CJASN ePress . c ng trn 07 Thng Mi Mt 2016 nh doi: 10,2215 / CJN.

05780616
bnh cu thn

Cp nht v Lupus vim thn

Salem Almaani, Alexa Meara v Brad H. Rovin

tru tng
SLE l mt mn tnh bnh ammatory fl c nh hng n thn khong 50% bnh nhn. Lupus vim thn l mt yu t nguy c chnh i vi bnh tt
ni chung v t l t vong trong bnh lupus ban , v mc d chng trong fl ammatory v c ch min dch liu php mnh vn kt thc bng CKD hoc
ESRD qu nhiu bnh nhn. nh gi ny nu bt cp nht gn y trong s hiu bit ca chng ta v dch t hc bnh, di truyn, bnh v iu tr trong
mt n lc thit lp mt khun kh cho vic qun l vim thn lupus c ngha l bnh nhn c hiu fi c v hng ti vic duy tr chc nng thn lu di
B of Internal Medicine, Trung
bnh nhn lupus.
tm y t bang Ohio Wexner,
Columbus, Ohio
Clin J Am Sc Nephrol : ccc - ccc, 2016. doi: 10,2215 / CJN.05780616

Th tn:
Dch t hc LN l mt yu t nguy c ln i vi andmortality bnh sut SLE v
Tin s Brad H. Rovin, Thn
SLE l mt mn tnh fl bnh ammatory c th nh hng n bt k c 10% bnh nhn vi LN s pht trin giai on cui (26). Nguy c ESRD cao Division, i hc bang Ohio
quan, nhng rt thng xuyn lm tn thng thn. SLE l ph bin hn hn cc tp con no ca LN. V d, trong lp 4 LN ri ro c th cao ti Wexner y t, Tng trt, 395
ph n so vi nam gii trn tt c cc la tui v dn s; t l n sang nam Ty 12 Avenue, Columbus,
44% so vi 15 nm (27). Bnh nhn LN cng c mt t l t vong cao hn
OH 43201. Email:
l cao nht tui sinh sn, dao ng t 8: 1 v 15: 1, v l thp nht tiu chun (6 - 6,8 so vi 2,4) v cht sm hn so vi bnh nhn SLE khng
Rovin.1@osu.edu
tr em trc tui dy th vo khong 4: 3 (1 - 3). S ph bin ca bnh lupus LN (28 - 31). Quan trng hn, s tn ti 10 nm ci thin t 46% xung cn
ban v cc c hi pht trin lupus vim thn (LN) khc nhau ng k 95% nu bnh thuyn gim c th t c (32).
gia cc vng khc nhau ca th gii v chng tc khc nhau v sc tc
(Bng 1) (2,4 - 14). Ti Hoa K, cc tn s cao hn ca LN trong cc qun
en vn cn sau khi iu chnh cc yu t kinh t x hi (15). Ngoi ra,
bnh nhn SLE en v gc Ty Ban Nha pht trin LN trc (16), v c
kt qu ti t hn bnh nhn trng vi SLE, k c t vong v ESRD (10). Di truyn hc v Sinh bnh hc
iu ny c th gii thch ti sao chim c nhn mu en cho gn mt na Mt cuc tho lun chi tit v di truyn hc v sinh bnh hc ca LN nm

trong s nhng ngi c ESRD do LN (17). Qu trnh bnh tch cc hn ngoi phm vi ca tng quan ny, nhng c th c tm thy trong Munroe v

nhng ngi da en c th l kt qu ca mt t l cao ca LN tng sinh James (33). y chng ta s tp trung vo gn y fi nhng pht hin m bn c

lan ta, hoc s hin din ca nhiu tnh nng c nguy c cao trong lp th p dng i vi cng tc qun l lm sng ca LN.

cng LN m hc khi so snh vi cc c nhn mu trng (18). Nhng khc

bit c th pht sinh do yu t di truyn nh mt s ri ro cao kiu gen v
cc t khng th l thng xuyn hn nhng bnh nhn en (19 - 21). V H thng Lupus so vi LN
d, dn en c mt tn s cao hn ca fc g RIIA- R131 alen c tham gia Cn c vo t l mc bnh lin quan n LN, kh nng xc nh chnh
vo vic lm trung gian thc bo ca IgG2 min dch phc (20). Gen xc bnh nhn SLE mnh pht trin LN c th thay i m hnh qun l
APOL1, m c lin quan n s pht trin ca giai on cui bnh hin ti t iu tr phng nga. Mc d n khng phi l kh nng suy
nhn da en, cng c gn lin vi s pht trin v pht trin ca giai thn v ESRD c th trnh c hon ton, v nhiu bnh nhn trnh by
on cui trong dn s LN (22,23). Trong LN bnh nhn c hai alen nguy vi LN l biu hin ban u ca bnh lupus ban ca h, mt chin lc
c APOL1 cc t s chnh (OR) cho giai on cui l 2,72 (95% con fi khong qun l phng nga c th Signi fi cantly gim CKD v ESRD. V d, bnh
dence [CI 95%], 1,76-4,19; P, 6.2 3 10 2 6). Mt kiu ph HLA-DR2 nhn SLE mnh pht trin LN c th c theo di cht ch hn rt
(HLA-DRB181503), c trng ca ngi dn en, c lin quan n xu i nhiu, c l vi gim st ngi nh ca nc tiu sinh thit thn v iu
protein niu (24). c nhn mu en cng c nhiu kh nng c tch cc tr c th c bt u khng chm tr. Ngoi ra, nhng bnh nhn ny c
chng Ro, chng Sm, v khng th-RNP chng, trong c mt lin kt th c xem xt iu tr pre-emptive suy nhc t min dch trc
cao vi LN (25). khi bt k biu hin lm sng ca s tham gia ca thn l r rng. Mc d
hin nay l khng th xc nh a priori

ngi vi SLE s pht trin LN, mt s cuc iu tra di truyn lupus tip
cn vn ny.
SLE pht sinh nhng ngi c ngun gc di truyn thch hp tip xc
vi trigger mi trng nht nh. Mt s gen c gn lin vi SLE nhy
cm, ni bt nht trong con ngi HLA

www.cjasn.org Vol , 2016 Bn quyn 2016 bi Hip hi Thn M 1

2 Clinical Journal of Society of Thn M

Bng 1. T l SLE v tn s ca lupus vim thn

Nhn khu hc Ph bin, mi 100.000 Tn s, % Ti liu tham kho

SLE
Khu vc
Hoa K, Canada 4.8 - 78,5 Danchenko et al. ( 2)
Chu u (Vng quc Anh, c, 25 - 91 Danchenko et al. ( 2)
Php, , Ty Ban Nha, Scandinavia)
Chu c 19 - 63 Danchenko et al. ( 2)
Trung Quc 30 - 50 Osio-Salido et al. ( 4)
Nht Bn s 8 - 18 Osio-Salido et al. ( 4)
lupus vim thn
Chng tc / dn tc
en 69 Bastian et al. ( s 8)
trng 29 Bastian et al. ( s 8)
Chu 40 - 82 Jakes et al. ( 99)
Ty Ban Nha 61 Bastian et al. ( s 8)

locus. Mt phn tch tng hp HLA-DRB1 alen trong SLE kt lun rng cc tu sn a dng ca cc nhm ngi nghin cu, m cho n nay ch yu tp trung vo
bay ca HLA-DR4 v DR11 c bo v chng li LN vi ORS ca CI 0,55 (95%, bnh nhn da trng v chu .
0,39-0,79; P, 0,01) v 0,6 (95% CI, 0,37-0,96; P, 0,05), tng ng (34). Ngc li HLA-DR3
v DR15 trao tng nguy c LN vi ORS ca CI 2.0 (95%, 1,49-2,7; P, 0,05) v 1,6 bnh
(95% CI, 0,37-0,96; P, 0,05). Nhng hip hi l trn c s ca 473 bnh nhn t fi Manh mi nh th no LN pht trin nhng bnh nhn SLE c cung cp
nghin cu bnh chng, v bnh nhn ch yu l mu trng v chu bao gm. bi mt nghin cu v cch thc transcriptome ca cc t bo mu ngoi vi thay
Controls l ngi khe mnh. Cc c ch ca i theo thi gian trong mt nhm bnh nhn LN nhi (40). LN xy ra khi s biu
hin ca gen bch cu trung tnh lin quan n tng ln. kch hot bch cu trung
tnh c trc bi s gia tng IFN v bng im plasmablast lin quan v tip
theo l tng bi xut t bo myeloid khc v proin fl bng im ammatory. Nhng
HLA- da nhy cm v bo v bnh vn cn cha r. N c gi rng iu d liu ny c tng hp trong mt m hnh ca lupus trong bnh khi
ny c th lin quan n mc n nh ca s tng tc gia t peptide v i preclinically vi mt phn ng IFN v s khc bit ca cc t bo B vo
tc lin kt HLA ca n (35,36). tng tc n nh hn c th dn n s bo v plasmablasts, v tin ti m-Speci fi c ( v d, thn) v h thng trong fl ammation
nh trong cc bnh t min khc nh vim khp dng thp. nh bch cu trung tnh v cc t bo myeloid kch hot.

Trong cch tip cn khc, mt phn tch tng hp ca ba nghin cu hip hi

genomewide c thc hin xc nh alen ri ro i vi LN nhng bnh Bch cu trung tnh c th gp phn vo c ch bnh sinh ca bnh lupus ban
nhn bit l c SLE (37). Tt c cc bnh nhn l ph n gc chu u ( n 5 2000) v LN thm ch t vong. Khi bch cu trung tnh cht h thng th by ngoi
v 588 c LN. LN c de fi c xc nh bi cc American College of bo bch cu trung tnh (NETS), trong bao gm cc nhim sc th fi brils,
Rheumatology tiu ch ca protein niu dai dng v bt thng ca trm tch nc histone, v bch cu trung tnh khng khun v protein kch thch min dch. y
tiu. y l trng yu nht fi cc hip hi khng th cho LN nh x ti cc th th l loi t bo cht, c gi l NETosis, thng l mt c ch bo v my ch
PDGF Mt gen (OR, 3,41; 95 CI%, 2,10-5,54; P 5 4,52 3 10 2 7) v gen cho SLC5A11 by v tiu dit vi sinh vt. Tuy nhin, NETS v bch cu trung tnh NETing cng
c th c tm thy trong thn ca bnh nhn SLE (41). NETS l mt ngun
glucose cotransporter natri ph thuc (OR, 2,85; 95% CI, 1,93-4,22; P 5 5,08 3 10 2 7). HLA
locus c lin kt cht ch vi t LN trong phn tch ny, c th v nhm i khng nguyn ht nhn trong SLE v c th gip duy tr khng nguyn c hiu- fi c
chiu c lupus, v do c lin kt cht ch vi HLA. Trong LN, PDGF th sn xut t khng th. NETS v bch cu trung tnh NETing iu kin thun li
trong fl ammation, c th gy thit hi mng, v c th gy ra cc t bo ui gai
trung gian ph bin v kh thn di ng, tch ly ma trn, v bn trong thn trong fl ammation.
Mi lin h gia SLC5A11 v LN l phc tp hn. Mt s hng cht tan ( SLC) gen plasmacytoid sn xut IFN- a ( 41), khuch i t min dch. Quan trng hn,
gia nh c lin quan n suy thn (38). Cc bin th trong SLC5A11 c th lm NET suy thoi l khim bnh nhn SLE, v ch yu l nhng ngi c LN (42).
trung gian gim trong huyt thanh v tng trong nc tiu myo-inositol, cho thy
vai tr tch cc ca SLC5A11 gn ti hp thu ng ln inositol (38). Thm vo
, hoc thng qua cc quy nh inositol, SLC5A11 th trung gian apoptosis qua
s cht t bo c lp trnh v TNF- mt con ng (39).
H thng C thng c kch hot trong LN v c th trc tip trung gian chn
thng thn qua ng b u cui, hoc gin tip lm tng thn trong fl ammation
bng cch tuyn dng bch cu i vi thn. Bi v C cng gip cc mnh vn
apoptosis r rng, iu quan trng trong vic lm gim tip xc vi autoantigens l.
V vn ny, cc t khng th vi cc thnh phn C c tm thy nhng
bnh nhn b lupus c th quan trng trong s pht trin ca LN. Trong mt nghin
cu thun tp ca 114 bnh nhn lupus, 23% bnh nhn c khng th thnh
Nhng hn ch ca nhng iu ny v cc nghin cu lin kt di truyn khc l phn C C1q v C3B (43). Trong nhng dual-khng th - bnh nhn dng tnh
nhng con s tng i nh ca bnh nhn b nh hng c sn phn tch, v nhng ngi
cc hn ch v chng tc v dn tc
Clin J Am Sc Nephrol : ccc - ccc, , 2016
phi hi t theo sau, chng C3B v mc chng C1q c xu hng tng trong
nhng thng dn n thn fl ang c.
Trong ng nghim th nghim ch ra rng chng C1q gn C1q trn cc t bo
apoptosis sm v ngn chn s hp thu ca h bi cc i thc bo (44).
Anti-C1q cng khi phc hp min dch gn vo cc t bo mu , mt c ch
phc hp min dch mt cch an ton r rng. Nhng d liu ny cho thy khng
th chng C1q c th tng cng tip xc autoantigen v c th to iu kin cho
s lng ng phc hp min dch trong c quan ch nh thn. Ph hp vi iu
ny, n ch ra rng s vng mt ca t khng th chng C1q c cht lng
gn vi bo v chng li LN trong mt nhm nh bnh nhn lupus (45). Hn na,
C3B trn phc hp min dch thc y phc hp min dch gn vo cc t bo
hng cu gii phng mt bng. iu ny c th b chn bi chng C3B, do lm
tng tc dng pro-LN chng C1q.
Cui cng, mt cuc iu tra gn y gn lin vi khi nim quan trng i vi
kh nng min dch ca virus t min dch, cung cp ci nhn su vo ti bnh
t min (46), mt vn m c bit lin quan n LN. t bo CD8 T tr thnh kit
sc trong bi cnh tip xc vi khng nguyn dai dng v s vng mt ca t bo
T CD4 costimulation. Nhng t bo CD8 kit sc mt chc nng effector v th
hin cc th th c ch mc cao. iu ny dn n khng c kh nng xa
nhim virus, nhng c th bo v chng li hay ti pht bnh t min. nhng
bnh nhn SLE (khng nht thit phi LN), mt nhm hn ch cc th th
coinhibitory upregulated c trng cc t bo T mt mi, m dch sang bnh nhn
c mt kha hc nonrelapsing ca lupus. Cc gen upregulated l 4 - 1BB, CTLA4,
PDCD1, LILRB4, v KLG1. Cc kiu hnh kit sc c th c cu bi
costimulation, v gen nht nh, nh KAT2B,
c th to iu kin ny. KAT2B l antiapoptotic v lm trung gian bo v chng
li cng thng trao i cht. Trong m hnh ny ti pht bnh, cha c th
nghim trong LN, can thip iu tr tng kit t bo T, c l bi upregulating
biu hin th th c ch hoc chn costimulation duy tr kiu hnh kit sc, c
th gip ngn nga thn
fl Ares. iu th v hn suy on rng bi din thuyt HLA n nh ca kt qu
t khng nguyn trong kit t bo T v bo v trong SLE, trong khi cc hip hi
HLA khng n nh vi t khng nguyn gy gin on hot ha t bo T, tng
cng costimulation, v c ch ca y (bo v) T t bo kiu hnh.
Clinicopathologic Tng quan
Cc biu hin lm sng ca LN thng tinh t v ph bin nht s c pht
hin bi kim tra nc tiu nh tri ngc vi thm khm lm sng (Bng 2). Do
, tt c bnh nhn SLE nn c nh gi cho s tham gia ca thn lc chn
on ban u v t nht mi nm sau ngay c khi h khng c triu chng ca
bnh thn. N cng c khuyn co rng cc bnh nhn c nh gi li cho thng phn loi RPS fi es LN trn c s ni phc hp min dch tch t trong tiu
LN nu SLE fl Ares. nh gi l n gin v nn bao gm mt phn tch nc tiu
v o chc nng thn, ni chung l mt nng creatinin huyt thanh hoc eGFR.
Bi v bnh nhn SLE thng c mt s vn y t ng thi v c th v loi thng cu thn (segmental ton cu hay), v cho d chn thng cu thn ang
thuc c kh nng gy c cho thn, iu quan trng l loi tr nguyn nhn
nonlupus ca insuf thn fi-
ciency, c bit l nu nc tiu khng hin th protein bt thng v tiu mu.
Nu tham gia thn nghi ng mt sinh thit thn cn c xem xt (xem di y).
Ngng lm sng lm mt sinh thit thn khng c tt de fi ned, nhng chng
ta nn tin hnh sinh thit nu protein niu
Cp nht v Lupus vim thn, Almaani et al. 3
Bng 2. T l biu hin lm sng bnh nhn lupus vim thn
Xp x T l,%
Biu hin lm sng
protein niu 100
Thn h phm vi m niu / 50
hi chng thn h
tiu mu vi 80
tiu mu v m , 5
phi t bo mu tit niu 30
phi t bo tit niu khc 30
insuf thn fi ciency 60
suy gim nhanh chng trong chc nng thn 15
tng huyt p 30
bt thng v hnh ng 70
$ 500 mg / ngy, c hoc khng c bt thng v lm sng khc, hoc bt k mc
protein niu hay tiu mu c chc nng thn suy gim m khng th c quy
cho nguyn nhn khc. C nhiu bng chng quan st rng protein ca 500 - 1000
mg / ngy (hoc thp hn) c th lin quan trng yu fi bnh l khng th thn (47),
v n c thit lp r rng chn on sm v iu tr LN ci thin tin lng
(48).
Cc Sinh thit thn trong LN
Mc d quyt nh thc hin mt sinh thit thn nhng bnh nhn SLE khi
c bng chng lm sng ca s tham gia ca thn c v n gin, n tr thnh
phn no gy tranh ci v mt ci nhn hin hnh m mi hnh thc LN c th c
iu tr y vi corticosteroid cng mycophenolate mofetil (MMF) ( 49). Tuy
nhin, sinh thit thn l rt quan trng de fi ne bn cht ca s tham gia ca
thn. Mc d phc hp min dch - qua trung gian GN l nguyn nhn ph bin
nht ca bnh thn trong bnh lupus ban , c nhng c ch khc dn n tn
thng thn m ch c th c chn on bng sinh thit, v i hi mt cch
tip cn khc nhau qun l hn LN phc hp min dch. V d nh
microangiopathy huyt khi v lupus podocytopathy (de fi ned nh hi chng thn
h trong SLE rng trn thn sinh thit cho thy khuch tn qu trnh chn lu m v
khng subendothelial hoc tin gi min dch subepithelial), c th c nhn thy
trong ln n 24% v 1,3% bnh nhn LN, tng ng (50,51). Cc fi nding ca vim
thn tubulointerstitial c lp l him (52).
LN phc hp min dch c m t bnh l s dng Hip hi Quc t nm
2003 ca Thn / Thn Bnh Society (ISN / RPS) danh php (53). Cc ISN / h
cu, s hin din hay vng mt ca mesangial hoc ph bin v kh endocapillary,
mc tng th ca s tham gia ca cu thn (khu tr hoc lan ta) v tn
hot ng ( trong fl ammatory) hoc mn tnh (x cng) (Bng 3). Mt cch tng
qut, quyt nh cc lp hng dn iu tr ISN / RPS. Bnh nhn b bnh gii hn
nhng mesangium (lp 2) thng khng cn Speci fi iu tr c cho bnh thn ca
h, nhng c th cn iu tr c ch min dch cho biu hin SLE extrarenal. Bnh
nhn b chn thng ch yu kinh nin (bt k lp) hoc kt thc giai on thit
hi (lp 6) cng khng cn suy gim min dch cho LN, nhng c th Bene fi t t
4 Clinical Journal of Society of Thn M

Bng 3. Cc m hc phn loi fi cation ca lupus vim thn

ISN / RPS
Kt qu m hc Modi fi cation M hc Kt qu lm sng thng thng
Lp

1 knh hin vi nh sng bnh thng; Khng lin quan n thn

phc hp min dch rt him khi c chn on hoc sinh
mesangial bi min dch fl knh thit
hin vi uorescence

2 phc hp min dch mesangial / Tiu mu, cp thp

pht trin t bo mesangial
3 Mesangial v subendothelial
phc hp min dch / segmental
ph bin v kh endocapillary ti,
50% tiu cu
protein niu; insuf thn fi ciency,
hi chng thn h khng mong
i
Tn thng canbeactive, mn tnh, Tiu mu, protein niu
hoc c nhng yu t ca c hai thy trong hu ht cc bnh nhn;
insuf thn fi ciency, hi chng thn h
khng bt thng

4 Mesangial v subendothelial Tn thng canbeactive, mn tnh, Tiu mu, protein niu

min dch phc / segmental hoc ph
bin ton cu trong endocapillary
$ 50% s tiu cu
5 subepithelial nhiu
phc hp min dch trong .50% ca cc
mao mch cu thn
hoc c nhng yu t ca c hai
thy trong hu ht cc bnh nhn;
insuf thn fi ciency, hi chng thn h
khng bt thng
Protein niu, thng thn h
phm vi; tiu mu c th; thng
khng insuf thn fi ciency

6 Glomerulosclerosis trong 0,90% insuf thn fi ciency;

ca tiu cu protein niu v tiu mu thng
xut hin

ISN / RPS, Hip hi Quc t ca Thn / Thn Bnh Society.

antiproteinuric, cc bin php bo v thn. Cc lp tng sinh (3 v 4) thng c
iu tr bng c ch min dch mnh, trong khi nonproliferative, mng LN (lp
5) c th c iu tr bo tn (iu tr antiproteinuric) nu bnh nhn c protein
niu subnephrotic, hoc vi suy gim min dch nu bnh nhn c phm vi protein
niu thn h.
Khi iu tr ca LN di chuyn vt qu ch c ch min dch nontargeted
hin c ca corticosteroid liu cao cng vi cyclophosphamide hoc MMF can
thip tp trung vo Speci fi c con ng min dch, mt bc tranh ton din hn v
bnh l thn thng qua hnh nh phn t ca sinh thit thn c th c mong
mun. Cc con ng min dch hot ng trong thn ti thi im chn on LN
khc nhau ng k gia cc bnh nhn. V d, khi tiu cu c m x t sinh
thit LN con ngi v chu s phn tch transcriptomic, bnh nhn tch bit thnh
nhm cho thy biu hin ni tri ca gen t bo B, gen myelomonocytic, gen
IFN-cm ng, hoc fi gen brosisrelated (54). con ng tng t nh c
chng minh c kch hot trong thn ca chut lupus d xy ra (55). Nhng
bin phn t c th ti fl vv tnh khng ng nht ni ti ca LN hoc c th xy ra
bi v bnh nhn c sinh thit ti cc im khc nhau trong qu trnh ca mt
bnh m nhanh chng tin ha. Bt k LN khng ng nht pht sinh nh th no,
nhng khc bit ny phn t cho thy mt liu php nhm mc tiu l khng c
kh nng lm vic cho tt c bnh nhn, nhng ch nhng ngi c hot ng
trong mt speci fi c t min hoc trong fl ng ammatory. Phm vi p dng ca
phn tch phn t ca sinh thit thn iu tr LN l
minh ha bng mt cuc kho st gn y ca biu thc bng im ca gen min
dch trong mu sinh thit thn c thc hin ti LN fl ang c. Bnh nhn c u
hon ton phn ng thn lm sng standardof chm sc tr liu cm ng c th
c phn bit vi ngi khng p ng trn c s bng biu pro fi les (56). Mt
cch tip cn tng t hnh dung c th c p dng cho bnh nhn c iu
tr bng liu php mi de fi ne m bnh nhn c kh nng p ng vi iu tr c
th.
Vai tr ca sinh thit thn giao thc lp li trong LN l gy tranh ci, nhng d
liu mi ni ngh sinh thit s-ri c th thng bo quyt nh iu tr lin tc v
d on tin lng thn lu di. Lp li sinh thit chng minh iu ng k
gia clinically- v histologicallyde fi Hot ng bnh ned. Sau khi hon thnh 6 - 8
thng iu tr c ch min dch, 20% - 50% phn ng hon ton thn lm sng vn
c bng chng m hc ca hot ng lin tc trong fl ammation, v 40% - 60% bnh
nhn khng c bng chng m hc ca hot ng bnh vn cn dai dng, cao
cp protein (57,58). Thm ch sau nhiu nm iu tr c ch min dch, hot ng
m hc c tm thy trong khong 20% bnh nhn thuyn gim lm sng bn
vng. Ngc li, 40% bnh nhn trong ton thuyn gim m hc sau khi iu tr
di hn dai dng lm sng fi nhng pht hin (59). Nhng kt qu ny gi rng
mt ng dng trc tip ca sinh thit lp li c th nh gi mt bnh nhn rt
ca iu tr duy tr c ch min dch. Hin nay khng c hng dn evidencebased
lin quan n thi gian iu tr LNmaintenance (60).
 Cp nht v Lupus vim thn, Almaani et al. 5

Gi tr tin lng ca sinh thit thn chn on d on di hn sc khe tion (66 - 70). Xem xt cc cuc iu tra vi nhau, mt s khi qut v sinh thit lp
thn trong LN tht vng (61). Tuy nhin, lp li sinh thit sau t nht 6 thng li lm sng cho thy c th c rt ra. Bnh nhn ban u c LN tng sinh
iu tr c ch min dch xut hin cung cp thng tin tin lng tt hn. bng thng thy LN tng sinh ti fl l, trong khi nhiu bnh nhn ban u c LN mng
chng m hc dai dng ca cu thn v k trong fl ammation, phc hp min dch thng pht trin mt thnh phn tng sinh ti fl ang c. Tng t nh vy,
mao mch cu thn, v i thc bo trong lumen ng sau khi hon thnh iu tr nhng bnh nhn c lp 2 LN n khng phi l bt thng fi nd mt m hnh
cm ng l yu t nguy c tng gp i tng lai ca nng creatinine huyt chn thng tch cc hn sinh thit lp li. nhng
thanh (62,63). Tng thit hi mn tnh trn sinh thit postinduction cng d on
kt qu thn lu di trong mt s nghin cu (57,58). Cc National Institutes of
Health (NIH) hot ng v mn tnh ch s (64) c o bng sinh thit lp li 12 - 18 fi nhng pht hin ngh lp i lp li mt sinh thit thn cho fl l l hu ht cc li
thng sau khi bt u iu tr, trong khi bnh nhn suy gim min dch trn bo tr ch fi cial cho bnh nhn vi lp trc 2 hoc 5 LN v c mt iu tr kh nng hp l
(65). Sau 10 nm theo di, kh nng tng gp i creatinine huyt thanh l c th intensi fi ed. Sinh thit cho protein niu dai dng hoc xu i hoc s gia
khong 56% i vi bnh nhn c sinh thit th hai c hot ng lin tc (mt ch tng nng creatinin huyt thanh khng nht thit li fl vv LN hot ng; chn
s hot ng .2), so vi 20% cho bnh nhn c mt ch s hot ng # 2 ( P, 0,001). on sinh thit tn thng mn tnh v bnh khng hot ng c th cho php
Tng t nh vy, s sng cn thn 10 nm l 0,90% nu ch s mn tnh ca gim trong iu tr.
sinh thit lp li l, 3, nhng 55% nu ch s mn tnh l 0,6 ( P 5 0.10).

Trn c s cc bng chng hin ti nh th no mt sinh thit thn c th ng

gp vo s qun l ca LN, mt thut ton ngh cho sinh thit thn ban u v
lp li trong lupus c trnh by trong Hnh 1.

sinh thit thn Lp li cng c thc hin trong LN cho du hiu lm sng, vi Cc iu tr LN
gi nh rng cc sinh thit c th h tr nhng thay i trong iu tr. Hu ht thi Chin lc qun l
gian ny l do LN fl l, protein niu dai dng, hoc gim func- thn Mc tiu tng th ca iu tr LN l ngn chn suy thn v ESRD. Nh kt
qu thn bt li xy ra hn rt nhiu

Hnh 1. | Mt thut ton xut khi thc hin sinh thit thn bnh nhn lupus vim thn (LN). Clin J Am Sc Nephrol : ccc - ccc, , 2016
6 Clinical Journal of Society of Thn M

thng xuyn trong LN tng sinh, chng ti s tp trung vo vic x l ca cc
tng lp 3 v 4. ngn nga suy thn v ESRD, chin lc iu tr ngn hn
tp trung vo vic o ngc hon ton hoc mt phn trong nhng du hiu lm
sng ca tn thng thn tho lun trc . Vo thi im LN l r rng trn lm
sng thn l khim tn hoc nghim trng trong fl Amed do s tch t ca phc
hp min dch t khng th cha. Do , bnh nhn c iu tr bng mt antiin fl inhn (77,78). Cc thng k kt qu cho thy c ch ng k ci thin trong
l ammatory ngay lp tc lm gim bt bn trong thn trong fl ammation v cho
php cha bnh bt u, cng vi mt tc nhn c ch min dch mnh gy
cn tr con ng t min dch m c th kch hot s hnh thnh phc hp min
dch thn v bt u chu k trong fl chn thng ammatory mt ln na (thn fl l).
Giai on cm ng iu tr thng ko di 3 - 6 thng v c theo sau bi mt giai
on duy tr ko di, nhng t d di, thng ko di nhiu nm. N khng phi l
r rng khi iu tr duy tr c th b thu hi. Mt sinh thit lp li thn cho thy
thuyn gim m hc trong bo dng nhng bnh nhn t c hon ton
thuyn gim lm sng, hoc nhng ngi c protein niu n nh nhng dai dng,
c th gip trong vic a ra quyt nh gim t t iu tr. Mt th nghim lm
sng ngu nhin hin ang c thc hin gii quyt cc vn v thi gian
iu tr duy tr (Clinicaltrials. Gov identi fi er: NCT01946880).
Th bo co cho chin lc qun l ny l hn hp. liu php cm ng v bo
tr c ci thin sng ca bnh nhn ni chung cn khong 80% sau 5 nm,
tuy nhin, hon chnh t l p ng thn 12month l ch c 10% - 40%, v vi tc
30% bnh nhn LN vn s tin n giai on cui (71 - 75). Hn na, mc d
khng c c tnh c bao nhiu bnh nhn LN l tri vi suy thn sau khi iu tr,
con s ny c th s ln. V d, sinh thit thn sau khi iu tr cm ng vi
corticosteroid liu cao v cyclophosphamide hoc MMF thng thy s gia tng
thit hi mn tnh, ngay c trong nhng bnh nhn t c mt s thuyn gim
lm sng y cm ng mt mnh (57). LN fl cng l mt yu t nguy c quan
trng i vi CKD v tin trin suy thn (76) v fl Ares c th xy ra 25% bnh
iu tr LN.
Phng php tip cn hin ti x l
Tt c cc phc iu tr rng ri chp nhn hin ti cho LN (tm tt trong
Hnh 2) kt hp corticosteroid liu cao iu khin nhanh chng ca trong fl ammation
v mt trong hai MMF hoc cyclophosphamide kim sot trong fl ammation v t
min dch (60,79). Tt c cc bnh nhn (tr khi c chng ch nh) nn c iu
tr bng thuc chng st rt cho cc bng chng cho thy thiu s dng thuc
chng st rt c th lin quan vi s gia tng tht bi iu tr LN (80).
Cyclophosphamide c th c a vo ng ming hoc tim tnh mch, v
nu tim tnh mch trong c hai tiu chun liu (c ch nh phc NIH) hoc
lowdose (gi tt l lowdose hoc ch Euro-lupus). suy gim min dch cng
cao c a ra cho cc fi u tin 3 - 6 thng v sau thay th bng MMF
(hoc mt liu thp hn MMF nu n c s dng cho cm ng) hoc
azathioprine duy tr c ch t min dch v trong fl ammation, v do ngn
nga fl ang c.
Chun liu cyclophosphamide (hoc ming hay NIH) ci thin s sng cn thn
lu di so vi mt mnh corticosteroid v thit lp cc tiu chun ca phng tin
chm sc iu tr LN (81). Bi v nhng lo ngi xung quanh c
cyclophosphamide, MMF v NIH cyclophosphamide

Hnh 2. | Hin ti cm ng v iu tr duy tr s la chn cho vim thn lupus tng sinh. Bnh nhn c xem l c vim thn lupus nghim trng nu h c chn thng thn chc nng vi mt
creatinine cao trong huyt thanh v / hoc protein niu nng, bng chng cho thy s mt chc nng thn xy ra trong khong thi gian tng i ngn thi gian v tn thng m hc tch cc
vi crescents cu thn v hoi t nh hng n nhiu tiu cu. AZA, azathioprine; CSA, cyclosporin A; MMF, mycophenolate mofetil; TAC, tacrolimus.
Clin J Am Sc Nephrol : ccc - ccc, , 2016
c so snh trc tip trong mt th nghim i chng ngu nhin ln v tm thy
l tng ng trong khi pht phn ng thn sau 6 thng iu tr (73). Mc d
cnh tay MMF c mt s tng t ca cc s kin bt li nh l cnh tay
cyclophosphamide, v kh nng lu di ca n bo tn chc nng thn l
khng r rng, MMF thay th cyclophosphamide nh fi Liu php cm ng u
tin-line cho LN trong nhiu lnh vc. Tip xc tng ca bnh nhn LN MMF
quyn gp c mt s lo ngi v vic liu n tng ng vi cyclophosphamide
cm ng i vi kt qu thn lu di (77) vi. Mt phn tch meta gn y cho
thy, gia nhng nm 1970 v nhng nm 1990 nguy c ESRD t LN gim v gi
nguyn, v y l trng vi iu tr cyclophosphamide tr thnh thi quen (27).
Trong nhng nm 2000, nh MMF tr thnh mt loi thuc cm ng chim u
th cho LN, nguy c ESRD tng ln, v cao nht 44% so vi 15 nm nhng
bnh nhn vi khuch tn LN tng sinh.
Trong mt n lc gim di v ngn hn c tnh ca cyclophosphamide, liu
thp, cyclophosphamide Euro-lupus c tm thy l tng ng vi NIH
cyclophosphamide cho cm ng thuyn gim v bo tn chc nng thn mc 5
v 10 nm, nhng c t tc dng ph hiu ng (78). Cuc th nghim Euro-lupus
ban u c thc hin trong mt nghin cu thun tp ch yu l mu trng
vi LN mc nghim trng nh n trung bnh, nhng gn y, liu thp
cyclophosphamide c tm thy c hiu qu trong mt nhm a sc tc / a
sc tc vi LN nng hn (82).
Thi hn ca chnh quyn corticosteroid trong LN vn cn gy nhiu tranh ci
v nonevidence-based. Mt nghin cu th im nh nhng th v nh gi tnh
kh thi ca lm mt de fi th nghim nitive vo vic corticosteroid bo tr l cn thit
trong LN c thc hin (83). Cuc th nghim bao gm 15 bnh nhn b tng
sinh ( 6 mng) LN cm ng vi cyclophosphamide hoc MMF ngi t c t nht
l mt phn ng mt phn v c gim dn xung # 20 mg prednisone. Sau 3
tun, prednisone c gim xung 5 - 7,5 mg / ngy trong tm bnh nhn, v liu
c duy tr. Prednisone b rt hon ton trong by bnh nhn theo tun 17.
Bnh nhn c theo di trong mt trung bnh l 12 thng, v im cui l thn
hoc ln ti pht nonrenal. Relapse xy ra ch trong mt bnh nhn t cc nhm
thu hi (14%; mt thn
fl l), nhng trong 50% bnh nhn prednisone liu thp (ba thn v mt ln
nonrenal fl l). Nhng d liu ny, mc d khng phn thng bi, l khiu khch.
C hi trong qun l LN
gim t l mc ESRD n s l cn thit ngn nga suy thn. Ngn chn
CKDwill yu cu iu khin nhanh hn v hon ton trong fl chn thng thn
ammatory v gim thiu LN fl Ares. C rt nhiu c hi thc hin nh mt m
hnh, trong bao gm cc phng php pht trin chn on v iu tr sm,
ci thin s tun th ca bnh nhn, v p dng phng php iu tr mi. y
chng ta s tp trung vo vic to ra cc c hi vi phng php iu tr mi.
Kim sot thn Trong ammation fl trong LN
V mt lch s, bn trong thn trong fl ammation c kim sot trong sut
cm ng bng corticosteroid liu cao, l hiu qu nhng c hi (81). C kh
nng rng nhiu kt qu bt li xy ra trong thi gian fi nm u tin iu tr LN
Cp nht v Lupus vim thn, Almaani et al. 7
c th l do corticosteroid, v tc dng ph ca h thng thch thc tun th ca
bnh nhn. Vay phng php iu tr hin c s dng cho cc bnh khc iu tr
thn trong fl ammation c th lm gim hoc loi b nhu cu corticosteroid. Trong bi
cnh ny, cc cht c ch C, immunomodulators quinolone, v cht c ch
proteasome cn c xem xt cho cc th nghim lm sng LN.
Mt s nghin cu trn ng vt chng minh mt li ch fi hiu lc thi hnh
cial chn con ng C thay th trong LN (84). Mc d t cng vic c thc
hin vi s c ch C trong LN con ngi, cc cht c ch hiu qu c sn, trong
c mt khng th n dng chng li C5 (eculizumab) v mt phn t nh C5a
thuc c ch angiotensine (CCX168) (85). iu th v l kh nng ca
corticosteroid lm gim bt hot ng C bn trong thn trong LN l khng r
rng, nhng t nht mt s c s y t, chng hn nh chy thn nhn to, h
khng chn kch hot C (86). Do , cc cht c ch C c th synergize vi
steroid cho php signi fi khng th gim liu steroid. Ngn chn cc con ng thay
th C kh nng c th lm gim bt trong- thn
fl ammation v tn thng bng cch c ch chemotactic v bch cu thuc tnh
ca C5a kch hot, v ngn chn s hnh thnh ca C5b-9 (cuc tn cng mng
phc tp) c th trc tip lm tn thng t bo thn.
Laquinimod, quinolone, l mt phn t nh c khi kch hot ca NF- k B, mt
yu t phin m quan trng trong s biu hin ca proin fl cytokine ammatory m
c nghin cu trong bnh a x cng ngi (87) v LN chut (88). Mt nh
giai on 2 th nghim trong LN cho thy ci thin chc nng thn v gim protein
niu lc 6 thng khi laquinimod c b sung vo tiu chun-of-chm sc, bao
gm corticosteroid (89). nhng fi nhng pht hin cn phi c nhn rng trong
mt th nghim ln hn, nhng ngh sc mnh tng hp vi steroid v cung
cp kh nng gim liu steroid.
Cc cht c ch proteasome c s dng ch yu iu tr khi u c tnh t
bo plasma, nhng c ch hot ng ca chng c th cung cp ef fi cacy ti hai
bc trong c ch bnh sinh ca LN v tn thng thn. Hiu qu tng th ca
cc cht c ch proteasome axit boronic (v d, bortezomib v xe fi lzomib) l
tiu dit t bo plasma, do , nhng thuc ngay lp tc c th lm gim bt sn
xut t khng th. iu ny s c d kin s ngng hoc gim sn xut phc
hp min dch v phc hp min dch do lin tc - chn thng thn qua trung
gian. Hn c lin quan trc tip n ti fl ammation, cc cht c ch proteasome
chn kch hot ca NF- k B, v do cng c th chng trong fl ammatory. Loi
thuc ny c iu tr thnh cng LN chut (90).
Gim thiu LN Pho sng
Tri ngc vi nhiu th nghim lm sng gn y liu php cm ng mi l
trong LN, fl l phng nhn c tng i t s ch . Tuy nhin, mt s cc th
nghim cm ng bao gm theo di v nh hng ca cc loi thuc th nghim
trn fl l t l c xc nh. Mt v d th v l abatacept v kt hp
cyclophosphamide ef fi cacy v nghin cu an ton (ACCESS) th nghim m
nghin cu nh hng ca chn CD28 / CD80 costimulatory ng trong LN vi
abatacept, mt CTLA4-Ig xy dng. Mc d abatacept khng cung cp bt k li
ch fi t khi pht thuyn gim khi thm vo cyclophosphamide liu thp, bnh
nhn cnh tay abatacept m t n mt s thuyn gim thn hon chnh vo 6
thng tui c theo di thm 6 thng m khng cn bt k iu tr duy tr c ch
min dch. Ti 12 thng bnh nhn cnh tay abatacept c t SLE
fl ares hn bnh nhn cnh tay gi dc ngi nhn
8 Lm Sng Tp ch ca Hip hi Thn M
bo tr azathioprine. Nghin cu ny khng c cung cp kim tra abatacept
trong duy tr s thuyn gim, v fl l t l ny l khng trng yu fi cantly khc nhau,
nhng kt qu cho thy rng abatacept c th ng c nghin cu nh mt tc
nhn bo tr ngn chn fl Ares. Quan trng hn, khng c tn hiu an ton quan
trng cho abatacept c pht hin trong phin ta ACCESS.
Tng t nh vy, mt bi hoc phn tch belimumab, mt khng th n dng
chng li BLyS yu t sng cn ca t bo B, th nghim trong lupus nonrenal cho
thy mt xu hng ph thuc vo liu hng ti mt t l gim ca thn fl ares
nhng bnh nhn nhn c belimumab (91). Phn tch ny gi rng
belimumab c th hiu qu trong vic ngn nga thn fl ares nhng bnh nhn c
LN hot ng hoc n nh. Ngc li, mt anti-BLyS th n dng khng th,
tabalumab, cng th nghim ti nonrenal SLE, khng ngn chn thn fl Ares (92).
nh hng ca BLyS phong ta trong LN ang c th nghim trc tip trong mt
phin ta ang din ra (NCT0139330), do phn gii ca nhng con fl kt qu
icting c th cn phi i cho n khi xt x l fi nished.
Liu php mi ni khc
IFN- mt c v l mt cytokine iu tit trung ng trong SLE v c bit l
trong LN, v c th thc y pht trin ca cc t bo t bo plasma, helper v b
nh T autoreactive, v mt s proin fl cytokine ammatory (93 - 95). Ngn chn cc
nh hng ca IFN- mt do c th ci thin trong fl ammation v lm gim bt t
min dch v ngn nga trong tng lai LN fl Ares. Anifrolumab, mt khng th n
dng chng li IFN- mt g 1 th, c tm thy c hiu qu trong lupus
nonrenal v hin ang c nh gi trong mt th nghim lm sng ngu nhin
trong LN (NCT02547922).
Cc cht c ch calcineurin (CNIs) cyclosporine A v tacrolimus c th
nghim rng ri trong LN, c bit l chu , vi nhng kt qu rt ng khch
l. CNIs nh bt trong fl ammation bng cch ngn chn pht hnh trong fl cytokine
ammatory t bch cu, v cng c th ngn chn hot ha t bo T (96), v do
c th c tc ng duy tr s thuyn gim. CNIs c s dng nh mt
phn ca mt cch tip cn multitarget iu tr LN, thm vo mt ch ca
MMF v corticosteroid, v c chng minh l vt tri so vi
cyclophosphamide trong vic gy thuyn gim bi 6 thng (97). Mt cch tip cn
multitarget c hp dn nh c ch bnh sinh ca bnh lupus ban lin quan
n nhiu con ng min dch. CNIs cng corticosteroid n c cng c
s dng cho LN cm ng v tm thy l hiu qu nh MMF cho LN tng sinh (98).
Ti thi im ny, cc nghin cu CNI cn phi c nhn nhn mt cch thn
trng. Tht bt ng, trong rt tin bnh nhn nghin cu multitarget do s kin bt
li cao cnh tay CNI hn cnh tay cyclophosphamide (97). nh hng ca CNIs
trong nhm ngi phn bit chng tc v sc tc a dng phi c nghin cu. fi ed.
Cui cng, v protein l ng gp ln cho tiu ch hin ti ca phn ng LN, v
CNIs th nh hng n protein niu bng cc c ch lin quan n iu ch
min dch, n khng phi l r rng rng protein niu l mt im kt thc thch
hp so snh CNIs ma ty vi cc c ch khc nhau ca hnh ng. Trong thit
lp ny mt sinh thit thn cn c xem xt xc minh m hc ci thin /
phn gii.
Kt lun
LN tip tc l mt ngun chnh gy bnh tt v t vong cho bnh nhn SLE.
Hu ht bnh nhn pht trin LN
trong cc nguyn t ca cuc sng ca h, v iu ny nh hng xu n i
sng v gia nh ca h, nh hng n tt c cc x hi. Nng cao hiu bit ca
bnh bnh vn cha dn n nhng tin b iu tr ln. Tuy nhin, s sn c ca
mt lot cc loi thuc mi iu chnh h thng min dch, kt hp vi mt cch
tip cn chu o thit k th nghim lm sng, c d on s vt qua s
tin b chm ny trong vic thc y qun l LN.
thuyt minh
BHR c tha thun t vn v nhn c honoraria
t Lilly, Genentech-Roche, v MALLINCKRODT, v nhn c ti tr nghin cu t Vin
Quc gia v bnh tiu ng, bnh tiu ha v Thn (NIDDK), MALLINCKRODT, v
Genentech.
Cng trnh ny c h tr mt phn bi NIDDK U01 DK096927 (
BHR)
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