c run, tng SCr mu v NODAT so vi sandimunne. Ngc li, Sandimmune
lm tng nguy c rm lng, tng lipid mu v tng sn li. Khng c s khc bit
gia 2 nhm v t l CMV. thi im 5 nm, khng c s khc bit gia 2 nhm v t l
t vong do mi nguyn nhn v ghp tht bi. Tacrolimus vn lm tng nguy c
NODAT v Sandimunne vn lm tng nguy c tng lipid mu sau 5 nm. So snh
tacrolimus v cyclosporine(neoral): thi im 12 thng, khng c s khc bit
v t l t vong do mi nguyn nhn v ghp tht bi gia 2 iu tr. Tuy nhin
tacrolimus lm gim c ngha t l BPAR v lm tng c nghi a nguy c run.
Neoral lm tng t l tng lipid mu, rm lng v tng sn li. Khng c s khc
bit gia 2 nhm v t l CMV hay NODAT.Cng khng c s khc bit trong khong
thi gian di (2 3 nm) v ti l t vong do mi nguyn nhn v ghp tht bi gia
2 nhm. 5 CellineCA vcs [5]So vi cyclosporin, nhm iu tr vi
Tacrolimus c t l T cao hn c ngha thi im 1 nm v 3 nm va nguy c ri
lon lipid mu thp hn c ngha thi im 1 nm. Khng c s khc bitno thi im
1nm v nguyc CMV, tng huyt p, nhim trng nichung, u c tnh,t bch huyt
(lymphoceles) hoc phi dng iu tr do ADR.Hensel.O v cs [23]Nhm dng
tacrolimus c t l NODAT cao hn c ngha so vi nhm dng cyclosporin (p
< 0.00001). BNG 6. C CH GY C TNH THN CA CNI [47] Loi c tnhC ch
gy c tnh c tnhcp tnh nh hng ln h mch: tng gii phng cc yu t gy co
mch bao gm endothelin, thromboxane v hot ha h RAA, ng thi gim cc yu
t gin mch nh prostacyclin, PG E2 v NO. nh hng trn cu thn: Tng kt tp
tiu cu v hot ha yu t prothrombin dn n huyt khi mao mch, gy gim dng
mu qua thn v gim sc lc cu thn (suy thn chc nng). nh hng trn ng thn:
thoi ha hc biu m ng thn ng u; ri lon chc nng ng thn v ri lon in
gii. c tnhmn tnh nh hng trn h mch: dy thnh tiu ng mch do qu trnh
hyaline ha, dn n hp lng tiu ng mch. Qu trnh ny thng khng o ngc c.
nh hng trn cu thn: x ha cu thn ton th do hyaline ha tiu ng mch (gy
hoi t cu thn). Hn na, s ph hy ng thn dn ti cc tn thng cu thn nh x
ha cu thn khu tr (tn thng do tng p lc lc, lin quan n hyalin ha tiu
ng mch hoc x ha cu thn ton th). nh hng trn ng thn: S thiu oxi v hoi
t cc bca ngk thn, gyra do scomchthn biCNI, dnn hnh thnhccgc t do
hocccdng oxihot ng. Chng gy tn thng t bo hoc lm t bo cht theo chu
trnh. Bn thn cyclosporin cng c th trc tip sinh racc dng oxy hot ng.
Ngoi ra, CNI iu ha ln s biu hin ca TGF-beta t bo biu m ng thn gy
tng x ha k thn thng qua gim phn hy v tng sn sinh protein matrix
ngoi bo, cm ng hiu tng chuyn i biu m trung m (EMT mt qu trnh khin t
bo biu m ng thn mt kiu hnh biu m v c c tnh ca cc t bo trung m). y l
c ch chnh gy x ha k thn. 6 BNG 7. MT S RCT SO SNH NGUY C GP ADR CA
TACROLIMUS DNG TRUYN THNG V GPKD Tc gi Thit k NC c im phc iu tr Kt
qu u ra lin quan n tnh an ton TsuchiyaT v cs [70]Tin cu, theo di
102 BN trong 1 nm. Liutacrolimuskhiu0.1 mg/kg/ngy c 2 nhm. thi im 1
nm,- T l bin chng nhim trng khng khc bit 2 nhm. Khng gp trng hp
nhim trng nng no trong thi gian theo di. - T l NODAT thp v khng khc
bit gia 2 nhm. Silva HT J r v cs [63] Th nghim pha 3, nhn m. Phn 3
nhm: - Nhm 1: Tacrolimus dng gii phng ko di (XL) +MMF
-Nhm2:Tacrolimusdngtruyn thng (Tac) +MMF -Nhm3:CsAdngvinhtng (CsA)
+MMF - XL/MMF v Tac/MMF c phn ng bt li tng t nhau. Khng c s khc bit
v t l nhimvikhun,nmhayvirus,CMV,nhimtrngchikhisosnhXL/MMFvi
CsA/MMF. - T l NODAT theo nh ngha ca ADA nhm Tac/MMF cao hn c ngha
bnh nhn c nguy c so vi CsA/MMF. Tuy nhin, khng c s khc bit gia
XL/MMF vs CsA/MMF. Cskhcbitcngha(p=0.011)vtlbnhnhnc cholesterolton
phn>= 300mg/dlgia cc nhm (XL/MMF 4.8%; TAC/MMF 3.4%; CsA/MMF
10.8%) Krmer BK v cs [34] M i 24 tun, sau nhn m ti ht 12 thng theo
di. c 2 nhm, liu khi u tacrolimus 0.1 mg/kg ung trc phu thut. Liu u
tin sau ghp l 0.2 mg/kg/ngy -
Vanton,tlxuthinAEvAEnghimtrngnhnhau2nhm.Tlnhim khun thng thng cao
hn c ngha nhm BID so vi OD (p = 0.032). T l CMV cao hn nhm OD (p =
0.043). T l nhim trng c hi cao hn nhm OD (p = 0.037). Tuy nhin v s
cas mc thc s ca bin c ny tng i thp, v vy cn thn trng trong phin gii
kt qu. - Khng c s khc bit v t l gp ri lon chc nng thn, TKTW, THA, T
v T mi mc thi im 1 nm. - T l bnh nhn dng iu tr do AE nh nhau 2 nhm.
7 BNG 8. CC THNG S THEO DI HIU QU IU TR VI TACROLIMUS Thng sBng
chng v khuyn co lin quan Nng yCn nhiu tranh ci v mi quan h gia thng
s ny v cc tiu ch u ra trn lm sng [75]. Cc nghin cu ng h mi quan h
nng y hiu qu iu tr c nhc im l thng khng nghin cu nng tacrolimus cc
thi im nh nhau sau ghp thn [11]. Cc nghin cu khng ng h mi quan h ny
li phn ln l hi cu, s lng bnh nhn nh, cc thuc CMD dng kmkhc nhau
[11]. R. Boumar v cs tin hnh phn tch dliu t 3 RCT ln v xem xt mi
quan h gia vic phi nhim tacrolimus v thi ghp cp tnh c bng chng sinh
thit [11]. Kt qu cho thy khng c mi lin h no gia nng y tacrolimus o
5 thi im (ngy 3, 10, 14, thng 1 v thng 6 sau ghp thn) vt l thi ghp
cp tnh xy ra 1 thng sau thi im hay trong phn cn li ca nm u tin sau
ghp. Cc d liu tip tc c phn tch su hn, nhng cng khng cho thy mi lin
h no gia gi tr Co vnguy c thi ghp [11]. Din tch di ng cong (AUC) c
cng nhn lch s tt nht nh gi s phi nhim tacrolimus.Tuy nhin, vn cn c
cc nghin cu tin cu phn tch thm hiu qu ca vic theo di iu tr bng thng
s ny [75].Hi ngh ng thun chu u nm 2007 a ra khong gi trAUC ch ca
tacrolimus l t 150 n 200 ng.h-1mL-1 [75]. Nhc im c bn ca AUC l rt
kh p dng trn lm sng do s tnh ton cn ly nhiu mu mu cc thi im khc
nhau [75]. Nng thuc trong lympho bo V hot ng c ch min dch ca cc CIs
c thc hin qua s c ch calcineurin trong t bo lympho, nng ni bo ca
CNI trong lympho bo c th s phn nh tt hn s CMD do CNI so vi nng mu
ton phn [15].Mi y, Arnaud Capron v cs cng b mt phng php LC-MS/MS
nhm nh lng tacrolimus trong t bo mu n nhn ngoi vi [12][39]. Mc d
thi gian cn thit phn lp cc PBMC v chit tacrolimus (5-6 gi cho 10
mu) tng i lu, phng php ny c th h l nhng trin vng mi trong theo di
hiu qu iu tr Tac.Tmax v MRT Mt phn tch cho thy vo N7 sau ghp, BN
thi ghp cp t Tmax nhanh hn so vi nhng BN khng thi ghp cp (P <
0.001) v MRT cng ngn hn (p = 0.02) [35]. Tuy nhin, s khc bit v MRT
quan st c gia 2 nhm BN gp/khng gp thi ghp trong nghin cu ny l kh
nh. Vn cn phi nh gi thm ngha lm sng thc s ca 2 thng s ny khi ng dng
trong theo di hiu qu iu tr. 8 BNG 9. CC YU T NH HNG NNG Y V LIU
TACROLIMUS CN T DUY TR NNG Y CH Yu tBng chng lin quan TuiTheo P.A.
Jacobson v cs, mc d bnh nhn nhm tui cao (65 84 tui) nhn mc liu thp
hn khong 1 n 2 mg/ngy so vi 2 nhm tui trung nin (35 64 tui) v tui
tr (18 34 tui), nhm ny vn c nng y cao hn t nht l trong 70 ngy u sau
ghp thn so vi nhm tui tr [28]. Mt s phn tch khc cng ch ra tui cao l
yu t gy chm chuyn ha tacrolimus dn ti tng nng y [60],[65]. C ch gy
ra s gim chuyn ha dn n nng y tacrolimus cao ngi cao tui vn cha r
rng, c th do NCT gim kh nng chuyn ha ca cc enzyme do gim kch thc
gan, gim dng mu qua gan, gim cc knh vn chuyn thuc trn thnh t bo
gan., thay i nng protein lin kt vi thuc v thay i v nhu ng d dy rut
v pH (21 24). NCT cng c lng m tng, d tr cm mu gim, nhiu yu t nguy
c, s dng nhiu thuc (tng nguy c tng tc) [28]. Cn nng v bo ph Theo E.
Rodrigo v cs, bnh nhn vi nng y o ln u tin cao hn 15 ng/ml c ch s
BMI ln hn (P < 0.05) so vi bnh nhnc nng y tacrolimus o ln u tin
thphn 15 ng/ml, (mcdliutacrolimus hiuchnh theocnnng gia 2 nhm khng
c s khc bit). Do cc i tng tui cao v tha cn rt d tin trin ri lon ng
huyt sau ghp thn, cn thn trng trnh nng y tacrolimus cao qu mc, bng
cch gim nhng liu u tin ca tacrolimus hoc c tnh gi tr liu ny t cn
nng l tng[60]. Elisabeth Storset v cs kho st mt khong dao ng cn nng
ln v nhn thy khi lng cht bo t do l mtyu t tin on dc ng hc
tacrolimus c cho l mt pht hin mi. Cc tc gi c nhng tnh ton cho thy
mc d trng lng c th c th chnh lch ti bn ln cc bnh nhn trong nghin cu
ny, liu lng cn thit chnh lch t hn hai ln[64]. Theo tc gi, cc cng
thc tnh liu ban u hin ang p dng c th lm tng nguy c c ch qu mc h min
dch bnh nhn bo ph. Vim gan virus C. Manzanares v cs thc hin mt phn
tch hi cu trn 14 bnh nhn ghp thn c hoc khng c HCV trong vng 4 nm v
nhn thy khi cha hiu chnh liu theo nng , liu tacrolimus trung bnh nh
nhau 2 nhm nhng nng y cao hn c ngha nhm HCVm tnh. Sau khi c hiu
chnh liu, thi im 4 nm, nng yca 2nhm khng c s khc bit (P > 0.05)
nhng liu nhm HCV dng tnhthp hn c ngha so vi nhm HCV m tnh (P <
0.05). [41] 9 nh hng ca HCV ln liu tacrolimus duy tr nng y ch cng c
ghi nhn trong mt s phn tch khc[25],[36]. C ch chnh xc s tc ng ca
virus ln chuyn ha tacrolimus cn cha c bit r. A. Latorre v cs a ra
gi thit rng trng thi nhn ln ca virus cc bnh nhn mang HCV c th l mt
trong nhng nguyn nhn [36].Hematocrit Mi ynht, sau khi phn tch 44 d
liu dc ng tacrolimus thi im sau 12h 29 bnh nhn v nng y 44 bnh nhn c
o trong 70 ngy u tin sau ghp, Elisabeth Storset v vsthy rng
hematocrit l yu t nh hng n nng mu ton phn ca tacrolimus. Cc tc gi
khuyn ngh rng nng mu ton phn ca tacrolimus nn c hiu chnh theo gi tr
hematocrit theo cng thc Chct=Ctot *0.45/Hct, phn nh cht ch hn t l
thuc dng t do (c hot tnh) . V hematocrit bin thin rng bnh nhn ghp
thn v tng sau khi ghp, y s l mt yu t quan trng phin gii gi tr nng
mu ca Tacrolimus [64]. Chng tc v yu t di truyn Hin nay, yu t di
truyn ang c quan tm rng ri trong mc tiu hng ti ti u ha v c th ha iu
tr bng tacrolimus. Trong cc ahnh n nucleotide(single nucleotides
polymorphisms)ca CYP3A5, CYP3A4, ABCB1 c nghincunhiu nht. nh hng ca
kiu gene CYP 3A4 v ABCB1 ln liu tacrolimus cn t duy tr nng y ch cha
c khng nh chc chn v cn phi lm r thm. Ngc li, a phncc nghin cu u cho
thy: trng thi ng hp t CYP3A5*3/*3, bnh nhn c liu cn t thp hn (khi c
cng khong Co ch) hoc nng y ch cao hn (khi dng cng mt liu) so vi cc
bnh nhn c mang t nht mt allele CY3A5*1 (c biu hin enzyme CYP3A5)
[54]. iu ny cng c ch ra trong mt s th nghim lm sng ngu nhin c i
chng [13],[68]. EnzymeAllele hoang dAllele t binnh hng v mt l thuyt
CYP 3A4CYP 3A4*1: A v tr 392CYP 3A4*1B: G ti v tr 392 trng thi ng
hp t, allele t bin m ha protein CYP3A4 hot ng chc nng km hn. CYP
3A5CYP3A5*1: A v tr 6986CYP 3A5 *3: G v tr 6986 trng thi ng hp t,
allele t bin gy ra s mt enzyme do hnh thnh nn mt protein khng hot
ng chc nng. ABCB1 (*) V tr 3435 trn exon 26: C V tr 1236 trn exon
12: C V tr 2677 trn exon 21: G - V tr 3435 trn exon 26: T - V tr
1236 trn exon 12: T - V tr 2677 trn exon 21: T/A 3 a hnh n nu. ny
thng xut hin cng nhau, to thnh mt haplotype. Huqu l
gimbiuhinP-gpinvivo vgimhotngcabmtng thuc. (*) ABCB1 cn c gi l gene
a khng thuc 1 (multidrug resistance 1 ; MDR 1), m ha cho
glycoprotein P knh vn chuyn mng ph thuc ATP gip bo v c th khi cc
cht l bng cch y chng ra khi t bo, vo trong ng tiu ha hoc mt. [54]
10 BNG 11. THEO DI HIU QU IU TR VI CYCLOSPORINE. UpToDate [22] 0 3
thngC2 800 n 1000 ng/mlT thng th 3 tr iC2 400 n 600 ng/ml [62] Thi
gianKhng cm ngIL-2 RAThymoglobulinc ch mTOR 0 3 thngC2 >1700
ng/ml N5;C2 1600 2000 ng/ml T1;C2 1400 1600 ng/ml T2 C2 1200 1400
ng/ml T3 C2 >1500 ng/ml 2 thng u C2 1200 1400 ng/ml T2 vT3 C2
1000 1200 ng/mlCo 75 125 ng/ml T1 vT2 Co 50 100 ng/ml T3 n T6. 3 12
thngC2 800 1000 ng/ml T4 T6.C2 600 800 ng/ml T7 T12. C2 600 1000
ng/mlC2 600 1000 ng/mlCo 50 100 ng/ml > 12 thngC2 xp x 800
ng/ml.C2 xp x 800 ng/mlC2 xp x 800 ng/mlCo 50 100 ng/ml 11 BNG 12.
CC CHIN LC GIM THIU S DNG CORTICOID TRONG PHC CMD DUY TR [43] S dng
mc liu rt thp giai onsm hn sau ghp thn Nu khng gp thi ghp cp tnh,
gim liu prednisone cn 5mg/ngy thi im mt thng sau ghp. Khng c li khi
duy tr liu cao corticoid hoc thc hin gim liu corticoid trong mt thi
gian di. Mc liu thp duy tr (5mg/ngy) c lin h vi s gim nguy c thi
ghp v bnh thn ghp mn tnh khi so vi phc ngng/khng s dng corticoid
giai on sm. Dngcorticoidhon tongiai onsm (3n6thngsau ghp) S ngng s
dng sm glucocorticoid lm tng t l thi ghp cp tnh v c th gim t l thn
ghp sng st di hn (hn 2 nm).a phn cc trung tm ghp tng khng p dng vic
ngng sm hoc khng s dng corti trong giai on sm (t hn 6 thng sau
ghp).Dngcorticoidhon tongiaion mun (sau 1 nm) Cc phc ngng corti
thnh cng giai onmun s dng s gim liu chm trong vng t 2 n 4thng. Vi
cc bnh nhn n nh, phc ngng corti thnh cng s gim mi tun 1 mg/ngy ti
khi liu l 5 mg/ngy, sau chuyn sang liu 10mg cch ngy v gim 1mg/2 ngy
mi tun cho ti ht. Mt phc khc gim liu 2.5mg/ngy mi 2 tun cho ti ht.
Kt qu ca cc nghin cu nh gi sngng s dng corti giai on mun thng i lp
nhau, tuy nhin s tht bi trong vic ngng corti gp vi trn 40% bnh nhn
a s cc nghin cu.Hiu qu ca vic ngng s dng corti giai on mun, chc nng
thn ghp di hn cng nh nguy c thi ghp mn tnh vn cha c nh gi. Mt s lng
ln cc nghin cu cng gi rng mt s bnh nhn khng t hiu qu no c ngha ng k
v mt lm sng khi t bphc liu thp glucocorticoid. Hn na, vn cha c phng
php xc nh cc bnh nhn c kh nng gp bin chng c hi trn thn do dng s dng
corticoid. Phchonton khngsdng corticoid Thnggp phc CMD nn tng CNI v
cm ng vi khng th a dng. Da trn d liu thi im hi n ti, UpToDate khng
khuyn co s dng cc phc ny. 12 BNG 14. C CH TC DNG V C IM CC IU TR C
S DNG TRONG AMR [39] Phng php iu tr C ch tc dng v c im Lc huyt tng
(Plassmapheresis/ Plasma exchange) Phng php nhanh nht v hiu qu nht
loi b cc DSA lu thng trong tun hon. Khng ngn chn c s tng hp khng th
v do c th gy tng tr li DSA lu hnh sau PP. Ct lch(Splenectomy) Lch l
c quan ng vai tr quan trng trong vic tng hp khng th khng tng ghp.
Ct lchlm gim p mc min dch ca t bo B v s lng cc t bo tin thn v tng
bo. Nguy c nhim trung huyt do cc vi khun c nang, nh hng ko di ln h
min dch v cc nguy c do phu thut V vy, thng t p dng phng php ny
trong iu tr AMR. Hpphmindch (IA):Huyt tng c x l thng qua ct hp ph v
ti truyn vo bnh nhn. C hai ct: Mt ct hp ph protein A s hp ph cc Ig
v mt ct khng nguyn ABO hp ph khng th anti-A hoc anti-B c hiu, bt k
lp hoc phn lp globulin min dch no. Do chi ph cao, khng c kh nng xm
nhp qua mng v vic s dng PP tng i d dng, IA khng thng c s dng iu tr
AMR. Immunoglobulin truyn TM IVIg l sn phm thng mi t huyt tng ca t
50.000- 100.000 ngi cho khe mnh. Bao gm hn 90% IgG cn nguyn vn,mt
vi dimers, mnh Fabs v vt IgM v IgA [55]. C ch tc ng c th ca IVIG lm
AMR l khng r rng. Cc c ch c xut bao gm c ch tng hp globulin min
dch, hot nganti-idiotypic chng li DSA (kt qu l gy trung ha DSA),
phong ta cc th th Fc, c ch b sung kch hot v hot ng anticytokine
[55]. IVIG thng c s dng kt hp vi PP nh kh nng b sung gamma globulin
mt trong PP, do gim nguy c nhim trng. BortezomibBortezomib l mt cht
c ch chn lc proteasome, c tc dng c ch hot ng ging chymotrypsin
(chymotrypsin-likeactivity) ca proteasome 26S trong t bo ng vt c v.
13 Cc 26S proteasome l mt phc hp protein ln thoi bin cc protein
ubiquitin. Con ng ubiquitin-proteasome ng mt vai tr quan trng trong
vic iu ha hot ng ca mt s protein c hiu, qua duy tr cn bng ni mi
trong t bo. c ch proteasome 26S ngn chn s phn gii protein ch
ubiquitin v nh hng n nhiu thc tn hiu bn trong t bo, v cui cng dn n
s cht t bo.RituximabRituximab l mt khng th n dng khng CD 20 trn cc
t bo B. Cc khng nguyn CD20 c biu hin sm trong qu trnh pht trin t bo
B, nhng n khng c mt trn cc t bo plasma trng thnh.Rituximab lin kt
vi CD20 thng qua mt s c ch khc nhau v tm cc t bo tiu hy, t dn n mt
s gim mnh v bn vng v s lng cc t bo B lu hnh Steroid v ATGVic b sung
corticoid v ATG c th c li trong iu tr AMR, k c khi khng c bng chng
m bnh hc ca ACR kt hp, bi cc iu tr ny c th iu ha xung p ng ca t bo
B thng qua gim hot ng ca t bo T [32],[39]. y l l do v sao mt s trng
hp AMR nh vn p ng vi corticoid v ATG [32]. Mt s nghin cu cng s dng
ATG lm mt phn phc iu tr AMR, c bit khi quan st thy c im ca c hai
dng thi ghp trn mu sinh thit [39] [EO]. 14 BNG 15. HIU QU CA PHNG
PHP LC HUYT TNG TRONG IU TR AMR Mt s phn tch hi cu v bo co cas ch
ra hiu qu ca PE/PP trong iu tr AMR, th hin s hi phc chc nng thn ghp
thng qua s bnh thng ha gi tr SCr sau iu tr [21],[48]. Theo tng quan
h thng ca Darren M. Roberts v cs, c 4 RCT c cng b nh gi hiu qu ca
PE: 1 nghin cu cho thy c hiu qu, 2 RCT cho thy khng c hiu qu v 1
RCT kt lun nguy c ln hn li ch (bng 15 ph lc). Tuy nhin, cc RCT s
dng phc khc bit nhau v liu, tn sut s dng v khong thi gian iu tr,v
vy khng th a ra kt lun [57]. Chi tit v c im ca cc RCT ny c tng hp
di y Tc gic im nhm th v nhm chngnh gi hiu qu iu tr Bonomini V v cs
[10] - Nhm th: s dng 1 t 3 7 PP hng ngy hoc cch nht, trao i 80%
huyt tng vi albumin hoc dd PPF v huyt tng ti ng lnh (n=23). -
Nhmchng:chthm1tliucaomethyl prednisolone sau 3 5 ngy. (n=21) - Hiu
gi khng th khng HLA v creatinine mu sau 2 tun thp hn c ngha so vi
trc iu tr nhm th, v khng c s thay i nhm chng. - S bnh nhn ghp tht
bi nhm th thp hn c ngha so vi nhm chng (p 0.05). 15 BNG 16. BNG
CHNG V HIU QU CA IVIG KHI PHI HP VI LC HUYT TNG TRONG IU TR AMR Tc
giPhc phi hp PP v IVIgHiu qu lm sng RuedigerW. Lehrichv cs. [37] -
PP : 3 6 ngy/t vi albumin 5%. S t ty vo p ng lmsng (th tch nc tiu v
Cr mu). - IVIg thng thng liu 2g/kg sau ln PP cui cng (ngoi tr 1
BN).20/23BNcpngvichcnng thnccithin.3/23BN khng tr. T l thn ghp sng
st v bnh nhn sng st sau 2 nm cao (100% v 75%) Nicole B. White vcs.
[80] - PP: thay 1 th tch huyt thng bng dd 5% albumin trong 90 pht.-
Sau thc hin PP truyn IVIg (tng liu 2g/kg: 500mg/kg vo 3 ngy u v 250
mg/kg cho 2 ln sau). 8/9 BN iu tr thnh cng, vi Scr thi im 3 thng v
1 nm l 1.9 v 1.8 ng/mL. 1/9 BN ghp tht bi. PauloN. Rochav cs.[58] -
PP : thay th bng albumin 5%. S t ty thuc vo p ng lm sng (Scr v nc
tiu). - IVIg: sau lm PP cui cng, vi tng liu trung bnh 2g/kg (30420g
chia lm13 liu).- 14/16 BN c iu tr vi PP + IVIg.- 15/16 BN c nhn iu
tr ngay sau khi c chn on AHR. Tt c u p ng iu tr (SCr mu gim v dng
thm tch).- 1/16BNciutrbanuvisteroid,vchcsdng PP/IVIg sau ln sinh
thit th 2 (sau 1 tun). BN ny khng tr. -2/16 BN ghp tht bi sau p ng
ban u vi iu tr(thng th 2 v 17 sau ghp). 1 BN t vong do nhim trng
huyt. Montgomery RA. v cs [45] - PP: thay 1 th tch huyt tng bng
dung dch 50% albumin 5% hoc 100% dung dch albumin 5%. Tnh trng ng
mu ca bnh nhn s quyt nh s cn thit ca huyt tng ti ng lnh trong dch
thay th. PP c thc hin hng ngy. - 3/10 bnh nhn AHR c xcnh DSA c a vo
phn tch: DSA gim mnh sau iu tr - 1/10bnhnhnghpthtbisau
8thngdoxuthintACR nng. 9/10 BN cn li vn c thn ghp hot ng tt. 16 -
IVIg100mg/kg(trnglngkh)saumilnPP.Dng phc PP/IVIg khi c ci thin trn
lm sng v/hoc DSA mtnh.IbernonM.v cs [26] - PP hng ngy vi 5% albumin
(cho 1 th tch huyt tng). S t PP da trn p ng lm sng.- t PP cui cng,
4 bnh nhn c nhn IVIg 2g/kg. - 6 BN c p ng. 1 BN khng tr sau 5 t
PP/IVIg v c iu tr bng rituximab. BNG 17. BNG CHNG V HIU QU CA HP PH
KHNG TH, RITUXIMAB V BORTEZOMIB TRONG IU TR AMR. Tc giThit k nghin
cuKt qu HP PH KHNG TH G.A.Bohmig vcs [9]Nhm A: nhn cc t IA, km theo
s chuyn sang dng tacrolimus trong phc duy tr.NhmBchchuynphcduytrvc
nhn IA saukhi kt thc 3 tuntheo di. C 2 nhm u c nhn iu tr ACR (nu
gp) Th nghim phi dng sm khi mi thc hin phn tch s b trn 10 bnh nhn u
tin. Mt trong nhng l do l t l p ng iu tr sau 3 tun (c nh ngha l
khng cn thc hin lc mu chc nng thn n nh hoc creatinin mu gim t nht
30% - n inh sau 21 ngy) 5 bnh nhn nhm A vttri hon ton so vi 5 bnh
nhn nhm B (p = 0.048).Ngoi ra, cc tc gi nhn thy ngy cng c nhiu cc
th nghim khng i chng gi hiu qu ca cc phng php iu tr ngoi c th trong
AMR RITUXIMAB Kaposztas Z v cs [29] AMR khng tr vi phc steroid +
khng thkhnglympho.Phntchhicutrn2 nhm: Nhm 1 iu tr bng rituximab +
PP (n =26). Nhm 2 ch iu tr bng PP (n = 26) - T l thn ghp sngst sau
2 nm nhm 1 cao hn c ngha nhm 2 (p = 0.005). Nguycghp tht bi thi im2
nm nhm 2cao hn 5 ln so vi nhm1 (p=0.042) 17 Mulley WR v cs [46]7 BN
AMR khng tr PE + liu thp IVIg, iu tr vi rituximab Trong khong thi
gian theo di 20 thng,creatinine mu gim c ngha so vi nng nh t c
trong t thi ghp (p=0.049). Tt c cc bnh nhn n cn sng v khng gp ghp
tht bi. 6 BN c theo di nhiu hn 12 thng sau iu tr vi rituximab, t l
sng st v t l thn ghp sng st cng t 100%. C 2 BN c theo di hn 30 thng
sau iu tr, chc nng thn mc tt Stanislas Faguer vcs [17]
8BNAMRiutrvirituximabIV+ PE+methylprednisoloneIV. Chuyn phc duy tr
MMF +steroids +tacrolimus. Sau khong thi gian theo di 10 thng: t l
bnh nhn sng st 100%, i l thn ghp sng st 75%. thi im cui ca qu trnh
theo di, DSA m tnh 2 bnh nhn.cbit,cthnhnthyssuygimtboBsau3n5lntruyn
rituximab BORTEZOMIB I.Tzvetanov v cs [71]3BNcphnngchodngtnhvingi
chogiimncmtrcghp.AMRxut hin giai on sm sau ghp, khng tr vi PP +
IVIgvctlch. iutrbngbortezomib methylprednisoloneIV.Sau dng phc thay
th, c 3 bnh nhn, chc nng thn c phc hi (gim
creatininemuvtngthtchnctiu).Bortezomibdungnpttccbnh nhn. Sau thi
gian theo di, 3 bnh nhn vn c chc nng thn ghp tt. OsamaGheith
vcs[18]2BNkhngtrviphcgmPE+IVIg + Rituximab.ciutrviphc:PE+
bortezomib +methyl prednisoloneIV Chc nng thn ghp c ci thin dn sau
mt vi thng, nng creatinine mu bnh thng 18 BNG 18. TIU CHUN KHI U IU
TR AMR [32] Chc nng thn ghp gim cp tnh S lng ng mc ln v lan ta ca
PTC C4d Pht hin DSA Bng chng trn m hc ca AMR. Quyt nh CCCCiu tr
CCCKhngiu tr CCKhngKhng Sinh thit li hoc iu tr khi khng tm thy
nguyn nhn no khc ca s ri lon chc nng thn ghp. C C nguy c cao lin
quan n AMR(da trn tin s lm sng) + 1/3 tiu ch iu tr
CKhngKhngKhngSinh thit li, k c khi C4d yu cng c YNLS 19 Khng Khng
khng C Hinh 1. Tip cn iu tr thi ghp cp tnh qua trung gian t bo
(ACR) theo UpToDate [14]. Mt iu quan trng l cn khng nh chc chn chn
on v mc ACR bng sinh thit trc khi bt u iu tr ko di bng liu cao
steroid hay b sung cc tc nhn nh ATG/alemtuzumab. Trong mt s trng
hp, steroid o ngc ACR, nhng chc nng thn vn khng phc hi dai dng do
hoi t ng thn cp v/hoc c tnh CNI u c th xut hin cng ACR. Sinh thit
ACR Banff I Methylprednisolone IV 3 7 mg/kg/ngy x 3 ngy +Chuyn dng
phc duy tr tacrolimus +mycophenolate hoc tng liu 2 tc nhn ny nu cn
thit p ng Gim liu corticoid v mc trcthi ghp ACR Banff IB km theo
biu hin thi ghp mc nng trn lm sng HOC ACR Banff II, III
Methylprednisolone IV 3 7 mg/kg/ngy x 3 ngy +RATG 3 mg/kg/ngy x 3
ngy hoc 1.5 mg/kg/ngy x 5 ngy (tng liu 7.5 9 mg/kg) p ng Sinh thit
li, nhum C4d v phn tch DSA C mt AMR? ACR khng tr vi
corticosteroid/ATG: rt him gp, cn nhc s dngalemtuzumab hoc IVIg iu
tr c hiu AMR C C 20 Hnh 2. S tip cn AMR theo Lucas J.G. v cs [39].
21 Khng Hnh 3. S tip cn AMR theo UpToDate [32] (*): Creatinine huyt
tng trong khong 20-30% gi tr ban u sau t nht 4 t iu tr. Ghi ch: Pht
hin DSA (v hiu gi, nu c) trc khi bt u iu tr, trong qu trnh iu tr
(nu nng creatinine huyt tng khng gim tng xng); v sau ln lc huyt tng
cui khi iu tr thnh cng. S gim 50% DSA bnh nhn vi AMR c th lm ci
thin t l thn ghp sng st, do nn theo di DSA nh gi p ng iu tr.Vi nhng
trng hp thi ghp mc nh, khi chc nng thn ghp vn n nh nhng C4d dng
tnh, khng co bng chng trn m hc ca AMR v c/khng c bng chng ca DSA, c
th ch cn tng liu tacrolimus + MMF, km theo sinh thit lp li khi gp
ri lon chc nng thn ghp. Chn on AMR . Chuyn phc tacrolimus + MMF hoc
tng liu . Methylprednisolone 300 500mg IV/ngy x 3 5 ngy. Sau gim
liu t t . PE (1 1.5 th tch trao i) hng ngy hoc cch nht
.IVIg100mg/kgsaumilnPE+ 500mg/kg/ngy sau ln PE cui cng 1 n 2 ngy
(tng liu tch ly ti thiu 1000mg/kg). p ng iu tr* B sung rituximab
375 mg/m2/liu/ngy AMR +bng chng m hc ca ACR ng thi mc nng (Banff 2A
hoc hn) . Sdngkthplchuyttng,IVIg, methylprednisolone v ATG.. PE +
IVIg (100mg/kg) th 2,4,6 v ch nht vi t nht 4 ln iu tr. IVIg liu
500mg/kg vo1n2ngysautPE,vitngliu trongsutqutrnhiutrtnht1000 mg/kg
IVIg. .3liuATG(1.5 3.0 mg/kg) vo 3 ngy cn li trong tun (th 3, 5,
7). AMRcp tnhkhng trhoc bnhcnh lm sng chothy AMRcp tnh nng 22 PH LC
2. KT QU NGHIN CU B SUNG Hnh 4. Bin thin nng tacrolimus theo ngy ca
mu nghin cu (mi mu ca chm trn tng ng vi 1 bnh nhn) 051015202530-5 0
5 10 15 20 25 30 35 40Nng y tacrolimus (ng/ml)Ngy23 Bng 22. Bin
thin SCr v eGFR theo thi gian ca 15 BN khng s dng TB. (*): trung
bnh (gi tr nh nht;gi tr ln nht) Ngy NamN S BNSCr v eGFR*S BNSCr v
eGFR* 012722.4 (465;1114) 8.38 (4.93;13.01) 3530 (509;565) 8.55
(7.71;9.03) 112241.2 (140;374) 30.98 (15.91;50.62) 3145.3 (116;180)
39.57 (28,85;49,78) 212142.8 (88;250) 56.68 (25.33;84.29) 399.7
(91;112) 59,23 (49,89;65,88) 312139.8 (97;230) 56.12 (27.89;73.27)
387.7 (84;93) 68,13 (61,82;72,25) 412130.1 (90;197) 60,98
(33,35;81,16) 393 (80;100) 64,36 (56,86;76,44) 512121.6 (82;166)
64.66 (42,40;93,85) 386.3 (78;95) 69,68 (62,69;78,70) 1012105,0
(76;150) 74.69 (51.24;102,45) 383 (76;91) 72,93 (63,39;81,10)
15587.4 (55;103) 92,47 (76,96;137,90) 0 20396.0 (71;118) 82,19
(63,30;102,71) 0 251127.0 58,16 0 301124.0 59,78 0 24 Bng 26. Kt qu
theo di ng mu v liu insulin bnh nhn tng ng huyt sau ghp thn (BN
03). NgyLiu corticoid* Glucose mu lc i (mmol/l) liu insulin (UI)
6h**11h**18h**21h*** 10M IV 120 12 613.5 615.9 718.1 7 11 M IV 40 P
O 16 10.1 713.2 78.8 79.9 9 12P O 4810.2 8? 810.8 89.9 8 13P O 32
8.8 87.2 8? 811.1 8 14P O 32 8.9 8? 86.2 817.4 8 15P O 24 6.3 0?
010.5 89.2 0 16P O 16 5.5 010.1 610.2 811 8 17P O 12 6.7 06.4 07.1
013.9 0 18P O 126.2 010.2 67.6 010 0 19P O 125.6 011.8 69.7 69.1 0
20P O 126.4 08.7 011.4 69.3 0 21P O 126.5 RV (*): biu din di dng
M/P IV/O liu: hot cht ng dng tng liu trong
ngy(mg).Trong,M:methylprednisolone;P: prednisone.IV:ngtimtnh mch;
O: ng ung. (**): s dng insulin actrapid tim di da. (***): s dng
insulin lactard tim di da. ?:mt d liu. RV: ra vin.
